ANNUAL REPORT FY 2014

ANNUAL REPORT FY 2014 This translation of the original Japanese text is for information purpose only (in the event of inconsistency, the Japapnese tex...

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Pharmaceuticals and Medical Devices Agency, Japan

ANNUAL REPORT FY 2014

This translation of the original Japanese text is for information purpose only (in the event of inconsistency, the Japa p nese text shall pr prev evai ail) l).

THE PHARMACEUTICALS AND MEDICAL DEVICES AGENCY ANNUAL REPORT FY 2014 (April 2014 - March 2015)

TABLE OF CONTENTS Page

I. THE PHARMACEUTICALS AND MEDICAL DEVICES AGENCY ............................................ 1 PART 1

History and Objective of PMDA ........................................................................................................ 3

PART 2

Outline of Operations........................................................................................................................ 5 2.1. Relief Services for Adverse Health Effects ............................................................................ 5 2.2. Reviews .................................................................................................................................. 5 2.3. Safety Measures ..................................................................................................................... 6

II. OPERATING PERFORMANCE FOR FY 2014 ........................................................................ 9 PART 1

Development of Fiscal Year 2014 Plan .......................................................................................... 11 1.1. Development and Implementation of Fiscal Year 2014 Plan ............................................... 11 1.2. Results of the Evaluation on Operating Performance for FY 2013 ...................................... 11 1.3. Results of Final Evaluation on Operating Performance for Effective Period of Mid-term Targets .................................................................................................................................. 13 1.4. Trends in Review of System/Organization of Incorporated Administrative Agencies.......... 15

PART 2

Improvement in Overall Management of Operations and Service Quality of PMDA ..................... 16 2.1. Efficient and Flexible Management of Operations ............................................................... 16 2.1.(1) Development of basic implementation policy for the Third Mid-term Plan ............ 16 2.1.(2) Operation through target management ................................................................. 16 2.1.(3) Reinforcement of operational management system and top-down management .......................................................................................................... 16 2.1.(4) Advisory Council meetings .................................................................................... 18 2.1.(5) Approaches for an efficient operation management system ................................. 20 2.1.(6) Standardization of operating procedures............................................................... 21 2.1.(7) Development of databases .................................................................................... 21 2.1.(8) Promotion of the optimization of operations and systems..................................... 21 2.2. Cost Control through Increased Efficiency of Operations .................................................... 22 2.2.(1) Retrenchment of general and administrative expense .......................................... 22 2.2.(2) Cost control of operating expenses ....................................................................... 22 2.2.(3) Competitive bidding ............................................................................................... 22 2.2.(4) Contract Review Committee meetings .................................................................. 23 2.2.(5) Collection and management of contributions ........................................................ 23 2.2.(6) Promotion of measures for reduction of unnecessary expenditures ..................... 26 2.3. Improvement of Services to the Public ................................................................................. 27 2.3.(1) General consultation service ................................................................................. 27 2.3.(2) Responses to consultations, complaints, and claims of dissatisfaction from companies regarding product reviews and product safety operations .................. 27 2.3.(3) Enrichment of the PMDA website .......................................................................... 27 2.3.(4) Proactive PR activities ........................................................................................... 28 2.3.(5) Disclosure requests for agency documents........................................................... 28 2.3.(6) Disclosure requests for personal information ........................................................ 30 2.3.(7) Auditing .................................................................................................................. 30

2.4.

2.5.

PART 3

2.3.(8) Report on the financial standing ............................................................................ 30 2.3.(9) Release of "Plan for the Review of Optional Contracts etc."................................. 31 Personnel Matters................................................................................................................. 31 2.4.(1) Personnel evaluation system ................................................................................. 31 2.4.(2) Systematic implementation of staff training ........................................................... 31 2.4.(3) Appropriate personnel allocation ........................................................................... 33 2.4.(4) Securing of human resources through open recruitment ...................................... 33 2.4.(5) Appropriate personnel management based on work regulations.......................... 35 2.4.(6) Optimization of standards for remuneration .......................................................... 36 2.4.(7) Development of better working environment ......................................................... 36 Ensuring Security.................................................................................................................. 36 2.5.(1) Entry/exit access control ........................................................................................ 36 2.5.(2) Security measures for information systems........................................................... 36

Improvement in Management of Operations and Quality of Services in Each Division ................ 38 3.1. Relief Services for Adverse Health Effects .......................................................................... 38 3.1.(1) Expansion and review of dissemination of information regarding the relief system .................................................................................................................... 38 (i) Release of payment cases etc., on the website .......................................... 38 (ii) Improvement of brochures etc. .................................................................... 38 3.1.(2) Proactive PR activities of the relief system............................................................ 39 3.1.(3) Securing of efficient management of the consultation service .............................. 45 3.1.(4) Promotion of improved efficiency of operations using databases ......................... 45 3.1.(5) Promotion of expeditious processing of relief benefit claims ................................ 46 (i) Relief Service for Adverse Drug Reactions ................................................. 47 (ii) Relief Service for Infections Acquired through Biological Products ............ 49 3.1.(6) Promotion of collaboration with the review and safety departments ..................... 50 3.1.(7) Appropriate conduct of health and welfare services.............................................. 51 (i) Investigative research for improvements in the quality of life of sufferers of serious and rare adverse health effects caused by drug products........................................................................................................ 51 (ii) Consultation services to address mental health problems etc. ................... 51 (iii) Distribution of the benefit recipient card ...................................................... 52 (iv) Investigative research for improvements in the QOL of patients with hepatitis C caused by treatment for congenital diseases ............................ 52 3.1.(8) Appropriate provision of healthcare allowances for SMON patients and HIV-positive patients affected through blood products .......................................... 52 (i) Services for SMON patients (commissioned payment of healthcare allowances) .................................................................................................. 52 (ii) HIV-related services (commissioned payment of healthcare allowances) .................................................................................................. 53 3.1.(9) Appropriate provision of the payment of benefits to assist individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus ........................ 54 3.2. Reviews and Related Services ............................................................................................. 55 3.2.(1) Accelerated access to drugs and medical devices................................................ 56 New drugs ........................................................................................................................ 56 (i) Appropriate and prompt reviews .................................................................. 56 (ii) Introduction of new review systems ............................................................. 64 (iii) Approaches to achieving "zero" review lag for drugs .................................. 65

(iv) Promotion of global clinical trials ................................................................. 68 (v) Efficient conduct of clinical trial consultations.............................................. 69 (vi) Promotion of evaluation of new technologies .............................................. 72 Generic drugs, etc. .......................................................................................................... 75 (i) Appropriate and prompt reviews .................................................................. 75 (ii) Approaches to shorten review times............................................................ 75 (iii) Efficient conduct of clinical trial consultations.............................................. 78 Behind-the-counter (BTC) drugs, over-the-counter (OTC) drugs, and quasi-drugs ....... 79 (i) Appropriate and prompt reviews .................................................................. 79 (ii) Approaches to shorten review times............................................................ 79 (iii) Efficient conduct of consultations ................................................................ 81 Medical devices ............................................................................................................... 83 (i) Appropriate and prompt reviews .................................................................. 83 (ii) Introduction of new review systems ............................................................. 87 (iii) Efforts to achieve “zero” review lag for medical devices ............................. 89 (iv) Efficient conduct of clinical trial consultations.............................................. 95 (v) Promotion of evaluation of new technologies .............................................. 98 In vitro diagnostics ......................................................................................................... 100 (i) Appropriate and prompt reviews ................................................................ 100 (ii) Expansion of consultation services............................................................ 100 Cellular and tissue-based products ............................................................................... 104 (i) Introduction of new review systems and the conducting of appropriate and prompt reviews .................................................................................... 104 (ii) Setting of target review time ...................................................................... 104 (iii) Efficient conduct of clinical trial consultations............................................ 104 (iv) Promotion of evaluation of new technologies ............................................ 105 (v) Promotion of the use of Pharmaceutical Affairs Consultations on R&D strategy....................................................................................................... 106 Promotion of GLP/GCP/GPSP compliance assessments and clinical trials, etc. ......... 107 (i) Efficient GLP/GCP/GPSP inspections and data integrity assessments for new drugs, etc....................................................................................... 107 (ii) Efficient GLP/GCP/GPSP inspections and data integrity assessments for medical devices .................................................................................... 107 (iii) Efficient GLP/GCP/GPSP inspections and data integrity assessments for cellular and tissue-based products ....................................................... 108 (iv) Efficient GLP inspections and data integrity assessments ........................ 108 (v) Efficient GLP/GCP/GPSP inspections and data integrity assessments for re-examination (including use-results evaluation) ................................ 108 (vi) Proper conduct of clinical trials, etc. .......................................................... 108 Promotion of GMP/GCTP/QMS inspections.................................................................. 109 (i) Efficient GMP/GCTP/QMS inspections...................................................... 109 (ii) Building of the inspection system based on the Act on Safety of Regenerative Medicine .............................................................................. 117 3.2.(2) Support for the initiative to facilitate the development of innovative drugs, medical devices, and cellular and tissue-based products ................................... 118 (i) Establishment and revision of review standards, etc., for innovative products...................................................................................................... 118 (ii) Expansion of Pharmaceutical Affairs Consultations on R&D Strategy...... 119 (iii) Implementation of approval system based on characteristics of cellular and tissue-based products ......................................................................... 119

3.3

3.4.

Safety measure services .................................................................................................... 119 (i) Proper assessment of reports on adverse drug reactions and medical device malfunctions.................................................................................... 119 (ii) Sophistication of safety measures ............................................................. 126 (iii) Establishment of a post-marketing safety system through information feedback ..................................................................................................... 130 Promotion of regulatory science, internationalization, etc.................................................. 145 3.4.(1) Promotion of regulatory science .......................................................................... 145 (i) Use of the Science Board .......................................................................... 145 (ii) Enhancement of regulatory science research ........................................... 145 (iii) Enhancement of staff training .................................................................... 146 (iv) Promotion of interaction with outside researchers and collaboration on investigative research ................................................................................ 147 3.4.(2) Action taken for internationalization ..................................................................... 148 (i) Strengthening of cooperation with the U.S., the EU, Asian countries, and relevant international organizations .................................................... 148 (ii) Strengthening of activities for international harmonization, etc. ................ 150 (iii) Promotion of personnel exchanges ........................................................... 153 (iv) Development of internationally oriented human resources with excellent communication skills ................................................................... 153 (v) Improvement and strengthening of international publicity and provision of information ............................................................................................. 153 3.4.(3) Measures for intractable diseases and orphan diseases, etc. ............................ 154 3.4.(4) Promoting provision of information such as review reports................................. 154 3.4.(5) Securing of impartiality in utilization of external experts ..................................... 155 3.4.(6) Provision of training in specially controlled medical device certification standards ............................................................................................................. 155 3.4.(7) Improvement of quality of reviews/safety operations through enhancement of information systems ............................................................................................. 156

III. SUPPLEMENTARY INFORMATION .................................................................................. 157 Table 1. Products Approved in FY 2014: New Drugs............................................................................. 159 Table 2. Products Approved in FY 2014: New Medical Devices ............................................................ 168 Table 3. Products Approved in FY 2014: Improved Medical Devices (with Clinical Data)..................... 177 Table 4. Post-marketing Safety Measures Implemented and Revision of PRECAUTIONS for Drugs etc., Directed by MHLW in FY 2014 ................................................................................................ 183 Table 5. Revision of PRECAUTIONS for Medical Devices Directed by MHLW in FY 2014 .................. 187 Table 6. FY 2014 Pharmaceuticals and Medical Devices Safety Information (No.312-321)................. 188 Table 7. FY 2014 PMDA Medical Safety Information ............................................................................. 190 Table 8. List of User Fees....................................................................................................................... 191 Appendix………………………………………………………………………………………………………………209

I. THE PHARMACEUTICALS AND MEDICAL DEVICES AGENCY

PART 1

History and Objective of PMDA

 As a lesson learned from drug-induced health damage such as thalidomide-induced fetal malformations and subacute myelo-optical neuropathy (SMON), the Fund for Adverse Drug Reactions Suffering Relief was established in October 1979 based on stipulations in the Adverse Drug Reaction Suffering Relief Fund Act (Act No. 55 of 1979), for the purpose of providing prompt relief to patients suffering from adverse drug reactions (ADRs). In 1987, the Fund started R&D-promoting operations under the name of the Fund for Adverse Drug Reaction Relief and R&D Promotion and was then reorganized into the Organization for Pharmaceutical Safety and Research (OPSR) in 1994 to play an additional role in equivalence reviews of generic drugs. Later, in 1997, the organization started to provide advice on clinical trials and conduct GCP/GLP inspections in relation to applications for approval of drugs.  In 1997, the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) was established at the National Institute of Health Sciences (NIHS) in order to develop a full-scale regulatory review system and to make the contents of the review more advanced. It was decided that at the Center, reviews should be conducted by teams consisting of experts specializing in pharmaceutical science, medical science, biostatistics, etc. In addition, the Japan Association for the Advancement of Medical Equipment (JAAME) began operations in 1995 to conduct equivalence reviews of medical devices as a designated investigative body under the Pharmaceutical Affairs Act.  From 1997 to 1999, there was a systematic and drastic increase in the number of the staff engaging in reviews and post-marketing safety measures at the former Ministry of Health and Welfare and the three organizations above (from 121 staff members in 1996 to 241 in 1999). However, there was a limit to further increasing the number of staff members and developing the structure as governmental organizations. In the midst of these situations, the Cabinet adopted the Special Service Agency Restructuring Plan in December 2001, in which it was decided that the OPSR should be dissolved and that the Pharmaceuticals and Medical Devices Agency (PMDA) should be newly founded by consolidating the operations allocated to PMDEC, OPSR, and JAAME in order to further enhance reviews and post-marketing safety measures. In 2002, a legislative bill for the Act on the Pharmaceuticals and Medical Devices Agency was discussed and passed at the 155th extraordinary session of the Diet, resulting in the establishment of PMDA on April 1, 2004 in accordance with the Act on the Pharmaceuticals and Medical Devices Agency (Act No.192 of 2002).  PMDA’s mission is to contribute to the improvement in public health by providing prompt relief to people who have suffered health damage caused by adverse drug reactions or infections from biological products (Relief for Adverse Health Effects); providing guidance and reviews regarding the quality, efficacy, and safety of drugs and medical devices through a system that integrates the entire process from pre-clinical research to approval (Reviews); and collecting, analyzing, and providing on post-marketing safety information (Safety Measures). Previously, one of the objectives of PMDA was to promote basic research and development of drugs and medical devices that contribute to maintaining and improving the health of the nation (Promotion of R&D). However, the Regulatory Division and the Research Promotion Division were separated, and services for promotion of R&D were transferred to the National Institute of Biomedical Innovation (NiBio) in April 2005, in order to allow PMDA to focus specifically on reviews, safety measures, and relief services for adverse health effects.

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Bureaus in the former Ministry of Health and Welfare (government) 1979

1987

The Fund for Adverse Drug Reactions Suffering Relief established

Fund reorganized into the Fund for Adverse Drug Reaction Relief and R&D Promotion R&D Promotion Service started

1994

1995

1997

Fund reorganized into the Organization for Pharmaceutical Safety and Research (OPSR)

Clinical trial consultations and inspections started

Transfer of operations to Japan Association for the Advancement of Medical Equipment

Pharmaceuticals and Medical Devices Evaluation Center established within the National Institute of Health Sciences

Equivalence review for medical devices

Safety measures Regulatory reviews started

2004

Pharmaceuticals and Medical Devices Agency established

R&D Promotion Services transferred to the National Institute of Biomedical Innovation (NiBio)

2005

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PART 2 2.1.

Outline of Operations

Relief Services for Adverse Health Effects  As a service inherited from the OPSR, PMDA provides benefits for medical expenses, disability pensions, and bereaved family pensions to the sufferers of illnesses or disabilities caused by adverse drug reactions (Relief Service for Adverse Drug Reaction).  Since April 2004, PMDA has provided benefits to sufferers of adverse health effects caused by infections from drugs and medical devices manufactured using ingredients and materials of biological origin (Relief Service for Infections Acquired through Biological Products).  Since January 2008, PMDA has also provided benefits to patients with drug-induced hepatitis C, in accordance with the Act on Special Measures concerning the Payment of Benefits to Assist Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus (Act No. 2 of 2008) (Specified Relief Service).  In November 2012, PMDA started to provide benefits for sufferers of adverse health effects caused by cellular and tissue-based products (as a part of Relief Service for Adverse Drug Reactions and Relief Service for Infections Acquired through Biological Products).  PMDA is also commissioned by the government and pharmaceutical companies to provide healthcare allowances and nursing care expenses to SMON patients (Service for Healthcare Allowances). In addition, PMDA works under the commission of the Yu-ai Welfare Foundation to make payments for healthcare expenses for HIV-positive and AIDS patients (Service for Healthcare Allowances).

2.2.

Reviews  In accordance with the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145 of 1960, PMD Act) and based on the current scientific and technological standards, PMDA evaluates the efficacy, safety, and quality of drugs and medical devices for which applications have been submitted for regulatory approval. In addition, PMDA conducts re-examinations/re-evaluations of drugs, medical devices, and cellular and tissue-based products, medical device use-result survey, and reviews of applications for confirmation of clinical use of genetically modified biological entities pursuant to the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms (Act No. 97 of 2003, Cartagena Law) (Reviews).  In response to requests from clinical trial sponsors, PMDA provides guidance and advice through face-to-face consultations on clinical trials of new drugs and medical devices as well as on clinical trials for re-examinations/re-evaluations of approved products (Consultations).  For products for which applications were made for reviews or re-examinations/re-evaluations, on-site and document-based inspections are conducted to determine whether documents attached to applications comply with Good Laboratory Practice (GLP), Good Clinical Practice (GCP), Good Post-marketing Surveillance Practice (GPSP), and the data integrity standards for product applications (GLP/GCP/GPSP Inspections).  PMDA conducts on-site and document-based inspections to determine whether manufacturing facilities and manufacturing control methods for drugs, medical devices, and cellular and tissue-based products, etc., comply with the requirements of the Ministerial Ordinance on Good Manufacturing -5-

Practices/Quality Management System, whereby products of appropriate quality can be manufactured. PMDA also inspects manufacturing sites of cellular and tissue-based products to determine whether their manufacturing facilities as well as manufacturing process and quality management system comply with the Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (Act No. 85 of 2013) (GMP/QMS/GCTP Inspections).  PMDA conducts research for developing various standards, such as the Japanese Pharmacopoeia (JP), which is set forth in the PMD Act (Research for Standards Development). 2.3.

Safety Measures  PMDA cooperates with the Ministry of Health, Labour and Welfare (MHLW) on the following services to improve the safety of marketed drugs and medical devices as well as to enable patients and healthcare professionals to use drugs and medical devices appropriately and with peace of mind. (i)

(ii) (iii) (iv)

Centrally collecting and organizing information on the post-marketing safety of drugs and medical devices from a broad range of sources, such as reports from companies, information from medical institutions, information from foreign regulatory agencies, and reports presented at academic conferences, relating to adverse drug reactions, device malfunctions, and infections (Collection and Organization of Information). Conducting research and reviews relating to safety measures based on the information collected in (i) above (Research and Reviews). Giving guidance and advice to marketing authorization holders (MAHs) as well as providing consultations to consumers upon request (Consultations). Providing safety information on drugs and medical devices widely to healthcare professionals, patients, companies, etc., in a timely manner (Information Provision).

 PMDA also utilizes electronic medical records to quantitatively evaluate the risk of adverse events, to assess the effects on safety measures, to investigate the realities of drug prescription, and to develop medical information database, aiming to build a system that enables safety measures based on pharmacoepidemiological methods.

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Structure of PMDA (as of March 31, 2015)

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II. OPERATING PERFORMANCE FOR FY 2014

PART 1 1.1.

Development of Fiscal Year 2014 Plan

Development and Implementation of Fiscal Year 2014 Plan  PMDA is required to develop the Mid-term Plan in accordance with the Mid-term Targets designated by the Minister of Health, Labour and Welfare, and to obtain the Minister's approval for the plan (effective period of the Third Mid-term Targets: April 2014 to March 2019). In order to achieve the Mid-term Plan, PMDA is required to develop a plan on its management of operations for each fiscal year (fiscal year plan), submit these plans to the Minister, and announce these plans to the public.  Also for FY 2014, the fiscal year plan was developed at the end of FY 2013 based on the Third Mid-term Targets and Mid-term Plan, the results of the evaluation on operating performance for FY 2012 provided by the Evaluation Committee for Incorporated Administrative Agencies of the Ministry of Health, Labour and Welfare (MHLW), and the opinions by the Commission on Policy Evaluation and Evaluation of Incorporated Administrative Agencies of the Ministry of Internal Affairs and Communications (MIC). The plan was submitted to the Minister of Health, Labour and Welfare and operations were performed in line with the plan.

1.2.

Results of the Evaluation on Operating Performance for FY 2013  It had been stipulated that each ministry in charge of incorporated administrative agencies should establish an "Evaluation Committee for Incorporated Administrative Agencies" to conduct administrative processing relating to the agencies under its control. (Article 12 of the Act on General Rules for Incorporated Administrative Agencies [Act No. 103 of 1999] prior to revision)  On August 26, 2014, PMDA received the "Results of the Evaluation on Operating Performance for FY 2013" from the Evaluation Committee for Incorporated Administrative Agencies of MHLW, which is responsible for evaluating the Agency's performance. The evaluation results showed that PMDA received "S" ratings for two evaluation items, "cost control efforts" and "expeditious operation and improvement of the system (drugs)," and "A" ratings for all other items. Note: S: Significantly exceeding the level prescribed in the Mid-term Plan A: Exceeding the level prescribed in the Mid-term Plan B: Somewhat exceeding the level prescribed in the Mid-term Plan C: Slightly below the level prescribed in the Mid-term Plan D: Below the level prescribed in the Mid-term Plan, therefore requiring drastic improvements  The "Results of the Evaluation on Operating Performance for FY 2013" was published on the PMDA website and reported to Advisory Council Meeting held on November 7, 2014.

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Results of the Evaluation on Operating Performance of PMDA Provided by the Evaluation Committee for Incorporated Administrative Agencies of MHLW Results of evaluation

Classification in the mid-term and fiscal year plan Part 1

Evaluation items

1 2

2

(2) Cost control by increased efficiency of operations

3 4

(3) Improvement of services to the public

5

(1) Expansion and review of dissemination of information regarding the Relief System (2) Proactive public relations activity toward 6 familiarity with the Relief System (3) Securing of efficient management of the consultation office (4) Promotion of improved efficiency of operations using databases 7 (5) Promotion of expeditious processing of relief applications (6) Promotion of collaboration with the review/safety offices 8 (7) Appropriate conduct and expansion of health and welfare services (8) Appropriate conduct of relief services for SMON patients and patients infected with HIV through blood preparations (9) Appropriate conduct of payment services for 9 individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C Reviews and related services/post-marketing safety measures

(1) Faster access to the latest drugs and medical devices

11 12

(2) Improvement in reliability of reviews and related services/post-marketing safety measures

13

14 (3) Reinforcement of post-marketing safety measures

15 16

Part 4 Part 5 Part 6 Part 7

A

A

A

A

S A

S A

A

A

Provision of information on the System and strengthening of the consultation system

A

A

Expeditious processing of applications and improvement of the system

A

A

Conduct of cross-functional collaboration and health and welfare services

A

A

Conduct of relief services for SMON patients and patients infected with HIV through blood preparations

A

A

S

S

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

A

2

2

16

16

0

0

0

0

0

0

Operation through target management and top management Ensuring of transparency by establishing deliberative bodies Cost control efforts Collection and management of contributions Strengthening of the consultation system and disclosure of the work of the Agency

Improvement in operations of each department and quality of other services e.g., services to the public Adverse health effect relief services

10

Part 3

FY 2013 Performance

Improvement in overall operations and quality in services of PMDA e.g., services to the public

(1) Efficient and flexible operations

Part 2 1

FY 2012 Performance

Expeditious operation and improvement of the system (drugs) Expeditious operation and improvement of the system (medical devices) Expeditious operation and improvement of the system (inspections) Improvement in reliability of review and related services/post-marketing safety measures Reinforcement of collecting, and systematization of organizing, assessing and analyzing information on adverse drug reactions/malfunctions Provision of safety information to companies/healthcare professionals and follow-up Provision of safety information to patients and consumers Budget, income and expenditure plan, and financial plan

Budget, income and expenditure plan, and financial 17 plan Limit of short-term borrowing Plan for transferring or mortgaging important asset if applicable Use of surplus funds Other operational matters specified by a ministerial ordinance of the competent ministry (1) Personnel matters Personnel matters and establishment of 18 security (2) Ensuring security Evaluation scale on performance of Incorporated Administrative Agency of MHLW

S A B C D

Significantly exceeding the level prescribed in the Mid-term Plan Exceeding the level prescribed in the Mid-term Plan Somewhat exceeding the level prescribed in the Mid-term Plan Slightly below the level prescribed in the Mid-term Plan Below the level prescribed in the Mid-term Plan, therefore requiring drastic improvements

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 The results of the evaluation conducted by the Evaluation Committee for Incorporated Administrative Agencies of MHLW were reviewed by the Commission on Policy Evaluation and Evaluation of Incorporated Administrative Agencies of MIC. The Commission endorsed the evaluation results in "Opinion on the Results of Evaluation on Operating Performance for Effective Period of Third Mid-term Targets" published on January 9, 2014. 1.3.

Results of Final Evaluation on Operating Performance for Effective Period of Mid-term Targets  On August 26, 2014, PMDA received the "Results of the Final Evaluation on Operating Performance for Effective Period of Mid-term Targets" from the Evaluation Committee for Incorporated Administrative Agencies of MHLW. The evaluation results were determined by averaging evaluation results for the previous 5 years, from FY 2009 to FY 2013. Among 18 evaluation items, "S" rating was given to "cost control efforts" and "expeditious operation and improvement of the system (drugs)" and "A" rating to all other items. Note: S: Significantly exceeding the level prescribed in the Mid-term Plan A: Exceeding the level prescribed in the Mid-term Plan B: Somewhat exceeding the level prescribed in the Mid-term Plan C: Slightly below the level prescribed in the Mid-term Plan D: Below the level prescribed in the Mid-term Plan, therefore requiring drastic improvements  The "Results of the Final Evaluation on Operating Performance for Effective Period of Mid-term Targets" was posted on the PMDA website and reported to Advisory Council Meeting held on November 7, 2014.

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Results of PMDA’s Final Evaluation on Operating Performance for Effective Period of Mid-term Targets Classification in the mid-term and fiscal year plan Part 1

2

(2) Cost control by increased efficiency of operations

1 2 3 4

(3) Improvement of services to the public

5

(1) Expansion and review of dissemination of information regarding the Relief System (2) Proactive public relations activity toward 6 familiarity with the Relief System (3) Securing of efficient management of the consultation office (4) Promotion of improved efficiency of operations using databases 7 (5) Promotion of expeditious processing of relief applications (6) Promotion of collaboration with the review/safety offices 8 (7) Appropriate conduct and expansion of health and welfare services (8) Appropriate conduct of relief services for SMON patients and patients infected with HIV through blood preparations (9) Appropriate conduct of payment services for 9 individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C Reviews and related services/post-marketing safety measures 10 11 12 (2) Improvement in reliability of reviews and related services/post-marketing safety measures

13 14

(3) Reinforcement of post-marketing safety measures

Part 4 Part 5 Part 6 Part 7

Tentative Evaluation

Operation through target management and top management Ensuring of transparency by establishing deliberative bodies Cost control efforts Collection and management of contributions Strengthening of the consultation system and disclosure of the work of the Agency

A A S A A

Improvement in operations of each department and quality of other services e.g., services to the public Adverse health effect relief services

(1) Faster access to the latest drugs and medical devices

Part 3

Results of evaluation

Improvement in overall operations and quality in services of PMDA e.g., services to the public

(1) Efficient and flexible operations

Part 2 1

Evaluation items

15

Provision of information on the System and strengthening of the consultation system

A

Expeditious processing of applications and improvement of the system

A

Conduct of cross-functional collaboration and health and welfare services

A

Conduct of relief services for SMON patients and patients infected with HIV through blood preparations

A

Expeditious operation and improvement of the system (drugs) Expeditious operation and improvement of the system (medical devices) Expeditious operation and improvement of the system (inspections) Improvement in reliability of review and related services/post-marketing safety measures Reinforcement of collecting, and systematization of organizing, assessing and analyzing information on adverse drug reactions/malfunctions Provision of safety information to companies/healthcare professionals and follow-up Provision of safety information to patients and consumers

16 Budget, income and expenditure plan, and financial 17 Budget, income and expenditure plan, and financial plan plan Limit of short-term borrowing Plan for transferring or mortgaging important asset if applicable Use of surplus funds Other operational matters specified by a ministerial ordinance of the competent ministry (1) Personnel matters 18 Personnel matters and establishment of security (2) Ensuring security Evaluation scale on performance of Incorporated Administrative Agency of MHLW

S A B C D

Significantly exceeding the level prescribed in the Mid-term Plan Exceeding the level prescribed in the Mid-term Plan Somewhat exceeding the level prescribed in the Mid-term Plan Slightly below the level prescribed in the Mid-term Plan Below the level prescribed in the Mid-term Plan, therefore requiring drastic improvements

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S A A A A A A A

A 2 16 0 0 0

1.4.

Trends in Review of System/Organization of Incorporated Administrative Agencies  Under the "Basic Policy for Reform etc. of Incorporated Administrative Agencies (adopted by the Cabinet on December 24, 2013)," it was decided that the government would make efforts as a whole so that this reform as the culmination of past efforts can be realized by promptly taking measures necessary for the reform, fully exerting the policy-implementing function of the agencies under the new system/organization, and ensuring that employees of each agency perform their duties with pride and contribute to the growth of the economy or the improvement of people's living as much as possible. Based on this policy, the Act for Partial Revision of the Act on General Rules for Incorporated Administrative Agencies (Act No. 66 of 2014) and the Act for Arrangement of Relevant Acts Incidental to Enforcement of the Act for Partial Revision of the Act on General Rules for Incorporated Administrative Agencies (Act No. 67 of 2014) were promulgated on June 13, 2014 and came into effect on April 1, 2015. The Acts are intended to review the common system based on which incorporated administrative agencies are managed, so that the agencies can fulfill their duties of public accountability and exert their full policy-conducting functions in accordance with the primary objectives of the agencies. * Basic Policy for Reform etc. of Incorporated Administrative Agencies (adopted by the Cabinet on December 24, 2013) [excerpt]  Measures to be taken for each agency [Pharmaceuticals and Medical Devices Agency (PMDA)] ○ It is a mid-term target management-type agency (Note) ○ Based on the Japan Revitalization Strategy, PMDA should aim at prompt realization of "zero" review lag for pharmaceuticals and medical devices, and should strive to strengthen the structure of this agency with the use of its own financial resources from the viewpoint of acceleration and quality improvement of its reviews. ○ In this regard, PMDA intends to consider the possibility of introducing a fixed-term employment contract and an annual salary system considered so that expert human resources can be secured. (Note) "Mid-term target management-type agency" conducts clerical and business operations while demonstrating significant independence/autonomy through mid-term target management, with the objective of improving the quality of its operations, such as services intended for the public. The Act on Pharmaceuticals and Medical Devices Agency was revised by the Act for Arrangement of Relevant Acts Incidental to Enforcement of the Act for Partial Revision of the Act on General Rules for Incorporated Administrative Agencies, and PMDA was defined as the mid-term target management-type corporate body provided in Article 2, Paragraph 2 of the Act on General Rules for Incorporated Administrative Agencies.

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PART 2

2.1.

Improvement in Overall Management of Operations and Service Quality of PMDA

Efficient and Flexible Management of Operations

2.1.(1)

Development of basic implementation policy for the Third Mid-term Plan  To implement the Third Mid-term Plan in changing operational circumstances, the "Basic Policy for Implementation of the Third Mid-term Plan," clarifying the viewpoints to be predominantly considered, was determined in an Executive Directors’ Meeting on November 25, 2014. PMDA is to steadily implement the Third Mid-term Plan by repeating PDCA cycle based on the Policy.

2.1.(2)

Operation through target management  In managing operations, PMDA clarifies the objectives and responsibilities of operations for each department, and strives to identify and resolve problems through managing its operational progress on a daily basis.  In conjunction with the development of PMDA's annual plan for FY 2014, each office and division formulated their operating plans for segregation of duties. PMDA has operated through management of the targets set in the operating plans.

2.1.(3)

Reinforcement of operational management system and top-down management  PMDA intends to reinforce its function of strategy planning for overall operations, as well as a system for managing operations such as for risk management or check functions, and also plans to build an organizational system in which management decisions by the Chief Executive are promptly reflected in operations.  To this end, PMDA regularly (once a week, in principle) held "Board of Directors meetings," attended by executives and office directors, to ensure that the Chief Executive directly comprehends operational progress and provides necessary direction.  Meetings of the “Steering Committee” were held to monitor the development status of optimization of operations and systems, and to hear opinions. Also, 3 meetings of the “Committee on Investment in Information Systems” were held to assess, from a comprehensive perspective, the necessity, cost-effectiveness, technical difficulty, etc., of new development and upgrading of the operations system. Then, well-planned and efficient investment options were selected.  In order to regularly monitor the financial conditions to maintain sound financial performance and effective operations, the "Financial Management Committee," headed by the Chief Executive, held 12 meetings in FY 2014. The following information was reported to the meetings: user fees paid and cash flow analysis for each division for each month; and the declared amount of contributions.  In March 2015, a "Meeting to Hear from Employees" was held, and policies to deal with opinions, requests, etc., from employees were examined.  Meetings of the health committee were held every month to deliberate measures etc., for maintaining and promoting the health of employees.  PMDA convened opinion exchange sessions with the pharmaceutical industry on new drugs (one session in October 2014) and on drug safety (one session in November 2014).

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Also, regarding medical devices and in vitro diagnostics, PMDA helped the MHLW to manage and hold regular opinion exchange forum on regulatory affairs for medical devices (July 2014) and the Action Program Review Committee's meetings (July 2014).  The "Risk Management Committee" meetings were held once a month to allow the directors to discuss PMDA's risks. PMDA has continued its efforts to familiarize the executives and employees with risk management in accordance with the risk management manual.  The Audit Office, which directly reports to the Chief Executive, has continued to conduct internal auditing and management of internal reporting systems.  In order to respond to disaster risks resulting from fires and earthquakes, PMDA duly informed all executives and employees of the disaster preparedness plan.  The "PMDA Business Continuity Plan in the Event of Large-scale Disasters" was developed in March 2015 to define the scopes of important services that PMDA should maintain in the event of a large-scale disaster, such as an inland earthquake that directly hits the capital city.  "Guidelines for return to work etc., for employees on administrative leave or leave of absence because of illness or injury" were formulated so that employees who recuperate for an extended period of time due to mental health problems etc., can smoothly return to work.

Risk Management System at PMDA PMDA Risk Management Committee

• Reporting of risk cases & Consideration of measures

Minister of Health, Labour and Welfare • Instruction on mid-term targets • Evaluation by Evaluation Committee • Appointment/dismissal of Chief Executive and Auditor

Chief Executive

Advisory Council

Submission of written opinion

Auditor

Notice of improvement results

Audit Office

Top management

Auditor's auditing

• Deliberation of important matters on management of operations

Internal auditing

Internal reporting Information system disclosure system

External auditing firm

Legal Advisor (labor affairs & administrative litigation) • Countermeasures against litigations & Legal consultation

System advisor

Employees

Each office

• Auditing of financial statement, etc.

Rules/Regulations • • • •

Risk management rules Work regulations Code of ethics Information management rules

• Guideline for implementation of health risk management • Rules for prevention of sexual harassment • Disaster preparedness plan

• Information security measures

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General consultation service

. PR activities through website, etc.

Public

 Risks PMDA may face: A. Risks to the organization  Possibility of an event that damages or may damage the reputation of PMDA in society  Possibility of an event that significantly hinders or may hinder the execution of PMDA's operations  Possibility of an event that financially damages or may damage PMDA B. Risks that PMDA should address as part of its tasks  Risks relating to PMDA's operations which might cause or expand serious adverse health effects due to drugs, medical devices, etc. (including drugs, medical devices, quasi-drugs, and cosmetics, as well as agents and equipment/devices, etc., subject to clinical trials)

 In order to systematically promote public relations (PR) activities in consideration of the public needs and international perspectives, PMDA developed the "PMDA Public Relations Strategic Plan" (July 11, 2008) as a basic policy for its overall PR activities. The Agency is striving to proactively provide information in line with the strategic plan. Further, in consideration of the development of PMDA’s philosophy, changing socioeconomic circumstances, etc., PMDA revised the Strategic Plan and determined to develop a PR plan every fiscal year based on the revised Strategic Plan, and to manage progress of PR plan to enable effective public relations designed separately for each stakeholder (came into force on April 1, 2015).  Based on the "PMDA International Vision" developed in 2011, a vision which makes clear what PMDA aims for in its overall international activities, PMDA formulated its roadmap and is conducting proactive international activities such as reinforcing collaboration with Western and Asian countries, participating in and contributing to international regulatory harmonization, and providing information to foreign countries. In addition, the role of the International Strategy Meeting established in September 2012 (core members, executives) was transformed from a place for annual information and opinion exchange into a decision-making body that develops strategies (2 meetings were held before transformation and 6 after transformation). In the meetings, members discussed strategies toward establishment of the PMDA's position in international society, including matters such as new international strategies and policies for dealing with major international conferences. The contents were made widely known at the international liaison conference (held 11 times in FY 2014) intended for persons in charge in each division/department of their thorough dissemination.  In response to a request for promotion of the "Kansai Innovation Comprehensive Global Strategic Special Zone," PMDA set up the Kansai Branch in Osaka City in October 2013. This office has conducted Pharmaceutical Affairs Consultation on R&D Strategy, and also GMP on-site inspections etc., from April 2014. Both operations are intended to target mainly users in the Kansai area. Aiming for the "enhancement of the PMDA function in the western Japan (Kansai region)," the request was submitted to the national government by the local governments of Kyoto Prefecture, Osaka Prefecture, Hyogo Prefecture, Kyoto City, Osaka City, and Kobe City. 2.1.(4)

Advisory Council meetings  In order to create opportunities for opinion exchange between knowledgeable individuals in various fields, PMDA holds meetings of the "Advisory Council" (chaired by Masataka Mochizuki, Professor, Faculty of Pharmaceutical Sciences, Tokyo University of Science), which are open to the public. The Council consists of academic experts, healthcare professionals, and representatives from relevant industries, consumers, and the people who have suffered from adverse health effects caused by drugs, etc. By seeking opinions on operations and the management system, the Council serves to secure fairness and transparency of PMDA's

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operations, in addition to contributing to streamlining the efficiency of its operations. Under the "Advisory Council," the "Committee on Relief Services" (chaired by Hideaki Mizoguchi, Professor Emeritus, Tokyo Women's Medical University) and the "Committee on Review and Safety Operations" (chaired by Masataka Mochizuki, Professor, Faculty of Pharmaceutical Sciences, Tokyo University of Science) were also formed to discuss specialized operational issues. The dates of the meetings and specific agenda for FY 2014 were as follows. [Advisory Council] (FY 2014) Agenda for the 1st Meeting (June 26, 2014) (1) (2) (3) (4) (5) (6) (7)

Annual Report FY 2013 Financial Report FY 2013 Revision of the Statement of Operating Procedures (draft) Situations of recent main efforts Employment status of personnel from the private sector Cash contributions etc., received by external experts commissioned for Expert Discussions etc. Others

Agenda for the 2nd Meeting (November 7, 2014) (1) (2)

(3) (4) (5) (6)

Selection of Chairperson and appointment of Acting Chairperson Results of evaluation of operating performance for FY 2013 and results of final evaluation of operating performance for the effective period of Mid-term Targets (Evaluation Committee for Incorporated Administrative Agencies of MHLW) Situations of recent main efforts Employment status of personnel from the private sector Cash contributions etc., received by external experts commissioned for Expert Discussions, etc. Others

Agenda for the 3rd Meeting (March 10, 2015) (1) (2) (3) (4) (5) (6) (7) (8)

FY 2015 plan (draft) and PMDA Public Relations Strategic Plan (draft) Budget for FY 2015 (draft) Revision of the Statement of Operating Procedures (draft) Employment status and extension of interim measures for restrictions on employment of personnel from the private sector Situations of recent main efforts Status of PMDA’s responses to opinions etc., given by members at the Advisory Council meetings for the past one year Cash contributions, etc., received by external experts commissioned for Expert Discussions, etc. Others

[Committee on Relief Services] (FY 2014) Agenda for the 1st Meeting (June 25, 2014) (1) (2) (3) (4)

Annual Report FY 2013 FY 2014 plan PR on the Relief System for Adverse Health Effects Others

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Agenda for the 2nd Meeting (December 10, 2014) (1)

Selection of Chairperson and appointment of Acting Chairperson

(2)

Results of the evaluation of operating performance for FY 2013 and results of final evaluation on operating performance for the effective period of mid-term targets (Evaluation Committee for Incorporated Administrative Agencies of MHLW) Operating performance so far in FY 2014 and current situation of recent major initiatives Others

(3) (4)

[Committee on Review and Safety Operations] (FY 2014) Agenda for the 1st Meeting (June 26, 2014) (1) (2) (3) (4) (5) (6) (7)

Annual Report FY 2013 FY 2014 plan Revision of the Statement of Operating Procedures on Reviews and Safety Measure Services (draft) Recent main situations Employment status of personnel from the private sector Cash contributions etc., received by external experts commissioned for Expert Discussions etc. Others

Agenda for the 2nd Meeting (December 24, 2014) (1)

Selection of Chairperson and appointment of Acting Chairperson

(2)

Results of the evaluation of operating performance for FY 2013 and results of final evaluation on operating performance for the effective period of the Mid-term Targets (Evaluation Committee for Incorporated Administrative Agencies of MHLW) Operating performance so far in FY 2014 and issues to be addressed in the future Employment status of personnel from the private sector Cash contributions etc., received by external experts commissioned for Expert Discussions etc. Others

(3) (4) (5) (6)

 The above meetings were open to the public, and the minutes and materials for the meetings of the Advisory Council and its sub-committees were publicly released on the PMDA website. 2.1.(5)

Approaches for an efficient operation management system  PMDA aims to establish an efficient operation system through flexible personnel allocation tailored to situations, as well as through effective use of external experts.  In review divisions that particularly require flexible approaches, PMDA continued the group system where review teams are led by Review Directors who report to the Office Director.  PMDA has continuously invited commissioned external experts to seek their professional opinions relating to scientifically significant matters on reviews and safety measures. (1,304 external experts are commissioned as of March 31, 2015.)  PMDA also has commissioned external experts to seek their opinions on the relief service for health damage caused by adverse drug reactions and infections acquired through biological products. (126 external experts are commissioned as of March 31, 2015.)  The list of the commissioned external experts is available on the PMDA website.

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 Based on the need to secure impartiality and transparency of judgment given by external experts, PMDA developed the "Rules for Convening Expert Discussions, etc., by the Pharmaceuticals and Medical Devices Agency" (December 25, 2008). The establishment of these rules enables PMDA to ensure the transparency by releasing review reports and information on conflict of interest of commissioned external experts, and also allows outside parties to check the decision making process. Cash contributions and contract payments received by external experts are disclosed immediately after confirmation of approval of designated products, implementation of safety measures, or development of approval standards for drugs or review guidelines, and are reported to the Advisory Council and the Committee on Review and Safety Operations.  In carrying out operations, PMDA has also commissioned lawyers and accountants as advisors to handle operations that require legal and tax expertise. In addition, the Agency has made use of private companies for operational management of information systems and minimized the increase in the number of its regular staff.  PMDA has continued to appoint a specialist with advanced expertise in information systems and knowledge of pharmaceutical affairs as an information system advisor, to ensure consistency and coordination of services across the Agency's information systems. 2.1.(6)

Standardization of operating procedures  In order to effectively utilize non-regular staff and limit the number of regular staff, PMDA has developed standard operating procedures (SOPs) for its major tasks. The contents of these SOPs have been examined and inspected, and revisions have been made as necessary. PMDA also used non-regular staff for routine operations.

2.1.(7)

Development of databases  Also in FY 2014, PMDA promoted the development of databases, including that of past final decision documents etc., for product approval by providing tags to the data, in order to systematically organize and store documents as well as to make it easy to collect and analyze information. PMDA also upgraded such databases to widely utilize such information to its operations of reviews etc.  Among the notifications etc., issued by the MHLW and PMDA, those that are relevant to the Agency's operations or those that should be broadly disseminated to the public are posted on the PMDA website:

2.1.(8)

Promotion of the optimization of operations and systems  Based on the "Plan for the Development of e-Government" (decided at the Liaison Meeting of the Chief Information Officers [CIO] of the Ministries and Agencies held on July 17, 2003) and the "Measures for the Realization of Optimal Operations/Systems at Incorporated Administrative Agencies" (decided at the Liaison Meeting of the CIOs of the Ministries and Agencies held on June 29, 2005), PMDA developed and publicized the Optimization Plan for Operations and Systems on March 28, 2008, and implemented works toward the creation of an optimum system for PMDA's operations in line with the revised version in June 2012 (A period from FY 2008 to FY 2014 is regarded as the implementation period).  In FY 2014, PMDA designed and developed an integrated review system in part in response to the revision of the Pharmaceutical Affairs Act, built information systems that connect safety monitoring and relief services, upgraded existing IT systems, designed and developed the accounting system

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and the personnel/salary system, and redesigned the PDMA website. The Agency also conducted research and reviews aimed at enhancing overall PDMA information management and IT control. 2.2.

Cost Control through Increased Efficiency of Operations

2.2.(1)

Retrenchment of general and administrative expense  PMDA has been making ongoing efforts to improve operations and increase management efficiency in order to attain the target of 15% or greater savings in the Mid-term Plan budget relating to general administrative expenses covered by administrative subsidies, as compared with that for FY 2014, by the end of the effective period of the Mid-term Plan/Targets (FY 2018).  In FY 2014, PMDA promoted streamlining of efficiency of its services, such as optimization of systems and reduction of unnecessary expenditure. As in the previous fiscal year, PMDA made efforts to reduce procurement costs by conducting, in principle, general competitive bidding, resulting in a 27.7% reduction against budget.

2.2.(2)

Cost control of operating expenses  PMDA has been making ongoing efforts to improve operations and increase management efficiency in order to attain the target of 5% or greater savings in the Mid-term Plan budget relating to operating expenses covered by administrative subsidies, as compared with that for FY 2014, by the end of the effective period of the Mid-term Plan/Targets (FY 2018).  In FY 2014, PMDA promoted streamlining of efficiency of its services, such as optimization of systems, promotion of computerization, and reduction of unnecessary expenditure. Similarly to the measures taken for general administrative expenses, PMDA made efforts to reduce procurement costs by concluding contracts through, in principle, general competitive bidding, resulting in a 14.2% reduction against budget

2.2.(3)

Competitive bidding  PMDA promoted bidding for all contracts by means of measures such as shifting to general competitive bidding based on the "Plan for Review of Optional Contracts etc. " In FY 2014, however, the ratio of competitive contract schemes, including competitive requests for proposals and invitations to bid, to total contracts decreased by 2.1% in terms of number of bids and by 35.5% in terms of monetary amount compared to the preceding fiscal year. The ratio of competitive contract in number decreased from FY 2013 to FY 2014 (-2.1%). This was due to a decrease of 2 competitive contracts and an increase of 3 non-competitive optional contracts. Other than contracts for office leases, there was an increase of 7 non-competitive optional contracts such as re-leasing contracts for leased properties with the specified contract party. Since FY 2014 is the first year of the effective period of the Third Mid-term Plan, PMDA entered into multi-year contracts for office leases, starting in FY 2014. Since the total contract amount for the multi-year contracts was included in the first fiscal year, the monetary amount for non-competitive operational contracts in FY 2014 increased by 71 million yen compared to the previous fiscal year, resulting in the decreased ratio in terms of the monetary amount for competitive contracts.

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General competitive bidding (including competitive planning competition and invitations to bids)

Non-competitive optional contracts

Excluding contracts in relation to office lease

Total

FY 2013 135 bids (83.9%) 5,838 million yen (76.8%) 26 bids (16.2%) 1,769 million yen (23.3%) 5 bids (3.1%) 35 million yen (0.5%) 161 bids 7,606 million yen

FY 2014 130 bids (91.8%) 6,240 million yen (41.3%) 29 bids (18.2%) 8,869 million yen (58.7%) 12 bids (7.5%) 321 million yen (2.1%) 159 bids 15,109 million yen

Change -5 bids (-2.1%) 402 million yen (-35.5%) 3 bids (2.0%) 7,100 million yen (35.4%) 7 bids (-4.4%) 286million yen (1.6%) -2 bids 7,503 million yen

Note: Since the figures are rounded off to the nearest number, the sum of the figures does not always match the sum of the totals.

2.2.(4)

Contract Review Committee meetings  Based on "Inspection/Review of the Contract Status of Incorporated Administrative Agencies" (adopted by the Cabinet on November 17, 2009), PMDA established the "Contract Review Committee" in the Agency. The Committee consists of external knowledgeable experts as well as internal auditors. In the Committee meetings, PMDA underwent a pre-inspection of procurement cases etc., for which contracts were planned to be concluded in FY 2014, regarding the appropriateness of the contract schemes and of corrective measures for ensuring the competitiveness. The Committee held 4 meetings in FY 2014 and disclosed the summary of review on the website.

2.2.(5)

Collection and management of contributions  Contributions from marketing authorization holders (MAHs) of the industry enable PMDA to secure the major part of financial resources for relief services for adverse health effects such as adverse drug reactions and infections acquired through biological products and other operations to improve the quality, efficacy, and safety of drugs and medical devices. Specifically, contributions to the adverse drug reaction fund ("ADR contributions") are declared and made by MAHs of approved drugs, contributions to the relief fund for infections acquired through biological products ("infection contributions") are declared and made by MAHs of approved biological products, and contributions to post-marketing safety measures are declared and made by MAHs of drugs and medical devices.  Basic data such as those concerning newly approved products (drugs and medical devices) and money transfer are automatically processed by the contribution collection management system, which is able to manage these contributions in an integrated fashion. Thus, PMDA efficiently conducted the operations of contribution collection and management, such as the calculation of products' transaction value which constitutes the basis of the contribution amount and the management of data concerning unpaid contributions. PMDA also ensured convenience for contributors through continuing consignment contracts with five major banks for receipt of contributions, resulting in a prompt transfer of funds.  Regarding ADR contributions, infection contributions, and post-marketing safety measure contributions, PMDA set the collection rates to be no less than 99% in the Mid-term Plan. In FY

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2014, the collection rates achieved for ADR contributions, infection contributions, and safety measure contributions were 99.7%, 100%, and 99.7%, respectively. FY 2014 Contribution Collection Results Number of parties obligated to make contributions

Number of parties who made contributions

Collection Rate

Contribution amount (Million yen)

MAHs of drugs

693

692

99.9%

3,852

MAHs of pharmacycompounded drugs

5,673

5,658

99.7%

6

Total

6,366

6,350

99.7%

3,857

MAHs of approved biological products

92

92

100%

93

MAHs of drugs

588

587

99.8%

1,035

MAHs of medical devices

2,291

2,288

99.8%

256

MAHs of drugs/ medical devices

224

224

100%

1,682

MAHs of pharmacycompounded drugs

5,673

5,658

99.7%

6

Total

8,776

8,757

99.7%

2,977

Category

ADR contributions

Infection contributions

Post-marketing Safety measures etc., contributions

Note: Since the figures for contribution amount are rounded off to the nearest thousand yen, the figures' sum does not always match the sum of the payment amounts.

 In order to efficiently improve contribution collection rates, the following efforts were made: 1) PMDA continued to commission the Japan Pharmaceutical Association (JPA) to collect contributions from MAHs of pharmacy-compounded drugs. 2) PMDA placed advertisements on websites and relevant trade journals, and tried to make the procedure known to all the parties obligated to make contributions by preparing and distributing a handbook on the procedure. Also, PMDA sent out written requests to all the contributors who have not yet made contributions. (i)

Collected ADR contributions and trends in the liability reserve a.

ADR contributions  In order to fund the relief service for adverse drug reactions, PMDA has collected ADR contributions from MAHs of approved drugs. In FY 2014, the contribution rate applied to such MAHs was set at 0.27/1000 and the collected amount was 3,857 million yen. (Million yen) Fiscal year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Contributions from MAHs of drugs

3,984 [716]

4,330 [713]

4,548 [688]

3,590 [688]

3,852 [692]

Contributions from MAHs of pharmacy-compounded drugs

7 [7,082]

7 [6,694]

6 [6,186]

6 [5,866]

6 [5,658]

Total amount

3,991

4,337

4,554

3,596

3,857

0.35/1000

0.35/1000

0.35/1000

0.27/1000

0.27/1000

Contribution rate

Note: Figures in [ ] represent the numbers of contributors.

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 The ADR contribution income and the contribution rate since the establishment of this service are shown below. Trends in ADR Relief Contribution Income

Contributions (Million yen) 5,000

Contribution rate (Permillage) 1.2

4,500 1.0

4,000

Contribution rate

Amount

3,500

0.8

3,000 0.6

2,500 2,000

0.4

1,500 1,000

0.2

500 0

0.0 1979

1985

1991

1997

2003

2009

Fiscal year

b.

Collected contributions for relief for infections acquired through biological products  In order to fund the relief service for infections acquired through biological products, PMDA has collected infection contributions from MAHs of approved biological products. In FY 2014, the contribution rate applied to such MAHs was set at 0.1/1000 and the collected amount was 93 million yen. (Million yen) Fiscal year Contributions from MAHs of approved biological products Contribution rate

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

693 [93]

785 [92]

866 [92]

869 [94]

93 [92]

1/1000

1/1000

1/1000

1/1000

0.1/1000

Note: Figures in [ ] represent the numbers of contributors.

c.

Liability reserve  In order to cover the estimated costs for relief benefits that eligible persons will receive in the future, PMDA calculates the amount that the Agency should possess at the end of every fiscal year and accumulates funds accordingly. The liability reserve at the end of FY 2014 was 20,141 million yen. In the settlement of accounts for FY 2014, 1,015 million yen of provision shortfall due to miscalculation of liability reserves in previous fiscal years was calculated as an extraordinary loss.

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(Million yen)

Trends of liability reserve

25,000

20,000

15,000

10,000

5,000

0

(ii)

Collected contributions for post-marketing safety measures  In order to fund services for improvements in the quality, efficacy, safety of drugs, etc., PMDA has collected contributions to post-marketing safety measures from MAHs of drugs and medical devices. In FY 2014, the contribution rate applied to such MAHs was set at 0.22/1000 for drugs excluding in vitro diagnostics and 0.11/1000 for in vitro diagnostics and medical devices, and the collected amount was 2,977 million yen. (Million yen) Fiscal year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

MAHs of drugs/ medical devices

2,530 [2,922]

2,596 [2,974]

2,768 [2,970]

2,810 [3.023]

2,972 [3,099]

MAHs of pharmacy-compounded drugs

7 [7,082]

7 [6,694]

6 [6,186]

6 [5,866]

6 [5,658]

Total amount

Contribution rate

2,537

2,603

2,774

2,816

2,977

0.22/1000

0.22/1000

0.22/1000

0.22/1000

0.22/1000

(Drugs excluding in vitro diagnostics)

(Drugs excluding in vitro diagnostics)

(Drugs excluding in vitro diagnostics)

(Drugs excluding in vitro diagnostics)

(Drugs excluding in vitro diagnostics)

0.11/1000

0.11/1000

0.11/1000

0.11/1000

0.11/1000

(Medical devices and in vitro diagnostics)

(Medical devices and in vitro diagnostics)

(Medical devices and in vitro diagnostics)

(Medical devices and in vitro diagnostics)

(Medical devices and in vitro diagnostics)

Note: Figures in [ ] represent the numbers of contributors. Since the figures for contribution amount are rounded off to the nearest million yen, the sum of the figures does not always match the sum of the contribution amounts.

2.2.(6)

Promotion of measures for reduction of unnecessary expenditures  To steadily implement measures for "Reinforcement of efforts to reduce unnecessary expenditures" (formulated in FY 2009) under the Third Mid-term Plan, "Reinforcement of efforts to reduce unnecessary expenditures" was revised and, along with "Standard practice for taking more efficient cost-cutting measures", announced to employees to promote efforts for cost-cutting.

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2.3.

Improvement of Services to the Public

2.3.(1)

General consultation service  Based on the "General Consultation Guidelines" that specifies how to handle inquiries directed to PMDA and how to make use of comments and opinions to improve its operations, PMDA provides a general consultation service and makes questionnaires available at the reception desk, enabling the collection of comments and opinions of visitors regarding its overall operations. In addition, PMDA receives opinions etc., via telephone, facsimile, and the website.  Since June 2010, PMDA has been disclosing the "Public Voice" sent to the Agency on its website on a weekly basis to make use of it to improve management of its operations.  Among the 1,731 inquiries that PMDA received in FY 2014, 480 or approximately 30% of the total inquiries received were those relating to applications and consultations for drugs, medical devices, etc.

FY 2014

Inquiry/ consultation

Complaint

Opinion/ request

Others

Total

1,604 (436)

10 (3)

117 (41)

0 (0)

1,731 (480)

Note 1: Figures in parentheses represent the number of cases related to consultations and applications for approval of drugs or medical devices. They are included in the total numbers above. Note 2:The Office of Review Administration also accepts inquiries on consultations and applications for approval of drugs, medical devices, etc. separately from this general consultation service.

2.3.(2)

Responses to consultations, complaints, and claims of dissatisfaction from companies regarding product reviews and product safety operations  In addition to responding to consultations and complaints from general consumers, PMDA also handles complaints from relevant companies regarding product reviews and product safety operations.  In FY 2004, PMDA established a system where, if an applicant files claims of dissatisfaction etc., regarding product reviews and product safety operations, the responsible office director (the Director of the Center for Product Evaluation or Chief Safety Officer, if the second claim of dissatisfaction has been filed in the same case) is to directly conduct an investigation and respond to the applicant within 15 working days. PMDA continued to operate the system in FY 2014.  In addition, PMDA developed a consultation manual to handle complaints from relevant companies. From among the complaints received, PMDA selects and reviews those that would be helpful in improving its operations.

2.3.(3)

Enrichment of the PMDA website  PMDA has enhanced the content of its website. For example, new information and updates, etc. of existing content are sequentially posted on the website in order of requests from relevant departments.  On March 16, 2015, PMDA integrated the "Medical Product Information" Web page (http://www.info.pmda.go.jp) into the Pharmaceuticals and Medical Devices Agency website (http://www.pmda.go.jp), and redesigned the whole website to make it more accessible to anyone. [Three ideas for improving the website to make required information more easily accessible for all users]

- 27 -

(1) (2) (3)

2.3.(4)

Newly designed topics area to display the latest and most important information Newly designed navigation area to enable rapid access to target information (menu navigation by visitors, by products, and by services, and local navigation) Comprehensive provision of information on individual products and enhancement of search function for materials such as package inserts

Proactive PR activities  In line with the PMDA Public Relations Strategic Plan (July 11, 2008), developed from the perspective of systematically promoting PR activities of the Agency as a whole, PMDA intends to improve services to the public by proactively providing information. In FY 2014, the following activities were implemented based on the Strategic Plan. In consideration of development of PMDA’s philosophy, changing socioeconomic circumstances, etc., PMDA revised the Strategic Plan and determined to develop a PR plan every fiscal year based on the revised strategy and to manage progress of PR plan to enable effective public relations designed separately for each stakeholder (came into force on April 1, 2015). In FY 2014, PMDA distributed leaflets, which are designed to introduce PMDA to the general public, at events in various locations. In addition, PMDA notified patient groups of the distribution of leaflets etc., and provided them to the groups that requested. For the occasion of "Drug and Health Week," PMDA conducted PR activities for the general public by distributing brochures/leaflets on PMDA's services, brochures on relief systems, give-away goods, etc., and giving lectures and running booths at events held in various regions, in cooperation with pharmaceutical associations in 17 prefectures. In addition, PMDA introduced its operations to researchers and healthcare professionals by making booth exhibitions at academic conferences. PMDA also issued monthly PMDA newsletters (e-mail magazines for prospective employees) and released them on its website. In addition, the Chief Executive delivered speeches etc., 29 times in Japan and 3 times overseas.

2.3.(5)

Disclosure requests for agency documents  The status of requests (over the last 5 years) for disclosure of documents under the Act on Access to Information Held by Incorporated Administrative Agencies is shown below. In FY 2014, the number of requests decreased by 14.3% and the number of disclosures increased by 32.5% compared to the previous fiscal year. PMDA appropriately processed requests in accordance with the relevant laws and regulations.

- 28 -

Number of Requests for Disclosure of Agency Documents (Unit: Case) Decisions* Total requests

Requests withdrawn

Full disclosure

Partial disclosure

Nondisclosure

Nonexisting documents

Refusal to answer whether the documents exist

Objections made

Carryover into FY 2015**

FY 2010

983

74

150

833

4

40

1

1

0

FY 2011

1,192

112

138

831

1

74

0

1

0

FY 2012

1,593

287

147

988

0

81

10

5

0

FY 2013

1,823

394

73

1,104

7

72

4

0

631

FY 2014

1,562

262

176

1,384

0

82

1

0

511

* If a request is received as one case and multiple notifications on decision of disclosure etc., are separately issued for the request, the number of notifications for each decision on disclosure etc., are shown. ** "Carry-over into FY 2015" includes cases for which requests for disclosure were made at the end of the fiscal year and cases to which the prolongation of due dates for decision of disclosure etc., pursuant to laws and regulations were applied for reasons such as large amounts of documents.

2000 1800 1600 1400 1200 1000 800 600 400 200 0

Total requests

請求件数

Number of cases of disclosure

開示件数

Number of cases of non-disclosure

不開示件数

Requests withdrawn

取下げ

22年度

FY 2010

23年度

FY 2011

24年度

FY 2012

25年度

FY 2013

26年度

FY 2014

Note 1:The number of cases of disclosure includes full and partial disclosure. Note 2:The number of cases of non-disclosure includes cases of non-existing documents and refusals to answer whether the documents exist.

- 29 -

Number of Requests for Disclosure of Agency Documents by Operational Category of Document (Unit: Case) Operational category/FY

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Examples

Product application Review

902

1,046

1,410

1,675

1,457

Marketing notification for products not subject to approval, Notification of the results of GCP inspections

Post-marketing Safety

78

139

176

131

97

ADR reports etc.,

Others

3

7

7

17

8

Total

983

1,192

1,593

1,823

1,562

Note: The numbers include requests that were withdrawn, those for the documents decided not to be disclosed, those for non-existing documents or those for the documents refused to answer whether the documents exist.

2.3.(6)

Disclosure requests for personal information  The status of requests for disclosure of personal information based on the Act on the Protection of Personal Information Held by Incorporated Administrative Agencies is shown below (for the past five years).

Number of Requests for Disclosure of Personal Information (Unit: Case) Decisions

2.3.(7)

Total requests

Requests withdrawn

FY 2010

3

FY 2011 FY 2012

Refusal to answer whether the documents exist

Objections made

Carryover into FY 2015

Full disclosure

Partial disclosure

Nondisclosure

Nonexisting documents

0

0

1

0

1

0

0

0

1

0

0

2

0

0

0

0

0

3

1

0

2

0

0

0

0

0

FY 2013

6

0

0

4

0

0

0

0

0

FY 2014

8

1

0

9

0

0

0

0

0

Auditing  PMDA undergoes audits conducted by an external auditing firm in accordance with the general rules for incorporated administrative agencies and by the Agency's Auditors. PMDA also conducts internal auditing systematically through the Audit Office for operations and accounts, from the perspective of internal control. The results of these audits are publicly reported to ensure transparency in the Agency's management and operations.  In FY 2014, PMDA conducted internal audits on the management status of documents, cash and cash equivalents, execution status of travel expenses, management status of competitive research funds, etc., and the status of compliance with rules restricting work assignments of personnel from the private sector.

2.3.(8)

Report on the financial standing  From the perspective of ensuring the transparency of expenditures, PMDA disclosed its financial standing for FY 2013, including the use of user fees and contributions, in government gazettes and on its website. PMDA also released the budget for FY 2014 on its website. - 30 -

2.3.(9)

Release of "Plan for the Review of Optional Contracts etc."  Following the inspection or review of optional contracts etc., PMDA released a report entitled "Follow-up on contract status of FY 2013" on the website in August 2014.

2.4.

Personnel Matters

2.4.(1)

Personnel evaluation system  According to the Mid-term Targets, PMDA is required to evaluate personnel properly taking individual performance of employees into consideration. Moreover, in the Third Mid-term Plan (FY 2014 to FY 2018), PMDA also intends to manage a personnel evaluation system in which the results of the evaluation and the attainment of individual goals are properly reflected in remuneration, pay raises, and promotions, to enhance the morale of employees.  To this end, PMDA appropriately reflected the results of personnel evaluation during the period from April 2013 to March 2014 in pay raises etc., as of July 2014. In order to ensure the proper implementation of this personnel evaluation system, PMDA provided briefing sessions for all employees, and explained the "personnel evaluation system" to the new recruits as a subject of their training course.  Starting in FY 2013, training programs for evaluators (managerial staff) has been conducted by outsourcees in order to enhance the evaluation capability and enable the personnel evaluation to more effectively cultivate human resources and capability development.  Interviews by secondary evaluators with evaluatees has been conducted since FY 2013 for the purposes of knowing the working conditions of employees on a routine basis and of creating an opportunity of communication to establish a favorable relationship.

2.4.(2)

Systematic implementation of staff training  In the operations for reviews, post-marketing safety measures, and relief service conducted by PMDA, highly specialized expertise is required. In addition, rapid strides are constantly being made in the advancement of technology for developing drugs and medical devices.  Thus to improve the quality of operations, PMDA needs to systematically provide training opportunities tailored to the objectives of each operation, for not only technical employees but also administrative employees who support organizational management. PMDA’s training programs are divided into 2 courses: General Training Course on important topics in light of the special nature of PMDA’s services (e.g., information technology and business manners) that employees should understand and address to fulfill their roles; and Specialized Training Course to develop expertise in quality, efficacy, safety evaluation, and other matters related to drugs, medical devices, etc. Employees systematically participate in both courses to learn about the knowledge and expertise. Furthermore, in order to provide efficient and effective training tailored to services, PMDA has actively utilized external institutions and experts, thereby enriching training content in order to improve the quality and capabilities of employees. PMDA also facilitated the participation of employees in academic conferences etc., both in Japan and overseas to improve their knowledge and technical expertise. For implementation of each training course, the Training Committee formulated plans based on the needs of the employees. Various training programs, as listed below, have been implemented. - 31 -

The training programs were evaluated and earned high marks in terms of participant satisfaction and acquisition of knowledge/skills. 1) General Training Course (i)

(ii) (iii)

(iv) (v) (vi)

New recruit training was conducted between April and May 2014. The major subjects are as follows:  Operations of each office, related systems/procedures  Human skills (e.g., business manner, communications, motivation)  Document management, reduction of unnecessary expenditures, etc. Training programs for follow-up, mid-level employees and management-level employees, as part of training programs by job level. One-to-one English conversation lessons (e.g. practical business English for international conferences) and correspondence courses in English language were subsidized and TOEIC tests were administered to improve employees’ English language skills. Legal compliance training for all executives and employees to promote awareness of legal compliance and protection of personal information. Three training program sessions were held, in which lecturers invited from organizations for adverse drug reaction sufferers and patient organizations delivered presentations. In order to utilize electronic documents more efficiently, IT literacy training (Microsoft Office) was carried out for a total of 50 members through e-learning in which trainees learn at the personal computer on their own desk.

2) Specialized Training Course (i) (ii)

(iii)

(iv)

(v) (vi)

Training courses on the basic knowledge needed for review, safety, and relief services (case studies, medical writing training, etc.) were provided mainly for new recruits. On-site training programs, such as visits to drug/medical device manufacturing facilities (8 facilities) and IRBs of medical institutions were provided. Hands-on training on medical devices was provided. Experts invited from Japanese or overseas regulatory authorities, corporations, and universities provided special training in technical issues (24 sessions) and training in the regulatory system including the Pharmaceutical Affairs Act (2 sessions).Training in clinical study design to learn biostatistics (12 sessions) and in pharmacoepidemiology to learn features of pharmacoepidemiological study design (4 sessions) were also provided. A total of 14 employees were dispatched to technical training programs conducted by external institutions (e.g., Pharmaceuticals Promotion Association's Regular Course, National Institute of Public Health, and Union of Japanese Scientists and Engineers). For the acquisition of basic knowledge about medical devices, class I and II ME (Biomedical Engineering) technical trainings were also provided (19 employees). Five employees were dispatched to 2 medical institutions for practical training with pharmacists conducted at hospitals to learn clinical practice. One employee was dispatched to an accounting training course provided by the Accounting Center, Ministry of Finance and another employee to courses for internal auditors provided by the Board of Audit of Japan, to improve administrative processing skills. In addition, 5 employees attended Grade 2 or 3 bookkeeping courses. Also, 18 employees attended either an external logical thinking course, a management course, a labor management course, or a course for the Japanese business law examinations, as training for administrative staff members who are on main career tracks.

- 32 -

Training and Human Resource Development

General training course

Specialized training course

Fourth year onwards

Second - third year

First year Training programs for new recruits

(philosophy, work regulations, etc.)

Follow-up training programs (business manner etc.)

Training programs for mid-level employees (coaching etc.)

Management level Training programs for managerial staff (e.g., management skill)

General training programs (e.g., foreign languages, risk management)

Specialized training programs (case study, medical writing) On-site training programs (e.g., medical institutions where clinical trials take place, pharmaceutical manufacturing plants)

Participation in and discussion at international conferences (ICH, IMDRF), etc., and dispatching of lecturers to universities

Special training programs (discussion on the latest scientific topics with experts invited from Japan and foreign countries) Participation in and presentation at academic conferences in Japan and foreign countries Mentoring system (established by reference to FDA's Orientation Mentoring Program)

Training at external institutions in Japan (e.g., medical institutions, research institutions) Long-term training at foreign organizations (e.g., foreign regulatory agencies)

Note: Training courses indicated in color are mandatory for all eligible employees.

2.4.(3)

Appropriate personnel allocation  In order to secure the expertise of staff members and operational continuity and make the best use of limited resources, in line with the basic policy of the Third Mid-term Plan, PMDA seeks to conduct appropriate personnel allocation. To achieve this target, PMDA deploys personnel taking into consideration the knowledge and work experience of individual staff members. PMDA conducts medium- and long-term rotation of personnel upon overall adjustment.  Also in FY 2014, personnel change and career progression were implemented in line with the basic policies for the PMDA Career Paths that were developed in March 2011.

2.4.(4)

Securing of human resources through open recruitment  It is an important task to recruit capable persons with professional expertise while paying due attention to the neutrality and impartiality of PMDA, in order to conduct its operation of reviews and post-marketing safety measures promptly and accurately.  In the Third Mid-term Plan, in accordance with the Act for Partial Revision of the Pharmaceutical Affairs Act, which reflects the content of the Japan Revitalization Strategy, the Healthcare and Medical Strategy, and the final recommendations of the Committee for Investigation of Drug-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Drug-induced Suffering, the target number of regular employees at the end of the period (end of - 33 -

FY 2018) is set to be 1,065. PMDA is required to recruit capable persons in relevant areas, based on the recruitment plan for each job category. Therefore, PMDA held information sessions on career opportunities, and conducted open recruitment of regular technical employees twice in FY 2014 by making use of its website as well as job information websites. Employment through Open Recruitment in FY 2014 (as of April 1, 2015) 1)

2)

Technical (specialist) employees [open recruitment conducted twice] Number of applicants Number of employments

430 68

Administrative staff members who are on main career track [open recruitment conduced once] Number of applicants Number of employments

125 11

FY 2014 Recruitment Activities  Information sessions on career opportunities January and February: Two sessions in Tokyo and one session each in Osaka, Nagoya, Sapporo, and Fukuoka (total 371 participants) May: Two sessions in Tokyo and one session in Osaka (total 171 participants)  Activities performed in collaboration with directors/employees  Lectures on and explanation of the services at universities etc., by directors/employees  Students visits by their alumni of young PMDA employees  Tools for recruitment activities  Brochures for recruitment, posters for recruitment  The brochures and posters were sent out to approximately 500 institutions including medical schools of universities, medical institutions such as university hospitals, faculties of pharmaceutical science of universities, pharmacy departments of hospitals, faculties relevant to biostatistics and veterinary science, and research institutions. Also, the brochures were distributed at recruitment information sessions etc.  Information to be posted on job information websites  Websites presenting job offers for new graduates in 2016 ("My Navi 2016" and "Rikunabi 2016")  Staff were recruited as needed for 10 job categories: toxicity, IT system, clinical medicine, biostatistics, epidemiology, clinical pharmacology/pharmacokinetics, information scienceNote, GLP, GMP/QMS, and foreign language (English). As a consequence, 25 individuals were employed on an as-needed basis. Note: Recruitment of information science staff was terminated in June 2014.

- 34 -

Numbers of Executives and Regular Employees FY 2009 April 1

FY 2010 April 1

FY 2011 April 1

FY 2012 April 1

FY 2013 April 1

FY 2014 April 1

FY 2015 April 1

At the end of the effective period of Third Mid-term Plan (end of FY 2018)

Total

521

605

648

678

708

753

820

1,065

Review Department Safety Department Relief Department

350 82 32

389 123 34

415 133 34

438 136 33

460 140 33

492 152 33

532 165 36

Note 1: The "Total" includes 6 executives (including one part-time auditor). However, the number of executives is 5 as of April 1, 2014. Note 2: The Review Department consists of the Director for Center for Product Evaluation, Associate Executive Directors (excluding the one responsible for the Information Technology Promotion Group), Associate Center Directors (excluding the one responsible for Office of Regulatory Science), Advanced Review with Electronic Data Promotion Group, Office of International Programs, International Liaison Officers, Office of Review Administration, Office of Review Management, Office of Standards and Guidelines Development, Offices of New Drugs I to V, Office of Cellular and Tissue-based Products, Office of Vaccines and Blood Products, Office of OTC/Quasi-Drugs, Office of Generic Drugs, Offices of Medical Devices I to III, Office of In Vitro Diagnostics, Office of Non-clinical and Clinical Compliance, Chief of Kansai Branch, Consultation Division of Kansai Branch, Principal Senior Scientists, and Senior Specialists. Note 3:The Safety Department consists of the Chief Safety Officer, Offices of Safety I and II, Office of Medical Infomatics and Epidemiology, Office of Manufacturing/Quality and Compliance, and Inspection Division of Kansai Branch.

2.4.(5)

Appropriate personnel management based on work regulations  PMDA is careful to conduct appropriate personnel management so that suspicion of inappropriate ties with pharmaceutical companies may not arise, by imposing certain restraints on recruitment and allocation of executives and employees as well as on employment with other organizations after resignation from PMDA.  For this purpose, PMDA's work regulations prescribe the requirement of submission of a written oath for newly-employed staff members, rules for personnel allocation, restrictions regarding re-employment after resignation, and work restrictions for employees whose family members work in the pharmaceutical industry. PMDA conducts appropriate personnel management by making a handbook which provides outlines of related regulations, Q&A, and other information and distributing it to executives and employees and by keeping its staff members informed of these regulations through training sessions for new employees.  Also, PMDA encouraged relevant employees to submit reports on donations etc., under the code of ethics, and also reviewed the details of the submitted reports.  As a set of countermeasures against power harassment in the workplace, a structure for efficient prevention and resolution of power harassment incidents has been developed, involving such measures as placing a counseling staff member in each office, based on the regulations relating to prevention of harassment and a manual on how to deal with issues related to power harassment.  For specially appointed experts accepted from universities, research institutes, etc., with the implementation of "Initiative to facilitate development of innovative drugs, medical devices, and cellular and tissue-based products," a handbook which briefly summarizes services and ethics in PMDA was made and distributed, and training sessions were provided to all specially appointed experts.

- 35 -

2.4.(6)

Optimization of standards for remuneration  PMDA compared its personnel remuneration system for FY 2013 against that for national government employees in order to facilitate public understanding of its remuneration levels, and released the results on its website.  Based on the recommendations of the National Personnel Authority in FY 2014, PMDA revised the overall remuneration system, including narrowing the disparities in remuneration standards between PMDA and private sector (in particular, lowering of the remuneration standards for older employees).

2.4.(7)

Development of better working environment  Based on discussions in the Work-Life Balance Promotion Committee, PMDA has enhanced support measures for child-rearing by expanding the eligibility for "time off for sick/injured child care," "time for child care," and "early/late shift," and by introducing a separate leave category for the caring of children with school-infectious diseases. 

2.5.

While promoting to generalize these child care support programs for employees, PMDA has also developed the General Business Owner Action Plan (third term) to address other issues, in order to support development of the next generation.

Ensuring Security

2.5.(1)

Entry/exit access control  To ensure security and protect confidential information, PMDA has installed a door access control system for each office to reinforce the internal security control.  Specifically, the ID card based "access control system" installed at each office can log every entry through designated doors and prevent outsiders from freely entering In May 2010, in order to reinforce security, PMDA set up non-stop floors at which elevators do not stop unless the passengers (PMDA executives and employees, etc.) have appropriate ID cards.  In order to ensure further strict access control, PMDA has also prescribed rules on its access control, and has made maximum efforts to thoroughly inform its staff members of these rules through the intranet and during new recruit training.

2.5.(2)

Security measures for information systems  Based on the FY 2014 plan, PMDA strove to maintain and improve the security of information in its information systems.  In order to reinforce the data backup function, PMDA has been storing backup data in the information systems at remote locations since FY 2007.  In order to reliably expand the use of secure e-mails in the audio transcription processes of records of consultations, PMDA improved the security.

- 36 -

Numbers of Users/Issued Certificates of the Secure e-mail System

Outside PMDA

Number of registered companies

Cumulative total of issued certificates

70

800

Within PMDA

1,403

Note: The numbers of registered companies and issued certificates as of the end of March 2015

- 37 -

PART 3

3.1.

Improvement in Management of Operations and Quality of Services in Each Division

Relief Services for Adverse Health Effects To ensure that the public is more widely informed of the Relief System for Sufferers from Adverse Drug Reactions and the Relief System for Infections Acquired through Biological Products (hereinafter collectively referred to as "relief systems"), PMDA, through its relief fund services, takes the following measures to provide adequate and swift relief for those suffering from health damage caused by adverse reactions to drugs or cellular and tissue-based products and infections acquired through biological products or cellular and tissue-based products.

3.1.(1) (i)

Expansion and review of dissemination of information regarding the relief system Release of payment cases etc., on the website  PMDA has promptly published the decision on approval/rejection of claims for adverse reaction relief benefits with due consideration to protecting personal information. Every month, claims approved or rejected in the previous month are posted on the website. PMDA also distributes the information through its email service called "PMDA medi-navi" concurrently with posting information on the website.  Based on relevant information obtained from claims submitted for relief benefits, PMDA calls users' attention to the cases of health damage which have repeatedly occurred although precautions have already been provided in package inserts. The information was described in the "PMDA Request for Proper Use of Drugs" on the web page and also distributed through "PMDA medi-navi" to further promote the proper use of drug products.  The PMDA website contains a trial web page entitled "Patient's Report for Adverse Drug Reactions” in order to identify trends in occurrence of adverse drug reactions and collect other information, so that safety measures for drugs will be improved. The web page has a link to the "Relief System for Adverse Health Effects" web page.  To make the administration of the relief system more transparent, PMDA released the operating performance until the end of September 2014 on the website.

(ii)

Improvement of brochures etc.  In order to raise public understanding of the relief systems and swiftly offer relief benefits, PMDA has made the following efforts: a) The leaflet for the general public is written in a conversational style instead of one-way statements. The setting used is as follows: First, a patient asks a health care professional, “Should adverse drug reactions not occur to me if I use a drug product properly?” The question from the first-person perspective helps patients regard possible adverse reactions as “own concern.” Next, the healthcare professional responds, “No. Even if you use a drug product properly, the drug product may cause a serious health damage in rare cases,” so as to raise patients’ awareness that anybody could be involved in adverse drug reactions. In the leaflet for healthcare professionals, it is stated “Please tell patients that a drug product may cause a serious health damage in rare cases even if they use it properly,” so that the healthcare professionals will become aware that they are expected to properly tell patients

- 38 -

about possible occurrence of adverse health damage and to work as a bridge to the use of the relief system. In addition, electronic files (PDF format) of the same leaflets are available on the website for users’ convenience. b) In association with the revised Pharmaceutical Affairs Act dated November 25, 2014, claim forms, including medical certificate, for medical expenses/allowances were revised. The revised forms and instructions are available on the website. c) PMDA is making efforts to ensure users know that claim forms can be downloaded from the following website, to improve the convenience of users. http://search.pmda.go.jp/fukusayo_dl/ d) The guidance for claims to be enclosed with claim forms and the checklists for claimants was revised, in accordance with the revision of amounts of payment as of April 1, 2015, in order to reduce the claimants’ burden by intelligibly indicating how to fill in the required information for the claiming and which documents should be enclosed with claim forms. 3.1.(2)

Proactive PR activities of the relief system

PMDA utilized an external consultant to implement efficient publicity including the following activities. Major activities conducted in FY 2014 (i)

As a PR campaign on TV, a 15-second infomercial was aired through 30 nationwide TV stations to familiarize the general public with the relief system in accordance with the “Drugs and Health Week” from October 14 to 27, 2014. (ii) An advertisement was placed in morning newspapers (5 national papers and 38 regional papers) for one day only in October 2014. (iii) Web advertisements were placed on the website of Yahoo! Japan using the behavioral targeting advertising*1 and search advertising*2 methods for one month from October 17 to November 16, 2014. (iv) PMDA renewed the home page and other pages of the special website for the relief system using PMDA’s original character "Doctor Q." (v) As transport advertising, digital signage (a still image on an upright LCD screen) that could attract the attention of train commuters was displayed at major stations nationwide for one week from October 20 to 26, 2014. (vi) Posters were displayed and a commercial was shown on the monitors in 679 dispensing pharmacies nationwide from November 4 to December 3, 2014. (vii) A 30-second commercial was aired 16 times a day from November 4 to 28 on the Hospital Channel shown on the monitors located in the waiting rooms of hospitals. In addition, PMDA placed an A4-sized leaflet racks in the waiting rooms and distributed 10,000 leaflets. (viii) An advertisement was placed in 11 medical newspapers/journals for one day only in October 2014. (ix) In collaboration with medical journals (Nikkei Medical, Nikkei Drug Information), publicity activities were conducted. (x) PMDA placed a banner advertisement on the special website for nurses (Nurse Senka) for one month from November 1 to 30, 2014. *1 A method to provide individual Internet users with advertisements that are relevant to their needs and interests based on the services they accessed via a browser or the keywords they entered into a search engine.

- 39 -

*2 A method of placing online advertisements on web pages that match keywords an Internet user has entered on a search engine. Search advertising is mostly text-type.

Activities conducted on-site (i)

Dispatching lecturers to training workshops held by medical institutions for their employees In November 2013, the MHLW issued a notification* to prefectural governments and healthcare-related organizations, to request them to utilize PR materials on the relief system in their training sessions for safety management of medical services and informed that PMDA is willing to send materials on the relief system and dispatch lecturers. After the issuance of the notification, PMDA staff members visited healthcare-related organizations to request for cooperation to implement training sessions for the relief system. In response to this approach, medical institutions and other organizations requested training sessions; therefore PMDA has dispatched its staff members as lecturers to 30 medical institutions, 25 relevant organizations, and one government body to explain the relief system, and sent the PR materials to 159 medical institutions etc. * Notification issued by Chief of the Office of Drug Induced Damages at General Affairs Division, Pharmaceutical and Food Safety Bureau, MHLW, dated November 29, 2013 “Enhancing public awareness of the Adverse Drug Reaction Relief System Implemented by the Pharmaceuticals and Medical Devices Agency (request for cooperation)”

(ii)

Academic conferences PMDA conducted publicity activities at academic conferences including the 6 occasions below:  Booth presentations  Annual Meeting of the Japanese Dermatological Association  Annual Meeting of the Japanese Society of Pharmaceutical Health Care and Sciences  Annual Meeting of the Japanese Society for AIDS Research  Distribution of booklets and brochures  Annual Meeting of the Japan Neurosurgical Society  Annual Meeting of the Molecular Biology Society of Japan  Annual Meeting of Japanese Society for Parenteral and Enteral Nutrition

(iii)

Requests for cooperation to government bodies, relevant organizations, etc. PMDA informed 30 government bodies and relevant organizations, etc., of the current level of awareness of the relief system, and requested cooperation in publicity activities. Others At the 16th Forum on Eradication of Drug-induced Sufferings (sponsored by Japan Federation of Drug-Induced Sufferers Organizations), PMDA opened a consultation desk for the relief systems and distributed leaflets.

(iv)

Others (i)

PMDA has continued to operate the special website, using its original character "Doctor Q."

(ii)

PR utilizing the brochure for healthcare professionals "Know it better than anyone and pass along. Relief System for Sufferers from Adverse Drug Reactions" was conducted. The brochure in PDF format was posted on the PMDA website.

(iii)

PMDA updated the presentation slides entitled “What is the Relief System for Sufferers from Adverse Drug Reactions?” to accelerate the use of the slides in lectures, training sessions, etc., on the relief system at universities and hospitals.

- 40 -

(iv)

PMDA posted, on the website, poster and medicine envelopes on which the advertisement of the relief systems is pre-designed for pharmacies to use.

(v)

PMDA posted “Summary of the Relief System for Sufferers from Adverse Drug Reactions and the Cases of Non-payment of Relief Benefits Due to Improper Use of Drugs” in the “Pharmaceuticals and Medical Devices Safety Information No. 319 (December 2014).”

(vi)

With cooperation of the Federation of Pharmaceutical Manufacturers' Associations of Japan, PMDA placed the information on the relief systems in a journal, Drug Safety Updates (DSU) published by the Federation, and distributed the journal to medical institutions nationwide.

(vii)

In collaboration with MHLW, PMDA enclosed the leaflet on The Relief System for Sufferers from Adverse Drug Reactions in the brochure "Pharmaceuticals and Medical Devices Safety Information Reporting System". The leaflets enclosed in the brochures were distributed to relevant organizations etc.

(viii) Information on the relief systems was provided in a brochure "Useful Information on Medicines" (published by MHLW and the Japan Pharmaceutical Association) in the "Drug and Health Week." (ix)

An advertisement for the Relief System for Sufferers from Adverse Drug Reactions was placed in scientific journals (the Journal of the Japan Medical Association, the Journal of the Japan Pharmaceutical Association, the journal of the Japan Dental Association, and the journal of the Japanese Society of Hospital Pharmacists). The advertisement and leaflet has the same design.

(x)

PMDA continued to place the banner link to the special web page for the relief system on the home page of the website of the Japan Pharmaceutical Association, to raise the visibility of the banner.

(xi)

PMDA inserted the website address of the relief system in the educational material entitled “Learn Yakugai (Drug-Induced Sufferings),” which had been prepared by MHLW, and enclosed a poster when distributing the material to junior high schools, boards of education, etc., nationwide.

(xii)

PMDA surveyed the level of awareness of the relief system among the general public and healthcare professionals, to understand how well the system is recognized and to make PR activities more effective. Survey period: February 5 to February 23, 2015.

- 41 -

Home page of the special website

- 42 -

Tie-up with healthcare journals Reproduced from December 2014 issue of Nikkei Medical

Pharmacy vision; In-hospital vision

Pharmacy vision

In-hospital vision

- 43 -

Transport advertising (digital signage in train stations)

- 44 -

3.1.(3)

Securing of efficient management of the consultation service  In FY 2014, the number of consultations at the Relief System Consultation Service was 21,300, with a ratio of 97.5% compared with the previous fiscal year (21,843 consultations).  In FY 2014, the number of access to the website was 137,359, with a ratio of 90.4% compared with the previous fiscal year (151,925 access).  The number of access to the web page of the relief system was 54,239, with a ratio of 77.9% compared with the previous fiscal year (69,616 access).  PMDA tried to keep the people who seek consultation informed of the fact that claim forms can be downloaded from the website. Fiscal Year

FY 2010

FY 2011

FY 2012

Number of consultations

16,123

21,577

22,324

Number of access to the website

89,500

72,688

113,182

FY 2014

Compared with FY2013

21,843

21,300

97.5%

151,925

137,359

90.4%

FY 2013

Number of consultations 180,000 Number of consultations

Number of accesses to the website

160,000

151,925 137,359

140,000 120,000

113,182

100,000

89,500

80,000

72,688

60,000 40,000 16,123

21,577

22,324

21,843

21,300

20,000 0 FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

 Toll-free number: 0120-149-931 (Office hours: Monday - Friday [except public holidays and New Year's holidays] 9:00 -17:00)  Relief System Consultation Service e-mail address: [email protected]

3.1.(4)

Promotion of improved efficiency of operations using databases  To optimize the systems for Relief Services for Adverse Health Effects based on the Optimization Plan for Operations and Systems, the function of the relief benefits service system was enhanced, information on relief benefits were stored in a single database (several databases were integrated

- 45 -

into one database) to manage the information in a unified manner, and other measures were taken. Promotion of expeditious processing of relief benefit claims  In order to conduct prompt administrative processing of relief benefit services, PMDA, upon receiving a claim for relief benefit, investigates and organizes the facts given in such a claim, and requests the Minister of Health, Labour and Welfare to make a medical and pharmaceutical judgment on the claim. For this purpose, the following operations are conducted: fact-finding investigations of the claimed event; preparation of a summary chart showing case narratives over time; and preparation of investigation reports etc. Flow of Adverse Health Effect Relief Services

(3) Consultation Minister of Health, Labour and Welfare

Adverse health effects

(5) Notice of judgment

(2) Request for judgment

3.1.(5)

Adverse health effects sufferers

(1) Claim for benefits (6) Notice of judgment & payment of benefits

(4) Advice

Pharmaceutical Affairs and Food Sanitation Council

Government (MHLW)

Subsidy (administrative fees)

Pharmaceuticals and Medical Devices Agency (PMDA)

General contribution

MAHs of drugs

Additional contribution

* Applicants who are not satisfied with the judgment on approval/rejection of claims for relief benefits may request the Minister of the MHLW to review the judgment.

 The Third Mid-term Plan specifies that, although the number of claims are expected to increase, at least 60% of claims that have been filed will be judged (approved or rejected) within 6 months, as before. In FY 2014, PMDA made efforts to judge at least 60% of claims within 6 months of filing. The number of claims filed increased from 1,371 in FY 2013 to 1,412 in FY 2014, and the number of claims judged also increased from 1,240 in FY 2013 to 1,400 in FY 2014. Furthermore, the number of claims judged within 6 months of filing was 867, which accounts for 61.9% of all claims filed and exceeds the annual target for FY 2014. This 867 in FY 2014 far exceeds 754 in FY 2013.

- 46 -

(i)

Relief Service for Adverse Drug Reactions PMDA provides benefits consisting of medical expenses, medical allowances, disability pensions, pensions for raising handicapped children, bereaved family pensions, lump-sum benefits for bereaved families, and funeral expenses for diseases, disabilities, and deaths that occurred on or after May 1, 1980, when caused by ADRs even though the drugs involved (or cellular and tissue-based products on or after November 25, 2014) were used properly.

a.

Performance of Relief Service for Adverse Drug Reactions The performance for FY 2014 is shown below. Fiscal Year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Number of claims filed

1,018

1,075

1,280

1,371

1,412

Number of claims judged

1,021

1,103

1,216

1,240

1,400

Approved

897

959

997

1,007

1,204

Rejected

122

143

215

232

192

2

1

4

1

4

434 42.5%

534 48.4%

553 45.5%

754 60.8%

867 61.9%

Claims in progress*2

743

715

779

910

922

Median processing time [months]

6.4

6.1

6.2

5.8

5.7

Withdrawn Within 6 months

Number of claims Achievement rate*1

1

* The percentages of the claims judged within 6 months of filing out of the total number of claims judged in each fiscal year. *2 The numbers of claims in progress at the end of each fiscal year.

b.

Number of claims by type of benefit The numbers of claims filed in FY 2014 by type of benefit are shown below. Fiscal Year Number of claims filed

Types of benefit

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

1,018

1,075

1,280

1,371

1,412

Medical expenses

854

909

1,101

1,200

1,221

Medical allowances

911

964

1,168

1,252

1,290

Disability pensions

74

77

83

88

95

Pensions for raising handicapped children

4

4

1

7

12

Bereaved family pensions

46

47

46

49

41

Lump-sum benefits for bereaved families

54

63

53

54

65

Funeral expenses

100

107

98

105

103

Note: A single claim could be classified into more than one type of benefit.

- 47 -

c.

Judgment status by type of benefit The number of approved cases and amounts of benefits in FY 2014 by type of benefit are shown below. (Unit: Thousand yen) FY 2010 Type

Number of cases

Medical expenses

803

Medical allowances Disability pensions

FY 2011

Amount paid

Number of cases

87,475

836

837

71,142

38

853,854

5

Bereaved family pensions

FY 2012

Amount paid

Number of cases

Amount paid

93,284

892

895

75,198

947

75,326

28

881,885

28

861,595

44,210

6

49,906

0

43,744

31

583,501

35

614,318

32

602,068

Lump-sum benefits for bereaved families

29

214,081

47

328,093

32

227,696

Funeral expenses

63

12,927

80

16,006

62

12,438

Total

1,806

1,867,190

1,927

2,058,389

1,993

1,920,771

Type

Number of cases

Pensions for raising handicapped children

FY 2013

FY 2014

Amount paid

Number of cases

Amount paid

Medical expenses

886

95,025

1,108

123,987

Medical allowances

945

82,730

1,151

95,457

Disability pensions

39

905,233

37

943,939

3

40,785

2

38,965

Pensions for raising handicapped children Bereaved family pensions

31

603,130

31

585,626

Lump-sum benefits for bereaved families

32

220,032

45

310,806

Funeral expenses Total

97,905

59

12,249

72

14,507

1,995

1,959,184

2,446

2,113,286

Note 1: "Number of cases" is the number of approved cases. "Amount paid" is the amounts of the benefits paid for both new and existing cases. Note 2: Since the amounts are rounded off to the nearest thousand yen, the sum of the figures in each column does not always match the total.

- 48 -

Payment of Relief Benefit

Cases 1400

Amount (Million yen) 2200

Approved

Rejected

Withdrawn

Number of claims

2000 1800

Amount paid

1200

1600 1000

1400 1200

800

1000 600

800 600

400

400 200 200 0

0 1980

1983

1986

1989

1992

1995

1998

2001

2004

2007

2010

2013

Fiscal Year

(ii)

Relief Service for Infections Acquired through Biological Products PMDA provides benefits consisting of medical expenses, medical allowances, disability pensions, pensions for raising handicapped children, bereaved family pensions, lump-sum benefits for bereaved families, or funeral expenses for diseases, disabilities, or deaths that occurred on or after April 1, 2004, when caused by infections even though the biological products involved (or cellular and tissue-based products on or after November 25, 2014) were used properly. a.

Performance of relief for infections The performance for FY 2014 is shown below Fiscal Year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Number of claims filed

6

9

4

7

3

Number of claims judged

7

7

6

4

7

Approved Rejected Withdrawn

6 1 0

3 4 0

4 2 0

4 0 0

6 1 0

2

4

2

5

1

42.9%

100.0%

83.3%

100.0%

42.9%

6.9

4.4

4.7

4.3

6.3

Claims in progress*1 Achievement rate

*2

Median processing time [months] 1

* Claims not judged at the end of each fiscal year. *2 The percentages of the claims judged within 6 months of filing out of the total number of claims judged during the fiscal year.

- 49 -

b.

Number of claims by type of benefit The numbers of claims filed in FY 2014 by type of benefit are shown below.

Types of benefit

Fiscal Year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Number of claims

6

9

4

7

3

Medical expenses

5

6

2

6

2

Medical allowances

5

8

4

7

3

Disability pensions

1

0

0

0

0

Pensions for raising handicapped children

0

1

0

0

0

Bereaved family pensions

0

0

0

0

1

Lump-sum benefits for bereaved families

1

0

0

1

1

Funeral expenses

1

0

0

1

2

Note: A single claim could be classified into more than one type of benefit.

c.

Judgment status by type of benefit The number of approved cases and amounts of benefits in FY 2014 by type of benefit are shown below. (Unit: Thousand yen) FY 2010 Type

FY 2011

FY 2012

FY 2013

FY 2014

Number Amount Number Amount Number Amount Number Amount Number Amount of cases paid of cases paid of cases paid of cases paid of cases paid

Medical expenses

5

425

3

213

2

83

3

258

5

336

Medical allowances

5

384

3

282

4

282

4

356

6

566

Disability pensions





















Pensions for raising handicapped children





















Bereaved family pensions



2,378



2,370



2,362



2,353



2,338

Lump-sum benefits for bereaved families

1

7,160

















Funeral expenses

1

193

















Total

12

10,540

6

2,865

6

2,726

7

2,967

11

3,239

Note: Since the amounts are rounded off to the nearest thousand yen, the sum of the figures in each column does not always match the total.

3.1.(6)

Promotion of collaboration with the review and safety departments  To enhance collaboration with the other divisions at PMDA, information on claims and decisions on approval/rejection of claims for adverse reaction relief benefits were provided to the Offices of Safety etc., with due consideration to protecting personal information. In addition, Office of Relief Funds and Offices of Safety conducted joint meetings about once a month to promote information sharing.  Based on relevant information obtained through claims submitted for relief benefits, PMDA calls users' attention to cases which have repeatedly occurred though precautions have been already provided in package inserts. The information was described in the "PMDA Request for Proper Use of Drugs" posted on the web page, explaining points for safe use of drugs etc., in an easy-to-understand way that allows healthcare professionals to readily use the information, in order to further promote the proper use of drug products. Reference: The "PMDA Request for Proper Use of Drugs" is distributed by e-mail service named as "PMDA medi-navi" to healthcare professionals etc.

- 50 -

 The Office of Relief Funds and the Offices of Safety promoted the collaboration by clarifying their roles and responsibilities regarding the "Relief System Consultation Service" and the "Drugs and Medical Devices Consultation Service." 3.1.(7)

Appropriate conduct of health and welfare services  In cases where it is necessary to offer any assistance other than benefit payment in order to provide swift relief for adverse health effects stemming from adverse drug reactions, PMDA conducts health and welfare services for sufferers from adverse health effects as below in accordance with the Act on the Pharmaceuticals and Medical Devices Agency:

(i)

Investigative research for improvements in the quality of life of sufferers of serious and rare adverse health effects caused by drug products As part of health and welfare services, PMDA established an Investigative Research Team for Improvements in the Quality of Life (QOL) of Sufferers from Serious and Rare Adverse Health Effects Caused by Drug Products in April 2006, and the team initiated investigative research to obtain information for examining the ideal way to provide necessary services and measures for improving the QOL of sufferers from serious and rare adverse health effects, who have not necessarily been supported sufficiently by general measures for disabled people. This research project was carried out, taking into account the results (March 2006) of a survey on the actual state of adverse health effects stemming from adverse drug reactions. In FY 2014, PMDA summarized the operating performance for FY 2013, prepared an investigative research report, and conducted an investigative research in 83 subjects with serious adverse health effects, including Stevens Johnson syndrome, Reye’s syndrome, and those similar to Reye’s syndrome. Contents of the Research PMDA collects, analyzes, and evaluates reports, such as survey forms etc., from sufferers from adverse health effects regarding the condition of various efforts in their daily life (83 volunteers in FY 2014). Research Team Team Leader:

(ii)

Atsushi Ozawa, Professor, Graduate School of Comprehensive Human Sciences, University of Tsukuba (Master’s Program in Lifespan Developmental Science) Takao Takahashi, Professor, School of Medicine, Keio University (Department of Pediatrics) Kazuo Tsubota, Professor, School of Medicine, Keio University (Department of Ophthalmology) Chieko Matsunaga, Associate Professor, School of Health and Welfare, International University of Health and Welfare

Consultation services to address mental health problems etc. The survey on the actual state of adverse health effects stemming from adverse drug reactions showed the necessity of care for persons with deep mental trauma due to adverse health effects such as diseases, disabilities, etc. caused by adverse drug reactions, as well as the importance of consultation support for persons with remarkable restrictions in daily living due to such adverse health effects. Therefore, PMDA held many discussions with organizations of adverse drug reaction sufferers etc., regarding the conduct of support services for persons who have received benefits

- 51 -

under the relief systems, and consequently, Consultation Services to Address Mental Problems etc., were initiated in January 2010. Consultation services by experts who are qualified for welfare were conducted, for the purpose of providing advice etc., on mental health care and on the use of welfare services to persons suffering from adverse health effects caused by adverse reactions to drugs, etc. or infections acquired through biological products, etc., and their families. In FY 2014, 44 consultations were performed. (iii)

Distribution of the benefit recipient card For beneficiaries of adverse reaction relief benefits, in January 2010, PMDA started a service to issue a handy, credit-card sized certificate upon request. The card shows specific information such as the name of the drug(s) that is considered or suspected to have caused the adverse reaction to the card holder. In FY 2014, the card was issued to 657 persons.

(iv)

Investigative research for improvements in the QOL of patients with hepatitis C caused by treatment for congenital diseases As part of health and welfare services, PMDA established an Investigative Research Group for Improvements in the QOL of Patients with Hepatitis C Caused by Treatment for Congenital Diseases in August 2010, and the group initiated research to study the actual living conditions of sufferers from infections acquired through biological products and thereby obtain information for examining the ideal way to provide necessary services and measures for improving the QOL of sufferers. In FY 2014, PMDA summarized the operating performance for FY 2013, prepared an investigative research report, and conducted research in 159 subjects. Contents of the Project PMDA collects, analyzes, and evaluates reports, such as survey forms etc., to clarify the various conditions in daily life of sufferers from serious infections among individuals affected by hepatitis C caused by treatment for congenital diseases (159 volunteers in FY 2014). Research Team Team Leader:

3.1.(8)

Kugahisa Teshima, Director, Graduate School of Social Service Management, Japan College of Social Work Namiki Izumi, Deputy Director, Musashino Hospital, Japanese Red Cross Society Midori Shima, Professor, Department of Pediatrics, Nara Medical University Akira Terashima, Professor, Faculty of General Welfare, Urawa University

Appropriate provision of healthcare allowances for SMON patients and HIV-positive patients affected through blood products  PMDA appropriately provided healthcare allowances etc., to SMON patients and HIV-positive patients affected through blood products under commission of relevant organizations, giving due consideration to the confidentiality of personal information.

(i)

Services for SMON patients (commissioned payment of healthcare allowances)  PMDA provides healthcare allowances and nursing care expenses to SMON patients for whom a settlement has been reached in court. At the end of FY 2014, the number of patients receiving such allowances was 1,533, and the total amount paid in FY 2014 was 1,083 million yen.

- 52 -

Fiscal Year

FY 2010

Number of recipients

FY 2012

FY 2013

FY 2014

1,960

1,855

1,748

1,639

1,533

1,375,622

1,306,329

1,241,368

1,160,994

1,082,992

1,031,376

975,567

924,669

864,462

811,727

Allowance for nursing care expenses (from companies)

250,946

241,890

233,050

219,630

201,919

Allowance for nursing care expenses (from government)

93,300

88,872

83,650

76,902

69,346

Amount paid (thousand yen) Healthcare allowances Break down

FY 2011

Note: Since the amounts of the benefits are rounded off to the nearest thousand yen, the amount paid does not always match the sum of the breakdown categories.

Amount (Million yen)

Payment of Healthcare Allowances, etc., to SMON Patients

Number of recipients

3,000

3,000

2,500

2,500

2,000

2,000

1,500

1,500

1,000

1,000

500

500

0

0 2003

(ii)

2004

2005

2006 2007 2008 2009 2010 2011 2012 Allowance for nursing care expenses (from companies) Allowance for nursing care expenses (from govenment) Healthcare allowances Number of recipients

2013

2014

HIV-related services (commissioned payment of healthcare allowances)  PMDA provides allowances relating to the following 3 services for HIV-positive patients affected through blood products under commission of the relevant organization. In FY 2014, 524 HIV-positive patients received allowances relating to the investigative research, 110 AIDS patients received allowances relating to the healthcare support service and 2 AIDS patients received special allowances. The total number of patients receiving allowances relating to the 3 services was 636, and the total amount paid in FY 2014 was 492 million yen. a. Payment of healthcare allowances for HIV-positive patients (who have not developed AIDS), as part of the investigative research b. Payment of healthcare allowances for AIDS patients for whom a settlement has been reached in court, as the healthcare support service c. Payment of special allowances etc., for AIDS patients for whom a settlement has not been reached in court

- 53 -

FY 2010 Fiscal Year

Number of recipients

FY 2011

Amount paid (thousand yen)

Number of recipients

FY 2012

Amount paid (thousand yen)

Number of recipients

Amount paid (thousand yen)

Investigative research

562

309,355

547

302,763

540

297,790

Healthcare support services

116

206,100

115

210,000

112

199,500

Special allowance Grand Total

2

6,300

2

6,276

3

6,362

680

521,755

864

519,039

655

503,652

FY 2013 Fiscal Year

Number of recipients

FY 2014

Amount paid (thousand yen)

Number of recipients

Amount paid (thousand yen)

Investigative research

529

292,349

524

288,736

Healthcare support services

112

199,650

110

197,400

Special allowance Grand Total

2

6,232

2

6,190

643

498,230

636

492,325

Note: Since the amounts of the benefits are rounded off to the nearest thousand yen, the amount paid does not always match the sum of the breakdown categories.

Allowances for HIV/AIDS Patients infected through Blood Products Amount (Million yen)

Number of recipients

800

800

700

700

600

600

500

500

400

400

300

300

200

200

100

100

0

0 2004

2005

2006

2007

2008

2009

Investigative research Healthcare support services

3.1.(9)

2010

2011

2012

2013

2014

Healthcare support services Number of recipients

Appropriate provision of the payment of benefits to assist individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus  PMDA started the service of providing benefits to individuals affected by hepatitis C according to the Act on Special Measures concerning the Payment of Benefits to Assist Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus* on January 16, 2008. The number of benefit recipients was 95, with 2,100 million yen as the total amount paid in FY 2014. * The revised Act went into effect on September 14, 2012, and thereby the time frame for claiming benefits was extended by 5 years (until January 15, 2018).

- 54 -

FY 2007

FY 2008

FY 2009

FY 2010

Number of recipients

108

660

661

305

(Of which: number of recipients of additional payment)

(0)

(4)

(22)

(20)

2,360,000

13,632,000

13,748,000

6,293,000

(0)

(68,000)

(272,000)

(324,000)

16,814

3,607

894

1,286

Amount paid (thousand yen) (Of which: amount of additional payment) Number of consultations

FY 2011

FY 2012

FY 2014

FY 2013

Number of recipients

220

129

133

95

(Of which: number of recipients of additional payment)

(20)

(28)

(18)

(20)

Amount paid (thousand yen)

4,732,000

2,624,000

2,888,000

2,100,000

(Of which: amount of additional payment)

(268,000)

(488,000)

(332,000)

(368,000)

674

982

473

660

Number of consultations

Payment of benefits to assist individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus Number of recipients

Amount paid (Million yen)

16,000

700

14,000

600

12,000

500

10,000 400 8,000 300 6,000 200

4,000

100

2,000 0

0 2007

2008

Amount paid

3.2.

2009

2010

2011

Additional amount paid

2012

2013

2014

Number of recipients

Reviews and Related Services Based on the Japan Revitalization Strategy (adopted by the Cabinet on June 14, 2013), Healthcare and Medical Strategy (adopted by the Cabinet on July 22, 2014), the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (PMD Act), and Act on the Safety of Regenerative Medicine, etc., PMDA took the following actions in order to accelerate the review process, achieve "zero" review lag*, and upgrade the quality of reviews by investigating drugs, medical devices, and cellular and tissue-based products according to their respective characteristics, as well as to enhance pharmaceutical affairs consultations on R&D strategy with the aim of eliminating development lag*.

- 55 -

* Drug lag and device lag are roughly classified into two types of lags: "review lag," caused by the difference in the review period from application to approval) between the US and Japan; and "development lag," caused by the difference in time which medical companies apply to regulatory agencies in the US and Japan (quoted from the "Japan Revitalization Strategy"). Resolution of the issues associated with review lag and development lag will lead to the elimination of the overall lag in the approval process.

To deal with products using advanced science and technologies in a more appropriate manner, the Science Board consisting of external experts in the areas of medicine, dentistry, pharmaceutical sciences, engineering, etc., and its secretariat, the Office of Review Innovation (reorganized and renamed the Science Board Management Office in FY 2014), were established in FY 2012. In FY 2014, PMDA focused on these efforts to continuously improve the quality of its operations ranging from reviews/consultations to post-marketing safety measures. 3.2.(1)

Accelerated access to drugs and medical devices

New drugs  Various measures were implemented or reviewed with the aim of increasing the number of reviewers and improving the quality of reviews, based on the “Japan Revitalization Strategy JAPAN is BACK-” and “Healthcare and Medical Strategy,” etc. (i)

Appropriate and prompt reviews a.

Structure for clinical trial consultations and reviews  The review system for drugs and medical devices, etc. has been significantly improved since 1997. In FY 2004, PMDA was founded to consolidate review functions while the final authority for approval of drugs and medical devices, etc. was left to the Ministry of Health, Labour and Welfare (MHLW). Further improvements in the review system were made by taking the following measures: 1) In order to ensure the consistency and efficiency, the roles of three review-related agencies were re-examined thoroughly, and integrated into one agency as "incorporated administrative agency, the Pharmaceuticals and Medical Devices Agency." 2) Substantial increase in the number of staff including reviewers. 3) Introduction of a coherent system in which the process from clinical trial consultations until reviews is conducted by the same team with the same staff members. 4) Enhancement of reviews of biological and biotechnology-derived products. 5) Reinforcement of functions for reviewing medical devices.

- 56 -

Transition of approval review system on drugs and medical devices

FY 1994

FY 1995

FY 1997

FY 2004

Bureau in MHW

Pharmaceuticals and Medical Devices Agency (PMDA)

Pharmaceuticals and Medical Devices Evaluation Center in MHS (PMDEC) •

Organization for Pharmaceutical Safety and Research (OPSR) • •

Equivalence review for generic drugs GLP inspections for drugs

• • •

Regulatory review

Clinical trial consultation system GCP inspections for drugs Data integrity assessment for drugs

Japan Association for the Advancement of Medical Equipment (JAAME) •

Equivalence review for medical devices

Review System (Consolidated Structure for Consultations and Reviews)

Advice

Approval

Pharmaceutical Affairs and Food Sanitation Council

MHLW

Applicant

Consultation

GMP/GLP/GCP Inspections

Inquiries/ Inquiries/ Responses Responses

Clinical trial consultation Filing of application Review Report

Guidance

PMDA

Clinical trial consultation & review (review team)

Expert Discussion

External experts

- 57 -

Flowchart of review process Applicant Initial Meeting

Applicant and

Pharmaceuticals and Medical Devices Agency (PMDA) Reviewers Inspectors

Appointment/ Consultation

Team Review GLP/GCP inspection

Inquiry from PMDA Presentation from applicant and response

External experts

Advice

Withdrawal request

Review report (1)

Manufacturing site

GMP inspection

Reviewers

Expert Discussion I

and External experts

Discussion on key issues Document-based discussion may be allowed

Summary of main issues

Interview Review Meeting (if necessary)

Applicant Specialists on the applicant side

and

Reviewers External experts

Opportunity of presentation by applicant Discussion on key issues Moderated by Office Director (or Review Director)

Expert Discussion II (if necessary)

Withdrawal request

and External experts Reviewers Continue after interview review meeting

Review report (2)

Notification of GMP Inspection Result

Approval/ Disapproval

Notification of Review Result

MHLW (Ministry of Health, Labour and Welfare)

Consultation Advice

Pharmaceutical Affairs and Food Sanitation Council

Review Performance for FY 2014 (drugs) (1) Number of Expert Discussions conducted: 211 (151 document-based discussions, 60 meetings) (2) Applications deliberated at the Drug Committees (under Pharmaceutical Affairs and Food Sanitation Council [PAFSC]): 80 Applications reported to the Drug Committees (under PAFSC): 39

 Reviews of new drugs were conducted by review teams under the guidance of an office director and a review director. As a general rule, each review team consists of experts who have academic degrees in pharmaceutical science, veterinary medicine, medicine, biostatistics, and other specialized courses. Each review team is typically comprised of team leader(s), deputy team leader(s), and reviewers specializing in quality, toxicology, pharmacology, pharmacokinetics, clinical medicine, or biostatistics. - 58 -

Organization Chart for Reviews of New Drugs

Office Director

Review Director

Review Director 2 Team Leaders (Review/Consultation)

Specification/ Stability (1 reviewer)

Pharmacology (1 reviewer)

Pharmacokinetics (1 reviewer)

Pharmaceutical Science

Toxicity (2 reviewers)

Clinical Medicine (2 reviewers)

Biostatistics (1 reviewer)

Veterinary Science

Medical Science

Biostatistics

 In order to strengthen the review system, PMDA increased the number of reviewers allocated to the categories where many new drug applications were being filed and the review process for them was likely to be prolonged.  Reviews of new drug applications are shared among the responsible offices and teams according to the review categories by therapeutic area. The review categories are as follows:

- 59 -

Review Categories Covered by the Offices of New Drugs Office

Review Categories Category 1

Gastrointestinal drugs, dermatologic drugs, immunosuppressive drugs, and others (not classified as other categories)

Category 6-2

Hormone drugs, drugs for metabolic disorders (including diabetes mellitus, osteoporosis, gout, and inborn errors of metabolism)

Category 2

Cardiovascular drugs, antiparkinsonian drugs, anti-Alzheimer's drugs

Category 5

Reproductive system drugs, drugs for urogenital system, combination drugs

Office of New Drug I

Office of New Drug II

Radiopharmaceuticals

Radiopharmaceuticals

In vivo diagnostics

Contrast agents, reagents for function tests (excluding in-vitro diagnostics)

Category 3-1

Central/peripheral nervous system drugs (excluding anesthetic drugs)

Category 3-2

Anesthetic drugs, sensory organ drugs (excluding drugs for inflammatory diseases), narcotics

Category 4

Antibacterial drugs, antiviral drugs (excluding AIDS drugs), antifungal drugs, antiprotozoal drugs, anthelmintic drugs

Category 6-1

Respiratory tract drugs, anti-allergy drugs (excluding dermatologic drugs), sensory organ drugs (drugs for inflammatory diseases)

AIDS drugs

Anti-HIV drugs

Oncology drugs

Antineoplastic drugs

Cellular and tissue-based products

Cell/tissue-processed products

Office of New Drug III

Office of New Drug IV

Office of New Drug V

Office of Cellular and Tissue-based Products

Office of Vaccines and Blood Products

Gene therapy products

Gene therapy products among cellular and tissue-based products, Cartagena

Bio-CMC

Quality of biologics, biosimilars

Biological devices (quality)

Biological devices (quality)

Vaccines

Vaccines (only those to be used for prevention of infection), antitoxic serum, etc.

Blood products

Blood products

 PMDA conducted clinical trial consultations for new drugs based on the team-reviewed guidance plan drafted by three persons, the Review Director as well as the consultation leader and the deputy consultation leader, who were appointed from among the review team members. b.

Reinforcement and improvement in the transparency of the progress management of reviews  As an effort to further accelerate reviews and related services, the project management system was introduced in FY 2008 for progress management and coordination of reviews of new drugs. In FY 2013, based on the experience accumulated so far, this scheme was further integrated into the review system.  In order to conduct reviews and related services promptly and appropriately to achieve the target review times as specified in the Mid-term Plan, PMDA held meetings of the Progress Management Committee for Reviews and Related Services once every 3 months to ensure that the Chief Executive and other executives of PMDA can accurately grasp the progress of reviews and related services and support improvement, as needed. In this way, operational progress was monitored, - 60 -

while particularly relevant information for new drugs was dealt with comprehensively and approaches for solving operational challenges were considered.  The Review Segment Committee for Progress Management with the Director of the Center for Product Evaluation as its head, to control the progress of reviews, was continuously convened throughout FY 2014. In the meetings, opinions for the advancement of the system were exchanged, information on the overall review status for new drugs and associated issues, including GCP and GMP inspections, were shared, measures addressing challenges and future approaches were examined, and the detailed review status of new drugs and other products under review were reported. (11 meetings were held in FY 2014.) At the Review Segment Committee for Progress Management, taking into account reports from office directors of review divisions, necessary guidance was continuously provided by the Director of the Center for Product Evaluation and the Associate Center Director, and the results of discussion of issues and improvement measures for products with a difficulty that required a prolonged review time were notified within review segments.  In accordance with the "Way of Explaining the Progress of Review of New Drug Applications" (PMDA Notification No. 1227001 dated December 27, 2010), the progress of the PMDA review is to be communicated to applicants in each review stage. The relevant office director appropriately held meetings with applicants upon their request to explain the progress and outlook of the review to them. If reviewing a new drug application is difficult, review-related issues including reasons for the difficulty and the possibility of approving the drug are to be provided in writing to the applicant in accordance with the “Handling of New Drug Application and Total Review Time to Improve the Predictability of New Drug Approvals” (PFSB/ELD Notification No. 1006-1 and PFSB/CND Notification No. 1006-1 dated October 6, 2014), in order to increase the transparency of the review process. c.

Standardization of review 

d.

To clarify review standards, reviewers were informed of the "Points to be Considered by the Review Staff Involved in the Evaluation Process of New Drug" released in FY 2008, which provides basic considerations for review. The document is posted on the PMDA website. In addition, review times for priority review products and standard review products were presented for each review process in “Timeline in the Standard Process of New Drug Application” (PFSB/ELD/MHLW Administrative Notice dated January 30, 2015). This document is also posted on the PMDA website. Consultations and reviews based on medical care needs

 PMDA actively exchanged opinions with healthcare professionals by participating in academic conferences etc., in and out of Japan, to comprehend their needs. The Agency conducted consultations and reviews, taking into account the information obtained in this manner.  In order to request pharmaceutical companies to develop drugs and indications that have been approved in Europe and the U.S. but not approved in Japan, the Investigational Committee on Medically Necessary Unapproved Drugs and Off-Label Use Drugs (chaired by Dr. Tomomitsu Hotta, President of National Cancer Center) was established in the MHLW in February 2010, and has been active. PMDA continuously supports this Committee, and offers clinical trial consultations and reviews based on the results of the investigations by the Committee.  In order to resolve the drug lag of unapproved drugs and off-label use drugs with high medical needs, PMDA promptly and timely grasped information on the approval status at FDA and EMA,

- 61 -

and collected/organized evidence information etc., and then expanded the unapproved drug database to compare the approval status between Japan and the US or Europe. Of drugs with a new active ingredient approved by FDA or EMA in or after April 2009, 113 (FDA) and 84 (EMA) have not been approved in Japan as of March 2015. The list of the unapproved drugs is available on the PMDA website. e.

Consistency between clinical trial consultations and reviews  In order to ensure the consistency between clinical trial consultations and reviews, review team members are involved in all the clinical trial consultations for products falling under the category to which they are assigned. Coherence from consultations to reviews is maintained and teams are flexibly organized as necessary. To further secure the consistency of clinical trial consultations etc., efforts to provide feedback information on previous clinical trial consultations were continued in FY 2014.

f.

Appropriate conduct of re-examination and re-evaluation  When a certain period has passed since approval of new drugs, re-examinations are conducted to confirm the efficacy and safety, based on data of use-results surveys that have been conducted by marketing authorization holders (MAHs) etc. Already-approved drugs that have been designated by the Minister of Health, Labour and Welfare are re-evaluated for their efficacy and safety, in the light of the current standards of medical/ pharmaceutical sciences, based on the data submitted by MAHs. In addition, re-evaluations for quality are conducted to ensure that the dissolution of drugs in solid oral dosage forms meets the quality requirements. Once the quality has been assured, an appropriate dissolution specification is established to ensure that the quality of the drug in solid oral dosage forms is maintained at a certain level.  In FY 2014, 86 products underwent re-examination; 139 products underwent re-evaluation for drug efficacy; and no product underwent re-evaluation for quality. Re-evaluation for drug efficacy had been completed for traditional Chinese medicines, non-steroidal anti-inflammatory agents, and antimetabolites by the end of FY 2014. Concerning products for which applications for re-examination are filed in or after FY 2014, PMDA is aiming to complete re-examination within 18 months (median) by FY 2018. For 102 products for which applications were filed in FY 2014, no notice of re-examination results was issued in FY 2014. Number of Re-examinations/Re-evaluations Conducted FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

115

81

50

121

86

Products that underwent re-evaluation for drug efficacy

0

0

0

0

139

Products that underwent re-evaluation for quality

53

0

0

0

0

Products that underwent re-examination

Re-evaluations

Note: Number of products for which a notice of re-examination/re-evaluation results was issued in respective fiscal year.

- 62 -

g.

Development of the Japanese Pharmacopoeia  In FY 2014, the Japanese Pharmacopoeia (JP) Draft Committee held a total of 79 meetings, and posted information on the PMDA website to seek public comments regarding 238 official monographs (56 new articles, 174 amendments, 8 deletions), 37 general tests (16 new tests, 19 amendments, 2 deletions), 9 ultraviolet-visible reference spectra, 15 infrared reference spectra, amendments to other General Notices, and partial revision of the General Rules for Preparations as a draft of the 17th edition of the Japanese Pharmacopoeia. The number of official monographs reported to MHLW thus far was as follows: Month and year reported

Mar. FY 2007

Nov. FY 2008

Mar. FY 2009

Aug. FY 2010

106

Aug. FY 2009 -

New monographs

90

1

Amendments

171

1

Mar. FY 2012

Jan. FY 2013

122

2

Sep. FY 2013

106

77

0

60

330

176

1

172

Note: The JP drafts prepared include drafts for the official monographs shown in this table as well as drafts for General Notices, General Rules for Preparations, General Rules for Crude Drugs, General Tests, Processes and Apparatus, and General Information. PMDA usually provides those drafts to MHLW 6 months before the publication. The next draft to be reported is for the 17th edition of the Japanese Pharmacopoeia, and no draft was reported in FY 2015.

Ministerial Announcement on the Japanese Pharmacopoeia by MHLW

Month and year announced New monographs Amendments Deleted monographs Total number of monographs

15th edition Mar. FY 2006 102 272

15th edition Supplement 1 Sep. FY 2007 90 171

Partial revision Mar. FY 2009 1 1

15th edition Supplement 2 Sep. FY 2009 106 122

Partial revision Jul. FY 2010 0 2

16th edition Mar. FY 2011 106 330

16th edition Supplement 1 Sep. FY 2012 77 176

16th edition Partial revision Supplement 2 May Feb. FY 2014 FY 2014 0 60 1 173

8

6

0

1

0

15

4

0

1

1,483

1,567

1,568

1,673

1,673

1,764

1,837

1,837

1,896

 PMDA provides information such as the status of the JP draft review or international harmonization of pharmacopoeial standards, in addition to calling for public comments on drafts on the Japanese Pharmacopoeia page of PMDA's Japanese website. In addition, the Agency gives information on international harmonization of pharmacopoeial standards to overseas users on the Japanese Pharmacopoeia page of the PMDA English website. (URL: http://www.pmda.go.jp/english/rs-sb-std/standards-development/jp/0009.html)

- 63 -

Flow of Revision of Japanese Pharmacopoeia

PMDA

h.

1. Decide the basic policy

2. List the candidate drugs

3. Finalize the candidate drugs list

4. Prepare the draft monographs

Companies' drafts PMDA's drafts

5. Seek public comments 6. Announcement

JP

JP Draft Committees Final drafts

7. Prepare the English edition

Seek public comments (PMDA website)

Request for drafts Submission of the drafts

Inquiry and Request for Reconsideration Response Seek public comments (PMDA website)

Pharmaceutical companies

Pharmaceutical Affairs and Food Sanitation Council

MHLW

English edition of JP

Implementation of a workshop on the master file  A pre-application checklist of application forms for master file registration was prepared and posted on the PMDA website, so that drug substance manufacturers, in-country representatives, MAHs, etc., would become familiar with overall pharmaceutical regulations including the master file registration system. In addition, one workshop was held to explain how to use the checklist, how to fill out the application forms, and how to respond to inquiries by PMDA after registration.

(ii)

Introduction of new review systems a.

Implementation of prior assessment consultations  To preliminarily evaluate the quality, efficacy and safety of drugs from the pre-application stage, PMDA had offered prior assessment consultations as a pilot scheme since FY 2009. The scheme has been formally implemented since FY 2011. In FY 2014, the request forms were separately received for consultations to be conducted in the first half and the second half of the fiscal year. PMDA made efforts to establish a consultation system to offer consultations upon request as much as possible. Consultations provided are broken down by review category, as follows. Review Category 2, 2 products (number of consultation categories, 7; the same applies hereinafter); Review Category 3-1, 3 products (16); Review Category 4, 2 products (5); Oncology drugs, 1 product (3); Vaccine, 1 product (1) (* When consultations were provided for an identical product in the first and second halves of the fiscal year for different consultation categories, it was included as 1 product).

- 64 -

b.

System of risk managers and risk management plans for drugs  To consistently manage the safety of drugs from the clinical trial stage to post-marketing stage, 13 risk managers were placed in 12 review teams. In each new drug review team, the safety assessment and reports on cancellation of conditions for approval in relation to post-marketing surveillance (PMS) were prepared.  Information regarding all the submitted risk management plans (RMPs) for drugs was shared among risk managers, and key issues in the review were discussed. In addition, case examples of post-marketing modification of RMPs were shared to ensure the consistency. In FY 2014, RMPs for 81 products were made public.

c.

Consideration toward the construction of the Advanced Review and Consultation with Electronic Data  The Advanced Review with Electronic Data Promotion Group (it was called Task Force for Advanced Review and Consultation with Electronic Data until the end of FY 2013) was set up in April, 2014 to consider issues related to the establishment of the system for advanced review and consultation with electronic data. The purposes of the system is to reduce the burden on applicants and improve the quality of reviews and consultations by electronically accumulating application data, analyzing the data using advanced methods, and utilizing the data. Toward the establishment of the system for advanced review and consultation with electronic data, PMDA continued to exchange opinions with the pharmaceutical industry regarding various issues, and cooperated on the issuance of "Basic Principles on Electronic Submission of Study Data for New Drug Applications" (PFSB/ELD Notification No. 0620-6 dated June 20, 2014) and Question and Answer Guide Regarding "Basic Principles on Electronic Submission of Study Data for New Drug Applications" (PFSB/ELD Administrative Notice dated June 20, 2014) based on the discussion with relevant industries and foreign regulatory authorities.  A system developer was appointed in September 2015 to build and maintain the Electronic Application Data System, which allows companies to submit electronic data, stores submitted electronic data in PMDA, and performs statistical analysis processing. As in the previous fiscal year, a pilot program for the system was performed to receive electronic clinical study data on a trial basis, analyze the data, and investigate how to utilize the data in review process.  The relevant personnel of PMDA were encouraged to participate in workshops held in and outside of PMDA about electronic data and usage of software to upgrade their skills.

(iii)

Approaches to achieving "zero" review lag for drugs  The targets for the total review time (from the application date to the approval date) for drugs for which applications were submitted on or after April 1, 2004, and approved in each fiscal year are 9 months for priority review products and 12 months for standard review products. PMDA aims to gradually increase the percentiles of products for which the targets are achieved to 80% by FY 2018. The regulatory authorities have been making efforts to achieve these targets while asking applicants for their cooperation.  New drug applications (for drugs that are clearly different from approved drugs in terms of active ingredients, contents, administration, dosage, indications, efficacy, etc.) were reviewed by PMDA review teams consisting of experts in pharmaceutical science, veterinary medicine, medicine, biostatistics, etc.

- 65 -

 In order to ensure consistency among the review teams and carry out review work promptly and appropriately with regard to new drugs, PMDA provided the services in accordance with the "Procedures for Reviews of New Drugs" regarding reviews and related procedures, and the SOPs for various related operations.  The status of reviews of new drugs (excluding applications of drug products* that are reviewed by PMDA and approved only through the administrative process at MHLW) in FY 2014 is shown below: * Drugs that are identical to approved drugs in terms of active ingredients, administration, dosage and indications or are within the scope of approved drugs in terms of administration, dosage and indications.

a.

Review times for new drugs (priority review products designated by the Minister of Health, Labour and Welfare; hereinafter referred to as "priority review products") Targets FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

Fiscal Year

9

9

9

9

9

Percentile

60

60

70

70

80

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

50

50

50

50

60

9.2 (12.6)

6.5 (9.2)

6.1 (9.0)

7.2 (9.1)

8.8 (9.2)

20

50

53

42

44

Results Fiscal Year Percentile Total review time [months] (Reference, 80th percentile) [months] Number of approved applications

Reference Regulatory review time [months]

4.9

4.2

3.8

3.6

4.0

Applicant’s time [months]

3.4

2.0

1.5

3.8

5.0

Note 1:Products covered were those for which applications were filed in or after April 2004. The number of approved applications is based on active ingredients. For details, refer to the list of approved products included in the III SUPPLEMENTARY INFORMATION Note 2:Public knowledge-based application products related to the “Study Group on Unapproved and Off-label Drugs of High Medical Need” are included in priority review products.

Reference: When excluding public knowledge-based applications for unapproved drugs Fiscal Year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

50

50

50

50

60

12.0 (13.2)

9.2 (10.7)

9.0 (10.0)

8.0 (9.9)

8.9 (9.2)

Regulatory review time [months]

5.3

4.1

3.4

3.4

3.8

Applicant's time [months]

6.0

5.0

4.6

4.1

5.2

Number of approved applications

13

18

25

31

37

Percentile Total review time [months] (Reference, 80th percentile) [months]

 Priority reviews are conducted for applications for orphan drugs and other drugs that are regarded as having particularly high medical need (drugs for serious diseases and with distinctly superior efficacy or safety as compared to existing drugs or therapies). In FY 2014, 44 priority review products (including 7 public knowledge-based applications for the “Study Group on Unapproved and Off-label Drugs of High Medical Need”) were approved. - 66 -

 In FY 2014, 6 applications requesting priority reviews were submitted for drugs regarded as having particularly high medical needs, and 7 applications (including 1 application submitted in FY 2013) were judged as “applicable” and no applications were judged as “not applicable.”  For priority review products approved in FY 2014, the total review time (60th percentile) was 8.8 months, achieving the target review time. The priority review products accounted for 38% of products approved in FY 2014, showing an increase from 30% in FY 2013. b.

Review times for new drugs (standard review products) Targets Fiscal Year

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

12

12

12

12

12

Percentile

60

70

70

80

80

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

50

50

50

50

60

14.7 (22.7)

11.5 (15.7)

10.3 (11.9)

11.3 (12.3)

11.9 (12.3)

92

80

81

96

73

Results Fiscal Year Percentile Total review time [months] (Reference, 80th percentile) [months] Number of approved applications

Reference Regulatory review time [months]

7.6

6.3

5.7

6.7

6.8

Applicant’s time [months]

6.4

5.1

4.2

4.6

5.4

Note: Products covered were those for which applications were filed in or after April 2004. The number of cases is based on active ingredients. For details, refer to the list of approved products included in the III SUPPLEMENTARY INFORMATION

 For standard review products approved in FY 2014, the total review time was 11.9 months, achieving the target time.  The number of applications under review at the end of FY 2014 was 105 (including 19 applications for orphan drugs and 5 public knowledge-based applications for unapproved drugs).

- 67 -

Review Status of New Drugs by Fiscal Year of Application New drugs (FY of submission)

Applications

Approved

Not approved

Withdrawn

Under review

In or before FY 2003 ending Mar. 31, 2004

140

109 (1)

0

29

2 [-1]

FY 2004

87

78

0

9

0

FY 2005

57

50

0

7

0

FY 2006

102

93

0

9

0

FY 2007

92

78

0

14

0

FY 2008

81

77 (1)

0

4

0 [-1]

FY 2009

106

87

1

18

0

FY 2010

116

105

0

11

0

FY 2011

130

128

0

2

0

FY 2012

140

135 (5)

0

5 (1)

0 [-5]

FY 2013

123

117 (81)

0

3 (3)

3 [-84]

FY 2014

130

30 (30)

0

0

100 [100]

Total

1,304

1,087 (118)

1

111 (4)

105 [9]

Note 1: Values in parentheses indicate those processed in FY 2014 (included in values on their left). Note 2: Values in brackets [] indicate difference from the status reported in FY 2013.

(iv)

Promotion of global clinical trials  In order to reduce the drug lag, PMDA has promoted global clinical trials and has conducted consultations and reviews based on the following documents: "Basic Principles on Global Clinical Trials" (PFSB/ELD Notification dated September 28, 2007), “Basic Principles on Global Clinical Trials (Reference Cases)” (PFSB/ELD Administrative Notice dated September 5, 2012), and “Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical Trials” (PFSB/ELD Administrative Notice dated October 27, 2014), which clarify basic concepts when conducting global clinical trials. Of 601 clinical trial notifications submitted in FY 2014, 178 were for global clinical trials. Number of Clinical Trial Notifications of Global Clinical Trials Fiscal Year Number of notifications

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

134

121

130

169

178

 PMDA intends to take an active approach to global clinical trials. In FY 2014, PMDA carried out 67 consultations on global clinical trials for drugs with new active ingredients, meeting all the requests for consultations.

- 68 -

Number of Consultations on Global Clinical Trials with New Active Ingredients Fiscal Year

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

66

73

64

59

67

Number of consultations

PMDA supported the efforts to promote global clinical trials in Asia based on the Multi Regional Clinical Trial Roadmap led by MHLW at APEC RHSC, and made a contribution in specialized fields by participating in the MRCT/GCP Inspection Workshop (in Qingdao in May) and the Steering Committee Meeting (in Beijing in August) as a champion of the roadmap project. Also, PMDA was appointed co-chair of the next RHSC meeting. (v)

Efficient conduct of clinical trial consultations a.

Conduct of priority consultations  In FY 2014, there were no requests for designation for priority consultations of drugs that are considered to have particularly high medical need. PMDA conducted no consultations for a designated ingredient.

b.

Acceleration of the procedure for clinical trial consultations  As for the acceleration of clinical trial consultations, PMDA streamlined the procedures for applicants to request consultations as well as for PMDA to receive requests. The revised procedures were implemented for requests for consultations to be provided in or after October 2010. The target duration from consultation request to consultation, about 2 months, has been firmly maintained.

c.

Implementation of clinical trial consultations and improvement of the system Number of Consultations FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

390

447

387

354

411

Withdrawn

44

30

20

30

38

Total (conducted and withdrawn)

434

477

407

384

449

Number of Prior Assessment Consultations for Drugs FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

30

33

19

32

32

Withdrawn

0

0

0

0

0

Total (conducted and withdrawn)

30

33

19

32

32

Number of Consultations on Pharmacogenomics/Biomarkers FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

1

1

0

0

0

Withdrawn

0

0

0

0

0

Total (conducted and withdrawn)

1

1

0

0

0

- 69 -

Number of Consultations on Drug Product Eligibility for Priority Review FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted



2

7

10

6

Withdrawn



0

0

0

0

Total (conducted and withdrawn)



2

7

10

6

Note 1: Prior assessment consultations for drugs and consultations on pharmacogenomics/biomarkers have been conducted since FY 2009, and consultations on drug product eligibility for priority review for drugs have been conducted since FY 2011. The numbers of both types of consultations were counted on the basis of delivery dates of consultation documents to PMDA. Note 2: Prior assessment consultations for drugs were counted on the basis of number of consultation categories (quality; non-clinical, toxicity; non-clinical, pharmacology; non-clinical, pharmacokinetics; phase I study; phase II study; and phase II/III study).

 In FY 2014, PMDA conducted a total of 411 consultations (including 38 withdrawals).  To respond to all the requests for clinical trial consultations (excluding prior assessment consultations, consultations on pharmacogenomics/biomarkers, and consultations on drug product eligibility for priority review), as a general rule, consultations are scheduled according to scheduling requests received, and when the consultation schedule cannot be fixed for a desired month, the consultation is scheduled within one month before or after that month. In FY 2014, PMDA provided a total of 373 consultations (including 38 withdrawals), responding to all of the clinical trial consultations requested (The target was achieved).  PMDA aimed to complete the process from conduct of clinical trial consultation to finalizing consultation records within 30 business days for 80% of products subjected to consultation. In FY 2014, the target was achieved in 357 (98.3%) of 363 consultations.  In order to improve the quality of consultations, in January 2007, PMDA introduced a system for all clinical trial consultations in which PMDA's opinions for content to be addressed in the consultations are presented to the applicants beforehand (preliminary opinion disclosure system).

- 70 -

Number of Consultations for Drugs by Review Category in FY 2014 Results

Review category Apr. May Jun.

Jul.

Total

Aug. Sep. Oct. Nov. Dec. Jan. Feb. Mar.

Category 1 (Gastrointestinal drugs etc.)

5

4

4

6

7

2

3

2

4

3

4

5

49

Category 6-2 (Hormone drugs)

3

1

3

4

2

1

2

0

1

2

4

2

25

Category 2 (Cardiovascular drugs)

5

1

4

7

2

7

2

4

7

3

2

2

46

Category 5 (Drugs for the urogenital system etc.)

4

2

2

1

0

0

0

1

4

0

4

1

19

Radiopharmaceuticals

1

0

0

0

0

0

0

0

0

2

0

0

3

In vivo diagnostics

1

0

0

1

0

0

1

0

1

0

0

0

4

Category 3-1 (Central nervous system drugs etc.)

3

3

6

10

2

8

6

0

4

2

1

7

52

Category 3-2 (Anesthetic drugs etc.)

1

2

1

4

0

2

1

4

1

1

2

3

22

Category 4 (Antibacterial agents etc.)

3

3

2

1

6

1

0

2

4

1

1

0

24

Category 6-1 (Respiratory tract drugs etc.)

3

2

2

1

4

4

6

6

2

5

2

3

40

AIDS drugs

0

0

0

0

0

0

0

0

0

0

0

1

1

Oncology drugs

10

2

7

7

3

4

4

6

13

3

4

8

71

Cellular and tissue-based products

0

0

1

1

0

2

1

0

0

0

-

-

5

Bio-CMC

1

4

4

1

1

4

3

3

2

1

2

1

27

Vaccines

1

1

2

2

1

2

0

1

0

0

0

4

14

Blood products

1

0

1

0

1

1

1

1

0

1

0

1

8

Generic drugs

0

0

0

0

0

0

1

0

0

0

0

0

1

[Re-listed] Prior assessment

2

0

0

6

6

11

0

3

0

0

0

4

32

[Re-listed] Drug product eligibility for priority review

0

2

0

1

0

0

0

0

0

1

1

1

6

Pharmacogenomics/biomarkers

0

0

0

0

0

0

0

0

0

0

0

0

0

GLP/GCP/GPSP compliance inspection

0

0

0

0

0

0

0

0

0

0

0

0

0

Total

42

25

39

46

29

38

31

30

43

24

26

38

411

Withdrawal

3

3

5

7

0

2

2

2

3

3

3

5

38

45

28

44

53

29

40

33

32

46

27

29

43

449

Grand Total

Note 1: A consultation covering several categories was counted in terms of its main category. Note 2: Consultations on cellular and tissue-based products for which applications were received on or after November 25, 2014 were counted as consultations belonging to the category of cellular and tissue-based products in the above table. Note 3: Prior assessment consultations are conducted for the following categories: quality; non-clinical, toxicity; non-clinical, pharmacology; non-clinical, pharmacokinetics; phase I study; phase II study; and phase II/III study. Note 4: The numbers of prior assessment consultations, consultations on pharmacogenomics/biomarkers, and consultations on drug product eligibility for priority review were counted on the basis of delivery dates of consultation documents to PMDA. Note 5: Consultations on pharmacogenomics/biomarkers were conducted by the Omics Project Team. Note 6: Consultations on GLP/GCP/GPSP compliance inspection were all conducted by the Office of Conformity Audit or Office of Manufacturing/Quality and Compliance, regardless of category.

d.

Reclassification of consultation categories and their uses  PMDA exchanged opinions with the relevant industries on clinical trial consultations and Pharmaceutical Affairs Consultations on R&D Strategy. As a result, PMDA started to offer a post-consultation meeting, in which PMDA provides advice on issues raised at a consultation within a rage requiring no additional data evaluation; what has been agreed in the meeting shall be - 71 -

recorded in the minutes. Also, PMDA revised other consultation services and started providing such revised services in November 2014, including the provision of advice on plans for post-marketing clinical studies or use-results surveys and the expansion of consultation items covering evaluation for the review of approval conditions. Taking into account requests from relevant industries, PMDA has completed detailed investigation of establishing a consultation service to assess the eligibility for minor change notifications based on data evaluation and another consultation service to evaluate application data for Sakigake designation products selected by MHLW for priority review. (vi) a.

Promotion of evaluation of new technologies Utilization of external experts  As PMDA is required to raise the expertise in the guidance and review, particularly in the fields of the latest technologies such as biotechnology and genomics, PMDA has continued to commission external experts who have a high-level knowledge to play a role of expert advisors for PMDA, in order to seek professional opinions on scientifically important matters at Expert Discussions for reviews and post-marketing safety measures. (As of March 31, 2015, the number of commissioned experts is 1,304 including external experts commissioned for issues relating to safety measures)  The number of Expert Discussions conducted in FY 2014 was 211 (151 through document-based discussions; 60 through meetings).  PMDA utilized external experts in Expert Discussions for application reviews and clinical trial consultations for biological pharmaceuticals. Also in this field, PMDA promoted exchanging information with FDA and EMA through telephone conferences etc.  PMDA integrated information on clinical trial consultations and reviews for nanomedicines and companion diagnostics through cross-sectional projects in order to maintain the uniformity of measures for nanomedicines and companion diagnostics, and used the comments made by external experts in the Expert Discussions for reviewing the applications of 3 products with companion diagnostics. The members of the Companion Diagnostics Working Group exchanged opinions with external experts on the development of genetic diagnosis technologies using next-generation DNA sequencers.  PMDA has dispatched personnel to iPS cell research institutes such as the Center for iPS Cell Research and Application (CiRA) of Kyoto University through programs to facilitate development of innovative drugs, medical devices, and cellular and tissue-based products and thereby collects the latest information in order to respond to the need to put innovative drugs and cellular and tissue-based products into clinical use.

b.

Support for the development of national guidelines  PMDA participated in the examination in a research project supported by Health and Labour Sciences Research Grants (Research on global health issues), which is titled "Research on Methods for Evaluating Quality, Efficacy, etc., of Travelers’ Vaccines" and led by Dr. Kazunobu Ouchi, the principal researcher. PMDA provided cooperation for studies of methods for developing vaccines for travelers.  PMDA participated in the examination in a research project supported by Health and Labour Sciences Research Grants (Research on global health issues), which is titled "Research on Standards for Investigation and Quality Control toward Practical Use of Next-Generation Vaccines” - 72 -

and led by Dr. Ken Ishii, the principal researcher. PMDA provided cooperation for studies on developing next-generation vaccines. (In this research, “next-generation vaccines” are defined as vaccines developed using novel adjuvants such as nucleic acid adjuvants or genetic engineering technologies.)  The team of the global clinical study project discussed an approach to the necessity of conducting a phase I clinical trial of an investigational product in the Japanese population before participating in a phase II or III global clinical trial, sorting out cases for reference. The project team cooperated in preparing “Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical Trials" (PFSB/ELD Administrative Notice dated October 27, 2014).  The team of the post-approval manufacturing changes project examined matters related to drug quality reviews, descriptions in approval documents, etc. and provided cooperation for issuing “Items to Be Entered in the Manufacturing Method Section of the Application Form for Marketing Approval for Drugs and Quasi-Drugs Containing at least Three Active Ingredients” (PFSB/ELD Notification No. 0530-8 dated May 30, 2014).  In addition to the above, about 10 or more notifications etc., were issued in FY 2014 with the cooperation of relevant review categories or offices in PMDA.

c.

Preliminary reviews under Cartagena Act  With regard to the use of genetically modified living organisms, preliminary reviews are conducted about approval of Type 1 Use and confirmation of Type 2 Use under the Cartagena Act. PMDA set the target regulatory review time to be 6 months for approval of Type 1 Use and 2 months for confirmation of Type 2 Use, with the goal of achieving 50% (median) of applications for each type. Review under the Cartagena Act (Median Regulatory Review Time) FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

No. of preliminary reviews for Type 1 Use Median review time [months]

0 –

0 –

0 –

0 –

3 0.8

No. of preliminary reviews for Type 2 Use Median review time [months]

13 2.5

15 2.0

21 1.2

24 0.9

25 1.3

Note: "Type 1 Use" refers to cases where measures are not taken to prevent the release to the environment and "Type 2 Use" refers to cases where such measures are taken.

d.

Implementation of Pharmaceutical Affairs Consultations on R&D Strategy  PMDA has been offering Pharmaceutical Affairs Consultations on R&D Strategy since July 2011 mainly to universities, research institutions and venture companies that have promising seed-stage resources to provide guidance and advice concerning studies and clinical trials that are necessary at the initial stage of product development, in order to facilitate the development of innovative pharmaceuticals, medical devices, and cellular and tissue-based products in Japan. The number of consultations in FY 2014 is as shown in the table below.  In FY 2014, a total of 122 on-site individual orientations were offered in Osaka, Kobe, Fukushima, Nagoya, Hiroshima, Fukuoka, etc., (included in the values on their left in the table below)  Introductory consultations and pre-consultation meetings were also conducted in the Kansai branch of PMDA, which was established in October 2013.

- 73 -

 To promote the practical application of seed-stage resources originating in Japan, in November 2014 PMDA started to provide consultations, as a pilot scheme, on the development process (roadmap) to pharmaceutical companies, etc. and on investigator-initiated confirmatory clinical trial protocols.

Number of Pharmaceutical Affairs Consultations on R&D Strategy Conducted FY 20111

FY 2012

FY 2013

FY 2014

Total

Introductory consultations (of which those conducted at the Kansai branch2)

118

302

237 (20)

271 (63)

928 (83)

Pre-consultations (of which those conducted at the Kansai branch2)

153

254

346 (26)

325 (57)

1,078 (83)

FY 20111

FY 2012

FY 2013

FY 2014

Total

Drugs

20

28

66

48

162

Medical devices

6 —

5 —

38 —

16

65

2

2

5 [7]

7 [13]

19 [32]

18 [44]

49 [96]







1

1

31 [33]

40 [46]

123 [136]

85 [111]

279 [326]

Introductory consultations/pre-consultations

Face-to-face consultations on:

Cellular and tissue-based products Quality and safety of cellular and tissue-based products4 Development plan5 Total

3

Note 1: Pharmaceutical Affairs Consultations on R&D strategy started in July 1, 2011. Note 2: Consultations in Kansai branch started in October 1, 2013. Note 3: Started in November 25, 2014 (before then consultations on cellular and tissue-based products had been included in consultations on drugs or medical devices). Note 4: This category includes Consultations on R&D Strategy for Drugs conducted until November 24, 2014. Some consultations were divided into multiple sessions over several days, to confirm the quality and safety of cellular and tissue-based products before the submission of clinical trial notifications. The figures in [] indicate the total number of sessions. Note 5: Started in November 25, 2014

- 74 -

Generic drugs, etc.  PMDA took or examined the following measures to take measures to accelerate reviews for generic drugs, etc. (i)

Appropriate and prompt reviews  PMDA established the Office of Generic Drugs in November 2014 and has made efforts to speed up reviews through more efficient operations. a.

Consultations and reviews based on medical care needs  PMDA staff members have participated in academic conferences etc., in and out of Japan, and actively exchanged opinions with healthcare professionals to comprehend their needs. The Agency has conducted consultations and reviews, taking into account the information obtained in this manner.

b.

Development of the Japanese Pharmacopoeia  See 3.2.(1) New drugs (i)-g.

c.

Implementation of master file workshop  See 3.2.(1) New drugs (i)-h

d.

Securing efficient and transparent reviews  PMDA, in collaboration with industry associations, prepared a draft of a mock-up CTD to encourage the use of CTD/eCTD for marketing applications with the aim of performing more efficient reviews. Companies submitted a trial version of the CTD, if possible, for new applications filed in February 2015.  To prepare review reports for new applications for generic drugs on a trial basis, PMDA discussed items to be included in a review report and examined a draft outline of review report for generic drugs.  In order to discuss the development of a bioequivalence study guidance for drugs that cannot be evaluated by the existing guidelines for bioequivalence testing, PMDA first examined the past approval status of ophthalmic solutions. The results of the examination suggested that the bioequivalence of a generic drug should be evaluated based on more detailed investigation with consideration of the drug’s pharmacological and pharmaceutical properties.

(ii)

Approaches to shorten review times  PMDA set up the following target regulatory review times for applications submitted on or after April 1, 2004 and approved in each fiscal year, and has made efforts to achieve these targets asking for cooperation of applicants.  For prompt and accurate reviews of generic drugs, etc., PMDA carried out reviews in accordance with the Procedures for Review of Generic Prescription Drugs, which specify the review methods and procedures associated with reviews, and SOPs for various operations. In addition to periodically collecting data on the achievement level of the target review time and informing the reviewers of these levels, meetings of the Progress Management Committee for

- 75 -

Reviews and Related Services were held to monitor and examine operational progress (4 meetings held in FY 2014).  The approval status of generic drugs in FY 2014 are as follows: a.

Review time for new application for generic drugs Target PMDA aims to achieve the following target for the 50th percentile (median) of products by FY 2018. Product

Regulatory review time [months]

New generic drugs

10

Results FY 2014 Approved products Of which those filed in or after April 2004 Median regulatory review time [months]

1,325 1,325 6.1

Note: The median was for the applications filed in or after April 2004.

b.

Review time for partial change application for generic drugs, etc. (standard review products)

Targets PMDA aims to achieve the following targets for the 50th percentile (median) of products by FY 2018. Fiscal Year Total review time [months]

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

15

14

13

12

10

Results FY 2014 Approved products Of which those filed in or after April 2004 Median total review time [months]

568 567 15.7

Note 1: The median was calculated based on the applications filed in or after April 2004. Note 2: Applications for partial change currently under submission are excluded from the table above.

c.

Review time for partial change applications for generic drugs, etc. (excluding the products that fall under “b” above) Targets PMDA aims to achieve the following targets for the 50th percentile (median) of products by FY 2018. Type

Total review time (months)

Applications for partial change (e.g., change of test methods)

6

Applications for partial change (expedited review)

3

- 76 -

Results FY 2014 Change of test methods, etc.

Approved products Of which those filed in or after April 2004 Median total review time [months]

1,233 1,233 7.6

Expedited review

Approved products Of which those filed in or after April 2004 Median total review time [months]

158 158 4.0

Note 1: The medians were calculated based on the applications filed in or after April 2004. Note 2: Applications for partial change currently under submission are excluded from the table above.

Reference: Results obtained during the Second Mid-term Plan (Regulatory Review Time) Generic drugs, etc.

FY 2009

FY 2010

FY 2011

FY 2012

FY 2013

3,271 3,245 7.5

2,633 2,590 6.9

3,091 3,046 6.5

3,421 3,388 5.9

3,504 3,502 5.3

Approved products Of which those filed in or after April 2004 Median regulatory review time [months]

Note 1: The number of approved products includes priority review products for which the standard regulatory review time is 6 months or less. Note 2: The medians were calculated based on the applications filed in or after April 2004. Note 3: Applications for partial change currently under submission are included in the table above.

Reviews and Related Services Conducted for Generic Drugs, etc. by Fiscal Year Fiscal Year

Application

Approved

Withdrawn, etc.

Under review

FY 2010

3,062

2,633

224

3,454

FY 2011

2,893

3,089

165

3,093

FY 2012

4,077

3,421

190

3,559

FY 2013

3,893

3,504

343

3,605

FY 2014

3,452

3,447

214

3,396

Note 1: Values in the “Withdrawn etc.” column do not include the number of products that were switched to other review categories during the review. Note 2: Applications for partial change currently under submission are included in the table above.

 The median regulatory review time for new generic drugs approved in FY 2014 was 6.1 months (target, 10 months), achieving the target. For partial change applications of generic drugs, the median total review time for standard review products was 15.7 months (target, 15 months), not achieving the target. This was because the median regulatory review time was 7.7 months while the median applicant’s time was 7.9 months, suggesting that an even greater collaboration with applicants is needed in the review process. The median total review time for partial change applications (e.g., change of test methods) was 7.6 months (target, 6 months) and that for partial change applications (expedited review) was 4.0 months (target, 3 months). PMDA aims to achieve the targets by FY 2018 by taking measures such as increasing the number of reviewers from the next fiscal year. Document-based Compliance Assessments for Generic Drugs by Fiscal Year

Generic drugs

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

1,040

1,118

1,188

1,086

1,080

- 77 -

 For generic drugs, PMDA conducted 1,080 assessments to examine whether application data comply with GLP, GCP, GPSP, and other standards by checking the application data against raw data such as test records, laboratory notebook, and case report forms. (iii)

Efficient conduct of clinical trial consultations  Regarding pre-application consultations for generic drugs, in January 2012, PMDA started to provide quality consultations for generic drugs and consultations on the bioequivalence of generic drugs on a trial basis, and 24 consultations were conducted in FY 2014. Since January 2015, PMDA has responded to all requests for consultations. Number of Consultations for Generic Drugs FY 2011

FY 2012

FY 2013

FY 2014

Conducted

3

10

17

24

Withdrawn

0

0

1

1

Total (conducted and withdrawn)

3

10

18

25

Note: Consultations for generic drugs were started in FY 2011.

Number of Consultations for Generic Drugs by Consultation Category in FY 2014 Conducted

Withdrawn

Total (conducted and withdrawn)

Consultations on bioequivalence of generic drugs

15

1

16

Quality consultation for generic drugs

9

0

9

24

1

25

Consultation category

Total

- 78 -

Behind-the-counter (BTC) drugs, over-the-counter (OTC) drugs, and quasi-drugs  PMDA took the following measures to promote public self-medication. (i)

Appropriate and prompt reviews a.

Reinforcement of the review system for BTC drugs and OTC drugs  PMDA made efforts to improve post-marketing surveillance by allocating human resources with experiences in safety measures in order to respond to the establishment of the BTC drugs system. Personnel with experience in compliance assurance were also assigned to handle newly initiated document-based compliance assessments at the Office of OTC/Quasi-drugs. While reviewers for toxicity and clinical matters have not yet been assigned, PMDA took steps in collaboration with experts and sought their opinions as needed on issues associated with products for reviews or consultations.  Reviewers actively participated in academic conferences, etc., held in and out of Japan, and exchanged opinions with healthcare professionals. The Agency conducted reviews and consultations, taking into account the information obtained in this manner.  For the development of Japanese Pharmacopoeia, see 3.2.(1) New drugs (i)-g.  PMDA made efforts to improve the quality of reviewers by exchanging opinions with experts in traditional Chinese medicines/crude drugs by having reviewers participate in the Japanese Pharmacopoeia Crude Drug Committee and also, as collaborative researchers, in the research group supported by Health and Labour Sciences Research Grants which involves the Division of Crude Drugs at the National Institute of Health Sciences (NIHS).

b.

Reinforcement of the review system for quasi-drugs  PMDA has accelerated reviews by increasing the number of reviewers and by newly allocating principle reviewers who specialize in the review of innovative products.  PMDA supported the MHLW's process of the revision of Japanese Standards of Quasi-drug Ingredients by assisting MHLW to hold meetings of the "Review Committee on Japanese Standards of Quasi-drug Ingredients." In addition to that, PMDA prepared “Standards of Quasi-drug Excipients” to publicize the standards in the appendix, which are used mainly for approved quasi-drug cosmetics, in order to accelerate reviews and reduce the time and effort involved in making an application.  PMDA has made efforts to improve the quality of reviewers by having them participate in training programs, academic conferences etc., in and out of Japan and exchange opinions with specialists. PMDA conducted reviews and consultations, taking into account the information obtained in this manner.

(ii)

Approaches to shorten review times  PMDA set up the target regulatory review times for applications for BTC drugs, OTC drugs, and quasi-drugs submitted on or after April 1, 2004, and has since conducted reviews toward the achievement of these targets.  In order to review BTC drugs, OTC drugs, and quasi-drugs promptly and accurately, PMDA executed operations in accordance with the Procedures for Review of OTC Drugs, Procedures for

- 79 -

Review of Insecticides/Rodenticides, and Procedures for Review of Quasi-drugs, all of which specify the review methods and associated procedures, and also SOPs for various operations. In addition, PMDA periodically collected data on the achievement level of the target review time, informed the reviewers of the level, and held meetings of the Progress Management Committee for Reviews and Related Services to monitor and examine operational progress. (4 meetings were held in FY 2014.)  The approval status of BTC drugs, OTC drugs, and quasi-drugs in FY 2014 are as follows: a.

Review time for BTC drugs and OTC drugs Target PMDA aims to achieve the following target for the 50th percentile (median) of products by FY 2018. Product

Regulatory review time [months]

BTC drugs, OTC drugs

7

Results BTC drugs, OTC drugs Approved products Of which those filed in or after April 2004 Median regulatory review time [months]

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

1,008 1,007 4.0

1,031 1,029 3.4

881 881 4.1

916 916 4.9

844 844 6.3

Note: The medians were calculated based on the applications filed in or after April 2004. These values were calculated excluding the period after completion of reviews up to notification of GMP inspection results from authorities such as prefectural governments.

b.

Review time for quasi-drugs Target PMDA aims to achieve the following target for the 50th percentile (median) of products by FY 2018. Product

Regulatory review time [months]

Quasi-drugs

5.5

Results Quasi-drugs Approved products Of which those filed in or after April 2004 Median regulatory review time [months]

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

1,976 1,976 5.2

1,938 1,938 5.0

1,968 1,968 4.9

2,028 2,028 4.9

1,779 1,779 4.9

Note: The medians were calculated based on the applications filed in or after April 2004. These values were calculated excluding the period after completion of reviews up to notification of GMP inspection results from authorities such as prefectural governments.

- 80 -

Reviews Conducted for BTC Drugs, OTC Drugs, and Quasi-drugs by Fiscal Year Classification

Fiscal Year

Applications

Approved

Withdrawn, etc.

Under review

BTC drugs, OTC drugs

FY 2010

1,092

1,008

133

1,834

FY 2011

1,130

1,031

92

1,841

FY 2012

1,005

881

90

1,875

FY 2013

1,013

916

63

1,909

Quasi-drugs

FY 2014

882

844

99

1,848

FY 2010

2,297

1,976

142

2,013

FY 2011

2,212

1,938

97

2,190

FY 2012

2,117

1,968

79

2,260

FY 2013

2,298

2,028

174

2,356

FY 2014

1,828

1,779

125

2,280

Note 1: Values in the "Withdrawn etc." column do not include the number of products that were switched to other review categories during the review. Note 2: Partial tabulation errors were found for FY 2010, 2011, and 2012, and the numbers of reviews conducted for quasi-drugs have been corrected as follows: Quasi-drugs The value in the "Withdrawn etc., column" for FY 2010 was corrected from 135 to 142. The value in the "Under review column" for FY 2010 was corrected from 2,030 to 2,013. The value in the "Withdrawn etc., column" for FY 2011 was corrected from 82 to 97. The value in the "Under review column" for FY 2011 was corrected from 2,222 to 2,190. The value in the "Withdrawn etc., column" for FY 2012 was corrected from 74 to 79. The value in the "Under review column" for FY 2012 was corrected from 2,297 to 2,260. The value in the "Under review column" for FY 2013 was corrected from 2,393 to 2,356.

 The median regulatory review time for approved products in FY 2014 was 6.3 months for BTC drugs and OTC drugs (target, 7 months) and 4.9 months for quasi-drugs (target, 5.5 months), showing that the targets were achieved for both categories. (iii) a.

Efficient conduct of consultations Improvement of pre-application consultations for BTC drugs and OTC drugs  PMDA started to offer pre-development and pre-application consultations for OTC drugs in FY 2010 based on opinions from the industry associations. Among them, consultations on appropriateness of development of new OTC drugs were started in FY 2011. Also, pre-application consultations for Switch OTC drugs and consultations on key points of clinical trial protocols were continuously provided on a trial basis. The number of consultations decreased in FY 2012 as compared to that in the previous year, but markedly increased in FY 2013, and this increased number was maintained in FY 2014. PMDA intends to make efforts to further improve the consultation service. Number of Pre-development and Pre-application Consultations for OTC Drugs FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

23

17

4

21

21

Withdrawn

0

2

0

0

0

Total (conducted and withdrawn)

23

19

4

21

21

- 81 -

Number of Pre-development and Pre-application Consultations for OTC Drugs by Consultation Category in FY 2014 Conducted

Withdrawn

Total (conducted and withdrawn)

Pre-application consultation for switch OTC drugs

0

0

0

Consultation on key points of clinical trial protocols for OTC drugs

1

0

1

Consultation on appropriateness of development of new OTC drugs

20

0

20

Total

21

0

21

Consultation category

b.

Improvement of pre-application consultations for quasi-drugs  PMDA exchanged opinions on specific issues with concerned parties such as the Japan Cosmetic Industry Association to start a new pre-application consultation system for quasi-drugs. PMDA continues to harmonize opinions aiming to implement the consultation system at an early date.

- 82 -

Medical devices  Various measures were implemented or investigated to accelerate reviews for new medical devices, based on the "Cooperation Plan to Accelerate Reviews of Medical Devices" (March 2014) (the successor of "Action Program to Accelerate Reviews of Medical Devices" [December 2008]), "Japan Revitalization Strategy -JAPAN is BACK-", and "Healthcare and Medical Strategy". (i)

Appropriate and prompt reviews a.

Structure for clinical trial consultations and reviews  In order to strengthen the review system and thereby achieve new targets, PMDA increased the number of reviewers allocated to the categories where a markedly greater number of new medical device applications were filed and the review process for such applications was likely to be prolonged.  Under the guidance of an office director and a review director, reviews of new medical devices and improved medical devices were basically conducted by review teams consisting of experts who have academic degrees in engineering, pharmaceutical science, physical science, medicine, dentistry, veterinary medicine, statistics, etc. The review team is typically comprised of team leader(s) and reviewers who specialize in biological evaluations, physicochemical/physical property evaluations, and clinical evaluations. (Note)

New medical devices:

 Medical devices subject to re-examination, which have a clearly different structure, usage, indications, performance, etc., compared to existing approved medical devices or certified medical devices (definition under the Pharmaceutical Affairs Act).

 Medical devices for which marketing approval has been granted (medical devices that have been specified as being subject to use results assessment according to the provisions of Paragraph 1, Article 23-2-9 of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (PMD Act) at the time of approval, excluding those for which the survey period has not expired; hereinafter referred to as "approved medical devices") (definition under the PMD Act) Improved medical devices: 

Medical devices that do not fall under "new medical devices" or "generic medical devices," and are not so novel as to be subject to re-examination, nor are substantially equivalent to existing medical devices in terms of structure, usage, indications, performance, etc. (definition under the Pharmaceutical Affairs Act)

 Medical devices that do not fall under "new medical devices" or "generic medical devices" (definition under the PMD Act) Generic medical devices:

 Medical devices that are regarded as substantially equivalent to existing approved medical devices in terms of structure, usage, indications, performance, etc. (definition under the Pharmaceutical Affairs Act).

 Medical devices that are regarded as equivalent to existing approved medical devices in terms of structure, usage, indications, and performance; that is, medical devices that are substantially equivalent to existing approved medical devices in terms of structure, usage, indications, and performance (definition from the PMD Act)

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Organization for New/Improved Medical Device Reviews

Office Director

Review Director

Review Director

Team Leader (Review/Consultation) Biological Evaluation (1 reviewer) Pharmaceutical Science

Physical Science

Physicochemical Evaluation Physical Property Evaluation (2 reviewers) Material, Mechanical

Electrical, Optics

Clinical Evaluation (1 reviewer) Medicine, Biostatistics Dentistry

 New and improved medical devices were reviewed by teams designated based on the review categories shown below. Review Categories Covered by the Offices of New/Improved Medical Devices Office

Office of Medical Devices I

Office of Medical Devices II (Note)

Review Categories Category 3-1

Materials aspects of intervention devices mainly in cerebral, cardiovascular, respiratory, and psychoneurologic areas

Category 3-2

Materials aspects of non-intervention devices mainly cardiovascular, respiratory, and psychoneurologic areas

Category 4

Mechanical aspects of medical devices mainly in cerebral, cardiovascular, respiratory, and psychoneurologic areas

Category 8

Mainly for multicategory medical devices, advanced electronic medical devices, other uncategorized medical devices

Category 1

Mainly for ophthalmology and otorhinolaryngology

Category 2

Mainly for dentistry

Category 5

Mainly for gastrointestinal and urinary systems, obstetrics and gynecology

Category 6-1

Mainly for medical devices for knee/upper limb joints, hip/digital joints, etc., in orthopedic surgery area

Category 6-2

Mainly for plates/screws, fixation materials for intramedullary nails/spines and related appliances/machines in orthopedic surgery area, and medical devices for plastic surgery and dermatology

Category 7

Mainly for laboratory tests (in vitro diagnostics)

in

cerebral,

Note: Operations of Category 7 were transferred from the Office of Medical Devices II to the Office of In Vitro Diagnostics (a new office) on April 1, 2015.

 To hear opinions from external experts in the course of reviews performed by review teams, expert discussions were held where necessary, and also, innovative medical devices etc., were deliberated at the Committee on Medical Devices and In-vitro Diagnostics of Pharmaceutical Affairs and Food Sanitation Council (PAFSC), MHLW.

- 84 -

Review Performance for FY 2014 (medical devices and in vitro diagnostics) (1) Number of Expert Discussions conducted: 51 (36 document-based discussions, 15 meetings) (2) Applications deliberated at the Committees on Medical Devices and in vitro Diagnostics (under PAFSC): 12 Applications reported to the Committee on Medical Devices and in vitro Diagnostics (under PAFSC): 321 (303 medical devices, 18 in vitro diagnostics)

 PMDA conducted clinical trial consultations for new/improved medical devices based on the team-reviewed guidance plan drafted by three staff members, i.e., the Review Director as well as the consultation leader and the deputy consultation leader in charge, who were appointed from among review team members.  For reviews of generic medical devices, PMDA uses the buddy system in which an experienced reviewer and a novice reviewer are paired to perform a review. Team leaders oversee buddy pairs and Review Directors take control of the whole process.

b.

Introduction of the 3-track review system  As one of the efforts to advance and accelerate reviews of medical devices, the 3-track review system (for new medical devices, improved medical devices, and generic medical devices) has been put in place in PMDA since FY 2011. In FY 2014, PMDA promoted the system based on the experiences in the previous year.

c.

Reinforcement and transparency of the progress management of reviews  In order to conduct reviews and related services promptly and appropriately to achieve the target review time as specified in the Mid-term Plan, PMDA held meetings of the Progress Management Committee for Reviews and Related Services once every 3 months to ensure that the Chief Executive and other executives of PMDA can accurately grasp the progress of reviews and related services and support improvement, as needed. In this way, operational progress was monitored, while particularly relevant information for new medical devices was dealt with comprehensively and approaches for solving operational challenges were considered.  The Review Segment Committee for Progress Management, with the Director of the Center for Product Evaluation as its head, to control the progress of reviews, was continuously convened in FY 2014. In the meetings, information on the overall review status for new medical devices including QMS inspections etc., and associated issues were shared, and measures to address the issues and future approaches were examined (11 meetings were held in FY 2014). At the Review Segment Committee for Progress Management, taking into account reports from office directors of review divisions, necessary guidance was continuously provided by the Director of the Center for Product Evaluation and the Associate Executive Director, and the results of discussions of issues and improvement measures for products with a difficulty that required a prolonged review time were notified within review segments.  In order to accelerate review times, timelines were strictly managed in accordance with the "On the Standard Review Timeline for New Medical Devices" (PFSD/ELD/OMDE Notification No. 1120-1 dated November 20, 2013), "On the Standard Review Timeline for Improved Medical Devices (with Clinical Data)" (PFSD/ELD/OMDE Notification No. 0328-4 dated March 28, 2014),

- 85 -

and "On the Standard Review Timeline for Improved Medical Devices (without Clinical Data) and Generic Medical Devices" (PFSD/ELD/OMDE Notification No. 0519-1 dated May 19, 2014).  In accordance with the "Information Sharing about the Progress of Reviews of New Medical Devices and Improved Medical Devices" (PFSD/ELD/OMDE Notification No. 0530001 dated May 30, 2014), PMDA communicated the progress of reviews at each review stage to applicants, and the relevant office director held meetings with applicants upon their request to explain to them the progress status and outlook for their reviews. d.

Standardization and transparency of review  To clarify review standards, PMDA posted on its website the following three documents on basic considerations for review: "Points to Consider in regard to Applications for New Medical Devices, etc.," "Points to Consider in regard to Applications for Improved Medical Devices," and "Points to Consider in regard to Applications for Generic Medical Devices." They were first published in FY 2008 and later revised in association with subsequent changes in the regulatory system. PMDA has also explained those points to relevant reviewers and has been using them for reviews etc.  To promote the transparency and efficiency of reviews, PMDA posted on its website the "Guidelines for Preparation of Summary Technical Documentation (STED) Submitted in Applications for Medical Devices (new medical devices)," which is a revised version of the "Guidelines for Preparation of Summary Technical Documentation (STED) Submitted in Applications for Medical Devices (new medical devices and improved medical device)" published in FY 2009, and introduced the guidelines at workshops to make them widely known. PMDA posted on its website the following guidance documents: "Points to Consider in Preparing Data for Applications of Improved Medical Devices" for improved medical devices, "Points to Consider in Preparing Data for Applications of Generic Medical Devices," "Guidelines for Preparation of Summary Technical Documentation (STED) Submitted in Applications for Medical Devices in the Category of Generic Medical Devices (without approval standards, without clinical data)," and "Confirmation of Application Documents for Generic Medical Devices" for generic medical devices. PMDA also presented these guidance documents in workshops to thoroughly disseminate them.

e.

Consultations and reviews based on medical needs  PMDA actively exchanged opinions with healthcare professionals by participating in academic conferences in and out of Japan, town hall meetings, requested lectures, etc., to comprehend their needs. The Agency has conducted consultations and reviews, taking into account the information obtained in this manner.  In order to encourage MAHs of medical devices to promote the development of medical devices that have been approved in Europe and the U.S. but not yet approved in Japan, the Study Group on the Early Introduction of Medical Devices etc., with High Medical Need (chaired by Dr. Soichiro Kitamura, President Emeritus of National Cerebral and Cardiovascular Center) was established in the MHLW in October 2006. The study group has been actively conducting investigations. PMDA has cooperated in the operation of the study group, and provided clinical trial consultations and reviewed product applications taking into account the results of investigations by the study group. Through this initiative, 7 medical devices were approved in FY 2014.

f.

Consistency between clinical trial consultations and reviews  In order to ensure the consistency between clinical trial consultations and reviews, review team members are involved in all the clinical trial consultations for products falling under the category to

- 86 -

which they are assigned. Coherence from consultations to reviews is maintained and teams are flexibly organized as necessary. g.

Efficient operation and implementation of the use-results evaluation system  With the enforcement of the Act for Partial Revision of the Pharmaceutical Affairs Act (Act No. 84, 2013), PMDA worked on the efficient operation and implementation of the use-results evaluation system for medical devices, which was introduced on November 25, 2014, in accordance with "Basic Principles on Products Subject to Use-results Evaluation at the Time of Approval" deliberated and approved at the 6th meeting of the Committee on Medical Devices and In-vitro Diagnostics (MHLW) in FY 2014. Based on this principle, 30 medical devices (including 7 medical devices selected for use-results survey) were approved in FY 2014.  In order to implement the new system smoothly, medical devices that had been designated as products subject to re-examination before the system revision were processed with greater collaboration with the division of surveillance (Office of Non-clinical and Clinical Compliance). As a result, 8 medical devices subject to re-examination were processed in FY 2014.

(ii)

Introduction of new review systems a.

Introduction of prior assessment consultation  To preliminarily evaluate the quality, efficacy and safety of medical devices in their development stage, PMDA started to offer prior assessment consultations as a pilot scheme in October 2010, and has been formally implementing them from FY 2012. In FY 2014, the request forms were received separately for consultations to be conducted in the first half of the fiscal year and for those in the second half. Consultations were provided for 3 products falling under Category 3.

b.

Short-term review of applications for specified partial changes  Applications for specified partial changes were reviewed in accordance with "Regarding Acceleration of the Procedure for Specified Changes Made to Medical Devices" (PFSB/ELD/OMDE Notification No. 1110001, dated November 10, 2008). As a result, regulatory review time for 19 products approved in FY 2014 was not more than 2 months excluding the period for GCP/GLP inspections.

c.

Support for the development of approval standards, certification standards, and review guidelines for medical devices  In order to support MHLW in developing approval standards etc., for medical devices, the Committee on Medical Device Approval Standards held 5 meetings in FY 2014. The number of approval or certification standards reported to MHLW in FY 2014 to be established or revised was as follows. The number of certification standards reported to MHLW was 129 (including 20 revised standards) for designated controlled medical devices and 3 for designated specially controlled medical devices (all of them were classified as Class III for risk level).

- 87 -

FY 2006

FY 2007

FY 2008

FY 2009

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Total

Approval standards

6

7

5

2

6

6

5

4

0

41

Certification standards (designated controlled medical devices)

0

14

86

64

294

84

67

82

129

820

Certification standards (designated specially controlled medical devices)

















3

3

Review guidelines

0

1

2

6

0

0

0

0

0

9

FY (for reporting)

The number of standards established by MHLW in FY 2014 based on the reports from PMDA is shown below. The number of certification standards established was 109 for designated controlled medical devices and 3 for designated specially controlled medical devices (all of them were classified as Class III for risk level). Numbers of Approval Standards, Certification Standards, and Review Guidelines Established for Medical Devices and In Vitro Diagnostics FY (for establishment)

FY 2004

FY 2005

FY 2006

FY 2007

FY 2008

FY 2009

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Total

Approval standards

0

17

8

10

-2*

5

3

0

0

4

0

45

Certification standards (designated controlled medical devices)

363

9

24

0

17

68

274

67

2

3

109

936

Certification standards (designated specially controlled medical devices)





















3

3

Review guidelines

0

0

0

0

3

1

4

0

0

0

0

8

* In FY 2008, 2 established approval standards were switched to certification standards, resulting in a negative number.

List of Certification Standards for Medical Devices (FY 2014) Established: Certification standards,112; Approval standards,0; Review guidelines, 0 Date of issue

Name of standard

MHLW Ministerial Announcement No. 404, dated November 5, 2014

Certification Standard for Insulin Pen (and other 1 certification standard)

MHLW Ministerial Announcement No. 445, dated November 25, 2014

Certification Standard for Programs for multipurpose Diagnostic X-ray Equipment (and other 107 certificate standards)

MHLW Ministerial Announcement No. 120, dated March 25, 2015

Certification Standard for Enteral Nutrition Pumps, etc. (and other 1 certification standard)

 The PMDA website for the information service on medical device standards provides the latest information on the certification standards and approval standards in relation to JIS, ISO/IEC, MHLW Notifications, Japanese Medical Device Nomenclature (JMDN), etc., as their components. The information has also been continuously provided on the dedicated pages of the PMDA English website for overseas users. The information on the website has been updated periodically, at least twice a month.

- 88 -

 PMDA provided advice on each individual product through simple consultations on the scope of changes for which partial change applications are not required, or minor change notifications are required, based on the "Procedures Associated with Partial Change for Medical Devices" (PFSB/ELD/OMDE Notification No.1023001, dated October 23, 2008).  PMDA dealt with the procedure for changing raw materials for each individual products through simple consultations based on "Regarding the Procedure for Changing Raw Materials of Medical Devices” (PFSB/ELD/OMDE Notification No. 0329-7, dated March 29, 2013), which clarifies the principle of the procedure.  When MAHs raised questions on whether or not clinical studies are necessary during consultations, PMDA appropriately responded to such questions, for each individual products, based on the notifications etc., issued by MHLW.  In order to clarify the scope of one product, PMDA conducted simple consultations etc., by referring to the "Partial Revision of ‘Points to Consider for Filing Applications for Medical Devices’" (PFSB/ELD/OMDE No. 1224007, dated December 24, 2010), "Handling of Applications for Dental Implants" (PFSB/ELD/OMDE No. 0713-1, dated July 13, 2012), and “Scope of Descriptions in Application Forms for Filing Application for Medical Devices and Procedures for Partial Change of Medical Devices (for orthopedic implant products)” (PFSB/ELD/OMDE No. 0701-10, dated July 1, 2013). d.

Equivalence review of generic medical devices  PMDA continuously conducted the equivalence review of generic medical devices filed in FY 2014 based on the notification titled "Points to Consider in Preparing Applications for Generic Medical Devices" (PFSB/ELD/OMDE Notification No.0327004, dated March 27, 2009).  In order to clarify the definition of substantial equivalence of generic medical devices based on the "Cooperation Plan to Accelerate Reviews of Medical Devices," PMDA held two meetings with related industry associations and strived to identify and summarize problems that needed to be resolved.

(iii)

Efforts to achieve “zero” review lag for medical devices  With respect to total review time for medical device applications filed on or after April 1, 2004 and approved in each fiscal year, PMDA has made efforts with the cooperation of applicants to achieve the targets "a" to "e," presented below, by FY 2018 by gradually increasing the target percentile.  Progress management was reinforced for products under review in any application category (new, improved, or generic medical devices). PMDA endeavored to reduce the backlog of pending applications. Specifically, to promptly complete the prolonged review of applications filed years earlier, PMDA and applicants had discussions to analyze reasons for prolonged review and resolve relevant issues for each product. In addition, reminder notices were frequently sent to applicants if their responses to PMDA's inquiries were delayed. For products for which new applications have been submitted, progress management was enhanced to accelerate reviews.  In order to eliminate review/development lag for medical devices being developed or to be developed in the near future, PMDA encouraged medical device-related industries, medical device companies, and academic institutions to take measures such as the proactive use of clinical trial consultations prior to regulatory submission, at academic conferences or periodic opinion exchange sessions with the industries. Moreover, PMDA provided specific examples of deficiencies often seen at the time of application for approval, at workshops, etc., to call for improvements to be made on the applicant’s side. - 89 -

 For reviews of generic medical devices, PMDA continued the buddy system in which an experienced reviewer and a novice reviewer are paired to perform a review. The buddy pairs are overseen by team leaders and Review Directors take control of the whole process so that the review practices are standardized among review teams. The Office of Medical Devices III, which was established in November 2011, has conducted reviews intensively, and for the review categories with many products under review, PMDA made efforts to flexibly operate the buddy system regardless of review categories in order to accelerate reviews as a whole by having one reviewer of a buddy pair help another reviewer as far as they are reviewing similar products.  To ensure consistency among review teams and to review medical device applications promptly and appropriately, PMDA developed SOPs relating to various operations, which describe reviews and related procedures for each type of new medical devices, improved medical devices, and generic medical devices. These SOPs were explained to relevant reviewers. PMDA also collected monthly data on the achievement level of the target review times and informed the reviewers of the achievement status.  For shortening the total review time, it is also important to improve environments for the smooth conduct of global clinical trials. For this purpose, PMDA participated in the Harmonization by Doing (HBD) project, which has been undertaken by both Japan and the U.S., and had discussions on the conduct of global clinical trials, the development of common protocols between Japan and the U.S., and the standardization of post-marketing surveillance database. In FY 2014, PMDA participated in HBD Think Tank West (held in Washington D.C. in September 2014) and promoted global clinical development through activities supporting the Proof of Concept (POC) project. In addition, from the previous year, PMDA has been making ongoing efforts to accelerate reviews by exchanging information with the U.S. FDA on review and consultation services. As part of the HBD activities, PMDA participated in scientific sessions held at academic conferences, such as the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) conference held in Nagoya in July 2014 and the Cardiovascular Research Technologies (CRT) conference held in Washington D.C. in February 2015, to discuss issues such as the challenges in the development of new medical devices and methods of utilizing a post-marketing registry with industry, governments, and academic circles.  Efforts were made to achieve the target total review time by taking these measures, and then, the status of reviews for medical devices in FY 2014 was as follows: a.

Review times for new medical devices (priority review products) Targets Fiscal Year

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

10

10

10

10

10

Percentile

60

60

70

70

80

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

50 15.1 (19.7) 3

50 4.3 (12.8) 6

50 9.3 (20.8) 5

50 9.0 (10.0) 14

60 8.8 (8.9) 5

Results

Percentile Total review time [months] (Reference, 80th percentile) [months] Number of approved applications

- 90 -

Reference Regulatory review time [months]

5.3

2.9

7.2

5.1

4.0

Applicant’s time [months]

10.7

1.3

3.4

3.5

3.3

Note: Products covered are those for which applications were filed in or after April 2004.

 Priority reviews are conducted for applications for orphan medical devices and other devices that are regarded as having particularly high medical need (medical devices for serious diseases and with distinctly superior efficacy or safety as compared to existing medical devices or therapies). In FY 2014, 5 priority review products (all were new medical devices) were approved. Four medical devices regarded as having particularly high medical need were designated for priority review.  The approval status of priority review products in FY 2014 was as follows: The total review time (60th percentile) was 8.8 months, and the achievement rate for the target total review time (10 months) was 100.0%, which was substantially higher than the target. The number of approvals was 5, which was close to the annual average. b.

Review times for new medical devices (standard review products) Targets Fiscal Year

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

14

14

14

14

14

Percentile

60

60

70

70

80

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Results

Percentile

50

50

50

50

60

Total review time [months] (Reference, 80th percentile) [months]

16.5 (21.6)

9.7 (17.8)

12.7 (15.5)

6.3 (14.8)

5.6 (10.6)

Number of approved applications

15

27

41

80

62

Regulatory review time [months]

7.1

5.1

5.4

4.0

3.5

Applicant’s time [months]

8.2

3.4

5.0

1.6

2.2

Reference

Note: Products covered are those for which applications were filed in or after April 2004.

 The approval status of standard review for new medical devices in FY 2014 was as follows: The total review time (60th percentile) was 5.6 months, and the achievement rate for the target total review time (14 months) was 98.4%, which was substantially higher than the target. The number of approvals in FY 2014 was 62, being the highest number next to FY 2013. This was probably because many applications for MRI-compatible pacemakers, ICD, etc., concentrated in FY 2014 as in FY 2013.  The number of product applications under review at the end of FY 2014 was 78 (including 4 orphan medical devices and 3 non-orphan priority review medical devices).

- 91 -

Review Status of New Medical Devices by Fiscal Year of Submission New medical devices (FY of submission)

Applications

Approved

Withdrawn

Under review

In or before FY 2003 ending Mar. 31, 2004

132

54

78

0

FY 2004

56

35

21

0

FY 2005

7

7

0

0

FY 2006

23

19

4

0

FY 2007

37

31

6

0

FY 2008

32

30

2

0

FY 2009

24

20

4

0

FY 2010

28

24

2

2

FY 2011

42

40

2 (1)

0 [-1]

FY 2012

64

63 (1)

0

1 [-1]

FY 2013

72

65 (29)

0

7 [- 29]

FY 2014

99

30 (30)

1 (1)

68 [68]

Total

616

418 (60)

120 (2)

78 [37]

Note 1:Values in the "Applications" column are the numbers of those submitted as new medical devices. Note 2:The number of approved products includes those approved as improved medical devices. Note 3:Figures in parentheses in the columns of "Approved" and "Withdrawn" represent those processed in FY 2014 (included in values on their left). Note 4:Figures in brackets [] represent difference from the status reported in FY 2013.

c.

Review times for improved medical devices (with clinical data) Targets Fiscal Year

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

10

10

10

10

10

Percentile

52

54

56

58

60

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Results

Percentile

50

50

50

50

52

Total review time [months] (Reference, 60th percentile) [months]

15.5 (17.5)

13.9 (18.0)

17.3 (19.8)

11.6 (13.2)

9.9 (10.5)

Number of approved applications

40

55

44

63

35

Regulatory review time [months]

7.6

7.0

7.9

5.7

5.0

Applicant’s time [months]

7.6

7.2

8.8

5.5

5.0

Reference

Note 1: Products covered are those for which applications were filed in or after April 2004. Note 2: Applications filed in or before FY 2008 have been re-categorized in this table according to the new categorization implemented in FY 2009.

 As regards the approval status of improved medical devices (with clinical data) approved in FY 2014, the total review time (52nd percentile) was 9.9 months, and the achievement rate for the target total review time (10 months) was 57.1%, which was substantially higher than the target.

- 92 -

number of approvals in FY 2014 was 35, showing a decrease from the previous fiscal year but being nearly equal to the number of approvals in other fiscal years.  This is due to the completion of the prolonged reviews of applications for improved medical devices (with clinical data) that were filed years earlier. Review Status of Improved Medical Devices (with Clinical Data) by Fiscal Year of Application Improved medical devices (with clinical data) (FY of submission)

Applications

FY 2009

34

33

1

0

FY 2010

34

33

1

0

FY 2011

26

21

5 (2)

0 [-2]

FY 2012

42

39 (5)

2

1 [-5]

FY 2013

46

36 (21)

2

FY 2014

45

8 (8)

0

Total

227

170 (34)

Approved

Withdrawn

Under review

8 [-21] 37 [37]

11 (2)

46 [9]

Note 1:The number of applications was counted based on the initial application categories for medical devices submitted and the dates the applications were received. Note 2:The number of approved products includes those approved under other application categories for medical devices. Note 3:Figures in parentheses represent those processed in FY 2014 (included in values on their left). Note 4:Figures in brackets [] represent difference from the status reported in FY 2013.

d.

Review times for improved medical devices (without clinical data) Targets Fiscal Year

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

6

6

6

6

6

Percentile

52

54

56

58

60

Results FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Percentile

50

50

50

50

52

Total review time [months] (Reference, 60th percentile) [months]

14.5 (17.3)

13.3 (14.9)

9.7 (11.1)

7.5 (9.2)

6.0 (7.4)

Number of approved applications

182

218

229

231

213

Reference Regulatory review time [months]

8.0

5.6

4.8

3.7

3.3

Applicant’s time [months]

6.2

6.5

4.7

3.7

3.4

Note 1:Products covered are those for which applications were filed in or after April 2004. Note 2:Applications filed in or before FY 2008 have been re-categorized in this table in accordance with the new categories implemented in FY 2009.

 As regards the approval status of improved medical devices (without clinical data) approved in FY 2014, the total review time (52nd percentile) was 6.0 months, and the achievement rate for the target total review time (6 months) was 52.6%, achieving the target. The number of approved

- 93 -

applications in FY 2014 was 213, showing a decrease from the previous fiscal year but being nearly equal to the number of approvals in other fiscal years. 

This is due to the completion of the prolonged reviews of applications for improved medical devices (without clinical data) that were filed years earlier.

Review Status of Improved Medical Devices (without Clinical Data) by Fiscal Year of Application Improved medical devices (without clinical data) (FY of submission)

Applications

Approved

Withdrawn

Under review

FY 2009

137

122

15

0

FY 2010

165

140 (3)

24 (1)

1 [-4]

FY 2011

176

159 (4)

15 (2)

2 [-6]

FY 2012

210

198 (18)

10

2 [-18]

FY 2013

190

169 (84)

10 (7)

11 [-90]

FY 2014

261

100 (100)

0

161 [161]

Total

1,139

888 (209)

74 (10)

177 [43]

Note 1:The number of applications was counted based on the initial application categories for medical devices submitted and the dates the applications were received. Note 2:The number of approved products includes those approved under other application categories for medical devices. Note 3:Figures in parentheses represent those processed in FY 2014 (included in values on their left). Note 4:Figures in brackets [] represent difference from the status reported in FY 2013.

e.

Review times for generic medical devices Targets Fiscal Year

FY 2014

FY 2015

FY 2016

FY 2017

FY 2018

Total review time [months]

4

4

4

4

4

Percentile

52

54

56

58

60

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Percentile

50

50

50

50

52

Total review time [months] (Reference, 60th percentile) [months]

11.0 (15.1)

5.0 (7.2)

4.0 (6.0)

3.9 (5.3)

3.9 (4.5)

Number of approved applications

1,391

907

1,216

958

920

Regulatory review time [months]

5.1

2.5

1.6

1.8

1.9

Applicant’s time [months]

4.7

2.3

2.3

2.1

1.8

Results

Reference

Note 1:Products covered are those for which applications were filed in or after April 2004. Note 2:Applications filed in or before FY 2008 have been re-categorized in this table in accordance with the new categories implemented in FY 2009.

- 94 -

 As for the approval status of generic medical devices approved in FY 2014, the total review time (52nd percentile) was 3.9 months, and the achievement rate for the target total review time (4 months) was 54.6%, which was substantially higher than the target.  Although the number of applications has tended to decrease, the number of applications in FY 2014 was increased in association with the enforcement of the Act for Partial Revision of the Pharmaceutical Affairs Act. The number of approved applications in FY 2014 was 920, almost the same as that in FY 2013.The number of applications under review at the end of fiscal year was lower in FY 2014 than in FY 2013.  Also, to further reduce the applicant’s time for generic medical devices, PMDA requested applicants, at regular industry-PMDA dialogue meetings, to take following measures: i) To actively utilize consultations in the pre-submission stage in order to receive advice or guidance regarding issues such as the adequacy of evaluation and how to compile submission documents, and to ensure that applications are filed after problems are completely resolved in terms of advice or guidance given, and ii) To secure resources in order to promptly respond to inquiries from the regulatory side if an applicant intends to file a number of applications at the same time. Moreover, regarding deficiencies often seen at the time of filing application, specific examples were provided at workshops etc., to call for improvements. Review Status of Generic Medical Devices by Fiscal Year of Application Generic medical devices (FY of submission)

Applications

FY 2009

1,126

FY 2010

1,020

Approved

Withdrawn

1,037 (6)

Under review

84 (4)

5 [-10]

916 (21)

93 (6)

11 [-27]

FY 2011

995

923 (12)

61 (5)

11 [-17]

FY 2012

1,075

1,021 (23)

35 (7)

19 [-30]

FY 2013

921

18 (6)

57 [-271]

FY 2014 Total

846 (262)

957

605 (605)

6,094

5,348 (929)

7 (7)

345 [345]

298 (35)

448 [-10]

Note 1:The number of applications was counted based on the initial application categories for medical devices submitted and the dates the applications were received. Note 2:The number of approved products includes those approved under other application categories for medical devices. Note 3:Figures in parentheses represent those processed in FY 2014 (included in values on their left). Note 4:Figures in brackets [] represent difference from the status reported in FY 2013.

(iv) a.

Efficient conduct of clinical trial consultations Conduct of priority consultations  For medical devices, there were no requests for designation for priority consultation or consultation on GLP/GCP compliance for priority consultation products.

b.

Implementation of clinical trial consultations and improvement of the system Number of Consultations

Conducted

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

105

136

165

162

196

Withdrawn

1

4

3

11

11

Total (conducted and withdrawn)

106

140

168

173

207

- 95 -

Number of Prior Assessment Consultations for Medical Devices (Among the Numbers Listed Above) FY 2010

FY 2011

FY 2012

FY 2013

Y 2014

Conducted

2

3

3

1

3

Withdrawn

0

0

0

0

0

Total (conducted and withdrawn)

2

3

3

1

3

Number of Consultations on Pharmacogenomics/Biomarkers (Among the Numbers Listed Above) FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

0

0

0

0

0

Withdrawn

0

0

0

0

0

Total (conducted and withdrawn)

0

0

0

0

0

Note 1:The numbers of prior assessment consultations for medical devices and consultations on pharmacogenomics/biomarkers were counted on the basis of delivery dates of consultation documents to PMDA. Note 2:Prior assessment consultations for medical devices are conducted for the categories of quality, non-clinical and clinical.

Number of Consultations for Medical Devices by Category in FY 2014 Consultations accepted by November 21, 2014 Conducted

Withdrawn

Total (conducted and withdrawn)

Pre-development consultation for medical devices

97

5

102

Safety consultation for medical devices (excluding biological medical devices)

2

0

2

Quality consultation for medical devices (excluding biological medical devices)

2

0

2

Safety consultation for biological medical devices

0

0

0

Quality consultation for biological medical devices

1

0

1

Performance testing consultation for medical devices

11

2

13

Clinical evaluation consultation for medical devices

12

1

13

Exploratory clinical trial consultation for medical devices

3

0

3

Clinical trial consultation for medical devices

27

1

28

Pre-application consultation for medical devices

5

0

5

Application procedure consultation for medical devices

3

0

3

Additional consultation for medical devices

2

0

2

Consultation on GLP/GCP compliance for medical devices

0

0

0

Prior assessment consultation for medical devices (quality)

0

0

0

Prior assessment consultation for medical devices (non-clinical)

1

0

1

Prior assessment consultation for medical devices (clinical)

2

0

2

168

9

177

Consultation category

Total

- 96 -

Consultations accepted on or after November 24, 2014 Conducted

Withdrawn

Total (conducted and withdrawn)

Pre-development consultation for medical devices

8

0

8

Pre-development consultation for medical devices (preliminary consultation completed)

9

0

9

Protocol consultation for medical devices (safety) (4 or more trials) (preliminary consultation completed)

1

0

1

Protocol consultation for medical devices (exploratory clinical trial)

1

0

1

Protocol consultation for medical devices (clinical trial)

2

0

2

Protocol consultation for medical devices (clinical trial) (preliminary consultation completed)

3

0

3

Protocol consultation for medical devices (clinical trial) (additional consultation)

0

2

2

Data sufficiency/application category consultation for medical devices

1

0

1

Safety evaluation consultation for medical devices (4 or more trials) (protocol not evaluated)

1

0

1

Performance evaluation consultation for medical devices (4 or more trials) (protocol not evaluated) (preliminary consultation completed)

1

0

1

Evaluation consultation for medical devices (protocol not evaluated)

1

0

1

Total

28

2

30

Consultation category*

* This table shows only the categories of the consultations implemented in FY 2014.

c.

Review of consultation categories  Regarding clinical trial consultations for medical devices, PMDA reviewed consultation categories and improved consultation methods (implemented on November 25, 2014) in order to better accommodate a diverse range of needs in each stage of development and enhance the efficiency and effectiveness of consultations, taking into account the demands of industry and previous experience.  In order to eliminate review/development lag for medical devices being developed or to be developed in the near future, PMDA encouraged medical device-related industries, medical device companies, and academic institutions, etc., to take measures such as the proactive use of clinical trial consultations prior to regulatory submission, at academic conferences or through periodic exchanges of opinions with the industry (reposted).

- 97 -

* In addition to the consultation menu in the above diagram, other categories such as additional consultation are also available.

(v)

Promotion of evaluation of new technologies a.

Utilization of external experts  As PMDA is required to raise the scientific level of its guidance and review, particularly in the fields of the latest technologies such as ICT and robotics, PMDA has continued to commission highly knowledgeable external experts to play the role of expert advisors to PMDA in order to obtain professional opinions on scientifically important matters at Expert Discussions for reviews and post-marketing safety measures (reposted). (As of March 31, 2015, the number of commissioned experts is 12 including experts in safety measures.)  The number of Expert Discussions conducted in FY 2014 was 51 (36 document-based discussions, 15 meetings).  In order to appropriately deal with medical devices developed with the latest scientific technologies, PMDA made efforts to strengthen the collaboration with academia and healthcare professionals and to collect relevant information at meetings of the Science Board (parent committee) and its Subcommittees on Application of Numerical Analysis to Non-clinical Evaluation and on Evaluation of Medical Devices in Pediatric Use.

b.

Support for the development of national guidelines  PMDA supported the preparation of the guidance documents for the evaluation of spinal implants for the maintenance of mobility and stability and orthopedic implants developed using three-dimensional layering technology, which were all included in “Publication of the Guidance Document for the Evaluation of Emerging Technology Medical Devices/Cellular and Tissue-based Products” (PFSB/ELD/OMDE Notification No. 0912-2 dated September 12, 2014), and released them on the PMDA website.

- 98 -

c.

Preliminary reviews under Cartagena Act  See 3.2.(1) New drugs (vi)-c.

d.

Implementation of Pharmaceutical Affairs Consultations on R&D Strategy  See 3.2.(1) New drugs (vi)-d.

e.

Support project for promoting consultations/applications for innovative medical devices  In order to prevent delays in developing innovative medical devices due to financial problems at small- and medium-sized enterprises (SMEs) and venture companies that discovered promising seed-stage technologies, PMDA implemented the “support project for promoting consultations/applications for innovative medical devices,” which gives a subsidy to SMEs and venture companies that meet certain requirements for the purpose of reducing financial burdens in consultations/applications for regulatory approval. This scheme reimburses 50% of the user fee for a consultation or a new medical device application after the user fee is paid by the relevant SME or venture company. In FY 2014, claims for fee subsidy were filed for 4 consultations/applications and all were subsidized.

- 99 -

In vitro diagnostics (i)

Appropriate and prompt reviews  It is planned to establish the Office of In Vitro Diagnostics on April 1, 2015 in accordance with “Cooperation Plan to Accelerate Reviews of In Vitro Diagnostics” (March 2014).  In order to encourage MAHs to develop in vitro diagnostics that have been approved in Europe and the U.S. but not yet approved in Japan, the Study Group on the Early Introduction of Medical Devices, etc. with High Medical Need was established in the MHLW in October 2006, and activities have been continuing. PMDA has cooperated in the operation of this Study Group. Review Status of In Vitro Diagnostics In vitro diagnostics (FY of submission)

Applications

Approved

Withdrawn

Under review

In or before FY 2003 ending Mar. 31, 2004

327

223

76

28

FY 2004

615

596

19

0

FY 2005

69

65

4

0

FY 2006

180

173

7

0

FY 2007

197

189

8

0

FY 2008

170

160

10

0

FY 2009

183

173 (1)

10

0 [-1]

FY 2010

164

157

7 (1)

0 [-1]

FY 2011

177

165 (3)

7 (2)

5 [-5]

FY 2012

165

153 (11)

8 (2)

4 [-13]

FY 2013

136

112 (45)

7 (5)

17 [-50]

FY 2014

163

49 (49)

2 (2)

112 [112]

Total

2,546

2,215 (109)

165 (12)

166 [42]

Note 1: Values in parentheses indicate those processed in FY2014 (included in values to their left) Note 2: Values in brackets [] indicate difference from the status reported in FY 2013. Note 3: Values are calculated based on the applications filed in or after 1994, when the equivalence review system was introduced (numerical values stored in the current application management system were used).

(ii)

Expansion of consultation services  Regarding clinical trial consultations for in vitro diagnostics, PMDA revised consultation categories (implemented on November 25, 2014) in order to better accommodate a diverse range of needs in each stage of development and enhance the efficiency and effectiveness of consultations, taking into account the demands of industry and previous experience. Number of Consultations FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

7

5

8

7

25

Withdrawn

0

0

0

1

0

Total (conducted and withdrawn)

7

5

8

8

25

- 100 -

Number of Prior Assessment Consultations for In Vitro Diagnostics (Among the Numbers Listed Above) FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

0

0

0

0

0

Withdrawn

0

0

0

0

0

Total (conducted and withdrawn)

0

0

0

0

0

Number of Consultations on Pharmacogenomics/Biomarkers (Among the Numbers Listed Above) FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Conducted

0

0

0

0

0

Withdrawn

0

0

0

0

0

Total (conducted and withdrawn)

0

0

0

0

0

Note 1: The numbers of prior assessment consultations for in vitro diagnostics and consultations on pharmacogenomics/biomarkers were counted on the basis of delivery dates of consultation documents to PMDA. Note 2: Prior assessment consultations for in vitro diagnostics are conducted for the categories of quality, non-clinical, and clinical.

- 101 -

Number of Consultations for In Vitro Diagnostics by Category in FY 2014 Consultations accepted by November 21, 2014 Conducted

Withdrawn

Total (conducted or withdrawn)

Pre-development consultation for in vitro diagnostics

5

0

5

Quality consultation for in vitro diagnostics

1

0

1

Consultation on conformity with standards for in vitro diagnostics

1

0

1

Clinical evaluation consultation for in vitro diagnostics

1

0

1

Clinical performance study consultation for in vitro diagnostics

7

0

7

Pre-application consultation for in vitro diagnostics

2

0

2

Application procedure consultation for in vitro diagnostics

1

0

1

Additional consultation for in vitro diagnostics

0

0

0

Prior assessment consultation for in vitro diagnostics (quality)

0

0

0

Prior assessment consultation for in vitro diagnostics (non-clinical)

0

0

0

Prior assessment consultation for in vitro diagnostics (clinical)

0

0

0

Consultation on pharmacogenomics/biomarkers

0

0

0

Total

18

0

18

Conducted

Withdrawn

Total (conducted or withdrawn)

Protocol consultation for in vitro diagnostics (quality)

1

0

1

Protocol consultation for in vitro diagnostics (correlativity) (preliminary consultation completed)

1

0

1

Protocol consultation for in vitro diagnostics (clinical performance study)

1

0

1

Protocol consultation for in vitro diagnostics (clinical performance study of companion diagnostics) (preliminary consultation completed)

1

0

1

Application procedure consultation for in vitro diagnostics

1

0

1

Quality evaluation consultation for in vitro diagnostics (protocol not evaluated)

1

0

1

Evaluation consultation for in vitro diagnostics (other than quality) (3 or more trials) (protocol not evaluated)

1

0

1

Total

7

0

7

Consultation category

Consultations accepted on or after November 24, 2014 Consultation category*

* This table shows only the categories of the consultations implemented in FY 2014.

- 102 -

* In addition to the consultation menu in the above diagram, other categories such as additional consultation are also available.

- 103 -

Cellular and tissue-based products (i)

Introduction of new review systems and the conducting of appropriate and prompt reviews  PMDA improved the review process for cellular and tissue-based products to appropriately address the introduction of a conditional and time-limited approval system for cellular and tissue-based products in accordance with the Act for Partial Revision of the Pharmaceutical Affairs Act. In order to ensure consistency between clinical trial consultations and reviews, PMDA flexibly organizes teams where necessary while maintaining communication between consultations and reviews and carries out reviews/consultations appropriately and promptly.

(ii)

Setting of target review time  The target standard regulatory review time from application to approval for cellular and tissue-based products approved in FY 2014 was set at 9 months, and review progress management was carried out based on this target review time. In FY 2014, 2 applications were filed for cellular and tissue-based products, but neither of them was approved.  PMDA took the following measures to achieve the target: (i)

(ii)

(iii)

Accurate information on the progress of reviews was obtained and provided to each review team. The Progress Management Committee for Reviews and Related Services analyzed and examined operational progress to carry out progress management effectively. When a problem was identified, the cause was analyzed and fed back to review teams, while, at briefing sessions for the industries, applicants were urged to exercise vigilance against the problem. Questions and answers related to applications were prepared/renewed as appropriate to promote the transparency and efficiency of reviews.

 In order to enhance the transparency and efficiency of reviews and application-related questions and answers, PMDA coordinated the views of related industries and academic societies by the enforcement date of the Act for Partial Revision of the Pharmaceutical Affairs Act in November 2014 and supported the preparation/publication of ordinances and notifications related to review process for cellular and tissue-based products. (iii)

Efficient conduct of clinical trial consultations  In order to conduct reviews promptly and efficiently, PMDA actively communicated with related parties and encouraged them to utilize consultations conducted by PMDA at meetings of academic societies such as the Japanese Society of Regenerative Medicine. Taking into account the characteristics of cellular and tissue-based products, consultations related to the quality, safety, and clinical trial protocols, etc., were established. Furthermore, consultation on cellular and tissue-based products was added to the menu of Pharmaceutical Affairs Consultation on R&D Strategy. PMDA informed related parties of these consultation services and started the services in accordance with the Act for Partial Revision of the Pharmaceutical Affairs Act enforced in November 2014.  Pre-CTN (confirmation) application for gene therapy products was abolished and included in Pharmaceutical Affairs Consultations on R&D Strategy for quality and safety of cellular and tissue-based products.  To make consultation more accessible to academic institutions and venture companies, in November 2014, PMDA started pilot consultation service to provide general advice on matters including development process (roadmap), as part of Pharmaceutical Affairs Consultations on R&D Strategy (Development Program Consultations on R&D Strategy). A dedicated consultation

- 104 -

category was established for cellular and tissue-based products, which had been treated as drugs or medical devices. The following consultations are offered under the category: Pharmaceutical Affairs Consultations on R&D Strategy for the quality or safety of cellular and tissue-based products; pre-consultations on cellular and tissue-based products, with minutes recorded; and other consultations. Number of Consultations on Cellular and Tissue-based Products FY 2014 Conducted

6

Withdrawn

0

Total (conducted and withdrawn)

6

Note: The consultation categories for cellular and tissue-based products were established on November 25, 2014. The figure is the number of consultations conducted since then (before November 25, 2014, consultations for cellular and tissue-based products had been included in consultations for drugs or medical devices).

(iv) a.

Promotion of evaluation of new technologies Utilization of external experts  PMDA proactively utilized the Science Board, in which highly knowledgeable external experts examined evaluation methods. In FY 2014, the CPC Subcommittee was established, and the members of the subcommittee discussed how to prepare a proposal on basic principles on quality assurance of cellular and tissue-based products. The viewpoints presented in the “Current Perspective on Evaluation of Tumorigenicity of Cellular and Tissue-based Products Derived from induced Pluripotent Stem Cells (iPSCs) and iPSCs as Their Starting Materials” finalized by the Science Board on August 20, 2013 were utilized in Pharmaceutical Affairs Consultations on R&D Strategy. At international academic conferences, etc., PMDA exchanged opinions with EMA and FDA, etc., about future international regulations on cellular and tissue-based products. In February 2015, PMDA and International Alliance for Biological Standardization (IABS) co-hosted an international conference on the global standardization of guidelines for the quality and safety of cellular and tissue-based products, and discussed the issues relating to the establishment of global standards with attendees from regulatory authorities, research institutions, and industries, in and out of Japan, that are involved in cellular and tissue-based products.

b.

Collecting knowledge  PMDA staff are dispatched to meetings held by relevant societies, including the Japanese Society for Regenerative Medicines, and to organizations facilitating development of cellular and tissue-based products (e.g., CiRA, Osaka University, Riken, Chiba University, and the Institute of Medical Science of the University of Tokyo). Through this, PMDA understands what is needed by medical institutions that develop cellular and tissue-based products and collects information on the practical application of such products.

c.

Support to the development of national guidelines  PMDA cooperated with MHLW in developing guidelines for evaluating products developed with the state-of-the-art technologies, such as cellular and tissue-based products, and in working on the initiative to facilitate development of innovative products. The results of these activities are described below.

- 105 -

 PMDA cooperated in developing seed-stage resources at each innovative development site and supported the study group for evaluating cellular and tissue-based products in developing guidelines, etc., and prepared drafts of 6 guidances, such as “Points to consider on the quality of human autologous iPS cells suitable for platelet induction (draft interim report)”, and drafts of 5 concept papers, such as “Concept paper on the treatment of sequelae of cerebral infarction with autologous bone-marrow-derived stem cells.” In the initiative to facilitate development of innovative products, PMDA, based on its experience in review, cooperated on the research that examined the standards for biological Ingredients to ensure the safety of raw materials for cellular and tissue-based products (Revision of Standards for Biological Ingredients; the notice was revised on September 26, 2014 and a related notice was issued on October 2, 2014).  PMDA worked with MHLW to develop shared research reports "Research on detection/risk of abnormal prion in cellular/tissue-based products and biological drugs," "Research on bacterial endotoxin test methods," and "Research on standards for bovine-derived materials", which were partial research reports of "Research of the safety of innovative drugs against viruses and infectious agents" (General/Shared Research Report FY 2013), the research project on regulatory science for drugs, medical devices, etc. supported by the Health and Labour Sciences Research Grants. The results of the "Research on standards for bovine-derived materials," together with the results of the initiative to facilitate development of innovative products described above, were used as data to support the need to revise standards for biological ingredients. Based on the results of these research projects, PMDA is considering developing 3 high-level guidelines (for tests of sterility, mycoplasma, and endotoxin) related to cellular and tissue-based products.  For the preparation of guidances for the evaluation of emerging technology medical devices and cellular and tissue-based products, PMDA cooperated with MHLW in establishing and issuing the guideline for cellular and tissue-based products (homologous iPS-cell-derived retinal pigment epithelial cells) issued as “Announcement of Guidance for the Evaluation of Emerging Technology Medical Devices/Cellular and Tissue-based Products” (PFSB/ELD/OMDE Notification No. 0912-2 dated September 12, 2014). (v)

Promotion of the use of Pharmaceutical Affairs Consultations on R&D strategy  PMDA had conducted preliminary reviews of cellular and tissue-based products (including gene therapy products) prior to the initiation of clinical trials to determine whether the quality and safety of the products conform to the guidelines. The preliminary reviews were abolished and replaced by pharmaceutical affairs consultations on R&D strategy in July 2011 for cellular and tissue-based products and medical devices and in July 2013 for gene therapy products. PMDA has promoted the use of the Pharmaceutical Affairs Consultations on R&D strategy by doing the following activities: issuance of notifications to inform relevant parties of consultation services as well as the new consultation category of cellular and tissue-based products established in accordance with the Act for Partial Revision of the Pharmaceutical Affairs Act enforced in November 2014; and provision of relevant information at academic conferences. As a result, 9 clinical trials of cellular and tissue-based products, including investigator-initiated trials by academia, were started in FY 2014 with the support of PMDA [for the results of Pharmaceutical Affairs Consultations on R&D strategy, see 2. (1) (vi)-d].  For preliminary reviews under the Cartagena Act, see 3.2.(1) New drugs (vi)-c.

- 106 -

Promotion of GLP/GCP/GPSP compliance assessments and clinical trials, etc.  PMDA took the following measures to promote the proper conduct of laboratory tests and clinical trials for drug and medical device applications for approval to secure the reliability of application data. (i)

Efficient GLP/GCP/GPSP inspections and data integrity assessments for new drugs, etc.  In collaboration with the Health and Labour Sciences Research Group conducting “Research on GCP-related activities for the vitalization of clinical trials,” PMDA examined foreign compliance assessments to develop inspection methods in consideration of risk. As one such activity, a questionnaire survey was conducted targeting GCP-related regulatory authorities in Europe, and the results of the survey were documented.  Office of Conformity Audit obtained information on products for which an application for approval was planned to file, at an earlier stage by having its staff participate in pre-review consultations introduced in FY 2014, and developed systems to exchange or share information of planned reviews/inspections with the relevant offices of the Review Division.  In April 2014, PMDA conducted a questionnaire survey that asked companies how electronic records were being used and whether Clinical Data Interchange Standards Consortium (CDISC) standards had already been introduced. The results of the survey were presented at a GCP/GPSP workshop held in January 2015.  With the cooperation of the Advanced Review with Electronic Data Promotion Group, Office of Clinical and Non-clinical Compliance started to investigate inspection methods using CDISC standard data (SDTM, ADaM) to be obtained by the Review Division and into risk-based methods, etc. In FY 2014, issues to be discussed were determined and prioritized.  PMDA started a pilot inspection using the GCP Management Sheet (tentative name) in June 2014 with the participation of 12 companies that are major applicants for marketing approval as well as interested companies, and had investigated 19 products of 11 companies by the end of November 2014. In October 2014, PMDA exchanged opinions with industry associations about the adoption and effective use of the GCP Management Sheet (tentative name).

(ii)

Efficient GLP/GCP/GPSP inspections and data integrity assessments for medical devices  The Offices of Medical Devices and Office of Non-clinical and Clinical Compliance held joint meetings to share information on the progress of both reviews and inspections, and conducted GLP/GCP/GPSP compliance assessments in an appropriate and timely manner. In FY 2014, GCP on-site inspections were conducted for 5 new medical devices (including 4 priority review products) using appropriate procedures under the relevant system.  PMDA participated in the Task Force for Medical Device Regulations to collect the industry’s opinions on specific requirements for application, etc.  From April 2014, applicants are required to submit a “checklist for application acceptance” when filing an application for generic medical devices. Office of Conformity Audit and Offices of Medical Devices started to discuss with medical devices industry which items, regarding the preparation of documents for GLP/GCP/GPSP compliance assessments, needed to be added to the “checklist for application acceptance”.

- 107 -

(iii)

Efficient GLP/GCP/GPSP inspections and data integrity assessments for cellular and tissue-based products  In November 2014, PMDA established procedures and SOPs for GLP/GCP/GPSP compliance assessments of cellular and tissue-based products. In addition, PMDA established procedures for selecting studies to be reviewed and for selecting inspecting medical institutions for GCP on-site inspections.

(iv)

Efficient GLP inspections and data integrity assessments  A PMDA staff member became a vice chair of OECD Working Group on GLP. In addition, PMDA dispatched an employee to OECD as the person in charge of GLP, and thereby introduced PMDA’s knowledge and know-how in international GLP-related activities.  Toward the international harmonization, PMDA reviewed and revised the Procedures for GLP related to the categories of evaluation results, findings, test items, etc., and the revision was notified in November 2014.

(v)

Efficient GLP/GCP/GPSP inspections and data integrity assessments for re-examination (including use-results evaluation)  In collaboration with the pharmaceutical industry, PMDA took the following 2 measures to improve the efficiency of GLP/GCP/GPSP compliance assessments by shortening the inspection time and increasing the efficiency of inspection: (i) reduction of duplicated confirmation process by utilizing the results of past inspections; and (ii) continuation of a pilot assessment using the safety information management sheet (process inspection).  PMDA shared problems revealed by inspections with the pharmaceutical industry in periodic opinion exchange sessions, and provided information obtained from these sessions at the GCP/GPSP workshop held in January 2015.  In terms of medical devices, opinions were exchanged among MHLW, the Offices of Medical Devices, and the medical device industry about data that should be submitted when applying for a use-results survey and the implementation of GLP/GCP/GPSP compliance assessments. In addition, PMDA participated in the Task Force for Medical Device Regulations to facilitate the efficient operation of the relevant system.  At the GCP/GPSP workshop held in January 2015, PMDA presented the issues revealed by GLP/GCP/GPSP compliance assessments for re-examination of medical devices.

(vi)

Proper conduct of clinical trials, etc.  Due to the enforcement of the Act for Partial Revision of the Pharmaceutical Affairs Act in November 2014, PMDA revised the procedures for consultations by taking the following measures: (i) consultations on GCP/GLP/GPSP and simple consultations on GCP/GLP/GPSP were introduced; (ii) new subcategories of consultation on GCP/GLP compliance for cellular and tissue-based products and consultations on GCP/GLP/GPSP were added to the existing category of consultation on GCP/GLP compliance; and (iii) contact point for consultation services, consultation procedures, and necessary forms were revised.  PMDA held GCP/GPSP workshops in Tokyo and Osaka and presented findings frequently revealed by document-based GLP/GCP/GPSP compliance assessments, GCP on-site inspections, and GLP/GCP/GPSP compliance assessments for re-examination, to promote the proper conduct of clinical trials. Materials used for the workshops were posted on the PMDA website to make them known to all related parties. In addition, PMDA representatives gave lectures about GLP/GCP/GPSP compliance assessments at academic conferences attended by healthcare professionals, exchanging opinions with related parties. - 108 -

 PMDA responded to any invitation for lecture on GCP/GLP/GPSP, etc., in so far as it could, to facilitate the understanding of GCP/GLP/GPSP compliance assessments. Number of Participants in GCP Workshops Venue

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Tokyo

1,048

1,086

1,254

1,189

1,242

Osaka

455

418

471

404

448

Total

1,503

1,504

1,725

1,593

1,690

Number of GLP/GCP/GPSP Compliance Assessments by Fiscal Year FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

2,359

2,437

2,737

2,610

2,396

251

280

286

364

370

Generic drugs

1,040

1,118

1,188

1,086

1,080

Medical devices

1,068

1,039

1,263

1,160

946

GCP on-site inspections

171

149

197

242

236

New drugs

158

140

187

222

221

10

8

9

15

10

3

1

1

5

5

138

111

127

80

79

135

109

112

71

74

3

2

15

9

5

135

109

112

71

74

135

109

112

71

74





















30

32

39

21

40

26

23

29

18

27

4

9

10

3

13

Document-based assessments New drugs

Generic drugs Medical devices Document-based assessments for re-examination New drugs New medical devices GPSP inspections New drugs New medical devices Document-based assessments for re-evaluation GLP inspections Drugs Medical devices

Note: The numbers of document-based assessments (excluding those for medical devices), GCP on-site inspections (excluding those for medical devices), document-based assessments for re-examination (excluding those for medical devices), GPSP inspections (excluding those for medical devices), document-based assessments for re-evaluation and GLP inspections represent numbers of products for which inspection/assessment was completed. The numbers of document-based assessments, GCP on-site inspections, document-based assessments for re-examination and GPSP inspections (all for medical devices) represent the numbers of products for which inspection/assessment and review was completed. (Products for which inspection/assessment is completed from January 2014)

Promotion of GMP/GCTP/QMS inspections (i)

Efficient GMP/GCTP/QMS inspections a.

Background of GMP/GCTP/QMS inspections  In accordance with the amended Pharmaceutical Affairs Act that came into effect in FY 2005, both manufacturing and quality control procedures used by manufacturing sites for drugs etc. must comply with the requirements specified in the Ministerial Ordinance on GMP for Drugs and Quasi-drugsa and/or Ministerial Ordinance on QMS for Medical Devices and In vitro Diagnosticsb, in order to satisfy regulatory requirements for approval. Therefore, in addition to the manufacturing sites already licensed by the Minister of Health, Labour and Welfare, the following manufacturing sites became subject to inspection by PMDA: (1) foreign manufacturing sites related to all - 109 -

products that require regulatory approval; and (2) domestic manufacturing sites for new drugs, new medical devices or Class IV medical devices (high-risk medical devices such as pacemakers).  In accordance with the Act for Partial Revision of the Pharmaceutical Affairs Act, which came into effect in November 2014, "Pharmaceutical Affairs Act" was changed to "Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (PMD Act)," in which the term “cellular and tissue-based products” was defined. Before the revision, a license was required to manufacture medical devices and in vitro diagnostics; after the revision only registration is required (change from license system to registration system).  The Ordinance on QMS was also revised, and manufacturers were newly included in targets for QMS inspections. QMS inspections for medical devices with no certification standards, which had previously been conducted by prefectural governments, are now to be conducted by PMDA.  GCTP Ordinancec and Regulations for Buildings and Facilities for Pharmacies and Manufacturing Establishments for cellular and tissue-based products were established and came into effect in 2014. PMDA issued "Questions and Answers Related to Good Manufacturing Practice for Cellular and Tissue-based Products" (PFSB/CND Notification No. 0317-1 dated March 17, 2015) to promote the efficient conduct of manufacturing control and quality control at manufacturing sites. a

Ministerial Ordinance on Good Manufacturing Practice (GMP) for Drugs and Quasi-drugs (MHLW Ministerial Ordinance No.179 of 2004) b Ministerial Ordinance on Quality Management System (QMS) for Medical Devices and In vitro Diagnostics (MHLW Ministerial Ordinance No.169 of 2004) c Ministerial Ordinance on Good Gene, Cellular, and Tissue-based Products (GCTP) (MHLW Ministerial Ordinance No.93 of 2014) Note 1: GMP (Good Manufacturing Practice): Note 2: QMS (Quality Management System): Note 3: GCTP (Good Gene, Cellular, and Tissue-based Products Manufacturing Practice)

b.

Establishment of the inspection system  PMDA had 47 GMP/GCTP/QMS inspectors (including inspectors in the Kansai Branch) as of April 1, 2014. In the areas of drugs and quasi-drugs, PMDA proceeded with building a system to supervise quality management, such as by setting up an inspection quality assurance group, based on the accession to the Pharmaceutical Inspection Cooperation Scheme (PIC/S: An international organization on GMP inspections, centering on European countries). In addition, PMDA enriched training programs through the use of external workshops etc., in order to strengthen the inspection system for cellular and tissue-based products.  The administrative processing status of GMP/GCTP/QMS inspections in FY 2014 is shown below:

- 110 -

GMP/QMS Inspections under the Pharmaceuticals and Medical Devices Act FY 2009 Applications Drugs* In vitro diagnostics Quasi-drugs Medical devices Cellular and tissue-based products

Withdrawn

In progress

Applications

Withdrawn

In progress

2,228

2,000 (297)

71

969

1,159

1,324 (131)

120

684

115

107 (3)

5

36

66

81 (0)

2

19

3

3(0)

0

2

1

0 (0)

1

2

1,285 (66)

39

237

896

944 (54)

40

149













115

1,244

2,122

2,349 (185)

163

854

Withdrawn

In progress

Applications

Withdrawn

In progress



— 3,395(366) FY 2011

Applications Drugs* In vitro diagnostics Quasi-drugs Medical devices Cellular and tissue-based products

Total

Completed

FY 2012

1,283 (185)

31

908

1,582

1,593 (198)

40

821

73

85 (0)

1

6

64

48 (0)

0

16

0

0 (0)

0

2

6

2 (0)

2

3

697

765 (36)

24

57

999

954 (81)

3

37

















2,308

2,133 (221)

56

973

2,651

2,597 (279)

45

877

Withdrawn

In progress

Applications

Withdrawn

In progress

FY 2013

In vitro diagnostics Quasi-drugs Medical devices Cellular and tissue-based products

Total

Completed

1,538

Applications Drugs*

Completed

1,201

3,547

Total

Completed

FY 2010

Completed

FY 2014 Completed

1,508

1,415 (168)

75

875

1,877

1,672 (163)

51

1,030 (0)

52

67 (1)

0

7

65

38 (1)

0

27 (0)

3

3 (1)

0

4

5

6 (0)

0

2 (0)

988

883 (61)

11

193

755

512 (42)

18

225 (86)









0

0 (0)

0 (0)

0 (0)

2,551

2,368 (231)

86

1,079

2,702

2,228 (206)

69

1,284 (86)

* Excluding in vitro diagnostics. Note: Figures in parentheses represent the numbers of on-site inspections out of completed inspections.

- 111 -

 The administrative processing times of GMP/QMS inspections in FY 2014 are shown below: Median Processing Time of GMP/QMS Inspections FY 2009

FY 2010

Total processing time (Median)

PMDA processing time (Median)

Drugs* (days)

162

In vitro diagnostics (days)

110

Quasi-drugs (days) Medical devices (days)

FY 2011

Total processing time (Median)

PMDA processing time (Median)

Total processing time (Median)

PMDA processing time (Median)

91

118

63

147

77

56

117

62

83

38

154

108









142

56

145

69

113

21













Total processing time (Median)

PMDA processing time (Median)

Total processing time (Median)

PMDA processing time (Median)

Total processing time (Median)

PMDA processing time (Median)

Drugs* (days)

176

90

118

71

172

76

In vitro diagnostics (days)

100

36

106

66

147

102

Quasi-drugs (days)

219

71

272

71

166

96

Medical devices (days)

21

44

106

56

118

74

Cellular and tissue-based products (days)













Cellular and tissue-based products (days)

FY 2012

FY 2013

FY 2014

* Excluding in vitro diagnostics.

 The processing status of inspections of manufacturing facilities conducted in FY 2014 at domestic manufacturing sites licensed by the Minister, as based on the Regulations for Buildings and Facilities for Pharmacies, Manufacturing Sites, etc., is shown below. Since the enforcement the registration system in accordance with the PMD Act, no inspections of manufacturing facilities have been conducted for medical devices or in vitro diagnostics. Number of Inspections of Buildings and Facilities for Domestic Manufacturing Sites

Drugs*

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

20 (19)

25 (19)

15 (9)

9 (4)

25 (11)

In vitro diagnostics

1 (1)

3 (3)

1 (1)

3 (3)

0 (0)

Medical devices

3 (3)

0 (0)

2 (1)

0 (0)

2 (2)









1 (1)

24 (23)

28 (22)

18 (11)

12 (7)

28 (14)

Cellular and tissue-based products Total * Excluding in vitro diagnostics.

Note: Values include withdrawn applications. Figures in parentheses represent the numbers of on-site inspections out of completed inspections.

 PMDA conducts for-cause inspections, questioning, and sampling at domestic manufacturers etc., under instructions from the MHLW. The number of for-cause inspections conducted in FY 2014 is shown below:

- 112 -

Number of For-cause Inspections (Domestic Manufacturers) FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Drugs*

6

12

13

6

5

In vitro diagnostics

2

3

1

1

0

Medical devices

1

0

0

0

0

Cellular and tissue-based products









0

Total

9

15

14

7

5

* Excluding in vitro diagnostics.

 PMDA conducts simple consultations on GMP/GCTP/QMS inspections. The number of simple consultations on GMP/GCTP/QMS inspections conducted in FY 2014 is shown below. There was an increase in number of simple consultations on QMS to accommodate the PMD Act. Number of Simple Consultations Conducted for GMP/QMS Inspections FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Drugs*

36

44

38

44

32

In vitro diagnostics

0

0

0

0

0

Quasi-drugs

1

0

0

0

0

Medical devices

6

6

8

3

51

Cellular and tissue-based products









0

Total

43

50

46

47

83

* Excluding in vitro diagnostics.

c.

Promotion of on-site inspections of foreign manufacturing sites  The number of on-site inspections of foreign manufacturing sites that were initiated in FY 2005 is shown below: On-site Inspections of Foreign Manufacturing Sites of Drugs by Region Europe

North, Central and South America

Asia/Oceania

Africa

Total

FY 2005

2

8

2

0

12

FY 2006

13

20

2

1

36

FY 2007

22

22

8

0

52

FY 2008

31

19

32

0

82

FY 2009

39

20

47

0

106

FY 2010

12

24

29

0

65

FY 2011

9

7

45

0

61

FY 2012

14

14

38

0

66

FY 2013

12

10

42

0

64

FY 2014

20

3

51

0

74

Note: Breakdown of FY 2014: Europe, France, Spain, Italy, Belgium, Austria, Germany, Turkey, Hungary, Cyprus, Latvia, Slovakia; North, Central and South America, the United States (including Puerto Rico); Asia, Oceania, China, India, South Korea, Taiwan, Thailand, Vietnam, Malaysia

- 113 -

On-site Inspections of Foreign Manufacturing Sites of Medical Devices by Region Europe

North, Central and South America

Asia/Oceania

Africa

Total

FY 2005

1

1

0

0

2

FY 2006

5

10

0

0

15

FY 2007

1

10

0

0

11

FY 2008

13

17

0

0

30

FY 2009

3

28

5

0

36

FY 2010

8

19

1

0

28

FY 2011

4

15

1

0

20

FY 2012

11

22

4

0

37

FY 2013

4

12

10

0

26

FY 2014

5

5

19 (2)

0

29 (2)

Note: Breakdown of FY 2014: Europe, Ireland, UK, Italy, India; North, Central and South America, the United States (including Puerto Rico), Mexico; Asia, Oceania, China, South Korea, Singapore, Taiwan, Malaysia

 The number of inspections of manufacturing facilities conducted in FY 2014 at foreign manufacturing sites based on the Regulations for Buildings and Facilities for Pharmacies and Manufacturing Establishments is shown below. Since the enforcement the registration system in accordance with the PMD Act, no inspections of manufacturing facilities have been conducted for medical devices or in vitro diagnostics. Number of Inspections of Buildings and Facilities for Foreign Manufacturing Sites FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Drugs*

230

579

530

383

384

In vitro diagnostics

27

60

68

79

23

Quasi-drugs

26

72

62

58

36

Medical devices

677

1,187

1,751

1,453

722

Cellular and tissue-based products Total









0

960

1,898

2,411

1,973

1,165

* Excluding in vitro diagnostics. Note: Values include withdrawn applications. All inspections were done on a document basis.

 PMDA conducts for-cause inspections, questioning, and sampling at foreign manufacturers etc., under instructions from MHLW. The number of for-cause inspections conducted in FY 2014 is shown below: Number of For-cause Inspections (Foreign Manufacturing Sites) FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Drugs*

1

1

4

2

1

In vitro diagnostics

0

0

0

0

0

Medical devices

4

1

1

0

0

Cellular and tissue-based products









0

Total

5

2

5

2

1

* Excluding in vitro diagnostics.

- 114 -

Number of On-site GMP Inspections of Foreign Manufacturing Sites of Drugs by Country Region

Europe

North, Central and South America

Asia/Oceania

Country

FY 2007 FY 2008 FY 2009 FY 2010 FY 2011 FY 2012 FY 2013 FY 2014

Total

France

6

5

6

1

3

2

1

3

27

Denmark

3

2

2

0

0

0

2

0

9

Ireland

2

5

3

2

0

1

1

0

14

UK

4

1

3

0

0

1

1

0

10

Netherlands

1

1

5

0

0

2

0

0

9

Spain

3

1

1

0

0

0

0

1

6

Italy

2

5

3

2

0

1

2

3

18

Belgium

1

2

4

3

1

0

2

3

16

Austria

0

2

2

0

1

2

0

1

8

Finland

0

0

2

0

0

1

0

0

3

Germany

0

3

7

0

3

1

0

1

15

Sweden

0

1

0

0

0

0

1

0

2

Romania

0

1

0

0

0

0

1

0

2

Czech

0

0

0

0

0

1

0

0

1

Ukraine

0

0

0

0

0

1

0

0

1

Lithuania

0

0

0

0

0

1

0

0

1

Slovenia

0

2

1

0

0

0

0

0

3

Portugal

0

0

0

3

0

0

0

0

3

Greece

0

0

0

0

1

0

0

0

1

Turkey

0

0

0

1

0

0

0

1

2

Iceland

0

0

0

0

0

0

1

0

1

Hungary

0

0

0

0

0

0

0

3

3

Cyprus

0

0

0

0

0

0

0

1

1

Latvia

0

0

0

0

0

0

0

2

2

Slovakia

0

0

0

0

0

0

0

1

1

Subtotal

22

31

39

12

9

14

12

20

159

USA

22

14

18

23

6

14

8

3

108

Canada

0

2

2

1

0

0

1

0

6

Mexico

0

1

0

0

1

0

0

0

2

Argentina

0

2

0

0

0

0

0

0

2

Brazil

0

0

0

0

0

0

1

0

1

Subtotal

22

19

20

24

7

14

10

3

119

China

5

11

25

10

20

16

18

23

128

India

1

12

4

7

4

4

3

4

39

Singapore

2

4

0

0

0

0

2

0

8

South Korea

0

3

9

10

18

14

11

13

78

Indonesia

0

0

0

0

0

1

0

0

1

Taiwan

0

2

6

1

1

2

6

6

24

Thailand

0

0

2

0

1

0

2

1

6

Vietnam

0

0

0

1

1

0

0

3

5

Israel

0

0

0

0

0

1

0

0

1

New Zealand

0

0

1

0

0

0

0

0

1

Malaysia

0

0

0

0

0

0

0

1

1

8

32

47

29

45

38

42

51

292

52

82

106

65

61

66

64

74

570

Subtotal Grand Total

Note 1: Excluded are for-cause inspections at foreign manufacturing sites under Article 75-4 of the PMD Act. Note 2: Puerto Rico was included in the USA.

- 115 -

Number of On-site QMS Inspections of Foreign Medical Devices Manufacturing Sites by Country Region

Country

Total

Ireland

0

6

0

4

1

3

0

1

15

UK

0

1

0

0

1

0

1

2

5

Italy

0

2

0

2

1

1

0

1

7

Netherlands

0

1

0

1

0

0

0

0

2

Switzerland

0

1

1

0

0

0

1

0

3

Spain

0

1

0

0

0

1

0

0

2

Europe

North, Central and South America

FY 2007 FY 2008 FY 2009 FY 2010 FY 2011 FY 2012 FY 2013 FY 2014

France

1

1

1

1

1

4

0

0

9

Denmark

0

0

1

0

0

0

0

0

1

Austria

0

0

0

0

0

1

0

0

1

Belgium

0

0

0

0

0

1

0

0

1

Turkey

0

0

0

0

0

0

1

0

1

Subtotal

1

13

3

8

4

11

3

4

47

USA

10

16

27

19

12

21

8

4

117

Mexico

0

1

0

0

1

0

0

1

3

Brazil

0

0

1

0

0

0

0

0

1

Canada

0

0

0

0

1

1

4

0

6

Costa Rica

0

0

0

0

1

0

0

0

1

Subtotal

10

17

28

19

15

22

12

5

128

China

0

0

3

0

0

1

1

6

11

South Korea

0

0

0

1

0

0

5

8

14

Thailand

0

0

0

0

0

1

0

0

1

Singapore

0

0

2

0

0

0

2

1

5

Philippines

0

0

0

0

0

2

0

0

2

Israel

0

0

0

0

1

0

1

0

2

Taiwan

0

0

0

0

0

0

1

3

4

UAE

0

0

0

0

0

0

1

0

1

Malaysia

0

0

0

0

0

0

0

1

1

India

0

0

0

0

0

0

0

1

1

Subtotal

0

0

5

1

1

4

11

20

42

11

30

36

28

20

37

26

29

217

Asia

Grand Total

Note 1: Excluded are for-cause inspections at foreign manufacturing sites under Article 75-4 of the PMDs Act. Note 2: Puerto Rico was included in the USA.

d.

Coordination between GMP/GCTP/QMS inspections and reviews  During the review process for drugs, quasi-drugs, and cellular and tissue-based products, the Office of Manufacturing/Quality and Compliance holds periodic meetings with the Review Division (once a month with Offices of New Drug) to exchange information on the progress of reviews and the quality of reviews related to manufacturing control and quality control, and thereby ensures that inspections are conducted at the appropriate times in the review process.  For applications for medical devices, QMS inspectors and reviewers share information at weekly meetings to check the progress of review and ensure that there are no discrepancies between the content of application documents and the specifications and test methods employed at manufacturing sites. Such collaboration is also maintained for reviewing medical devices designated for priority review or expedited review, where the progress is managed to ensure that QMS inspections do not affect the progress of reviews.

- 116 -

e.

For-cause inspections of registered certification bodies  As the regulatory authority governing registered certification bodies was transferred to PMDA from the MHLW, PMDA conducted for-cause inspections at 6 registered certification bodies on or after November 25, 2014.

(ii)

Building of the inspection system based on the Act on Safety of Regenerative Medicine a.

Building of the inspection system  In accordance with the Act on the Safety of Regenerative Medicine enacted in 2013 and enforced in 2014, the Office of Manufacturing/Quality and Compliance started to conduct inspections in order to ascertain conformity to the standards for buildings and facilities specified under Article 42 of the Act of Safety of Regenerative Medicine required for obtaining license/certification of manufacturing at cell processing centers, at the request of the Health Policy Bureau in MHLW or Regional Bureau of Health and Welfare. For-cause inspections are also to be conducted under instructions from the Health Policy Bureau of the MHLW. In FY 2014, on-site inspections of manufacturing facilities were started at Japanese cell processing centers that had submitted application for license/certification of manufacturing. To secure a sufficient number of inspectors, PMDA started to provide trainings in inspection methods to inspectors of the Office of Manufacturing/Quality and Compliance. PMDA is making efforts to obtain the number of inspectors needed in order to deal with all applications filed.

Number of Applications for License/Accreditation of Manufacturing Based on the Act on Securing of Safety of Regenerative Medicine, etc. FY 2014 Application

Processed

Withdrawn

Under inspection

Application for license of manufacturing (in Japan)

19

0

0

19

Application for approval of manufacturing (in foreign countries)

0

0

0

0

19

0

0

19

Total

Administrative Processing Time for Inspection for License/Certification of Manufacturing FY 2014 Median total processing time

Median PMDA processing time

Application for license of manufacturing (in Japan)





Application for approval of manufacturing (in foreign countries)





Number of For-cause Inspections Conducted by PMDA Region

FY 2014

Japan

0

Foreign countries

0

Total

0

- 117 -

b.

Establishment of inspection methods With respect to standards for cell processing centers under Article 42 of the Act on the Safety of Regenerative Medicine, PMDA prepared a checklist that explains what is required to meet the standards and presents PMDA’s viewpoints for inspection. The checklist is available on the PMDA website.

3.2.(2)

(i)

Support for the initiative to facilitate the development of innovative drugs, medical devices, and cellular and tissue-based products Establishment and revision of review standards, etc., for innovative products  Science Board was established in May 2012, in which PMDA reviewers exchange opinions with leading researchers in Japan about evaluation methods, etc., for advanced science and technologies. The Science Board completed activities for the first term at the end of FY 2014, and summarized the following 3 reports: "Current Perspective on Evaluation of Tumorigenicity of Cellular and Tissue-based Products Derived from induced Pluripotent Stem Cells (iPS) and iPSCs as Their Starting Materials," "Summary of Discussions on Non-clinical Pharmacology Studies on Anticancer Drugs," and "Summary of Discussion on the Assessment of the Current Status of Personalized Medicine Related to the Development and Regulatory Review."  Based on the initiative to facilitate development of innovative drugs, medical devices, and cellular and tissue-based products (a project funded by MHLW), PMDA conducted personnel exchange and information sharing by accepting specially appointed experts from research institutions and dispatching employees of PMDA to such research institutions, and supported not only the establishment of methods to evaluate the safety and efficacy of innovative drugs, medical devices, and cellular and tissue-based products but also the conduct of research projects for the preparation of guidelines needed to accelerate reviews. In addition, PMDA has worked to develop human resources with expertise in innovative technologies and regulatory science both in academia and in the Agency.  In order to properly conduct reviews, safety measures, and relief services for adverse health effects and to enhance the quality of these activities, PMDA is striving to promote regulatory science research on topics including the preparation of standards, guidelines and guidance, and research on how to conduct scientific prediction, evaluation, and judgment in PMDA’s operations. Among regulatory science researches conducted by PMDA, those designated by the Chief Executive are carried out as part of PMDA’s operations. Designation is based on research purpose, how research is related to PMDA’s operations, and comments from the Regulatory Science Research Evaluation Committee. In FY 2014, 13 projects (7 new projects and 6 ongoing projects) were selected for designated research and the results of 2 of these projects were published in academic journals (reposted).  In FY 2014, PMDA cooperated in the preparation of the government’s evaluation guidelines through the activities of 11 standards development projects and working groups as the Projects Across Multi-offices in PMDA. These activities were intended to promote product development, facilitate international collaborations for review standards etc., and accelerate reviews by making clear scientific principles for reviews of drugs and medical devices. Specifically, PMDA cooperated in the issuance of one notification from the Post-approval Manufacturing Changes Project and one administrative notice from the Global Clinical Trial Project.  In FY 2014, in order to share and investigate issues to be addressed by the Pediatric Drugs Working Group and Orphan Drug Working Group, which were Projects Across Multi-offices in PMDA, PMDA held teleconferences on a regular basis with experts from regulatory authorities in

- 118 -

the EU and the US. Members of the QbD Assessment Project participated in presentation sessions and panel discussions in workshops and international academic conferences, and thus explained how reviews and consultations are regarded in Japan and exchanged opinions with participants from foreign regulatory authorities toward international harmonization.  In Vitro Companion Diagnostic Devices Working Group in the Companion Diagnostic and Omics Project (hereinafter referred to as “Companion Diagnostics Devices WG”) held a PMDA workshop entitled “Companion Diagnostics - Regulatory Perspective and Challenges in Development and Evaluation” on September 1, 2014 in association with the administrative notice issued in the previous fiscal year. With the aim of enhancing the efficiency of development and reviews, the regulatory agency, industry, and academia exchanged opinions and discussed proposals from academia and questions raised by companies. The Companion Diagnostics Devices WG also examined “Methodology in Clinical Trials Using Genomic Biomarkers and Selection of Patients (draft)” prepared in a project (Nagoya City University Graduate School of Pharmaceutical Sciences; cancer and personalized medicine) supported by the initiative to facilitate the development of innovative drugs, medical devices, and cellular and tissue-based products. (ii)

Expansion of Pharmaceutical Affairs Consultations on R&D Strategy  Pharmaceutical Affairs Consultations on R&D strategy have been expanded since November 2014, and PMDA started to provide general advice on the development process (roadmap) and confirmatory clinical trial protocols to applicants including pharmaceutical companies on a trial basis. Furthermore, PMDA provided on-site introductory consultation and distributed brochures to relevant academic conferences for the purpose of publicity. Through collaboration between relevant offices, activities were carried out promptly and appropriately. Pharmaceutical Affairs Consultations on R&D Strategy were explained at relevant academic conferences by persons in charge from Tokyo Headquarters and the Kansai Branch.  PMDA promoted the use of Pharmaceutical Affairs Consultations on R&D Strategy (introductory consultations and pre-application consultations) at Kansai Branch by providing relevant information at the first anniversary symposium of Kansai Branch of PMDA in November 2014 and other opportunities. Pharmaceutical Affairs Consultations on R&D Strategy continued to be conducted with collaboration between the offices in Tokyo and the Kansai Branch.  In order to promote the establishment of an exit strategy at an early stage of development, in November 2014 PMDA started to offer consultations on R&D strategy for development program to advise on the development process (roadmap) on a trial basis, and thus enhanced the services offered by Pharmaceutical Affairs Consultations on R&D Strategy.

(iii)

Implementation of approval system based on characteristics of cellular and tissue-based products  In order to address the introduction of the conditional and time-limited approval system for cellular and tissue-based products, relevant offices collaborated in conducting Pharmaceutical Affairs Consultations on R&D Strategy, and provided relevant information at academic conferences, etc., and thus promoted the use of the system.

3.3 (i)

Safety measure services Proper assessment of reports on adverse drug reactions and medical device malfunctions  In order to improve the safety of marketed drugs, medical devices, and cellular and tissue-based products, and to enable patients and healthcare professionals to use them properly, PMDA - 119 -

efficiently collects and examines safety information, rapidly processes such information, devises appropriate safety measures, and promptly provides easy-to-understand safety information, to ensure that reviews and safety measures function in an integrated manner.  There were approximately 350,000 reports from companies on adverse reactions and infections attributable to drugs and approximately 32,000 reports on medical device malfunctions and infections attributable to medical devices submitted to PMDA from within and outside of Japan, and 17 reports on cellular and tissue-based product malfunctions and infections attributable to such products submitted to PMDA in FY 2014 (on and after enforcement of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics [PMD Act] on November 25, 2014). PMDA inputs the collected information into a database and shares such information with MHLW. In addition, PMDA monitors information on new measures taken for medical products by foreign regulatory agencies, including FDA and EMA, in order to consider and evaluate PMDA’s responses to products marketed in Japan on a daily basis, while reviewing academic literature for the purpose of analyzing, sharing and evaluating information on adverse drug reactions. In addition, PMDA is making efforts to implement comprehensive safety measures for drugs, medical devices, and cellular and tissue-based products in the post-marketing stage by enhancing cooperation between review offices and safety offices, and between the relief office and safety offices.  Based on daily reviews conducted by the product safety teams, PMDA assesses and reviews such reports on adverse drug reactions etc., and reports on medical device malfunctions etc., with the Safety Division of MHLW every week, seeks opinions from external experts and companies, and proposes necessary safety measures, such as revision of precautions in package inserts, to MHLW. Particularly urgent issues are responded to immediately in cooperation with MHLW.  The numbers of reports (in terms of the number of active ingredients for the drugs, and the number of generic names for the medical devices) submitted to MHLW for the products judged to require safety measures, such as revision of package inserts, were as follows.

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Drugs

339

185

198

160

100

Medical devices

19

17

15

14

4

Cellular and tissue-based products

-

-

-

-

0*1

Medical safety*2

5

6

6

6

6

*1 Number of reports after enforcement of the PMD Act on November 25, 2014 *2 "Medical safety" indicates the number of reports on near-incident cases, which are collected by the Japan Council for Quality Health Care. PMDA analyzes the data in the light of expertise for drugs and medical devices, after seeking opinions from experts, and reports the analysis results for safe use of drugs and medical devices to MHLW.

 Post-marketing safety measures taken by MHLW based on reports from PMDA were as follows (includes duplicated measures).

- 120 -

Drugs

Medical devices

Cellular and tissue-based products*

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Directions for revision to precautions in package insert

339

185

198

160

100

Posting articles and cases on PMDSI

32

41

36

40

29

Directions for revision to precautions in package insert or issuance of notifications on self-check

3

5

4

3

2

Posting articles on PMDSI

3

4

1

4

1

Directions for revision to precautions in package inserts or issuance of notifications on self-checking

-

-

-

-

0

Posting articles on PMDSI

-

-

-

-

0

* Number of reports after enforcement of the PMD Act on November 25, 2014

 As collaborative activities with the review offices, the Offices of Safety I and II evaluate adverse drug reactions reported via early post-marketing phase vigilance (EPPV) in collaboration with the reviewers of the product applications. Staff members of the safety offices also participate in the review process (clinical trial consultations, assessment of post-marketing surveillance plans, review of draft package inserts, Expert Discussions, etc.) for new drugs, new medical devices, and new cellular and tissue-based products. As for the collaboration with the Office of Relief Fund, information such as names of drugs and adverse drug reactions in judged cases for payment/non-payment of benefits is provided to the safety offices and is reflected to the safety measures. In accordance with the PMD Act, PMDA started to organize and examine data on applications for relief benefits on November 25, 2014.  In FY 2014, PMDA made the following efforts to appropriately collect, organize, and examine the reports on adverse drug reactions, medical device malfunctions etc., submitted by MAHs and medical institutions: a. Upgraded the information management system for adverse drug reactions and the safety measures support system b. Updated the master files in terms of names of drug products, adverse drug reactions, and MAHs c. Encouraged staff members to attend academic conferences (a total of 360 participants) to gather information d. Held regular liaison meetings on drugs, medical devices, and cellular and tissue-based products with MHLW (every week)  PMDA's information management system for adverse drug reactions and the safety measures support system will need to comply with the ICH-E2B (R3) guideline, which is the next international data exchange standard for adverse drug reaction reporting. In FY 2014, PMDA continued developing the reception system from FY 2013. In addition, PMDA began modifying the safety measures support system in FY 2014.  In accordance with the enforcement of Act for Partial Revision of the Pharmaceutical Affairs Act on November 25, 2014, PMDA was designated to receive reports from healthcare professionals on adverse reactions, infections, and malfunctions attributable to drugs or medical devices, and reports on adverse reactions associated with vaccination by healthcare professionals. PMDA developed the necessary system and structure for receiving such reports and made efforts to evaluate and discuss such matters more promptly.

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○ Collection of adverse reaction reports etc. 1-1) Number of reports relating to drugs FY 2010 Reports from MAHs

FY 2011

FY 2012

FY 2013

FY 2014

207,772

260,473

306,410

308,383

352,908

(34,578) (99) (169,994) (27) (940) (1,033) (1,101)

(36,641) (100) (220,410) (45) (841) (1,347) (1,089)

(41,254) (159) (261,823) (39) (884) (1,134) (1,117)

(38,329) (98) (266,506) (33) (962) (1,317) (1,138)

(49,198) (78) (300,191) (25) (1,099) (1,219) (1,098)

Reports from healthcare professionals

4,809

5,231

4,147

5,420

6,180

(1) Safety information reporting system (2) Vaccines*

3,656 1,153

3,388 1,843

3,304 843

4,067 1,353

4,782 1,398

212,581

265,704

310,557

313,803

359,088

(adverse drug reactions, in Japan) (infections caused by drugs, in Japan) (adverse drug reactions, out of Japan) (infections caused by drugs, out of Japan) (research reports) (foreign safety measure reports) (periodic infection reports)

Total

* For FY 2010 through 2012, the figures indicate the total numbers of reports on adverse reactions following vaccination with cervical cancer vaccine, Hib vaccine, pediatric pneumococcal conjugate vaccine, and influenza vaccines. From FY 2013 onward, the figures indicate the total numbers of reports on adverse reactions following vaccination with all vaccines.



PMDA began receiving individual case reports on adverse reactions attributable to quasi-drugs/cosmetics from April 1, 2014 and, up until the end of FY 2014, had received 561 reports on quasi-drugs and 116 reports on cosmetics.

Changes in the Number of Reports on Adverse Drug Reactions/Infections Reports from MAHs (ADRs etc., in Japan) Reports from MAHs (ADRs etc., out of Japan) Reports from healthcare professionals

FY 2010

FY 2011

FY 2012

- 122 -

FY 2013

FY 2014

Flowchart for Processing Adverse Drug Reaction Reports Healthcare professional

MAHs

PMDA Report

Collect, check, and analyze ADR information Consider safety measures

Information regarding overseas regulations and publications

Report

Receive ADR Reports

Hearing

Daily confirmation in a team

Corporate hearing Research and analyze necessary data

Further consider safety measures A/N

Notify considered issues /exchange opinions

Contact and meeting with MHLW A/N Contact and meeting with MHLW every week

Cases difficult to judge medical significance

Discuss with experts

Results of review/analyses

Share all info

Database

Urgently respond to issues that may inflict heavy damage on people

Compile information every 5 weeks and notify

Information provision via Internet

Disseminate information Implement safety measures

MHLW

Organize data

Instruct revision of package insert, give guidance for product improvement, issue recall, etc.

Plan /develop safety measures

Notify the results Pharmaceutical Affairs and Food Sanitation Council

Implement safety measures

1-2) Reports on adverse reactions following vaccination based on the Preventive Vaccination Act Pursuant to Article 14 of the Preventive Vaccination Act (Act No. 68 of 1948), PMDA has been conducting projects for investigating and organizing vaccination adverse reaction reports. As of November 25, 2014, vaccination adverse reaction reports are required to be submitted to PMDA in accordance with the revisions to the Preventive Vaccination Act and the Ministerial Ordinance for Enforcement of the Preventive Vaccination Act (see diagram, below). The number of vaccination adverse reaction reports received in FY 2014 was 1,398. Upon receiving vaccination adverse reaction reports, PMDA provides information to MAHs on suspect vaccines, and also issues directions on how to properly deal with such events under the PMD Act. Regarding reported cases of vaccination adverse reactions, PMDA conducted an interview with doctors who diagnosed the adverse reactions and those who gave the vaccination, as needed. In the cases of deaths and particular serious adverse reactions (e.g., anaphylactic reaction), PMDA sought opinions from experts regarding matters such as the validity of diagnosis for the adverse reactions and causal relationship between the adverse reactions and vaccines, thereby contributing to safety assessment of vaccines at MHLW.

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(i) Vaccination adverse reaction reports (integrated into adverse drug reaction reports defined by the pharmaceutical regulations)

(i) Adverse reaction reports (protector reports) Local government (iii) Provision of information on the adverse reaction reports (medical institution reports) (ix) Necessary measures (information provision, suspension of vaccination, etc.)

MHLW (Cooperation with National Institute of Infectious Diseases)

(viii) Opinion Pharmaceutical Affairs and Food Sanitation Council

Collaboration

(vi) Notification of investigation results, etc.

(v) Investigation

(iv) Commission of investigation and information organization

Pharmaceuticals and Medical Devices Agency (PMDA) (ii) Sharing the adverse reaction reports

Medical institutions (cooperation with investigation)

(vii) Reporting of investigation results, etc. and hearing of opinions

Health Sciences Council (Deliberation/evaluation)

1-3) Adverse drug reaction reports from patients The final recommendations drawn up in April 2010 by the Committee for Investigation of Drug-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Similar Sufferings highlighted the necessity of establishing a system which utilizes information from patients for safety measures. Also in the report submitted in January 2012 by the Investigational Sub-committee on Revision of Pharmaceutical Regulatory Systems of the Health Science Council, it was suggested that information on adverse drug reactions reported by patients themselves should be utilized. Based on these recommendations, PMDA set up the Direct Patient Reporting System for Adverse Drug Reactions on March 26, 2012 with reference to the outcomes of a study supported by the Health and Labour Sciences Research Grants from FY 2009 to FY 2011 ("Research on System for Receiving Adverse Drug Reaction Reports from Patients"), and has been conducting a project for receiving adverse drug reaction reports from patients on a trial basis via the Internet. In this project, adverse drug reaction reports are to be collected from patients who developed drug-induced adverse reactions or their family. The purpose of those reports is to improve safety measures for drugs through such means as identifying trends in occurrence of adverse reactions to drugs. Based on reports and questionnaire results collected during the trial period, PMDA intends to revise the reporting system and then formally start receiving reports. The number of adverse drug reaction reports from patients collected by FY 2014 is shown in the following table. In FY 2014, PMDA also released information on cases reported between April 2013 and March 2014. In October 2014, PMDA changed the display design of and added functions to the patient adverse drug reaction reporting system, based on results of a questionnaire survey of users of the system.

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Adverse drug reaction reports from patients (total number)*

FY 2011

FY 2012

FY 2013

FY 2014

30

154

122

91

* The number of reports is that at the end of each fiscal year. Reports may be withdrawn at the request of reporters. Reports on items not classified as adverse drug reaction reports from patients (i.e., items other than drugs and vaccine) are excluded.

1-4) PMDA's detailed investigation on reports from medical institutions (excluding vaccination adverse reaction reports) In the final recommendations drawn up in April 2010 by the Committee for Investigation of Drug-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Similar Sufferings, it was indicated that a system to conduct necessary investigations such as direct inquiries to healthcare professionals should be developed for death/serious cases among adverse drug reactions etc., reported from medical institutions. PMDA developed a system to conduct follow-up investigations of reports from medical institutions. In addition, PMDA considered the mechanism for feedback to MAHs etc., prepared necessary notifications, and then made inquiries to medical institutions regarding fatal cases starting on July 29, 2010. After that, PMDA has expanded cases subject to follow-up investigation in a step-by-step manner, and currently not only fatal cases but also cases of serious adverse reactions are subject to detailed investigation. The number of cases investigated by PMDA by the end of FY 2014 is shown in the following table.

Number of cases investigated by PMDA

FY 2012

FY 2013

FY 2014

663

862

1,067

For adverse drug reaction/infection reports investigated by PMDA through inquiries after being submitted by healthcare professionals to the Minister of Health, Labour and Welfare (and to PMDA from November 25, 2014 onwards), data on individual adverse reactions/infections in the reports were communicated, via the internet (dedicated server), to the MAHs of the primary suspect drugs. 2)

Number of reports relating to medical devices

Reports from MAHs (medical device malfunctions, in Japan) (medical device malfunctions, out of Japan) (infections caused by medical devices, in Japan) (research reports) (foreign safety measure reports) (periodic infection reports) Reports from healthcare professionals Total

- 125 -

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

15,874

17,192

23,643

27,303

32,490

(10,444) (4,367) (0) (27) (978) (58)

(8,637) (7,431) (0) (2) (1,060) (62)

(11,242) (10,992) (0) (3) (1,337) (69)

(12,791) (12,763) (0) (5) (1,669) (75)

(13,994) (16,624) (0) (20) (1,779) (73)

374

385

522

489

420

16,248

17,577

24,165

27,792

32,910

Changes in the Number of Reports on Medical Device Malfunctions/Infections Reports from MAHs (medical device malfunctions, in Japan) Reports from MAHs (medical device malfunctions, out of Japan) Reports from healthcare professionals

FY 2010

3)

FY 2011

FY 2012

FY 2013

FY 2014

Number of reports relating to cellular and tissue-based products

Reports from MAHs (product malfunctions, in Japan) (product malfunctions, outside of Japan) (infections caused by products, in Japan) (infections caused by products, outside of Japan) (research reports) (foreign safety measure reports) (periodic infection reports) Reports from healthcare professionals Total

FY 2010

FY 2011

FY 2012

FY 2013

-

-

-

-

FY 2014 17

-

-

-

-

12 0 0 0 0 0 5

-

-

-

-

0

-

-

-

-

17

* Reporting in respect of cellular and tissue-based products was initiated on November 25, 2014, the date of enforcement of the PMD Act. The figures for FY 2014 indicate the number of reports submitted on and after the date.

(ii)

Sophistication of safety measures a.

Use of electronic medical records etc.  In accordance with the Third Mid-term Plan, PMDA intends to perform pharmacoepidemiological analysis using digitized medical information such as medical information database and to advance the analytical method, to utilize digitized information for risk-benefit assessment or safety measures for drugs. Accordingly, through the "MIHARI Project", starting in FY 2009, based on results obtained during the period of the Second Mid-term Plan, PMDA is promoting "(1) actual operation of safety measures for drugs using electronic medical records" and "(2) advancement of risk analytical methods for adverse drug reactions" during the period of the Third Mid-term Plan, to proactively - 126 -

utilize investigation and analytical methods that use electronic medical records, including claims data and hospital information system data, for post-marketing drug safety evaluation (see figure below).

Direction of the MIHARI Project in the Third Mid-term Plan

PMDA’s Second Mid-term Plan (Excerpt) The Agency shall develop infrastructures for access to medical record databases and shall establish a system for conducting investigations on the incidence of adverse drug reactions, together with pharmaceutical and epidemiological analyses. Various trial investigations were conducted on the theme of known adverse drug reactions to discuss how to secure access to, understand the characteristics of, and utilize electronic medical record data.

PMDA’s Third Mid-term Plan 2014-2018 (Excerpt) The Agency shall conduct pharmacoepidemiological analyses using electronic medical information, such as the medical information database, and shall improve those analysis methods to promote their utilization for risk/benefit assessments of pharmaceuticals and for post-marketing safety measures. (i) Start of actual operation of safety measures for drugs using electronic medical records - Conduct pharmacoepidemiological investigation using electronic medical records - Pharmacoepidemiological investigation Expert Committee on the Use of and literature review

Electronic Medical Records etc., (ii) Improvement of analysis methods for adverse drug reaction risk for Safety Measures - Discuss the feasibility of new data source - Discuss the feasibility of new epidemiological investigation method

 For "(i) actual operation of drug safety measures using electronic medical records," PMDA will act to review literature on pharmacoepidemiology, investigation reports, etc. submitted by pharmaceutical companies, etc. regarding individual drug safety issues identified in the post-marketing phase, and to conduct investigations using electronic medical records as necessary, and to provide useful information for determination of safety measures to be implemented, such as revision of package inserts and issuance of notifications. In FY 2014, PMDA conducted an investigation to assess "risk of developing dyslipidemia after prescription of atypical antipsychotics" using claims data from health insurance societies. In addition, the Offices of Safety I & II and Offices of New Drugs collaboratively reviewed evidential literature submitted by pharmaceutical companies and investigated how drugs are actually prescribed.  For "(ii) improvement of analysis methods for adverse drug reaction risk," PMDA will discuss utilization of a new database of electronic medical records and new pharmacoepidemiological methods. In FY 2014, PMDA planned a trial survey, "Comparison of cardiovascular risk by antidiabetic drug classes,” using “National Claim Data" managed by the Health Insurance Bureau of MHLW as a new data source. PMDA asked the Bureau to provide claim data (special sampling), and gained the consent from the Bureau. Going forward, PMDA will receive, analyze, and evaluate the data.  In FY 2014, PMDA redesigned the MIHARI Project pages (e.g., rearrangement of the archives) within the PMDA website to make them more user-friendly, and sequentially disclosed the reports on respective trial surveys conducted during the effective period of the Second Mid-term Plan. - 127 -

Furthermore, in FY 2014, PMDA started to release “MIHARI Communication,” summaries of the survey results written in relatively simple language, as a communication tool so that healthcare professionals who are not specialized in pharmacoepidemiology could understand the pharmacoepidemiological studies conducted under the MIHARI Project.  The purpose of the "Project for developing the medical information database infrastructure” is to build a database that collects electronic medical information from 10 cooperating medical institutions nationwide, such as university hospitals, selected by MHLW through open recruitment. The project aims to establish a linked system for medical information databases (MID-NET®) covering 10 million patients, nationwide. In this project, PMDA is responsible for establishing the system in the cooperating medical institutions. The Agency also intends to develop its internal analysis system so as to utilize this database for safety measures (see diagram).

Project for Developing the Medical Information Database

Data will be retrieved or examined at 10 medical institutions as hubs to analyze/assess adverse drug reactions.

Utilization by PMDA and pharmaceutical companies/ researchers

Cooperating medical institutions (7 institutions) Tohoku University

Cooperating healthcare groups (3 groups) Kyushu University

NTT Hospital Tokushukai

Saga University

The University of Tokyo Kagawa University

Chiba University

Hamamatsu University School of Medicine

Kitasato Institute

 Development of the medical information database system was initiated in FY 2011 and was completed at 10 cooperating medical institutions by the beginning of April 2014. In FY 2014, PMDA promoted data accumulation in the database introduced to the 10 medical institutions and took the lead in conducting verification to control and improve the quality of stored data based on the results of the validation project that was carried out in FY 2013 (see below). In FY 2015, PMDA will continuously conduct validation to control and improve the quality of data and will promote trial utilization of medical information stored in the database for practical application in safety measures. However, data quality issues were identified by validation, and a certain amount of time is required to address the issues and ensure data quality. PMDA therefore reviewed the - 128 -

project plan with MHLW and changed the time for the full-scale launch of the medical information database, including the start of utilization by third parties such as pharmaceutical companies, from FY 2016 to FY 2018.  In FY 2013, PMDA started a data validation project to sophisticate analytical methods for the medical information database. This project is intended to evaluate the validity of outcome or exposure data extracted under certain conditions by cross-checking with medical records, etc., that are actually kept by each hospital. Examination of them will also lead to confirmation of the reliability of the medical information database toward full-scale utilization. In 7 medical institutions, validation starting in FY 2013 or FY 2014 will continue in FY 2015. In the remaining 3 medical institutions, validation will start in FY 2015. Progress and Plan for Project for Development of the Medical Information Database Infrastructure FY 2012

FY 2013

FY 2014

FY 2015

FY 2016

FY 2017

System development/introduction phase

System/data validation phase

Start of operation

Development of specifications

Procedure consideration/system establishment/announcement phase

PMDA analysis system developed/introduced One hospital with the system developed and introduced

System establishment project for practical use for safety measures Validation (Univ. of Tokyo)

Six hospitals with the system introduced

Validation (Kyushu Univ., Kagawa Univ., Saga Univ., Tohoku Univ., Hamamatsu Univ. School of Medicine, Tokushukai)

Three hospitals with the system introduced

Validation of pooled analysis

Validation (Chiba Univ., Kitasato Univ., NTT Hospital) Procedure consideration/system establishment/announcement phase - Consideration of use for use-results surveys - Consideration of various rules on utilization

b.

Collection of data on medical devices (implantable ventricular-assist devices [IVADs])  In accordance with the Third Mid-term Plan, based on discussions held up until the effective period of the previous Mid-term Plan, PMDA intends to reinforce a post-marketing information collection system, such as construction of a patient registration system (registry) for confirming long-term safety, in collaboration with relevant academic societies, companies, etc.  In FY 2014, PMDA continued with the "Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS)" project, which had been built and operated as a registry model project under industry-government-academia collaboration during the effective period of the previous Mid-term Plan. In FY 2014, PMDA began discussing with relevant academic societies, companies, etc. how the system will operate going forward. As of March 30, 2015, a total 449 patients (351 for IVAD, 98 for extracorporeal VAD) had been enrolled at 31 medical institutions participating in J-MACS. The number of enrolled patients, survival rates, and other data have been progressively updated on the PMDA website.

- 129 -

c.

Evaluation of medical device malfunctions  In accordance with the First and Second Mid-term Plans, PMDA intended to develop methods for evaluation of medical devices by ascertaining the incidence of device malfunctions that could unavoidably occur at a certain rate due to the nature of particular devices, rather than to structural defects, and it conducted pilot studies of an implantable central venous port system and coronary stents.  In FY 2014, PMDA published the final report on analysis results of a pilot study of coronary stents, followed for 5 years, in a total of 15,792 patients undergoing percutaneous coronary intervention (13,592) or coronary artery bypass graft (2,200) who were enrolled in 26 medical institutions. The report was released on the PMDA website.

 In addition, based on the pilot studies of an implantable central venous port system and coronary stents, PMDA summarized the points to be considered in conducting a study to evaluate medical device malfunctions, and released the report on its website. d.

Building the patient registration system (registry) for cellular and tissue-based products  In the "Project for developing a patient registration system for cellular and tissue-based products" at MHLW, a plan for building the "patient registration system" for registering information on patients using cellular and tissue-based products was prepared in order to enhance post-marketing safety measures for cellular and tissue-based products. To this end, under the Third Mid-term Plan, PMDA will build the patient registration system (registry) for verifying long-term safety in collaboration with relevant academic societies, companies, etc.  In FY 2014, PMDA prepared the specifications for the patient registration system and began constructing the system.

(iii) a.

Establishment of a post-marketing safety system through information feedback Provision of information via website and pharmaceuticals and medical devices information e-mail service (PMDA medi-navi)  PMDA promptly posts on its website important safety information issued on a daily basis, including revisions of precautions in package inserts, and distributes that information to healthcare professionals and relevant persons at companies by e-mail (PMDA medi-navi) upon issuance thereof. PMDA has also been making efforts to enhance and reinforce provision of information by posting various safety information, including package inserts, on its website. The PMDA Medical Product Information Web page, on which safety information had mainly been posted, was integrated into the PMDA website on March 15, 2015.  In FY 2014, a new drug category of behind-the-counter (BTC) drugs was added, as an option, to the search page for package inserts, in accordance with enforcement of the revised Pharmaceutical Affairs Act in June 2014; therefore package inserts for BTC drugs are now available on the PMDA website. Furthermore, “BTC drugs” was added to “Risk Category” on the search page, so that BTC drugs can be searched.  PMDA medi-navi provides safety information, by email, such as Dear Healthcare Professional Letters of Emergent Safety Communications, directions for revising precautions in package insert, and Class I recalls. To enhance public recognition of the service and increase the number of subscribers, PMDA reinforced PR activities by publishing articles on interviews with PMDA medi-navi users in professional journals, distributing an introductory video on PMDA medi-navi - 130 -

operation, providing leaflets on practical training to pharmacy faculties at universities, distributing leaflets at the time of issuance of a pharmacist licenses., and conducting PR activities at academic conferences.  Among 112,079 subscribers registered as of the end of FY 2014 (showing an increase of 9,289 in the course of FY 2014), approximately 36,400 were hospitals or clinics, 33,500 pharmacies, 7,300 dental clinics or other medical facilities, and 16,000 MAHs or distributors.  In June 2011, PMDA began providing "My Drug List for Safety Update" as an additional function of PMDA medi-navi. As of the end of FY 2014, a total 7,974 subscribers had been registered.  This service "My Drug List for Safety Update" enables a user to prepare a customizable drug list on the website. When the user registers particular drugs (My Drugs), a list of links to Web pages for package inserts, Interview Forms, Drug Guides for Patients, etc., for My Drugs is displayed. Additional functions include displaying a warning message when safety information (e.g., Dear Healthcare Professional Letters of Emergent Safety Communications) has been issued for any of My Drugs.

Pharmaceuticals and Medical Devices Information E-mail Service (PMDA medi-navi) Medical Institutions, MAHs, etc.

PMDA

MHLW, MAHs, PMDA

1) Prior registration of e-mail address Medical institutions, marketing authorization holders of drugs/ medical devices, etc.

4) Checking summary with e-mails

Information sources

New information 2) Posting information

3) Quick e-mail delivery

PMDA's website 5) Checking details on website

- 131 -

Breakdown of Contents of PMDA medi-navi Distributed in FY 2014 Contents of e-mails Dear Healthcare Professional Letters of Rapid Safety Communications (Blue Letter)

Number of cases 3

Recalls (Class I)

19

Pharmaceuticals and Medical Devices Safety Information

10

Drug Safety Update (DSU)

10

Revision of PRECAUTIONS of drugs

12

Revision of PRECAUTIONS of medical devices

2

Notification on self-check (medical devices)

0

PMDA Medical Safety Information

2

Approval information (medical devices)

6

Approval information (prescription drugs)

39

Notifications on drugs, Notifications on medical devices

35

Information on proper use of drugs

9

Information on drug risk under evaluation

10

Information on products submitted for public knowledge-based applications that are covered by insurance

4

Notice of decision on payment/non-payment of adverse reaction relief benefits

12

Risk Management Plan (RMP)

42

Others*1

20

*1 Except for RMP.

- 132 -

Number of Information Documents Released on the PMDA's Web Page as of the End of FY 2014 FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Prescription drugs

12,256

12,064

12,435

12,921

14,912

Medical devices

13,979

15,584

17,539

19,309

20,504

-

-

-

-

2

OTC drugs

9,884

10,136

10,158

10,234

11,127

BTC drugs

-

-

-

-

20

3,984

3,994

4,054

4,076

4,247

1,338

1,307

1,748

2,155

2,701

(2,311 products)

(1,951 products)

(2,453 products)

(3,409 products)

(4,842 products)

Guidance for persons who undergo vaccination*1

-

-

-

-

72 (74 products)

Safety information issued by MHLW

409

438

464

Package insert information*1

Cellular and tissue-based products

In vitro diagnostics Drug Guide for Patients*1

 Directions for revision of package inserts  Pharmaceuticals and Medical Devices Safety Information

 Press release Urgent safety information (by pharmaceutical companies)*2

494

519

257

272

168

178

69

69

24

24

25

27

30

-

-

-

6

117

71

81

91

101

111

Notification on self-check

50

50

51

51

52

Notification of revisions of labeling

33

41

45

48

50

Other related notification

74

83

93

111

145

Information about case reports on suspected ADR

175,360

210,412

254,392

292,720

338,224

Information about case reports on suspected malfunction

51,169

62,898

73,012

84,766

98,407

Notification related to preventive measures for medical accidents

68

77

87

96

108

PMDA Medical Safety Information

22

29

36

43

45

Manuals for management of individual serious adverse drug reactions

63

75

75

75

75

513 active ingredients

592 active ingredients

666 active ingredients

700 active ingredients

834 active ingredients

(1,034 products)

(1,189 products)

(1,314 products)

(1,416 products)

(1,652 products)

1,977

2,299

1,907

1,913

1,817

203

259

207

215

234

35,719

55,372

84,146

102,790

112,079

*3

Risk Management Plan (RMP)

Drug Safety Update (by Federation of Pharmaceutical Manufacturers' Associations of Japan [FPMAJ]) Notification of safety measures for medical devices

Information on approved new drugs

 Review reports, summaries of product applications Information on recalls of drugs or medical devices*4 Pharmaceuticals and Medical Devices Information E-mail Service (PMDA medi-navi) E-mails issued*5 Subscribers 1

* The numbers of package inserts and products are indicated. The numbers may decrease due to discontinuation of products. *2 In and after October 2011, the total number of Dear Healthcare Professional Letters of Emergent Safety Communications (Yellow Letter) and Dear Healthcare Professional Letters of Rapid Safety Communications (Blue Letter) issued is indicated. *3 Since the figures denote the total numbers of new or revised RMPs, the sum of the figures does not match the sum of the products. *4 Added as necessary; and deleted after two years, in principle *5 The figures are the total number of e-mails sent in each fiscal year. A single e-mail may contain several subject matters; therefore when counted according to the number of subject matters contained, the number of emails does not match the the figures in the columns.

- 133 -

b.

Provision of information on package inserts  PMDA constructed a system for handling notifications of package inserts, in line with enforcement of the Act for Partial Revision of the Pharmaceutical Affairs Act on November 25, 2014. As for pharmacy-compounded drugs and medical devices, PMDA modified the system so that an MAH can carry out the whole process on-line, from submitting the notification through posting the package insert on the PMDA website for MAHs, and it began accepting such information in line with enforcement of the Act. As for BTC drugs and cellular and tissue-based products, PMDA accepts notifications delivered by hand or sent by post.  By the end of FY 2014, PMDA had posted 14,912 package inserts for prescription drugs on its website. Upon issuance of notifications directing revisions of package inserts, PMDA posts such notifications on its website within 2 days and provides links to the corresponding package inserts.  Instructions for use of medical devices have been available on the PMDA website since FY 2005, with 20,504 instructions at the end of FY 2014. The Agency has also posted notifications directing revisions of instructions for use in conjunction with the issuance of such information, and has provided links to the corresponding instructions for use.  For cellular and tissue-based products, PMDA disclosed two package inserts following enforcement of the PMD Act on November 25, 2014.  For OTC drugs, PMDA started posting package inserts for OTC drugs on its website in March 2007. A total of 11,127 package inserts were accessible on the website as of the end of FY 2014.  For BTC drugs, PMDA started providing information on package insert for BTC drugs upon enforcement of the revised Pharmaceutical Affairs Act in June 2014. A total of 20 package inserts were accessible on the website as of the end of FY 2014.  For in vitro diagnostics, information on package insert has also been accessible since FY 2008. A total of 4,247 package inserts could be accessed from the website as of the end of FY 2014.

c.

Public release of adverse drug reaction cases and malfunction cases 1) Public release of adverse drug reaction cases  Since January 2006, PMDA has sequentially and publicly released adverse drug reaction reports submitted by MAHs in and after April 2004 on its website. In March 2012, PMDA expanded the scope of data items and reports to be released in order that the content could be more easily utilized by relevant parties. Currently, PMDA discloses the following data from adverse drug reaction reports in Japan within approximately 4 months of receipt: fiscal year and quarter of a year reported, reporting category, type, job category of reporter, investigation status, gender, age, primary disease, body height, body weight, suspected drug/brand name, reason for use, route of administration, single-dose, start date of administration, end date of administration, action against suspected drug, adverse events (onset date), presence/absence of recurrence due to re-administration, outcome, suspected concomitant drug, and other concomitant drug.  Among adverse drug reaction/infection reports from healthcare professionals to the Minister of Health, Labour and Welfare (to PMDA on and after November 25, 2014), those investigated by PMDA (e.g., inquiries) are also published. By the end of FY 2014, PMDA had posted 338,224 reports submitted up until November 2014.  In addition, in April 2012, PMDA started providing data sets of adverse drug reaction reports exported into the CSV format for public release, expanding the scope of data to be disclosed.

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Until then, the database had only been available in line-listing format. As a result, the data can now be used for research and studies. 2) Public release of information on medical device malfunction cases  For reports on medical device malfunctions submitted by MAHs in or after April 2004, the following data have been available on the PMDA website since March 2006: fiscal year reported, gender, age, outcome, generic name, condition of the medical device, and adverse events experienced by patient In total, 98,407 reports (submitted by September 2014) were published on the PMDA website by March 2014. 3) Access by MAHs to adverse drug reactions reports associated with their products  PMDA investigates information on adverse drug reactions which has been reported to the regulatory authorities, but not to the relevant MAHs, by medical institutions. The Agency has shared the investigation results with MAHs through a system which enables the MAHs to access and download ICH-E2B-compliant SGML files on such adverse drug reactions from the PMDA website, so that the MAHs can analyze the information and take measures accordingly. d.

Provision of the PMDA Request for Proper Use of Drugs If proper use (including dose and frequency as well as frequency of testing for adverse reaction monitoring) of a drug has already been recommended in its package insert or the company's document but the drug is not used properly or testing is not properly conducted, patients’ claims for relief benefits for adverse drug reactions may be rejected. In order to avoid such a case, PMDA started providing relevant information to healthcare professionals and related academic societies to promote proper use of drugs in FY 2010. PMDA provided one Request for Proper Use of Drugs in FY 2014.

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e.

Provision of information such as Drug Guide for Patients and manuals for management of individual serious adverse drug reactions 1) Provision of Drug Guide for Patients  In accordance with the "Guidelines for Developing the Drug Guide for Patients" (PFSB Notification No. 0630001 dated June 30, 2005), PMDA has reviewed and revised the Drug Guide for Patients while continuously obtaining advice from experts (a study supported by the Health and Labour Science Research Grants, titled "Research on how to provide patients and people with drug safety information").  To promote proper understanding of prescription drugs among patients and to enable detection of serious adverse drug reactions at an earlier stage, the Drug Guide for Patients has been available on the PMDA website since January 2006. In FY 2014, 102 Drug Guides for Patients (including 13 for generic drugs) were prepared for products newly marketed or products that required preparation of Drug Guide for Patients due to a revision of precautions in the package insert. A total of 2,701 Drug Guides for Patients (4,842 products) were posted by the end of FY 2014.

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Package Inserts for Prescription Drugs and Drug Guide for Patients

Drug Guide for Patients

Package Insert  Described in technical terms

 Described in clear and simple terms of high school level

 Comprehensive description of ADRs

 Showing subjective symptoms of serious ADRs and such ADRs by body part

 Information that needs attention of doctors and pharmacists

 Medication instructions for patients, e.g., medication regimen and missed dose instructions

Physicians, pharmacists, etc.  Can obtain accurate and comprehensive information on the drugs  Can obtain necessary information for proper use of the drugs

Patients and their family Explanatory & instructive materials for patients Proper prescription of drugs

 Can detect serious ADRs in an early stage  Can access information on proper use of drugs including how to take and instruction for storage condition

2) Provision of guide for persons who undergo vaccination  In accordance with "Guidelines for Developing the Guide for Persons Who Undergo Vaccination" (PFSB Notification No. 0331-7 dated March 31, 2014), PMDA discussed the guide for persons who undergo vaccination while continuously obtaining advice from experts.  "Guide for Persons Who Undergo Vaccination" has been available on the PMDA website since June 2014 to promote proper understanding of vaccines among persons who undergo vaccination and their families and to enable detection of serious adverse reactions at an earlier stage. In FY 2014, 29 Guides for Persons Who Undergo Vaccination were prepared for vaccines or toxoids against the following diseases or infections: influenza, yellow fever, mumps, polio (acute poliomyelitis), rabies, tuberculosis (BCG), diphtheria, varicella (chickenpox), meningococcal infection, Japanese encephalitis, pneumococcal infection, tetanus, Hib infection, rubella, measles, rotavirus gastroenteritis, hepatitis A, hepatitis B, diphtheria-pertussis-polio-tetanus combined vaccine (quadruple vaccine), diphtheria-pertussis-tetanus combined vaccine (triple vaccine), diphtheria-tetanus combined vaccine, and measles-rubella vaccine (MR vaccine). A total of 72 Guides for Persons Who Undergo Vaccination (74 products) were posted by the end of FY 2014. 3) Provision of manuals for management of individual serious adverse drug reactions  The manuals for management of individual serious adverse drug reactions prepared by MHLW in its initiative of comprehensive actions for serious adverse drug reactions have been made available on the PMDA website since November 2006. As of the end of FY 2011, manuals for a total of 75 adverse drug reactions were posted on the website. These manuals contain information for patients and their family members, which allow early detection of serious adverse drug reactions based on subjective symptoms, and also contain methods of their diagnosis and management for healthcare professionals. - 137 -

 The MHLW’s initiative of comprehensive actions for serious adverse drug reactions was terminated in FY 2010, and consequently, no information was added to the manual in FY 2014, but the manuals are being reviewed for a future revision. f.

Provision of medical safety information  PMDA has been extracting, evaluating, and examining near-incident cases associated with drugs, medical devices, and cellular and tissue-based products from the "Project Report on Collection of Medical Incident Information," "Annual Report of the Project to Collect and Analyze Near-incident Cases from Pharmacies," etc. published by the Japan Council for Quality Health Care. In FY 2014, 2,064 cases associated with drugs and 314 cases associated with medical devices were evaluated and the results were reported to MHLW. The details of 2,378 cases, for which deliberations had been completed by MHLW, were posted on the PMDA website and also shown in the following table.

Cases

Drugs

Medical Devices

Total applicable cases: 2,378 cases

2,064

314

1) Cases in which safety measures for the use of drugs, medical devices, or cellular and tissue-based products taken by MAHs, etc. were considered necessary or possible.

0

1

2) Cases in which measures have already been taken, or are currently under consideration, by the MAHs, etc.

18

35

3) Cases in which information is insufficient for the MAHs to consider safety measures, or cases that were likely to have resulted from human errors or human factors.

2,046

278

 Since November 2007, PMDA has issued PMDA Medical Safety Information, which is prepared by reference to opinions given by healthcare professionals such as physicians, pharmacists, nurses, and clinical engineers and specialists in fields such as ergonomics. It provides precautions with not only text but also easy-to-understand charts for healthcare professionals to use medical products safely. The information addresses events that were reported repeatedly or that led to issuance of revisions to package inserts, among near-incident cases, adverse drug reaction reports, and malfunction reports. In FY 2014, the following 2 issues of PMDA Medical Safety Information were posted on the web page.

g.

No.

Posted on

No.44

May 2014

No.45

August 2014

PMDA Medical Safety Information titles Medication Errors in Prescription Orders Precautions in Handling of Indwelling Venous Needles

Release of information on drug risks under evaluation  From the perspective of further enhancing safety measures for drugs, PMDA releases (1) risk information which PMDA monitors closely because it could lead to revision of Precautions in package inserts and (2) risk information which has attracted attention from foreign regulatory authorities, academic societies, etc. and is under evaluation by MHLW/PMDA. These types of information have been posted on the PMDA website, as appropriate, since July 2011, as preliminary information that could lead to implementation of safety measures such as revisions to Precautions. - 138 -

h.

Information provision in English  In order to promote dissemination of information on safety measures to foreign countries, PMDA translated into English "Frequently Asked Questions," information on revision of Precautions, and safety-related documents issued by MHLW in relation to the PMD Act and posted the information on the PMDA’s English website. The Agency also continued to translate into English the PMDA Risk Communications, the PMDA Medical Safety Information and the Pharmaceuticals, and Medical Devices Safety Information issued by MHLW and to post them on its English website.

i.

Responses to consultation requests from MAHs  In order to contribute to improvement of post-marketing safety measures by MAHs, PMDA provided various consultations (on drugs, medical devices, cellular and tissue-based products, and medical safety) requested by MAHs. These medical safety consultations were in particular related to revisions to package inserts, post-marketing risk management plans, creation of drug guides for patients, naming and labeling of drugs to prevent medical accidents, and improvements in products to prevent medical accidents based on analyses of near-incident cases.  The number of provided consultations by category for FY 2014 is shown below:

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Drugs

752

670

704

776

869

Medical devices

171

163

179

95

325

Medical safety

83

59

80

31

72

-

-

-

-

0

Cellular and tissue-based products*

* The figure indicates the number of consultations following enforcement of the PMD Act on November 25, 2014.

 Consultations for medical safety conducted in FY 2014 were mainly in respect of names of new drugs, packaging/labeling, and near-incident cases for drugs, medical devices, and cellular and tissue-based products. PMDA provided all consultations in an appropriate and prompt manner. j.

Consultations on drugs/medical devices  In order for general consumers and patients to use drugs and household medical devices safely and securely, PMDA offers a telephone consultation service.  In FY 2014, the number of persons receiving consultations was 11,556 (14,345 calls) for drugs and 370 (419 calls) for medical devices.  PMDA has extracted consultation cases on generic drugs from consultations on drugs and provided them to the secretariat of the Generic Drug Quality Information Review Group (a review group consisting of experts established at the National Institute of Health Sciences [NIHS]). Number of Consultations on Drugs/Medical Devices FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

Consultations on drugs [cases/day] (of which consultations on generic drugs)

8,846 [36.4] (617)

8,945 [36.7] (453)

9,679 [39.5] (493)

10,244 [42.0] (626)

11,556 [47.4] (543)

Consultations on medical devices [cases/day]

574 [2.4]

660 [2.7]

700 [2.9]

547 [2.2]

370 [1.5]

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Contents of Consultations on Drugs Contents of consultation

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

(1) Safety

5,553 (45.0%)

5,146 (41.3%)

5,267 (41.9%)

4,437 (35.2%)

5,401 (37.6%)

(2) Indications

890 (7.2%)

1.,147 (9.2%)

1,158 (9.2%)

1,302 (10.3%)

1,517 (10.6%)

(3) Dosage and Administration

784 (6.4%)

981 (7.9%)

1,259 (10.0%)

1,278 (10.1%)

1,345 (9.4%)

(4) Interactions

784 (6.4%)

986 (7.9%)

1,206 (9.6%)

1,426 (11.3%)

1,606 (11.2%)

(5) Ingredients

181 (1.5%)

199 (1.6%)

222 (1.8%)

255 (2.0%)

286 (2.0%)

Others

4,144 (33.6%)

4,014 (32.1%)

3,446 (27.5%)

3,919 (31.1%)

4,190 (29.2%)

12,336 (100.0%)

12,473 (100.0%)

12,558 (100.0%)

12,617 (100.0%)

14,345 (100.0%)

Total

Percentages of Consultations on Drugs by Therapeutic Category in FY 2014

Prescription drugs (n = 23,263)

Over-the-counter drugs (n = 1,151)

Nutrients and tonics 1.4% Dental drugs 1.4%

Others 14.0%

Dermatologic drugs 2.9%

Anti-allergy drugs 2.6%

Blood and body fluid agents 3.1% Central nervous system drugs 38.8%

Chinese herbal 3.5% Drugs for other metabolic disorders 3.7%

Respiratory tract drugs 3.6%

Others 5.8%

Vitamin preparations 4.8% Central nervous system drugs 44.7%

Chinese herbal 5.3% Dermatologic drugs 6.4%

Anti-allergy drugs 4.5% Antibiotics 4.5%

Sensory organ drugs 8.7%

Respiratory tract drugs 5.7% Cardiovascular drugs 7.6%

Gastrointestinal drugs 11.7%

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Gastrointestinal drugs 15.3%

* Including BTC drugs

Breakdown of Persons Receiving Consultations on Drugs in FY 2014 (by Profession etc.) Consultations on drugs (n = 11,556)

Consultations on generic drugs (n = 543)

Physicians/Dentists 医師・歯科医師 0.1% 0.1% その他 Others Pharmacists 薬剤師 0.6% 0.6% 2.3% 2.3%

Physicians/Dentists 医師・歯科医師 その他 Others 0.6% 0.6% 4.4% 4.4% 薬剤師 Pharmacists 3.1% 3.1%

General Consumers 一般消費者 91.9% 91.9%

General Consumers 一般消費者 97.0% 97.0%

Breakdown of Persons Receiving Consultations on Drugs in FY 2014 (by Age/Gender*) Consultations on drugs (n = 11,556)

Consultations on generic drugs (n = 543)

Persons

1800 1600

140

1400

120

1200

100

1000

80

Persons





800 600

60 40

400

20

200

0

0

Unknown/ Other

Unknown/ Other

Age 歳 Age 歳 男性 Men

男性 Men

女性 Women 不明・その他 Unknown/Other

Women 女性

Unknown/Other 不明・その他

* Persons taking/using drugs were counted by age/gender

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Contents of consultations on medical devices Contents of consultation

FY 2010

FY 2011

FY 2012

FY 2013

FY 2014

(1) Safety

78 (12.5%)

85 (12.4%)

106(14.5%)

68 (11.5%)

48 (11.5%)

(2) Indications

61 (9.8%)

69 (10.1%)

62 (8.5%)

43 (7.3%)

64 (15.3%)

(3) Performance

17 (2.7%)

24 (3.5%)

36 (4.9%)

13 (2.2%)

9 (2.1%)

(4) Method of use

12 (1.9%)

10 (1.5%)

7 (0.9%)

9 (1.5%)

6 (1.4%)

454 (73.0%)

498 (72.5%)

522 (71.2%)

458 (77.5%)

292 (69.7%)

622 (100.0%)

686 (100.0%)

733 (100.0%)

591 (100.0%)

419 (100.0%)

Others Total

Breakdown of Persons Receiving Consultations on Medical Devices in FY 2014 (by Age/Gender)** (n=223)

80 70 60

Persons

50

人 40 30 20 10 0 Unknown/ Other

Age 歳 Men 男性

Women 女性

Unknown/Other 不明・その他

** Consultations from general consumers and consultations received via the national consumer affairs center of Japan were counted by age/gender.

k.

Status of communication and use of transmitted safety information within medical institutions  To promote proper use of drugs and medical devices, it is important that necessary safety information, such as safety measures to be taken is appropriately communicated to and used by healthcare professionals in clinical settings. Accordingly, in FY 2010, PMDA initiated a survey to ascertain the status of procurement, communication, and use of safety information in medical - 142 -

institutions and pharmacies, and to discuss methods for providing information, and measures for procurement, communication, and use of information in clinical settings, in order that healthcare professionals in clinical settings can appropriately use such safety information. The survey results to date are available on the PMDA website, etc.  Based on a survey on good practices related to the status of procurement, communication, and use of drug safety information conducted in FY 2013, PMDA in October 2014 produced a leaflet designed to raise awareness of appropriate management of drug safety information in hospitals, etc. and circulated it to some 9,000 hospitals and 49,000 pharmacies, as well as distributing it in the Agency’s workshops, at academic conferences, etc.  In FY 2014, PMDA conducted the following two surveys: 1) a survey on the status of procurement, communication, and use of drug safety information in hospitals nationwide (8,481 institutions), and 2) a survey on the statuses of procurement, communication, and use of medical device safety information in 500 randomly sampled general hospitals. PMDA plans to release the survey results upon completion of compilation and to use the results and materials to promote proper procurement, communication, and use of information at medical institutions.

PMDA medi-navi, etc.

(i) Specialized journals, etc.

Other sources

Method of survey  Written questionnaire survey  On-site survey

Contact point

MAHs

Provision of information (Article 68-2 (1) of the PMD Act)

Medical institutions/ (Users of information) Pharmacies

(ii)

 Prescribing physicians  Pharmacists  Other concerned parties (iii)

Major points to be ascertained are: (i) Is information communicated appropriately within a medical institution or pharmacy? (ii) Is information communicated to right persons at the right time? (iii) Do medical institutions take appropriate actions (utilize information) at the right time upon receipt of information?

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Outline of surveys conducted to date FY

Title

Target

Remarks

January 13, 2011 to February 10, 2011

Questionnaire survey (response rate, 41.2%)

Hospitals nationwide 2011 Survey on the status of communication and use of drug (8,640 institutions) safety information

January 20, 2012 to February 10, 2012

Questionnaire survey (response rate, 25.9%)

Hospitals nationwide 2012 Survey on the status of procurement, communication, (8,541 institutions) and use of drug safety Half of all pharmacies information nationwide (26,915 institutions)

January 7, 2013 to February 28, 2013

Questionnaire survey (response rate, 53.4%)

January 7, 2013 to February 28, 2013

Questionnaire survey (response rate, 64.6%)

2013 Survey on the status of procurement, communication, and use of good practices on drug safety information

14 hospitals and clinics/pharmacies near the hospitals in Japan

October 2013 to February 2014

Door-to-door survey

Basic survey on the status of procurement, communication, and use of medical device safety information

9 hospitals/clinics in Japan

October 2013 to February 2014

Door-to-door survey

Hospitals nationwide 2014 Survey on the status of procurement, communication, (8,481 institutions) and use of drug safety information Survey on the status of procurement, communication, and use of medical device safety information

l.

Period

Hospitals nationwide 2010 Survey on the status of communication and use of drug (8,679 institutions) safety information

December 15, 2014 to Questionnaire survey March 13, 2015 (response rate, 57.8%)

500 general hospitals February 9, 2015 to (sampled randomly) March 13, 2015

Questionnaire survey (response rate, 40.0%)

Post-marketing safety measures workshops  At various workshops and academic conferences, PMDA gave presentations on its approaches to improving and strengthening safety measures, the safety measures including recent revisions of precautions in package inserts, the effective use of the PMDA’s web page, and PMDA's consultation services.

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3.4.

Promotion of regulatory science, internationalization, etc.

3.4.(1) (i)

Promotion of regulatory science Use of the Science Board  The Science Board (parent committee) was established in May 2012 as an external body to deliberate on the scientific aspects of drug, medical device, and cellular and tissue-based product reviews in order to more appropriately review products that utilize advanced science and technologies, and to advance regulatory science and reinforce collaboration and communication with academia and medical professionals with a view to future promotion of healthcare innovation. Materials relating to individual products may be used for discussion; therefore, meetings are closed to the public. Members are external experts in such areas as medicine, dentistry, pharmacy, and engineering.  The following three reports summarizing discussions were prepared and published in the First Term (up to March 2014) (reposted). 1) Current Perspective on Evaluation of Tumorigenicity of Cellular and Tissue-based Products Derived from induced Pluripotent Stem Cells (iPSCs)* and iPSCs as Their Starting Materials 2) Summary of Discussion on Non-clinical Pharmacology Studies on Anticancer Drugs 3) Summary of Discussion on the Assessment of the Current Status of Personalized Medicine Related to Development and Regulatory Review  In the Second Term, commencing April 2014, the parent committee determined issues to be discussed and new subcommittees were established according to the identified issues. As of March 31, 2015, 4 meetings of the parent committee had been held (2 of which were not actually meetings but document-based inquiries, and the following five subcommittees were established, in which specific discussions are being advanced. 1) Subcommittee on Placebo-controlled Studies (3 meetings held) 2) Subcommittee on Non-clinical Studies (4 meetings held) 3) Subcommittee on Application of Numerical Analysis to Non-clinical Evaluation (3 meetings held) 4) Subcommittee on Evaluation of Medical Devices in Pediatric Use (3 meetings held) 5) CPC (Cell Processing Center) Subcommittee (5 meetings held)  Minutes and materials of the subcommittee meetings are available on the PMDA website.

(ii)

Enhancement of regulatory science research  With respect to electronic submission of clinical trial data on new drugs, see 3. 2. (1) New Drugs (ii)-c.  In order to properly conduct reviews, safety measures, and relief services for adverse health effects and to enhance the quality of these activities, PMDA is striving to promote regulatory science research on topics including the preparation of standards, guidelines, and guidance and how to conduct scientific forecasting, evaluation, and judgment. Among regulatory science researches conducted by PMDA, those designated by the Chief Executive are carried out as part of PMDA’s operations. Designation is based on research purpose, how research is related to

- 145 -

PMDA’s operations, and comments from the Regulatory Science Research Evaluation Committee. In FY 2014, 13 projects (7 new projects and 6 ongoing projects) were selected for designated research and the results of 2 of these projects were published in academic journals (reposted).  Regarding innovative products, see 3.2. (2) (i).  PMDA conducted regulatory science research in cooperation/collaboration with external organizations such as academic institutions (26 projects used public research funds, such as Health and Labour Science Research Grants).  PMDA developed rules, formats, etc. for regulatory science research to match actual situations and established an ethical review board to improve the environment and systems for such research activities.  In a global clinical trial project, based on the "Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical Trials" (PFSB/ELD Administrative Notice dated October 27, 2014), a PMDA workshop "Global Clinical Trials – What Japan Can Do for Drug Development" was held in December 15, 2014. In the workshop, measures and issues to be considered in order for Japan to be able to participate in global clinical trials and to contribute to drug development in an effective and efficient manner were widely discussed among industry, government, and academia, based on specific cases.  PMDA established a system for concluding comprehensive partnership agreements to develop and reinforce the collaborative graduate school program, and established a framework for promoting joint research activities with academia, etc. (See (iv) Promotion of interaction with outside researchers and collaboration on investigative research, c. Development and expansion of collaborative graduate school program)  PMDA made presentations on the activities of the projects across multi-offices at academic conferences to publicize the activities and also exchanged opinions with experts regarding how to evaluate the activities. (iii) a.

Enhancement of staff training Lectures and guidance given by experts  In order to improve the quality of reviews and safety measures, PMDA provided its employees with the following training opportunities: special training programs including lectures in which experts invited from within and outside of Japan presented on product development activities at companies, and training in respective review parts with the cooperation of the National Institute of Health Sciences (NIHS) (24 sessions); training programs in laws and regulations, such as the Pharmaceutical Affairs Act, to learn about the regulatory system etc. (2 sessions); training programs in clinical study design, to learn biostatistics (12 sessions); and training programs in pharmacoepidemiology to learn features of pharmacoepidemiological study design (4 sessions).  A total 14 employees were dispatched to technical training programs conducted by external institutions (e.g., Pharmaceuticals Promotion Association's Regular Course, National Institute of Public Health, and Union of Japanese Scientists and Engineers). For acquisition of basic knowledge concerning medical devices, Class I and Class II medical engineering (ME) technical training courses were also provided (19 employees).

b.

Overseas dispatch  In order to develop human resources with the abilities to take the initiative in global negotiations and conferences, and to cooperate with representatives of other countries on establishing - 146 -

standards and guidelines, PMDA dispatched employees on long-term assignments to overseas institutions such as US FDA (5 employees).  To provide opportunities to learn about actual situations regarding review and safety measures provided by overseas authorities, PMDA dispatched employees for short-term attendance at training seminars, etc. conducted by overseas regulatory authorities (12 employees).

c.

On-site training  PMDA conducted on-site training programs, including visits to drug and medical device manufacturing facilities (8 facilities), IRBs of medical institutions, etc.  Product hands-on training using medical devices was provided (3 facilities).  To enable learning about technical knowledge and skills in radioactivity, radioactivity training, including hands-on training such as radioactivity measurement, was provided (11 employees).  To enable personnel to acquire knowledge about biological safety testing, training on biological safety testing, including hands-on training, was provided (4 employees).  Five employees were dispatched to two medical institutions for practical training under hospital pharmacists in order to enable reviews and safety measures in line with the reality of clinical practice. In addition, 12 employees were dispatched to 2 medical institutions to observe testing procedures, treatments, etc. using medical devices.

(iv) a.

Promotion of interaction with outside researchers and collaboration on investigative research Promotion of initiative to facilitate development of innovative drugs, medical devices, and cellular and tissue-based products  PMDA works to develop personnel who are familiar with regulatory science through personnel exchanges with research institutions, including universities, based on the initiative to facilitate development of innovative drugs, medical devices, and cellular and tissue-based products (a project funded by MHLW), and also promotes cooperation on research projects concerning methods for evaluating the efficacy and safety of products developed using advanced technologies. In FY 2014, PMDA conducted personnel exchanges with 24 universities, etc., accepted 26 researchers as specially appointed experts (including non-regular staff), and dispatched a total 38 employees (including non-regular staff).

b.

Promotion of collaborative graduate school program  In order to contribute to diffusion of regulatory science and provision of information, PMDA continued the Joint Graduate School Program. PMDA had concluded joint graduate school agreements with 19 universities by the end of FY 2014.  PMDA accepted 2 graduate students (one from the Gifu Pharmaceutical University Graduate School and the other from the University of Shizuoka Graduate School) as pre-doctoral fellows, to provide research education and guidance in accordance with “Implementation Guidelines for Acceptance of Pre-Doctoral Fellow at PMDA for FY 2014.” In a regulatory science promotion liaison meeting (July 2014), PMDA decided to accept students from joint graduate school without employment relationship under the new system.  As a part of efforts to increase recognition of regulatory science, PMDA arranged to send PMDA staff members to give lectures upon request from universities (FY 2014: 27 universities, 56 lectures).

- 147 -

c.

Development and expansion of collaborative graduate school program  In order to develop and enhance education and research guidance systems conducted by directors and staff members, PMDA ascertained the status of doctoral degree acquisition by technical employees (July 2014).  PMDA provided executives and employees with information on entrance examinations for joint graduate schools, via the Intranet.  PMDA collected reference information on the support system of the National Personnel Authority (system for supporting acquisition of degrees, etc.).  In a regulatory science promotion liaison meeting (January 2015), PMDA decided to go into partnership with the National Center for Global Health and Medicine and medical and research institutions that conduct high-quality clinical trials, in addition to universities, for the development of distinctive and varied collaborations under comprehensive agreements making the most of the advantages of individual institutions, in order to establish a broad cooperation and collaboration system beyond conventional research and educational activities. This was reported to the Advisory Council (March 2015).

3.4.(2)

Action taken for internationalization  PMDA should carry out international activities in a planned and systematic manner, being clearly aware of roles the Japanese regulatory agencies (MHLW and PMDA) should play, in order to fulfill the needs of the public in Japan and across the world. To this end, PMDA has been proactively promoting activities in line with the PMDA International Strategic Plan (developed in November 2011) clarifying the concrete goals to be attained in the next 5 to 10 years, and the "Road Map for the PMDA International Vision" (developed in April 2013) summarizing those concrete efforts. PMDA aims to steadily implement those efforts by following them up in a timely manner. In addition, in order to respond to the rapidly changing international situation, PMDA has been discussing a new international strategy incorporating the Plan and Vision, and aims to develop it in early FY 2015, maintaining consistency with the international strategy being discussed by MHLW.

(i)

Strengthening of cooperation with the U.S., the EU, Asian countries, and relevant international organizations  In order to exchange information concerning consultations, reviews, and post-marketing safety measures with authorities in the U.S. and the EU, PMDA, in collaboration with MHLW, has had discussions with the US FDA and the EC/EMA, gathered information on review systems, safety measures, etc., and also exchanged opinions on international cooperation.  PMDA dispatched employees as liaison officers to the U.S. Pharmacopeial Convention, the EMA, and Swissmedic, in order to gather information and exchange views.  PMDA dispatched 4 employees (2 employees for 3 months and 2 for 1 year) to the U.S. FDA to collect information and exchange opinions, and arranged dispatch activities for the following fiscal years.  PMDA participated in the 2nd Meeting of the Global Coalition for Regulatory Science Research (GCRSR) held in Montreal (Canada) in August 2014, and exchanged opinions on regulatory science research with regulators and academia in relevant countries, including the U.S., Canada, and Australia.

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 PMDA participated in the 8th International Summit of Heads of Medicines Regulatory Agencies held in Beijing (China) in November 2014 and exchanged opinions on regulatory affairs with regulators from relevant countries, including the US FDA and the EMA.  In 2013, executives of regulatory authorities from various countries established the International Coalition of Medicines Regulatory Authorities (ICMRA), an international collaborative organization to strategically control/coordinate various issues relating to international cooperation and harmonization and to support enhancement of the capabilities of regulatory authorities. Dr. Kondo, Chief Executive of PMDA, served as vice-chair of the Management Committee, leading discussions on international cooperation at the level of the heads of the respective regulatory authorities.  In April 2014, PMDA representatives visited the State of Bahrain and exchanged opinions on regulatory affairs with local regulators. At the same time, it was clarified that products approved in Japan would be covered by brief reviews in Bahrain.  In May 2014, PMDA held the 2nd Indonesia-Japan Symposium and exchanged opinions on quality control, drug recalls, and international activities in both countries. Concurrently, the two regulatory agencies held a bilateral conference and agreed to continue to reinforce their cooperative relationship, as had been done in the 1st Symposium.  In August 2014, PMDA held a Brazil-Japan seminar on regulations on pharmaceuticals and medical devices and exchanged views on improvement of review efficiency, GMP, pharmacopoeia, and opinions from industry. At the same time, a bilateral conference was held and both regulators agreed to the creation of a close collaborative relationship, going forward.  In October 2014, PMDA held the 2nd Thailand-Japan Symposium and exchanged opinions on new drug reviews, GMP, pharmacovigilance, and pharmacopoeia. Concurrently, a bilateral conference was held and it was decided to discuss regulatory systems for drugs and medical devices, and to promote future cooperation.  In October 2014, PMDA participated in the 2nd Joint Conference of Taiwan and Japan on Medical Products Regulation and exchanged opinions on regulations, such as drug and medical device regulations. At the same time, bilateral conference was held and continuous discussions on regulatory systems for drugs and medical devices and reinforcement of cooperative relationship were agreed.  In March 2015, PMDA held the 1st Malaysia-Japan Symposium and exchanged opinions on regulatory systems, in particular on drug reviews, pharmacopoeia, bio-products, etc. Concurrently, a bilateral conference was held and representatives from both parties exchanged opinions on the reference pharmacopoeia system and the orphan drug system, and agreed to the creation of a close collaborative relationship, going forward.  PMDA continued to have discussions with the regulatory authorities in countries participating in the above bilateral symposiums, using various opportunities such as meetings and conferences. Also, PMDA held bilateral conferences with US FDA, EMA in the EU, AIFA in Italy, MHRA in the UK, HSA in Singapore, TGA in Australia, MFDS in Korea, CFDA in China, etc., exchanged information and opinions, and discussed the status of progress on currently active cooperative projects and directions for further development.  PMDA conducted overseas GCP inspections, accompanied where possible by representatives of the regulatory authorities of the investigated countries, which had been contacted by PMDA in advance. When regulatory authorities of foreign countries conducted GCP inspections in Japan, PMDA staff in the Office of Non-clinical and Clinical Compliance accompanied the inspections, and exchanged and shared information on GCP inspection methods, etc. PMDA exchanged

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information with US FDA and EMA, centered on product issues in global clinical trials. PMDA discussed collaboration and improvement of circumstances regarding GCP through having employees in the Office of Non-clinical and Clinical Compliance participate in training programs, etc. conducted by US FDA and EMA.  PMDA participated in the Third and Fourth International Meetings of World Pharmacopoeias, which were held by WHO in April and October 2014, respectively, and cooperated in the preparation of Good Pharmacopoeia Practice as a member of the draft formulation group.  In November 2014, a bilateral conference between PMDA and the Chinese Pharmacopoeia Commission was held and both parties agreed to develop a mutual cooperative relationship on pharmacopoeia. (ii)

Strengthening of activities for international harmonization, etc.  In FY 2014, PMDA continued to actively participate in international harmonization initiatives for drugs such as ICH. PMDA improved the consistency of Japanese standards with international standards (e.g., standards for data prepared for regulatory submission) agreed by Japan, the U.S., and the EU in ICH Meetings, thereby promoting further international harmonization.  Toward development of international standards and international regulatory harmonization, PMDA actively participated in Steering Committee Meetings and Expert Working Group Meetings of ICH, Steering Committee Meetings and Expert Working Group Meetings of IGDRP, Steering Committee Meetings of APEC LSIF RHSC, and the Expert Working Group Meetings of PDG. Also, at the conference of the IPRF, which has been newly established for exchange of opinions/information among drug regulatory authorities, PMDA served as vice-chair and cooperated with the chair, Swissmedic, thereby contributing to efforts for reinforcing international harmonization among regulatory authorities. * ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use * IPRF: International Pharmaceutical Regulators Forum * IGDRP: International Generic Drug Regulators Pilot * APEC LSIF RHSC: Asia Pacific Economic Cooperation, Life Science Innovation Forum, Regulatory Harmonization Steering Committee * PDG: Pharmacopoeial Discussion Group  In FY 2014, in the area of medical devices, PMDA continued to actively participate in Management Committee Meetings and Working Group Meetings of IMDRF, Steering Committee Meetings and Working Group Meetings of HBD, ISO, etc. * HBD: Harmonization by Doing * ISO: International Organization for Standardization * IMDRF: International Medical Devices Regulators Forum  For IMDRF, Japan has served as chair of Management Committee Meetings since January 2015 (tenure of 1 year), and PMDA’s Associate Executive Director (for International Programs) has acted as a chair. In March 2015, PMDA hosted the 7th Management Committee Meeting at PMDA. The meeting adopted a resolution to start a new project, proposed by Japan, for internationally harmonizing terms for medical device malfunctions, with Japan acting as chair for the project.

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 For HBD, PMDA supported the activities of each working group as a co-chair with U.S. academia, and contributed to regulatory harmonization on a practical level through teleconferences or meetings of respective working groups. Also, in September 2014, PMDA participated in the HBD West 2014 Think Tank Meeting held in Washington D.C. and delivered a presentation on activity results and future prospects. In addition, PMDA held HBD town hall meetings within academic conferences, including CVIT2014, TCT2014, and CRT2015, and provided presentations and discussion about the latest medical devices and technique. Through the HBD-derived project titled "Information Exchange with US FDA for Consultations and Reviews for Approval of Medical Devices," PMDA shared information with the US FDA regarding specific issues raised in the process of product reviews. Main international harmonization conferences on drugs in which PMDA participated (relating to reviews and post-marketing safety measures) * ICMRA (International Coalition of Medical Regulatory Authorities) * GCRSR (Global Coalition for Regulatory Science Research) * ICH: Minneapolis meeting and Lisbon meeting      

Impurities: Guideline for Metal Impurities (Q3D) Q&A on GMP for Active Pharmaceutical Ingredients (Q7 IWG) Lifecycle Management (Q12) ICH Medical Dictionary for Regulatory Activities (MedDRA) (M1PtC) Electronic Standards for Transmission of Regulatory Information (M2) CTD (Common Technical Document) 2.5.6 Enhancing the Format and Structure of Benefit-Risk Information (M4E [R2])  Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (M7)  Electronic Common Technical Document (M8)  Data Elements for Transmission of Individual Case Safety Reports (E2B [R3])  Good Clinical Practice (E6 [R2])  Statistical Principles for Clinical Trials (E9)  Clinical Investigation of Medicinal Products in the Pediatric Population (E11 [R1])  Multi-Regional Clinical Trials (E17)  Genomic Sampling Methodologies for Future Use (E18)  Clinical Safety Data Management: Periodic Benefit-Risk Evaluation Reports (E2C [R2]) * PDG: Pharmacopoeial Discussion Group: Rockville meeting and Strasbourg meeting * ISO TC/215 (Health informatics) * HL7 (Standards for interoperability of health information technology) * ICCR (International Cooperation on Cosmetics Regulation) * IGDRP: (International Generic Drug Regulators Pilot)*1: Taiwan meeting and Singapore meeting (*1: changed from Pilot to Program) * CIOMS (Council for International Organizations of Medical Sciences) Working Group * Working Group on Good Laboratory Practice (GLP) of OECD * WHO INN (International Nonproprietary Names) meeting * APEC LSIF RHSC (Life Science Innovation Forum, Regulatory Harmonization Steering Committee): Qingdao meeting and Beijing meeting

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Main international harmonization conferences on medical devices in which PMDA participated (relating to reviews and post-marketing safety measures) * ISO     

ISO/TC/276 (Biotechnology) ISO/TC/194 (Biological and clinical evaluation of medical devices) ISO/TC/150 (Implants for surgery) ISO/TC/106 (Dentistry) ISO/TC/210 (Quality management and corresponding general aspects for medical devices)

* IEC  IEC/TC62 (Electrical equipment in medical practice) * Regulatory Affairs Professionals Society (RAPS) * Harmonization by Doing (HBD) * APEC LSIF RHSC (Life Science Innovation Forum, Regulatory Harmonization Steering Committee) * IMDRF: International Medical Device Regulators Forum     

RPS (Regulated Product Submission) MDSAP (Medical Device Single Audit Program) UDI (Unique Device Identification) NCAR (National Competent Authority Report) Recognized Standards

* AHWP (Asian Harmonization Working Party)  PMDA participated in the PDG meetings held in June and November 2014, at which 4 excipients and 1 general test resulted in new harmonization. In addition, PMDA sought public comments in Japan for 2 drafts proposed by PDG.  PMDA held a total 5 Expert Discussion meetings on drug names and reported 68 Japanese accepted names (JAN) to MHLW. Five consultations on applications for international non-proprietary names (INN) were also conducted. PMDA participated in the WHO-hosted conferences on INN in April and October 2014.  PMDA participated in the International Generic Drug Regulators Pilot (IGDRP) meeting held in November 2014 and exchanged opinions on, in particular, the master file, handling of bioequivalence with the regulatory authorities. In addition, PMDA discussed the probability of harmonization of regulations on bioequivalence evaluation between Japan and overseas in a research project supported by Health and Labour Science Research Grants.  PMDA participated in the 8th International Cooperation on Cosmetics Regulation meeting (ICCR-8) held in Canada in July 2014 and exchanged information on regulations of cosmetics with regulators from the U.S., Europe, Canada, Brazil, and China.  For contribution to enhancement of the international status of the Japanese Pharmacopoeia through cooperation on international activities of pharmacopoeia conducted by WHO, etc., see 4. (2) (i).

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 PMDA cooperated with the Medical Device International Standardization Strategy Promotion Project conducted by MHLW. The project was started in FY 2014 with the purpose of reinforcing PMDA’s function in order to achieve more rapid and rational reviewing of medical devices by promoting international standardization. As the first step, PMDA conducted the following activities: 1) identifying the international standards and Japanese review groups that should be covered by this project; 2) preparing a list of international meetings and corresponding Japanese committees to be held to deliberate on standardization; and 3) developing the infrastructure for PMDA to participate in international meetings, such as collaborative arrangements with Japanese review groups. Specifically, PMDA participated in the 51 ISO-related committee meetings (4 international meetings) and 9 IEC-related committee meetings (2 international meetings) as well as committees of Japanese review groups that are essential for ISO/IEC activities. PMDA developed the project procedure and draft road map for conducting the project, in consideration of information such as the importance of standards obtained from these activities.  In addition to assuming the position of vice chair of the Working Group on GLP of OECD, PMDA dispatched an employee to OECD as the person in charge of GLP, and thereby introduced PMDA’s knowledge and know-how into international GLP-related activities.  PMDA has conducted mutual acceptance of GLP investigation results based on the OECD’s mutual data acceptance system.  PMDA exchanged opinions with representatives from relevant industries on expanding the scope of data in English permitted for product application. (iii)

Promotion of personnel exchanges  PMDA accepted 4 trainees from the Thai-FDA, 2 from Malaysia NPCB, and 1 from the US FDA. PMDA also hosted government research teams from China, Taiwan, and Vietnam, and explained PMDA’s services, etc. 

For personnel from overseas regulatory authorities, PMDA held 2 training seminars on its services and case studies of regulatory review for drugs and medical devices.

 As preliminary research into whether or not PMDA should dispatch employees to Health Canada, the Head of the International Department of Health Canada visited PMDA for 4 days. During the visit, PMDA’s operations in each office/division were explained to the Health Canada officer. (iv)

Development of internationally oriented human resources with excellent communication skills  In order to develop human resources with the abilities to take the initiative in global negotiations and conferences, and to cooperate with representatives of other countries on establishing standards and guidelines, PMDA dispatched employees for long-term assignments to overseas institutions such as US FDA (5 employees).  In order to improve employees’ English language skills, PMDA subsidized one-to-one English conversation lessons (e.g. practical business English for international conferences) taken by 53 employees and correspondence courses in English language taken by 44 employees.

(v)

Improvement and strengthening of international publicity and provision of information  PMDA made efforts to provide information in English through such measures as posting monthly PMDA Updates on its English website.  In order to provide information on its reviews and related services and safety measures to international audiences, PMDA prepares and releases English translations of review reports and - 153 -

safety information on its website. In FY 2014, the Agency prepared and published English translations of 9 review reports. PMDA also prepared lists of approved new drugs/new medical devices in English, and released them approximately every quarter.  At the DIA Annual Meetings, RAPS Annual Meetings, etc., held in Japan, the U.S., and Europe, PMDA speakers gave presentations on the Agency's reviews and safety measures to raise international recognition of PMDA’s services, and also made booth exhibitions for the publicity of PMDA's services.  Information on projects across multi-offices in PMDA is posted on the English website. An administrative notice "Basic Principles for Conducting Phase I Trials in the Japanese Population Prior to Global Clinical Trials" (in Japanese) was issued in October 2014. Within 15 days of issuance, an English translation was published on the PMDA website to provide timely information to overseas readers. PMDA provided information on the concept for reviews in Japan by occasionally uploading presentations on projects across multi-offices, in particular the QbD Evaluation Project, given at international academic conferences. 3.4.(3)

Measures for intractable diseases and orphan diseases, etc.  In the Orphan Drug Working Group, one of the projects across multi-offices in PMDA, the Agency has been discussing methods for promoting orphan drug development by collaborating with MHLW and by exchanging information with EMA.  For efficient operation of notifications on companion diagnostics, see 2. (2) (i).  In association with the establishment of Expert Working Group on the ICH E18 guideline "Genomic Sampling Methodologies for Future Use," the omics working group was newly restructured, centering on E18 members, to share information and exchange opinions within PMDA.

3.4.(4) a.

Promoting provision of information such as review reports Improving provision of information  To promote proper use of drugs and medical devices and ensure transparency of reviews, PMDA releases information on reviews of new drug applications (e.g., review reports) on the PMDA website, in collaboration with MHLW and with the cooperation and understanding of relevant companies.

b.

Releasing information related to review reports (Review reports on new drugs)  Based on submitted information, new drugs fall into 2 categories: those to be deliberated in the Drug Committees of the Pharmaceutical Affairs and Food Sanitation Council (PAFSC) (hereinafter referred to as "deliberation products"); and those to be reported to the Drug Committees of PAFSC (hereinafter referred to as "report products"). For "deliberation products," both "review reports" that describe details and results of reviews and "summaries of product applications" that summarize submitted data are subject to public release. For "report products," "review reports" are subject to public release. These documents are published on the PMDA website after conferring with the relevant companies regarding the content to be released for each product, based on a Notification Issued by ELD, PFSB at MHLW.

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 In FY 2014, PMDA released 130 review reports (median time from approval to release, 13 days; median adjustment time [Note], 21 days), 88 summaries of product applications (median time from approval to release, 56 days; median adjustment time, 32 days), and 40 re-examination reports (median time from result notification to release, 22 days; median adjustment time, 11 days). Note: Adjustment time means the number of days from the date of receipt of a masked draft of release materials prepared by the applicant to the date on which the applicant is requested to submit the release materials after adjustment and confirmation.

The percentage of review reports released within 1 month after approval was 70% (99% in FY 2013) and the percentage of summaries of product applications released within 3 months after approval was 94% (95% in FY 2013).

(Review reports on new medical devices)  In FY 2014, PMDA released 9 review reports (median time from approval to release, 62 days; median adjustment time, 35 days), 13 summaries of product applications (median time from approval to release, 136 days; median adjustment time, 78 days) and 6 re-examination reports (median time from result notification to release, 8 days; median adjustment time, 6 days). The percentage of review reports released within one month after approval was 44% (74% in FY 2013) and the percentage of summaries of product applications released within 3 months after approval was 38% (78% in FY 2013). (Review reports on OTC drugs and quasi-drugs)  In FY 2014, PMDA released 3 review reports, 4 summaries of product applications, and 3 re-examination reports for OTC drugs (which were retrospectively released for products with notification of results in and after FY 2009). PMDA also released 1 review report and 1 summary of a product application for a quasi-drug. 3.4.(5)

Securing of impartiality in utilization of external experts  It is necessary to secure impartiality and transparency of judgments made by commissioned external experts. The "Rules for Convening Expert Discussions etc., by the Pharmaceuticals and Medical Devices Agency” (December 25, 2008; revised on February 26, 2015) was set forth with the aim of ensuring transparency of PMDA's services by releasing review reports and information on conflicts of interest among commissioned external experts, thereby allowing outside parties to verify the decision-making process. In accordance with the rules, PMDA reports to the Advisory Council and the Committee on Review and Safety Operations regarding cash contributions and contract payments received by external experts commissioned by PMDA for Expert Discussions on reviews and safety measures.

3.4.(6)

Provision of training in specially controlled medical device certification standards  In association with the establishment of specially controlled medical device certification standards (3 standards), reviewers at the registered certification bodies were trained by PMDA to conduct product certification review and compliance assessments based on the standards.

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3.4.(7)

Improvement of quality of reviews/safety operations through enhancement of information systems  On August 25, 2014, PMDA began operating an application/review system constructed based on the Optimization Plan for Operations and Systems. On November 25, 2014, PMDA began accepting applications for cellular and tissue-based products in accordance with enforcement of the PMD Act. In addition, on February 16, 2015, PMDA issued "Points to Consider for Reports on Post-marketing Adverse Drug Reactions and Reports on Clinical Trial Adverse Drug Reactions," for implementation of E2B/R3 and took actions for operation of the system.  Final decision documents for regulatory approval of drugs, etc., clinical trial notifications for agents and devices, etc., were converted into digital image data to reduce storage space and enable long-term storage. Review process was streamlined and accelerated by using the search function for digital image data.  With regard to the new eCTD viewer system, PMDA upgraded the hardware and software and modified the system related to collaboration with the application/review system. The modified system began to operate on August 25, 2014. For a secure environment in which external expert advisors can access eCTD data, PMDA renewed and verified the hardware and software to expand the available PC environment and improve convenience for expert advisors.  PMDA published the implementation guide (draft) for eCTD ver. 4.0 under development by ICH and began seeking public comments and information. The eCTD ver. 4.0 was considered to pose difficulties in respect of manual creation of messages and viewing of messages visually due to characteristics of its specifications. PMDA made a simple tool to assist in making and viewing eCTD ver. 4.0 messages and uploaded it on the PMDA website (available for free download) to support the understanding of technical specifications.

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III. SUPPLEMENTARY INFORMATION

Table 1. Products Approved in FY 2014: New Drugs New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Approval (1) Calcipotriol hydrate/ A new combination drug indicated for the treatment of (2) Betamethasone psoriasis vulgaris. dipropionate

Brand Name (Applicant Company)

Review Category

Approval Date

No.

1

Jul. 4, 2014

1

Dovobet Ointment (Leo Pharma K.K.)

1

Aug. 29, 2014

2

Rituxan Injection 10 mg/mL (Zenyaku Kogyo Co., Ltd.)

Change

Rituximab (genetical recombination)

1

Sep. 19, 2014

3

Thymoglobuline for Intravenous Infusion 25 mg (Sanofi K.K.)

Change

Anti-human thymocyte A drug with a new additional indication and a new immunoglobulin, rabbit dosage for the treatment of acute rejection after the liver, heart, lungs, pancreas, or small intestinal transplantation.

1

Sep. 26, 2014

4

Fomepizole Intravenous Infusion 1.5 g "Takeda" (Takeda Pharmaceutical Company Limited)

Approval

Fomepizole

A drug with a new active ingredient indicated for the treatment of ethylene glycol and methanol poisonings.

A drug with a new additional indication and a new dosage for the treatment of refractory nephrotic syndrome (for use in patients with frequent recurrence or steroid-dependent). [Orphan drug]

1

Dec. 26, 2014

5

Pariet Tablets 5 mg Pariet Tablets 10 mg (Eisai Co., Ltd.)

Approval Change

Rabeprazole sodium

A drug with a new additional indication and a new dosage in a newly-added dosage form, and a drug with a new additional indication and a new dosage for the prevention of recurrence of gastric ulcer or duodenal ulcer in patients treated with low-dose aspirin.

1

Dec. 26, 2014

6

Takecab Tablets 10 mg Takecab Tablets 20 mg (Takeda Pharmaceutical Company Limited)

Approval Approval

Vonoprazan fumarate

Drugs with a new active ingredient indicated for the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis, prevention of recurrence of gastric or duodenal ulcer in patients treated with low-dose aspirin, prevention of recurrence of gastric or duodenal ulcer in patients treated with non-steroidal antiinflammatory drugs (NSAIDs), and aid to eradication of Helicob acter pylori in patients with gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicob acter pylori gastritis, and stomach after endoscopic treatment for early gastric cancer.

1

Dec. 26, 2014

7

Methylene Blue Intravenous Injection 50 mg "Daiichi Sankyo" (Daiichi Sankyo Company, Limited)

Approval

Methylthioninium chloride hydrate

A drug with a new active ingredient indicated for the treatment of toxic methemoglobinemia.

1

Dec. 26, 2014

8

Bepio Gel 2.5% (Maruho Co., Ltd.)

Approval

Benzoyl peroxide

A drug with a new active ingredient indicated for the treatment of acne vulgaris.

2

Jul. 4, 2014

9

Stalevo Combination Tablets L50 Stalevo Combination Tablets L100 (Novartis Pharma K.K.)

Approval Approval

Levodopa/ Carbidopa hydrate/ Entacapone

New combination drugs indicated for the treatment of Parkinson's disease [for use in patients having wearing-off phenomenon in the symptoms following administration of levodopa/carbidopa].

2

Sep. 19, 2014

10

Aricept Tablets 3 mg Aricept Tablets 5 mg Aricept Tablets 10 mg Aricept D Tablets 3 mg Aricept D Tablets 5 mg Aricept D Tablets 10 mg Aricept Fine Granules 0.5% Aricept Oral Jelly 3 mg Aricept Oral Jelly 5 mg Aricept Oral Jelly 10 mg Aricept Dry Syrup 1% (Eisai Co., Ltd.)

Change Change Change Change Change Change Change Change Change Change Change

Donepezil hydrochloride Drugs with a new additional indication and a new dosage for inhibiting progress of dementia symptoms in patients with dementia with Lewy bodies.

2

Sep. 26, 2014

11

Lixiana Tablets 15 mg Lixiana Tablets 30 mg Lixiana Tablets 60 mg (Daiichi Sankyo Company, Limited)

Change Change Approval

Edoxaban tosilate hydrate

Drugs with new additional indications and new dosages, and a drug with a newly-added dosage form indicated for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation, or for the treatment and prevention of the recurrence of venous thromboembolism (deep vein thrombosis and pulmonary thromboembolism).

12

Inderal Tablets 10 mg Inderal Tablets 20 mg (AstraZeneca K.K.)

Change Change

Propranolol hydrochloride

Drugs with a new additional indication and a new dosage for the prevention of hypoxic attack caused by right ventricular outflow tract obstruction. [Public knowledge-based application after preliminary assessment by the Pharmaceutical Affairs and Food Sanitation Council (PAFSC)]

2

Nov. 18, 2014

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Review Category

Approval Date

No.

New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Change Riociguat Drugs with a new additional indication for the treatment Change of pulmonary arterial hypertension. Change

Brand Name (Applicant Company)

2

Feb. 20, 2015

13

Adempas Tablets 0.5 mg Adempas Tablets 1.0 mg Adempas Tablets 2.5 mg (Bayer Yakuhin, Ltd.)

2

Mar. 26, 2015

14

Opsumit Tablet 10 mg (Actelion Pharmaceuticals Japan Ltd.)

Approval

Macitentan

A drug with a new active ingredient indicated for the treatment of pulmonary arterial hypertension.

3-1

Jul. 4, 2014

15

E Keppra for I.V. Infusion 500 mg (UCB Japan Co., Ltd.)

Approval

Levetiracetam

A drug with a new route of administration indicated for use as an adjunctive therapy with other antiepileptic drugs to treat partial seizure (including secondary generalized seizure) in patients with epilepsy who have not responded sufficiently to other antiepileptic drugs. It is used as an alternative therapy for levetiracetam oral formulation in patients who are temporarily unable to be administered orally.

3-1

Aug. 29, 2014

16

Lamictal Tablets 25 mg Lamictal Tablets 100 mg (GlaxoSmithKline K.K.)

Change Change

Lamotrigine

Drugs with a new additional indication and a new dosage for use in the monotherapy for treatment of partial seizures (including secondary generalized seizure) and tonic-clonic seizures in patients with epilepsy.

3-1

Sep. 26, 2014

17

Belsomra Tablets 15 mg Belsomra Tablets 20 mg (MSD K.K.)

Approval Approval

Suvorexant

Drugs with a new active ingredient indicated for the treatment of insomnia.

3-1

Sep. 26, 2014

18

Midafresa Injection 0.1% (Alfresa Pharma Corporation )

Approval

Midazolam

A drug with a new additional indication and a new dosage in an additional dosage form indicated for the treatment of status epilepticus. Drugs with a revised indication and a new dosage for the treatment of partial seizure in patients with epilepsy (including secondary generalized seizure).

3-1

Feb. 20, 2015

19

E Keppra Tablets 250 mg E Keppra Tablets 500 mg E Keppra Dry Syrup 50% E Keppra for I.V. Infusion 500 mg (UCB Japan Co., Ltd.)

Change Change Change Change

Levetiracetam

3-1

Mar. 20, 2015

20

J Zoloft Tablets 25 mg J Zoloft Tablets 50 mg J Zoloft Tablets 100 mg J Zoloft OD Tablets 25 mg J Zoloft OD Tablets 50 mg J Zoloft OD Tablets 100 mg (Pfizer Japan Inc.)

Change Change Change Change Change Change

Sertraline hydrochloride Drugs with a new additional indication for the treatment of posttraumatic stress disorder.

3-1

Mar. 26, 2015

21

ABILIFY Prolonged Release Aqueous IM Injection 300 mg ABILIFY Prolonged Release Aqueous IM Injection 400 mg ABILIFY Prolonged Release Aqueous IM Injection 300 mg Syringe ABILIFY Prolonged Release Aqueous IM Injection 400 mg Syringe (Otsuka Pharmaceutical Co., Ltd.)

Suspension for Approval Approval Suspension for Approval Approval Suspension for

Aripiprazole hydrate

Drugs with a new route of administration indicated for the treatment of schizophrenia.

Suspension for

3-2

Jun. 20, 2014

22

Fentos Tape 1 mg Fentos Tape 2 mg Fentos Tape 4 mg Fentos Tape 6 mg Fentos Tape 8 mg (Hisamitsu Pharmaceutical Co., Inc.)

Change Change Change Change Change

Fentanyl citrate

Drugs with a new indication for analgesia in moderate to severe chronic pain which cannot be managed by treatments with non-opioid analgesics and weak opioid analgesics (for use only in patients who switch from an opioid analgesic).

3-2

Sep. 19, 2014

23

Eylea Intravitreal Injection 40 mg/mL Eylea Intravitreal Injection Kit 40 mg/mL (Bayer Yakuhin, Ltd.)

Change Change

Aflibercept (genetical recombination)

Drugs with a new additional indication for the treatment of choroidal neovascularization in patients with pathologic myopia.

3-2

Sep. 26, 2014

24

Glanatec Ophthalmic Solution 0.4% (Kowa Company, Ltd.)

Approval

Ripasudil hydrochloride A drug with a new active ingredient indicated for the treatment of glaucoma or ocular hypertension in hydrate patients who have not sufficiently responded to other therapeutic drugs for glaucoma or who are unable to use them.

3-2

Nov. 18, 2014

25

Eylea Intravitreal Injection 40 mg/mL Eylea Intravitreal Injection Kit 40 mg/mL (Bayer Yakuhin, Ltd.)

Change Change

Aflibercept (genetical recombination)

Drugs with a new additional indication and a new dosage for the treatment of diabetic macular edema.

3-2

Dec. 26, 2014

26

Nopicor Capsules 2.5 μg (Toray Medical Co., Ltd.)

Approval

Nalfurafine hydrochloride

A drug with a new active ingredient indicated for the improvement of pruritus in patients with chronic liver diseases (for use only when conventional therapies are not sufficiently effective).

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Review Category 3-2

Approval Date Mar. 26, 2015

No.

Brand Name (Applicant Company)

27

Onetram Tablets 100 mg (Nippon Shinyaku Co., Ltd.)

New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Approval Tramadol hydrochloride A drug in a new dosage form indicated for analgesia in patients with cancers-associated pain or chronic pain, which cannot be managed by treatments with nonopioid analgesics.

4

May 23, 2014

28

Vancomycin Hydrochloride for Intravenous Drip Infusion 0.5 g (Shionogi & Co., Ltd.)

Change

Vancomycin hydrochloride

A drug with new additional indications for the treatment of: (1) sepsis, infective endocarditis, secondary infection of trauma, burn or surgical wounds, osteomyelitis, arthritis, peritonitis and purulent meningitis caused by vancomycin-sensitive methicillin-resistant coagulasenegative Staphylococcus (MRCNS); or (2) febrile neutropenia which is suspected of MRSA or MRCNS infection. [Public knowledge-based application after PAFSC's preliminary assessment]

4

Jul. 4, 2014

29

Clenafin Topical Solution 10% for Nail (Kaken Pharmaceutical Co., Ltd.)

Approval

Efinaconazole

A drug with a new active ingredient indicated for the treatment of tinea unguium caused by dermatophyte (trichophyton ).

4

Jul. 4, 2014

30

Deltyba Tablets 50 mg (Otsuka Pharmaceutical Co., Ltd.)

Approval

Delamanid

A drug with a new active ingredient indicated for the treatment of multidrug-resistant pulmonary tuberculosis caused by delamanid-sensitive Mycob acterium tub erculosis . [Orphan drug]

4

Jul. 4, 2014

31

Anaemetro Intravenous Infusion 500 mg (Pfizer Japan Inc.)

Approval

Metronidazole

A drug with a new route of administration indicated for the treatment of different kinds of anaerobic bacterial infections, infectious enteritis, and amebic dysentery.

4

Jul. 4, 2014

32

Daklinza Tablets 60 mg (Bristol-Myers K.K.)

Approval

Daclatasvir hydrochloride

Sunvepra Capsules 100 mg (Bristol-Myers K.K.)

Approval

Asunaprevir

Drugs with new active ingredients indicated for the improvement of viremia in patients with chronic hepatitis C or compensated cirrhosis type C in serogroup 1 (genotype 1) who are untreated and ineligible for, or are intolerant to therapy including interferon; or who did not respond to therapy including interferon. [Priority review]

4

Sep. 19, 2014

33

Telavic 250 mg Tablet (Mitsubishi Tanabe Pharma Corporation)

Change

Telaprevir

A drug with a new additional indication for the improvement of viremia in serogroup 2 (genotype III [2a] or IV [2b]) chronic hepatitis C in patients who did not respond to, or in whom the symptom relapsed with, interferon monotherapy or interferon-ribavirin combination therapy. [Priority review]

4

Sep. 26, 2014

34

Vfend Tablets 50 mg Vfend Tablets 200 mg Vfend for Intravenous Use 200 mg Vfend Dry Syrup 2800 mg (Pfizer Japan Inc.)

Change Change Change Approval

Voriconazole

Drugs with new additional pediatric dosages, and a drug with a new additional pediatric dosage in an additional dosage form of dry syrup indicated for the treatment of severe or refractory fungus infection.

4

Sep. 26, 2014

35

Vanihep Capsules 150 mg (MSD K.K.)

Approval

Vaniprevir

A drug with a new active ingredient indicated for the improvement of viremia in the following patients with serogroup 1 (genotype I [1a] or II [1b]) chronic hepatitis C: Patients with high levels of blood HCV RNA who are treatment-naive, or Patients who are non-responders or relapsed to therapy including interferon. [Priority review]

4

Nov. 18, 2014

36

Valtrex Tablets 500 Valtrex Granules 50% (GlaxoSmithKline K.K.)

Change Change

Valaciclovir hydrochloride

Drugs with a new additional indication and revised indications with a new dosage for prevention of herpes simplex virus infection in adult or pediatric haematopoietic stem cell transplant patients, for treatment of herpes simplex /herpes zoster, and for prevention of recurrent genital herpes in pediatric patients.

4

Dec. 18, 2014

37

Cancidas for Intravenous Drip Infusion 50 mg Cancidas for Intravenous Drip Infusion 70 mg (MSD K.K.)

Change Change

Caspofungin acetate

Drugs with a new additional pediatric dosage indicated for the treatment of febrile neutropenia with suspected fungal infection, esophageal candidiasis, invasive candidiasis, and aspergillosis caused by Candida or Aspergillus .

- 161 -

Review Category

Approval Date

No.

Brand Name (Applicant Company)

New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Approval Metronidazole A drug with a new route of administration indicated for disinfection/deodorisation of odorous fungating tumours.

4

Dec. 26, 2014

38

Rozex Gel 0.75% (Galderma S.A.)

4

Mar. 20, 2015

39

Pentcillin for Injection 1 g Pentcillin for Injection 2 g Pentcillin Intravenous Injection 1 g Bag Pentcillin Intravenous Injection 2 g Bag (Toyama Chemical Co., Ltd.)

Approval Approval Approval Approval

Piperacillin sodium

Drugs with a new dosage indicated for the treatment of sepsis, acute bronchitis, pneumonia, lung abscess, thoracic empyema, secondary infection of chronic respiratory disease, cystitis, pyelonephritis, cholecystitis, choledochitis, bartholinitis, intrauterine infection, uterine adnexitis, parametritis, and purulent meningitis.

4

Mar. 20, 2015

40

Daklinza Tablets 60 mg (Bristol-Myers K.K.)

Change

Daclatasvir hydrochloride

Sunvepra Capsules 100 mg (Bristol-Myers K.K.)

Change

Drugs with a revised indication for the improvement of viremia in patients with chronic hepatitis C or compensated cirrhosis type C in serogroup 1 (genotype 1). [Priority review]

Asunaprevir

4

Mar. 26, 2015

41

Duac Combination Gel (GlaxoSmithKline K.K.)

Approval

Clindamycin phosphate A new combination drug with a new active ingredient hydrate/ Benzoyl indicated for the treatment of acne vulgaris. peroxide

4

Mar. 26, 2015

42

Sovaldi Tablets 400 mg (Gilead Sciences, Inc.)

Approval

Sofosbuvir

A drug with a new active ingredient indicated for the improvement of viremia in patients with chronic hepatitis C or compensated cirrhosis type C in serogroup 2 (genotype 2) . [Priority review]

4

Mar. 26, 2015

43

Copegus Tablets 200 mg (Chugai Pharmaceutical Co., Ltd.)

Change

Ribavirin

A drug with a new additional indication and a new dosage for the improvement of viremia with the concomitant use of sofosbuvir in patients with chronic hepatitis C or compensated cirrhosis type C in serogroup 2 (genotype 2) . [Expedited review]

4

Mar. 26, 2015

44

Aldreb for Injection 150 mg (GlaxoSmithKline K.K.)

Approval

Colistin sodium methanesulfonate

A drug with a new route of administration indicated for the treatment of infections caused by colistin-sensitive Escherichia coli, Citrob acter, Kleb siella, Enterob acter, Pseudomonas aeruginosa, and Acinetob acter (limited to the strains resistant to other antimicrobial drugs). [Orphan drug] A drug with a new additional indication for the treatment of hypermenorrhea. [Public knowledge-based application after PAFSC's preliminary assessment]

5

Jun. 20, 2014

45

Mirena 52 mg (Bayer Yakuhin, Ltd.)

Change

Levonorgestrel

5

Jul. 4, 2014

46

Pareplus for IV. Infusion (Ajinomoto Pharmaceutical Co., Ltd.)

Approval

N/A for this combination A combination prescription drug with similar drug formulations indicated for the supplementation of amino acids, electrolyte, hydrosoluble vitamins, and water. It is used in patients with mild hypoproteinemia or in a mild malnutrition state due to insufficient oral intake or used in perioperative patients.

5

Sep. 26, 2014

47

Lutinus Vaginal Tablet 100 mg (Ferring Pharmaceuticals Co.,Ltd.)

Approval

Progesterone

A drug with a new route of administration indicated for luteal support as part of assisted reproductive technology for infertile women.

Nov. 18, 2014

48

Mirena 52 mg (Bayer Yakuhin, Ltd.)

Change

Levonorgestrel

A drug with a new additional indication for the treatment of dysmenorrhoea. [Public knowledge-based application after PAFSC's preliminary assessment]

6-1

Jul. 4, 2014

49

Anoro Ellipta 7 doses Anoro Ellipta 30 doses (GlaxoSmithKline K.K.)

Approval Approval

(1) Umeclidinium bromide/ (2) Vilanterol trifenatate

New combination drugs with a new active ingredient indicated for the relief of symptoms secondary to airway obstructive disorder in chronic obstructive pulmonary disease (chronic bronchitis, emphysema) (when a combination treatment of an inhaled long-acting anticholinergic and a long-acting beta-2 agonist is needed).

6-1

Jul. 4, 2014

50

Rapalimus Tablets 1 mg (Nobelpharma Co., Ltd.)

Approval

Sirolimus

A drug with a new active ingredient indicated for the treatment of lymphangioleiomyomatosis. [Orphan drug]

6-1

Jul. 4, 2014

51

kenketu Glovenin-I for I.V. Injection 2500 mg kenketu Glovenin-I for I.V. Injection 500 mg kenketu Glovenin-I for I.V. Injection 5000 mg (Nihon Pharmaceutical Co., Ltd.)

Change Change Change

Freeze-dried polyethylene glycol treated human normal immunoglobulin

Drugs with new additional indications for the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis (for use when steroid drugs are not sufficiently effective). [Orphan drug]

5

- 162 -

Review Category

Approval Date

No.

Brand Name (Applicant Company)

6-1

Aug. 29, 2014

52

Solu-Medrol for Intravenous Solu-Medrol for Intravenous Solu-Medrol for Intravenous Solu-Medrol for Intravenous (Pfizer Japan Inc.)

6-1

Sep. 26, 2014

53

Calonal Tab. 500 (Showa Yakuhin Kako Co., Ltd.)

Use 40 mg Use 125 mg Use 500 mg Use 1000 mg

New Active Ingredient(s) Approval/ (underlined: new active Partial ingredient) Change Methylprednisolone Change Change sodium succinate Change Change

Approval

Acetaminophen

Notes Drugs with new additional indications and a new dosage for the treatment of the following treatmentresistant rheumatic diseases: systemic vasculitis (including microscopic polyangiitis, Wegener's granulomatosis, polyarteritis nodosa, Churg-Strauss syndrome, aortitis syndrome), systemic lupus erythematosus, polymyositis, dermatomyositis, scleroderma, mixed connective tissue disease, and refractory rheumatic disease. [Public knowledge-based application after PAFSC's preliminary assessment]

A drug in an additional dosage form. Note: the product was submitted for an approval application as a drug with a new additional indication for the treatment of osteoarthrosis and with an expanded dosage of acetaminophen in an additional dosage form. The new additional indication and the expanded dosage were approved on January 21, 2011, whereas approval of the additional dosage form had been under review.

6-1

Nov. 18, 2014

54

Spiriva 2.5 μg Respimat 60 puffs (Nippon Boehringer Ingelheim Co., Ltd.)

Change

Tiotropium bromide hydrate

A drug with a new additional indication for the relief of symptoms secondary to airway obstructive disorders in bronchial asthma (for use only in patients with the severe persistent type).

6-1

Dec. 26, 2014

55

Allergen Extract for Subcutaneous Injection-HDM "TORII"100,000 JAU/mL Allergen Extract for Subcutaneous Injection-HDM "TORII"10,000 JAU/mL (Torii Pharmaceutical Co., Ltd.)

Approval

Dermatophagoides farinae extract 10,000 AU/mL, Dermatophagoides pteronyssinus extract 10,000 AU/mL

Drugs with new active ingredients indicated for the allergen immunotherapy for house dust mite antigeninduced allergic rhinitis and bronchial asthma.

Approval

6-1

Dec. 26, 2014

56

Cosentyx for S.C. Injection 150 mg Syringe Cosentyx for S.C. Injection 150 mg (Novartis Pharma K.K.)

Approval Approval

Secukinumab (genetical Drugs with a new active ingredient indicated for the recombination) treatment of plaque psoriasis and psoriatic arthritis in patients who have not responded sufficiently to conventional therapies.

6-1

Dec. 26, 2014

57

Allergen Extract for Scratch Test - HDM "TORII" 100,000 JAU/mL (Torii Pharmaceutical Co., Ltd.)

Approval

Dermatophagoides farinae extract 10,000 AU/mL, Dermatophagoides pteronyssinus extract 10,000 AU/mL

6-1

Mar. 20, 2015

58

Dopram Injectable 400 mg (Kissei Pharmaceutical Co., Ltd.)

Change

Doxapram hydrochloride A drug with a new additional indication and a new hydrate dosage for the treatment of primary apnoea (apnea of prematurity) in immature or low birth weight infants who have not responded sufficiently to conventional therapies.

6-1

Mar. 26, 2015

59

Eklira 400 μg Genuair 30 doses Eklira 400 μg Genuair 60 doses (Kyorin Pharmaceutical Co., Ltd.)

Approval Approval

Aclidinium bromide

Drugs with a new active ingredient indicated for the relief of symptoms secondary to airway obstructive disorder in chronic obstructive pulmonary disease (chronic bronchitis, emphysema).

6-1

Mar. 26, 2015

60

Actair 100 IR Sublingual Tablets-HDM Actair 300 IR Sublingual Tablets-HDM (Shionogi & Co., Ltd.)

Approval Approval

Dermatophagoides farinae extract bulk powder, Dermatophagoides pteronyssinus extract bulk powder

Drugs with new active ingredients indicated for the allergen immunotherapy for house dust mite antigeninduced allergic rhinitis.

6-1

Mar. 26, 2015

61

Encruse 62.5 μg Ellipta 7 doses Encruse 62.5 μg Ellipta 30 doses (GlaxoSmithKline K.K.)

Approval Approval

Umeclidinium bromide

Other drugs with a new dosage indicated for the relief of symptoms secondary to airway obstructive disorder in chronic obstructive pulmonary disease (chronic bronchitis, emphysema).

- 163 -

A drug with new active ingredients indicated for the identification of allergen in patients with allergic diseases.

Review Category

Approval Date

No.

6-2

May 23, 2014

62

Brand Name (Applicant Company) Januvia Tablets Januvia Tablets Januvia Tablets Januvia Tablets (MSD K.K.)

12.5 mg 25 mg 50 mg 100 mg

New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Change Sitagliptin phosphate Drugs with a new indication for the treatment of type 2 Change hydrate diabetes mellitus. Change Change

Glactiv Tablets 12.5 mg Glactiv Tablets 25 mg Glactiv Tablets 50 mg Glactiv Tablets 100 mg (Ono Pharmaceutical Co., Ltd.)

Change Change Change Change

6-2

May 23, 2014

63

Nesina Tablets 6.25 mg Nesina Tablets 12.5 mg Nesina Tablets 25 mg (Takeda Pharmaceutical Company Limited)

Change Change Change

Alogliptin benzoate

Drugs with a new indication for the treatment of type 2 diabetes mellitus.

6-2

May 23, 2014

64

Aredia for I.V. Infusion 15 mg Aredia for I.V. Infusion 30 mg (Novartis Pharma K.K.)

Change Change

Pamidronate disodium hydrate

Drugs with a new additional indication and a new dosage for the treatment of osteogenesis imperfecta. [Public knowledge-based application after PAFSC's preliminary assessment]

6-2

Jul. 4, 2014

65

Canaglu Tablets 100 mg (Mitsubishi Tanabe Pharma Corporation)

Approval

Canagliflozin hydrate

A drug with a new active ingredient indicated for the treatment of type 2 diabetes mellitus.

6-2

Jul. 4, 2014

66

Vpriv for Intravenous Injection 400 U (Shire Japan KK)

Approval

Velaglucerase alfa (genetical recombination)

A drug with a new active ingredient indicated for the improvement of various symptoms of Gaucher disease (anemia, thrombocytopenia, hepatosplenomegaly, and bone disease). [Orphan drug]

6-2

Jul. 4, 2014

67

Nicystagon Capsules 50 mg Nicystagon Capsules 150 mg (Mylan Seiyaku Ltd.)

Approval Approval

Cysteamine bitartrate

Drugs with a new active ingredient indicated for the treatment of nephropathic cystinosis. [Orphan drug]

6-2

Aug. 29, 2014

68

Victoza Subcutaneous Injection 18 mg (Novo Nordisk Pharma Ltd.)

Change

Liraglutide (genetical recombination)

A drug with a new indication for the treatment of type 2 diabetes mellitus.

6-2

Aug. 29, 2014

69

Metgluco Tablets 250 mg Metgluco Tablets 500 mg (Sumitomo Dainippon Pharma Co., Ltd.)

Change Change

Metformin hydrochloride Drugs with a new dosage indicated for the treatment of type 2 diabetes mellitus (for pediatric use).

6-2

Nov. 18, 2014

70

Surepost Tablets 0.25 mg Surepost Tablets 0.5 mg (Sumitomo Dainippon Pharma Co., Ltd.)

Change Change

Repaglinide

Drugs with a revised indication for the treatment of type 2 diabetes mellitus.

6-2

Dec. 26, 2014

71

Orfadin Capsules 2 mg Orfadin Capsules 5 mg Orfadin Capsules 10 mg (Astellas Pharma Inc.)

Approval Approval Approval

Nitisinone

Drugs with a new active ingredient indicated for the treatment of type I hypertyrosinemia.

6-2

Dec. 26, 2014

72

Jardiance Tablets 25 mg Jardiance Tablets 10 mg (Nippon Boehringer Ingelheim Co., Ltd.)

Approval Approval

Empagliflozin

Drugs with a new active ingredient indicated for the treatment of type 2 diabetes mellitus.

6-2

Dec. 26, 2014

73

Vimizim Intravenous Infusion 5 mg (BioMarin Pharmaceutical Japan K.K. )

Approval

Elosulfase alfa (genetical recombination)

A drug with a new active ingredient indicated for the treatment of mucopolysaccharidosis type IVA. [Orphan drug]

6-2

Mar. 26, 2015

74

Zafatek Tablets 50 mg Zafatek Tablets 100 mg (Takeda Pharmaceutical Company Limited)

Approval Approval

Trelagliptin succinate

Drugs with a new active ingredient indicated for the treatment of type 2 diabetes mellitus.

6-2

Mar. 26, 2015

75

Cerdelga Capsule 100 mg (Genzyme Japan K.K)

Approval

Eliglustat tartrate

A drug with a new active ingredient indicated for the improvement of various symptoms of Gaucher disease (anemia, thrombocytopenia, hepatosplenomegaly, and bone disease). [Orphan drug]

In vivo Dec. 26, 2014 diagnostics

76

Patch Test Panel (S) (Sato Pharmaceutical Co., Ltd.)

Approval

N/A for this drug used for patch tests

A drug indicated for use in patch tests to identify allergens in patients with allergic dermatitis.

In vivo Mar. 26, 2015 diagnostics

77

Gadovist IV Inj. 1.0 mol/L 7.5 mL Gadovist IV Inj. 1.0 mol/L Syringe 5 mL Gadovist IV Inj. 1.0 mol/L Syringe 7.5 mL Gadovist IV Inj. 1.0 mol/L Syringe 10 mL (Bayer Yakuhin, Ltd.)

Approval Approval Approval Approval

Gadobutrol

Drugs with a new active ingredient indicated for visibility of brain/spinal cord and trunk/extremities in magnetic resonance computer tomographic imaging as a contrast agent.

78

Imunomax-γ for Injection 50 Imunomax-γ for Injection 100 (Shionogi & Co., Ltd.)

Change Change

Interferon gamma-1a (genetical recombination)

Drugs with new additional indications and a new dosage for the treatment of mycosis fungoides and Sé zary syndrome. [Orphan drug]

Oncology drugs

May 23, 2014

- 164 -

Review Category

New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Change Denosumab (genetical A drug with a new additional indication and a new recombination) dosage for the treatment of giant cell tumor of bone. [Orphan drug]

Brand Name (Applicant Company)

Approval Date

No.

Oncology drugs

May 23, 2014

79

Ranmark Subcutaneous Injection 120 mg (Daiichi Sankyo Company, Limited)

Oncology drugs

Jun. 20, 2014

80

Nexavar Tablets 200 mg (Bayer Yakuhin, Ltd.)

Change

Sorafenib tosilate

A drug with a new additional indication for the treatment of unresectable differentiated thyroid carcinoma. [Orphan drug]

Oncology drugs

Jul. 4, 2014

81

Zytiga Tablets 250 mg (Janssen Pharmaceutical K.K.)

Approval

Abiraterone acetate

A drug with a new active ingredient indicated for the treatment of castration-resistant prostate cancer. [Priority review]

Oncology drugs

Jul. 4, 2014

82

Jevtana 60 mg I.V. Infusion (Sanofi K.K.)

Approval

Cabazitaxel acetonate

A drug with a new active ingredient indicated for the treatment of prostate cancer. [Priority review]

Oncology drugs

Jul. 4, 2014

83

Jakavi Tablets 5 mg (Novartis Pharma K.K.)

Approval

Ruxolitinib phosphate

A drug with a new active ingredient indicated for the treatment of myelofibrosis. [Orphan drug]

Oncology drugs

Jul. 4, 2014

84

Alecensa Capsule 20 mg Alecensa Capsule 40 mg (Chugai Pharmaceutical Co., Ltd.)

Approval Approval

Alectinib hydrochloride

Drugs with a new active ingredient indicated for the treatment of unresectable advanced/relapsed ALK fusion gene-positive non-small-cell lung cancer. [Orphan drug]

Oncology drugs

Jul. 4, 2014

85

Opdivo Intravenous Infusion 20 mg Opdivo Intravenous Infusion 100 mg (Ono Pharmaceutical Co., Ltd.)

Approval Approval

Nivolumab (genetical recombination)

Drugs with a new active ingredient indicated for the treatment of unresectable malignant melanoma. [Orphan drug]

Oncology drugs

Sep. 26, 2014

86

G-Lasta Subcutaneous Injection 3.6 mg (Kyowa Hakko Kirin Co., Ltd.)

Approval

Pegfilgrastim (genetical A drug with a new active ingredient indicated for decreasing the incidence of cancer chemotherapyrecombination) induced febrile neutropenia.

Oncology drugs

Sep. 26, 2014

87

Agrylin Capsules 0.5 mg (Shire Japan KK)

Approval

Anagrelide hydrochloride hydrate

Oncology drugs

Sep. 26, 2014

88

MabCampath Intravenous infusion 30 mg (Sanofi K.K.)

Approval

Alemtuzumab (genetical A drug with a new active ingredient indicated for the treatment of relapsed or refractory chronic lymphocytic recombination) leukemia. [Orphan drug]

Oncology drugs

Sep. 26, 2014

89

Bosulif Tablets 100 mg (Pfizer Japan Inc.)

Approval

Bosutinib hydrate

A drug with a new active ingredient indicated for the treatment of chronic myelogenous leukemia with resistance or intolerance to prior drug therapies. [Orphan drug]

Oncology drugs

Sep. 26, 2014

90

Zanosar for Intravenous Injection 1 g (Nobelpharma Co., Ltd.)

Approval

Streptozocin

A drug with a new active ingredient indicated for the treatment of neuroendocrine tumors of the pancreas and gastrointestinal tract. [Orphan drug]

A drug with a new active ingredient indicated for the treatment of essential thrombocythemia. [Orphan drug]

Oncology drugs

Dec. 18, 2014

91

Nesp Injection 5 μg Plastic Syringe Nesp Injection 10 μg Plastic Syringe Nesp Injection 15 μg Plastic Syringe Nesp Injection 20 μg Plastic Syringe Nesp Injection 30 μg Plastic Syringe Nesp Injection 40 μg Plastic Syringe Nesp Injection 60 μg Plastic Syringe Nesp Injection 120 μg Plastic Syringe Nesp Injection 180 μg Plastic Syringe (Kyowa Hakko Kirin Co., Ltd.)

Change Change Change Change Change Change Change Change Change

Darbepoetin alfa (genetical recombination)

Drugs with a new additional indication and a new dosage for the treatment of anemia due to myelodysplastic syndrome. [Orphan drug]

Oncology drugs

Dec. 18, 2014

92

Abraxane I.V. Infusion 100 mg (Taiho Pharmaceutical Co., Ltd.)

Change

Paclitaxel

A drug with a new additional indication and a new dosage for the treatment of unresectable pancreatic cancer. [Priority review]

Oncology drugs

Dec. 18, 2014

93

Poteligeo Injection 20 mg (Kyowa Hakko Kirin Co., Ltd.)

Change

Mogamulizumab (genetical recombination)

A drug with a revised indication and a new dosage for the treatment of CCR4-positive adult T-cell leukemia/lymphoma. [Expedited review]

Oncology drugs

Dec. 18, 2014

94

Adriacin Injection 10 Adriacin Injection 50 (Kyowa Hakko Kirin Co., Ltd.)

Change Change

Doxorubicin hydrochloride

Drugs with a revised indication and a new dosage for the relief of symptoms of malignant lymphoma. [Expedited review]

Oncology drugs

Dec. 18, 2014

95

Doxorubicin Hydrochloride for Injection 10 mg “NK” Doxorubicin Hydrochloride for Injection 50 mg “NK” (Nippon Kayaku Co., Ltd.)

Change Change

Doxorubicin hydrochloride

Drugs with a revised indication and a new dosage for the relief of symptoms of malignant lymphoma. [Expedited review]

- 165 -

Review Category

Approval Date

No.

New Active Ingredient(s) Approval/ (underlined: new active Partial ingredient) Change Cytarabine Change Change Change Change Change

Brand Name (Applicant Company)

Notes

Oncology drugs

Dec. 18, 2014

96

Cylocide Injection 20 mg Cylocide Injection 40 mg Cylocide Injection 60 mg Cylocide Injection 100 mg Cylocide Injection 200 mg (Nippon Shinyaku Co., Ltd.)

Drugs with a new route of administration indicated for the treatment of acute leukemia (including acute erythroid leukemia and blast crisis of chronic myelogenous leukemia). [Expedited review]

Oncology drugs

Dec. 18, 2014

97

Cymerin 50 mg Injection Cymerin 100 mg Injection (Mitsubishi Tanabe Pharma Corporation)

Change Change

Ranimustine

Drugs with a new dosage indicated for the treatment of malignant lymphoma. [Expedited review]

Oncology drugs

Dec. 26, 2014

98

Zelboraf Tablet 240 mg (Chugai Pharmaceutical Co., Ltd.)

Approval

Vemurafenib

A drug with a new active ingredient indicated for the treatment of unresectable malignant melanoma with BRAF mutation. [Orphan drug]

Oncology drugs

Mar. 20, 2015

99

Lonsurf Combination Tablet T15 Lonsurf Combination Tablet T20 (Taiho Pharmaceutical Co., Ltd.)

Change Change

(1) Trifluridine (2) Tipiracil hydrochloride

Drugs with a revised indication for the treatment of unresectable advanced or recurrent colorectal cancer. [Expedited review]

Oncology drugs

Mar. 20, 2015

100 Elplat I.V. Infusion Solution 50 mg Elplat I.V. Infusion Solution 100 mg Elplat I.V. Infusion Solution 200 mg (Yakult Honsha Co., Ltd.)

Change Change Change

Oxaliplatin

Drugs with a new additional indication and a new dosage for the treatment of unresectable advanced or recurrent gastric cancer. [Public knowledge-based application after PAFSC's preliminary assessment]

Oncology drugs

Mar. 26, 2015

101 Lenvima Capsule 4 mg Lenvima Capsule 10 mg (Eisai Co., Ltd.)

Approval Approval

Lenvatinib mesilate

Drugs with a new active ingredient indicated for the treatment of unresectable thyroid cancer. [Orphan drug]

Oncology drugs

Mar. 26, 2015

102 Pomalyst Capsules Pomalyst Capsules Pomalyst Capsules Pomalyst Capsules (Celgene K.K.)

1 mg 2 mg 3 mg 4 mg

Approval Approval Approval Approval

Pomalidomide

Drugs with a new active ingredient indicated for the treatment of relapsed or refractory multiple myeloma. [Orphan drug]

Oncology drugs

Mar. 26, 2015

103 Cyramza Injection 100 mg Cyramza Injection 500 mg (Eli Lilly Japan K.K.)

Approval Approval

Ramucirumab (genetical recombination)

Drugs with a new active ingredient indicated for the treatment of unresectable advanced or recurrent gastric cancer. [Priority review]

HIV/AIDS drugs

Nov. 18, 2014

104 Complera Combination Tablets (Janssen Pharmaceutical K.K.)

Approval

Rilpivirine hydrochloride, A new combination drug indicated for the treatment of Emtricitabine, Tenofovir HIV-1 infection. disoproxil fumarate [Orphan drug]

HIV/AIDS drugs

Mar. 16, 2015

105 Triumeq Combination Tablets (ViiV Healthcare K.K.)

Approval

Dolutegravir sodium, Abacavir sulfate, Lamivudine

A new combination drug indicated for the treatment of HIV infection. [Orphan drug]

106 Prevenar 13 Suspension Liquid for Injection (Pfizer Japan Inc.)

Change

Pneumococcal 13valent conjugate vaccine adsorbed (mutated diphtheria CRM197 conjugate)

A drug with a new additional indication and a new dosage for the prophylaxis of pneumococcal disease. (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in the elderly.

A drug with a new active ingredient indicated for the prophylaxis of invasive meningococcal disease. (serotypes A, C, Y, and W-135).

Vaccines

Jun. 20, 2014

Vaccines

Jul. 4, 2014

107 Menactra Intramuscular Injection (Sanofi K.K.)

Approval

Meningococcal quadrivalent vaccine (diphtheria toxoid conjugate)

Vaccines

Jul. 4, 2014

108 Squarekids Subcutaneous Injection Syringe (Kitasato Daiichi Sankyo Vaccine Co., Ltd.)

Approval

Adsorbed diphtheriaA new combination drug indicated for the prevention of purified pertussispertussis, diphtheria, tetanus, and acute poliomyelitis. tetanus-inactivated polio (salk vaccine) combined vaccine

Vaccines

Mar. 26, 2015

109 Cell Culture-derived Influenza Emulsion HA Vaccine (prototype) for Intramuscular Injection “Kaketsuken” (Kaketsuken [The Chemo-Sero-Therapeutic Research Institute])

Approval

Cell culture-derived influenza emulsion HA vaccines (prototype)

A drug with a new active ingredient indicated for the prevention of pandemic influenza. [Orphan drug]

Vaccines

Mar. 26, 2015

110 Synflorix Aqueous Suspension for Intramuscular Injection (Japan Vaccine Co., Ltd.)

Approval

Pneumococcal 10valent conjugate vaccine adsorbed (NonTypeable Haemophilus influenzae (NTHi) protein D, diphtheria or tetanus toxoid conjugates)

A drug with a new active ingredient indicated for the prophylaxis of pneumonia and pneumococcal invasive disease. (serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F)

- 166 -

Review Category

Brand Name (Applicant Company)

New Active Ingredient(s) Approval/ (underlined: new active Notes Partial ingredient) Change Change Anti-inhibitor coagulant Drugs with a revised indication and a new dosage for Change inhibition of bleeding tendency by promoting the blood complex coagulation in the plasma in patients with inhibitors to blood coagulation factor VIII or factor IX.

Approval Date

No.

Blood products

Jun. 20, 2014

111 Feiba NF for Injection 500 Feiba NF for Injection 1000 (Baxter Limited)

Blood products

Jul. 4, 2014

112 Byclot Combination Intravenous Injection (Kaketsuken [The Chemo-Sero-Therapeutic Research Institute])

Approval

Freeze-dried activated human blood coagulation factor VII concentrate containing factor X

A new combination drug with a new active ingredient indicated for prevention of bleeding in patients who have inhibitors against blood coagulation factor VIII or IX. [Orphan drug]

Blood products

Jul. 4, 2014

113 Alprolix Intravenous 250 Alprolix Intravenous 500 Alprolix Intravenous 1000 Alprolix Intravenous 2000 Alprolix Intravenous 3000 (Biogen Idec Japan Ltd.)

Approval Approval Approval Approval Approval

Eftrenonacog alfa (genetical recombination)

Drugs with a new active ingredient indicated for inhibition of bleeding tendency in patients with blood coagulation factor IX deficiency.

Blood products

Dec. 26, 2014

114 Rixubis Intravenous Rixubis Intravenous Rixubis Intravenous Rixubis Intravenous Rixubis Intravenous (Baxter Limited)

250 500 1000 2000 3000

Approval Approval Approval Approval Approval

Nonacog gamma (genetical recombination)

Drugs with a new active ingredient indicated for the control of bleeding tendency in patients with blood coagulation factor IX deficiency.

Blood products

Dec. 26, 2014

115 Eloctate Intravenous 250 Eloctate Intravenous 500 Eloctate Intravenous 750 Eloctate Intravenous 1000 Eloctate Intravenous 1500 Eloctate Intravenous 2000 Eloctate Intravenous 3000 (Biogen Idec Japan Ltd.)

Approval Approval Approval Approval Approval Approval Approval

Efraloctocog alfa (genetical recombination)

Drugs with a new active ingredient indicated for the control of bleeding tendency in patients with blood coagulation factor VIII deficiency.

Blood products

Feb. 2, 2015

116 Venoglobulin IH 5% I.V. 2.5 g/50 mL (Japan Blood Products Organization)

Change

Polyethylene glycol treated human normal immunoglobulin

A drug with a new indication and a new dosage for the prevention of acute otitis media, acute bronchitis, or pneumonia caused by Pneumococcus or Haemophilus influenzae in patients associated with a decrease in serum IgG2 levels. (for use only in patients who have not responded sufficiently to prevention by vaccination and other appropriate treatments, and have repeated the relapse of these diseases).

Blood products

Mar. 26, 2015

117 NovoThirteen i.v.injection 2500 (Novo Nordisk Pharma Ltd.)

Approval

Catridecacog (genetical A drug with a new active ingredient indicated for the control of bleeding tendency in patients with congenital recombination) blood coagulation factor XIII A-subunit deficiency. [Orphan drug]

Bio-CMC

Jul. 4, 2014

118 (1) Infliximab BS for I.V. Infusion 100 mg “NK” (Nippon Kayaku Co., Ltd.)

Approval

Infliximab (genetical recombination) [infliximab biosimilar 1]

Follow-on biologics indicated for the treatment of rheumatoid arthritis in patients who have not responded sufficiently to conventional treatments (including prevention of structural joint damage), the treatment and maintenance therapy of Crohn's disease (for use only in patients in an active phase of moderate to severe Crohn's disease or with external fistula who have not responded sufficiently to conventional treatments), or the treatment of moderate to severe ulcerative colitis (for use only in patients who have not responded sufficiently to conventional treatments).

Insulin glargine (genetical recombination) [Insulin glargine biosimilar 1]

Follow-on biologics indicated for the treatment of diabetes mellitus where insulin therapy is indicated.

(2) Infliximab BS for I.V. Infusion 100 mg “CTH” (Celltrion Inc.)

Bio-CMC

Dec. 26, 2014

119 Insulin Glargine BS Inj. Cartridges [Lilly] Insulin Glargine BS Inj. MirioPen [Lilly] (Eli Lilly Japan K.K.)

Approval

Approval Approval

- 167 -

Table 2. Products Approved in FY 2014: New Medical Devices Review Category 1

3-1

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Mar. 10, 2015

-

Total review time: 126 days Regulatory review time: 80 days

No clinical study results

Apr. 7, 2014

Nov. 21, 2013

No. 1

3-1

3-1

3-1

3-1

3-1

Global clinical trial and foreign clinical study results

May 20, 2014

Dec. 21, 2012

Total review time: 110 days Regulatory review time: 76 days

Domestic clinical study results

Jun. 12, 2014

-

Total review time: 43 days Regulatory review time: 41 days

No clinical study results

Jul. 25, 2014

-

Total review time: 91 days Regulatory review time: 48 days

No clinical study results

Sep. 25, 2014

Nov. 7, 2012

Total review time: 360 days Regulatory review time: 218 days

Domestic clinical study results

Sep. 25, 2014

Nov. 7, 2012

Total review time: 360 days Regulatory review time: 218 days

Domestic clinical study results

New Approval /Partial Change Change

Hoya CTR (Hoya Corporation)

Classification Generic Name Medical products 4 Ophthalmic intracapsular ring

2 Total review time: 255 days Regulatory review time: 110 days

Brand Name (Applicant Company)

Promus Premier Stent System (Boston Scientific Japan K.K.)

Approval

Instrument & apparatus 7 Coronary stent

3

XIENCE Xpedition Drug Eluting Stent (Abbott Vascular Japan Co., Ltd.)

Change

Instrument & apparatus 7 Coronary stent

4

5

XIENCE PRIME SV Drug-Eluting Stent System (Abbott Vascular Japan Co., Ltd.)

Change

Zilver Flex Vascular Stent for SFA (Cook Japan Inc.)

Change

Instrument & apparatus 7 Coronary stent

Instrument & apparatus 7 Stent for blood vessel

6

Change

SMART CONTROL Stent (Johnson & Johnson K.K.)

Instrument & apparatus 7 Stent for iliac artery

7

Change

SMART Stent (Johnson & Johnson K.K.)

Instrument & apparatus 7 Stent for blood vessel

- 168 -

Notes An intracapsular ring inserted into a lens capsule is used when surgical difficulty can be expected in a cataract surgery because of the risks associated with completion of the surgery due to a weakness or rupture of Zinn's Zonule. An application for partial changes of approval application for medical device to mainly add the insertion method using an injector in the usage instructions. (A partial change during the reexamination period)

A stent system consisting of a drug-eluting stent coated with everolimus to inhibit neointimal proliferation and a delivery catheter. The delivery catheter was improved by adding a link at the proximal end of a stent to produce axial strength to be superior to the original product. Clinical studies were conducted to confirm the efficacy and safety of this product in the treatment of symptomatic ischemic diseases.

A coronary stent consisting of a drug-eluting stent used for the treatment of patients with symptomatic ischemic heart disease who have a new coronary lesion (a lesion length of 32 mm or less) with a reference vessel diameter of 2.253.75 mm and a delivery catheter used to implant a stent to the coronary stenosis site. This application for partial changes of approval application for medical device to add a stent size of 2.25mm diameter and change a drug release profile determination method. The added stent is identical to the company’s approved product “XIENCE PRIME SV Drug-Eluting Stent (22500BZX00070000, hereinafter referred to as XIENCE PRIME SV). The stent delivery system is identical to that of the product of 2.5 mm diameter except for the balloon size. Results from clinical studies on “XIENCE PRIME SV” were submitted to confirm the efficacy and safety of this product in the treatment of symptomatic ischemic diseases.

A coronary stent used for the treatment of patients with symptomatic ischemic heart disease who have a new coronary lesion (a lesion length of 22 mm or less) with a reference vessel diameter of 2.25-2.5 mm. This application for a partial change of approval application for medical device to modify inconsistent information provided in the raw material or component field. (A partial change during the reexamination period)

A vascular stent to be used in patients with symptomatic vascular diseases of the above-the-knee femoropopliteal artery with reference vessel diameter of 4-7 mm. This product is used for the treatment for acute or impending occlusion caused by failure of intervention therapy or for dissection, etc. after the maximum number of “Zilver PTX Drug-Eluting Peripheral Stent” implantations. This application for a partial change of approval application for medical device to add a manufacturing site. (A partial change during the reexamination period)

A self-expanding nickel-titanium alloy stent inserted into the site of lesion in the iliac artery and/or the superficial femoral artery to expand/maintain a vascular lumen. This application for a partial change to add an elective therapy for symptomatic vascular diseases to indications for the superficial femoral artery. A clinical study was conducted to evaluate the safety and efficacy of this product in elective patients. (A partial change during the reexamination period)

A self-expanding nickel-titanium alloy stent inserted into the site of lesion in the superficial femoral artery to expand/maintain a vascular lumen. This application to add an indication of elective therapy for symptomatic vascular diseases. A clinical study was conducted to evaluate the safety and efficacy of this product in elective patients. (A partial change during the reexamination period)

Review Category 3-1

3-2

3-2

3-2

3-2

3-2

3-2

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Jan. 14, 2015

May 22, 2015

Total review time: 404 days Regulatory review time: 178 days

Domestic and global clinical study results

May 29, 2014

Jun. 12, 2012

Total review time: 358 days Regulatory review time: 172 days

Foreign clinical study results

Nov. 7, 2014

-

Total review time: 728 days Regulatory review time: 281 days

Foreign clinical study results

Nov. 14, 2014

-

Total review time: 135 days Regulatory review time: 81 days

No clinical study results

Dec. 24, 2014

Oct. 26, 2001

Total review time: 398 days Regulatory review time: 146 days

Clinical evaluation report

Mar. 24, 2015

Jun. 16, 2014

Total review time: 361 days Regulatory review time: 240 days

Domestic and foreign clinical study results

Mar. 25, 2015

Jan. 17, 2014

Total review time: 357 days Regulatory review time: 198 days

Domestic and foreign clinical study results

No. 8

Brand Name (Applicant Company)

New Approval /Partial Change Change

Misago (Terumo Corporation)

Classification Generic Name Instrument & apparatus 7 Stent for blood vessel

9

AMPLATZER Vascular Plug 4 (St. Jude Medical Japan Co., Ltd.)

Approval

Instrument & apparatus 51 Prosthetic material for embolization in vessels of the central circulation system

10

11

COOK Zenith Dissection Endovascular System (Cook Japan Inc.)

Approval

Codman Enterprise VRD (Johnson & Johnson K.K.)

Change

Instrument & apparatus 7 Aortic stent graft

Instrument & apparatus 51 Prosthetic material for embolization in vessels of the central circulation system

12

BIOPATCH Protective Disk with CHG (Johnson & Johnson K.K. )

Approval

Medical products 4 Protective patch for puncture site

13

Sapien XT (Edwards Lifesciences Limited)

Change

Instrument & apparatus 7 Transcatheter bovine pericardial valve

14

CoreValve (Medtronic Japan Co., Ltd.)

Approval

Instrument & apparatus 7 Transcatheter porcine pericardial valve

- 169 -

Notes A stent system consisting of a self-expanding nickeltitanium alloy stent and a delivery system to deliver the stent to the site of lesion, used for the treatment of symptomatic artery disease by dilatation of artery and maintenance of the lumen with target vessel diameter of 47 mm and target lesion of 40-150 mm in the superficial femoral artery region, and for the treatment of acute or impending occlusion associated with unsuccessful intervention treatment in the lesion. An application for a partial change to add palliative treatment for symptomatic vascular disease to the indications of this product. Clinical studies were conducted to evaluate efficacy and safety of this product for palliative cases.

This device is used to occlude blood vessels, and reduce, block, or modify blood flow, by transdermally inserting and placing it in arteries/veins, except blood vessels within the heart and the skull. It was changed to a form with two conical blocks, and improved its components to reduce the profile of the whole plug (the diameter in its closed state) so that the device can be advanced through an imaging catheter, maintaining the same barrier area to blood flow as that of the approved product “AMPLATZER Vascular Plug (approval No.: 22400BZX00361000) (hereinafter referred to as AVP). Results from domestic clinical studies using AVP were submitted as clinical data of this product because several non-clinical studies including design verification and animal studies had shown that the same efficiency of this product is secured as that of AVP.

A stent graft system used for the treatment of acute complicated Stanford type B aortic dissection, consisting of a stent graft that is placed to close the primary entry tear, a bare stent that enlarges compressed or narrowed intravascular lumen due to aortic dissection, and a delivery system that delivers/places them in the lesions. Results from clinical studies were submitted to evaluate efficacy and safety on this product for patients with acute complicated Stanford type B aortic dissection.

A prosthetic material for embolization in vessels of the central circulation system to prevent the protrusion and/or dropout of embolic coils into/from the parent artery during coil embolization. An application for partial changes to add VRD that improves conformability and visibility of the vascular wall, and a delivery system that improves the operability. This product is an orphan medical device. (A partial change during the reexamination period)

A sterilized disk pad with a slit, which consists of a layer of polyurethane foam impregnated with chlorhexidine gluconate antimicrobial constituent and a covering layer of foam. This product protects the insertion site of various percutaneous devices by covering the site and absorbing the fluids like wound exudate. In patients who are inserted with central venous or arterial catheters, this product also reduces the incidence of catheter-related bloodstream infections and local infections. Clinical evaluation report summarizing the clinical results on this product was submitted to evaluate the reduction of catheter-related bloodstream infections and safety of this product.

A prosthetic heart valve system is used for transcatheter valve implantation for patients with symptomatic severe aortic valve stenosis and for whom surgical aortic valve replacement cannot be performed due to the risks of complications. An application for a partial change of approval application to add the 20 mm- and 29 mmdiameter valves as the variation in size. A clinical study was conducted to confirm the equivalence in efficacy and safety between the new sizes and approved existing sizes. (A partial change during the reexamination period)

A self-expanding biological percutaneous aortic valve (porcine pericardial valve) system is used for transcatheter valve implantation in the native aortic valve for patients with symptomatic severe aortic stenosis attributed to sclerosis and degeneration of the cusp of the native aortic valve, for whom surgery cannot be performed. A clinical study was conducted to evaluate the efficacy and safety of this product and to confirm the compatibility to the domestic medical environment.

Review Category 4

4

4

4

4

4

4

4

4

4

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date May 30, 2014

-

Total review time: 287 days Regulatory review time: 144 days

Clinical evaluation report

May 30, 2014

-

Total review time: 287 days Regulatory review time: 144 days

Clinical evaluation report

Jun. 5, 2014

-

Total review time: 108 days Regulatory review time: 106 days

Clinical evaluation report

Jun. 5, 2014

-

Total review time: 108 days Regulatory review time: 106 days

Clinical evaluation report

Jun. 30, 2014

-

Total review time: 271 days Regulatory review time: 95 days

No clinical study results

Jul. 31, 2014

-

Total review time: 265 days Regulatory review time: 177 days

No clinical study results

Aug. 5, 2014

-

Total review time: 89 days Regulatory review time: 73 days

Clinical evaluation report

Aug. 5, 2014

-

Total review time: 60 days Regulatory review time: 51 days

Clinical evaluation report

Aug. 5, 2014

-

Total review time: 60 days Regulatory review time: 51 days

Clinical evaluation report

Aug. 5, 2014

-

Total review time: 60 days Regulatory review time: 51 days

Clinical evaluation report

No.

Brand Name (Applicant Company)

New Approval /Partial Change

Classification Generic Name

15

Entovis MRI (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

16

Safio S (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

An implantable cardiac pacemaker to be used by connecting it to electrodes placed within the heart. The patients implanted with the device can conditionally Implantable cardiac undergo an MRI scan. A clinical evaluation report was pacemaker submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

Endocardial implantable pacemaker lead

17

Etrinsa 8-T ProMRI (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

18

Etrinsa 6 ProMRI (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

19

Implantable Ventricular Assist System EVAHEART (Sun Medical Technology Research Corp.)

Change

Instrument & apparatus 7

Solia JT (Biotronik Japan, Inc.)

Change

20

Iforia 7 ICD ProMRI (Biotronik Japan, Inc.)

An implantable cardiac pacemaker to be used by connecting it to electrodes placed within the heart. The patients implanted with the device can conditionally Implantable cardiac undergo an MRI scan. A clinical evaluation report was pacemaker submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

Implantable ventricular assist device

Approval

Instrument & apparatus 7

Instrument & apparatus 12 Automatic implantable defibrillator

22

Linox Smart Pro S (Biotronik Japan, Inc.)

Change

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

23

Linox Smart Pro SD (Biotronik Japan, Inc.)

Change

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

24

Linox Smart Pro S DX (Biotronik Japan, Inc.)

Change

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

- 170 -

An endocardial implantable pacemaker lead connected with an implantable cardiac pacemaker. The patients implanted with the device can conditionally undergo an MRI scan. A clinical evaluation report was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

An implantable cardiac pacemaker to be used by connecting it to electrodes placed within the heart. The patients implanted with the device can conditionally Implantable cardiac undergo an MRI scan. A clinical evaluation report was pacemaker submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

Endocardial implantable pacemaker lead

21

Notes

An implantable ventricular assist device used to improve circulation until heart transplantation in patients with severe heart failure for whom the need for cardiac transplantation is indicated, showing continuous decompensation in spite of drug therapy or circulation assist techniques such as an external ventricular assist system, and for whom it is considered difficult to survive without a heart transplant. An application for a partial change to alter the alarm setting when the automatic restart function of a blood pump (automatic return mechanism) works. (A partial change during the reexamination period) [Orphan device]

An endocardial implantable pacemaker lead connected with an implantable cardiac pacemaker. The patients implanted with the device can conditionally undergo an MRI scan. An application for a partial change to add a new lead size of 45 cm in length. (A partial change during the reexamination period) An implantable defibrillator connected with electrodes placed within the heart. The patients implanted with the device can conditionally undergo an MRI scan. A clinical evaluation report summarizing clinical data on this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

A catheter electrode connected with an implantable defibrillator. The patients implanted with the device can conditionally undergo an MRI scan. This application for a partial change of approval application to change conditions of MRI compatibility. A clinical evaluation report summarizing clinical data on this product was submitted to evaluate the safety of this device in MRI scans. (A partial change during the reexamination period)

A catheter electrode connected with an implantable defibrillator. The patients implanted with the device can conditionally undergo an MRI scan. This application for a partial change of approval application to change conditions of MRI compatibility. A clinical evaluation report summarizing clinical data on this product was submitted to evaluate the safety of this device in MRI scans. (A partial change during the reexamination period)

A catheter electrode connected with an implantable defibrillator. The patients implanted with the device can conditionally undergo an MRI scan. This application for a partial change of approval application to change conditions of MRI compatibility. A clinical evaluation report summarizing clinical data on this product was submitted to evaluate the safety of this device in MRI scans. (A partial change during the reexamination period)

Review Category 4

4

4

4

4

4

4

4

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Sep. 9, 2014

-

Total review time: 187 days Regulatory review time: 126 days

Clinical evaluation report

Sep. 9, 2014

Jul. 26, 2013

Total review time: 102 days Regulatory review time: 31 days

No clinical study results

Sep. 17, 2014

Apr. 27, 2010

Total review time: 265 days Regulatory review time: 158 days

Foreign clinical study results

Sep. 25, 2014

-

Total review time: 209 days Regulatory review time: 154 days

Foreign clinical study results

Sep. 25, 2014

-

Total review time: 209 days Regulatory review time: 142 days

Foreign clinical study results

Sep. 25, 2014

-

Total review time: 209 days Regulatory review time: 142 days

Foreign clinical study results

Sep. 25, 2014

Dec. 10, 2010

Total review time: 87 days Regulatory review time: 44 days

No clinical study results

Oct. 9, 2014

Oct. 13, 2014

Total review time: 164 days Regulatory review time: 95 days

Foreign clinical study results

No. 25

Brand Name (Applicant Company) Sentus ProMRI OTW BP (Biotronik Japan, Inc.)

New Approval /Partial Change Approval

Classification Generic Name Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

26

27

Arctic Front Advance Cryoablation Catheter (Medtronic Japan Co., Ltd.)

Change

Alair Bronchial Thermoplasty System (Boston Scientific Japan K.K.)

Approval

Instrument & apparatus 51 Cardiovascular ablation catheter

Instrument & apparatus 51 Bronchial thermoplasty catheter system

28

Evera MRI ICD Series (Medtronic Japan Co., Ltd.)

Approval

Instrument & apparatus 12 Automatic implantable defibrillator

29

Sprint Quattro MRI Screw-In Lead (Medtronic Japan Co., Ltd.)

Approval

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

30

Sprint Quattro MRI Screw-In Lead S (Medtronic Japan Co., Ltd.)

Approval

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

31

Medtronic CryoConsole (Medtronic Japan Co., Ltd.)

Change

Instrument & apparatus 31 Versatile cryosurgical unit

32

CapSureFIX Novus Lead (Medtronic Japan Co., Ltd.)

Change

Instrument & apparatus 7 Endocardial implantable pacemaker leads

- 171 -

Notes A pacemaker lead connected with an implantable pulse generator and implanted in the coronary vein. The patients implanted with the device can conditionally undergo an MRI scan. A clinical evaluation report summarizing clinical data on this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

A flexible over-the-wire balloon catheter inserted into a blood vessel using a conventional minimally invasive procedure. It is used in cryoablation of cardiac tissue. This application for partial changes of approval application to remove a leak detection wire traveling in an outer lumen, and to add a manufacturing site. (A partial change during the reexamination period)

A catheter system used to apply high frequency energization to the bronchial wall to reduce asthmatic symptoms in patients aged 18 or older with severe asthma whose asthmatic symptoms are not well controlled with high-dose inhaled steroids and long-acting beta2agonists. Foreign clinical studies were conducted to demonstrate its relieving effect on asthmatic symptoms.

An implantable defibrillator intended for the treatment of ventricular tachycardia, etc. The patients implanted with the device can conditionally undergo an MRI scan. This is a new application for the product with which an MRI scan can be conditionally conducted, based on the company’s own approved products. In order to evaluate the safety of this product in MRI scans, results of clinical studies using the original product were submitted, in which the extrapolability in the evaluation was explained. (The original product is in a reexamination period)

An implantable catheter electrode connected with an implantable defibrillator and a defibrillator with biventricular pacing. The patients implanted with the device can conditionally undergo an MRI scan. This is a new application for the product with which an MRI scan can be conditionally conducted, based on the company’s own approved products. In order to evaluate the safety of this product in MRI scans, results of clinical studies using the original product were submitted, in which the extrapolability in the evaluation was explained. (The original product is in a reexamination period)

An implantable catheter electrode connected with an implantable defibrillator and a defibrillator with biventricular pacing. The patients implanted with the device can conditionally undergo an MRI scan. This is a new application for the product with which an MRI scan can be conditionally conducted, based on the company’s own approved products. In order to evaluate the safety of this product in MRI scans, results of clinical studies using the original product were submitted, in which the extrapolability in the evaluation was explained. (The original product is in a reexamination period)

A cryosurgical unit to be used for the treatment of arrhythmia. The device is for the exclusive use of cryoablation catheters. This application for a partial change of approval application for medical device to add a manufacturing site. The application falls under "expedited review of changes of manufacturing site" stated in “Acceleration of the Procedure for Changing or Adding Manufacturing Site of Medical Devices and In-vitro Diagnostics” (PFSB/ELD Notification No. 0330004, PFSB/CND Notification No. 0330012 dated on March 30, 2007). (A partial change during the reexamination period)

The device is an implantable pacing lead used by connecting it to an implantable cardiac pacemaker or defibrillator. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for requirements for imaging. The application is for a partial change to conditionally allow MRI scan with this device. Data on foreign clinical study results related to this product were submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

Review Category 4

4

4

4

4

4

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date 2014/10/20

Oct. 13, 2014

Total review time: 343 days Regulatory review time: 86 days

Foreign clinical study results

Nov. 14, 2014

-

Total review time: 162 days Regulatory review time: 95 days

Foreign clinical study results

Nov. 17, 2014

-

Total review time: 130 days Regulatory review time: 83 days

Clinical evaluation report

Nov. 17, 2014

-

Total review time: 105 days Regulatory review time: 80 days

Clinical evaluation report

Nov. 17, 2014

-

Total review time: 41 days Regulatory review time: 40 days

Clinical evaluation report

Nov. 17, 2014

-

Total review time: 41 days Regulatory review time: 40 days

Clinical evaluation report

No. 33

Brand Name (Applicant Company) CapSureFIX Novus MRI Lead (Medtronic Japan Co., Ltd.)

New Approval /Partial Change Approval

Classification Generic Name Instrument & apparatus 7 Endocardial implantable pacemaker leads

34

Medtronic Advisa MRI (Medtronic Japan Co., Ltd.)

Change

Instrument & apparatus 7

35

Iperia 7 ICD DF-1 ProMRI (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 12

36

Itrevia 7 CRT-D ProMRI (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

37

Linox Smart Pro S ( Biotronik Japan Co., Ltd.)

Change

Instrument & apparatus 7

Change

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

- 172 -

The device is an implantable cardiac defibrillator used by connecting it to electrodes placed in the heart. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. This product was developed based on the approved product "Ilesto 7 ICD Pro" (Approval No.: 22500BZX00292000). The major improvements from the approved product include the addition of conditions for the strength of static magnetic field used in MRI and an additional function for detecting ventricular tachycardia. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

The device is an implantable biventricular pacing pulse generator with defibrillator function used by connecting it to electrodes placed in the heart. Patients implanted with the Implantable device can conditionally undergo an MRI scan only when biventricular pacing the patient's condition is suitable for the requirements for pulse generator with imaging. This product was developed based on the defibrillator function approved product "Ilesto 7 CRT-D Pro" (Approval No.: 22500BZX00293000). The major improvement from the approved product is an additional function of ventricular tachycardia detection. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

Implantable defibrillator/ pacemaker lead

Linox Smart Pro SD (Biotronik Japan, Inc)

The device is an endocardial implantable pacemaker lead used by connecting it to pulse generators including an implantable cardiac pacemaker or defibrillator. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. Data on foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

The device is an implantable cardiac pacemaker. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the Implantable cardiac requirements for imaging. The application is for a partial pacemaker change to add a single-chamber type which conditionally allows MRI scan to the existing dual-chamber type. Data on foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

Automatic implantable defibrillator

38

Notes

The device is an implantable defibrillator/pacemaker lead used by connecting it to an implantable defibrillator. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change to add the condition for the strength of static magnetic field used in MRI scans. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (A partial change during the reexamination period)

The device is an implantable defibrillator/pacemaker lead used by connecting it to an implantable defibrillator. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change to add the condition for the strength of static magnetic field used in MRI scans. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (A partial change during the reexamination period)

Review Category 4

4

4

4

4

4

4

4

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Nov. 17, 2014

-

Total review time: 41 days Regulatory review time: 40 days

Clinical evaluation report

Nov. 20, 2014

-

Total review time: 168 days Regulatory review time: 105 days

No clinical study results

Nov. 20, 2014

-

Total review time: 168 days Regulatory review time: 105 days

No clinical study results

Nov. 20, 2014

-

Total review time: 168 days Regulatory review time: 105 days

Clinical evaluation report

Nov. 20, 2014

-

Total review time: 168 days Regulatory review time: 105 days

Clinical evaluation report

Dec. 22, 2014

-

Total review time: 115 days Regulatory review time: 59 days

No clinical study results

Jan. 19, 2015

-

Total review time: 109 days Regulatory review time: 62 days

No clinical study results

Jan. 21, 2015

Jun. 29, 2012

Total review time: 125 days Regulatory review time: 55 days

No clinical study results

No. 39

Brand Name (Applicant Company) Linox Smart Pro S DX (Biotronik Japan Co., Ltd.)

New Approval /Partial Change Change

Classification Generic Name Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

40

Nuance MRI RF (St. Jude Medical Japan Co., Ltd.)

Change

Instrument & apparatus 7

41

Accent MRI RF (St. Jude Medical Japan Co., Ltd.)

Change

Instrument & apparatus 7

42

IsoFlex Optim J (St. Jude Medical Japan Co., Ltd.)

Change

Instrument & apparatus 7

IsoFlex Optim (St. Jude Medical Japan Co., Ltd.)

Change

The device is an implantable cardiac pacemaker to regulate the heart rhythm by cardiac stimulation for a long term. Patients implanted with the device can undergo an Implantable cardiac MRI scan under specific conditions. The application is for a pacemaker partial change to add concomitant medical devices to perform MRI scan. (A partial change during the reexamination period)

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

44

Ingenio MRI (Boston Scientific Japan K.K.)

Change

Instrument & apparatus 7

45

Jarvik 2000 Implantable Ventricular Assist Device (Century Medical, Inc.)

Change

Instrument & apparatus 7

LifeVest Wearable Cardioverter Defibrillator (ZOLL Lifecor Corporation)

Change

46

- 173 -

The device is an implantable defibrillator/pacemaker lead used by connecting it to an implantable defibrillator. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change to add the condition for the strength of static magnetic field used in MRI scans. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (A partial change during the reexamination period)

The device is an implantable cardiac pacemaker to regulate the heart rhythm by cardiac stimulation for a long term. Patients implanted with the device can undergo an Implantable cardiac MRI scan under specific conditions. The application is for a pacemaker partial change to add concomitant medical devices to perform MRI scan. (A partial change during the reexamination period)

Implantable defibrillator/ pacemaker lead

43

Notes

The device is an implantable defibrillator/pacemaker lead. The patient implanted with the device except for the 46 cm straight lead can undergo an MRI scan under specific conditions. The application is for a partial change to conditionally allow MRI scan with this device. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

The device is an implantable defibrillator/pacemaker lead. The patient implanted with the device except for the 46 cm straight lead can undergo an MRI scan under specific conditions. The application is for a partial change to conditionally allow MRI scan with this device. A clinical evaluation report summarizing foreign clinical study results related to this product was submitted to evaluate the safety of this device in MRI scans. (The original product is in a reexamination period)

The device is an implantable cardiac pacemaker to regulate the heart rhythm by cardiac stimulation for a long term in order to perform the treatment of bradycardia. The Implantable cardiac application is for a partial change to change the materials pacemaker of the header part. (A partial change during the reexamination period)

Implantable ventricular assist device

Instrument & apparatus 12 Wearable defibrillator

The device is an axial-flow implantable ventricular assist device system used to improve the blood circulation until heart transplant. The device is used for severe cardiac failure patients who is are qualified to receive heart transplant, shown continuous decompensation in spite of drug therapy or circulation assist techniques, such as an external ventricular assist system and considered difficult to survival without heart transplant. The application is for partial changes to mainly change the battery cell incorporated into the portable battery. (A partial change during the reexamination period)

The device is a wearable cardioverter defibrillator intended for the following patients: Patients for whom indication for an implantable cardiac defibrillator (ICD) is unconfirmed despite having a high risk of sudden cardiac death due to ventricular tachycardia or ventricular fibrillation; Patients in whom an ICD cannot be implanted immediately due to their medical conditions although ICD is indicated. This wearable cardioverter defibrillator is used in the period until the propriety of indication of ICD is determined or the implantation is performed. The application is for a partial change to add an attaching method of velocro to electrocardiogram electrodes without an adhesive to the existing direct adhesive method. (A partial change during the reexamination period)

Review Category 4

4

4

4

4

4

4

4

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Feb. 3, 2015

-

Total review time: 418 days Regulatory review time: 174 days

Clinical evaluation report

Feb. 3, 2015

-

Total review time: 417 days Regulatory review time: 173 days

Clinical evaluation report

Mar. 4, 2015

-

Total review time: 132 days Regulatory review time: 87 days

Clinical evaluation report

Mar. 4, 2015

-

Total review time: 132 days Regulatory review time: 87 days

Clinical evaluation report

Mar. 23, 2015

-

Total review time: 101 days Regulatory review time: 84 days

No clinical evaluation report

Mar. 23, 2015

-

Total review time: 101 days Regulatory review time: 84 days

No clinical evaluation report

Mar. 23, 2015

-

Total review time: 101 days Regulatory review time: 84 days

No clinical study results

Mar. 23, 2015

-

Total review time: 101 days Regulatory review time: 84 days

No clinical study results

No. 47

Brand Name (Applicant Company) Beflex lead (Sorin CRM SAS)

New Approval /Partial Change Change

Classification Generic Name Instrument & apparatus 7 Endocardial implantable pacemaker leads

48

Kora 100 (Sorin CRM SAS)

Approval

Instrument & apparatus 7

49

Itrevia 7 CRT-D QP ProMRI (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

50

Sentus ProMRI OTW QP (Biotronik Japan, Inc.)

Approval

Instrument & apparatus 7

Linox Smart Pro DF4 SD (Biotronik Japan, Inc.)

Change

The device is an implantable biventricular pacing pulse generator with a defibrillator function implanted in the chest or abdomen for the treatment of ventricular tachycardia, etc. Implantable by ventricular sensing, pacing and defibrillation. Patients biventricular pacing implanted with the device can conditionally undergo an MRI pulse generator with scan only when the patient's condition is suitable for the defibrillator function requirements for imaging. A clinical evaluation report was submitted to confirm the safety of this device in MRI scans. (The original product is in a reexamination period)

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

52

Protego Pro S (Biotronik Japan, Inc.)

Change

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

53

Iforia 7 ICD ProMRI (Biotronik Japan, Inc.)

Change

Instrument & apparatus 12 Automatic implantable defibrillator

54

Solia S (Biotronik Japan, Inc.)

Change

Instrument & apparatus 7 Endocardial implantable pacemaker leads

- 174 -

The device is an endocardial implantable pacemaker lead used by connecting it to an implantable cardiac pacemaker. The application is for a partial change to allow MRI scan only when the patient's condition is suitable for the requirements for imaging. A clinical evaluation report was submitted to confirm the safety of this device in MRI scans. (The original product is in a reexamination period)

The device is an implantable cardiac pacemaker used by connecting it to electrodes placed in the heart. Patients implanted with the device can conditionally undergo an MRI Implantable cardiac scan only when the patient's condition is suitable for the pacemaker requirements for imaging. A clinical evaluation report was submitted to confirm the safety of this device in MRI scans. (The original product is in a reexamination period)

Implantable defibrillator/ pacemaker lead

51

Notes

The device is a pacemaker lead with four electrodes at its tip used by placing it in the coronary vein and connecting it to an implantable pulse generator. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. A clinical evaluation report was submitted to confirm the safety of this device in MRI scans. (The original product is in a reexamination period)

The device is an implantable defibrillator/pacemaker lead used for conducting ventricular sensing and pacing, antitachycardia pacing, and defibrillation by connecting it to an implantable defibrillator, etc. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change to change the condition allowed an MRI scan when the device is connected to a specific implantable defibrillator. (A partial change during the reexamination period)

The device is an implantable defibrillator/pacemaker lead used for conducting ventricular sensing and pacing, antitachycardia pacing, and defibrillation by connecting it to an implantable defibrillator, etc. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change to change the condition allowed an MRI scan when the device is connected to a specific implantable defibrillator. (A partial change during the reexamination period)

The device is an implantable defibrillator used by connecting it to electrodes placed in the heart. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change of approval application to add a model having a different header. (A partial change during the reexamination period)

The device is an endocardial implantable pacemaker lead used by connecting it to an implantable defibrillator, etc. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change of approval application to change the condition allowed an MRI scan when the device is connected to a specific implantable defibrillator. (A partial change during the reexamination period)

Review Category 4

4

5

6-1

6-1

6-1

8

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Mar. 26, 2015

-

Total review time: 125 days Regulatory review time: 97 days

Foreign clinical study results

Mar. 26, 2015

-

Total review time: 125 days Regulatory review time: 97 days

Foreign clinical study results

Sep. 30, 2014

Apr. 18, 2014

Total review time: 305 days Regulatory review time: 202 days

No clinical study results

Jun. 5, 2014

Jul. 20, 2006

Total review time: 160 days Regulatory review time: 40 days

Clinical evaluation report

Sep. 25, 2014

Oct. 11, 2012

Total review time: 118 days Regulatory review time: 79 days

No clinical study results

Oct. 9, 2014

Aug. 18, 2011

Total review time: 197 days Regulatory review time: 90 days

Clinical evaluation report

Jul. 3, 2014

-

Total review time: 415 days Regulatory review time: 200 days

Domestic and foreign clinical study results

No. 55

Brand Name (Applicant Company) Sprint Quattro Screw-In Lead S (Medtronic Japan Co., Ltd.)

New Approval /Partial Change Change

Classification Generic Name Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

56

Sprint Quattro Screw-In Lead (Medtronic Japan Co., Ltd.)

Change

Instrument & apparatus 7 Implantable defibrillator/ pacemaker lead

57

58

59

60

InterStim II Neurostimulator for Sacral Neuromodulation (Medtronic Japan Co., Ltd.)

Change

Aequalis Reversed Shoulder Prosthesis (Tornier S.A.S.)

Change

Trabecular Metal Reverse Shoulder System (Zimmer K.K.)

Change

Lima Reverse Shoulder System (Lima Japan K.K.)

Approval

Instrument & apparatus 12 Implantable stimulator for bladder and bowel control

Medical products 4 Total shoulder prosthesis

Medical products 4 Total shoulder prosthesis

Medical products 4 Total shoulder prosthesis

61

Radioactive Pharmaceutical Synthesizer NEPTIS Plug-01 (Eli Lilly Japan K.K.)

- 175 -

Approval

Instrument & apparatus 10

Notes The device is an implantable catheter electrode used by connecting it to an implantable defibrillator and a defibrillator with biventricular pacing. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change for some components with which an MRI scan can be conditionally conducted. In order to evaluate the safety of this product in MRI scans, the results of clinical studies using the original product were submitted, in which the extrapolability in the evaluation was explained. (The original product is in a reexamination period)

The device is an implantable catheter electrode used by connecting it to an implantable defibrillator and a defibrillator with biventricular pacing. Patients implanted with the device can conditionally undergo an MRI scan only when the patient's condition is suitable for the requirements for imaging. The application is for a partial change for some components with which an MRI scan can be conditionally conducted. In order to evaluate the safety of this product in MRI scans, the results of clinical studies using the original product were submitted, in which the extrapolability in the evaluation was explained. (The original product is in a reexamination period)

An implantable nerve stimulation system consisting of an electric stimulator and leads to be used in sacral nerve stimulation therapy for fecal incontinence. This application for a partial change of approval application to change a testing stimulator to a new type. A testing stimulator control is changed from a constant voltage control to a constant current control, while an implantable electric stimulator remains to be controlled by a constant voltage. (A partial change during the reexamination period)

A reversed shoulder prosthesis system used in patients with shoulder rotator cuff dysfunction. This application for partial changes to add new components (eccentric or other type of inserts and glenoid sphere, small-diameter and HAcoated base plate, conversion adaptor for anatomical type) and to add usage (fixation of glenoid component with specific bone graft: BIO-RSA). A clinical evaluation report was submitted to demonstrate that this device is equivalent to the approved product and that there is no new unacceptable risk while option for the product is extended by the added components and the usage.

A reversed shoulder prosthesis system used in patients with shoulder rotator cuff dysfunction including arthropathy with tendon rupture and massive rotator cuff tears. This application for a partial change of approval application to add a new component with a changed base plate (extended post length and off-set model), which is intended to improve suitability to patients' bone shapes. Based on the results of non-clinical studies, it was judged that new additional clinical evaluation is not required, because it is difficult to assume that a new clinical risk is actualized by the difference from the approved product. (A partial change during the reexamination period)

A shoulder prosthesis having the concept of a reversed shoulder prosthesis system in which the anatomical structure is reversed. It is used for cases of rotator cuff dysfunction such as a massive rotator cuff tears or rotator cuff tear arthropathy. When it is difficult to be combined with a reversed shape, it can be combined with an anatomical shape in humerus or total shoulder joint replacement. A clinical evaluation report was submitted to confirm that the efficacy and safety of this device are equivalent to the existing approved devices based on overseas usage histories and publications of this device and similar devices.

A radioactive pharmaceutical synthesizer used for the semi-automated preparation of a radioisotope labeled compound, florbetapir (18F) injection by remote control Radiopharmaceutic system indicated for the visualization of beta-amyloid al synthesizer plaque in the brain in patients with cognitive impairment who are suspected of having Alzheimer's disease. Results from non-clinical studies, and domestic and foreign clinical studies were submitted as evaluation data on the efficacy and safety of this product and florbetapir (18F) injection.

Review Category 8

8

8

Approval Date in US Clinical Study Results: Domestic/Foreign

Approval Date Nov. 7, 2014

Oct. 18, 2012

Total review time: 322 days Regulatory review time: 180 days

Foreign clinical study results

Dec. 12, 2014

Jan. 21, 2010

Total review time: 73 days Regulatory review time: 19 days

No clinical study results

Mar. 25, 2015

Apr. 8, 2011

Total review time: 266 days Regulatory review time: 174 days

Foreign clinical study results

Specified May 1, 2014 partial change Total review time: 76 days Regulatory review time: 32 days

-

Specified Jul. 25, 2014 partial change Total review time: 121 days Regulatory review time: 36 days

Jan. 4, 2008

Specified Aug. 29, 2014 partial change Total review time: 80 days Regulatory review time: 80 days

-

No.

Brand Name (Applicant Company)

New Approval /Partial Change

Classification Generic Name

MR-Guided Focused Ultrasound Surgery System ExAblate 2000 (GE Healthcare Japan Corporation)

Change

63

Magnetic Navigation System Niobe (Medix Japan, Inc.)

Change

Instrument & apparatus 51

64

NovoTTF-100A System (NovoCure Ltd.)

Approval

Instrument & apparatus 12

62

Instrument & apparatus 12 Ultrasound hyperthermia system

No clinical study results

66

Kawasumi Najuta Thoracic Stent Graft System (Kawasumi Laboratories, Incorporated)

Change

NaviStar RMT ThermoCool (Johnson & Johnson K.K.)

Change

Instrument & apparatus 7 Aortic stent graft

No clinical study results

Instrument & apparatus 51 Cardiovascular ablation catheter

67

Matsudaito (Sanyo Chemical Industries, Ltd.)

No clinical study results

Change

Medical products 4 Non-absorbable topical hemostatic material for central circulatory system

- 176 -

The device is a focused ultrosonic surgery system intended for heating and necrotizing target tissues by focusing ultrasound generated using an external transducer on internal targets. The application is for partial changes to (1) add a new indication, "relief of pain due to painful metastatic bone cancer" and (2) make an improvement intended to enhance operability in a previously approved indication, "improvement of symptoms of symptomatic uterine myoma." For (1), results of clinical study conducted to evaluate the efficacy and safety of this device in the new additional indication were submitted. For (2), results of non-clinical study conducted to evaluate efficiency of the additional capability, etc. in previously approved indication were submitted.

The device is a guiding system that navigates an exclusive catheter for this system to a target region in the diagnosis of arrhythmia and intervention procedures. This device is Cardiac Mapping used in combination with cardiovascular fluoroscopic X-ray System Workstation diagnosing apparatus, and consists of a magnetic positioner, a control cabinet, a user interface, a ceilingsuspended monitor and a catheter advancement system. The application is for partial changes to add an image control support device, and to change the monitor size and emergency switch. (A partial change during the reexamination period)

Alternating electric field tumor treatment system

65

Notes

The medical device is a non-invasive device that delivers alternating electric fields -referred to as Tumor Treating Fields (TTfield) - that inhibit cancer cell replication and cause cancer cell death. TTFields are delivered to the tumor in the brain through insulated transducer arrays (INE transducer array) that are placed on the scalp. A clinical trial was conducted to compare the efficacy and safety of the device to chemotherapy in patients with recurrent glioblastoma multiforme after receiving all possible surgery and radiation therapy options. [Priority review]

An aortic stent graft used for the treatment of thoracic aortic aneurysm. This application for a partial change of approval application for medical device to add a PFOA-free raw material to a raw material of graft “polytetrafluoroethylene.” The application was submitted as a "specified partial change” based on “Acceleration of Procedure for Specified Change for Medical Devices” (PFSB/ELD/OMDE Notification No.1110001 dated on November 10, 2008).

An electrode catheter for the radiofrequency catheter ablation and for the electrophysiological study; it is used to treat symptomatic drug refractory paroxysmal and persistent atrial fibrillation, atrial flutter and ventricular tachycardia which is not treated effectively in other ways. This device is manipulated with a magnetic navigation system. It also has an irrigation system that flows with saline from an irrigation hole at the tip of the electrode. This application for a partial change of approval application for medical device to change a raw material of the hub (polycarbonate). The application was submitted as a "specified partial change” based on “Acceleration of Procedure for Specified Change for Medical Devices” (PFSB/ELD/OMDE Notification No.1110001 dated on November 10, 2008). (A partial change during the reexamination period)

A non-absorbable topical hemostatic material consisting of sealant liquid (main body) filled in a syringe and accessory sheets and spatula. This application for a partial change of approval application for medical device to add a manufacturer of a raw material of sealant liquid, fluorinecontaining diisocyanate. The application was submitted as a "specified partial change" based on “Acceleration of Procedure for Specified Change for Medical Devices” (PFSB/ELD/OMDE Notification No.1110001 dated on November 10, 2008). (A partial change during the reexamination period)

Table 3. Products Approved in FY 2014: Improved Medical Devices (with Clinical Data) Review Category 1

1

Date Approved in US Clinical Study Results: Domestic/Foreign

Approval Date Apr. 3, 2014

-

Total review time: 83 days Regulatory review time: 58 days

Domestic clinical study results

Jun. 30, 2014

Mar. 8, 2012

No.

Brand Name (Applicant Company)

New Approval/ Partial Change Approval

1

Alcon Acrysof IQ Restor +2.5D SinglePiece (Alcon Japan Ltd.)

Advanced Femtosecond Laser (AMO Japan K.K.)

Change

2

Aug. 25, 2014

Oct. 18, 2010

LenSx Laser System (Alcon Japan Ltd.)

Approval

Total review time: 299 days Foreign clinical study results Regulatory review time: 66 days

Jun. 11, 2014

Jan. 23, 2015

Jun. 30, 2004

Straumann Implant (SLActive) BL (Straumann Japan K.K.)

Approval

Medical products 4

4

Tapered Screw-Vent X (Zimmer K.K.)

Approval

Medical products 4

5

MOMO Coronary Stent System (Japan Stent Technology Co., Ltd.)

Approval

6

Instrument & apparatus 7

Dec. 14, 2011

Total review time: 1488 Clinical evaluation report days Regulatory review time: 319 days

3-1

Jul. 25, 2014

Instrument & apparatus 31 Ophthalmic pulsed laser surgical instrument

Total review time: 168 days Domestic clinical study result Regulatory review time: 76 and clinical evaluation report days

2

Instrument & apparatus 31 Ophthalmic laser corneal surgical instrument

3

2

Instrument & apparatus 72 Multifocal posterior chamber lens

Total review time: 349 days Clinical evaluation report Regulatory review time: 178 days

1

Classification Generic Name

-

Total review time: 512 days Domestic clinical study results Regulatory review time: 183 days

An ophthalmic laser corneal surgical instrument to create lamellar cut/resection of the cornea by irradiating a focused ultrashort pulsed laser beam (wavelength 1053 nm, few hundred femtosecond) on corneal tissue. It is used for creation of a corneal flap in LASIK (laser in-situ keratomileusis) and for corneal resection in keratoplasty. An application for partial changes to mainly add arcuate incisions in the cornea (penetrating incision or intrastromal incision) in ophthalmic surgery to the intended use. A clinical evaluation report was submitted to confirm the safety of intrastromal incision in actual clinical practice because an intrastromal incision cannot be performed with a diamond knife.

An ophthalmic pulsed laser surgical instrument used for incision of anterior lens capsule, split of crystalline lens and corneal incision in cataract surgery. It consists of main body of the laser oscillator and patient interface that sucks and fixes the affected patient's eye. Although in conventional cataract surgery, incision of the anterior lens capsule, split of crystalline lens and corneal incision are performed using a cystotome, ultrasonic shock wave generated by cataract surgery instrument and ophthalmic knife, respectively, this device enables these procedures to be performed consecutively or in arbitrary combinations of each function using a femtosecond laser having a maximum energy of 15 microjoules. A foreign clinical study was conducted to confirm that this product has no particular problems by comparing this method to existing methods in cataract surgery.

Pure titanium dental implant body having the roughened surface by sandblasting and acid etching. This product is a bone level type of the company's Dental implant body approved product "Straumann Implant (SLActive) TL" (Approval No.: 22600BZX00016000), which accelerates osteointegration and enables earlier loading by providing the product sealed into a vial filled with normal saline to keep the hydrophilic nature of titanium until just before use. A domestic clinical study on an implant of 4.1mm in diameter was conducted to evaluate its efficacy and safety in early loading compared to in conventional loading. In addition, results of foreign clinical studies on a thinner implant of 3.3mm in diameter were submitted.

An implant fixture partially or wholly implanted in the jawbone, which supports for the upper structure. In order to confirm the bone fixation performance of the Intraosseous dental new structure with a porous structure on the surface, a implant clinical evaluation report created from clinical results in published literatures on this product was submitted to evaluate the clinical performance in addition to the normal performance evaluation test.

Coronary stent

- 177 -

Notes A multifocal posterior chamber lens to be inserted as a substitute for a crystalline lens to correct near and/or far vision in patients with aphakia. The raw materials, basic form and principle of the multifocal mechanism are identical to those of the company's approved product, "Alcon Acrysof IQ Restor Single-Piece" (Approval No.: 22000BZX00970000). However, the diameter of apodized diffraction region, diffraction region number and central refractive region are different from the existing approved product. Domestic clinical study results were submitted to evaluate the efficacy and safety of the multifocal mechanism.

A coronary stent consisting of a stent to be inserted and placed at the site of a lesion to maintain the patency of the vascular lumen and a delivery catheter used to deliver the stent to the site of the lesion in percutaneous coronary stent placement. This stent is made of a cobalt-chromium alloy and the surface is coated with a diamond-like carbon to reduce in-stent restenosis. A domestic clinical study was conducted to verify the efficacy and safety of this product in patients with symptomatic ischemic heart disease who have a new stenosis or restenosis of a coronary lesion (lesion length is 26 mm or less) with a reference vascular diameter ranging from 3.0 mm to 4.0 mm.

Review Category 3-1

Approval Date Aug. 29, 2014

Date Approved in US Clinical Study Results: Domestic/Foreign Jan. 11, 2013

No.

7 Total review time: 336 days Clinical evaluation report Regulatory review time: 118 days

3-1

Oct. 30, 2014

Feb. 17, 2012 8

Total review time: 269 days Foreign clinical study results Regulatory review time: 195 days

3-1

Nov. 17, 2014

9

Brand Name (Applicant Company)

New Approval/ Partial Change

TransForm Occlusion Balloon Catheter (Stryker Japan K.K.)

Approval

Resolute Integrity Coronary Stent System (Medtronic Japan Co., Ltd.)

Change

Vival Coronary Stent (Goodman Co., LTD.)

Approval

Nov. 28, 2014

Coronary stent

Nov. 21, 2013

Promus Premier LV Stent System (Boston Scientific Japan K.K.)

Approval

Total review time: 246 days Global clinical trial and foreign Regulatory review time: 164 clinical study results days

Jan. 19, 2015

Jan. 21, 2005

Outback Re-entry Catheter (Johnson & Johnson K.K.)

Approval

Total review time: 528 days Clinical evaluation report Regulatory review time: 220 days

Feb. 12, 2015

Oct. 26, 2011

ASSURANT COBALT Stent (Medtronic Japan Co., Ltd.)

Approval

Total review time: 240 days Foreign clinical study results Regulatory review time: 116 days

May 19, 2014

Scepter C:Sep. 29, 2011, Scepter XC:Jan. 13, 2012

Instrument & apparatus 7

Instrument & apparatus 51 Vascular recanalization catheter

12

3-2

Instrument & apparatus 7

Coronary stent

11

3-1

Instrument & apparatus 7

Coronary stent

10

3-1

Instrument & apparatus 51 Intravascular catheter for embolization of the central circulation system

Total review time: 836 days Domestic clinical study results Regulatory review time: 250 days

3-1

Classification Generic Name

Instrument & apparatus 7 Stent for iliac artery

13

Scepter C (Terumo Corporation)

Total review time: 220 days Clinical evaluation report Regulatory review time: 92 days

Change

Instrument & apparatus 51 Intravascular catheter for embolization of the central circulation system

- 178 -

Notes An intravascular catheter for embolization of the central circulation system used for temporary interruption of blood flow in percutaneous intravascular surgery or for prevention of a coil mass from protruding into and/or prolapsing into the parent artery as an adjunct of coil embolization for cerebral aneurysms. A clinical evaluation report was submitted to confirm the efficacy and safety of balloon-assisted coil embolization using this device.

A stent system for percutaneous coronary stent placement consisting of a zotarolimus-eluting stent to be inserted and placed at the site of a lesion to maintain the patency of the vascular lumen and a delivery catheter used to deliver the stent to the site of the lesion. An application for a partial change to add a 4.0-mm diameter stent. Foreign clinical study results were submitted to evaluate the efficacy and safety of a stent having a diameter of 4.0 mm.

A stent system for percutaneous coronary stent placement consisting of a stent to be placed at the narrowed or blocked segment of coronary artery to maintain the patency of the vascular lumen and a delivery catheter used to deliver the stent to the site of the lesion and dilate the stent. The raw materials were changed from those of the "Duraflex Coronary Stent" (Approval No.: 21500BZY00516000) to reduce the thickness of the stent, and the delivery catheter was also changed. A domestic clinical study was conducted to evaluate the efficacy and safety of this product in patients with symptomatic ischemic heart diseases who have a new stenosis or restenosis lesion in a coronary artery (a lesion length of 25 mm or less).

A stent system for percutaneous coronary stent placement consisting of a everolimus-eluting stent with diameter of 4.0 mm to be inserted and placed at the site of a lesion to maintain the patency of the vascular lumen and a delivery catheter used to deliver the stent to the site of the lesion. The product having a diameter of 2.25 - 3.5 mm was previously approved in Japan as "Promus Premier Stent System" (Approval No.: 22600BZX00181000). A clinical study was conducted to evaluate the efficacy and safety of the stent with a 4.0 mm diameter.

A catheter consisting of a cannula, an outer shaft, a lure assembly and a handle. It assists recanalization back into the true lumen with a guidewire advanced via the subintimal space during percutaneous angioplasty to treat chronic total occlusion in the region of the femoropopliteal artery. A clinical evaluation report has been created based on the reports that were collected from an adverse-event database with clinical results and published literatures. The clinical report was submitted to confirm the performance and safety of this product to be used for the lesions with chronic total occlusion.

A balloon expandable stent and the delivery system used to maintain the patency of the vessel lumen of de novo and restenotic symptomatic lesions in the common iliac artery and external iliac artery. A clinical study was conducted to evaluate the efficacy and safety of this product in clinical use. A balloon catheter used for temporary interruption of blood flow in percutaneous intravascular surgery or for prevention of a coil clot protruding into and/or dropping out from the parent artery as an adjunct of coil embolization for cerebral aneurysms. A clinical evaluation report was submitted to confirm the efficacy and safety of balloon-assisted coil embolization using this device.

Review Category 3-2

Approval Date Aug. 1, 2014

Date Approved in US Clinical Study Results: Domestic/Foreign Feb. 14, 2013

No.

14

Brand Name (Applicant Company) AORFIX AAA Stent Graft System (Medico's Hirata Inc. )

New Approval/ Partial Change Approval

Nov. 20, 2014

15

Steering Microcatheter (Akita Sumitomo Bakelite Co., Ltd.)

Approval

Total review time: 262 days Domestic clinical study results Regulatory review time: 181 days

3-2

Jan. 23, 2015

Apr. 9, 2013

Gore Acuseal Vascular Graft (W.L. GORE & Associates, Co., Ltd.)

Approval

Total review time: 490 days Foreign clinical study results Regulatory review time: 100 days

Aug. 8, 2014

Aug. 19, 2014

ccNexfin Hemodynamic Monitor (Edwards Lifescience Limited)

Approval

17

Instrument & apparatus 21

TVC Imaging System (Nipro Corporation)

Approval

18

Instrument & apparatus 12

Oct. 28, 2010

Jun. 30, 2010

Total review time: 560 days Foreign clinical study results Regulatory review time: 252 days

4

Aug. 19, 2014

Jun. 30, 2010

Nov. 26, 2014

TVC Insight Catheter (Nipro Corporation)

Approval

19

Instrument & apparatus 51

Vercise DBS System (Boston Scientific Japan K.K.)

Approval

20

Instrument & apparatus 12

-

Total review time: 299 days Foreign clinical study results Regulatory review time: 115 and clinical evaluation report days

An aortic stent graft system consisting of a stent graft and delivery system used for intravascular treatment of abdominal aortic aneurysms and aortic aneurysms extended from the abdominal aorta to the iliac artery. For the indication of infrarenal aortic aneurysm, although an existing approved stent graft for abdominal aortic aneurysms is limited to treat patients with an aortic neck angle not greater than 60 degrees, this product enable to treat patients with the angles of up to 90 degrees. A foreign clinical study was conducted to evaluate the efficacy and safety of this product in case groups where the aortic neck angles are ranging from 60 degrees to 90 degrees.

An intravascular microcatheter for the central circulation system (except for the cardiac and cerebral [intracranial] vessels) used for selective angiography, drug infusion and embolization. The direction of the catheter tip can be controlled by rotating a dial and thereby the catheter can be inserted selectively into the bent vessels without a guidewire. The results of a domestic clinical study was submitted to confirm the efficacy and safety of this product that enables directional operation of the catheter tip by the dial.

An artificial triple-layered blood vessel used for vascular access. The lumen is coated with heparin. A clinical study was conducted to evaluate the efficacy and safety of this product in patients requiring hemodialysis.

The device is a device to visualize the form and characteristics of the vascular lumen and wall in the central circulation system and to provide the image data for diagnosis. This device has a function to detect a lipid core plaque using near-infrared light and to provide image data combined with an ultrasonogram. However, the image detected by this function is not intended to diagnose. A clinical study was conducted to evaluate that the device can detect a lipid core plaque using near-infrared light.

The device is a catheter equipped with a transducer for sending and receiving ultrasound on the tip to visualize the form and characteristics of the vascular lumen and Central circulation wall in the central circulation system. This device is system also equipped with an optical mirror and an optical fiber intravascular that irradiate and collect near-infrared light to detect a ultrasound catheter lipid core plaque and to provide image data combined with an ultrasonogram. However, the image detected by near-infrared light is not intended to diagnose. A clinical study was conducted to evaluate that the device can detect a lipid core plaque using near-infrared light.

Electrical brain stimulation device for tremor

- 179 -

Notes

The device is an apparatus for continuously monitoring hemodynamic parameters including systolic/diastolic blood pressures (BP), heart rate (HR), stroke volume Monitor of arterial (SV), cardiac output (CO) and systemic vascular blood pressure and resistance (SVR). The hemodynamic parameters are cardiac output calculated from arterial blood pressure waveform at the fingertips measured non-invasively and continuously by using the volume-clamp method. Non-clinical study and foreign clinical study results were submitted as the evaluation data on the efficacy and safety of this product.

Cardiovascular ultrasonic diagnostic imaging instrument

Total review time: 512 days Foreign clinical study results Regulatory review time: 159 days

4

Instrument & apparatus 7 Artificial blood vessel using heparin of the noncentral circulation system

Total review time: 294 days Foreign clinical study results Regulatory review time: 197 days

4

Instrument & apparatus 51 Central circulation system Microcatheter

16

4

Instrument & apparatus 7 Aortic stent graft

Total review time: 458 days Foreign clinical study results Regulatory review time: 265 days

3-2

Classification Generic Name

The device is an electrical brain stimulation device used to reduce tremors that do not sufficiently respond to drug therapy and symptoms of movement disorder associated with Parkinson's disease by providing an electrical stimulus unilaterally or bilaterally to the deep brain (thalamus, subthalamic nucleus or internal globus pallidus). This device consists of an implantable pulse generator and lead, an external trial stimulator to evaluate presence or absence of effect by test stimulation, and a remote controller to control stimulation parameter. Foreign clinical study results to evaluate the efficacy and safety in patients with Parkinson's disease and a clinical evaluation report summarizing foreign clinical studies and published papers to evaluate the efficacy and safety in patients with tremors were submitted.

Review Category 4

Approval Date Dec. 22, 2014

Date Approved in US Clinical Study Results: Domestic/Foreign Jan. 30, 2014

No.

Brand Name (Applicant Company) Navvus Catheter (ACIST Medical Systems, Inc.)

Approval

21

Instrument & apparatus 51

EHL Autolith (AMCO Inc.)

Approval

22

Instrument & apparatus 12

New Approval/ Partial Change

Total review time: 361 days Foreign clinical study results Regulatory review time: 268 days

5

Jul. 9, 2014

Jan. 28, 1993

Total review time: 575 days Clinical evaluation report Regulatory review time: 159 days

5

Sep. 10, 2014

Mar. 29, 2011

Total review time: 376 days Clinical evaluation report Regulatory review time: 84 days

May 7, 2014

May 31, 2007 24

Cook Evolution Duodenal Stent System (Cook Japan Inc.)

Approval

VEPTR II System (Johnson & Johnson K.K.)

Approval

6-2

May 26, 2014

Apr. 11, 2013

HEALICOIL RG Suture Anchor (Smith & Nephew Endoscopy KK)

Approval

Total review time: 124 days Domestic clinical study results Regulatory review time: 91 days

May 26, 2014

Medical products 4 Absorbable ligament fixation

May 18, 2012 26

Total review time: 180 days Domestic clinical study results Regulatory review time: 119 days

Medical products 4 Internal fixation system

25

6-2

Instrument & apparatus 7 Gastroduodenal stent

Total review time: 303 days Clinical evaluation report Regulatory review time: 116 days

PICO Wound Therapy System (Smith & Nephew Wound Management KK)

- 180 -

Approval

Notes

The device is a catheter with a pressure sensor at the distal tip. It is used for invasive measuring of intravascular pressure in the central and non-central Central circulation circulation systems excluding the cerebral blood vessel system transducerand carotid artery, and also used for evaluation of tipped catheter hemodynamics. The catheter type was adopted to enhance the operability by comparing with a conventional wire type of a similar medical device. The data on results of clinical study to compare the measurement accuracy with that of a previously approved product "SJM PressureWire Certus" (Approval No.: 22300BZX00247000) was submitted.

Intracorporeal electrohydraulic shock wave lithotriptor

23

6-2

Classification Generic Name

Medical products 4

An intracorporeal electrohydraulic shock wave lithotriptor used to crush calculuses in the kidney and bladder (urinary calculus) and bileduct stone using an electrohydraulic shock wave. A clinical evaluation report was submitted to evaluate the efficacy and safety of this product in patients with bile duct stone. A stent system to place a stent by endoscopically inserting a delivery system to maintain patency in gastroduodenal obstruction and duodenal stenosis associated with malignant tumors in patients for whom alleviative gastrectomy is considered difficult to be performed or other treatments is unlikely to have an effect. A clinical evaluation report was submitted to confirm the efficacy and safety of treatment using this stent in patients with malignant gastric outlet obstruction.

An internal fixation system made of titanium alloy and titanium which corrects thoracic deformity while allowing further growth of thorax by implanting an expandable metallic rod which is extendable along body axial direction in the thorax of the patients with thoracic insufficiency syndrome. Based on the approved product "VEPTR system (Approved No.: 22000BZX01655000)", and major difference from the approved product is that the usability and compatibility of this device with the patient's thorax were enhanced by adding variations on the components or improving the components. A clinical evaluation was conducted with the literatures on this product and the approved product, overseas safety information and clinical evaluation report based on a use-results survey of the approved product to confirm that efficacy and safety of this device equivalent to or greater than that of the approved product were also maintained by the differences.

A suture anchor used to fix soft tissues of the tendons and ligaments to the bones of the shoulder, elbow, groin (gluteal tendons), knee and foot/ankle. It consists of an absorbable anchor that adopts the hollow coil configuration of the approved product "HEALICOIL Suture Anchor" (Approval No.: 22500BZX00193000), sutures and an inserter. The point of improvement is that a glycolic acid/L-lactic copolymer and a mixture of calcium sulfate and beta-tricalcium phosphate which are new bioabsorbable materials, were adopted as raw materials. The results of a domestic clinical study on arthroscopic labrum repair in shoulder for traumatic shoulder instability using "Osteoraptor OS Anchor" (Approval No.: 22600BZX00228000) made of the same raw materials as this product were submitted to confirm the efficacy and safety of the new bioabsorbable materials.

A negative pressure wound therapy system to promote wound healing by providing a locally managed negative-pressure for patients with a refractory wound Single-use negative who have not responded to or are considered to be pressure wound unlikely to respond to existing treatment. This device therapy system consists of a negative pressure maintenance unit, dressing and a tube to connect the unit and the dressing. Exudate is retained in the dressing applied to wound area and transpired through the backing film. The point of improvement from the approved product "RENASYS Wound Therapy System" (Approval No: 22400BZX00276000) is a downsizing and weight lightening of the main body of the device which allows the device to be used for outpatient. A clinical study on inpatients and outpatients was conducted to evaluate if the performance of this device was equivalent to that of approved product, and to confirm any defects or adverse events specific to this product.

Review Category 6-2

Approval Date May 26, 2014

Date Approved in US Clinical Study Results: Domestic/Foreign Jan. 27, 2011

No.

27

Brand Name (Applicant Company) Osteoraptor OS Anchor (Smith & Nephew Endoscopy KK)

New Approval/ Partial Change Approval

Total review time: 124 days Domestic clinical study results Regulatory review time: 103 days

6-2

Jun. 23, 2014

Apr. 30, 1998

OASIS Extracellular Matrix (Cook Japan Inc.)

Approval

Total review time: 1242 Foreign clinical study results days Regulatory review time: 281 days

Dec. 3, 2014

Mar. 18, 1998

Orthofix HA Coating Pin (Orthofix S. r. l.)

Approval

Total review time: 244 days Clinical evaluation report Regulatory review time: 85 days

Feb. 6, 2015

-

Duolith SD1 (Storz Medical AG)

Approval

Total review time: 267 days Foreign clinical study results Regulatory review time: 196 days

Mar. 26, 2015

-

Leksell Gamma Knife C (Elekta K.K.)

Change

Total review time: 209 days Clinical evaluation report Regulatory review time: 150 days

Mar. 26, 2015

-

Leksell Gamma Knife 4C (Elekta K.K.)

Change

Total review time: 209 days Clinical evaluation report Regulatory review time: 150 days

Mar. 26, 2015

Instrument & apparatus 10 Radionuclide system for stereotactic radiotherapy

32

8

Instrument & apparatus 12 Extracorporeal shock wave pain therapy system

31

8

Medical products 4 Internal fixation pin

30

8

Medical products 4 Collagen-based artificial skin

29

6-2

Medical products 4 Absorbable ligament fixation

28

6-2

Classification Generic Name

Instrument & apparatus 10 Radionuclide system for stereotactic radiotherapy

33

Leksell Gamma Knife Model-C (Elekta K.K.)

Total review time: 209 days Clinical evaluation report Regulatory review time: 150 days

Change

Instrument & apparatus 10 Radionuclide system for stereotactic radiotherapy

- 181 -

Notes A suture anchor used to fix the soft tissues of tendons and ligaments to the bone in the shoulder, elbow, wrist/hand, groin, knee and foot/ankle. It consists of an absorbable anchor, sutures and an inserter. The point of improvement is that a glycolic acid/L-lactic acid copolymer and a mixture of calcium sulfate and betatricalcium phosphate which are new bioabsorbable materials, were adopted as raw materials for the anchor. The results of a domestic clinical study on arthroscopic labrum repair in shoulder for traumatic shoulder instability using this device were submitted to confirm the efficacy and safety of the new bioabsorbable materials.

Collagen-based artificial skin for control and treatment of full and partial thickness wounds. Porcine smallintestinal submucosa is used as a raw material. Viral clearance study results were submitted to evaluate the virus safety of this product. In addition, foreign postmarketing clinical study results were submitted to evaluate the efficacy and safety in clinical use for patients with venous ulceration and pressure ulcers (decubitus ulcers).

A stainless steel pin used with external fixators. No products such as pins coated with hydroxyapatite to enhance the fixation have been approved in Japan. Therefore, in addition to the results of a tensile strength test, a clinical evaluation report summarizing overseas published papers was submitted to evaluate the efficacy and safety of fixation with this product.

An extracorporeal shock wave pain therapy system designed to enable adjustment of output by the conventional electromagnetic induction-type extracorporeal shock wave lithotripter to the low power output. It is used for pain relief in patients with refractory plantar aponeurositis. A clinical study was conducted to evaluate the efficacy and safety of this product in patients with refractory plantar aponeurositis.

The device is a gamma knife used for non-incisional surgery by gamma ray irradiation in patients with brain diseases including cerebral vascular disorder or brain tumor, and brain functional disorder. The application is for a partial change to add the indication for trigeminal neuralgia for which pain control is difficult by drug therapy. A clinical evaluation report summarizing domestic and overseas published papers was submitted to evaluate the efficacy and safety of gamma knife treatment for trigeminal neuralgia with difficult pain control by drug therapy.

The device is a gamma knife used for non-incisional surgery by gamma ray irradiation in patients with brain diseases including cerebral vascular disorder or brain tumor, and brain functional disorder. The application is for a partial change to add the indication for trigeminal neuralgia for which pain control is difficult by drug therapy. A clinical evaluation report summarizing domestic and overseas published papers was submitted to evaluate the efficacy and safety of gamma knife treatment for trigeminal neuralgia with difficult pain control by drug therapy.

The device is a gamma knife used for non-incisional surgery by gamma ray irradiation in patients with brain diseases including cerebral vascular disorder or brain tumor, and brain functional disorder. The application is for a partial change to add the indication for trigeminal neuralgia for which pain control is difficult by drug therapy. A clinical evaluation report summarizing domestic and overseas published papers was submitted to evaluate the efficacy and safety of gamma knife treatment for trigeminal neuralgia with difficult pain control by drug therapy.

Review Category 8

Approval Date Mar. 26, 2015

Date Approved in US Clinical Study Results: Domestic/Foreign May. 24, 2012

No.

34

Brand Name (Applicant Company) Leksell Gamma Knife Perfexion (Elekta K.K.)

New Approval/ Partial Change Change

Total review time: 209 days Clinical evaluation report Regulatory review time: 150 days

8

Mar. 26, 2015

Classification Generic Name Instrument & apparatus 10 Radionuclide system for stereotactic radiotherapy

35

Leksell Gamma Knife (Elekta K.K.)

Total review time: 209 days Clinical evaluation report Regulatory review time: 150 days

Change

Instrument & apparatus 10 Radionuclide system for stereotactic radiotherapy

- 182 -

Notes The device is a gamma knife used for non-incisional surgery by gamma ray irradiation in patients with brain diseases including cerebral vascular disorder or brain tumor, and brain functional disorder. The application is for a partial change to add the indication for trigeminal neuralgia for which pain control is difficult by drug therapy. A clinical evaluation report summarizing domestic and overseas published papers was submitted to evaluate the efficacy and safety of gamma knife treatment in trigeminal neuralgia with difficult pain control by drug therapy.

The device is a gamma knife used for non-incisional surgery by gamma ray irradiation in patients with brain diseases including cerebral vascular disorder or brain tumor, and brain functional disorder. The application is for a partial change to add the indication for trigeminal neuralgia for which pain control is difficult by drug therapy. A clinical evaluation report summarizing domestic and overseas published papers was submitted to evaluate the efficacy and safety of gamma knife treatment for trigeminal neuralgia with difficult pain control by drug therapy.

Table 4. Post-marketing Safety Measures Implemented and Revision of PRECAUTIONS for Drugs etc., Directed by MHLW in FY 2014  Post-marketing safety measures implemented by MHLW in FY 2014

Directions for revision to precautions in package insert Information published in the Pharmaceuticals and Medical Devices Safety Information

Drugs

Medical devices

102

2

30

1

* Note: Including the issuance of notifications on self-check for medical devices, etc.

- 183 -

 Revision of PRECAUTIONS for Drugs Directed by MHLW in FY 2014 Date

Drug name

Apr. 17, 2014

01. Paliperidone palmitate

Apr. 23, 2014

01. Pentamidine isetionate

Jun 4, 2014

01. Azilsartan Azilsartan/Amlodipine besilate Irbesartan tablets Irbesartan/Amlodipine besilate Olmesartan medoxomil Olmesartan medoxomil/Azelnidipine Candesartan cilexetil tablets Valsartan tablets Valsartan/Amlodipine besilate Valsartan/Cilnidipine 02. Alacepril Imidapril hydrochloride tablets Enalapril maleate tablets Captopril Quinapril hydrochloride Cilazapril hydrate Temocapril hydrochloride Delapril hydrochloride Trandolapril Benazepril hydrochloride Perindopril erbumine Lisinopril hydrate 03. Irbesartan/Trichlormethiazide 04. Candesartan cilexetil/Amlodipine besilate Candesartan cilexetil/Hydrochlorothiazide Valsartan/Hydrochlorothiazide Losartan potassium/Hydrochlorothiazide 05. Telmisartan Telmisartan/Amlodipine besilate 06. Telmisartan/Hydrochlorothiazide 07. Losartan potassium Losartan potassium 08. Rosuvastatin calcium 09. Imidafenacin 10. Nartograstim (genetical recombination) 11. Filgrastim (genetical recombination) (biosimilar 1) Filgrastim (genetical recombination) (biosimilar 2) Filgrastim (genetical recombination) (biosimilar 3) Lenograstim (genetical recombination)

Jul 9, 2014

01. Paroxetine hydrochloride hydrate 02. Teriparatide (genetical recombination)

- 184 -

Date

Drug name 03. 04. 05. 06. 07.

Loratadine Inchinkoto Amphotericin B [non-liposome preparation (injectable dosage form)] Simeprevir sodium Ibuprofen/Pseudoephedrine hydrochloride/Chlorpheniramine maleate/Dihydrocodeine phosphate/Caffeine anhydrous (OTC drugs) Ibuprofen/Pseudoephedrine hydrochloride/L-Carbocisteine/d-Chlorpheniramine maleate/Dihydrocodeine phosphate/Caffeine anhydrous (OTC drugs) 08. Inchinkoto (OTC drugs) Aug. 6, 2014

01. 02. 03. 04. 05. 06. 07. 08. 09. 10.

Pramipexole hydrochloride hydrate Tolvaptan Carvedilol Infliximab (genetical recombination) Infliximab (genetical recombination) (biosimilar 1) Sugammadex sodium Carboplatin Doxycycline hydrochloride hydrate Lansoprazole/Amoxicillin hydrate/Metronidazole Rabeprazole sodium/Amoxicillin hydrate/Metronidazole Linezolid Metronidazole (oral dosage form)

Sep. 16, 2014

01. Pregabalin 02. Imatinib mesilate

Oct. 21, 2014

01. 02. 03. 04.

Oct. 21, 2014

01. Acetaminophen (oral dosage form, injectable dosage form, suppository)

Oct. 24, 2014

01. Simeprevir sodium

Nov. 20, 2014

01. Galantamine hydrobromide

Dec. 22, 2014

01. Cabazitaxel acetonate

Jan. 9, 2015

01. Levetiracetam 02. Ipragliflozin L-proline Empagliflozin Canagliflozin hydrate Dapagliflozin propylene glycolate hydrate Luseogliflozin hydrate Tofogliflozin hydrate 03. Tofogliflozin hydrate 04. Linagliptin 05. Amoxicillin hydrate

Teneligliptin hydrobromide hydrate Enzalutamide Vancomycin hydrochloride (for oral use) Vancomycin hydrochloride (for injection)

- 185 -

Date

Drug name Amoxicillin hydrate/ Potassium clavulanate Lansoprazole/Amoxicillin hydrate/Clarithromycin Lansoprazole/Amoxicillin hydrate/Metronidazole Rabeprazole sodium/Amoxicillin hydrate/Clarithromycin Rabeprazole Sodium/amoxicillin hydrate/Metronidazole 06. Simeprevir sodium 07. Freeze-dried live attenuated mumps virus vaccine

Feb. 2, 2015

01. Abiraterone acetate

Feb. 4. 2015

01. Lamotrigine

Feb. 17, 2015

01. 02. 03. 04.

Mar. 24, 2015

01. Rebamipide (Ophthalmic solution) 02. Triamcinolone acetonide (Injectable dosage form for Intramuscular/Intradermal/ Intra-articular) 03. Sitagliptin phosphate hydrate 04. Cyclophosphamide hydrate 05. Pazopanib hydrochloride 06. Panitumumab (genetical recombination)

Memantine hydrochloride Apixaban Montelukast sodium Telaprevir

*Note: Detailed information is available at the PMDA's web page.

- 186 -

Table 5. Revision of PRECAUTIONS for Medical Devices Directed by MHLW in FY 2014 Date Title Jul 28, 2014

Revision of the Precautions in the package insert of Drug-eluting coronary stent or Drug-coated balloon dilatation catheter for coronary angioplasty

Dec. 9, 2014

Revision of the Precautions in the package insert of the Small-intestinal capsule endoscope

*Note: Detailed information is available at the PMDA's web page.

- 187 -

Table 6. FY 2014 Pharmaceuticals and Medical Devices Safety Information (No.312-321) Date

No.

Table of Contents 1. 2.

Apr. 30, 2014

312 3. 4. 1. 2.

May 27, 2014

313

3. 4. 1.

Jul 29, 2014

314

2. 3. 1. 2.

Aug. 26, 2014

315 3. 4. 1. 2.

Sep. 30, 2014

316

3. 4. 1. 2.

Oct. 28, 2014

317

3.

4.

Use of Topical Ketoprofen (dermatologic preparation) during Pregnancy Important Safety Information [1] Ketoprofen (tapes) [2] Paclitaxel (excluding paclitaxel protein-bound particles for injectable suspension) [3] Levetiracetam Revision of Precautions (No. 255) Ketoprofen (injectable dosage form, suppository) (and 7 others) List of Products Subject to Early Post-marketing Phase Vigilance Fatal cases with XEPLION® Aqueous Suspension for IM injection Important Safety Information [1] Paliperidone Palmitate Revision of Precautions (No. 256) Pentamidine Isetionate List of Products Subject to Early Post-marketing Phase Vigilance Revision of Report Form in Drugs and Medical Devices Safety Information Reporting System Revision of Precautions (No. 257) Azilsartan (and 7 others) List of Products Subject to Early Post-marketing Phase Vigilance Safety Measures for New Drugs during the Early Post-marketing Phase Important Safety Information [1] Inchinkoto [2] Simeprevir Sodium [3] Teriparatide (Genetical Recombination) [4] Loratadine Revision of Precautions (No. 258) Paroxetine Hydrochloride Hydrate (and 3 others) List of Products Subject to Early Post-marketing Phase Vigilance Project of Japan Drug Information Institute in Pregnancy Effects of Angiotensin II Receptor Blockers and Angiotensin Converting Enzyme Inhibitors on Pregnant Women and Foetuses Revision of Precautions (No. 259) Paroxetine Hydrochloride Hydrate (and 9 others) List of Products Subject to Early Post-marketing Phase Vigilance Guidelines for Use of Mobile Phones and Other Devices in Hospitals Change in the Submission Place for Reports in the Safety Information Reporting System Important Safety Information [1] Imatinib Mesilate [2] Pregabalin List of Products Subject to Early Post-marketing Phase Vigilance

- 188 -

Date

Nov. 25, 2014

No.

318

Table of Contents List of errata for MHLW Pharmaceuticals and Medical Devices Safety Information No. 318 1. Simeprevir Sodium and Hyperbilirubinaemia 2. Surveillance on Access to, Dissemination, and Utilization of Drug Safety Information in Medical Institutions and Pharmacies 3. Adverse Reactions to Influenza Vaccine in the 2013 Season 4. Important Safety Information [1] Enzalutamide [2] Teneligliptin Hydrobromide Hydrate [3] Vancomycin Hydrochloride (for Injection) [4] Simeprevir Sodium 5. Revision of Precautions (No. 260) Acetaminophen (and 1 other) 6. List of Products Subject to Early Post-marketing Phase Vigilance 1.

Dec. 24, 2014

319

Summary of Relief System for Sufferers from Adverse Drug Reactions and Cases of Non-payment of Relief Benefits Due to Improper Use of Drugs 2. Revision of Precautions (No. 261) Galantamine Hydrobromide 3. List of Products Subject to Early Post-marketing Phase Vigilance (Reference) Handling of Fire during Long-term Oxygen Therapy

1. 2. 3. Jan, 29, 2015

320

4. 5.

Cabazitaxel Acetonate and Severe Febrile Neutropenia Use of Capsule Endoscopy for Small Intestine Screening in Pediatrics and Geriatrics Important Safety Information [1] Cabazitaxel Acetonate [2] Sodium-Glucose Co-Transporter 2 Inhibitors [3] Freeze-Dried Live Attenuated Mumps Virus Vaccine [4] Levetiracetam Revision of Precautions (No. 262) Linagliptin (and 2 others) List of Products Subject to Early Post-marketing Phase Vigilance

1. 2. 3. 4.

Mar. 30, 2015

321

Lamotrigine and Serious Skin Disorders Abiraterone Acetate and Hypokalaemia The MIHARI Project Important Safety Information [1] Abiraterone Acetate [2] Lamotrigine [3] Apixaban [4] Memantine Hydrochloride 5. Revision of Precautions (No. 263) Montelukast Sodium (and 1 other) 6. List of Products Subject to Early Post-marketing Phase Vigilance (Reference) The Drug and Medical Devices Safety Information Reporting System – Reporting via e-Gov was closed

*Note: Detailed information is available at the PMDA's web page.

- 189 -

Table 7. FY 2014 PMDA Medical Safety Information No.

Month and year published

44

May 2014

45

August 2014

Title Medication Errors in Prescription Orders Precautions in Handling of Indwelling Venous Needles

*Note: Detailed information is available at the PMDA's web page.

- 190 -

Table 8. List of User Fees 8-1. List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) [On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

User fees

Classification

Inspection

Review

152,300

152,300

114,700

114,700

Document

On-site

100,200

100,200

56,900

56,900

100,200

100,200

56,900

56,900

Article 31, Paragraph 1, Item 2 (a)

Document

On-site

Article 31, Paragraph 1, Item 3 (a)

Document

152,300

114,700

Article 16, Paragraph 1, Item 1 (b) 100,200

On-site

100,200

Article 16, Paragraph 1,Item 2 (a)

Change/addition of classification

56,900

Document

56,900

Article 16, Paragraph 1,Item 2 (b) 100,200

On-site

Article 16, Paragraph 1, Item 3 (a)

Document

Article 16, Paragraph 1, Item 3 (b)

Renewal of existing license

Article 31, Paragraph 1, Item 3 (b)

Assessment for foreign manufacturers' accreditation of drugs

152,300

114,700

Document

Article 31, Paragraph 1, Item 2 (b)

Renewal of existing license

56,900

100,200

56,900

Assessment for foreign manufacturers' accreditation of drugs 137,100 + overseas travel expenses 137,100 + overseas travel expenses

On-site

Article 31, Paragraph 2, Item 1 (a)

New accreditation

59,700

Document

59,700

On-site

Article 31, Paragraph 2, Item 2 (a) Article 31, Paragraph 2, Item 2 (b)

40,900

40,900

On-site

Article 31, Paragraph 2, Item 3 (a)

Document

Article 31, Paragraph 2, Item 3 (b)

Renewal of existing accreditation

40,900

40,900

Review for approval of drugs (new approval)

59,700

59,700

Article 16, Paragraph 2, Item 1 (b) 66,400 +travel expenses

On-site

Article 16, Paragraph 2, Item 2 (a)

Document

Article 16, Paragraph 2,, Item 2 (b)

Change/addition of classification

66,400 + overseas travel expenses 66,400 + overseas travel expenses

137,100 +travel expenses

Article 16, Paragraph 2, Item 1 (a)

Document

66,400 + overseas travel expenses 66,400 + overseas travel expenses

Document

137,100 +travel expenses

On-site New accreditation

Article 31, Paragraph 2, Item 1 (b)

Change/addition of classification

40,900 66,400 +travel expenses

On-site

Article 16, Paragraph 2, Item 3 (a)

Document

Article 16, Paragraph 2, Item 3 (b)

Renewal of existing accreditation

40,900

66,400 +travel expenses 40,900 66,400 +travel expenses 40,900

Review for approval of drugs (new approval) First application products

New drugs (No. 1) (non-orphan drugs) Line extension products

23,788,100 Article 32, Paragraph 1, Item 1 (a)-(1)

2,464,000 Article 32, Paragraph 1, Item 1 (a)-(3)

19,934,100

First application products

Article 32, Paragraph 1, Item 1 (a)-(2)

Line extension products

Article 32, Paragraph 1, Item 1 (a)-(4)

New drugs (No. 1) (orphan drugs)

2,061,500

11,353,100

First application products

Article 32, Paragraph 1, Item 1 (a)-(5)

Line extension products

Article 32, Paragraph 1, Item 1 (a)-(7)

1,174,300

9,345,700

First application products

Article 32, Paragraph 1, Item 1 (a)-(6)

Line extension products

Article 32, Paragraph 1, Item 1 (a)-(8)

New drugs (No. 2) (orphan drugs)

with inspections Generic prescription drugs without inspection

with inspections without inspection with inspections

Line extension products

Total

Article 16, Paragraph 1, Item 1 (a)

New license

Article 31, Paragraph 1, Item 1 (b)

Change/addition of classification

Switch to OTC status, etc.

Inspection

On-site

Article 31, Paragraph 1, Item 1 (a)

New license

First application products

Review

Assessment for manufacturing license of drugs On-site

New drugs (No. 2)

(non-orphan drugs)

(Yen)

User fees

Classification

Total

Assessment for manufacturing license of drugs

BTC/OTC drugs

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Pharmaceutical Affairs Act (Act No. 145, 1960) Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

without inspection with inspections

Others without inspection

1,004,100

618,200 Article 32, Paragraph 1, Item 1 (a)-(9)

6,747,000 + overseas travel expenses 30,535,100 + overseas travel expenses Article 32, Paragraph 2, Item 1 (a) and Paragraph 3 1,686,600 + overseas travel expenses 4,150,600 + overseas travel expenses Article 32, Paragraph 2, Item 1 (c) and Paragraph 3 3,379,900 + overseas travel expenses 23,314,000 + overseas travel expenses Article 32, Paragraph 2, Item 1 (b) and Paragraph 3 841,500 + overseas travel expenses 2,903,000 + overseas travel expenses 2,533,600 + overseas travel expenses 13,886,700 + overseas travel expenses 633,600 + overseas travel expenses 1,807,900 + overseas travel expenses

New drugs (No. 2) (non-orphan drugs)

Article 32, Paragraph 2, Item 1 (g) and Paragraph 3 1,267,700 + overseas travel expenses 10,613,400 + overseas travel expenses Article 32, Paragraph 2, Item 1 (f) and Paragraph 3 319,000 + overseas travel expenses 1,323,100 + overseas travel expenses 948,400 + overseas travel expenses

Article 32, Paragraph 2, Item 1 (i) and Paragraph 3

618,200

6,747,000 Article 17, Paragraph 2, Item 1 (a)

Line extension products

2,464,000

1,686,600

Article 17, Paragraph 1, Item 1 (a)-(3)

Article 17,Paragraph 2, Item 1 (c)

19,934,100

3,379,900

First application products

Article 17, Paragraph 1, Item 1 (a)-(2)

Line extension products

2,061,500

841,500

Article 17, Paragraph 1, Item 1 (a)-(4)

Article 17, Paragraph 2, Item 1 (d)

11,353,100

2,533,600

Article 17, Paragraph 1, Item 1 (a)-(5)

Article 17, Paragraph 2, Item 1 (e)

Line extension products

1,174,300

633,600

Article 17, Paragraph 1, Item 1 (a)-(6)

Article 17, Paragraph 2, Item 1 (f)

First application products

9,345,700

1,267,700

Article 17, Paragraph 1, Item 1 (a)-(7)

Article 17,Paragraph 2, Item 1 (g)

Line extension products

1,004,100

319,000

Article 17, Paragraph 1, Item 1 (a)-(8)

Article 17,Paragraph 2, Item 1 (h)

412,100

220,100

Article 17, Paragraph 1, Item 1 (a)-(9)

Article 17,Paragraph 2, Item 1 (i)

Generic prescription drugs (with inspections)

30,535,100

4,150,600

23,314,000

Article 17, Paragraph 2, Item 1 (b)

First application products

New drugs (No. 2) (orphan drugs)

Article 32, Paragraph 2, Item 1 (h) and Paragraph 3 330,200 + overseas travel expenses

23,788,100 Article 17, Paragraph 1, Item 1 (a)-(1)

New drugs (No. 1) (orphan drugs)

Article 32, Paragraph 2, Item 1 (d) and Paragraph 3 Article 32, Paragraph 2, Item 1 (e) and Paragraph 3

First application products New drugs (No. 1) (non-orphan drugs)

2,903,000

13,886,700

1,807,900

10,613,400

1,323,100

632,200

618,200

Article 32, Paragraph 1, Item 1 (a)-(9)

1,291,600 Article 32, Paragraph 1, Item 1 (a)-(10)

330,200 + overseas travel expenses

1,621,800 + overseas travel expenses

Article 32, Paragraph 2, Item 1 (i) and Paragraph 3

1,291,600 Article 32, Paragraph 1, Item 1 (a)-(10)

1,291,600 Article 32, Paragraph 1, Item 1 (a)-(10)

1,291,600 First application products Article 17, Paragraph 1, Item 1 (a)-(10)

1,291,600

1,291,600

1,291,600

1,291,600 330,200 + overseas travel expenses

1,291,600

Switch to OTC status, etc.

1,621,800 + overseas travel expenses

Article 32, Paragraph 2, Item 1 (i) and Paragraph 3 1,291,600

Line extension products

OTC drugs

Article 17, Paragraph 1, Item 1 (a)-(10)

Article 32, Paragraph 1, Item 1 (a)-(10)

110,300 Article 32, Paragraph 1, Item 1 (a)-(11)

110,300

330,200 + overseas travel expenses

440,500 + overseas travel expenses

Article 32, Paragraph 2, Item 1 (i) and Paragraph 3

110,300

Others

110,300

Article 17, Paragraph 1, Item 1 (a)-(11)

110,300

Article 32, Paragraph 1, Item 1 (a)-(11)

584,100

In vitro diagnostics (without approval standards)

See “List of user fees for reviews etc. of medical devices” for in vitro diagnostics.

Basic In vitro diagnostics (with approval standards) Addition of series

- 191 -

584,100

Article 17, Paragraph 1, Item 1 (a)-(14)

282,900

282,900

Article 17, Paragraph 1, Item 1 (a)-(13)

60,300 Article 17, Paragraph 1, Item 1 (a)-(12)

60,300

[On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Pharmaceutical Affairs Act (Act No. 145, 1960)

User fees

Classification

Review

Inspection

New dosage, etc. Others

2,981,100

2,981,100

Cosmetics

Inspection

Total

63,500

Quasi-drugs/cosmetics

Article 32, Paragraph 1, Item 1 (b)-(1)

63,500

Article 17, Paragraph 1, Item 1 (b) (c)

246,600

246,600 Article 32, Paragraph 1, Item 1 (b)-(2)

63,500

63,500 Article 32, Paragraph 1, Item 1 (b)-(6)

4,987,900

4,987,900 New active ingredients Article 32, Paragraph 1, Item 1 (a)(12) and (b)-(4) 392,200 New dosage, etc. Article 32, Paragraph 1, Item 1 (a)(13) and (b)-(5) 95,500 Others Article 32, Paragraph 1, Item 1 (a)(14) and (b)-(6) 63,500

Pest control agents

Review

Review for approval of drugs (new approval) New active ingredients

Quasi-drugs

User fees

Classification

Total

Review for approval of drugs (new approval)

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

392,200

95,500

63,500

Article 32, Paragraph 1, Item 1 (c)

New application for change or replacement of brand name

35,600

35,600

Article 32, Paragraph 1, Item 1 (d)

First application products Changes in indications, etc. New drugs (No. 1) (non-orphan drugs)

Line extension products

First application products Line extension products

875,600 Article 32, Paragraph 1, Item 2 (a)-(5) Article 32, Paragraph 1, Item 2 (a)-(6)

10,190,500 Article 32, Paragraph 1, Item 2 (a)-(1)

Line extension products

Article 32, Paragraph 1, Item 2 (a)-(2)

1,057,400

205,100

Others

Article 32, Paragraph 1, Item 2 (a)-(3)

8,434,300

First application products

Article 32, Paragraph 1, Item 2 (a)-(4)

Line extension products

Article 32, Paragraph 1, Item 2 (a)-(5)

Changes in indications, etc.

875,600

132,700

Others

Article 32, Paragraph 1, Item 2 (a)-(6)

10,190,500

First application products

Article 32, Paragraph 1, Item 2 (a)-(1)

Line extension products

Article 32, Paragraph 1, Item 2 (a)-(2)

Changes in indications, etc.

Generic prescription drugs Changes based on guidelines, etc.

Others

8,434,300 Article 32, Paragraph 1, Item 2 (a)-(4)

First application products Changes in indications, etc.

New drugs (No. 2) (orphan drugs)

Article 32, Paragraph 1, Item 2 (a)-(2)

132,700

Others

New drugs (No. 2) (non-orphan drugs)

1,057,400

Article 32, Paragraph 1, Item 2 (a)-(3)

Changes in indications, etc. New drugs (No. 1) (orphan drugs)

10,190,500 Article 32, Paragraph 1, Item 2 (a)-(1)

205,100

Others

New application for change or replacement of brand name

35,600

35,600

Article 17, Paragraph 1, Item 1 (e)

Review for approval of drugs (approval for partial changes to approved matters)

Review for approval of drugs (approval for partial changes to approved matters)

1,057,400

2,533,600 + overseas travel expenses 12,724,100 + overseas travel expenses Article 32, Paragraph 2, Item 2 (a) and Paragraph 3 633,600 + overseas travel expenses 1,691,000 + overseas travel expenses Article 32, Paragraph 2, Item 2 (b) and Paragraph 3

1,267,700 + overseas travel expenses 9,702,000 + overseas travel expenses Article 32, Paragraph 2, Item 2 (d) and Paragraph 3 319,000 + overseas travel expenses 1,194,600 + overseas travel expenses Article 32, Paragraph 2, Item 2 (e) and Paragraph 3

Changes in indications, etc.

2,533,600 + overseas travel expenses 12,724,100 + overseas travel expenses Article 32, Paragraph 2, Item 2 (a) and Paragraph 3 633,600 + overseas travel expenses 1,691,000 + overseas travel expenses

New drugs (No. 2) (non-orphan drugs)

124,200 + overseas travel expenses 329,300 + overseas travel expenses

Changes in indications, etc.

1,267,700 + overseas travel expenses 9,702,000 + overseas travel expenses Article 32, Paragraph 2, Item 2 (d) and Paragraph 3 319,000 + overseas travel expenses 1,194,600 + overseas travel expenses

New drugs (No. 2) (orphan drugs)

112,900 + overseas travel expenses 245,600 + overseas travel expenses

Changes in indications, etc.

2,533,600 + overseas travel expenses 12,724,100 + overseas travel expenses Article 32, Paragraph 2, Item 2 (a) and Paragraph 3

Changes in indications, etc.

633,600 + overseas travel expenses 1,691,000 + overseas travel expenses 53,400 186,200 + overseas travel expenses

493,900 + overseas travel expenses

Article 32, Paragraph 2, Item 2 (g) and Paragraph 3

- 192 -

Line extension products

Generic prescription drugs (with inspections)

2,533,600 Article 17, Paragraph 2, Item 2 (a)

1,057,400

633,600

Article 17, Paragraph 1, Item 2 (a)-(2)

Article 17, Paragraph 2, Item 2 (b)

205,100

124,200

Article 17, Paragraph 1, Item 2 (a)-(3)

Article 17, Paragraph 2, Item 2 (c)

8,434,300

1,267,700

Article 17, Paragraph 1, Item 2 (a)-(4)

Article 17,Paragraph 2, Item 2 (d)

875,600

319,000

Article 17, Paragraph 1, Item 2 (a)-(5)

Article 17,Paragraph 2, Item 2 (e)

132,700

112,900

Article 17, Paragraph 1, Item 2 (a)-(6)

Article 17,Paragraph 2, Item 2 (f)

10,190,500

2,533,600

Article 17, Paragraph 1, Item 2 (a)-(1)

Article 17, Paragraph 2, Item 2 (a)

Line extension products

1,057,400

633,600

Article 17, Paragraph 1, Item 2 (a)-(2)

Article 17, Paragraph 2, Item 2 (b)

205,100

124,200

Article 17, Paragraph 1, Item 2 (a)-(3)

Article 17, Paragraph 2, Item 2 (c)

First application products

8,434,300

1,267,700

Article 17, Paragraph 1, Item 2 (a)-(4)

Article 17,Paragraph 2, Item 2 (d)

Line extension products

875,600

319,000

Article 17, Paragraph 1, Item 2 (a)-(5)

Article 17,Paragraph 2, Item 2 (e)

132,700

112,900

Article 17, Paragraph 1, Item 2 (a)-(6)

Article 17,Paragraph 2, Item 2 (f)

First application products

10,190,500

2,533,600

Article 17, Paragraph 1, Item 2 (a)-(1)

Article 17, Paragraph 2, Item 2 (a)

Line extension products

1,057,400

633,600

Article 17, Paragraph 1, Item 2 (a)-(2)

Article 17, Paragraph 2, Item 2 (b)

Changes based on guidelines, etc.

Others

10,190,500 Article 17, Paragraph 1, Item 2 (a)-(1)

First application products

Others

Article 32, Paragraph 2, Item 2 (f) and Paragraph 3

Article 32, Paragraph 2, Item 2 (b) and Paragraph 3

First application products

Others

Article 32, Paragraph 2, Item 2 (c) and Paragraph 3

Article 32, Paragraph 2, Item 2 (e) and Paragraph 3

Line extension products

Others

Article 32, Paragraph 2, Item 2 (f) and Paragraph 3

Article 32, Paragraph 1, Item 2 (a)-(7) Article 32, Paragraph 1, Item 2 (a)-(8)

New drugs (No. 1) (orphan drugs)

112,900 + overseas travel expenses 245,600 + overseas travel expenses

Article 32, Paragraph 2, Item 2 (b) and Paragraph 3

First application products

Others

Article 32, Paragraph 2, Item 2 (c) and Paragraph 3

53,400

307,700

New drugs (No. 1) (non-orphan drugs)

124,200 + overseas travel expenses 329,300 + overseas travel expenses

Changes in indications, etc.

35,600

12,724,100

1,691,000

329,300

9,702,000

1,194,600

245,600

12,724,100

1,691,000

329,300

9,702,000

1,194,600

245,600

12,724,100

1,691,000

35,600

Article 17, Paragraph 1, Item 2 (a)-(7)

205,100

124,200

Article 17, Paragraph 1, Item 2 (a)-(3)

Article 17, Paragraph 2, Item 2 (c)

329,300

[On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Pharmaceutical Affairs Act (Act No. 145, 1960)

User fees

Classification

Review

Total

186,200 + overseas travel expenses

10,376,700 + overseas travel expenses

Review for approval of drugs (approval for partial changes to approved matters) First application products Switch to Changes in OTC status, indications, etc. etc.

with inspections without inspection with inspections

Line extension products

without inspection

BTC/OTC drugs with inspections Changes based on guidelines, etc. without inspection with inspections Others without inspection

User fees

Classification

Inspection

Review

Article 32, Paragraph 2, Item 2 (g) and Paragraph 3

10,190,500

Changes in

First application products

etc.

Line extension products

Switch to OTC indications, status, etc.

10,190,500

Article 32, Paragraph 1, Item 2 (a)-(1)

1,057,400 Article 32, Paragraph 1, Item 2 (a)-(2)

186,200 + overseas travel expenses

35,600 Article 32, Paragraph 1, Item 2 (a)-(10)

OTC drugs

221,800 + overseas travel expenses

Changes based on guidelines, etc.

Article 32, Paragraph 2, Item 2 (g) and Paragraph 3

35,600

35,600

35,600

Article 17, Paragraph 1, Item 2 (a)-(7)

Article 32, Paragraph 1, Item 2 (a)-(10)

56,400 Article 32, Paragraph 1, Item 2 (a)-(9)

186,200 + overseas travel expenses

242,600 + overseas travel expenses

56,400

Others

Article 32, Paragraph 2, Item 2 (g) and Paragraph 3

56,400

56,400

Article 17, Paragraph 1, Item 2 (a)-(8)

56,400

Article 32, Paragraph 1, Item 2 (a)-(9)

295,800

35,600

35,600

295,800

Article 17, Paragraph 1, Item 2 (a)-(11)

Basic

143,500

143,500

Article 17, Paragraph 1, Item 2 (a)-(10)

31,900

31,900

Article 17, Paragraph 1, Item 2 (a)-(9)

35,600

Quasi-drugs/cosmetics

Article 32, Paragraph 1, Item 2 (b)-(1) and (c)

35,600

Article 17, Paragraph 1, Item 2 (b) and (c)

48,400

48,400 Article 32, Paragraph 1, Item 2 (a)(11) and (b)-(2)

GMP inspection of drugs

New drugs Overseas

Domestic Biological drugs/Radiopharmaceuticals, etc. Overseas

Domestic Sterile drugs/Sterile quasi-drugs Overseas

Domestic Other Drugs/quasi-drugs Overseas

760,900

Packaging, labeling, storage, external testing, etc. Overseas

Domestic Basic Overseas

Domestic New drugs

960,200 + overseas travel expenses 960,200 + overseas travel expenses

Overseas

Article 32, Paragraph 5, Item 1 (b)-(2) and Paragraph 7 685,100

685,100

Article 32, Paragraph 5, Item 1 (a)-(1) 868,600 + overseas travel expenses 868,600 + overseas travel expenses Article 32, Paragraph 5, Item 1 (a)-(2) and Paragraph 7 522,600

522,600

Article 32, Paragraph 5, Item 1 (c)-(1) 658,300 + overseas travel expenses 658,300 + overseas travel expenses Article 32, Paragraph 5, Item 1 (c)-(2) and Paragraph 7 379,500

379,500

Article 32, Paragraph 5, Item 1 (d)-(1) 478,000 + overseas travel expenses 478,000 + overseas travel expenses Article 32, Paragraph 5, Item 1 (d)-(2) and Paragraph 7 65,600

Domestic

760,900

Article 32, Paragraph 5, Item 1 (b)-(1)

65,600

Approval, partial change and manufacture for export

Domestic

Overseas

Domestic Basic Overseas

Domestic Addition of products Overseas

Biological drugs/Radiopharmaceuticals, etc. Overseas

Domestic Sterile drugs/Sterile quasi-drugs Overseas

Domestic Other Drugs/quasi-drugs Overseas

Domestic Packaging, labeling, storage, external testing, etc.

87,200 + overseas travel expenses 87,200 + overseas travel expenses Article 32, Paragraph 5, Item 2 (b) and Paragraph 6, Item 1 (b) and Paragraph 7 448,500 448,500

Overseas

Domestic

Article 32, Paragraph 5, Item 3 (a)-(1)

Basic

570,100 + overseas travel expenses 570,100 + overseas travel expenses 31,400

Overseas

31,400

31,400

Article 32, Paragraph 5, Item 3 (a)-(2) 390,900

390,900

Article 32, Paragraph 5, Item 3 (b)-(1) 493,800 + overseas travel expenses 493,800 + overseas travel expenses Article 32, Paragraph 5, Item 3 (b)-(2) and Paragraph 7 12,800

12,800

Article 32, Paragraph 5, Item 3 (b)-(1) 12,800

Biological drugs/ Radiopharmaceuticals, etc.

31,400

Article 32, Paragraph 5, Item 3 (a)-(1)

12,800

Article 32, Paragraph 5, Item 3 (b)-(2)

- 193 -

Domestic

Renewal of the above

Addition of products

Domestic

Article 32, Paragraph 5, Item 2 (a) and Paragraph 6, Item 1 (a)

Article 32, Paragraph 5, Item 3 (a)-(2) and Paragraph 7

Domestic

Sterile drugs/Sterile quasi-drugs

1,057,400

Article 17, Paragraph 1, Item 2 (a)-(2)

35,600

GMP inspection of drugs

Renewal of approval/ Renewal of manufacture for export

10,190,500

1,057,400

1,057,400

186,200 + overseas travel expenses

Addition of series

Biological drugs/ Radiopharma ceuticals, etc.

10,190,500 Article 17, Paragraph 1, Item 2 (a)-(1)

Article 32, Paragraph 2, Item 2 (g) and Paragraph 3

1,057,400 Article 32, Paragraph 1, Item 2 (a)-(2)

In vitro diagnostics (with approval standards)

Approval, partial change and manufacture for export

Total

1,243,600 + overseas travel expenses

See “List of user fees for reviews etc. of medical devices” for in vitro diagnostics.

Pest control agents

Inspection

Review for approval of drugs (approval for partial changes to approved matters) 10,190,500 Article 32, Paragraph 1, Item 2 (a)-(1)

In vitro diagnostics (without approval standards)

Quasi-drugs/cosmetics

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

Addition of products Overseas

Domestic Basic Overseas Sterile drugs/ Sterile quasi-drugs Domestic Addition of products Overseas

760,900

760,900

Article 17, Paragraph 4, Item 1 (b)-(1)

960,200 +travel expenses

960,200 +travel expenses

Article 17, Paragraph 4, Item 1 (b)-(2)

685,100

685,100

Article 17, Paragraph 4, Item 1 (a)-(1)

868,600 +travel expenses

868,600 +travel expenses

Article 17, Paragraph 4, Item 1 (a)-(2)

207,100

207,100

Article 17, Paragraph 4, Item 1 (c)-(1)

236,400 +travel expenses

236,400 +travel expenses

Article 17, Paragraph 4, Item 1 (c)-(2)

145,300

145,300

Article 17, Paragraph 4, Item 1 (d)-(1)

159,900 +travel expenses

159,900 +travel expenses

Article 17, Paragraph 4, Item 1 (d)-(2)

65,600 Article 17, Paragraph 4, Item 2 (a) and Paragraph 5, Item 1 (a) 87,200 +travel expenses Article 17, Paragraph 4, Item 2 (b) and Paragraph 5, Item 1 (b) 448,500

65,600

87,200 +travel expenses

448,500

Article 17, Paragraph 4, Item 3 (a)-(1)

570,100 +travel expenses

570,100 +travel expenses

Article 17, Paragraph 4, Item 3 (a)-(2)

31,400

31,400

Article 17, Paragraph 4, Item 3 (a)-(1)

31,400

31,400

Article 17, Paragraph 4, Item 3 (a)-(2)

390,900

390,900

Article 17, Paragraph 4, Item 3 (b)-(1)

493,800 +travel expenses

493,800 +travel expenses

Article 17, Paragraph 4, Item 3 (b)-(2)

12,800

12,800

Article 17, Paragraph 4, Item 3 (b)-(1)

12,800 Article 17, Paragraph 4, Item 3 (b)-(2)

12,800

[On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Pharmaceutical Affairs Act (Act No. 145, 1960)

User fees

Classification

Inspection

Review

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

User fees

Classification

Total

GMP inspection of drugs

Review

Inspection

Total

GMP inspection of drugs 346,100

Domestic Overseas

9,900

Overseas Renewal of approval/ Renewal of manufacture for export

9,900

265,900

265,900

Article 32, Paragraph 5, Item 3 (c)-(2)

Domestic

Article 32, Paragraph 5, Item 3 (d)-(1) and Paragraph 6, Item 2 (a)

Basic Packaging, labeling, storage, external testing, etc.

9,900

347,800 + overseas travel expenses 347,800 + overseas travel expenses Article 32, Paragraph 5, Item 3 (d)-(2) and Paragraph 6, Item 2 (b) and Paragraph 7 6,900 6,900

Overseas

Domestic

6,900 Overseas

9,900

9,900

Overseas

265,900 Article 17, Paragraph 4, Item 3 (d)(1) and Paragraph 5, Item 2 (a) 347,800 +travel expenses Article 17, Paragraph 4, Item 3 (d)(2) and Paragraph 5, Item 2 (b) 6,900 Article 17, Paragraph 4, Item 3 (d)(1) and Paragraph 5, Item 2 (a) 6,900 Article 17, Paragraph 4, Item 3 (d)(2) and Paragraph 5, Item 2 (b)

Domestic

Overseas Packaging, labeling, storage, external testing, etc. Domestic Addition of products

6,900

Overseas

GLP inspection of drugs

9,900

Article 17, Paragraph 4, Item 3 (c)-(2)

Basic

Article 32, Paragraph 5, Item 3 (d)-(2) and Paragraph 6, Item 2 (b)

9,900

Article 17, Paragraph 4, Item 3 (c)-(1)

Addition of products

Article 32, Paragraph 5, Item 3 (d)-(1) and Paragraph 6, Item 2 (a)

Addition of products

421,100 +travel expenses

Article 17, Paragraph 4, Item 3 (c)-(2)

Domestic

Article 32, Paragraph 5, Item 3 (c)-(1)

Addition of products

421,100 +travel expenses

Other Drugs/quasi-drugs

9,900

346,100

Article 17, Paragraph 4, Item 3 (c)-(1)

Overseas

Article 32, Paragraph 5, Item 3 (c)-(2) and Paragraph 7

Domestic

346,100

Domestic Basic

421,100 + overseas travel expenses 421,100 + overseas travel expenses

Renewal of the above

Other Drugs/quasidrugs

346,100

Article 32, Paragraph 5, Item 3 (c)-(1)

Basic

265,900

347,800 +travel expenses

6,900

6,900

GLP inspection of drugs 2,121,400 Domestic

2,121,400

GLP

2,347,900 + overseas travel expenses 2,347,900 + overseas travel expenses Article 32, Paragraph 4, Item 1 (b) and Paragraph 10, Item 2 (a)-(2) and Paragraph 11

Overseas

2,121,400 Article 17, Paragraph 3, Item 1 (a) and Paragraph 9, Item 2 (a)-(1) 2,347,900 +travel expenses Article 17, Paragraph 3, Item 1 (b) and Paragraph 9, Item 2 (a)-(2)

Domestic

Article 32, Paragraph 4, Item 1 (a) and Paragraph 10, Item 2 (a)-(1)

GLP Overseas

GCP inspection of drugs

2,121,400

2,347,900 +travel expenses

GCP inspection of drugs 2,801,000

Domestic

2,801,000

First application products Overseas

Article 32, Paragraph 4, Item 2 (a)-(2) and (b)-(2) 741,400

Domestic

741,400

Line extension products

Article 32, Paragraph 4, Item 2 (a)-(4) and (b)-(4) 663,600

Domestic

663,600

Article 32, Paragraph 4, Item 2 (a)-(5) and (b)-(5)

GCP inspection of generic drugs

977,400 + overseas travel expenses 977,400 + overseas travel expenses

Overseas

663,600

Article 17, Paragraph 3, Item 2 (b)

Domestic

Article 17, Paragraph 3, Item 2 (c)

Overseas

Article 17, Paragraph 3, Item 2 (d)

741,400 773,300 +travel expenses 663,600

Domestic

3,098,000 +travel expenses 741,400 773,300 +travel expenses 663,600

Article 17, Paragraph 3, Item 2 (e)

GCP inspection of generic drugs

977,400 +travel expenses

Overseas

Article 32, Paragraph 4, Item 2 (a)-(6) and (b)-(6)

Domestic

Overseas

Line extension products

773,300 + overseas travel expenses 773,300 + overseas travel expenses

Overseas

3,098,000 +travel expenses

New GCP

Article 32, Paragraph 4, Item 2 (a)-(3) and (b)-(3)

2,801,000

Article 17, Paragraph 3, Item 2 (a)

First application products

3,098,000 + overseas travel expenses 3,098,000 + overseas travel expenses

New GCP

2,801,000

Domestic

Article 32, Paragraph 4, Item 2 (a)-(1) and (b)-(1)

977,400 +travel expenses

Article 17, Paragraph 3, Item 2 (f)

663,600

Article 32, Paragraph 4, Item 2 (a)-(5) and (b)-(5)

GCP inspection of BTC /OTC drugs

977,400 + overseas travel expenses

Overseas

977,400 + overseas travel expenses

Article 32, Paragraph 4, Item 2 (a)-(6) and (b)-(6)

Re-examination of drugs

Re-examination of drugs

First application products Re-examination Line extension products

Domestic First application products Overseas GPSP Domestic Line extension products Overseas

806,600

2,750,100 + overseas travel expenses 3,556,700 + overseas travel expenses

Article 32, Paragraph 9, Item 1 Article 32, Paragraph 10, Item 1 (a) and Paragraph 11

271,500

917,600 + overseas travel expenses 1,189,100 + overseas travel expenses

First application products Re-examination Line extension products

Article 32, Paragraph 9, Item 2 Article 32, Paragraph 10, Item 1 (b) and Paragraph 11

2,256,000

2,256,000

Domestic

Article 32, Paragraph 10, Item 2 (b)-(1)

First application products

2,478,500 + overseas travel expenses 2,478,500 + overseas travel expenses Article 32, Paragraph 10, Item 2 (b)-(2) and Paragraph 11

774,100

774,100

Article 32, Paragraph 10, Item 2 (b)-(3) 794,400 + overseas travel expenses 794,400 + overseas travel expenses Article 32, Paragraph 10, Item 2 (b)-(4) and Paragraph 11

- 194 -

Overseas GPSP Domestic Line extension products Overseas

806,600

2,750,100

Article 17, Paragraph 8, Item 1 (a)

Article 17, Paragraph 9, Item 1 (a)

271,500

917,600

Article 17, Paragraph 8, Item 1 (b)

Article 17, Paragraph 9, Item 1 (b) 2,256,000

3,556,700

1,189,100

2,256,000

Article 17, Paragraph 9, Item 2 (b)-(1)

2,478,500 +travel expenses

2,478,500 +travel expenses

Article 17, Paragraph 9, Item 2 (b)-(2)

774,100

774,100

Article 17, Paragraph 9, Item 2 (b)-(3)

794,400 +travel expenses Article 17, Paragraph 9, Item 2 (b)-(4)

794,400 +travel expenses

8-2. List of user fees for reviews etc. of medical devices under the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) [On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of medical devices and in vitro diagnostics under the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960)

List of user fees for reviews etc. of medical devices under the Pharmaceutical Affairs Act (Act No. 145, 1960)

Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

Classification

(Yen)

User fees Review

Inspection

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

User fees

Classification

Total

Review

Inspection

Total

Assessment for manufacturing license of medical devices 152,300

On-site

152,300

Article 16, Paragraph 1, Item 1 (a)

New license

114,700

Document

114,700

Article 16, Paragraph 1, Item 1 (b) 100,200

On-site

Article 16, Paragraph 1, Item 2 (a)

Document

Article 16, Paragraph 1, Item 2 (b)

Change/addition of classification

56,900

100,200

On-site

Article 16, Paragraph 1, Item 3 (a)

Document

Article 16, Paragraph 1, Item 3 (b)

Renewal of existing license

56,900

100,200

56,900

100,200

56,900

Assessment for foreign manufacturers accreditation of medical devices 137,100 +travel expenses

On-site

59,700

Document

Article 16, Paragraph 2, Item 1 (b)

On-site

Article 16, Paragraph 2, Item 2 (a)

66,400 +travel expenses

Change/addition of classification

40,900

Document

New medical devices (Class IV)

New medical devices (Class II/III)

Improved medical devices with clinical data (Class IV)

Improved medical devices with clinical data (Class II/III) Improved medical devices without clinical data, without approval standards (Class IV)

10,881,700 Article 33, Paragraph 1, Item 1 (a)-(1)

7,766,200 Article 33, Paragraph 1, Item 1 (a)-(3)

6,213,000 Article 33, Paragraph 1, Item 1 (a)-(2)

3,721,200 Article 33, Paragraph 1, Item 1 (a)-(4)

2,355,400 Article 33, Paragraph 1, Item 1 (a)-(7)

1,767,700 Article 33, Paragraph 1, Item 1 (a)-(8)

Improved/generic medical devices without clinical data, without approval standards (Class II/III)

Article 33, Paragraph 1, Item 1 (a)-(9)

Generic medical devices with approval standards (Class II/III)

66,400 +travel expenses

66,400 +travel expenses

40,900

On-site

Article 16, Paragraph 2, Item 3 (a)

Document

Article 16, Paragraph 2, Item 3 (b)

40,900

66,400 +travel expenses 40,900

Review for approval of medical devices (new approval)

Generic medical devices without clinical data, without approval standards (Class IV)

Generic medical devices with approval standards (Class IV)

59,700

Article 16, Paragraph 2, Item 2 (b)

Renewal of existing accreditation

Review for approval of medical devices and in vitro diagnostics (new approval)

137,100 +travel expenses

Article 16, Paragraph 2, Item 1 (a)

New accreditation

1,409,900

429,200 Article 33, Paragraph 1, Item 1 (a)-(5)

344,100 Article 33, Paragraph 1, Item 1 (a)-(6)

854,300 + overseas travel expenses 11,736,000 + overseas travel expenses Article 33, Paragraph 2, Item 1 (a) and Paragraph 3 Article 33, Paragraph 2, Item 1 (a) and Paragraph 3 683,500 + overseas travel expenses 6,896,500 + overseas travel expenses Article 33, Paragraph 2, Item 1 (b) and Paragraph 3 683,500 + overseas travel expenses 4,404,700 + overseas travel expenses

8,705,500

683,500

Article 17, Paragraph 1, Item 1 (d)-(1)

Article 17, Paragraph 2, Item 1 (j)

Improved medical devices

6,213,000

683,500

Article 17, Paragraph 1, Item 1 (d)-(2)

Article 17, Paragraph 2, Item 1 (j)

6,213,000

683,500

Medical devices (with clinical data)

Article 17, Paragraph 1, Item 1 (d)-(3)

Article 17, Paragraph 2, Item 1 (j)

Improved medical devices

3,721,200

683,500

Article 17, Paragraph 1, Item 1 (d)-(4)

Article 17, Paragraph 2, Item 1 (j)

New medical devices

6,213,000

683,500

Article 17, Paragraph 1, Item 1 (d)-(3)

Article 17, Paragraph 2, Item 1 (j)

New medical devices Class III

Article 33, Paragraph 2, Item 1 (b) and Paragraph 3 70,500 + overseas travel expenses 2,425,900 + overseas travel expenses Article 33, Paragraph 2, Item 1 (c) and Paragraph 3

Class II

70,500 + overseas travel expenses 1,838,200 + overseas travel expenses Article 33, Paragraph 2, Item 1 (c) and Paragraph 3 70,500 + overseas travel expenses 1,480,400 + overseas travel expenses Article 33, Paragraph 2, Item 1 (c) and Paragraph 3

Improved medical devices

3,721,200

683,500

Article 17, Paragraph 1, Item 1 (d)-(4)

Article 17, Paragraph 2, Item 1 (j)

Improved medical devices

2,355,400

70,500

Article 17, Paragraph 1, Item 1 (d)-(7)

Article 17, Paragraph 2, Item 1 (l)

Class IV

70,500 + overseas travel expenses 499,700 + overseas travel expenses Article 33, Paragraph 2, Item 1 (c) and Paragraph 3 70,500 + overseas travel expenses 414,600 + overseas travel expenses Article 33, Paragraph 2, Item 1 (c) and Paragraph 3

New medical devices Class IV

854,300 + overseas travel expenses 8,620,500 + overseas travel expenses

Medical devices (without approval standards, without clinical data)

Generic medical devices

1,767,700

70,500

Article 17, Paragraph 1, Item 1 (d)-(8)

Article 17, Paragraph 2, Item 1 (l)

Improved medical devices

1,409,900

70,500

Article 17, Paragraph 1, Item 1 (d)-(9)

Article 17, Paragraph 2, Item 1 (l)

1,409,900

70,500

Article 17, Paragraph 1, Item 1 (d)-(9)

Article 17, Paragraph 2, Item 1 (l)

Improved medical devices

1,409,900

70,500

Article 17, Paragraph 1, Item 1 (d)-(9)

Article 17, Paragraph 2, Item 1 (l)

Generic medical devices

1,409,900

70,500

Article 17, Paragraph 1, Item 1 (d)-(9)

Article 17, Paragraph 2, Item 1 (l)

429,200

70,500

Article 17, Paragraph 1, Item 1 (d)-(5)

Article 17, Paragraph 2, Item 1 (k)

Class III Generic medical devices

Class II

Class IV Medical devices (with approval standards, without clinical data)

Class III

Class II

- 195 -

344,100

70,500

Article 17, Paragraph 1, Item 1 (d)-(6)

Article 17, Paragraph 2, Item 1 (k)

344,100

70,500

Article 17, Paragraph 1, Item 1 (d)-(6)

Article 17, Paragraph 2, Item 1 (k)

9,389,000

6,896,500

6,896,500

4,404,700

6,896,500

4,404,700

2,425,900

1,838,200

1,480,400

1,480,400

1,480,400

1,480,400

499,700

414,600

414,600

[On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of medical devices and in vitro diagnostics under the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960)

List of user fees for reviews etc. of medical devices under the Pharmaceutical Affairs Act (Act No. 145, 1960)

Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

User fees

Classification

Inspection

Review

New products

Out of scope of approval standards

Total

2,147,500

Article 33, Paragraph 1, Item 1 (b)-(2)

2,147,500

Without clinical data

Addition of series

2,147,500

3,887,300 Article 33, Paragraph 1, Item 2 (a)-(3)

Improved medical devices with clinical data (Class II/III)

Generic medical devices without clinical data, without approval standards (Class IV) Improved/generic medical devices without clinical data, without approval standards (Class II/III) Generic medical devices with approval standards (Class IV)

Generic medical devices with approval standards (Class II/III)

3,109,900 Article 33, Paragraph 1, Item 2 (a)-(2)

1,872,400 Article 33, Paragraph 1, Item 2 (a)-(4)

1,181,200 Article 33, Paragraph 1, Item 2 (a)-(7)

884,200 Article 33, Paragraph 1, Item 2 (a)-(8)

709,500 Article 33, Paragraph 1, Item 2 (a)-(9)

217,600 Article 33, Paragraph 1, Item 2 (a)-(5)

173,600 Article 33, Paragraph 1, Item 2 (a)-(6)

143,500

Others (medical devices)

Article 33, Paragraph 1, Item 2 (a)-(10)

35,600

35,600

Change of brand name

854,300 + overseas travel expenses 6,300,900 + overseas travel expenses

New medical devices

Article 33, Paragraph 2, Item 2 (a) and Paragraph 3

Class IV

854,300 + overseas travel expenses 4,741,600 + overseas travel expenses Article 33, Paragraph 2, Item 2 (a) and Paragraph 3 683,500 + overseas travel expenses 3,793,400 + overseas travel expenses Article 33, Paragraph 2, Item 2 (b) and Paragraph 3 683,500 + overseas travel expenses 2,555,900 + overseas travel expenses

Medical devices (with clinical data)

38,200 + overseas travel expenses 1,219,400 + overseas travel expenses Article 33, Paragraph 2, Item 2 (c) and Paragraph 3 38,200 + overseas travel expenses 922,400 + overseas travel expenses 38,200 + overseas travel expenses 747,700 + overseas travel expenses Article 33, Paragraph 2, Item 2 (c) and Paragraph 3 Article 33, Paragraph 2, Item 2 (c) and Paragraph 3 38,200 + overseas travel expenses 211,800 + overseas travel expenses Article 33, Paragraph 2, Item 2 (c) and Paragraph 3 38,200 + overseas travel expenses 181,700 + overseas travel expenses Article 33, Paragraph 2, Item 2 (c) and Paragraph 3

Medical devices (without approval standards, without clinical data)

In vitro diagnostics

Nonconformity with approval standards Conformity with approval standards

With clinical data Without clinical data Without clinical data

Addition of series

Others (in vitro diagnostics)

Article 17, Paragraph 1, Item 2 (d)-(2)

Article 17, Paragraph 2, Item 2 (g)

3,109,900

683,500 Article 17, Paragraph 2, Item 2 (g)

1,872,400

683,500

Improved medical devices

Article 17, Paragraph 1, Item 2 (d)-(4)

New medical devices

3,109,900

683,500

Article 17, Paragraph 1, Item 2 (d)-(3)

Article 17, Paragraph 2, Item 2 (g)

Improved medical devices

1,872,400

683,500

Article 17, Paragraph 1, Item 2 (d)-(4)

Article 17, Paragraph 2, Item 2 (g)

Improved medical devices

1,181,200

38,200

Article 17, Paragraph 1, Item 2 (d)-(7)

Article 17, Paragraph 2, Item 2 (i)

Generic medical devices

884,200

38,200

Article 17, Paragraph 1, Item 2 (d)-(8)

Article 17, Paragraph 2, Item 2 (i)

709,500

38,200

Article 17, Paragraph 1, Item 2 (d)-(9)

Generic medical devices

709,500

38,200

Article 17, Paragraph 1, Item 2 (d)-(9)

Article 17, Paragraph 2, Item 2 (i)

Class III

709,500

38,200

Article 17, Paragraph 1, Item 2 (d)-(9)

Article 17, Paragraph 2, Item 2 (i)

Generic medical devices

709,500

38,200

Article 17, Paragraph 1, Item 2 (d)-(9)

Article 17, Paragraph 2, Item 2 (i)

217,600

38,200

Article 17, Paragraph 1, Item 2 (d)-(5)

Article 17, Paragraph 2, Item 2 (h)

173,600

38,200

Article 17, Paragraph 1, Item 2 (d)-(6)

3,793,400

2,555,900

3,793,400

2,555,900

1,219,400

922,400

747,700

Article 17, Paragraph 2, Item 2 (i)

Improved medical devices

Class III

5,041,000

3,793,400

Article 17, Paragraph 2, Item 2 (g)

Improved medical devices

Class II Review for approval of medical devices and in vitro diagnostics (approval of partial changes to approved matters)

683,500

Article 17, Paragraph 1, Item 2 (d)-(3)

Class IV

38,200 + overseas travel expenses 255,800 + overseas travel expenses

683,500 Article 17, Paragraph 2, Item 2 (g)

3,109,900

New medical devices

Class II

Article 33, Paragraph 2, Item 2 (c) and Paragraph 3

4,357,500 Article 17, Paragraph 1, Item 2 (d)-(1)

Improved medical devices

Class III

Article 33, Paragraph 2, Item 2 (b) and Paragraph 3

Medical devices (with approval standards, without clinical data)

Without clinical data

35,600

Article 17, Paragraph 1, Item 1 (e)

Class IV

With clinical data

60,300

Article 17, Paragraph 1, Item 1 (a)-(12)

60,300

Class II

Out of scope of approval standards

282,900

60,300

Review for approval of medical devices (approval of partial changes to approved matters)

Article 33, Paragraph 1, Item 2 (a)-(1)

Improved medical devices without clinical data, without approval standards (Class IV)

Addition of series

282,900 Article 17, Paragraph 1, Item 1 (a)-(13)

Article 33, Paragraph 1, Item 1 (b)-(1)

5,446,600

New medical devices (Class II/III)

Basic In vitro diagnostics (with approval standards)

584,100

Article 17, Paragraph 1, Item 1 (a)-(14)

362,000

60,300

Review for approval of medical devices and in vitro diagnostics (approval of partial changes to approved matters)

Improved medical devices with clinical data (Class IV)

Total

Article 33, Paragraph 1, Item 1 (b)-(3)

Article 33, Paragraph 1, Item 1 (c)

New medical devices (Class IV)

Inspection

584,100

996,900

362,000

35,600

Change of brand name

In vitro diagnostics (without approval standards)

2,147,500

Article 33, Paragraph 1, Item 1 (b)-(2)

With clinical data Article 33, Paragraph 1, Item 1 (b)-(2) Nonconformity with approval standards Without clinical 996,900 data Article 33, Paragraph 1, Item 1 (b)-(4) Conformity with approval standards

Review

Review for approval of drugs (new approval) 2,147,500

2,147,500

In vitro diagnostics

User fees

Classification

Review for approval of medical devices and in vitro diagnostics (new approval)

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

747,700

747,700

747,700

255,800

211,800

Article 17, Paragraph 2, Item 2 (h)

173,600

38,200

Article 17, Paragraph 1, Item 2 (d)-(6)

Article 17, Paragraph 2, Item 2 (h)

211,800

Review for approval of drugs (approval for partial changes to approved matters) 998,300

998,300

Article 33, Paragraph 1, Item 2 (b)-(2)

503,600 Article 33, Paragraph 1, Item 2 (b)-(3)

998,300

998,300

Article 33, Paragraph 1, Item 2 (b)-(2)

503,600

503,600

Article 33, Paragraph 1, Item 2 (b)-(3)

206,200

206,200

Article 33, Paragraph 1, Item 2 (b)-(4)

31,900

31,900

Article 33, Paragraph 1, Item 2 (b)-(1)

143,500

In vitro diagnostics (without approval standards)

503,600

143,500

Article 33, Paragraph 1, Item 2 (b)-(5)

- 196 -

Basic In vitro diagnostics (with approval standards) Addition of series

295,800

295,800

Article 17, Paragraph 1, Item 2 (a)-(11)

143,500

143,500

Article 17, Paragraph 1, Item 2 (a)-(10)

31,900 Article 17, Paragraph 1, Item 2 (a)-(9)

31,900

[On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of medical devices and in vitro diagnostics under the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960)

List of user fees for reviews etc. of medical devices under the Pharmaceutical Affairs Act (Act No. 145, 1960)

Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

Review

QMS inspection of medical devices and in vitro diagnostics

Class IV

New

Biological products

Others

Fee paid by MAH

In vitro diagnostics

Class IV

Biological products Partial change

386,600

Class IV

Biological products Renewal Others

In vitro diagnostics

Design

New

Sterilization

Assembly

Others

Unregistered

Design

Partial change

Sterilization Assembly

374,500

Renewal

Design

Sterilization

374,500

398,500

398,500

Article 33, Paragraph 5, Item 1 (a)-(1) 374,500

374,500

Article 33, Paragraph 5, Item 1 (a)-(4) 272,900

272,900

Article 33, Paragraph 5, Item 1 (a)-(5) 134,000

134,000

Article 33, Paragraph 5, Item 2 (a)-(2) 145,600

145,600

Article 33, Paragraph 5, Item 2 (a)-(1)

Overseas

127,800

Domestic Biological medical devices, specially controlled medical devices (Class IV), etc. Overseas

Domestic Sterile medical devices Overseas

Domestic Other medical devices Overseas

Domestic

Article 33, Paragraph 5, Item 2 (a)-(3)

Packaging, labeling, storage, external testing, etc.

93,200

Overseas

Article 33, Paragraph 5, Item 2 (a)-(4) 167,600

167,600

Domestic

Article 33, Paragraph 5, Item 3 (a)-(2) 176,900

Basic

176,900

Biological medical devices, specially controlled medical devices (Class IV), etc.

Article 33, Paragraph 5, Item 3 (a)-(1) 149,200

149,200

Article 33, Paragraph 5, Item 3 (a)-(3) 129,700

Overseas

Domestic Addition of products

129,700

Overseas

Article 33, Paragraph 5, Item 3 (a)-(4) 86,100 Article 33, Paragraph 5, Item 1 (b)-(1) and Paragraph 9, Item 1 (a) 91,200 Article 33, Paragraph 5, Item 1 (b)-(3) and Paragraph 9, Item 1 (c) 104,100 Article 33, Paragraph 5, Item 1 (b)-(2) and Paragraph 9, Item 1 (b) 90,500 Article 33, Paragraph 5, Item 1 (b)-(4) and Paragraph 9, Item 1 (d) 87,500 Article 33, Paragraph 5, Item 1 (b)-(5) and Paragraph 9, Item 1 (e) and Paragraph 10, Item 1 64,400

86,100

Inspection

Total

Domestic

75,900 Article 33, Paragraph 5, Item 2 (b)-(3) 87,700

Basic

Sterile medical devices

104,100

87,500

Overseas

Other medical devices 75,900

Domestic Addition of products

87,700

Overseas

75,800 Domestic

Article 33, Paragraph 5, Item 2 (b)-(4) Basic

75,900

68,800

80,100

Overseas

Packaging, labeling, storage, external testing, etc.

Domestic Addition of products Overseas

- 197 -

960,200 +travel expenses 685,100

Article 17, Paragraph 4, Item 1 (a)-(1)

868,600 +travel expenses

868,600 +travel expenses

Article 17, Paragraph 4, Item 1 (a)-(2)

207,100

207,100

Article 17, Paragraph 4, Item 1 (c)-(1)

236,400 +travel expenses

236,400 +travel expenses

Article 17, Paragraph 4, Item 1 (c)-(2)

145,300

145,300

Article 17, Paragraph 4, Item 1 (d)-(1)

159,900 +travel expenses

159,900 +travel expenses

Article 17, Paragraph 4, Item 1 (d)-(2)

65,600 Article 17, Paragraph 4, Item 2 (a) and Paragraph 5, Item 1 (a) 87,200 +travel expenses Article 17, Paragraph 4, Item 2 (b) and Paragraph 5, Item 1 (b) 448,500

65,600

87,200 +travel expenses

448,500

Article 17, Paragraph 4, Item 3 (a)-(1)

570,100 +travel expenses

570,100 +travel expenses

Article 17, Paragraph 4, Item 3 (a)-(2)

31,400

31,400

Article 17, Paragraph 4, Item 3 (a)-(1)

31,400

31,400

Article 17, Paragraph 4, Item 3 (a)-(2)

390,900

Article 17, Paragraph 4, Item 3 (b)-(1)

493,800 +travel expenses

Article 17, Paragraph 4, Item 3 (b)-(2)

12,800

Article 17, Paragraph 4, Item 3 (b)-(1)

12,800

Article 17, Paragraph 4, Item 3 (b)-(2)

346,100 Domestic Basic

Article 33, Paragraph 5, Item 2 (b)-(2)

68,800 Article 33, Paragraph 5, Item 3 (b)-(1) and Paragraph 9, Item 2 (a) 80,100 Article 33, Paragraph 5, Item 3 (b)-(3) and Paragraph 9, Item 2 (c)

685,100

12,800 Overseas

64,400

Article 33, Paragraph 5, Item 2 (b)-(3)

960,200 +travel expenses Article 17, Paragraph 4, Item 1 (b)-(2)

12,800 Domestic Addition of products

760,900

Article 17, Paragraph 4, Item 1 (b)-(1)

493,800 +travel expenses Overseas

90,500

760,900

390,900

91,200

Article 33, Paragraph 5, Item 2 (b)-(1)

75,900 Unregistered

386,600

Article 33, Paragraph 5, Item 1 (a)-(3)

75,800 Others

New medical devices

Article 33, Paragraph 5, Item 1 (a)-(2)

93,200 In vitro diagnostics

Domestic

Article 33, Paragraph 5, Item 1 (a) and Item 2 (a) and Item 3 (a)

127,800 Others

50,400

Approval, partial change and manufacture for export

New medical devices

Review

QMS inspection of medical devices 50,400

Renewal of the above

Issuance fee for certification of conformity with approval standards

User fees

Classification

Total

Inspection

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

User fees

Classification

346,100

Article 17, Paragraph 4, Item 3 (c)-(1)

421,100 +travel expenses

421,100 +travel expenses

Article 17, Paragraph 4, Item 3 (c)-(2)

9,900

9,900

Article 17, Paragraph 4, Item 3 (c)-(1)

9,900

9,900

Article 17, Paragraph 4, Item 3 (c)-(2)

265,900 Article 17, Paragraph 4, Item 3 (d)(1) and Paragraph 5, Item 2 (a) 347,800 +travel expenses Article 17, Paragraph 4, Item 3 (d)(2) and Paragraph 5, Item 2 (b) 6,900 Article 17, Paragraph 4, Item 3 (d)(1) and Paragraph 5, Item 2 (a) 6,900 Article 17, Paragraph 4, Item 3 (d)(2) and Paragraph 5, Item 2 (b)

265,900

347,800 +travel expenses

6,900

6,900

[On and after November 25, 2014]

[Until November 24, 2014]

List of user fees for reviews etc. of medical devices and in vitro diagnostics under the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960)

List of user fees for reviews etc. of medical devices under the Pharmaceutical Affairs Act (Act No. 145, 1960)

Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

Review

Inspection

(Yen)

Note: The lower rows in the User fees column indicate the applicable articles of the Cabinet Order on Fees related to the Pharmaceutical Affairs Act.

User fees

Classification

User fees

Classification

Total

Review

Inspection

Total

QMS inspection of medical devices and in vitro diagnostics 97,400 Article 33, Paragraph 5, Item 3 (b)-(2) and Paragraph 9, Item 2 (b) 79,600

Renewal

Assembly

Others

Article 33, Paragraph 5, Item 3 (b)-(4) and Paragraph 9, Item 2 (d)

Unregistered

Article 33, Paragraph 5, Item 3 (b)-(5) and Paragraph 9, Item 2 (e) and Paragraph 10, Item 2

Micro machine

Article 33, Paragraph 6, Item 1

Options

76,100

Nano materials

79,600

76,100

47,500

47,500

47,500

47,500

Article 33, Paragraph 6, Item 2

Others Travel expenses for on-site inspection (per day)

97,400

47,500

47,500

212,400

212,400

Article 33, Paragraph 6, Item 3 Domestic

Article 33, Paragraph 7, Item 1 and Paragraph 11

Overseas

Article 33, Paragraph 7, Item 2 (a) and (b)

179,500 +overseas travel expenses 11,000

Re-issue/renewal of compliance certification

179,500 +overseas travel expenses

11,000

Article 33, Paragraph 15

GLP inspection of medical devices and in vitro diagnostics

GLP Inspection of medical devices 2,121,400 2,121,400 Article 33, Paragraph 4, Item 1 (a) and Paragraph 13, Item 2 (a)-(1) 2,347,900 + overseas travel expenses 2,347,900 + overseas travel expenses Article 33, Paragraph 4, Item 1 (b) and Paragraph 13, Item 2 (a)-(2) and Paragraph 14

Domestic GLP Overseas GCP inspection of medical devices

944,700 + overseas travel expenses 944,700 + overseas travel expenses

Overseas

GPSP Overseas

653,400

Domestic

2,347,900 +travel expenses

653,400

Article 17, Paragraph 3, Item 3 (a)

GCP

944,700 +travel expenses

Overseas

Article 33, Paragraph 4, Item 2 (b)

Use-results surveys of medical devices and in vitro diagnostics

Domestic

Overseas

653,400

Article 33, Paragraph 4, Item 2 (a)

GCP

Child items with multiple brand names of the target medical device

GLP

2,121,400

GCP inspection of medical devices 653,400

Domestic

Target medical devices and in vitro diagnostics

2,121,400 Article 17, Paragraph 3, Item 1 (a) and Paragraph 9, Item 2 (a)-(1) 2,347,900 +travel expenses Article 17, Paragraph 3, Item 1 (b) and Paragraph 9, Item 2 (a)-(2)

Domestic

944,700 +travel expenses

Article 17, Paragraph 3, Item 3 (b)

Re-examination of medical devices 502,600 Article 33, Paragraph 12, Item 1 (a) and Item 2 35,600

642,400 + overseas travel expenses 1,145,000 + overseas travel expenses New medical devices

Article 33, Paragraph 13, Item 1 and Paragraph 14 35,600

Article 33, Paragraph 12, Item 1 (b) 628,200

Medical devices other than the new ones

628,200

Article 33, Paragraph 13, Item 2 (b)-(1) 976,100 + overseas travel expenses 976,100 + overseas travel expenses Article 33, Paragraph 13, Item 2 (b)-(2) and Paragraph 14

- 198 -

Domestic GPSP Overseas

502,600

642,400

Article 17, Paragraph 8, Item 2 (a)

Article 17, Paragraph 9, Item 1 (c)

51,600

642,400

Article 17, Paragraph 8, Item 2 (b)

Article 17, Paragraph 9, Item 1 (c) 628,200

1,145,000

694,000 628,200

Article 17, Paragraph 9, Item 2 (b)-(5)

976,100 +travel expenses Article 17, Paragraph 9, Item 2 (b)-(6)

976,100 +travel expenses

8-3. List of user fees for reviews etc. of cellular and tissue-based products based on the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics (Act No. 145, 1960) Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

User fees

Classification

Review

Inspection

Total

Assessment for manufacturing license of cellular and tissue-based products 152,300

On-site

Article 34, Paragraph 1, Item 1 (a)

Document

Article 34, Paragraph 1, Item 1 (b)

On-site

Article 34, Paragraph 1, Item 2 (a)

Document

Article 34, Paragraph 1, Item 2 (b)

On-site

Article 34, Paragraph 1, Item 3 (a)

Document

Article 34, Paragraph 1, Item 3 (b)

New license

114,700

100,200

Renewal of existing license

56,900

100,200

Change/addition of classification

56,900

152,300

114,700

100,200

56,900

100,200

56,900

Assessment for foreign manufacturers accreditation of cellular and tissue-based products 137,100 + overseas travel expenses

On-site

137,100 + overseas travel expenses

Article 34, Paragraph 2, Item 1 (a)

New accreditation

59,700

Document

Article 34, Paragraph 2, Item 1 (b)

On-site

Article 34, Paragraph 2, Item 2 (a)

Document

Article 34, Paragraph 2, Item 2 (b)

On-site

Article 34, Paragraph 2, Item 3 (a)

Document

Article 34, Paragraph 2, Item 3 (b)

66,400 + overseas travel expenses

Renewal of existing license

40,900 66,400 + overseas travel expenses

Change/addition of classification

40,900

59,700 66,400 + overseas travel expenses 40,900 66,400 + overseas travel expenses 40,900

Review for approval of cellular and tissue-based products (new approval) 10,881,700 New cellular and tissue-based products

Cellular and tissue-based products in case of new application for approval after the time-limited conditional approval Application for change of brand name

Article 35, Paragraph 1, Item 1 (a) 5,446,600 Article 35, Paragraph 1, Item 1 (b) 35,600

854,300 + overseas travel expenses 11,736,000 + overseas travel expenses Article 35, Paragraph 2, Item 1 and Paragraph 3 854,300 + overseas travel expenses 6,300,900 + overseas travel expenses Article 35, Paragraph 2, Item 1 and Paragraph 3 35,600

Article 35, Paragraph 1, Item 1 (c)

Review for approval of cellular and tissue-based products (approval of partial changes to approved matters) 854,300 + overseas travel expenses 6,300,900 + overseas travel expenses Article 35, Paragraph 2, Item 2 (a) and Paragraph 3 1,181,300 38,200 + overseas travel expenses 1,219,500 + overseas travel expenses Article 35, Paragraph 2, Item 2 (b) and Article 35, Paragraph 1, Item 2 (b) Paragraph 3 5,446,600

Cellular and tissue-based products (change of indications, etc.)

Cellular and tissue-based products (other changes)

Article 35, Paragraph 1, Item 2 (a)

- 199 -

Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics.

(Yen)

User fees

Classification

Review

Inspection

Total

GCTP inspection of cellular and tissue-based products 760,900

Domestic

Approval/partial change

Manufacturing sites other than those conducting only packaging, labelling, or storage

960,200 + overseas travel expenses Article 35, Paragraph 5, Item 1 (b) and Paragraph 7 65,600

Overseas

Domestic

87,200 + overseas travel expenses Article 35, Paragraph 5, Item 2 (b) and Paragraph 7 65,600

Overseas

Domestic

65,600 87,200 + overseas travel expenses

65,600

Article 35, Paragraph 6, Item 1 (a)

Testing institutions

87,200 + overseas travel expenses Article 35, Paragraph 6, Item 1 (b) and Paragraph 7 448,500

Overseas

Domestic

87,200 + overseas travel expenses

448,500

Article 35, Paragraph 5, Item 3 (a)-(1)

Basic

570,100 + overseas travel expenses Article 35, Paragraph 5, Item 3 (a)-(2) and Paragraph 7 31,400

Overseas

Domestic

570,100 + overseas travel expenses

31,400

Article 35, Paragraph 5, Item 3 (a)-(1)

Addition of products

31,400

Overseas

Article 35, Paragraph 5, Item 3 (a)-(2)

Domestic

Article 35, Paragraph 5, Item 3 (b)-(1)

265,900

Basic Renewal

960,200 + overseas travel expenses

Article 35, Paragraph 5, Item 2 (a)

Packaging, labelling, or storage

Manufacturing sites other than those conducting only packaging, labelling, or storage

760,900

Article 35, Paragraph 5, Item 1 (a)

347,800 + overseas travel expenses Article 35, Paragraph 5, Item 3 (b)-(2) and Paragraph 7 6,900

Overseas Packaging, labelling, or storage Domestic

31,400

265,900 347,800 + overseas travel expenses

6,900

Article 35, Paragraph 5, Item 3 (b)-(1)

Addition of products

6,900

Overseas

6,900

Article 35, Paragraph 5, Item 3 (b)-(2) 265,900

Domestic

265,900

Article 35, Paragraph 6, Item 2 (a)

Basic

347,800 + overseas travel expenses Article 35, Paragraph 6, Item 2 (b) and Paragraph 7 6,900

Overseas Testing institutions Domestic

347,800 + overseas travel expenses

6,900

Article 35, Paragraph 6, Item 2 (a)

Addition of products

6,900

Overseas

6,900

Article 35, Paragraph 6, Item 2 (b)

GLP inspection of cellular and tissue-based products 2,121,400 2,121,400 Article 35, Paragraph 4, Item 1 (a) and Paragraph 10, Item 2 (a)-(1) 2,347,900 + overseas travel expenses 2,347,900 + overseas travel expenses

Domestic GLP

Article 35, Paragraph 4, Item 1 (b) and Paragraph 10, Item 2 (a)-(2) and Paragraph 11

Overseas

GCP inspection of cellular and tissue-based products 653,400

Domestic

653,400

Article 35, Paragraph 4, Item 2 (a)

GCP

944,700 + overseas travel expenses

Overseas

944,700 + overseas travel expenses

Article 35, Paragraph 4, Item 2 (b)

GPSP inspection of cellular and tissue-based products 628,500

Domestic

628,500

Article 35, Paragraph 4, Item 3 (a)

GPSP

976,100 + overseas travel expenses

Overseas

976,100 + overseas travel expenses

Article 35, Paragraph 4, Item 3 (b)

Re-examination of cellular and tissue-based products 504,400 Cellular and tissue-based products

Article 35, Paragraph 9

Domestic

642,400 + overseas travel expenses 1,146,800 + overseas travel expenses Article 35, Paragraph 10, Item 1 and Paragraph 11 628,500 628,500 Article 35, Paragraph 10, Item 2 (b)-(1)

GPSP

976,100 + overseas travel expenses Article 35, Paragraph 10, Item 2 (b)(2) and Paragraph 11

Overseas

- 200 -

976,100 + overseas travel expenses

8-4. List of user fees for PMDA’s investigation based on the Act on Securing Safety of Regenerative Medicine (Act No. 85, 2013) Note: The lower rows in the “User fees” column indicate the applicable articles of the Cabinet Order on Fees related to the Act on Securing Safety of Regenerative Medicine (Cabinet Order No. 278).

Classification

Inspection

(Yen) Total

Investigation into license for manufacturing specified cellular products On-site New license Document

On-site Renewal of license Document

144,000

144,000

Article 8, Paragraph 1, Item 1 98,200

98,200

Article 8, Paragraph 1, Item 2 97,100

97,100

Article 8, Paragraph 2, Item 1 48,600

48,600

Article 8, Paragraph 2, Item 2

Investigation into accreditation for manufacturing specified cellular products On-site New accreditation Document

On-site Renewal of accreditation Document

- 201 -

120,500 + overseas travel expenses

120,500 + overseas travel expenses

Article 8, Paragraph 3, Item 1 54,200

54,200

Article 8, Paragraph 3, Item 2 56,500 + overseas travel expenses

56,500 + overseas travel expenses

Article 8, Paragraph 4, Item 1 37,100 Article 8, Paragraph 4, Item 2

37,100

8-5. List of user fees under Article 4 of the Administrative Instructions for the Statement of Operating Procedures on Reviews and Related Services of the Pharmaceuticals and Medical Devices Agency [On and after November 25, 2014]

[Until November 24, 2014] Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen)

User fees

(Yen)

Timing of payment

User fees Consultations

Consultations Procedural consultation for drugs

per consultation

143,800

Procedural consultation for drugs

per consultation

Consultation on bioequivalence testing, etc. for drugs

per consultation

571,900

Consultation on bioequivalence testing, etc. for drugs

per consultation

571,900

143,800

Safety consultation for drugs

per consultation

1,833,700

Safety consultation for drugs

per consultation

1,833,700

Quality consultation for drugs

per consultation

1,520,500

Quality consultation for drugs

per consultation

1,520,500

Consultation before start of phase I study for drugs (non-orphan drugs)

per consultation

4,360,500

Consultation before start of phase I study for drugs (non-orphan drugs)

per consultation

4,360,500

Consultation before start of phase I study for drugs (orphan drugs)

per consultation

3,277,200

Consultation before start of phase I study for drugs (orphan drugs)

per consultation

3,277,200

Consultation before start of early phase II study for drugs (non-orphan drugs)

per consultation

1,669,400

Consultation before start of early phase II study for drugs (non-orphan drugs)

per consultation

1,669,400

Consultation before start of early phase II study for drugs (orphan drugs)

per consultation

1,257,400

Consultation before start of early phase II study for drugs (orphan drugs)

per consultation

1,257,400

Consultation before start of late phase II study for drugs (non-orphan drugs)

per consultation

3,114,900

Consultation before start of late phase II study for drugs (non-orphan drugs)

per consultation

3,114,900

Consultation before start of late phase II study for drugs (orphan drugs)

per consultation

2,339,200

Consultation before start of late phase II study for drugs (orphan drugs)

per consultation

2,339,200

Consultation after completion of phase II study for drugs (non-orphan drugs)

per consultation

6,183,300

Consultation after completion of phase II study for drugs (non-orphan drugs)

per consultation

6,183,300

Consultation after completion of phase II study for drugs (orphan drugs)

per consultation

4,644,800

Consultation after completion of phase II study for drugs (orphan drugs)

per consultation

4,644,800

Pre-application consultation for drugs (non-orphan drugs)

per consultation

6,183,200

Pre-application consultation for drugs (non-orphan drugs)

per consultation

6,183,200

Pre-application consultation for drugs (orphan drugs)

per consultation

4,642,000

Pre-application consultation for drugs (orphan drugs)

per consultation

4,642,000

Consultation on protocols of post-marketing clinical trials of drugs

per consultation

1,664,800

Consultation on protocols of clinical trials for reevaluation and re-examination of drugs

per consultation

3,415,500

Consultation at completion of post-marketing clinical trials of drugs (preparation of application data, etc.)

per consultation

1,664,800

Consultation at completion of clinical trials for reevaluation and re-examination of drugs

per consultation

3,414,200

Consultation at completion of post-marketing clinical trials of drugs (review of conditions for approval, etc.)

per consultation

826,800

Additional consultation for drugs (non-orphan drugs)

per consultation

2,752,100

Additional consultation for drugs (non-orphan drugs)

per consultation

2,752,100

Additional consultation for drugs (orphan drugs)

per consultation

2,067,900

Additional consultation for drugs (orphan drugs)

per consultation

2,067,900

Consultation on GLP/GCP/GPSP compliance for drugs

per consultation

2,957,700

Consultation on GLP/GCP compliance for drugs (non-orphan drugs)

per consultation

2,957,700

Consultation on GLP/GCP compliance for drugs (orphan drugs)

per consultation

2,218,900

Prior assessment consultation for drugs (quality)

per consultation

3,136,500

Prior assessment consultation for drugs (non-clinical: toxicity)

per consultation

2,120,000

(Deleted) Payment by the date of consultation application after arrangement of the consultation date

Prior assessment consultation for drugs (quality)

per consultation

3,136,500

Prior assessment consultation for drugs (non-clinical: toxicity)

per consultation

2,120,000

Prior assessment consultation for drugs (non-clinical: pharmacology)

per consultation

2,120,000

Prior assessment consultation for drugs (non-clinical: pharmacology)

per consultation

2,120,000

Prior assessment consultation for drugs (non-clinical: pharmacokinetics)

per consultation

2,120,000

Prior assessment consultation for drugs (non-clinical: pharmacokinetics)

per consultation

2,120,000

Drugs

Drugs

Timing of payment

Prior assessment consultation for drugs (phase I study)

per consultation

3,584,300

Prior assessment consultation for drugs (phase I study)

per consultation

3,584,300

Prior assessment consultation for drugs (phase II study)

per consultation

4,625,900

Prior assessment consultation for drugs (phase II study)

per consultation

4,625,900

Prior assessment consultation for drugs (phase II / III study)

per consultation

7,185,300

Prior assessment consultation for drugs (phase II / III study)

per consultation

7,185,300

Consultation on drug product eligibility for priority review

per consultation

846,800

Consultation on drug product eligibility for priority review

per consultation

846,800

Consultation on drug product eligibility for priority review (with pre-application consultation for drugs)

per consultation

173,500

Consultation on drug product eligibility for priority review (with pre-application consultation for drugs)

per consultation

173,500

Consultation on pharmacogenomics/biomarkers (qualification)

per consultation

3,114,900

Consultation on pharmacogenomics/biomarkers (qualification)

per consultation

3,114,900

Consultation on pharmacogenomics/biomarkers (key points of clinical trial protocols)

per consultation

1,142,800

Consultation on pharmacogenomics/biomarkers (key points of clinical trial protocols)

per consultation

1,142,800

Additional consultation on pharmacogenomics/biomarkers (qualification)

per consultation

948,300

Additional consultation on pharmacogenomics/biomarkers (qualification)

per consultation

948,300

Additional consultation on pharmacogenomics/biomarkers (key points of clinical trial protocols)

per consultation

414,600

Additional consultation on pharmacogenomics/biomarkers (key points of clinical trial protocols)

per consultation

414,600

Consultation on R&D strategy for drugs

per consultation

1,541,600

(Transferred to the classification of R&D strategy)

Consultation on R&D strategy for drugs (universities/research institutions and venture companies meeting requirements specified separately*)

per consultation

154,100

Consultations on bioequivalence of generic drugs

per consultation

1,026,000

Quality consultation for generic drugs

per consultation

505,800

Pre-application consultation for switch OTC drugs

per consultation

1,544,000

516,800

Consultation on key points of clinical trial protocols for OTC drugs

per consultation

516,800

204,800

Consultation on appropriateness of development of new OTC drugs

per consultation

204,800

Consultations on bioequivalence of generic drugs

per consultation

Quality consultation for generic drugs

per consultation

505,800

Pre-application consultation for switch OTC drugs

per consultation

1,544,000

Consultation on key points of clinical trial protocols for OTC drugs

per consultation

Consultation on appropriateness of development of new OTC drugs

per consultation

Post-consultation for drugs (with recording)

per consultation

94,500

Consultation on GCP/GLP/GPSP for drugs

per consultation

289,200

1,026,000

- 202 -

Payment by the date of consultation application after arrangement of the consultation date

[On and after November 25, 2014]

[Until November 24, 2014]

Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen)

User fees Consultations

User fees

Timing of payment

Consultations

Preparatory interview of consultations for medical devices

per consultation

29,400

Pre-development consultation for medical devices

per consultation

294,100

per consultation

139,100

Clinical evaluation consultation for medical devices

per consultation

1,055,900

98,000

Safety consultation for medical devices (excluding biological medical devices)

per consultation

845,600

68,600

Safety consultation for biological medical devices

per consultation

936,200

per consultation

264,700

Pre-development consultation for medical devices (additional consultation)

per consultation

147,000

Consultation on necessity of clinical trials for medical devices

per consultation

980,300

Consultation on necessity of clinical trials for medical devices (after the preparatory interview)

per consultation

950,600

Consultation on necessity of clinical trials for medical devices (additional consultation)

per consultation

490,200

Consultation on necessity of clinical trials for medical devices (ascertained with reference to clinical literature, etc.)

per consultation

1,960,900

Consultation on necessity of clinical trials for medical devices (ascertained with reference to clinical literature, etc.) (after the preparatory interview)

per consultation

1,931,500

Consultation on necessity of clinical trials for medical devices (ascertained with reference to clinical literature, etc.) (additional consultation)

per consultation

980,300

Safety (1 test)

per consultation

Safety (1 test) (after the preparatory interview)

per consultation

Safety (1 test) (additional consultation)

per consultation

46,800

Safety (2 tests)

per consultation

196,000

Safety (2 tests) (after the preparatory interview)

per consultation

166,600

Safety (2 tests) (additional consultation)

per consultation

98,000

Safety (3 tests)

per consultation

293,800

Safety (3 tests) (after the preparatory interview)

per consultation

264,400

Safety (3 tests) (additional consultation)

per consultation

147,000

Safety (4 or more tests)

per consultation

390,100

Safety (4 or more tests) (after the preparatory interview)

per consultation

360,700

Safety (4 or more tests) (additional consultation)

per consultation

196,000

Quality

per consultation

390,100

Quality (after the preparatory interview)

per consultation

360,700

Quality (additional consultation)

per consultation

196,000

Performance (1 test)

per consultation

98,000

Performance (1 test) (after the preparatory interview)

per consultation

68,600

Performance (1 test) (additional consultation)

per consultation

46,800

Performance (2 tests)

per consultation

196,000

Performance (2 tests) (after the preparatory interview)

per consultation

166,600

Performance (2 tests) (additional consultation)

per consultation

98,000

Performance (3 tests)

per consultation

293,800

Performance (3 tests) (after the preparatory interview)

per consultation

264,400

Performance (3 tests) (additional consultation)

per consultation

147,000

Performance (4 or more tests)

per consultation

390,100

Performance (4 or more tests) (after the preparatory interview)

per consultation

360,700

Performance (4 or more tests) (additional consultation)

per consultation

196,000

Exploratory clinical trial

per consultation

1,076,200

Exploratory clinical trial (after the preparatory interview)

per consultation

1,046,800

Exploratory clinical trial (additional consultation)

per consultation

539,100

Clinical trial

per consultation

2,353,100

Clinical trial (after the preparatory interview)

per consultation

2,323,700

Clinical trial (additional consultation)

per consultation

1,176,500

per consultation

134,800

Payment by the date of consultation application after arrangement of the consultation date

Medical devices

Pre-development consultation for medical devices

Pre-development consultation for medical devices (after the preparatory interview)

Consultation on protocol for medical devices

Medical devices

(Yen)

Timing of payment

(Deleted) Consultation on data sufficiency/category of application for medical devices (Deleted) Consultation on GLP/GCP/GPSP compliance investigation for medical devices

per consultation

399,700

Consultation on GLP/GCP/GPSP compliance investigation for medical devices (after the preparatory interview)

per consultation

370,300

Consultation on GLP/GCP/GPSP compliance investigation for medical devices (additional consultation)

per consultation

197,900

- 203 -

Quality consultation for medical devices (excluding biological medical devices)

per consultation

797,500

Quality consultation for biological medical devices

per consultation

947,700

Performance testing consultation for medical devices

per consultation

870,100

Exploratory clinical trial consultation for medical devices

per consultation

1,136,900

Clinical trial consultation for medical devices

per consultation

2,482,000

2,482,000

Pre-application consultation for medical devices

per consultation

Application procedure consultation for medical devices

per consultation

139,100

Additional consultation for medical devices

per consultation

1,162,400

Consultation on GLP/GCP compliance for medical devices

per consultation

795,000

Payment by the date of consultation application after arrangement of the consultation date

[Until November 24, 2014]

[On and after November 25, 2014] Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen)

User fees

User fees

Timing of payment

Consultations Safety (1 test)

per consultation

98,000

Prior assessment consultation for medical devices (quality)

per consultation

3,067,600

Safety (1 test) (after the preparatory interview)

per consultation

68,600

Prior assessment consultation for medical devices (non-clinical)

per consultation

3,067,600

Safety (1 test) (unevaluated protocol)

per consultation

147,000

Safety (1 test) (unevaluated protocol) (after the preparatory interview)

per consultation

115,500

Safety (1 test) (additional consultation)

per consultation

46,800

Safety (2 tests)

per consultation

196,000

Safety (2 tests) (after the preparatory interview)

per consultation

166,600

Safety (2 tests) (unevaluated protocol)

per consultation

293,800

Safety (2 tests) (unevaluated protocol) (after the preparatory interview)

per consultation

264,400

Safety (2 tests) (additional consultation)

per consultation

98,000

Safety (3 tests)

per consultation

293,800

Safety (3 tests) (after the preparatory interview)

per consultation

264,400

Safety (3 tests) (unevaluated protocol)

per consultation

441,200

Safety (3 tests) (unevaluated protocol) (after the preparatory interview)

per consultation

411,800

Safety (3 tests) (additional consultation)

per consultation

147,000

Safety (4 or more tests)

per consultation

390,100

Safety (4 or more tests) (after the preparatory interview)

per consultation

360,700

Safety (4 or more tests) (unevaluated protocol)

per consultation

588,200

Safety (4 or more tests) (unevaluated protocol) (after the preparatory interview)

per consultation

558,800

Safety (4 or more tests) (additional consultation)

per consultation

196,000

Quality

per consultation

390,100

Quality (after the preparatory interview)

per consultation

360,700

Quality (unevaluated protocol)

per consultation

588,200

Quality (unevaluated protocol) (after the preparatory interview)

per consultation

558,800

Quality (additional consultation)

per consultation

196,000

Performance (1 test)

per consultation

Performance (1 test) (after the preparatory interview)

per consultation

68,600

Performance (1 test) (unevaluated protocol)

per consultation

147,000

Performance (1 test) (unevaluated protocol) (after the preparatory interview)

per consultation

115,500

Performance (1 test) (additional consultation)

per consultation

46,800

98,000

Performance (2 tests)

per consultation

196,000

Performance (2 tests) (after the preparatory interview)

per consultation

166,600

Performance (2 tests) (unevaluated protocol)

per consultation

293,800

Performance (2 tests) (unevaluated protocol) (after the preparatory interview)

per consultation

264,400

Performance (2 tests) (additional consultation)

per consultation

98,000

Performance (3 tests)

per consultation

293,800

Performance (3 tests) (after the preparatory interview)

per consultation

264,400

Performance (3 tests) (unevaluated protocol)

per consultation

441,200

Performance (3 tests) (unevaluated protocol) (after the preparatory interview)

per consultation

411,800

Performance (3 tests) (additional consultation)

per consultation

147,000

Performance (4 or more tests)

per consultation

Payment by the date of consultation application after arrangement of the consultation date

Medical devices

Assessment consultation for medical devices

Consultations

Medical devices

(Yen)

Timing of payment

390,100

Performance (4 or more tests) (after the preparatory interview)

per consultation

360,700

Performance (4 or more tests) (unevaluated protocol)

per consultation

588,200

Performance (4 or more tests) (unevaluated protocol) (after the preparatory interview)

per consultation

558,800

Performance (4 or more tests) (additional consultation)

per consultation

196,000

- 204 -

Payment by the date of consultation application after arrangement of the consultation date

[On and after November 25, 2014]

[Until November 24, 2014]

Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen) User fees

Exploratory clinical trial

per consultation

980,300

Exploratory clinical trial (after the preparatory interview)

per consultation

950,900

Exploratory clinical trial (unevaluated protocol)

per consultation

1,519,700

Exploratory clinical trial (unevaluated protocol) (after the preparatory interview)

per consultation

1,488,100

per consultation per consultation

1,470,700

Clinical trial (after the preparatory interview)

per consultation

1,441,300

Clinical trial (unevaluated protocol)

per consultation

2,647,200

Clinical trial (unevaluated protocol) (after the preparatory interview)

per consultation

2,617,700

Clinical trial (additional consultation)

per consultation

733,000

Consultation on GCP/GLP/GPSP for medical devices (after the preparatory interview)

per consultation

166,600

Consultation on GCP/GLP/GPSP for medical devices (additional consultation)

per consultation

98,000

Preparatory interview of consultations for in vitro diagnostics

per consultation

29,400

Pre-development consultation for in vitro diagnostics

per consultation

196,000

Pre-development consultation for in vitro diagnostics (after the preparatory interview)

per consultation

166,600

Pre-development consultation for in vitro diagnostics (additional consultation)

per consultation

98,000

Pre-development consultation for companion diagnostics

per consultation

293,800

Pre-development consultation for companion diagnostics (after the preparatory interview)

per consultation

264,400

Pre-development consultation for companion diagnostics (additional consultation)

per consultation

147,000

Consultation on protocol for in vitro diagnostics

Consultation on R&D strategy for medical devices

per consultation

874,000

venture companies meeting requirements specified separately*)

per consultation

87,400

Pre-development consultation for in vitro diagnostics

per consultation

143,900

Quality

per consultation

98,000

Quality (after the preparatory interview)

per consultation

68,600

Quality (additional consultation)

per consultation

46,800

Performance (other than quality) (1 test)

per consultation

98,000

Performance (other than quality) (1 test) (after the preparatory interview)

per consultation

68,600

Performance (other than quality) (1 test) (additional consultation)

per consultation

46,800

Performance (other than quality) (2 tests)

per consultation

196,000

Performance (other than quality) (2 tests) (after the preparatory interview)

per consultation

166,600

Performance (other than quality) (2 tests) (additional consultation)

per consultation

98,000

Performance (other than quality) (3 or more tests)

per consultation

293,800

Performance (other than quality) (3 or more tests) (after the preparatory interview)

per consultation

264,400

Performance (other than quality) (3 or more tests) (additional consultation)

per consultation

147,000

per consultation

196,000

Correlation (after the preparatory interview)

per consultation

166,600

Correlation (additional consultation)

per consultation

98,000

Clinical performance study

per consultation

490,200

Clinical performance study (after the preparatory interview)

per consultation

Clinical performance study (additional consultation)

per consultation

245,100

Clinical evaluation study for companion diagnostics

per consultation

733,000

Payment by the date of consultation application after arrangement of the consultation date

Quality consultation for in vitro diagnostics

per consultation

355,400

Consultation on conformity with standards for in vitro diagnostics

per consultation

455,400

Clinical performance study consultation for in vitro diagnostics

per consultation

1,640,300

Pre-application consultation for in vitro diagnostics

per consultation

1,640,300

Application procedure consultation for in vitro diagnostics

per consultation

139,100

Additional consultation for in vitro diagnostics

per consultation

954,100

In vitro diagnostics

196,000

458,700

Clinical evaluation study for companion diagnostics (after the preparatory interview)

per consultation

703,600

Clinical evaluation study for companion diagnostics (additional consultation)

per consultation

367,600

per consultation

78,300

(Deleted) Application procedure consultation for in vitro diagnostics

4,619,100

Consultation on R&D strategy for medical devices (Universities/research institutions and

per consultation

Correlation

per consultation

490,200

Clinical trial

Consultation on GCP/GLP/GPSP for medical devices

Prior assessment consultation for medical devices (clinical)

Medical devices

Exploratory clinical trial (additional consultation)

(Transferred to the classification of R&D strategy)

In vitro diagnostics

Timing of payment

Consultations

medical devices

Assessment consultation for

Consultations

Medical devices

(Yen) User fees

Timing of payment

(Deleted)

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Payment by the date of consultation application after arrangement of the consultation date

[On and after November 25, 2014]

[Until November 24, 2014]

Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen)

User fees

User fees

Timing of payment

Consultations Quality

per consultation

98,000

Quality consultation for in vitro diagnostics

per consultation

355,400

Quality (after the preparatory interview)

per consultation

68,600

Prior assessment consultation for in vitro diagnostics (quality)

per consultation

3,067,600

Quality (unevaluated protocol)

per consultation

147,000

Quality (unevaluated protocol) (after the preparatory interview)

per consultation

115,500

Quality (additional consultation)

per consultation

46,800

Performance (other than quality) (1 test)

per consultation

98,000

Prior assessment consultation for in vitro diagnostics (non-clinical)

per consultation

3,067,600

Performance (other than quality) (1 test) (after the preparatory interview)

per consultation

68,600

Consultation on conformity with standards for in vitro diagnostics

per consultation

455,400

Performance (other than quality) (1 test) (unevaluated protocol)

per consultation

147,000

Performance (other than quality) (1 test) (unevaluated protocol) (after the preparatory interview)

per consultation

115,500

Performance (other than quality) (1 test) (additional consultation)

per consultation

46,800

Performance (other than quality) (2 tests)

per consultation

196,000

Performance (other than quality) (2 tests) (after the preparatory interview)

per consultation

166,600

Performance (other than quality) (2 tests) (unevaluated protocol)

per consultation

293,800

Performance (other than quality) (2 tests) (unevaluated protocol) (after the preparatory interview)

per consultation

264,400

Prior assessment consultation for in vitro diagnostics (clinical)

per consultation

4,619,100

Clinical evaluation consultation for in vitro diagnostics

per consultation

694,700

Performance (other than quality) (2 tests) (additional consultation)

per consultation

98,000

Performance (other than quality) (3 or more tests)

per consultation

293,800

Performance (other than quality) (3 or more tests) (after the preparatory interview)

per consultation

264,400

Performance (other than quality) (3 or more tests) (unevaluated protocol)

per consultation

441,200

Performance (other than quality) (3 or more tests) (unevaluated protocol) (after the preparatory interview)

per consultation

411,800

Performance (other than quality) (3 or more tests) (additional consultation)

per consultation

147,000

Correlation

per consultation

196,000

Correlation (after the preparatory interview)

per consultation

166,600

Correlation (unevaluated protocol)

per consultation

293,800

Correlation (unevaluated protocol) (after the preparatory interview)

per consultation

264,400

Correlation (additional consultation)

per consultation

98,000

Clinical performance study

per consultation

293,800

Clinical performance study (after the preparatory interview)

per consultation

264,400

Clinical performance study (unevaluated protocol)

per consultation

539,100

Clinical performance study (unevaluated protocol) (after the preparatory interview)

per consultation

509,700

Clinical performance study (additional consultation)

per consultation

147,000

Clinical evaluation study for companion diagnostics

per consultation

441,200

Clinical evaluation study for companion diagnostics (after the preparatory interview)

per consultation

411,800

Clinical evaluation study for companion diagnostics (unevaluated protocol)

per consultation

809,000

Clinical evaluation study for companion diagnostics (unevaluated protocol) (after the preparatory interview)

per consultation

779,600

Clinical evaluation study for companion diagnostics (additional consultation)

per consultation

220,600

Procedural consultation for cellular and tissue-based products

per consultation

134,800

Pre-development consultation for cellular and tissue-based products

per consultation

299,800

Pre-development consultation for cellular and tissue-based products (additional consultation)

per consultation

149,900

Non-clinical consultation for cellular and tissue-based products (effectiveness)

per consultation

899,500

Non-clinical consultation for cellular and tissue-based products (effectiveness) (additional consultation)

per consultation

449,700

Non-clinical consultation for cellular and tissue-based products (safety)

per consultation

946,200

Non-clinical consultation for cellular and tissue-based products (safety) (additional consultation)

per consultation

473,200

Quality consultation for cellular and tissue-based products

per consultation

946,200

Quality consultation for cellular and tissue-based products (additional consultation)

per consultation

473,200

Consultation before therapeutic exploratory study for cellular and tissue-based products

per consultation

1,098,500

Consultation before therapeutic exploratory study for cellular and tissue-based products (additional consultation)

per consultation

549,700

Consultation after therapeutic exploratory study for cellular and tissue-based products

per consultation

1,098,500

Consultation after therapeutic exploratory study for cellular and tissue-based products (additional consultation)

per consultation

549,700

In vitro diagnostics

Consultation on evaluation for in vitro diagnostics

In vitro diagnostics

Consultations

Cellular and tissue-based products

(Yen)

Timing of payment

Payment by the date of consultation application after arrangement of the consultation date

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Payment by the date of consultation application after arrangement of the consultation date

[On and after November 25, 2014]

[Until November 24, 2014]

Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen)

User fees Consultations

Cellular and tissue-based products

User fees

per consultation

2,398,600

Prior assessment consultation for cellular and tissue-based products (therapeutic exploratory study)

per consultation

1,098,500

Prior assessment consultation for cellular and tissue-based products (confirmatory clinical study)

per consultation

2,398,600

Pre-application consultation for cellular and tissue-based products

per consultation

2,398,600

Pre-application consultation for cellular and tissue-based products (additional consultation)

per consultation

1,199,300

Consultation on protocols of clinical trials for cellular and tissue-based products after the time-limited conditional approval (with protocol)

per consultation

1,098,500

Consultation on protocols of clinical trials for cellular and tissue-based products after the time-limited conditional approval (with protocol) (additional consultation)

per consultation

549,700

per consultation

824,500

per consultation

412,200

per consultation

1,098,500

Consultation at completion of clinical trials for cellular and tissue-based products after the time-limited conditional approval (with protocol) (additional consultation)

per consultation

549,700

Consultation at completion of clinical trials for cellular and tissue-based products after the time-limited conditional approval (only for investigation)

per consultation

824,500

Consultation at completion of clinical trials for cellular and tissue-based products after the time-limited conditional approval (only for investigation) (additional consultation)

per consultation

412,200

Consultation on protocols of post-marketing clinical trials for cellular and tissuebased products (with protocol)

per consultation

1,098,500

Consultation on protocols of post-marketing clinical trials for cellular and tissuebased products (with protocol) (additional consultation)

per consultation

549,700

Consultation on protocols of post-marketing clinical trials for cellular and tissuebased products (only for investigation)

per consultation

824,500

Consultation on protocols of post-marketing clinical trials for cellular and tissuebased products (only for investigation) (additional consultation)

per consultation

412,200

Consultation at completion of post-marketing clinical trials for cellular and tissuebased products (with protocol)

per consultation

1,098,500

Consultation at completion of post-marketing clinical trials for cellular and tissuebased products (with protocol) (additional consultation)

per consultation

549,700

Consultation at completion of post-marketing clinical trials for cellular and tissuebased products (only for investigation)

per consultation

824,500

Consultation at completion of post-marketing clinical trials for cellular and tissuebased products (only for investigation) (additional consultation)

per consultation

412,200

Consultation on GLP/GCP (including GCTP) compliance for cellular and tissuebased products

per consultation

399,700

Consultation on GLP/GCP (including GCTP) compliance for cellular and tissuebased products (additional consultation)

per consultation

197,900

Pre-interview for cellular and tissue-based products (with recording)

per consultation

94,500

Post-consultation for cellular and tissue-based products (with recording)

per consultation

94,500

per consultation

1,541,600

Payment by the date of consultation application after arrangement of the consultation date

(Deleted)

Pharmaceutical affairs consultation on R&D strategy

Consultation on R&D strategy for drugs Consultation on R&D strategy for drugs (universities/research institutions and venture

Payment by the date of consultation application after arrangement of the consultation date

Consultation on preparation of documents for gene therapy products (Transferred from the “Drugs” classification)

companies meeting requirements specified separately*)

per consultation

154,100

Consultation on quality and safety for cellular and tissue-based products

per consultation

1,541,600

Consultation on quality and safety of cellular and tissue-based products

(universities/research institutions and venture companies meeting the requirements

per consultation

154,100

per consultation

874,000

specified separately*) Consultation on R&D strategy for medical devices Consultation on R&D strategy for medical devices (Universities/research institutions and venture companies meeting requirements specified separately*)

per consultation

87,400

Consultation on R&D strategy for cellular and tissue-based products

per consultation

874,000

Consultation on R&D strategy for cellular and tissue-based products (universities/research institutions and venture companies meeting the requirements

per consultation

87,400

per consultation

73,600

(Transferred from the “Medical Devices” classification)

specified separately*) Consultation on R&D strategy for pharmaceutical development plans, etc.

Timing of payment

Consultations

Prior assessment consultation for cellular and tissue-based products (safety, quality, effectiveness)

Consultation on protocols of clinical trials for cellular and tissue-based products after the time-limited conditional approval (only for investigation) Consultation on protocols of clinical trials for cellular and tissue-based products after the time-limited conditional approval (only for investigation) (additional consultation) Consultation at completion of clinical trials for cellular and tissue-based products after the time-limited conditional approval (with protocol)

(Yen)

Timing of payment

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per consultation

229,900

[On and after November 25, 2014]

[Until November 24, 2014]

Attached Table (related to Article 4)

Attached Table (related to Article 4)     Classification of user fees, etc.

    Classification of user fees, etc. (Yen)

User fees

User fees

Timing of payment

Consultations

Generic drugs

per consultation

21,600

Generic drugs

per consultation

OTC drugs

per consultation

21,600

OTC drugs

per consultation

Quasi-drugs (including pest control agents)

per consultation

21,600

Quasi-drugs (including pesticides and rodenticides)

per consultation

21,600

Medical devices or in vitro diagnostics

per consultation

39,400

Medical devices or in vitro diagnostics

per consultation

35,300

Preparation of new drug applications

per consultation

21,600

Preparation of new drug applications

per consultation

21,600

Cellular and tissue-based products

per consultation

21,600

GCP/GLP/GPSP for drugs

per consultation

19,400

GCP/GLP/GPSP for medical devices

per consultation

19,400

GCP/GLP/GPSP for cellular and tissue-based products

per consultation

GMP/QMS inspection

per consultation

25,400

GMP/QMS inspection

per consultation

25,400

GCTP inspection

per consultation

25,400

Assessment for designation of drugs for priority consultation

per application

842,200

Assessment for designation of medical devices or in vitro diagnostics for priority consultation

per application

842,200

Payment by the date of consultation application after arrangement of the consultation date

Simple consultations

Simple consultations

Consultations

Assessment for designation of drugs for priority consultation

per application

842,200

Assessment for designation of medical devices or in vitro diagnostics for priority consultation

per application

842,200

Request to PMDA after advanced payment

All test items (for drugs and medical devices) With animal-rearing facility

per facility

1,299,600

Without animal-rearing facility

per facility

799,500

General toxicity studies

per study

399,700

Reproduction toxicity studies

per study

199,800

Safety pharmacology core battery (only for drugs)

per study

199,800

Hemocompatibility studies (only for medical devices)

per study

199,800

In vitro studies

per study

199,800

Other studies (dependence, TK, pathology, and other studies)

per study

199,800

Drugs

per facility

199,800

Medical devices

per facility

199,800

Cellular and tissue-based products

per facility

199,800

Additional compliance accreditation

per facility

959,300

Additional inspection

per inspection from the second inspection onwards

396,500

GMP certification on investigational products (with on-site inspection)

per product of one facility

760,900

GMP certification on investigational products (without on-site inspection)

per product of one facility

15,500

Certification of drug products

per product

15,500

Other certifications (including GMP/QMS certification)

per matter of one product

Additional fee for target classification

Payment by the date of consultation application after arrangement of the consultation date

Request to PMDA after advanced payment

GLP inspection of test facilities

(Deleted)

Additional fee for target tests

21,600

Assessment for designation of priority consultation products

GLP inspection of test facilities

Basic fee

21,600

19,400

Assessment for designation of priority consultation products

All test items

(Yen)

Timing of payment

Domestic

per facility

3,110,300

per facility

2,121,400

All test items (for drugs or medical devices) Request to PMDA after advanced payment

Request to PMDA after advanced payment

Overseas

(Deleted) (Deleted)

Confirmation of certification on drugs, etc.

per facility

2,347,900 + travel expe

Limited test items

per facility

1,023,600

Additional compliance accreditation

per facility

959,300

GMP certification on investigational products (with on-site inspection)

per product of one facility

760,900

GMP certification on investigational products (without on-site inspection)

per product of one facility

15,500

Certification of drug products

per product

15,500

Other certifications (including GMP/QMS certification)

per matter of one product

8,700

per day per room

3,000

Confirmation of certification on drugs, etc.

Request to PMDA after advanced payment

8,700

Use of document storage rooms

Request to PMDA after advanced payment

Use of document storage rooms per day per room

3,000

Payment upon invoice sent from PMDA after the end of the period of use

* Universities/research institutions and venture companies meeting requirements specified separately.  All of the following requirements should be met in principle: For universities/research institutions • Having not received the following specified amount or more from the government, to proceed with the research on the seed-stage resource   For the consultation on R&D strategy for drugs or consultation on quality and safety for cellular and tissue-based products,  90 million yen   For the consultation on R&D strategy for medical devices or consultation on R&D strategy for cellular and tissue-based products,  50 million yen • Having not received research expenses from a pharmaceutical company, medical device company, etc. under a joint research agreement, etc., toward practical application of the seed-stage resource For venture companies

* Universities/research institutions and venture companies meeting requirements specified separately.  All of the following requirements should be met in principle: For universities/research institutions • Having not received 90 million yen or more (in the case of drugs) or 50 million yen or more (in the case of medical devices) from the government, to proceed with the research on the seed-stage resource • Having not received research expenses from a pharmaceutical company/medical device company under a joint research agreement, etc., toward practical application of the seed-stage resource For venture companies

• Being a small or medium-sized company (with 300 employees or less, or capitalized at 300 million yen or less)

• Any other corporation does not hold 1/2 or more of the total number of shares or investments • Two or more other corporations do not hold 2/3 or more of the total number of shares or investments • For the preceding fiscal year, profits of the term have not been reported, or profits of the term have been reported but without operating revenue

• Any other corporation does not hold 1/2 or more of the total number of shares or investments • Two or more other corporations do not hold 2/3 or more of the total number of shares or investments • For the preceding fiscal year, profits of the term have not been reported, or profits of the term have been reported but without operating revenue

• Being a small or medium-sized company (with 300 employees or less, or capitalized at 300 million yen or less)

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Payment upon invoice sent from PMDA after the end of the period of use

Mid-term Targets of the Pharmaceuticals and Medical Devices Agency (PMDA) *(Provisional Translation)

the Study Group on Internal Control and Evaluation in Incorporated Administrative Agencies held by the Ministry of Internal Affairs and Communications, and opinions on evaluation results of the operating performance in incorporated administrative agencies from the Ministry of Internal Affairs and Communications and the Evaluation Committee of Incorporated Administrative Agencies. b) Promote computerization of the operations to increase efficiency of the operation management system. c) Based on a re-examination of systems control operation of the common information and the review operation, PMDA shall control costs by re-examining the system configuration of the overall PMDA and its procurement method, in order to reduce system costs, to ensure transparency of system procurement, and to streamline operation management. For this reason, PMDA shall promote approaches to optimize operations and systems by integrating the individual review systems and by establishing a system to promote information sharing among review services, post-marketing safety measures, and relief services for adverse health effects, based on the Optimization Plan for Operations and Systems established at the end of FY 2007.

* This translation of the original Japanese text is for information purposes only (in the event of inconsistency, the Japanese text shall prevail).

Instruction No. 0307-73 (dated March 7, 2014) of Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare (MHLW)

Targets to be achieved by the Pharmaceuticals and Medical Devices Agency in its operation management shall be established as below, based on the provision of Article 29, Paragraph 1 of the Act on General Rules for Incorporated Administrative Agency for Incorporated Administrative Agency (Act No. 103, 1999),. March 7, 2014 Minister of Health, Labour and Welfare Norihisa Tamura

Part 1 Effective Period for Mid-term Targets The effective period for Mid-term Targets according to Article 29, Paragraph 2, Item 1 of the Act on General Rules for Incorporated Administrative Agency (Act No. 103, 1999) shall be 5 years, from April 2014 through March 2019. Part 2 Matters Regarding Improvement in Operation Management of the Overall Corporation and Matters Regarding Improvement in the Quality of Services and Other Operations Rendered to the Public The targets related to the overall corporation regarding improvement in efficiency of operations, as stipulated in Article 29, Paragraph 2, Item 2 of the Act on General Rules for Incorporated Administrative Agency, and the targets regarding improvement in the quality of services and other operations rendered to the public, as stipulated in Article 29, Paragraph 2, Item 3 of the Act on General Rules for Incorporated Administrative Agency, shall be as follows. 1) Efficient and Flexible Management of Operations a) The Pharmaceuticals and Medical Devices Agency (hereinafter referred to as the “PMDA”) shall establish an efficient and flexible system for managing operations, confirm the way of operational control and methods for implementing operations through external evaluation, and improve the management of operations based on the following points. Improve internal controls including the way of implementing duties in accordance with instructions from accounting auditors, and proactively disclose measures taken. Examine the way of internal control by utilizing professional knowledge from experts of third-parties. PMDA shall refer to the matters that were notified to each evaluation committee of the incorporated administrative agencies of the government ministries, which are opinions on the report (Internal Control and Evaluation in Incorporated Administrative Agencies) released by

2) Improvement of Operation Management a) By continuously improving the operation and increasing efficiency in management, the following reduction in the budget for the Mid-term Plan is expected to have been achieved by the end of the effective period for Mid-term Targets, regarding general administrative expenses (excluding personnel expenses) in which the administrative subsides are to be applied. No less than 15% as compared to FY 2014. Appropriately utilize outsourcing (outsource when possible to prevent increase in personnel, etc.). b) By increasing efficiency in operations, the following reduction, regarding operating expenses (excluding personnel expenses, and single fiscal-year expenses, etc., that were paid for the establishment of operations) in which the administrative subsidies are to be applied, is expected to be made by the end of the effective period for Mid-term Targets. No less than 5% as compared to FY 2014. Appropriately utilize outsourcing (outsource when possible to prevent increase of personnel, etc.). c) Yearly administrative subsidies are to be rigorously calculated with consideration of its debt balance. d) Promote efficiency and improvements of operations by consolidating the management of the marketing authorization holder’s product data, etc. of contributions for adverse drug reaction (ADR), contributions for relief for infections, and contributions for post-marketing safety measures. e) As a general rule, contracts shall be concluded through open competitive bidding, etc., and the following approaches shall be made. Fully secure competitiveness and transparency even when contracts are not concluded by open competitive bidding such as planning competition and invitation to bids. Conduct bids and conclude contracts appropriately, by having them thoroughly checked by auditors and accounting auditors as well as by utilizing opinions of experts. f) Provide and disseminate genuinely useful information from the public perspective Let the public be aware of the services and role of PMDA by disseminating and providing information from the public’s perspective, which enables the public and patients to readily access to the information they need. Enhance the consultation system and ensure transparency of operations and its details in order to improve the services rendered to the public.

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g)

Analyze issues of the operation system Analyze the issues of the operation system appropriately and revise them if necessary. h) Considerations related to financial base Consider a financial base that is appropriate for the role of PMDA and take necessary measures.

2.

Part 3 Matters Regarding Improvement in Operation Management of Each Division and Matters Regarding Improvement in the Quality of Services and Other Operations Rendered to the Public 1.

Relief Fund Services for Adverse Health Effects With regard to the relief fund services for Adverse Health Effects (hereinafter referred to as “relief services”), it is important not only to fully disseminate more people the Adverse Drug Reaction Relief System and the Relief System for Infections Acquired through Biological Products (hereinafter referred to as “relief systems”) and appropriately operate them, but also adequately and promptly provide relief for those suffering from ADR and infections acquired through biological products or regenerative medical products (hereinafter, including cellular and tissue-based products and gene therapy products). Based on this concept, the following targets shall be achieved. 1) Enhance Public Relations and Dissemination of Information Regarding the Relief Systems a) Conduct proactive public relations so that the relief systems are definitely utilized when necessary. b) Make more efficient operations by reducing the number of cases where inadequate operations of claim documents, etc., result in need of extra processing time. 2) Promptly Process Relief Benefit Claims by Investigating and Organizing the Facts of the Claims a) Promptly process relief benefit claims b) Set up standard administrative processing times* and steadily achieve those standards. * Standard administrative processing time includes a certain period for medical and pharmaceutical judgments of the Ministry of Health, Labour and Welfare. However, administrative processing time shall exclude the period when processing could not be continued because additional or supplementary documents and investigations of the claimant or medical institutions were required to make medical and pharmaceutical judgments. 3) Promote Appropriate Information Transmission in cooperation with Divisions Cooperation shall be promoted among the divisions of PMDA, and information especially regarding cases of relief payment shall be appropriately disseminated to the Review Divisions and the Safety Measures Divisions, with attention to ensuring protection of personal information. 4) mplement Appropriate Health and Welfare Services Steadily implement health and welfare services. 5) Appropriately Provide Healthcare Allowances to SMON Patients and Patients infected with HIV through Blood Products Appropriately conduct services regarding healthcare allowances to SMON patients and HIV-positive patients infected with blood products. 6) Appropriately Pay Benefits to Assist Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus Appropriately conduct services regarding payment of benefits to assist individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus.

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Reviews and Related Services In the review services and post-marketing safety measures, PMDA shall enable better pharmaceuticals and medical devices, etc., to be provided to medical settings more promptly and safely, so that the public can use global standard pharmaceuticals and medical devices, etc., at ease. It is important to ensure that pharmaceuticals and medical devices, etc., are appropriately used, prevent health hazards from occurring while accurately and promptly taking measures in cases where health hazards occur, and make pharmaceuticals and medical devices, etc., fulfill their mission in the long term. Along with this conception, and based on the Japan Revitalization Strategy (adopted by the Cabinet on June 14,2013) and the Healthcare and Medical Strategy (an agreement among the Chief Cabinet Secretary, Minister of Health, Labour and Welfare, and Minister of Internal Affairs and Communications on June 14, 2013) , Act to Ensure Quality, Efficacy, and Safety of Pharmaceuticals and Medical Devices (Act No. 145, 1960) that were revised as a result of the Act for Partial Revision of the Pharmaceutical Affairs Act, (Act No. 84, 2013) , as well as the Act to Ensure Safety of Regenerative Medicine (Act No. 85, 2013), etc. , PMDA shall accelerate reviews speed for s and medical devices, aim to achieve elimination of review lag*, and aim to improve the quality of the reviews, etc. Pharmaceutical Affairs Consultation on R&D Strategy, etc., shall also be enhanced as a support to eliminate the developmental lag*. In order to achieve these targets, PMDA’s financial resources shall be utilized in enhancing the system. *Drug lag and device lag are defined as delay of approvals of pharmaceuticals and medical devices, respectively, from United States in Japan. Drug lag or device lag can be divided into review lag, which are differences in review time (time from application to approval) between the United States and Japan, and development lag, which are differences in time at which the companies submit applications to the regulatory agencies of the United States and Japan (from the Japan Revitalization Strategy [approved by the Cabinet on June 14, 2013]). The overall lag shall be eliminated by eliminating the review lag and development lag. Following measures shall be promoted in order for the above mentioned measures to be implemented appropriately and smoothly, while maintaining cooperation with MHLW. 1) Make pharmaceuticals, medical devices, etc. accessible by the public more quickly Efforts shall be made to enable the public and healthcare professionals to promptly gain advantage of advanced and safe pharmaceuticals and medical devices, etc., based on their needs so that they can receive the maximum benefit from them. PMDA shall proactively support and cooperate with MHLW and its approaches, including acceleration of clinical trials, to promote development of pharmaceuticals and medical devices that are still unapproved in Japan but are of high medical need, in order to reduce development lag. a) Conduct various measures, while evaluating and verifying their state of progress, and take additional measures when necessary. b) In order to achieve reduce review lag while improving the quality of reviews, PMDA shall improve the services by setting time reduction targets (targets at ordinary times without any exceptional cases such as substantial changes in the systems or social conditions) for the processing time of applications (regulatory review time for products approved in the respective years) that were submitted after April 1, 2004. PMDA shall develop a review system to achieve these targets. c) Promote multiregional clinical trials by cooperating with the United States, Europe, and Asian countries. d) Prioritize clinical trial consultations for pharmaceuticals and medical devices that are expected to be highly useful by enhancing pre-application consultations, so as to reduce review period.

Correctly understand the accurate needs of companies at the stage of development and reevaluate system of the consultation service whenever necessary. e) Improve PMDA’s own scientific levels for skills of consultations and reviews, with consideration of the rapid development of the latest technologies such as biotechnology, genomics, and regenerative medicine, and shall take necessary measures for the consultations and reviews along with the development of new pharmaceuticals, new medical devices, and regenerative medical products that utilize the latest technologies. f) Take necessary measures to accelerate reviews for generic drugs, etc., as in the case of new pharmaceuticals. g) Take measures to accelerate reviews for behind-the-counter (BTC) drugs*, over-the-counter (OTC) drugs, and quasi-drugs as with new pharmaceuticals. * Behind-the counter (BTC) drugs are defined as switch OTC drugs and powerful OTC drugs which require pharmacist's intervention. h) Set targets to aim for eliminating review lag for medical devices, as with new pharmaceuticals, and take measures to accelerate reviews. Develop a review system to achieve these targets. Regarding reviews of improved medical devices and generic medical devices, PMDA shall take measures to systematically and intensively review items which had taken long time for the reviews after submission, and shall make efforts to reduce the applicant’s time (the time within the review time that is necessary for the applicants to reply to inquiries from the regulatory side). i) Take measures to accelerate reviews for regenerative medical products by enhancing the relevant review divisions necessary to conduct accurate and prompt reviews, while introducing conditional and time-limited approval system as well as setting target review times. j) Appropriately and efficiently conduct conformity inspections. k) Conduct appropriate and efficient GMP/QMS/GCTP (Good gene, Cellular and Tissue Practice) etc. inspections. 2) Provide Support to be the First in the World to Facilitate Practical Use of Innovative Pharmaceuticals, Medical Devices, and Regenerative Medical Products Make the following approaches in order to be first in the world to facilitate practical use of innovative pharmaceuticals, medical devices, and regenerative medical products. a) Establish and update review standards for innovative products. b) Proactively conduct Pharmaceutical Affairs Consultation on R&D Strategy, etc. c) Operate the approval system based on the characteristics of regenerative medical products. 3.

assemble of information on ADR, etc., and its evaluation analysis system in order to accurately respond to the advanced and specialized evaluation of information on ADR, etc. Furthermore, find out new relationships among multiple ADR information, and establish an efficient and effective evaluation system for safety information such as researching and utilizing methods to identify and analyze new safety information, and improved it when necessary, by using IT technology. b) Have healthcare professionals and companies increase utilization of feedback information on the analysis results of collected safety information, etc., and enhance methods of disseminating information on appropriate use to the patients, in order to enhance the rigorous system for disseminating safety information to improve safety measures at medical institutions. At the same time, PMDA shall also establish standards that enable the accomplishments of safety measures to be more accurately understood in a manner in which the public are able to understand easily. c) Conduct appropriate post-marketing safety measures based on the Risk Management Plan of pharmaceuticals. d) Cooperation shall be promoted among the relief services and the review services to enable appropriate assessment of safety. e) Establish a system that enables confirmation of the current status and effectiveness of post-marketing safety measures taken by PMDA in companies and medical institutions, etc. f) Appropriately collect information on Adverse Reaction reports regulated in the Preventive Vaccination Act and appropriately conduct investigations and analyses. 4.

Safety Measures In the review services and post-marketing safety measures, PMDA shall promptly and safely provide superior pharmaceuticals and medical devices, etc., to medical settings in order to enable the public to use global standard pharmaceuticals and medical devices, etc., at ease. It is important to ensure that pharmaceuticals and medical devices, etc., are appropriately used, prevent health hazards from occurring while accurately and promptly taking measures in cases where health hazards occur, and make pharmaceuticals and medical devices, etc., fulfill their mission in the long term. In accordance with this concept, utilize finances including PMDA’s own financial resource and enhance the system when necessary to improve post-marketing safety measures of pharmaceuticals and medical devices, etc., based on the Act for Partial Revision of the Pharmaceutical Affairs Act that reflects the details of Japan Revitalization Strategy, the Healthcare and Medical Strategy, the final recommendation of the Committee for Investigation of Pharmaceutical-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Similar Sufferings, etc. a) Systematically and continuously conduct comprehensive evaluations of information on ADR, Malfunction, and Adverse Reaction (here in after ADR, etc.), by substantially enhancing

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Promotion of Regulatory Science, Globalization, etc. Note: Regulatory science = Science for coordinating results of science and technology into the most desirable form for harmonizing people and society, by conducting accurate and evidence-based estimations, evaluations, and decisions in order for the results of science and technology to be used for people and society. (from the Science and Technology Basic Plan, adopted by the Cabinet on August 19, 2011) a) Enhance regulatory science research Develop an environment and system for conducting regulatory science research (hereinafter referred to as the “RS research”) aimed at improving the quality of the services provided by PMDA. Make efforts to train human resources to be experts in RS research through conducting it, and make efforts to contribute to increase the efficiency of development of pharmaceuticals, etc., through establishment of guidelines, etc. b) Response to globalization Reinforce partnerships with foreign regulatory agencies, promote global harmonization activity to proactively collect foreign information, and make efforts to promote dissemination of information in English. Furthermore, enhance the English website of PMDA, and enhance measures in order for Asian countries to increase their understanding of Japanese regulations and standards regarding pharmaceutical applications, etc. c) Enhance staff training By enhancing staff training, PMDA shall establish a group of engineering supervisors that have a global level in review services and post-marketing safety measures so as to increase the quality of the services, and shall make efforts to train human resources to be experts in RS research.

d)

Promote interaction with external researchers and investigative research Promote investigative research by proactively interacting with external researchers in order to contribute to activate development and to establish guidelines regarding innovative seed-stage resources. e) Promptly facilitate practical use of pharmaceuticals for intractable diseases and orphan diseases. f) Promote further transparency of review services and post-marketing safety measures such as revealing in public review reports. g) Develop an information system basis that ensures reliability and increases efficiency of review services and post-marketing safety measures.

4) Other Matters Steadily conduct approaches based on the government policy indicated in past Cabinet decisions, etc.

Part 4 Matters Regarding Improvement in Financial Affairs The following is the target for improving financial affairs specified in Article 29, Paragraph 2, Item 4 of the Act on General Rules for Incorporated Administrative Agency. For matters specified in Part 2, items 1) and 2) of this Mid-term Targets, a Mid-term budget shall be developed with an estimation of cost reductions, and PMDA shall operate based on this budget. Part 5 Important Matters Regarding Other Operation Management The following are important targets regarding other operation management specified in the Article 29, Paragraph 2, Item 5 of the Act on General Rules for Incorporated Administrative Agency. 1) Matters Regarding Personnel Affairs a) Secure enough personnel necessary to reviews and post-marketing safety measures, based on the Act for Partial Revision of the Pharmaceutical Affairs Act, etc., that reflects the details of Japan Revitalization Strategy, the Healthcare and Medical Strategy, and the final recommendation of the Committee for Investigation of Pharmaceutical-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Similar Sufferings, etc. In order to avoid any suspicion of inappropriate relationships with pharmaceutical companies, etc., PMDA shall take appropriate measures in employment, allocation, post-retirement reemployment, etc., of executives and employees, while thoroughly ensuring its neutrality, etc. PMDA shall make efforts to adjust the salary levels of the employees to achieve an appropriate and efficient level, taking into consideration competitiveness for stable securement of excellent human resources. b) Appropriately develop personnel capacities by having them interact with external institutions to increase their expertise, and appropriately conduct personnel evaluations based on their work performance. PMDA shall also increase motivation of the personnel through these measures, etc. 2) Ensure Security Ensure security of the offices, etc. and take all measures to thoroughly manage information, in order to thoroughly protect information of personal, corporate, etc. 3) Matters Regarding Disposition of the Reserve Funds Specified in Article 31, Paragraph 1 of the Act on the Pharmaceuticals and Medical Devices Agency Appropriately dispose the reserve funds that are still left even after adjusting profit and loss according to Article 44 of the Act on General Rules for Incorporated Administrative Agency at the end of the last fiscal-year of the effective period for the Second Mid-term Targets.

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Mid-term Plan of the Pharmaceuticals and Medical Devices Agency (PMDA) *(Provisional Translation)

* This translation of the original Japanese text is for information purposes only (in the event of inconsistency, the Japanese text shall prevail).

Notification No. 0331-44 (dated March 31, 2014) of Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare To achieve the Mid-term Targets of the Pharmaceuticals and Medical Devices Agency assigned on March 7, 2014 by the Minister of Health, Labour and Welfare based on the provisions of Article 29, Paragraph 1 of the Act on General Rules for Incorporated Administrative Agency (Act No. 103, 1999), the Pharmaceuticals and Medical Devices Agency (PMDA) has developed the following Mid-term Plan based on the provisions of Article 30, Paragraph 1 of the same act.

improving public health and safety. PMDA will also promote cooperation with the United States, Europe, and Asian countries, etc., and approach issues from a global perspective in order to further improve health of people not only in Japan but also in the world. Based on the Japan Revitalization Strategy (adopted by the Cabinet on June 14, 2013), the Healthcare and Medical Strategy (an agreement among the Chief Cabinet Secretary, Minister of Health, Labour and Welfare, and Minister of Internal Affairs and Communications, etc., on June 14, 2013), the Act to Ensure Quality, Efficacy, and Safety of Pharmaceuticals and Medical Devices (Act No. 145, 1960; hereinafter referred to as the “Pharmaceutical and Medical Devices Act”), and the Act to Ensure Safety of Regenerative Medicine (Act No. 85, 2013; hereinafter referred to as the “The Act of the Safety of Regenerative Medicine”), etc., PMDA will further accelerate and improve the review services in order to promote to be the first in the world in practical use of innovative pharmaceuticals, medical devices, and regenerative medical products, while taking post-marketing safety measures, such as ensuring quality of post-marketing products and preventing occurrence and spread of health hazards. In order to achieve these goals, the review and post-marketing safety measures in this term shall be improved by further enhancing the system and by introducing new review methods, etc., while pursuing elimination of review lag. Efforts will be made to have the public be aware of the relief services to ensure utilization of them. With these targets, the Third Mid-term Plan is to be established and implemented as follows:

March 7, 2014 Tatsuya Kondo, Chief Executive, Pharmaceuticals and Medical Devices Agency

Development toward global PMDA based on the PMDA Philosophy PMDA was established in April 2004, after several times of reorganization by integrating the services of review and post-marketing safety measures, and has its roots in the “Fund for Relief Services for Adverse Drug Reactions”, which was established following tragic pharmaceutical-induced sufferings caused by pharmaceuticals such as thalidomide and diseases such as subacute myelo-optical neuropathy (SMON). Based on this history, and in order to carry out its mission to promptly provide the public with more effective and safer pharmaceuticals and medical devices, PMDA has been dedicating itself to improve its services for review, post-marketing safety measures, and relief services for adverse health effects. Essential targets have been accomplished by accelerating reviews and enhancing post-marketing safety measures in its efforts during the first and second terms. PMDA will need to further strengthen and enhance its system to aim to be a world-class institution responsible for reviews and post-marketing safety measures, in order to equal the United States and Europe in the future. PMDA will promote comprehensive risk management through “Safety Triangle”, a system based on three major services, which are the review, post-marketing safety measures for pharmaceuticals and medical devices, and relief services for adverse health effects, to secure safety and efficacy, based on the following organizational philosophy of action (PMDA Philosophy). 1) We pursue the development of medical science while performing our duty with greater transparency based on our mission to protect public health and the lives of our citizens. 2) We will be the bridge between the patients and their wishes for faster access to safer and more effective pharmaceuticals and medical devices. 3) We make science-based judgments on quality, safety, and efficacy of medical products by training personnel to have the latest technical knowledge and wisdom in their field of expertise. 4) We play an active role within the global community by promoting global harmonization. 5) We conduct services in a way that is trusted by the public based on our experiences from the past. In promoting its risk management, PMDA will especially make efforts to develop an environment that enables judgments from an ethical perspective based on regulatory science, and to proactively contribute in

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Part 1 Measures to be taken in Order to Achieve Targets Related to Matters Regarding Improvement in Operation Management of the Overall Corporation and Matters Regarding Improvement in the Quality of Services and Other Operations Rendered to the Public The following are the measures to be taken in order to achieve targets regarding improvement in efficiency of operations, as stipulated in Article 30, Paragraph 2, Item 1 of the Act on General Rules for Incorporated Administrative Agency (Act No. 103, 1999; hereinafter referred to as the “Act on General Rules”), and to achieve targets regarding improvement in the quality of services and other operations rendered to the public, as stipulated in Article 30, Paragraph 2, Item 2 of the Act on General Rules. 1) Efficient and Flexible Management of Operations a) Manage transparent and appropriate operations through thorough compliance risk management Clarify the operational targets and responsibilities of each division, and identify and resolve problems by managing the operational progress on a daily basis. Develop and appropriately utilize internal control processes to achieve efficacy and efficiency of operations, reliability of financial reports, compliance with acts related to operational activities, and maintenance of assets, and proactively disclose the details of those measures that were taken. Gather opinions on operational performance for each fiscal year and utilize them in managing the operations. - Hold advisory councils as an opportunity to exchange opinions with experts from various fields, and seek proposals and improvement measures for operations and the management system, in order to increase efficiency as well as to ensure fairness and transparency of the operations. Efficiently manage the operations by flexibly allocating personnel according to situations and by effectively utilizing external experts. Utilize manuals for emergency management appropriately by reviewing them from time to time in response to particular situations, in order to thoroughly manage risks in the management of operations. Develop a system necessary to support the operations of the review, post-marketing safety measures, and relief service in order to respond to the expansion of the organization due to system reinforcement, and to enable reviewers to concentrate on technical and specialized operations. b) Standardize operation procedures Standardize the procedures of each operation so that they can be conducted appropriately, which will enable utilization of non-regular staff, and as a result limit the number of regular staff members. c) Develop materials and information databases Utilize an electronic format for documentary information whenever possible, and promote the development of databases that enable the information to be systematically organized and stored, as well as to enable material and information to be collected and analyzed. d) Optimize the system to improve efficiency of operations Continue operations based on the basic policies of the Pharmaceuticals and Medical Devices Agency (hereinafter referred to as the “Agency”) for developing the system environment. Based on the Optimization Plan for Operations and Systems that was established at the end of FY 2007, a system shall be developed to promote information sharing in the operations of review, post-marketing safety measures, and relief services for adverse health effects, and further approaches shall be promoted for the optimization of operations and systems, which was revised in FY 2012 for the purpose of enhancing the accounting and personnel

management functions to respond to changes such as increase in personnel. Expenses for system development and improvement shall be invested systematically and efficiently by comprehensively judging at the Committee on Investment in Information Systems from such perspectives as appropriateness, cost-effectiveness, and technical difficulty. Along with the Optimization Plan for Operations and Systems, increase efficiency of operations by revising the information system according to the actual status of the operations in each division. 2) Rationalize Operation Management a) Retrench general administrative expenses (management divisions) By continuously improving the operation and increasing efficiency in management, the following reduction in the budget for the Mid-term Plan is expected to have been achieved by the end of the effective period for Mid-term Targets, regarding general administrative expenses (excluding personnel expenses) in which the administrative subsidies are to be applied. No less than 15% as compared to FY 2014 Appropriately utilize consolidation and outsourcing for management operations such as payroll accounting, fund balancing, and calculation of travel expenses. b) Retrench operating expenses for efficient operation management By increasing efficiency in operations such as promoting computerization, the following reduction in the budget for the Mid-term Plan is expected to have been made by the end of the effective period for Mid-term Targets, regarding operating expenses (excluding personnel expenses, and single fiscal-year expenses that were paid for the establishment of operations) in which the administrative subsidies are to be applied. No less than 5% as compared to FY 2014 Appropriately utilize consolidation and outsourcing for management operations such as payroll accounting, fund balancing, and calculation of travel expenses. c) Calculate administrative subsidies Yearly administrative subsidies are to be rigorously calculated with consideration of its debt balance. d) Stable collection of contributions Have the marketing authorization holders (MAHs) of pharmaceuticals and medical devices understand the significance of the contribution system for adverse drug reaction (ADR) fund, relief for infections, and contributions to post-marketing safety measures, in order for contributions to be appropriately declared and paid, and to ensure stable collection of each contribution. The collection rate for the contributions of ADR fund, relief for infections, and contributions to post-marketing safety measures shall be no less than 99%. e) Secure contract competitiveness and transparency Contracts shall be concluded through open competitive bidding as a principle, and the following approaches shall be made. Fully secure competitiveness and transparency even when contracts are not concluded by general competitive bidding such as planning competition and invitation to bids. To conduct biddings and conclusion of contracts appropriately, contracts should be pre-inspected, etc., by the Contract Review Committee and thoroughly checked by auditor and accounting auditor. f) Provide and disseminate genuinely useful information from the public perspective Take the following measures to steadily implement the PMDA Public Relations Strategic Plan.

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1.

Enhance dissemination of information by improving the website so that it can be easily understood in order for the public and patients to be able to readily access information regarding safety and efficacy of pharmaceuticals and medical devices. 2. Conduct public relations using newsletters related to PMDA. 3. Provide and publish information regarding PMDA in television and magazines. 4. Create newsletters in English and disseminate information to Foreign Correspondents’ Club of Japan and to foreign media. 5. Enhance and improve the system for responding to consultations and complaints from the public. Enhance dissemination of information to the general public by disclosing the details of PMDA’s services and achievements when appropriate, through various media including its website in order for the public to better understand the safety of pharmaceuticals and medical devices, as well as the overall services of PMDA. Conduct external audit in accordance with the incorporated administrative agencies system, together with systematic internal audit and accounting audit, and disclose those results. Disclose PMDA’s overall financial standing as well as its financial standing for each account and segment in order to ensure transparency of the expenditures. g) Analyze issues of the operation system Quantitatively analyze and examine issues of each division regarding the current operation processes as well as their systems as much as possible by the midpoint of the effective period for the Third Mid-term Targets, based on the understanding of the past operating performances of the relief service, review, and safety divisions, and those processes and systems shall be revised if necessary in order to confirm whether the personnel are allocated appropriately for the system enhancement and whether the operations are conducted efficiently. h) Considerations related to financial base Consider a financial base that is appropriate for the role of PMDA, and take necessary measures based on the current situation where PMDA’s revenue such as user fees from companies accounts for the majority of the financial base of PMDA, because the review and safety services of pharmaceuticals and medical devices greatly influence the life and safety of the public. Part 2 Measures to be taken in Order to Achieve Targets Related to Matters Regarding Improvement in Operation Management of Each Division and Matters Regarding Improvement in the Quality of Services and Other Operations Rendered to the Public - Make all efforts to promote the safety triangle of review, safety, and relief as a mission of PMDA 1.

Relief Fund Services for Adverse Health Effects The Relief System for ADR and the Relief System for Infections Acquired through Biological Products (hereinafter referred to as the “relief systems”) are systems unique to Japan, which, along with reviews and post-marketing safety measures, are responsible for being part of the safety triangle. The following measures shall be taken for the necessity of having the relief systems to be definitely utilized through consultations with physicians and pharmacists in case of emergencies of health damage due to ADR of pharmaceuticals or regenerative medical products, or due to infections through biological products or regenerative medical products, as well as for the necessity of continuing appropriate operations, such as prompt processing of relief benefit claims.

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1)

Enhance Public Relations and Dissemination of Information Regarding the Relief Systems a) Proactively develop public relations in order for the relief systems to be definitely utilized. Consider and proactively conduct effective public relations regarding the relief systems. Continue informing more of the public regarding the relief systems by utilizing such media as websites and newspapers. Current measures, including dissemination of thorough information with the cooperation of relevant organizations, etc., shall be promoted, and the following measures shall be focused in order to increase the awareness by the end of the effective period for the Mid-term Targets, in order to further gain awareness and understanding from the public, health care professionals and MAHs, etc., regarding the relief systems. Surveys shall be conducted every fiscal year to find out the degree of their awareness, and those results shall be examined. 1. Public relations activities shall be proactively conducted by utilizing the opportunities of training at medical institutions for health care professionals and opportunities of informing pharmacists regarding the systems, in order to properly make patients know the existence of relief systems by healthcare professionals including physicians and pharmacists, in case health damage occurs due to ADR or infections through biological products. 2. Develop public relations nationwide through professional medical organizations. 3. Conduct public relations for the general public using such media as websites, television, and newspapers. 4. Develop effective public relations through other media aside from the above that is appropriate for promoting the relief systems. b) Announce cases of benefit payment Further understanding of the current situation of benefit payment and dissemination of the relief systems to the public, healthcare professionals shall be promoted, by announcing cases of benefit payment and operational statistics on the website. c) Disseminate information regarding the relief systems Review the methods of disseminating information from the perspective of making it user-friendly and easy to be understood, by revising the pamphlets and claim guidelines, by improving the content of information disseminated through the Internet, etc. d) Ensure an efficient system for the consultation services Allocate regular staff for the consultation services, and ensure a system where specialized consultations can be received regarding use of the relief systems as well as the procedures to process benefit payments for ADR and infections. 2) Accelerate the Processing of Relief Benefit Claims a) Investigate and organize the facts of the claim In order for relief benefit claims to be promptly processed, the facts of the claims shall be investigated and organized when received, before requesting the Minister of Health, Labour and Welfare for medical and pharmaceutical judgment. b) Promptly process within the standard administrative processing time The target administrative processing time from receipt of the claim until the decision of payment (within 6 months, more than 60%) shall be maintained even in situations where the number of claims is expected to increase, by taking appropriate measures such as by enhancing the system for receiving and investigating claims, further enhancing and improving instructions for filling medical certificates, and accurately managing the time to use a system. Administrative processing time shall exclude the period when processing could not be continued because additional or supplementary documents and investigations of the

3)

4)

5)

6)

2.

claimant or medical institutions were necessary in order to make medical and pharmaceutical judgments. c) Promote efficient operation with the use of databases Data of information related to the operation of relief services of ADR, especially information on the causative pharmaceutical, etc., and health damages shall be accumulated on the database, and those accumulated data shall be statistically processed so that they can be analyzed from various perspectives, in order to operate a system that enables prompt and efficient payment of relief benefits using those results. - Upgrade the systems, develop operation support tools, and enhance systems if necessary, in order to respond to increases in relief benefit claims and to operational situations accordingly. Promote Cooperation with the Review Divisions and the Safety Divisions Cooperate with each division of PMDA and appropriately disseminate information, especially regarding cases of relief payment to the divisions of review and the post-marketing safety measures, with attention to ensuring protection of personal information. Implement Appropriate Health and Welfare Services Based on the results of a survey that investigated the current situation of health damages due to ADR, investigative research shall be continued in order to obtain information for considering measures to improve QOL of patients suffering from serious and rare health damages. Steadily conduct consultations regarding mental issues. Provide Healthcare Allowances for SMON Patients and HIV-positive Patients Infected with Blood Products Appropriately In providing healthcare allowances to SMON patients and HIV-positive patients infected with blood products, appropriate services shall be implemented based on the details of the consignment contract, with special attention to ensuring protection of personal information. Pay Benefits to Assist Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C virus Appropriately In providing benefits to assist individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus, appropriate operations shall be implemented, with special attention to ensure protection of personal information.

Reviews and Related Services Based on the Japan Revitalization Strategy and the Healthcare and Medical Strategy, as well as the Pharmaceutical and Medical Devices Act and the Regenerative Medicine Act that were revised as a result of the Act for Partial Revision of the Pharmaceutical Affairs Act, (Act No. 84, 2013), reviewing speed shall be accelerated, aiming to reduce review lag*, and the quality of the reviews shall be improved through approaches according to the characteristic of each pharmaceutical, medical device, and regenerative medical product (hereinafter, including cellular and tissue-based product and gene therapy product). Pharmaceutical Affairs Consultation on R&D Strategy shall also be enhanced as a support to eliminate the development lag*. In order to achieve these targets, PMDA’s financial resources shall be utilized in enhancing the system. * Drug lag and device lag are defined as delay of approvals of pharmaceuticals and medical devices, respectively, from United States in Japan. Drug lag or device lag can be divided into review lag, which are differences in review time (time from application to approval) between the United States and Japan, and development lag, which are the differences in time at which the companies submit application to the regulatory agencies of the United States and Japan (from the Japan

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Revitalization Strategy [approved by the Cabinet on June 14, 2013]). The overall lag shall be eliminated by eliminating the review lag and development lag. Following measures shall be promoted in order for the above mentioned measures to be implemented appropriately and smoothly, while maintaining cooperation with MHLW. Note: The organization responsible for implementing the following measures is PMDA unless otherwise stated as MHLW, or other corporations. 1) Make pharmaceuticals, medical devices, etc. accessible by the public more quickly New pharmaceuticals a) Conduct accurate and prompt reviews Enhance system in order to improve quality of the reviews by utilizing the Science Board and by enhancing training, with aiming to achieve elimination of review lag. Steadily implement the project management system in order to improve the progress management function of the review services and to increase transparency of the progress and outlook of reviews for applicants as well. Continue considering the efficiency and transparency of the review services and processes through exchange of opinions with the industry. Strengthen cooperation with academia and healthcare professionals in order to conduct consultations and reviews based on the latest medical care trends and needs, and to promote cooperation toward appropriate use of pharmaceuticals. Proactively support and cooperate in discussions and in requesting development for unapproved pharmaceuticals etc., at the Study Group on Unapproved and Off-label Pharmaceuticals of High Medical Need organized by MHLW. Continue making approaches to reduce unapproved pharmaceuticals and off-label pharmaceuticals by enhancing database for the current status of pharmaceutical approval in major overseas nations. Secure consistency between clinical trial consultations and reviews by maintaining cooperation between these two services, and flexibly organize groups to conduct accurate and prompt reviews and consultations. Conduct accurate and prompt re-examinations for new pharmaceuticals. Take appropriate measures for re-evaluations as well. Promote establishment of standards regarding quality of pharmaceuticals, such as the Japanese Pharmacopoeia established by MHLW, in order to conduct accurate and prompt reviews. b) Introduce new methods for reviews and others Systematically enhance the system for prior assessment consultations and respond to all consultations that were requested regarding superior pharmaceuticals of high medical need by the FY 2018. Develop a system in PMDA that enables to accept electronic submission of clinical study data regarding new pharmaceutical applications after FY 2016. Improve the quality of reviews and consultations by conducting PMDA-initiated analyses using the clinical trial data and by giving indications and suggestions based on those analyses results. Consider a system that enables cross-sectional analyses of products using advanced methods of analysis and prediction evaluation, and further improve reviews and consultation by establishing guidelines, etc., and increase efficiency of pharmaceutical development.

c)

-

Targets to aim for eliminating review lag in pharmaceuticals Regarding pharmaceuticals which new pharmaceutical applications were submitted after April 1, 2004, the percentile of the standard total review time from application to approval for the items approved in respective fiscal years, shall rise in stages as shown in the following table. The review time of 9 months for priority review products and 12 months for standard review products shall be achieved at 80th percentile by FY 2018. The review services shall be enhanced to achieve these targets. 1. Review time for new pharmaceuticals (priority review products) Fiscal year Percentile Review time FY 2014 60% 9 months FY 2015 60% 9 months FY 2016 70% 9 months FY 2017 70% 9 months FY 2018 80% 9 months

f)

2. Review time for new pharmaceuticals (standard review products) Fiscal year Percentile Review time FY 2014 60% 12 months FY 2015 70% 12 months FY 2016 70% 12 months FY 2017 80% 12 months FY 2018 80% 12 months -

Regarding re-examination of new pharmaceuticals, the review time shall be reduced in stages regarding pharmaceuticals that are to be submitted for re-examination after FY 2014, with review results issued in respective fiscal years, and the total review time of 18 months shall be achieved at 50th percentile (median) by FY 2018. Products re-examined before FY 2014 shall also be sequentially processed. Regarding re-evaluations, evaluation and confirmation shall be conducted without delay by setting the appropriate standard review time to each pharmaceutical, based on the points of the application. d) Promote multi-regional clinical trials In order to promote multi-regional clinical trials, appropriately respond to requests for consultations related to multi-regional clinical trials, based on the guidance regarding study design, etc. In order to promote multi-regional clinical trials especially in Asian countries, PMDA shall support the approaches of the Multi Regional Clinical Trial Roadmap led by MHLW at APEC RHSC, and develop an environment for conducting multi-regional clinical trials in Asian countries. PMDA shall promote multi-regional clinical trials in clinical trial consultations, etc., including information sharing with foreign regulatory agencies so as to increase the rate of conducting multi-regional clinical trials that Japan will participate amongst foreign clinical trials by FY 2018, to eliminate pharmaceutical development lag. e) Conduct smooth clinical trial consultations, etc. Priority consultations and advance confirmation of application documents shall be continued, in order to increase opportunities to provide guidance and consultations before applications.

Firmly maintain the time it currently takes from request for clinical trial consultation of new pharmaceuticals to direct consultation (about 2 months), while at any time accepting requests for priority clinical trial consultations so as to accelerate procedures for clinical trial consultations on new pharmaceuticals. Regarding categories such as prior assessment consultations, Pharmaceutical Affairs Consultation on R&D Strategy, and simple consultations, categories shall be added or altered according to the needs of the applicants by exchanging opinions with relevant industries and by analyzing the content of consultations, so as to enhance clinical trial consultations. Promote evaluation of new technologies, etc. For pharmaceuticals developed using new technologies, concepts regarding development and evaluation shall be established in cross-sectional projects, along with guidelines if necessary, by using the knowledge of the Science Board and opinions of external experts. PMDA shall increase its scientific knowledge in order to lead the development of pharmaceuticals using latest technologies such as iPS cells. Cooperate with MHLW in establishing guidelines for evaluating products using the latest technologies, and proactively disclose the points to consider for evaluations. For preliminary reviews regarding the Act Concerning the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms (hereinafter referred to as the “Cartagena Act”), the regulatory review time shall be 6 months for approval of first-class use and 2 months for confirmation of second-class use, with a target of achieving 50th percentile (median) for each class. Enhance the Pharmaceutical Affairs Consultation on R&D Strategy by conducting consultations where suggestions can be made on development processes (roadmap) as well as confirmatory trial protocols, and by conducting consultations for pharmaceutical companies on developmental strategies.

Generic drugs, etc. The following measures shall be taken to promote wide use of generic drugs, etc. a) Conduct accurate and prompt reviews 1. Establish a new office for generic drugs, etc. Enhance and accelerate reviews by appropriately increasing and allocating members for the generic drug, etc. group and by establishing a new office. 2. Ensure efficient and transparent reviews Strengthen cooperation with academia and healthcare professionals, etc. to conduct consultations and reviews based on the latest medical care trends and needs, and to promote cooperation toward appropriate use of pharmaceuticals. Promote establishment of standards regarding quality of pharmaceuticals, etc., such as the Japanese Pharmacopoeia, etc., established by MHLW, in order to conduct accurate and prompt reviews. Recommend application by CTD/eCTD format in order to increase efficiency in reviews. Ensure transparency of the reviews by preparing and disclosing review reports on new generic drugs. Establish guidelines for bioequivalence testing in order to respond to the increased complexity of bioequivalence assessments and the diverse pharmaceutical products that are being developed. Cooperate with relevant offices to take appropriate measures to steadily implement the risk management plan.

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b) Targets for reducing review time Regarding pharmaceuticals which applications were submitted after April 1, 2004, the target review times for the items approved in respective fiscal years, shall be as shown in the following table. The regulatory authority shall make efforts to achieve these targets with the cooperation of the applicants. The review system shall be enhanced to achieve these targets.

c)

1.

Review time for new application of generic drugs The following targets shall be achieved at 50th percentile (median) by FY 2018. Product Regulatory review time New generic drugs 10 months

2.

Review time of application for partial change approval in generic drugs, etc. (standard review products) Targets shall be achieved at 50th percentile (median) by FY 2018, based on the following plan. Fiscal year Total review time FY 2014 15 months FY 2015 14 months FY 2016 13 months FY 2017 12 months FY 2018 10 months

3.

Review time of application for partial change approval in generic drugs, etc. (products other than standard review products) The following targets shall be achieved at 50th percentile (median) by FY 2018. Products Total review time Products applied for partial change approval 6 months (change in procedure of study, etc.) Products applied for partial change approval 3 months (prompt review)

Conduct smooth clinical study consultations, etc. All consultations shall be conducted for those requested for quality consultation or bioequivalence consultation (face to face consultation). Enhance consultation services by considering whether setting up new consultation categories are necessary to meet the needs of the applicants.

Behind-the-counter (BTC) drugs*, over-the-counter (OTC) drugs, and quasi-drugs The following measures shall be taken to promote public self-medication. a) Conduct accurate and prompt reviews In order to conduct accurate and prompt reviews for BTC drugs, OTC drugs, and quasi-drugs, etc., the following measures shall be taken to enhance the review system, etc., including safety assessments. 1. Enhance system for BTC drugs and OTC drugs, etc. In order to respond to the establishment of BTC drugs system, etc., that was newly developed by the Act for Partial Revision of the Pharmaceutical Affairs Act and the Pharmacists Act (Act No. 103 of 2013), the review system shall be enhanced by allocating

reviewers for toxicity and clinical matters (including biostatistics), and by securing human resources who have experience in post-marketing safety measures and conformity assessment. Strengthen cooperation with academia and healthcare professionals, etc., in order to conduct consultations and reviews based on the latest medical care trends and needs, and to promote cooperation toward appropriate use of BTC drugs and OTC drugs. Conduct accurate and prompt reviews by establishing standards regarding quality of pharmaceuticals, such as the Japanese Pharmacopoeia as well as official specification for excipients. Increase efficiency and enhance the review service for Chinese herbal medicines and crude drugs. 2. Enhance system for quasi-drugs, etc. Increase the number of reviewers in order to accelerate reviews for innovative products. Increase efficiency of the reviews by establishing standards for quasi-drugs, such as the Japanese Standards of Quasi-drug Ingredients established by MHLW, as well as establishing quality standards for excipients, etc. Improve quality of the reviewers through training, etc. Strengthen cooperation with academia and healthcare professionals, etc., in order to conduct consultations and reviews based on the latest medical care trends and needs, and to promote cooperation toward appropriate use of quasi-drugs. * Behind-the-counter (BTC) drugs are defined as switch OTC drugs and powerful OTC drugs which require pharmacist's intervention. b) Targets for reducing review time Regarding BTC drugs, OTC drugs and quasi-drugs which applications were submitted after April 1, 2004, and were approved in respective fiscal years, the target review times shall be as shown in the following table. Approaches shall be made to achieve these targets.

c)

1.

Review time for BTC drugs and OTC drugs The following target shall be achieved at 50th percentile (median) by FY 2018. Product Regulatory review time BTC drugs and OTC drugs 7 months

2.

Review time for quasi-drugs The following target shall be continuously achieved at 50th percentile (median) by FY 2018. Product Regulatory review time Quasi-drugs 5.5 months

Conduct smooth consultation services For BTC drugs and OTC drugs, conduct consultations on the appropriateness of developing new OTC drugs, etc., pre-application consultations for switch OTC drugs, and consultations on confirming the key points of the protocols. For quasi-drugs, develop and conduct pre-application consultations.

Medical devices a) Conduct accurate and prompt reviews Systematically enhance the review system for new medical devices in order to accelerate the reviews for innovative medical devices. Accelerate reviews by making efforts to conduct rational reviews based on the characteristic of medical devices which constantly being improved, etc.

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Strengthen cooperation with academia and healthcare professionals in order to conduct consultations and reviews based on the latest medical care trends and needs, and to promote cooperation toward appropriate use of medical devices. Proactively support and cooperate in requesting development for medical devices, including unapproved medical devices, at the Study Group on the Early Introduction of Medical Devices, etc. with High Medical Need held by MHLW. Make efforts to smoothly operate and implement the new use-results evaluation system for medical devices. For new medical devices, improved medical devices, and generic medical devices, thoroughly manage the timeline for the standard review process so as to be conducted adequately. b) Clarify review standards, etc. Compile and disclose the concept regarding clinical evaluation. In order to accelerate the reviews, cooperate with MHLW in establishing approval standards, certification standards, and review guidelines for medical devices, and disclose those standards and guidelines on the website, etc. Clarify, share, and establish the concept of substantial equivalence for generic medical devices. c) Smoothly transfer specially controlled medical devices to the third party certification system Transfer to the third party certification system sequentially from the products whose standards have been established among specially controlled medical devices (class III). d) Targets to aim for eliminating review lag in medical devices Regarding medical devices which applications were submitted after April 1, 2004, the percentile of the standard total review time from application to approval for the items approved in respective fiscal years, shall be raised in stages as shown in the following table, in order for the targets to be achieved by FY 2018. Approaches shall be made to achieve these targets by systematically and intensively completing processing of the devices that were submitted for application in the past as soon as possible, and the regulatory authority shall make efforts to improve the lag with the cooperation of the applicants. 1.

Review time for new medical devices (priority review products) Achieve 10 months at 80th percentile by FY 2018 based on the following plan. Fiscal year Percentile Review time FY 2014 60% 10 months FY 2015 60% 10 months FY 2016 70% 10 months FY 2017 70% 10 months FY 2018 80% 10 months

2.

Review time for new medical devices (standard review products) Achieve 14 months at 80th percentile by FY 2018 based on the following plan. Fiscal year Percentile Review time FY 2014 60% 14 months FY 2015 60% 14 months FY 2016 70% 14 months FY 2017 70% 14 months FY 2018 80% 14 months

3.

Review time for improved medical devices (with clinical data) Achieve 10 months at 60th percentile by FY 2018 based on the following plan. Fiscal year Percentile Review time FY 2014 52% 10 months FY 2015 54% 10 months FY 2016 56 % 10 months FY 2017 58 % 10 months FY 2018 60 % 10 months

4.

Review time for improved medical devices (without clinical data) Achieve 6 months at 60th percentile by FY 2018 based on the following plan. Fiscal year Percentile Review time FY 2014 52% 6 months FY 2015 54% 6 months FY 2016 56 % 6 months FY 2017 58 % 6 months FY 2018 60 % 6 months

5.

Review time for generic medical devices Achieve 4 months at 60th percentile by FY 2018 based on the following plan. Fiscal year Percentile Review time FY 2014 52% 4 months FY 2015 54% 4 months FY 2016 56 % 4 months FY 2017 58 % 4 months FY 2018 60 % 4 months

e) Conduct smooth clinical trial consultations, etc. Reconsider the consultation category and improve consultation methods in order for the consultation service to be easier to utilize, and to be efficient and effective. Address the relevant industries to proactively utilize the consultation service, in order to eliminate review lag and development lag. f) Promote evaluation of new technologies, etc. For medical devices using new technologies, guidelines, etc., shall be established if necessary, utilizing knowledge of the Science Board and opinions of external experts. Make efforts to accumulate relevant knowledge, etc., in order to appropriately respond to the development of medical devices using the latest technologies. Cooperate with MHLW in establishing guidelines for evaluating products that were developed using the latest technologies, and proactively disclose the points to consider for evaluations. For preliminary reviews regarding the Cartagena Act, the regulatory review time shall be 6 months for approval of first-class use and 2 months for confirmation of second-class use, with a target of achieving 50th percentile (median) for each class. Enhance the Pharmaceutical Affairs Consultation on R&D Strategy by conducting consultations where suggestions can be made on development processes (roadmap) and confirmatory trial protocol, and by conducting consultations for medical devices related companies on developmental strategies.

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In vitro diagnostics a) Conduct accurate and prompt reviews Appropriately increase and allocate members for the in vitro diagnostics group, in order to accelerate and increase transparency of the reviews. Strengthen cooperation with the academia and healthcare professionals, etc., to conduct consultations and reviews based on the latest medical care trends and needs, and to promote cooperation toward appropriate use of in vitro diagnostics. Proactively support and cooperate in requesting development of in vitro diagnostics, including those that are still unapproved, that were discussed at the Study Group on the Early Introduction of Medical Devices, etc., with High Medical Need held by MHLW. b) Enhance consultation service Reconsider the consultation category and improve consultation methods in order for the consultation service to be easier to utilize, and to be efficient and effective. Regenerative medical products a) Conduct accurate and prompt reviews Enhance the services of the division of Pharmaceutical Affairs Consultation and its relevant divisions, as well as the division of biologics reviews. Strengthen cooperation with academia such as the Japanese Society for Regenerative Medicine, the National Institute of Health Sciences, and the Center for iPS Cell Research and Application (CiRA), etc., in order to conduct consultations and reviews based on the latest medical care trends and needs. Conduct consultations. b) Introduce new review methods With the implementation of the Act for Partial Revision of the Pharmaceutical Affairs Act, respond appropriately to conditions related to regenerative medical products and to the introduction of time-limited approvals. Develop a system for this, along with its review process, and conduct them accurately. c) Target review time For regenerative medical products which applications were submitted based on the Pharmaceutical Medical Devices Act, standard review time (regulatory time) for the items approved in respective fiscal years shall be set to 9 months. The review system shall be enhanced to achieve this target. d) Conduct smooth clinical study consultations, etc. Make efforts to conduct thorough consultations so as to be understood easily, since regenerative medical products are a new field. Conduct high-quality consultations by utilizing the Science Board for considering evaluation methods, etc., and highly-qualified external experts, etc., to obtain the latest knowledge. PMDA shall make efforts to have applications of regenerative medical products after going through consultations such as the Pharmaceutical Affairs Consultation on R&D Strategy (as the substitute of pre-confirmation application) and pre-application consultations, and develop a system necessary to conduct prompt and smooth reviews considering the current situation of consultations and reviews. In order to enable the academia and ventures to consult easily, the target details, etc., of the Pharmaceutical Affairs Consultation on R&D Strategy shall be considered for regenerative medical products, based on the current situation. e) Promote evaluation of new technologies, etc. Conduct appropriate evaluations for regenerative medical products, by utilizing the Science Board for considering evaluation methods, etc., and highly-qualified external experts.

-

-

-

Make efforts to accumulate relevant knowledge, etc., in order to be able to appropriately respond to the development of regenerative medical products using the latest technologies, such as iPS cells, etc. Clarify and rationalize the review standards by promoting the initiative to facilitate development and designated research. Enhance the post-marketing surveillance, considering especially the surveillance methods for those conducted after conditional and time-limited approvals, cooperating with the safety division. Cooperate with the MHLW in establishing evaluation guidelines regarding products using the latest technologies, and proactively disclose the points to consider for evaluations. Enhance consultations to enable proactive utilization of Pharmaceutical Affairs Consultation on R&D Strategy as the substitute of preliminary reviews conducted before clinical trials regarding regenerative medical products and gene therapy products. For preliminary reviews regarding the Cartagena Act, the regulatory review time shall be 6 months for approval of first-class use and 2 months for confirmation of second-class use, with a target of achieving 50th percentile (median) for each class.

Promotion of conformity assessments and clinical trials, etc. The following measures shall be taken to enhance, with strengthening the organization, studies related to the application such as clinical trials, and to ensure reliability of submitted application documents, with focus on an importance of ensuring the reliability of clinical trial data, etc., at the application of pharmaceuticals and medical devices. a) Implement smooth and efficient conformity assessments for new pharmaceuticals, etc. Strengthen the organization to conduct timely assessments which will not affect the time of approval. New assessment methods with efficiency and effectiveness shall also be introduced. As for the items concurrently submitted with the applications in the world, etc., strengthen the coordination on partnership with foreign regulatory agencies and strengthen the organization, for example, considering the assessment in collaboration with them. Make clear policy on the procedure for clinical trials in which CDISC was introduced from data gathering step. b) Implement smooth and efficient conformity assessments for medical devices Strengthen the organization to conduct timely assessments which will not affect the time of approval. Strengthen the organization conduct GCP on-site assessment, in particular, focus on innovative medical devices and multi-regional clinical trials, etc. Establish and disseminate detailed requirements that are necessary for applications, in order to implement conformity assessments smoothly and promptly. c) Implement smooth and efficient conformity assessments for regenerative medical products Cope with the introduction of a conditional and time-limited approval system. In order to implement appropriate conformity assessments, coordinate with the division of biologics review sufficiently considering assessment methods and processes that are based on the characteristics of regenerative medical products. d) Implement smooth and efficient GLP compliance assessment Train GLP inspectors that has global competency. Examine how to establish a smooth operation of the GLP regulation considering global consistency, and implement the GLP compliance assessment more appropriately and efficiently. e) Implement smooth and efficient conformity assessment for re-examinations (including conformity assessment on use-results evaluation) Implement efficient and effective GPSP on-site assessments and document-based conformity assessments.

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-

f)

To enable high quality post-marketing surveillances, examine to establish such as consultation to provide guidance and advices regarding the compliance for GPSP, etc., during the re-examination period. Examine and disseminate effective assessment methods, to enable smooth and prompt conformity assessments for re-examination, etc. Promote appropriate clinical trials, etc. Enlighten the further promotion for implementation of appropriate clinical trials, etc., through the conformity assessment at medical institutions and sponsors, and training course, etc., in the period of the Mid-term targets, to ensure the quality of clinical trials, etc. in Japan. Examine the establishment of advice system that enables individual cases on GCP, etc.

Promotion of GMP/QMS/GCTP inspection In order for manufacturers to appropriately maintain and control manufacturing processes and the quality management system for pharmaceuticals, medical devices, and regenerative medical products, the following improvements shall be made to improve inspectional quality. a) Conduct efficient GMP inspections In response to accelerated reviews and increased numbers of bio-products, methods to improve GMP inspection efficiency shall be considered and conducted. This includes system enhancements to conduct timely inspections and clarify application time, while not affecting the time of approval. Increase the efficiency of inspections by using the assessment results of other regulatory agencies under PIC/S etc., in risk evaluation to decide if inspections shall be conducted on-site or off-site. In response to globalization of active pharmaceutical ingredients supply, partnerships with foreign regulatory agencies shall be reinforced and inspectional information shall be exchanged. A system to enhance on-site inspections at manufacturers overseas, especially in Asian countries, shall be developed. Quality of inspections shall be improved by having reviewers accompany the GMP inspection team and by promoting cooperation between GMP inspectors and reviewers. Enhance staff training for GMP inspectors by letting them proactively participate in training and meetings conducted overseas. Overseas training will increase staff with knowledge of global GMP harmonization and practices. b) Conduct smooth and efficient QMS inspections QMS inspection and related operations streamlined by the Act for Partial Revision shall be established. Promote cooperation between the review groups and the QMS inspection group. Standardize inspection methods with other domestic and overseas inspection agencies, such as registered certification bodies. Build expertise in global QMS harmonization and practices, through enhancing training for QMS inspectors and let them proactively participate in training and meetings conducted overseas, etc. Share inspection information with relevant domestic authorities to efficiently use resources. c) Conduct smooth GCTP inspections For accurate and prompt GCTP (Good gene, Cellular and Tissue Practice) inspections by PMDA that will start after enactment of the Act for Partial Revision, appropriate inspection methodology and necessary resources shall be established and secured. For buildings/facilities conformity assessments and relevant on-site inspections by PMDA into establishments that are processing cell/tissue products, that will start after enactment of the Regenerative Medicines Safety Act. Necessary resources shall be immediately secured and managed and current domestic and overseas situation regarding production of such products shall be figured out.

d) Increase efficiency of inspectional efficiency by utilizing the Kansai Branch and by conducting GMP inspections. Establishment of control function for the registered certification bodies 1) Improve the quality of certification bodies by ensuring the quality of the inspectors and by conducting appropriate training, etc., for those bodies. 2) Provide Support to be the First in the World to Facilitate Practical Use of Innovative Pharmaceuticals, Medical Devices, and Regenerative Medical Products a) Establish and update review standards regarding innovative products Utilize the Science Board, the initiative to facilitate practical use of innovative pharmaceuticals, medical devices, and regenerative medical products, and regulatory science research (hereinafter referred to as the “RS research”), etc., in order to establish guidelines and guidance and to consider RS research, etc., that PMDA shall make approaches on. Establish guidelines and guidance, etc., in cross-sectional projects regarding development and evaluation of pharmaceuticals, etc., that uses new technologies, and make necessary approaches in order to smoothly implement them. b) Proactively conduct Pharmaceutical Affairs Consultation on R&D Strategy, etc. Conduct consultations where suggestions can be made on development processes (roadmap) and confirmatory trial protocol. Conduct consultations for pharmaceutical companies on developmental strategies as well. Promote medical innovations by utilizing the Kansai Branch to fully educe technological capacity of Japan regarding biopharmaceuticals, medical devices, and regenerative medical products, etc. Regarding PMDA’s function to mediate between clinical study and practical use, support, etc., shall be proactively provided through Pharmaceutical Affairs Consultation on R&D Strategy, etc., in establishing exit strategies, with the cooperation of the Japan National Institutes of Health, etc. c) Operation of approval system based on the characteristics of regenerative medical products In order to appropriately cope with conditions related to regenerative medical products as well as the system for time-limited approval that were both introduced by the enforcement of the Act for Partial Revision of the Pharmaceutical Affairs Act, information dissemination and utilization of the consultations shall be promoted, by enhancing Pharmaceutical Affairs Consultation on R&D Strategy and by cooperating with relevant academia and industry. 3.

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Safety Measures Utilize finances including PMDA’s own financial resource and enhance system necessary to improve post-marketing safety measures of pharmaceuticals, medical devices, etc., based on the Act for Partial Revision of the Pharmaceutical Affairs Act that reflects the details of Japan Revitalization Strategy, the Healthcare and Medical Strategy, the final recommendation by the Committee for Investigation of Pharmaceutical-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Similar Sufferings, the discussions held by the Investigational Sub-committee on Revision of Pharmaceutical Regulatory Systems of the Health Science Council, etc. The following measures shall be taken in order to promote appropriate and efficient approaches mentioned above, with close cooperation with MHLW. Note: The organization responsible for implementing the following measures is PMDA unless otherwise stated to be MHLW, etc., or other corporations, etc.

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1) Enhance Collection of ADR and Malfunction Information Establish a system in which patients can easily report ADR, based on opinions, etc., from the patients and patients’ families, etc., who have reported them, and officially commence accepting and evaluating ADR reports, including reports on OTC drugs and Switch OTC and powerful drugs. Accept reports from MAHs as well as healthcare professionals, and take measures to increase reports from healthcare professionals with the cooperation of MHLW. Enhance and improve the systems to report information on ADR and malfunctions, etc., based on the current situation of global development such as ICH E2B and on the advancement of information technology, etc., and promote efficient and effective collection of safety information, etc. Enhance measures to collect information on ADR of quasi-drugs and cosmetics. 2) Systematize Information of ADR, etc., and Its Evaluation Analysis In order to appropriately respond to the evaluation approach for ADR which is increasingly sophisticated and specialized, substantially enhance current framework to assemble and analyze information on ADR. For this purpose, it is necessary to increase the number of staff members in each group organized according to pharmaceutical effect classification and area of medical practice that correspond to the review divisions. Measures, such as utilizing IT technology, shall also be taken to carefully investigate the overall domestic reports on ADR and infections. Modify a PMDA-initiated system step-by-step to follow-up on ADR reported from medical institutions, and ensure its application for all reports that needs investigation by FY 2018. Standardize and increase transparency of the process from obtaining information of ADR to take post-marketing safety measures including revision of package inserts, and increase accuracy and expediting of the process. Steadily accelerate the process taken to prepare post-marketing safety measures by setting a target time, and by increasing efficiency of the process with standardization. For the target time, consider, reducing the current median time from the first meeting with the MAHs until notification of investigation results. Modify submission process for package inserts to enable MAHs to smoothly submit package inserts. Establish a system to check contents of submitted package inserts and ensure that the submitted information is based on the latest knowledge. Respond promptly to consultations from MAHs when it voluntarily develop or revise either package inserts or communication tools for healthcare professionals and patients. Respond promptly to medical safety consultations from MAHs regarding safer use of pharmaceuticals and medical devices at clinical practice. 3) Establish Database, etc., for Medical Information Conduct pharmacoepidemiological analyses using electronic medical information, such as the Medical Information Database Network, and improve those analysis methods to promote its utilization for risk/benefit assessments of pharmaceuticals and for post-marketing safety measures. Promote MAHs to utilize the Medical Information Database Network for post-marketing safety measures, with its conditions of utilization determined by MHLW for post-marketing surveillance, etc., based on results of utilization obtained through pilot studies. Data accumulation shall be promoted in order to improve the quantity and quality of the Medical Information Database Network as well as to improve post-marketing safety measures.

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In order to promptly and safely provide useful medical devices and regenerative medical products, discussions up to the previous effective period for the Mid-term Targets shall be put into consideration to enhance the system of collecting post-marketing information, for example, by establishing a patient registry system for confirming long-term safety, with the cooperation of relevant academia and companies, etc. Promote investigational research regarding utilization of pharmacogenomics in post-marketing safety measures. 4) Establish a System for Post-marketing Safety Measures by Providing Information Feedback, etc. Regarding line listing of ADR, the time from ADR reporting to disclosure shall remain as within 4 months. ADR reports from medical institutions shall be promptly disclosed in the line listing for those that have been investigated by PMDA. The instructions for revising the package inserts shall be published on the website within 2 days after issuance of those instructions. Disseminate information related to cases of ADR and malfunction, etc., for those that served as the basis for revising package inserts for prescription pharmaceuticals and medical devices, etc. Consider with MHLW about measures to enable medical institutions to discern the urgency and importance of the disseminated information more easily. Enhance dissemination of information to promote appropriate use of generic drugs. Regularly disseminate medical safer information so that pharmaceuticals and medical devices, etc., will be used safely at clinical settings. Collect medical safety information from vocational groups, etc., and enhance dissemination of the information. Aim for a wider use of the Pharmaceuticals and Medical Devices Information E-Mail Alert Service by enhancing the content of the service and by increasing the number of registries at an early period before the end of FY 2018 by more than 1.5 times that at the end of FY 2013, by means of strongly promoting registry of healthcare professionals working at medical institutions and pharmacies with the cooperation of relevant organizations, and so on. Let healthcare professionals, including physicians and pharmacists, etc., increase understanding of the information that PMDA provides. 5) Enhance Dissemination of Information to the Public Regarding Safety of Pharmaceuticals and Medical Devices, etc. Improve the method of disseminating information on the website regarding safety of pharmaceuticals and medical devices, etc., in order to respond to changes in the environment in which pharmaceuticals, medical devices, and regenerative medical products are provided, such as internet marketing of OTC drugs. Promptly release important safety information in a manner that is easy to understand from the patients’ perspective. Enhance dissemination of information to patients by further increasing patient’s awareness of the Pharmaceutical Guide for Patients and by increasing its convenience. Enhance dissemination of information that can be used for medication instructions for patients. Conduct consultations services for general consumers and patients for a safe and secure use of pharmaceuticals and medical devices, etc. Further improve the contents of information to the public, etc.

6)

Conduct Appropriate Post-marketing Safety Measures Based on the Risk Management Plan of Pharmaceuticals Consultation and instruction systems shall be strengthened and enhanced to appropriately conduct pharmacovigilance activities and risk minimization activities, based on the new Risk Management Plan (RMP) of pharmaceuticals. The new pharmaceuticals review divisions and the safety divisions shall cooperate together through discussions with the applicant in confirming RMP before reviews of new pharmaceuticals concludes. Regarding generic drugs, the generic drugs review division and the safety divisions shall cooperate together in order to confirm in the reviews the pharmacovigilance activity and the risk minimization activity that the MAHs are required to conduct. 7) Enhance Safety Measures in Response to the Introduction of New Review Service, and a Safety Management System Consistent from the Review Stage Safety management system shall strengthen cooperation with the relief services and maintain consistency from the review stage. Information from the relief services shall be utilized in the post-marketing safety measure operation, with special attention to ensuring protection of personal information. The safety divisions and the review divisions shall share information on adverse reactions caused by regenerative medical products (including time during conditional and time-limited approvals), and shall cooperate in taking post-marketing safety measures. Information on malfunctions of new medical devices and certified medical devices shall be shared among the safety divisions, the review divisions, and the registered certification body assessment division, for taking post-marketing safety measures. The system of safety management shall be enhanced in order to maintain consistency from the review stage, by allocating multiple risk managers for each field according to the number of new pharmaceutical products. The management function of the overall post-marketing safety measures shall be enhanced and the groups shall coordinately cooperate, to conduct appropriate operation. For products which need investigation on all cases as an approval condition, safety and efficacy information obtained from post-marketing surveillance shall be promptly provided to the public and health care professionals? 8) Enhance Follow-ups of the Safety Measures Conducted Conduct investigations to confirm the current status of post-marketing safety measures in MAHs, for example, whether information is definitely conveyed from the MAHs to medical institutions, and to confirm whether information from MAHs is conveyed and utilized within medical institutions and pharmacies. Based on the investigation results, information regarding methods of utilizing safety information in medical institutions and pharmacies shall be disseminated as best practices to use pharmaceuticals and medical devices safely. Investigate the status of whether the information provided from PMDA is utilized by general consumers and healthcare professionals, and analyze their needs and satisfaction level, to reflect them in the information service improvement. 9) Data Collection, Investigation, and Analysis on Adverse Reactions Reports in Accordance with the Preventive Vaccination Act Adverse reactions shall be promptly disclosed on the website for those that were reported from medical institutions and were investigated by PMDA. Details of adverse reactions reports shall be investigated in accordance with the Preventive Vaccination Act, with special attention to ensuring protection of personal information, and investigations and analyses shall be conducted in order to ensure safety of vaccination.

4.

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Promotion of Regulatory Science and Globalization, etc. In order to promptly provide clinical settings with necessary pharmaceuticals and medical devices, etc., it is essential for the quality, efficacy, and safety of pharmaceuticals and devices to be accurately estimated, evaluated, and determined based on scientific rationale and to be ascertained from an ethical perspective on whether to allow the public to use them. Regulatory science (RS) pursue this, and it has become increasingly important to be promoted, and research needs to be conducted on establishing prompt and accurate evaluation methods, etc., based on the latest results of technology, by utilizing external experts and by improving PMDA’s capability. In the midst of global development, manufacturing, distribution, and marketing of pharmaceuticals and medical devices, the services of PMDA have increasingly become globalized. Under these circumstances, improvement in medical services as well as establishment of PMDA’s global standing shall be made by cooperating with MHLW, the United States, Europe, and Asian countries, etc., and by proactively promoting global activities based on the PMDA International Strategic Plan, PMDA International Vision, and Road map for the PMDA International Vision. Note: Regulatory science = Science for coordinating results of science and technology into the most desirable form for harmonizing people and the society, by conducting accurate and evidence-based estimations, evaluations, and decisions in order for the results of science and technology to be used for the people and the society (from the Science and Technology Basic Plan, adopted by the Cabinet on August 19, 2011). 1) Promotion of Regulatory Science 1. Utilize the Science Board Proactively utilize the Science Board comprising external experts from the fields of medical science, dentistry, pharmaceutics, and engineering, to strengthen cooperation and communication with universities, research institutions, etc., and clinical settings regarding evaluation methods for innovative pharmaceuticals, medical devices, and regenerative medical products, and to make approaches to advanced technology products more adequately, for example, by utilizing Pharmaceutical Affairs Consultation on R&D Strategy. 2. Enhance regulatory science research Establish a system in PMDA to enable electronic submission of clinical study data for new pharmaceuticals that are to be submitted after FY 2016. Conduct PMDA-initiated cross-sectional analyses on cross-sectional clinical study data, etc., using advanced methods of analysis and prediction evaluation, and consider a system that increases the efficiency of pharmaceutical development through establishment of guidelines, etc. As a part of RS research aimed at improving the quality of PMDA’s services, a system and environment shall be developed by cooperating with external organizations (NIHS, academia, etc.) when necessary, so PMDA can take initiative in reaching solutions for issues that become evident through its services and issues of making practical use of the latest technologies. Develop an environment to easily engage in RS research, to promote and enhance designated research. Promote RS research, and encourage those results to be presented at conferences or to be submitted to scientific journals. Through RS research, train human resources to be experts in it.

As for cross-sectional activities, establish the concept of developing and evaluating pharmaceuticals to enable exchange of opinions between industry, government, and academia, and to establish guidelines and GRP, etc. 3. Enhance staff training Besides improving the quality of review, etc., and post-marketing safety measures, from the perspective of developing experts in RS research, status of the current training programs shall be evaluated for their implementation status, and their content shall be improved and conducted steadily. Enhance staff training to raise staff members with abilities to take the initiative in discussions at global negotiations and conferences, and to cooperate with foreign countries in establishing standards and guidelines, etc. Enhance on-site training at clinical settings and at manufacturing sites of companies, etc., as it is necessary, when conducting reviews, etc., and post-marketing safety measures, to have experience in clinical settings and increase in knowledge of manufacturing processes and quality controls for pharmaceuticals and medical devices. 4. Promote Interaction and investigative research with external researchers Proactively accept personnel from universities and research institutions in the field to facilitate practical use of innovative pharmaceuticals, medical devices, and regenerative medical products conducted by MHLW, while also dispatching staff from PMDA in order to help promote the development of innovative seed-stage resources and to establish guidelines. Develop and enhance education and research guidance systems that are conducted by directors and staff members at joint graduate school program, including regulations for those systems. These approaches will target increasing staff members who have a doctoral degree, etc. 2) Response to Globalization 1. Reinforce partnerships with the United States, Europe, Asian countries, and global organizations, etc. Cooperation with the United States FDA, the European Commission, EMA, and Swissmedic, etc., in promoting bilateral conferences based on confidentiality agreement and promoting exchange of information. Establish partnerships with other countries in America, Europe, and Asia, and global organizations. Continue dispatching liaison personnel to the United States, Europe, and Switzerland as much as possible, while promoting further dispatches to other countries in America, Europe, and Asia, etc., and global organizations, etc., as well. Utilize the liaison personnel dispatched to foreign countries to proactively collect information from their dispatched country, and to strengthen cooperation with those countries. Regarding GLP, GCP, GMP, and QMS inspections, further strengthen cooperation with foreign countries by proactively exchanging information on inspection notifications and investigation reports, etc. Respond to globalization of pharmaceutical distribution by enhancing globalization measures, for example, by promoting support in issuing an English version of the Japanese Pharmacopoeia as soon as possible, by disseminating information in English, and by promoting partnerships with the pharmacopoeias of Europe, the United States and Asia, etc.

-

-

2.

3.

4.

5.

- 224 -

Reinforce partnerships with regulatory agencies in the United States and Europe in order to conduct accurate reviews and consultations based on the latest science and technology, and to take post-marketing safety measures based on the latest information. Promote cooperation necessary to deepen mutual understanding regarding pharmaceutical regulations with the regulatory agencies in Asian countries, which are becoming increasingly important as sites of clinical development and manufacturing of pharmaceuticals, etc. Make necessary efforts for the pharmaceuticals and medical devices approved in Japan to be accepted by regulatory agencies in foreign countries, by enhancing information dissemination regarding review and post-marketing safety measures in Japan, etc. Enhance approaches toward global harmonization Contribute to the establishment of global standards and provide cooperation at global conferences regarding establishment of standards, such as at ICH and International Medical Device Regulators Forum (hereinafter referred to as “IMDRF”), etc., by proposing new topics, taking the initiative in establishing global standards, and proactively stating opinion on topics initiated by other countries. Promote harmonization with other global standards, such as standards for establishing application data that were defined in these conferences, and the ISO and others. For medical devices, continue promoting activities of the Harmonization by Doing (HBD) conducted with the United States and promote exchange of information. Promote globalization of the Japanese Pharmacopoeia through global harmonization of pharmacopoeia, etc., at the Pharmacopoeial Discussion Group (PDG). Participate in discussions at IGDRP, where global collaboration is held for generic drugs, and promote cooperation with foreign countries regarding reviews for generic drugs. Cooperate with MHLW in discussions at the International Cooperation on Cosmetics Regulation (ICCR) in order to promote cooperation with foreign countries. Participate in and contribute to global cooperation activities such as WHO and OECD. Consider accepting a wider range of submission data for new pharmaceutical applications that are in English. Promote interaction of personnel In order to promote establishment of networks with foreign regulatory agencies, have staff members proactively participate in global academic meetings and conferences, and increase opportunities to dispatch staff to organizations other than FDA, EMA, and Swissmedic. Promote personnel interactions through PMDA training seminars with Asian countries, etc., and global organizations, etc., and accepting trainees, etc., in order to establish a system to regularly exchange information related to reviews and post-marketing safety measures. Also have Asian countries, etc., increase their understanding of Japanese regulations, etc., and standards regarding pharmaceutical applications, etc., through symposiums co-hosted by multiple countries, etc. Train and enhance human resources to acquire global perspectives and communication skills In order to train human resources to be globally involved in establishing guidelines such as ICH and IMDRF, staff training programs shall be established and conducted, including attendance at meetings and global conferences where guidelines are established, and research opportunities at foreign institutions and graduate schools, etc. Improve linguistic ability by continuing and enhancing English training for executives and staff members, etc. Enhance and improve global public relations and information dissemination Enhance system to improve ability of disseminating information globally.

3)

4)

5)

6)

Enhance and improve the content of PMDA’s website in English to promote exchange of opinions and information with foreign countries. To be more specific, proactively release English versions of pharmaceutical regulations, details of services, review reports, and safety information, etc. Make certain that review reports are translated into English especially for products having significance in disseminating information, such as products that are the first in the world to be approved. (Forty products per year by the end of FY 2014. Thereafter, targets will be set in each fiscal year plan, with consideration of the utilization status of relevant people and the application status of pharmaceuticals and medical devices, etc.) Continuously conduct lectures and present booth exhibits, etc., at global conferences. Measures for Intractable Diseases and Orphan Diseases, etc. Develop review guidelines and enhance consultation services regarding pharmaceuticals for intractable diseases and orphan diseases. Take necessary measures to operate notifications and guidance regarding companion diagnostics pharmaceuticals, etc., smoothly. Take necessary measures through discussions with foreign regulatory agencies regarding points to be considered in developments, etc., using biomarkers. In order to promote utilization of pharmacogenomics in pharmaceutical development, PMDA shall take initiative in establishing evaluation guidelines at ICH, cooperate and share information with foreign regulatory agencies to establish a system that enables the 3 regions, including FDA and EMA, to make recommendations together, and thereby contributing to the development of global methods. Provide Information Including Review Reports, etc. In order to promote transparency of the services, PMDA shall proactively promote efforts to enhance disclosure of information by cooperating with MHLW to promptly provide information related to review reports, including results of priority reviews, and other review services, in an easily accessible manner for the public and healthcare professionals, and by enhancing the content of information related to review. Both the regulatory authority and the applicants shall make efforts to reveal in public review reports of new pharmaceuticals and new medical devices under the concept of rational use on the website immediately after approval, and also take appropriate measures to release re-examination reports of pharmaceuticals, etc. The outlines of the documents related to new pharmaceuticals and new medical devices shall also be released on the website within three months after approval. In addition to the integration of the services of releasing information, such as the service of information disclosure based on the Act on Access to Information Held by Independent Administrative Agencies, and the service of revealing in public review reports, so that PMDA can cope with the yearly increasing disclosure requests of documents, PMDA shall further improve efficiency of the services with the cooperation of relevant divisions. Ensuring Fairness when Utilizing External Experts Utilize external experts with relevant knowledge. When utilizing external experts, PMDA shall ensure neutrality and fairness in both the review, etc., and post-marketing safety measures services based on fair rules, and shall review those rules when necessary. Improving the Quality of Review and Safety Services by Enhancing the Information System Improve the quality of services by enhancing the function of information system to cope with the changes in review and post-marketing safety measures services where increase of the amount of information to be handled and deepening of the correlation and accuracy of information are expected.

-

-

Consider Enhancing computerization of review procedures, including eCTD, and improving the IT literacy of the staff.

Part 3 Budget, Income and Expenditure Plan and Cash Flows Plan 1. Budget: see Attachment 1 2. Income and expenditure plan: see Attachment 2 3. Cash flows plan: see Attachment 3 Part 4 Limit of Short-term Borrowing 1) Limit of Borrowing 2.2 billion yen 2) Expected Reasons for Short-term Borrowing a) Shortage of funds due to delayed receipt of administrative subsidies, subvention, and agent service fees, etc. b) Unexpected retirement payments. c) Shortage of funds due to other unexpected situations. Part 5 Plans for Transferring or Mortgaging Important Property if Applicable None Part 6 Use of Surplus Funds Surplus funds can be allocated to the review account for the following purposes. Resources for expenditure related to operational improvement. Financial resources for training and research, etc., to improve personnel qualifications and service quality. Regarding the ADR relief account and the infection relief account, surplus funds shall be adjusted as reserve funds, as specified in the provision of Article 31, Paragraph 4 of the Act on the Pharmaceuticals and Medical Devices Agency (Act No. 192, 2002). Part 7 Other Matters Regarding Operation Management Specified in the Ordinance of the Competent Ministry, etc. The following measures shall be taken for matters regarding operation management, etc., specified in Article 4 of the Ministerial Ordinance Regarding Operation Management, Finance, and Accounting of the Pharmaceuticals and Medical Devices Agency (MHLW Ministerial Ordinance No. 55, 2004), etc.

- 225 -

1) Matters Regarding Personnel Affairs a) Plans regarding personnel affairs of staff members In order to increase regular staff, PMDA shall employ highly specialized and capable human resources, mainly through open recruitment based on the Act for Partial Revision of the Pharmaceutical Affairs Act that reflects the final proposals of the Japan Revitalization Strategy, the Healthcare and Medical Strategy, and the Committee for Investigation of Pharmaceutical-induced Hepatitis Cases and Appropriate Regulatory Administration to Prevent Similar Sufferings. Note: Standards regarding personnel affairs The number of regular staff at the end of the term shall not exceed 141.9% of that at the beginning of the term. Reference 1)

Number of regular staff members at the beginning of the term: 751 Number of regular staff members at the end of the term: 1,065

Reference 2)

Total personnel expenses for effective period for the Mid-term Targets: 36,535 million yen (estimate) Note that the above amount is equivalent to the expenses for the executive compensation and basic pay, miscellaneous allowances, and overtime work pay for staff members. Improve qualification and capacity of the staff members by interacting with the government, research institutions, and universities with a consideration of a mobilization of human resources, and reduce proportion of transferees from the government with a consideration of appropriate balance. Therefore, PMDA shall strive to make reductions in accordance with the Basic Policy for Review of System/Organization of Incorporated Administrative Agencies (adopted by the Cabinet) established on December 7, 2010, and shall disclose those statuses every year. PMDA shall also systematically make approaches to steadily increase staff members, including specialized technical employees, etc., as specified in Part 7-1). Employment terms shall also be revised systematically to make a more attractive work environment. To ensure employment of highly specialized human resources, PMDA shall determine strategic methods, including an increase in number of fixed-term staff and introduce an annual salary system. In order to avoid any suspicion of inappropriate relationships with pharmaceutical companies, etc., PMDA shall appropriately manage personnel by establishing certain restrictions in employment, allocation, and post-retirement reemployment, etc., for executives and employees. b) Develop a comfortable working environment Consider developing a comfortable working environment for employees by improving working environment such as a promotion of work-life balance. Make approaches that enable a good balance between family life and career and that allows especially the women staff members, accounting for about half of the total employees, to keep fulfilling their abilities. c) Adjust salary standards Based on the Basic Policy Regarding Reform of Incorporated Administrative Agency (adopted by the Cabinet on December 24, 2013), PMDA shall take necessary measures to adjust the salary standards of the employees to achieve an appropriate and efficient level, taking into consideration the salary standards of national government employees as well as its competitiveness to stably securing distinguished human resources.

2)

3) 4)

5)

- 226 -

PMDA shall also inspect its state of approaches for adjusting salary standards every year from the following perspectives and shall disclose those results. 1) Appropriateness in salary standards of the employees when compared to the national government employees in view of factors such as their office locations and academic backgrounds, etc. 2) Room to improve the causes of high salary standards, for example, high proportion of employees dispatched form the government. 3) Ability to thoroughly explain the appropriateness of the current salary standards when the large government spending, the accumulated losses, and the salary standards of private companies engaged in similar services are pointed out. 4) Competitive salary standards of PMDA’s staff members compared to the standards in the relevant fields, such as pharmaceutical companies and research institutes at universities, etc., when we need to secure human resources with highly specialized knowledge and experience in technical matters. 5) Other explanations for the salary levels must be rational to gain sufficient public consent. d) Improve qualifications of the staff members In order to improve the quality of the services, PMDA shall improve qualification of the staff members by systematically providing opportunities for training according to targets of the services, etc., by enhancing training conducted with the cooperation of companies, and by interacting with MHLW, as well as domestic and foreign universities and research institutions, etc. Training for new staff members shall especially be enhanced in order to ensure effectiveness of enhancing system by increasing staff numbers. Enhance staff training programs for administrative staff members who are on main career tracks, so as to improve the quality of staff members at clerical positions supporting the organizational management. Implement a personnel evaluation system that allows motivation of the staff members to increase, and appropriately reflect those evaluations and the status of achieving their goals on their salary, pay raise, and promotion. Strategically allocate the staff members in view of their future career development to maintain their specialization as well as the continuity of operations. Ensure Security Continue enhancing the internal control system for security and confidentiality reasons by thoroughly controlling entrances and exits 24 hours a day, using the entrance and exit control system at the office. Continue ensuring security of information related to the information system. Continue ensuring the document control system based on the property of the stored documents. Matters Regarding Facilities and Equipment None Matters Regarding Disposition of the Reserve Funds Specified in Article 31, Paragraph 1 of the Act on the Pharmaceuticals and Medical Devices Agency In cases where there are still reserve funds for the review account even after adjusting profit and loss according to Article 44 of the Act on General Rules at the end of the last fiscal-year of the effective period for the Second Mid-term Targets, the amount approved by the MHLW out of those reserve funds can be applied to the financial resources of the review service and post-marketing safety measures service, as specified in Article 15 of the Act on Pharmaceuticals and Medical Devices Agency. Other Matters Steadily conduct approaches based on the government policy indicated in past Cabinet decisions, etc.

Attachment 1 Budget Budgets for Mid-term Plan (FY 2014 - FY 2018)

(Unit: million yen) Amount

Classification

Adverse drug reactions relief account

Infection relief account

Review account

Specified relief account

Commission and loan account

Commissioned payment account

Total

Income Administrative subsidies Governmental subsidies Contributions

6,350

6,350 3,444

883

707

1,854

20,322

553

16,043

User fees

Miscellaneous income Total

55,308

60,151

Commissioned operations Management income

18,390

60,151

926 1,671

312

7

1

146

22,883

1,572

85,471

16,501

1,300

1,254

130

15,247

1,170

5,410

3,262

9,598 1,983

8

5

167

18,390

5,418

3,268

137,001

81,659

18,585

5,380

3,243

126,667

38,056

85

188

99

39,813

18,500

5,192

3,143

43,252

Expenditure Operating expenses Personnel expenses Administrative expenses Expenses for reviews and related services Expenses for safety measures, etc.

29,533

29,533

14,069

14,069

General administrative expenses

541

Personnel expenses

270

Non-personnel expenses

271

74

6,899

12

38

25

7,319

17,043

1,374

92,184

18,597

5,418

3,268

137,883

Total

74

10,526

12

38

25

3,626

3,897

Personnel expenses were calculated as expenses based on self-financial resources for increases in and after FY 2015. In principle, all figures have been rounded off; therefore, individual totals shown may not coincide with the actual totals.

- 227 -

11,216

Attachment 2 Income and Expenditure Plan Income and Expenditure Plan for the Mid-term Plan (FY 2014 - FY 2018)

(Unit: million yen) Amount

Classification

Adverse drug Infection relief reactions account relief account

Review account

Specified relief account

Commission Commissione d payment and loan account account

Total

Expenditure Ordinary expenses

24,163

1,495

93,471

18,600

5,422

3,269

146,420

75,708

18,585

5,383

3,243

120,498

 

Operating expenses

16,346

1,233

 

Relief benefits

12,270

155

12,425

197

621

818

Operating expenses for health and welfare Operating expenses for reviews

29,719

29,719

Operating expenses for safety measures

11,317

11,317

Specified relief benefits

18,390

Benefits (healthcare allowances, etc.)

18,390 5,118

5,118

Benefits (special allowances, etc.)

1,294

1,294

Operating expenses for research and study

1,768

1,768

Administrative expenses

2,619

331

117

93

88

3,249

 

Personnel expenses

1,260

126

34,673

78

172

92

36,399

 

General administrative expenses

542

78

10,520

12

38

25

11,214

 

Personnel expenses

272

 

Non-personnel expenses

270

Depreciation expenses Provision for liability reserve  

Miscellaneous losses

3,306

3,577

78

7,214

12

38

25

7,636

7,243

4

1

1

7,507

241

16

7,030

163

7,192

5

5

10

22,876

1,572

883 20,322

Income Ordinary income Governmental subsidies Contributions

85,713

18,600

707

1,854

207

553

16,043

36,918

60,151

60,151

User fees Commissioned operations

5,418

Administrative subsidies Reversal of asset offset subsidies

3,262

8,672

926

926

6,350

6,350

89

Reversal of asset offset administrative subsidies

137,447 3,651

5,410

Other governmental grants

3,268

4

92

207

207

Reversal of asset offset gifts received Financial income (no operating income)

1,671

312

1,983

Gain on reversal of specified relief fund deposit received  

Miscellaneous income

Net income (∆net loss) Reversal of appropriated surplus Gross income (∆gross loss)

18,390 1

92

△ 1,287

77

△ 7,759

△ 1,287

77

△ 7,759

18,390 8

5

107

0

△4

△1

△ 8,974

0

△4

△1

△ 8,974

Administrative subsidies are assumed to be the financial resource for retirement allow ances for staff members in charge of operations financed by administrative subsidies under the review account.

How ever, this excludes the amount arranged through administrative subsidies as retirement allow ances equivalent to tenure, as provided for in Article 8-2 of the supplementary provisions in the Act for Pharmaceuticals and Medical Devices Agency.

In principle, all figures have been rounded off; therefore, individual totals shown may not coincide with the actual totals.

- 228 -

Attachment 3 Cash Flows Plan Cash Flows Plan for the Mid-term Plan (FY 2014 - FY 2018)

(Unit: million yen) Amount

Classification

Adverse drug Infection relief reactions relief account account

Review account

Specified relief account

Commission and loan account

Commissione d payment account

Total

Cash Outflows Cash outflows from operating activities  

Relief benefits Operating expenses for health and welfare

16,462

1,210

86,230

18,599

12,251

155

12,406

197

621

818

3,304

131,234

Operating expenses for reviews

29,012

29,012

Operating expenses for safety measures

10,811

10,811

Specified relief benefits

18,390

Benefits (healthcare allowances, etc.)

18,390 5,131

5,131

Benefits (special allowances, etc.)

1,294

1,294

Operating expenses for research and study

1,768

1,768

Administrative expenses General administrative expenses Personnel expenses Cash outflows from investing activities  

5,430

Payments for purchases of investment in securities Payments for purchases of intangible fixed assets

2,275

243

114

86

119

2,837

266

69

6,882

12

31

25

7,286

1,472

121

39,525

83

183

97

41,480

20,532

2,664

5,357

20,000

2,500

532

164

5,357

438

422

9,440

123

40

96

10,559

37,431

4,296

101,026

18,721

5,471

3,400

170,345

22,906

1,575

86,332

18,423

5,433

3,268

137,937

885

708

1,854

3,447

6,350

6,350

28,552 22,500 6,052

Cash outflows from financial activities Amount carried forward to the next mid-term plan period Total Cash Inflows Cash inflows from operating activities  

Governmental subsidies Administrative subsidies Contributions

20,322

553

User fees  

Cash inflows from investing activities

18,422

55,340

60,975

Commissioned operations Miscellaneous income

16,043

60,975

382 728

1

5,423

3,262

9,067

10

6

2,757

1,698

315

14,100

2,500

426

221

14,694

299

37

132

15,808

37,431

4,296

101,026

18,721

5,471

3,400

170,345

16,600

Cash inflows from financial activities Amount brought forward at the beginning of the mid-term plan period Total

In principle, all figures have been rounded off; therefore, individual totals shown may not coincide with the actual totals.

- 229 -

Rules of Calculation of the Running Expenses Grant for Accounts for Reviews, etc. The rules of calculation of the running expenses grant in the target mid-term period (FY 2014 - FY 2018) are as follows.

1.

FY 2014 Expenses required for implementation of services are individually estimated and calculated.

2.

In or after FY 2015 The following calculation formula is used: Running expenses grant

=

Service division personnel expenses

+

Expenses

+

Special factor

-

Self-generated income



Service division personnel expenses = Basic salaries, etc. (A) + Termination benefits (S)

A:

Personnel expenses including basic salaries, various benefits, and contribution to mutual aid association (excluding termination benefits) which are calculated by using the following formula:

A = [{P1 × α × β} + {P2 × β} + P3] A: P1: P2: P3: α: β:

Basic salaries, etc. for the said fiscal year Those influenced by salary raises and salary revisions among basic salaries in the preceding fiscal year Those influenced by salary revisions among basic salaries in the preceding fiscal year Those not influenced by salary raises and salary revisions among basic salaries in the preceding fiscal year Salary raise resource rate in view of running status, etc. Salary revision rate in view of running status, etc.

S:

Amount of termination benefits for the said fiscal year corresponding to persons expected to terminate in the said fiscal year and persons expected to terminate in the preceding fiscal year or before



Expenses = ((General administrative expenses (B) × γ1 × δ) + (Operating expenses (R) × γ2 × δ))

B: R: γ1: γ2: δ:

Non-personnel expenses related to the management division in the preceding fiscal year Non-personnel expenses related to services in the preceding fiscal year Efficiency coefficient (general administrative expenses) Efficiency coefficient (operating expenses) Consumer price index



Special factor = A measure required in association with law/regulation revision, etc. or a demand for fund occurring due to a reason unpredictable at present which is determined in the process of budget-making for every fiscal year. - 230 -



Self-generated income = The estimated mount of an income that may occur from clerical works/projects implemented with the running expenses grant as the financial resource

[Notes] 1. For α, β, δ, γ1, and γ2, concrete discrete values are determined for the said fiscal year in the process of budget-making for the year in view of the followings: δ (consumer price index): The actual value in the preceding fiscal year is used. 2. Budgets for the overall mid-term plan were estimated, [1] assuming that the increase rate is 0 for α, β, and δ. [2] assuming that γ1 (efficiency coefficient) is 3.75% in FY 2015, 3.90% in FY 2016, 4.05% in FY 2017, and 4.23% in FY 2018. [3] assuming that γ2 (efficiency coefficient) is 1.25% in FY 2015, 1.27% in FY 2016, 1.28% in FY 2017, and 1.30% in FY 2018.

- 231 -

      Attachment 1

Budgets Budgets for Fiscal Year Plan (FY 2014)

  (Unit: million yen)

Classification

Adverse drug reactions relief account

Amount of money Review account Specified relief Review Safety Total account segment segment

Infection relief account

Commission and loan account

Commissioned payment account

Total

Income Administrative subsidies Governmental subsidies Contributions

177

142

3,878

91

User fees Commissioned operations Management income Miscellaneous income Total

403

532

749

1,281

1,281

269

304

574

892

2,911

2,911

11,012

11,012

185

185

4,927

11,807 11,012 1,197

646

78

2,028 481

1

0

28

7

36

0

2

1

40

4,459

311

12,027

3,972

15,999

4,928

1,198

647

27,541

3,049

307

11,540

5,041

16,581

8,105

1,191

642

29,876

241

27

4,960

1,189

6,149

18

37

19

6,490

2,808

281

6,581

3,852

10,433

8,087

1,154

623

23,385

126

19

1,752

371

2,123

3

7

5

2,284

617

134

752

Expenditure Operating expenses Personnel expenses Administrative expenses General administrative expenses Personnel expenses

67

Non-personnel expenses

59

19

1,135

237

1,371

3

7

5

1,465

3,174

327

13,293

5,412

18,704

8,108

1,198

647

32,159

Total

 As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

- 232 -

819

      Attachment 2

Income and Expenditure Plan Income and Expenditure Plan for Fiscal Year Plan (FY 2014)

  (Unit: million yen) Amount Classification

Review account

Adverse drug reactions relief account

Infection relief account

Review segment

Ordinary expenses

4,716

440

Relief benefits

2,107

31

37

124

Operating expenses for health and welfare Operating expenses for reviews

Safety segment

13,734

Adjusted

5,079

△ 5

Specified relief account

Total

18,808

Commission Commissioned and loan payment account account

8,108

1,199

648

33,919 2,138 161

4,885

4,885

Operating expenses for safety measures

2,770

4,885

2,770

Specified relief benefits

2,770 8,064

Benefits (healthcare allowances, etc.)

8,064 1,133

1,133

Benefits (special allowances, etc.)

255

Operating expenses for research and study

349

Provision for liability reserve

Total

255 349

1,521

111

923

154

7,061

1,917

8,978

41

57

38

10,190

227

25

4,497

1,092

5,589

17

34

18

5,910

27

3

816

505

1,321

0

1

0

1,352

Retirement benefit expenses

6

1

197

47

244

0

1

0

253

Provision for accrued bonuses

7

1

278

41

319

1

2

1

331

655

124

1,272

232

1,504

23

19

18

2,344

126

20

2,166

3

7

5

2,327

Other administrative expenses Personnel expenses Depreciation expenses

Other expenses General administrative expenses

1,632

△ 5

1,782

388

64

521

123

644

708

Depreciation expenses

0

73

12

85

85

Retirement benefit expenses

2

24

4

28

30

Provision for accrued bonuses

1

36

8

43

1,129

241

6

3

8

1

1

Personnel expenses

45

59

Financial expenses

0

Miscellaneous losses

1

1

4,432

309

12,023

4,027

177

142

269

304

574

892

532

674

1,206

1,206

2,911

2,911

6,879

11,012

11,012

Ordinary income Governmental subsidies

20

△ 5

Other expenses

Administrative subsidies

△ 5

1,366

16,045

3

2

1

6

8,108

1,198

647

30,740

42 3,878

91

User fees

11,012

Gain on reversal of specified relief fund deposit received 185

Reversal of asset offset subsidies

185

17

119

137

Reversal of asset offset administrative subsidies

0

17

17

Reversal of asset offset gifts received

0

1,460

42

8,066

Commissioned operations

Financial income (no operating income)

5

8

Other governmental grants Contributions

7

8,066 1,197

646

0

2,028 137 17

0

0

378

77 7

0

2

1

5

Ordinary net income (△ net loss)

△ 284

△ 131

△ 1,711

△ 1,052

△ 2,763

0

△ 1

△ 1

△ 3,179

Current net income before tax (△ net loss)

△ 284

△ 131

△ 1,711

△ 1,052

△ 2,763

0

△ 1

△ 1

△ 3,179

Current net income (△ net loss)

△ 284

△ 131

△ 1,711

△ 628

△ 2,339

0

△ 1

△ 1

△ 3,179

Reversal of appropriated surplus

-

-

0

0

0

-

-

-

0

△ 284

△ 131

△ 1,711

△ 1,052

△ 2,763

0

△ 1

△ 1

△ 3,179

Miscellaneous income

Current gross income (△ gross loss)

455 △ 5

3

[Note] As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

- 233 -

      Attachment 3

Cash Flow Plan Cash Flow Plan for Fiscal Year Plan (FY 2014)

  (Unit: million yen) Amount

Classification

Review account

Adverse drug reactions relief account

Infection relief account

Review segment

Safety segment

Adjusted

Specified relief account

Total

Commission Commissioned and loan payment account account

Total

Cash Outflows   Cash outflows from operating activities Relief benefits Operating expenses for health and welfare

3,203

363

2,109

30

37

124

Operating expenses for reviews

15,456

▲6

8,109

1,215

655

34,254

161 7,938

7,938 3,537

673

20,710

2,139

Operating expenses for safety measures Administrative expenses

5,260

7,938

3,537

3,537

126

24

Specified relief benefits

20

18

8,064

Benefits (healthcare allowances, etc.)

862 8,064

1,135

1,135

Benefits (special allowances, etc.)

255

255

Operating expenses for research and study

349

349

General administrative expenses

59

20

1,450

319

1,768

3

7

5

1,863

298

26

5,326

1,265

6,590

18

36

19

6,986

1

1

1

1

2

1

6

25

37

0

15

7

960

  Cash outflow from investing activities

4,000

300

5

802

807

0

5,107

  Amount carried forward to next fiscal year

1,919

217

8,259

936

9,195

1,743

39

131

13,245

9,122

880

23,720

6,998

▲6

30,713

9,852

1,253

786

52,606

4,465

311

12,200

3,981

▲6

1,201

647

3,878

91

177

142

Personnel expenses Repayment money Other cash outflow from operating activities

Total

743

139

▲6

876

Cash Inflows   Cash inflows from operating activities Contributions Administrative subsidies Governmental subsidies User fees

Commissioned operations Amount of interests received

403

  Cash inflows from investing activities Amount brought forward from preceding fiscal year Total

4,934

2,911

4,934

532

749

1,281

269

304

574

892

11,177

11,177

11,177

150

150

1,199

646

82

2

1

0

0

1,281

0

2,904

302

1,995 481

66 8

27,734 11,813

78

Miscellaneous incomes Other incomes

16,176

2,911

16 ▲6

6

0

0

85 9 3,206

1,753

267

11,520

3,017

9,122

880

23,720

6,998

▲6

14,537

4,918

53

138

21,666

30,713

9,852

1,253

786

52,606

[Note]  As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

- 234 -

Plan for FY 2013

Plan for FY 2014

      Attachment 1

Budgets Budgets for Fiscal Year Plan (FY 2013)

      Attachment 1

Budgets Budgets for Fiscal Year Plan (FY 2014)

  (Unit: million yen)

Classification

Adverse drug reactions relief account

Amount of money Review account Specified relief Safety Review Total account segment segment

Infection relief account

Commission and loan account

Commissioned payment account

  (Unit: million yen)

Classification

Total

Income

Adverse drug reactions relief account

Amount of money Review account Specified relief Review Safety Total account segment segment

Infection relief account

Commission and loan account

Commissioned payment account

Total

Income Administrative subsidies Governmental subsidies Contributions

145

140

3,533

877

User fees Commissioned operations Management income Miscellaneous income Total

118

211

329

329

Administrative subsidies

301

903

1,204

1,489

Governmental subsidies

2,864

2,864

10,590

10,590

150

150

6,415

1,260

649

13,690

Contributions

10,590

User fees

2,059

397

71

1

0

24

5

29

0

2

22

468 55

4,077

1,088

11,183

3,984

15,167

6,415

1,262

671

28,680

2,681

233

11,154

4,875

16,029

13,142

1,255

666

34,006

199

23

4,205

1,023

5,228

16

34

18

5,518

2,482

209

6,949

3,852

10,801

13,126

1,221

648

28,488

93

14

2,217

528

2,745

2

7

4

2,865

512

133

645

Expenditure

177

142

3,878

91

Commissioned operations Management income Miscellaneous income Total

532

749

1,281

269

304

574

2,911

2,911

11,012

11,012

185

185

1,281 892 4,927

11,807 11,012 1,197

646

2,028

403

78

1

0

28

7

36

0

2

1

481 40

4,459

311

12,027

3,972

15,999

4,928

1,198

647

27,541

3,049

307

11,540

5,041

16,581

8,105

1,191

642

29,876

241

27

4,960

1,189

6,149

18

37

19

6,490

2,808

281

6,581

3,852

10,433

8,087

1,154

623

23,385

126

19

1,752

371

2,123

3

7

5

2,284

617

134

752

Expenditure

Operating expenses Personnel expenses Administrative expenses General administrative expenses Personnel expenses

49

Non-personnel expenses

45

14

1,704

395

2,100

2

7

4

2,171

2,774

246

13,371

5,403

18,774

13,144

1,262

671

36,871

Total

694

[Note]  As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

Operating expenses Personnel expenses Administrative expenses General administrative expenses Personnel expenses

67

Non-personnel expenses

59

19

1,135

237

1,371

3

7

5

1,465

3,174

327

13,293

5,412

18,704

8,108

1,198

647

32,159

Total

 As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

- 235 -

819

Plan for FY 2013

Plan for FY 2014       Attachment 2

Income and Expenditure Plan Income and Expenditure Plan for Fiscal Year Plan (FY 2013)

      Attachment 2

Income and Expenditure Plan Income and Expenditure Plan for Fiscal Year Plan (FY 2014)

  (Unit: million yen)

  (Unit: million yen)

Amount Classification

Amount

Review account

Adverse drug reactions relief account

Infection relief account

Review segment

Safety segment

Adjusted

▲3

Specified relief account

Total

Commission Commission and loan payment account account

Classification

Total

Review account

Adverse drug reactions relief account

Infection relief account

Review segment

Ordinary expenses

4,129

362

35,591

Ordinary expenses

4,716

440

Relief benefits

1,984

31

2,015

Relief benefits

2,107

31

38

124

162

37

124

Operating expenses for health and welfare Operating expenses for reviews

11,474

4,547

13,148

1,262

672

4,522

4,522

Operating expenses for safety measures

16,018

2,647

2,647

Specified relief benefits

13,104

Benefits (healthcare allowances, etc.)

4,522

Operating expenses for reviews

2,647

Operating expenses for safety measures

13,104 1,201

Operating expenses for health and welfare

1,201

Safety segment

13,734

Adjusted

5,079

△ 5

Specified relief account

Total

18,808

Commission Commissioned and loan payment account account

8,108

1,199

648

161 4,885

4,885 2,770

4,885

2,770

Specified relief benefits

2,770 8,064

Benefits (healthcare allowances, etc.)

8,064 1,133

1,133

259

259

Benefits (special allowances, etc.)

255

Operating expenses for research and study

354

354

Operating expenses for research and study

349

1,317

110

695

82

5,624

1,551

7,176

41

53

187

22

3,937

953

4,890

15

31

52

6

266

305

571

4

Retirement benefit expenses

6

1

165

38

204

Provision for accrued bonuses

7

1

246

41

443

53

1,009

215

94

14

Other administrative expenses Personnel expenses Depreciation expenses

Other expenses

▲3

1,426

Provision for liability reserve

33

8,080

Other administrative expenses

17

5,161

1

1

634

Depreciation expenses

0

1

1

213

287

1

2

1

298

1,224

22

18

14

1,774

1,643

2

7

4

1,764

772

1,073

201

357

Contributions

3,533

877

2,864 10,590

User fees

Commissioned operations Reversal of asset offset subsidies

150

671

35,363

124

1,272

232

1,504

23

19

18

2,344

126

20

2,166

3

7

5

2,327

General administrative expenses Personnel expenses

△ 5

1

1

4,432

309

12,023

4,027

177

142

269

304

574

532

674

1,206

1,358

Governmental subsidies

357

Administrative subsidies

Contributions User fees

13,104

Gain on reversal of specified relief fund deposit received

0

3

3

3

Reversal of asset offset gifts received

0

0

0 453

16,045

3

91

2

1

8,108

6

1,198

647

30,740 892 1,206 42

2,911

2,911 11,012

6,879

11,012

11,012 8,066

Commissioned operations

185

Reversal of asset offset subsidies

185

17

119

137

Reversal of asset offset administrative subsidies

0

17

17

Reversal of asset offset gifts received

0

Financial income (no operating income)

5

42 3,878

378

77

1,460

7

8

Other governmental grants

10,590

2,059

△ 5

45

1,366

0

Ordinary income

20

△ 5

Miscellaneous losses

Reversal of asset offset administrative subsidies

▲3

331

655

Other expenses

Financial expenses

96

70

1

27

80

383

2

30

99

4

1

59

16

Financial income (no operating income)

0

319

Other expenses

40

649

41

1

1,261

1,260

278

1,003

7,275

150

1

8

22

13,104

7

1

2

10,590

Gain on reversal of specified relief fund deposit received

253

Provision for accrued bonuses

3

4

2,864

0

6

7

40

1

241

1

155

0

1,129

29

301

244

30

1

140

47

43

3

145

197

8

27

Other governmental grants

1

36

202

Administrative subsidies

6

1

732

Governmental subsidies

1,352

Retirement benefit expenses

Provision for accrued bonuses

41

13,148

0

43

8

15,134

1

85

33

▲3

0

28

2

3,920

1,321

4

Provision for accrued bonuses

11,217

505

24

21

1,088

816

2

3

4,061

3

Retirement benefit expenses

17

Ordinary income

5,910

27

23

2

1

10,190

18

708

Retirement benefit expenses

1

38

34

85

57

0

57

17

12

57

Miscellaneous losses

41

5,589

73

8

Financial expenses

8,978

1,092

0

49

2

1,917

4,497

Depreciation expenses

0

931

7,061

25

644

Depreciation expenses

▲3

154

227

123

638

14

923

Personnel expenses

388

593

45

111

521

124

Other expenses

349 1,632

1,521

1,782

345

469

Personnel expenses

255

64

1,300

45

General administrative expenses

33,919 2,138

Benefits (special allowances, etc.)

Provision for liability reserve

Total

8,066 1,197

646

0

2,028 137 17

0

0 455

△ 5

0

0

4

0

2

22

25

7

0

2

1

5

Ordinary net income (△ net loss)

▲ 67

726

▲ 257

▲ 628

▲ 884

0

▲1

▲1

▲ 228

Ordinary net income (△ net loss)

△ 284

△ 131

△ 1,711

△ 1,052

△ 2,763

0

△ 1

△ 1

△ 3,179

Current net income before tax (△ net loss)

▲ 67

726

▲ 257

▲ 628

▲ 884

0

▲1

▲1

▲ 228

Current net income before tax (△ net loss)

△ 284

△ 131

△ 1,711

△ 1,052

△ 2,763

0

△ 1

△ 1

△ 3,179

Current net income (△ net loss)

▲ 67

726

▲ 257

▲ 628

▲ 884

0

▲1

▲1

▲ 228

Current net income (△ net loss)

△ 284

△ 131

△ 1,711

△ 628

△ 2,339

0

△ 1

△ 1

-

-

555

62

617

-

-

-

617

Reversal of appropriated surplus

▲ 67

726

298

▲ 565

▲ 267

0

▲1

▲1

389

Current gross income (△ gross loss)

Miscellaneous income

Reversal of appropriated surplus Current gross income (△ gross loss)

2

[Note] As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

Miscellaneous income

3

-

0

0

0

-

-

-

0

△ 131

△ 1,711

△ 1,052

△ 2,763

0

△ 1

△ 1

△ 3,179

[Note] As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

- 236 -

△ 3,179

△ 284

Plan for FY 2013

Plan for FY 2014       Attachment 3

Cash Flow Plan Cash Flow Plan for Fiscal Year Plan (FY 2013)

      Attachment 3

Cash Flow Plan Cash Flow Plan for Fiscal Year Plan (FY 2014)

  (Unit: million yen)

  (Unit: million yen)

Amount

Classification

Amount

Review account

Adverse drug reactions relief account

Infection relief account

Review segment

Safety segment

Adjusted

Specified relief account

Total

Commission Commissioned and loan payment account account

Classification

Total

Cash Outflows

Review account

Adverse drug reactions relief account

Infection relief account

Review segment

Safety segment

Adjusted

Specified relief account

Total

Commission Commissioned and loan payment account account

Total

Cash Outflows

  Cash outflows from operating activities Relief benefits Operating expenses for health and welfare

2,856

280

12,121

▲4

16,150

13,144

1,281

679

34,390

1,987

30

2,017

38

124

162

Operating expenses for reviews

5,660

Operating expenses for safety measures Administrative expenses

4,034

5,660 2,674

513

2,674

60

22

Specified relief benefits

19

15

13,104

Benefits (healthcare allowances, etc.)

Relief benefits Operating expenses for health and welfare

5,660

Operating expenses for reviews

2,674

Operating expenses for safety measures

629 13,104

1,204

  Cash outflows from operating activities

1,204

Administrative expenses

3,203

363

2,109

30

37

124

15,456

5,260

▲6

8,109

1,215

655

34,254 2,139 161

7,938

7,938 3,537 673

20,710

7,938

3,537

3,537 24

126

Specified relief benefits

20

18

8,064

Benefits (healthcare allowances, etc.)

862 8,064

1,135

1,135

Benefits (special allowances, etc.)

259

259

Benefits (special allowances, etc.)

255

Operating expenses for research and study

354

354

Operating expenses for research and study

349

349

General administrative expenses Personnel expenses Repayment money Other cash outflow from operating activities

46

14

1,751

16

1,767

2

7

5

1,840

General administrative expenses

238

22

4,514

1,110

5,625

15

33

17

5,951

Personnel expenses

1

1

1

1

3

22

28

33

28

16

8

508

195

232

▲4

423

0

  Cash outflow from investing activities

3,300

1,188

1,136

0

6,324

  Amount carried forward to next fiscal year

2,126

463

8,972

2,763

11,735

299

37

132

14,793

8,282

1,443

22,281

7,933

▲4

30,209

13,443

1,318

811

55,507

4,081

1,091

10,880

3,993

▲4

14,868

6,429

1,265

671

28,405

3,533

877

2,864

2,864

6,429

118

211

329

301

903

Total

700

2,324

Repayment money Other cash outflow from operating activities

255

59

20

1,450

319

1,768

3

7

5

1,863

298

26

5,326

1,265

6,590

18

36

19

6,986

1

1

1

1

2

1

6

25

37

15

7

960

743

139

▲6

876

0

  Cash outflow from investing activities

4,000

300

0

5,107

  Amount carried forward to next fiscal year

1,919

217

8,259

936

9,195

1,743

39

131

13,245

9,122

880

23,720

6,998

▲6

30,713

9,852

1,253

786

52,606

4,465

311

12,200

3,981

▲6

1,201

647

27,734

3,878

91

Total

5

802

807

Cash Inflows

Cash Inflows   Cash inflows from operating activities Contributions Administrative subsidies Governmental subsidies

145

140

User fees

Commissioned operations Amount of interests received Miscellaneous incomes Other incomes

Governmental subsidies

1,204

1,489 10,322

73

73

71

0

0

60

5

3

6

1,263

649

1,985 468

14

74 ▲4

2,180

Amount brought forward from preceding fiscal year

2,022

352

11,400

3,940

8,282

1,443

22,281

7,933

1

0

2

22

0

0

98 10 2,180

▲4

15,340

7,014

53

139

24,921

30,209

13,443

1,318

810

55,506

[Note]  As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

Contributions Administrative subsidies

10,322

397

  Cash inflows from operating activities

329

10,322

  Cash inflows from investing activities

Total

13,704

177

142

User fees

Commissioned operations Amount of interests received

403

4,934

2,911

4,934

532

749

1,281

269

304

1,281

574

892

11,177

11,177

11,177

150

150

1,199

646

82

2

1

0

0

16 ▲6

8

0

2,904

302

Amount brought forward from preceding fiscal year

1,753

267

11,520

3,017

6

9,122

880

23,720

6,998

0

0

85 9 3,206

▲6

14,537

4,918

53

138

21,666

30,713

9,852

1,253

786

52,606

[Note]  As each count was obtained by rounding off in principle, some fractions are not consistent with the total.

- 237 -

1,995 481

66

  Cash inflows from investing activities

Total

11,813

78

Miscellaneous incomes Other incomes

16,176

2,911

Basic Implementation Policy for the Third Mid-term Plan The Executive Board Decision November 25, 2014

1.

Goals for PMDA to attain by the end of the third mid-term period In order to meet the public expectations at a higher level in ever-changing business environment, PMDA, as the one and only organization that performs three regulatory operations (review, safety, and relief services) in Japan, aims for the goals described below by the end of the effective period of the mid-term plan, in accordance with the Third Mid-term Plan based on the universally applicable "PMDA Philosophy." PMDA aims to:  Provide fast and high-quality review, safety measures, and relief services for adverse health effects, using the latest scientific knowledge in accordance with the concept of regulatory science;  Collaborate with regulatory authorities of other countries and take the lead to promote international harmonization;  Contribute to improvement of medical standards in terms of ensuring the efficacy, safety, and quality of medical products and assuring their reliability, in collaboration with academia, etc.;  Act and communicate in a way that will earn trust of stakeholders including the general public; and  Enhance the standardization, efficiency, and advancement of operations and thereby reduce workload of applicants, persons receiving consultation, and employees of PMDA, while creating a comfortable work environment attracting highly qualified and competent employees and allowing them to pursue long-term careers with PMDA.

2.

Basic strategic perspective and policy for implementing the Third Mid-term Plan  In order to ensure high-quality and reliable operations, PMDA will:  Respond to reform of the systems appropriately;  Improve quality of reviews and enhance transparency of review results;  Deepen the possessed scientific knowledge and sophisticate the efficiency and efficacy of data analysis; and  Reinforce the consultation for practical application of promising seed-stage resources in academia and companies.  In order to play its expected roles and to increase its presence, PMDA will:  Enhance its contribution to the international harmonization of regulations and standards and strengthen commitment particularly to Asian countries;  Strengthen the training function for transferring knowledge and technique/methods of conformity audit and quality control, etc., to stakeholders; and  Reinforce provision of information about the operations and achievements of PMDA in a clear and transparent manner.

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 In order to make full use of limited resources, PMDA will:  Promote prioritization/rationalization of operations and systematic implementation while accommodating any situational change in a flexible manner;  Increase the productivity of individual employees and thereby enhance the performance of PMDA as a whole;  Work on development or modification of IT systems and cost reduction in order to standardize and streamline operations; and  Establish appropriate systems for personnel management and training in order to be able to secure competent personnel and to train them.

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Balance Sheet (corporate basis) (As of March 31, 2015) (Unit: yen) Account item

Amount

Account item

Assets

Liabilities

I

I

Current assets Cash and deposits

22,920,110,097

Amount

Current liabilities 99,576,603

Administrative subsidy obligations

Securities

3,998,995,734

Deposit subsidy, etc.

135,403,253

Expenses for work-in-process reviews, etc.

1,593,413,594

Accrued benefits

364,967,830

Prepaid expenses Accounts due Accrued income Other current assets

Total of current assets

196,088

Accounts payable

3,053,474,842

579,366,425

Advances received

8,175,749,053

47,265,702

Deposits received

142,436,978

330,508

Lease obligations

34,738,052

Allowance Accrued bonuses

29,139,678,148

466,079,064

12,472,425,675

Total of current liabilities

II

Fixed assets

II

Tangible fixed assets Tools, equipment and fixtures Cumulative total of depreciation Total of tangible fixed assets

Software in progress Telephone subscription right Total of intangible fixed assets

Fixed liabilities Per contra liabilities for property acquisition

2,299,275,215

Administrative subsidies for assets as per contra

△ 881,691,491

1,417,583,724

Governmental subsidies, etc. for assets as per contra

1,417,583,724

Amount of received goods for assets as per contra Deposits of specific relief funds Long-term deposit subsidy, etc.

Intangible fixed assets Software

5,393,401,398

Deposit contribution

374,392,800

Allowances Allowances for retirement benefits

286,000

Total of investments and other assets

643,613,222

191,853,874 4,590,836,642

4,782,690,516 62,092,673

1,799,941,872

1,799,941,872

32,738,175,557

20,141,170,146 27,429,508,429

Total of liabilities

39,901,934,104

8,714,160 Net assets 32,746,889,717 I

Capital funds 1,179,844,924

39,932,553,639 Total of capital funds II

Capital surplus Capital reserves

Cumulative total of depreciation that are not recorded as expenses (△) Loss on retirement or sale of fixed assets that are not recorded as expenses (△) Total of capital surplus III

Retained earnings Total of net assets

Total of assets

149,088

Total of fixed liabilities

Government investment Total of fixed assets

562,494,697

5,768,080,198

Investments and other assets

Rental deposit

80,969,437

Long-term lease obligations

Liability reserve

Investment securities

466,079,064

69,072,231,787 Total of liabilities and net assets

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1,179,844,924

4,670,640

△ 658,940,661 △ 98,706,116

△ 752,976,137

28,743,428,896 29,170,297,683 69,072,231,787

Profit and Loss Statement (Corporate basis) (From April 1, 2014 to March 31, 2015) (Unit: yen) Amount

Account item Ordinary expenses Adverse drug reaction relief benefits

2,113,286,412

Infection relief benefits

3,238,831

Operating expenses for health and welfare

127,425,120

Operating expenses for reviews

3,177,760,590

Operating expenses for safety measures

1,623,621,196

Specific relief benefits

2,100,000,000

Benefits for healthcare allowances, etc.

1,082,991,904

Benefits for special allowances, etc.

203,589,600

Investigative research

288,735,800

Provision of liability reserves

1,184,206,725

Other operating expenses Personnel expenses

5,460,506,177

Depreciation expenses

1,467,542,893

Retirement benefit expenses

230,704,790

Provision for accrued bonuses

304,476,585

Estate rental fees

1,337,347,239

Other expenses

525,872,566

9,326,450,250

General administrative expenses Personnel expenses

672,935,124

Depreciation expenses

175,019,127

Retirement benefit expenses

26,040,487

Provision for accrued bonuses

44,513,639

Estate rental fees

252,667,211

Other expenses

975,879,140

2,147,054,728

Financial expenses Interest paid

6,088,775

Miscellaneous losses

2,521,600

Total of ordinary expenses

23,386,971,531

Ordinary revenues Administrative subsidies

1,148,620,621

Reversal of provision for deposits of specific relief funds Revenues from contributions

2,100,000,000

User fees

10,066,401,757

Contributions

6,927,565,700

Revenue from governmental subsidies

656,914,254

Commissioned operations for government

69,801,190

Commissioned operations for others

1,754,282,390

Return of administrative subsidies for assets as per contra

10,793,944

Return of subsidies, etc. for assets as per contra

142,231,240

Return of amount of received goods for assets as per contra

36,220

Return of liability reserves

992,748

Financial revenue Interest on securities

442,297,876

Miscellaneous gains

442,297,876 19,231,856

Total of ordinary revenues

23,339,169,796 △ 47,801,735

Ordinary losses Extraordinary losses Loss on retirement of fixed assets

4

Provision of liability reserves

1,015,346,126

1,015,346,130 △ 1,063,147,865

Current net losses Reversal of reserve carried forward from the previous Mid-term target period Current gross losses

1,342,439,372 279,291,507

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Cash Flow Statement (Corporate basis) (From April 1, 2014 to March 31, 2015)

(Unit: yen) Account item

Amount of money

I. Cash flow from operating activities Expenditure for adverse drug reaction relief benefits Expenditure for infection relief benefits Expenditure for operating expenses for health and welfare Expenditure for operating expenses for reviews Expenditure for operating expenses for safety measures

△ 2,133,497,485

△ 3,239,431

△ 125,732,946

△ 3,690,835,106

△ 1,502,421,842 △ 2,100,000,000

Expenditure for specific relief benefits

△ 1,023,778,114

Expenditure for benefits for healthcare allowances, etc.

△ 204,041,200

Expenditure for benefits for special allowances, etc. Expenditure for expenses for investigative research Expenditure for personnel expenses Expenditure for money refunded for settlement of subsidies, etc.

△ 290,070,300

△ 6,511,475,627

△ 198,590,916

△ 3,339,468,314

Other operating expenditures Income from administrative subsidies

1,280,986,000

Income from governmental subsidies

1,022,658,750

Income from contributions

7,798,259,700

Income from user fees

10,957,671,841

Income from commissioned operations for government

69,801,190

Income from commissioned operations for others

1,704,647,540

Other incomes

145,842,809

Subtotal

1,856,716,549 △ 6,088,775

Interest paid Interest received

469,647,837

△ 865,144,900

Payment to national treasury   Cash flow from operating activities

1,455,130,711

II. Cash flow from investing activities Expenditure for acquisition of investment securities Income from redemption of investment securities at maturity

△ 4,298,111,000 3,200,000,000

△ 709,930,562

Expenditure for acquisition of tangible fixed assets

△ 2,069,340,184

Expenditure for acquisition of intangible fixed assets

△ 4,043,520

Expenditure for payment of lease deposits

△ 3,881,425,266

  Cash flow from investing activities

III. Cash flow from financing activities △ 106,005,102

Expenditure for repayment of finance lease obligations

△ 106,005,102

  Cash flow from financing activities

△ 2,532,299,657

IV. Increase in funds V. Beginning-of-term balance of funds

25,452,409,754

VI. End-of-term balance of funds

22,920,110,097

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Government Service Implementation Cost Statement (Corporate basis) (From April 1, 2014 to March 31, 2015) (Unit: yen) Account item

Amount of money

I. Operating expenses (1) Expenses in the profit and loss statement Adverse drug reaction relief benefits

2,113,286,412

Infection relief benefits

3,238,831 127,425,120

Operating expenses for health and welfare services Operating expenses for reviews

3,177,760,590

Operating expenses for safety measures

1,623,621,196

Specific relief benefits

2,100,000,000

Benefits for healthcare allowances, etc.

1,082,991,904

Benefits for special allowances, etc.

203,589,600

Expenses for investigative research

288,735,800

Provision of liability reserves

1,184,206,725

Other operating expenses

9,326,450,250

General administrative expenses

2,147,054,728

Financial expenses

6,088,775

Miscellaneous losses

2,521,600 4

Loss on retirement of fixed assets Provision of liability reserves

1,015,346,126

24,402,317,661

(2) (Exemption) Self-generated income, etc. △ 9,027,565,700

Income from contributions

△ 10,066,401,757

Income from user fees

△ 69,801,190

Income from commissioned operations for government

△ 1,754,282,390

Income from commissioned operations for others

△ 992,748

Return of liability reserves

△ 442,297,876

Financial revenue

△ 19,231,856

Miscellaneous gains Total of operating expenses

△ 21,380,573,517

3,021,744,144

II. Amount equivalent to depreciation that are not recorded as expenses

14,024,581

III. Estimated amount of non-allowance bonuses

17,906,148

IV. Estimated increased amount of non-allowance retirement benefits

104,462,099

V. Opportunity costs Opportunity costs of investments by the government or local governments, etc.

1,716,841

VI. Government service implementation costs

3,159,853,813

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Notes I.

Important Accounting Policies

1.

Criteria for allocation of revenue from administrative subsidies Percentage-of-expense method has been employed. Services implemented by the PMDA do not progress with a certain period of time and it is difficult to reasonably estimate the degree of achievement of results, and therefore it is difficult to clearly show a correspondence relationship between certain services, etc., and the financial resource of administrative subsidies. It is most reasonable to grasp the actual status of progress of services based on the amount of expenses required for activities, and therefore the percentage-of-expense method has been employed.

2.

Evaluation criteria and evaluation methods for securities Held-to-maturity bonds They are handed by the amortized cost method (straight-line method).

3.

Evaluation criteria and evaluation methods for expenses for work-in-process reviews, etc. They are handled by the lower-of-cost-or-market method based on specific identification method.

4.

Methods of accounting for depreciation (1) Tangible fixed assets [1] Tangible fixed assets other than lease assets The straight-line method has been employed. Durable years of main assets are as follows. Tools, equipment and fixtures 2 - 18 years The amount equivalent to depreciation of particular depreciable assets (Accounting Standards for Incorporated Administrative Agencies No. 87) is shown to be deducted from the capital surplus as cumulative total of depreciation that are not recorded as expenses. [2] Lease assets Lease assets related to non-ownership-transfer finance lease transactions The straight-line method, in which the lease period is durable years and the residual value is zero, has been employed. (2) Intangible fixed assets The straight-line method has been employed. Software is used within the corporate body based on an available period (5 years) within the corporate body.

5.

Criteria for allocation of allowances and estimated amounts related to bonuses Amounts occurring for the current term are allocated from among the expected amounts of payment of bonuses for the next term to executives, regular employees, etc. However, allowances are not allocated for amounts which are funded from the administrative subsidies and governmental subsidies from among the said expected amounts of payment. 6.

Criteria for allocation of allowances and estimated amounts related to retirement benefits To prepare for retirement benefits for executives and regular employees, the allowances and estimated amounts are allocated based on the expected amounts of retirement benefit obligations at the end of the current fiscal year. Actuarial differences are to be collectively amortized in the next fiscal year after the

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occurrence. However, allowances related to retirement benefits are not allocated for amounts which are funded from the administrative subsidies. 7.

Criteria for allocation of liability reserves To prepare for the payment of relief benefits in the future, amounts specified in the statement of operation procedures are allocated pursuant to the provisions of Article 30 of the Act on Pharmaceuticals and Medical Devices Agency (Act No.192 of 2002). 8.

Method of allocating opportunity costs in government service implementation cost statements Interest rate used for calculation of opportunity costs of investments by the government or local governments, etc.: Costs are calculated at a rate of 0.400% with reference to the yield rate at the end of March 2015 for 10-year fixed rate government bond. 9.

Methods of accounting for lease transactions Finance release transactions for which the total of lease fees is 3 million yen or more are handled by accounting method according to the method for usual sales transactions. Finance release transactions for which the total of lease fees is less than 3 million yen are handled by accounting method according to the method for usual lease transactions. 10.

Methods of accounting for consumption tax, etc. These are handled by the tax-included method.

II.

Items to note

1.

Notes for balance sheets (1) Notes regarding matters including current prices of financial products [1] Items related to the status of financial products Deposits are to be deposits for settlement. Also, financial products invested for fund management are limited to long-lived deposits, public and corporate bonds, etc. As investment securities, the PMDA holds only public bonds, FILP agency bonds, and class A or higher corporate bonds and does not hold stocks, etc. based on rules such as the provisions of Article 47 of the Act on General Rules for Incorporated Administrative Agencies. [2] Items related to matters including current prices of financial products Balance sheet amounts, current prices, and amounts of difference between them on closing date are as follows. (Unit: yen) Classification

Balance sheet amount (*)

Current price on closing date (*)

Amount of difference

A. Cash and deposits

22,920,110,097

22,920,110,097

0

B. Securities and investment securities

36,737,171,291

38,005,700,000

1,268,528,709

C. Accounts payable

(3,053,474,842)

(3,053,474,842)

0

(*) Those allocated in liabilities are shown in ( ).

(Notes) Method of calculating current prices of financial products and items related to securities, etc.

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A. B.

Cash and deposits Current prices approximate book values, and therefore are based on these book values. Securities and investment securities Current prices are based on prices at the stock exchange or prices offered by correspondent financial institutions. Items to note for securities are as follows. 1) Held-to-maturity bonds with current price (Unit: yen) Classification

Balance sheet amount

Current price on closing date

Amount of difference

Bonds with current prices exceeding balance sheet amount

36,737,171,291

38,005,700,000

1,268,528,709

Bonds with current prices not exceeding balance sheet amount

0

0

0

36,737,171,291

38,005,700,000

1,268,528,709

Total

2)

Scheduled amounts of redemption after closing date for held-to-maturity bonds (Unit: yen) Classification

Government bonds

≤ 1 year

≤ 10 years

> 10 years

7,200,000,000

0

0

4,600,000,000

12,300,000,000

0

2,500,000,000

0

0

0

0

2,000,000,000

0

0

500,000,000

3,300,000,000

0

0

0

0

0

13,100,000,000

19,500,000,000

0

Bonds issued by agency under a special act Total

≤ 5 years 3,200,000,000

Corporate bonds FILP agency bonds

> 5 years

1,000,000,000

Government-guaranteed bonds Local government bonds

> 1 year

4,000,000,000

C.

(2)

(3)

2.

Accounts payable The accounts are settled in short period and current prices approximate book values, and therefore are based on these book values. Estimated amount of non-allowance bonuses Estimated amount of bonuses to be covered by the administrative subsidies and governmental subsidies: 70,024,512 yen Estimated amount of non-allowance retirement benefits Estimated amount of retirement benefits to be covered by the administrative subsidies: 64,381,558 yen

Notes for profit and loss statements (1) Expenses for health and welfare services are expenses required for investigative research conducted to improve the QOL (Quality of Life) of people such as those covered by the system who suffered a serious and rare adverse drug reaction for which supports are not necessary sufficient when taking general measures intended for disabled people. These expenses consist of rewards for cooperation for investigation, etc.

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(2)

(3)

(4) (5)

(6)

Expenses for reviews and related services are expenses required for the operation of reviews and related services for drugs, medical devices, etc. These expenses consist of rewards, travel expenses, expenses at government offices in charge of clerical works, etc. Also, expenses for safety measures, etc. are expenses required for the operation of post-marketing safety measures for drugs, medical devices, etc. These expenses consist of rewards, travel expenses, expenses at government offices in charge of clerical works, etc. Expenses for investigative research are expenses required for investigative research of persons infected with HIV through blood products which is intended to contribute to the prevention of onset of AIDS. All of these expenses are healthcare expenses for HIV-infected persons. Income from user fees is an income paid by applicants for approval as a financial source for conducting review services for drugs, etc. Income from contributions is an income paid by marketing authorization holders of drugs, etc. as a financial resource for conducting relief services for adverse health effects and post-marketing safety measure services. The amount of 1,015,346,126 yen of provision shortfall due to miscalculation of liability reserves in previous fiscal years was calculated as an extraordinary loss.

3.

Notes for cash flow statements Relationship between the end-of-term balance of funds and money amounts of accounting items shown in the balance sheet Cash and deposits: 22,920,110,097 yen End-of-term balance of funds: 22,920,110,097 yen

4.

Notes for government service implementation cost statements The estimated increased amount of non-allowance retirement benefits includes 66,505,100 yen for executives and regular employees temporally transferred from the government.

5.

Notes for asset retirement obligations The PMDA has obligations for restoration to original state at the time of leaving business office based on the real estate leasehold contract, but the actual period of use of lease assets related to these obligations are not clear. Therefore, it is difficult to predict the timing of implementing these obligations and it is not possible to reasonably estimate asset retirement obligations. For this reason, asset retirement obligations that match these obligations have not been allocated.

6.

Notes for allowances for retirement benefits (1) Outline of the retirement benefits system employed The PMDA has established a retirement lump sum grants system as a defined-benefit system. (2) Items related to retirement benefit obligations (Unit: yen) Classification

As of March 31, 2015

[1] Retirement benefit obligations

1,575,538,051

[2] Unrecognized actuarial difference

224,403,821

[3] Allowance for retirement benefits ([1] + [2])

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1,799,941,872

(3) Items related to retirement benefits expenses (Unit: yen) April 1, 2014

Classification [1] Service expenses

250,206,648

[2] Interest expenses

15,972,635

[3] Amortization expenses for actuarial difference

9,434,006

[4] Retirement benefits expenses ([1] + [2] + [3])

256,745,277

(Note)

(4)

- March 31, 2015

As burdens of retirement benefits expenses for workers temporally transferred from other institution, [1] 4,327,183 yen for service expenses and [2] 323,678 yen for interest expenses were allocated.

Items related to the basis for calculation of retirement benefit obligations, etc. Classification

As of March 31, 2015

Discount rate

1.1%

Method of periodic allocation of estimated amounts of retirement benefits Amortized period of actuarial difference

Straight-line attribution 1 year Actuarial differences are to be collectively amortized in the next fiscal year after the occurrence.

III. Important Acts of Bearing Obligation There are no corresponding events.

IV. Important Subsequent Events There are no corresponding events.

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Pharmaceuticals and Medical Devices Agency (PMDA) Shiin Sh in-k kas asum umiigas igasek eki ki Buil Buil ildi ding di ng,, 3-3-2 Kasu Kasumi miga igase seki ki Chiyoda-ku, Tokyo 100-0013 Japa Ja pan n Tel : +81-3-3506-9456 Fax : +81-3-3506-9572 Website : http://www.pmda.go.jp