ANNUAL REPORT FY 2007

ACTUAL OPERATION RESULTS FOR FY 2007 ... state-of-the-art technology, etc ... Innovation (NiBio) in April 2005,...

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ANNUAL REPORT FY 2007

TABLE OF CONTENTS I.

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

PART 1

History and Objective of PMDA................................................................................................ 2

PART 2

Outline of Operations ............................................................................................................... 4 2.1 Relief Services for Adverse Health Effects ............................................................................. 4 2.2 Review Services ..................................................................................................................... 4 2.3 Safety Measures..................................................................................................................... 5

II.

ACTUAL OPERATION RESULTS FOR FY 2007 ........................................... 7

PART 1

The Reorganization and Rationalization Plan for Independent Administrative Institutions and the Review of the Overall Organization/Services.............................................................. 8 1.1 Establishment of the Reorganization and Rationalization Plan for Independent Administrative Institutions ....................................................................................................... 8 1.2 Implementation of the Review of Overall Organization/Services ............................................ 9

PART 2

Development of Fiscal Year 2007 Plan.................................................................................. 11 2.1 Development and Implementation of Fiscal Year 2007 Plan ................................................ 11 2.2 Evaluation Results of Operational Performance in FY 2006................................................. 11 2.3 Modifications in the Mid-term Plan (Approved on January 15, 2008).................................... 14

PART 3

Improvement in Overall Management of Operations and Service Quality of the Agency ...... 16 3.1 Efficient and Flexible Management of Operations ................................................................ 16 3.1.(1) Operation through management by objectives....................................................... 16 3.1.(2) Reinforcement of operational management system and top management ............ 16 3.1.(3) Advisory council meetings...................................................................................... 18 3.1.(4) Approaches for an efficient operation system ........................................................ 21 3.1.(5) Standardization of operating procedures................................................................ 21 3.1.(6) Development of databases..................................................................................... 22 3.1.(7) Approaches to developing the optimization plan for operations and systems ........ 22 3.2 Cost Control by Increased Efficiency of Operations.............................................................. 22 3.2.(1) Retrenchment of general administrative expenses ................................................ 22 3.2.(2) Cost control of operating expenses ........................................................................ 23 3.2.(3) Collection and management of contributions ......................................................... 25 (i) Collected contributions for adverse drug reaction fund and shifts in the liability reserve ................................................................................................................... 26 a. Adverse drug reaction fund ............................................................................. 26 b. Liability reserve ............................................................................................... 27 (ii) Collected contributions for relief for infections derived from biological products .... 27 (iii) Collected contributions for safety measures........................................................... 28 3.2.(4) Reduction in personnel expenses and overhaul of the pay system........................ 28 3.3 Improvement of Services to the Public ................................................................................. 29 3.3.(1) General consultation service .................................................................................. 29 3.3.(2) Responses to consultations, complaints, and claims of dissatisfaction from the private sector regarding reviews and safety operations................................................. 29 3.3.(3) Improvement in PMDA website .............................................................................. 30

3.3.(4) National forum on pharmaceuticals and medical devices....................................... 31 3.3.(5) Disclosure request for corporate documents.......................................................... 32 3.3.(6) Auditing and related matters .................................................................................. 34 3.3.(7) Report on the financial standing............................................................................. 34 3.3.(8) Official announcement of the plan for the review of optional contracts .................. 34 3.4 Personnel Issues .................................................................................................................. 34 3.4.(1) Review of a personnel evaluation system .............................................................. 34 3.4.(2) Systematic implementation of staff training ............................................................ 35 3.4.(3) Appropriate personnel allocation ............................................................................ 36 3.4.(4) Securing human resources through open recruitment ........................................... 36 3.4.(5) Appropriate personnel management based on work regulations ........................... 38 3.5 Ensuring Security.................................................................................................................. 39 3.5.(1) Management of entries and exits ........................................................................... 39 3.5.(2) Security measures for information systems............................................................ 39

PART 4

Improvement in Management of Operations and Quality of Services in Each Division ......... 40 4.1 Relief Fund Services............................................................................................................. 40 4.1.(1) Expansion and reconsideration of the provision of Information .............................. 40 (iv) Disclosure of cases of payment of benefits on the website .................................... 40 (v) Improvement of brochures, etc............................................................................... 40 4.1.(2) Active implementation of public relations activities................................................. 40 4.1.(3) Expansion of the consultation service .................................................................... 42 4.1.(4) Central management of information through databases......................................... 43 4.1.(5) Prompt processing of relief benfit claims................................................................ 43 (vi) Adverse drug reaction relief services ..................................................................... 45 a. Actual performance of adverse drug reaction relief......................................... 45 b. Number of claims by type of benefits .............................................................. 45 c. Judgment status according to types of benefits .............................................. 46 (vii) Infections derived from biological products relief.................................................... 46 a. Actual performance of relief for infections ....................................................... 46 b. Number of claims by type of benefits .............................................................. 47 c. Judgment status by type of benefits................................................................ 47 4.1.(6) Promotion of appropriate communication of information through collaboration between divisions .......................................................................................................... 47 4.1.(7) Surveys on actual status of effects from adverse drug reactions (investigative research as part of health and welfare services) ........................................................... 47 4.1.(8) Appropriate implementation of healthcare allowances for sMON patients and HIV-positive patients affected through blood products .................................................. 48 (i) Services for SMON patients (healthcare allowances) ............................................ 48 (ii) AIDS-related services (healthcare allowances)...................................................... 49 4.1.(9) Appropriate implementation of the service of the payment of benefits to assist the individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus......... 50 4.2 Reviews and Related Services/Safety Measures ................................................................. 50 4.2.(1) Faster access to the latest pharmaceuticals and medical devices ......................... 50 (iii) Ensuring the benefits of pharmaceuticals and medical devices for the public and healthcare professionals ................................................................................. 50 a. Implementation structure for clinical trial consultations and reviews ............... 50 b. Comprehension of the needs of the public and healthcare professionals ....... 55 (iv) Efforts for efficient and prompt reviews .................................................................. 56

a. b. c.

Increasing personnel....................................................................................... 56 Improvements in training................................................................................. 57 Reducing the development period through large-scale improvements in consultation..................................................................................................... 57 d. Reinforcement and improvements in the transparency of the progress management of reviews .................................................................................. 57 e. Responses to multi-national clinical trials, state-of-the-art technology, etc. .... 58 f. Clarification of the review standards ............................................................... 58 g. Development of the guidance for the introduction of a system by which preliminary evaluation (evaluation of efficacy and safety from the clinical Trial consultation stage) is conducted............................................................. 59 h. Trial of the project management system ......................................................... 59 (v) Implementation of approval review......................................................................... 59 a. Approval reviews for new drugs ...................................................................... 59 b. Approval reviews for new medical devices...................................................... 62 c. Document conformity audit of application documents, GLP conformity audits, GCP conformity audits, and GPMSP conformity audits....................... 65 d. Approval reviews for generic drugs, over-the-counter (OTC) drugs and quasi-drugs ..................................................................................................... 67 (vi) Improvement of clinical trial consultations .............................................................. 70 a. Conducting priority clinical trial consultations.................................................. 70 b. Acceleration of clinical trial consultations for pharmaceuticals........................ 71 (vii) Promotion of international harmonization ............................................................... 73 a. Approaches toward international harmonization such as through ICH............ 73 b. Efforts to introduce a total review time ............................................................ 74 4.2.(2) Improvement in reliability of operations .................................................................. 75 (i) Planned recruitment of staff with advanced expertise and systematic provision of training opportunities .......................................................................................... 75 a. Staff recruitment.............................................................................................. 75 b. Systematic training.......................................................................................... 75 (ii) Development of a GMP/QMS audit system............................................................ 75 (iii) Use of outside experts............................................................................................ 78 (iv) System development for more efficient review services......................................... 78 (v) Reinforcement of partnerships with foreign regulatory authorities.......................... 79 (vi) Evaluation of the latest technologies, such as biotechnology and genomics and cooperation in developing national guidelines........................................................ 80 (vii) Promotion of appropriate clinical trials.................................................................... 81 (viii) Prompt provision of information such as review reports ......................................... 81 (ix) Preparation and publication of the english version of review reports ..................... 82 4.2.(3) Enhancement/reinforcement of post-marketing safety measures (reinforcement of information management and risk management system) .......................................... 82 (i) Basic direction of post-marketing safety measures ................................................ 82 (ii) Introduction of a new method (review of the data mining method) ......................... 85 (iii) Building a sentinel medical institution network ....................................................... 87 (iv) Review of the system for comprehending and evaluating medical device malfunctions ........................................................................................................... 88 (v) Proper implementation of surveys on reports on adverse drug reactions and medical device malfunctions .................................................................................. 90 (vi) Digitization of adverse drug reaction reports and medical device malfunction reports .................................................................................................................... 92

(vii) Establishment of post-marketing safety system based on seedback of information ............................................................................................................. 92 a. Feedback to the private sector........................................................................ 92 b. Feedback to healthcare professionals ............................................................ 93 c. Provision of information to general consumers and patients........................... 97

III. SUPPLEMENTARY INFORMATION .......................................................... 105 Table 1. FY2007 List of Approved Products: New Drugs.......................................................................... 106 Table 2. FY2007 List of Approved Products: New Medical Devices..........................................................114 Table 3. FY2007 List of Approved Products: Medical Devices Approved with Clinical Data (Other Than New Medical Devices) ........................................................................................................117 Table 4. Safety Measures Implemented by MHLW and Revision of PRECAUTIONS for Pharmaceuticals, etc. in FY 2007 ............................................................................................... 120 Table 5. Revision of PRECAUTIONS for and Instructions for Self-inspection of Medical Devices in FY 2007……… ................................................................................................................................. 125 Table 6. FY 2007 Pharmaceuticals and Medical Devices Safety Information (No. 235-245) ................... 126 Table 7. PMDA Medical Safety Information .............................................................................................. 128 Table 8. Lists of User Fees (partially revised on April 1, 2007; refer to the Attachment revised on April 1, 2008 for a comparison of former and revised fees.) ............................................................... 129

I.

THE PHARMACEUTICALS AND MEDICAL DEVICES AGENCY

PART 1

History and Objective of PMDA

As lessons learned from diseases caused by pharmaceuticals 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 Law (Law 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/Kiko) in 1994 to play a role in equivalency reviews of generic drugs. Later, in 1997, the organization started to provide advice on clinical trials and conduct conformity audits on applications for approval of pharmaceuticals. 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 approval 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 equivalency reviews of medical devices as a designated investigative body under the Pharmaceutical Affairs Law. 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 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/Kiko should be dissolved and that the Pharmaceutical and Medical Devices Agency (PMDA) should be newly founded by consolidating the operations allocated to PMDEC, OPSR/Kiko, and JAAME in order to further enhance reviews and safety measures. In 2002, a legislative bill for the Law for 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 Law for the Pharmaceuticals and Medical Devices Agency (Law No.192 of 2002). The objective of PMDA is to contribute to improvement in public health by providing prompt relief services for sufferers of adverse health effects resulting from infections derived from biological products in addition to adverse drug reactions (Relief for Adverse Health Effects); providing guidance and reviews regarding the quality, efficacy, and safety of pharmaceuticals and medical devices through a system that is consistent from pre-clinical research to approval (Reviews); and collecting, analyzing, and providing information on post-marketing safety (Safety Measures). Previously, one of the objectives of the Agency was to promote basic research and development of pharmaceuticals 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 the Agency to focus specifically on reviews, safety measures, and relief services for adverse health effects.

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PART 2

Outline of Operations

2.1 Relief Services for Adverse Health Effects As a service inherited from the OPSR/Kiko, the Agency provides benefits for medical expenses, disability pensions, and bereaved family pensions to the sufferers of illnesses or disabilities caused by adverse drug reactions (Adverse Drug Reaction Relief Service). In April 2004, the Agency started to provide benefits to sufferers of adverse health effects caused by infections from pharmaceuticals and medical devices manufactured by using ingredients and materials derived from biological entities (Relief Service for Infections Derived from Biological Products). In January 2008, the Agency also started the service of providing benefits to individuals affected by hepatitis C according to the Law on Special Measures concerning the Payment of Benefits to Assist the Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus (Specific Relief Service). The Agency 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, the Agency 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 Review Services In accordance with the Pharmaceutical Affairs Law, the Agency reviews the efficacy, safety, and quality of pharmaceuticals and medical devices for which applications for approval have been submitted, based on the current scientific and technological standards. In addition, the Agency conducts re-examinations/re-evaluations of pharmaceuticals and medical devices and reviews of applications for pre-clinical assurance of products processed with cell tissue as well as reviews of applications for genetically modified biological entities in accordance with the Law Concerning the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms (Law No. 97 of 2003) (Approval Review Services). In response to requests from clinical trial sponsors, the Agency provides face-to-face guidance and consultations on clinical trials of new drugs and medical devices as well as on clinical trials for reexaminations/re-evaluations of approved products (Face-to-face Consultation Service). For items for which applications were made for approval reviews and re-examinations/re-evaluations, on-site and document inspections are implemented to determine whether documents attached to approval applications conform to Good Laboratory Practice (GLP), Good Clinical Practice (GCP), and conformity standards for application documents (Conformity Audit Services). In addition, on-site and document inspections are conducted to determine whether manufacturing equipment and manufacturing control methods for new drugs and medical devices, etc., conform with ministry ordinances relating to standards for manufacturing control and quality control, and whether there is a system for manufacturing products of appropriate quality (GMP/QMS Conformity Audits Services).

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

(ii) (iii) (iv)

(v)

Services for centrally collecting and organizing information on the safety of pharmaceuticals and medical devices from a broad range of sources, such as reports from the private sector, information from medical institutions, information from foreign regulatory agencies, and conference papers, relating to adverse drug reactions, malfunctions, and infections (Collection and Organization of Information). Services for conducting research and reviews relating to safety measures based on the information collected in (i) above (Research and Review Services). Services for giving guidance and advice to marketing authorization holders (MAHs) as well as providing advice in response to consultations from consumers (Consultation Services). Services to provide information on the safety of pharmaceuticals and medical devices widely to healthcare professionals, patients, private companies, etc., in a timely manner (Information Provision Services). Surveys related to developing various standards, such as the Japanese Pharmacopoeia (JP) that is stipulated in the Pharmaceutical Affairs Law (Standards Development-related Survey Services)

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Structure of the PMDA (FY 2007)

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II. ACTUAL OPERATION RESULTS FOR FY 2007

PART 1

The Reorganization and Rationalization Plan for Independent Administrative Institutions and the Review of the Overall Organization/Services

1.1 Establishment of the Reorganization and Rationalization Plan for Independent Administrative Institutions The Basic Guidelines for Economic and Fiscal Reform in FY 2007 (approved at the cabinet meeting held on June 19, 2007) lays down that all 101 independent administrative institutions should be reviewed for their organizations/services in line with the principles of shift from public to private sector, competition, and consistency, and on the basis of the results of the review, a Reorganization and Rationalization Plan for Independent Administrative Institutions should be formulated toward the end of FY 2007. In this regard, the Basic Policy for the Establishment of the Reorganization and Rationalization Plan for Independent Administrative Institutions was approved at the cabinet meeting held on August 10, 2007. After that, the Council of advisers on downsizing/streamlining public administration played a central role in scrutinizing the reorganization and rationalization plan formulated by each independent administrative institution in line with the above basic policy, and the Reorganization and Rationalization Plan for Independent Administrative Institutions was approved at the cabinet meeting held on December 24, 2007.

Reference: Items Relating to PMDA Highlighted in the Reorganization and Rationalization Plan for Independent Administrative Institutions (1) Review of Services and Operations New drug reviews In order to achieve the target of clearing up 2.5 years of drug lag in FY 2011, the Agency shall set an annual target for each year and formulate action plans for expediting the procedures and improving the quality of reviews, assess/verify its progress each year, and make necessary revisions on the basis of the progress status. As for the action plans, the achievements shall be evaluated without delay after the end of the target fiscal year for clearing up the drug lag that falls in the period of the next Mid-term plan.

New medical device reviews The Agency shall understand the current status of the device lag and analyze the causes behind it. On the basis of the results of the analysis, the Agency shall expedite reviews by taking necessary measures such as the standardization of the review process, strengthening of management, and improvement in the efficiency of services.

Safety measures With regard to safety measures, including the swift and timely collection, analysis, and provision of safety information on pharmaceuticals and medical devices, in the next Mid-term plan, the Agency shall set an indicator, which will facilitate a more suitable evaluation of the achievements

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of each service, so that the safety measures are implemented more efficiently and steadily.

(2) Review of the Organization Streamlining of the organization The Agency shall review the organization, including the feasibility of relocating the head office, and take the necessary measures during the period of the next Mid-term plan.

(3) Improvement in the Efficiency and Promotion of Autonomy of Overall Operations Streamlining the structure of the operation of services Taking into account the fluctuations in the number of staff, the Agency shall make comprehensive efforts to ensure the effective and efficient operation of services.

1.2 Implementation of the Review of Overall Organization/Services With respect to the review of the overall organization/services upon the expiration of the Mid-term plan, the Basic Guidelines for Economic and Fiscal Reform in FY 2007 laid down that along with formulating the Reorganization and Rationalization Plan for Independent Administrative Institutions, the institutions that were originally scheduled to conduct reviews in FY 2008 shall conduct their reviews ahead of schedule in FY 2007 together with the institutions that were already scheduled to conduct reviews in FY 2007. Because of this decision, the Agency was required to review the overall organization/services one year ahead of schedule. In line with the above decision, the chairman of the Committee for the Evaluation of Policy/Independent Administrative Institutions notified the Minister of Health, Labour and Welfare of the direction of recommendation for the improvement or elimination of principal operations/services in independent administrative institutions. On the basis of the above notification, the Ministry of Health, Labour and Welfare drafted a proposal of review taking into account the issues pointed out in the direction of recommendation for the improvement or elimination of principal operations/services at the Pharmaceuticals and Medical Devices Agency and submitted it to the Administrative Reform Promotion Office. The proposal was finally approved by the Administrative Reform Promotion Office on December 24, 2007.

Reference: Outline of the Proposal of Review Taking into Account the Issues Pointed out in the Direction of Recommendation for the Improvement or Elimination of Principal Operations/Services at PMDA (1) Review of Services/Operations During the period of the next Mid-term plan, the Agency shall endeavor to make reviews expeditious, improve the quality of services, and steadily implement safety measures, while simultaneously reviewing services and trying to improve their efficiency. These measures will be taken so that the Agency can cope with an increase in the workload of reviews/safety measures as well as with a higher level of expertise and it assumes an international role along with the U.S. and Europe as a

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member of a tripolar structure. The following are the measures in this regard: (i) (ii) (iii) (iv)

Reviewing drug evaluation-related services to clear up the drug lag Reviewing medical device evaluation-related services to clear up the device lag Steady implementation of safety measures Exhaustive efforts toward improvement in efficiency in overall services

(2) Review of Other Services In addition to (1) above, the Agency shall tackle the following tasks: (i) Setting the target for improvement in efficiency (ii) Realizing the reasonable pay standard, etc. (iii) Reviewing the practice of optional contracts

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PART 2

Development of Fiscal Year 2007 Plan

2.1 Development and Implementation of Fiscal Year 2007 Plan The Agency 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 (the first period for the Mid-term targets is between April 2004 and March 2009). In order to achieve the Mid-term plan, the Agency is required to develop a plan for each fiscal year, submit these plans to the Minister, and announce these plans to the public. The Agency developed a fiscal year 2007 plan and submitted this plan to the Minister at the end of FY 2006 and is implementing operations based on this plan in FY 2007. In addition, on January 15, 2008, the agency submitted an application to the Minister of Health, Labour and Welfare for approval for the modification of the Mid-term plan necessitated by the launch of the payment of benefits pursuant to the Law on Special Measures concerning the Payment of Benefits to Assist the Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus, and obtained the approval on the same day. The fiscal year 2007 plan was developed based on the modified Mid-term targets and Mid-term plan as well as operational performance for FY 2006 as evaluated by the Evaluation Committee for Incorporated Administrative Agencies of the Ministry of Health, Labour, and Welfare and opinions from the Commission on Policy Evaluation and Evaluation of Incorporated Administrative Agencies of the Ministry of Internal Affairs and Communications. The Agency has implemented various approaches, such as through making efforts to improve the organizational structure and reinforce management so that a performance level that meets the public’s expectations can be realized. In the same way as for FY 2006, the Agency announced its three priority issues for FY 2007 at the 1st Advisory Council Meeting held on June 22, 2007. The priority issues are as follows: (i) Enhancement of review services (ii) Enhancement of safety measures services (iii) Improvement of adverse health effects relief services In addition, to steadily promote the Mid-term plan, fiscal year plan, and priority issues for FY 2007, the Agency organized the issues that should be implemented within FY 2007 and announced these issues as Priority Issues for Operations in the Second Half of FY 2007 at the 3rd Advisory Council Meeting held on December 26, 2007.

2.2 Evaluation Results of Operational Performance in FY 2006 It is stipulated that the each ministry in charge of an independent administrative agency should establish an Evaluation Committee for Incorporated Administrative Agencies to conduct administrative processing of the agencies under its control (Article 12 of the Law on General Rules of Incorporated Administrative Agencies). The Agency received results of an evaluation on its performance in FY 2006 on August 17, 2007 by the Evaluation Committee for Incorporated Administrative Agencies of MHLW, which is responsible for conducting evaluations on the Agency. The overall evaluation results consisted of 1 S, 17 As and 2 Bs

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out of 20 evaluation items (the S was for expeditious provision of relief benefits, the 2 Bs were for improvement in the provision of services to citizens [e.g., publication of the agency’s services] and clinical trial consultations). The Agency posted these evaluation results on PMDA website and reported the results at the meeting of the Advisory Council that was held on September 18, 2007. Note: Five-level grading of S, A, B, C, and D with S being the highest 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 As for the results of the evaluations conducted by the Committee on the Evaluation of Independent Administrative Institutions at the Ministry of Health, Labour and Welfare, the Committee on the Evaluation of Policies/Independent Administrative Institutions at the Ministry of Internal Affaires and Communications submitted its conclusions on January 31, 2008, in which it highlighted the following issues concerning the evaluation results for the Agency. (1) “In the adverse drug reactions relief account and infection relief account of FY 2006, the current gross income of about ¥520 million and about ¥480 million, respectively, as well as the year-end surplus of about ¥3,150 million and about ¥1,520 million, respectively, are credited. Although it is explained in the Actual Operation Results of FY 2006 that such surplus is attributable to the fact that the payment of benefits was below the estimates, there is no convincing explanation for the appropriateness of the operation which supposedly contributed to such surplus. In view of the fact that the bulk of the income in these accounts is contributed by private companies, the appropriateness of operation contributing to the surplus should be evaluated in the future.” (2) “According to the important policies for administrative reform, the Committee on the Evaluation of Independent Administrative Institutions established at each ministry is required to conduct stringent ex post evaluations of the suitability of the pay standard at independent administrative institutions in the case where their pay standard is higher than that of the national government employees. Despite the fact that the Agency’s pay standard was 1.211 times that of national government employees (clerical/technical employees) in FY 2006, thereby far exceeded the national government employees’ pay standard, there is no reference to the suitability of the pay standard in the evaluation results. In the future, rigorous evaluation of the suitability of the pay standard should be conducted from the citizen’s perspective and take into account III-1-(4) of the Reorganization and Rationalization Plan, that is, ‘Realizing a Reasonable Pay Standard, etc.’” (3) “Regarding the proper management of optional contracts, the Proper Management of Optional Contracts at Independent Administrative Institutions instructs every ministry to conduct ex post evaluations along with annual evaluations by taking into account the issues pointed out by the committee in November 2006. However, there is no reference to the proper management of optional contracts in the evaluation results. In the future, rigorous evaluation of the progress of the optional contract review plan should be conducted by taking into account III-1-(1) of the Reorganization and Rationalization Plan, that is, ‘Review of the Practice of Optional Contracts.’”

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Performance Evaluation of the Agency by the "Evaluation Committee on Incorporated Administrative Agencies", MHLW Evaluation result

Classification in the mid-term and fiscal year plan

Evaluation items

FY2005 performance

FY2006 performance

Part 1 Improvement in overall operations and quality in services of the Agnecy eg. Services to the publilc (1) Efficient and Flexible Operations

(2) Cost reduction by increased efficiency of operations

(3) Improvement of services to the public

1

Operation through target management/top management

A

A

2

Ensuring of transparency by establishing deliberative bodies

A

A

3

Expense savings

A

A

4

Collection and management of contributions

A

A

5

Strengthening of the consultation system and disclosure of the work of the Agency

A

B

Part 2 Improvement in operations of each department, and quality of other services eg. services to the public

1 Adverse health effect relief services Expansion and review of dissemination of information regarding the System Proactive public relations activity toward familiarity with the (2) System

(1)

6

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

A

A

7

Expeditious processing of applications and improvement of the system

B

S

8

Conduct of cross-functional collaboration and surveys on adverse health effects

A

A

9

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

A

A

Expeditious operation and improvement of the system (drugs)

A

A

(3) Expansion of the scale of the consultation office (4) Unified management of information through the database (5)

Expeditious processing of relief applications through fact-finding study and other measures

Promotion of appropriate communication of information through cross-functional collaboration Consideration of conducting surveys on adverse health effects, (7) etc. Appropriate conduct of relief services for SMON patients and (8) those patients infected with HIV from blood preparations

(6)

2 Reviews and related operations/ post-marketing safety measures 10 Faster access to leading-edge pharmaceuticals and medical (1) devices

A

A

B

B

13

Expeditious operation and improvement of the system (medical devices) Expeditious operation and improvement of the system (clinical trial consultations) Improvement in quality of review and related operations/postmarketing safety measures

A

A

14

Promotion of appropriate clinical trials

A

A

15

Promotion of transparency of review and related operations/ post-marketing safety measures

A

A

16

Collection of ADR information

A

A

17

Provision of safety information to companies and healthcare professionals

A

A

18

Provision of safety information to patients and consumers

A

A

19

Budget, income and expenditure plan, and financial plan

B

A

A

A

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

Reinforcement of information management and emergency (3) management

Part 3 Budget, income and expenditure plan, and financial plan Part 4 Limit of short-term borrowing Part 5 Plan for transferring or mortgaging Part 6 Use of surplus funds

Part 7 Other operational issues determined by orders from the competent ministry (1) Personnel matters (2) Ensuring security Evaluation scale on performance of Incorporated Administrative Agency of MHLW

20

Personal issues and establishment of security

S

Significantly exceeding the level prescribed in the midterm-plan

A

Exceeding the level prescribed in the midterm-plan

B

Somew hat exceeding the level prescribed in the midterm-plan

C

Slightly below the level prescribed in the midterm-plan

D

Below the level prescribed in the midterm-plan, therefore requiring drastic improvements

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0 17 3 0

1 17 2 0

0

0

2.3 Modifications in the Mid-term Plan (Approved on January 15, 2008) Pursuant to the Law on Special Measures concerning the Payment of Benefits to Assist the Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus, the Agency is in charge of the payment of benefits to individuals infected with hepatitis C though specified products. In order to carry out this task, the Agency was required to modify the Mid-term plan. Therefore, the Agency submitted the application for approval for the modification of the Mid-term plan to the Minister of Health, Labour and Welfare on January 15, 2008 and obtained the approval on the same day. (Major modifications to the Mid-term plan: (i) inclusion of the description concerning the payment of benefits to individuals infected with hepatitis C by the administration of specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus and (ii) amendment of the Mid-term budget, including the creation of a new account that is necessary for the commencement of the payment of benefits to individuals infected with hepatitis C by the administration of specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus.)

1.

Outline of the Law on Special Measures concerning the Payment of Benefits to Assist the Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus

(1) Persons Eligible for Benefits Persons who meet both the criteria given below are eligible for benefits: (i)

Persons who have been infected with hepatitis C virus by administration of a specified fibrinogen product or blood coagulation factor IX product contaminated by hepatitis C virus (ii) Persons who, through the process of settlement/arbitration in court or by definitive judgment, are recognized as persons described above (i) or are their successors (inclusive of those who have been cured as well as those who have been infected by the mother-to-child transmission). Note: The fact of the administration of the virus and the existence of causal relations and symptoms shall be determined by the court. (2) Details of the Benefits (i) Benefits are classified into three levels according to symptoms: a. Persons who have suffered from cirrhosis or liver cancer due to the progress of chronic hepatitis C ........................................................................................................ ¥40 million b. Persons who have suffered from chronic hepatitis C.................................................... ¥20 million c. Asymptomatic carriers .................................................................................................. ¥12 million (ii) Additional benefits Additional benefits shall be paid in case where the symptoms progress within ten years after the benefits are received. In this case, the amount payable is the difference between the amount corresponding to progression of symptoms and the amount paid earlier. (3) Period for Claims (i) Claims for seeking benefits shall be made within five years after the law comes into effect (hereinafter referred to as expiration date).

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Notwithstanding the above, in the case where litigation or application for settlement/arbitration is filed on the expiration date and the final decision thereof is made or a settlement/arbitration is reached/established after the expiration date, the period for claims shall be within one month after the day of the final decision or the day of the settlement/arbitration. (ii) Claims for additional benefits shall be made within three years after diagnosis of the progression of symptoms. (4) Clerical Job Pertaining to Payment The clerical job pertaining to the payment of benefits shall be handled by the Pharmaceuticals and Medical Devices Agency, an independent administrative institution, and the fund for this purpose shall be established by the Agency. 2.

Claim for Benefits and Additional Benefits

(1) Claim for Benefits - Flowchart Individuals affected by hepatitis C (or their successors)

(iv) Payment

(i) Filing a case

Court (ii) Successful settlement/arbitration or definitive judgment (the fact of drug administration, a causal relationship, and symptoms are recognized)

(iii) Claims for benefits based on the result of settlement, definitive judgment, etc.

Pharmaceuticals and Medical Devices Agency (2) Claim for additional benefits

Doctors

(i) Request for preparing a medical certificate in the case where the Individuals symptom worsens affected by hepatitis C (or their (ii) Preparation of a successors) medical certificate describing the symptom (iii) Claims for additional benefits based on the medical certificate

(iv) Payment of additional benefits

Pharmaceuticals and Medical Devices Agency

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PART 3

Improvement in Overall Management of Operations and Service Quality of the Agency

3.1 Efficient and Flexible Management of Operations 3.1.(1) Operation through management by objectives In managing operations, the Agency clarifies the objectives and responsibilities of operations for each department, in addition to striving to identify and resolve problems through managing its operational progress on a daily basis. In order to do so, the Agency has managed operations through management of objectives by developing operating plans based on the duties for each responsible office and division in conjunction with the development of PMDA’s annual plan for FY 2007. To comprehend the progress of operating plans in each office, in November 2007, the Agency conducted a hearing with its directors about the actual operating performance up to the end of October 2007 in light of the operating plans, and the issues that were pointed out by the directors during this hearing were reported in the Board of Directors Meeting that was held on Feburuary 5, 2008. 3.1.(2) Reinforcement of operational management system and top management The Agency considers it necessary to reinforce its function to develop overall strategies for operations, as well as the system for managing operations such as for risk management and check functions. In addition, the Agency also plans to build an organizational system where management decisions by the Chief Executive are speedily reflected in operations. To this end, since FY 2006, the Agency has been establishing opportunities for the Chief Executive to directly comprehend the progress of operations and provide necessary instructions, and has also been reinforcing liaison and coordination of its general operations. Specifically, the Agency has regularly (usually once a week) held Board of Directors meetings, attended by the Chief Executive and management personnel who are division heads or hold a higher position. In meetings (held 4 times in FY 2007) for the Headquarters for PMDA Reform, which is headed by the Chief Executive, the results of operations reform at each office, including the ones in charge of reviews, as well as the status of studies concerning basic principles for reviews (reviews policy) were reported. In order to appraise the reviews of pharmaceuticals/medical devices and clinical trial consultations, the Agency regularly (12 times in FY 2007) held meetings of the Committee for Progress Management of Reviews Operations, headed by the Chief Executive, which facilitated a thorough management of the progress of reviews. The Headquarters of Information Systems Management was established with the aim of reinforcing the structure of information systems management and was headed by the Chief Executive. The basic approach to the review concerning the optimization of operations and systems, which constitutes the premise for the formulation of an Optimization Plan for Operations and Systems, has been studied in - 16 -

cooperation with the deputy CIO. In the course of the study, we engaged in comprehensive discussions, taking into consideration the opinions expressed by offices in charge of operations, with regard to the optimization of operations and systems, and tried to build consensus within the Agency. The establishment of the Optimization Plan for Operations and Systems and its publication was approved at the Headquarters of Information Systems Management (held twice in FY 2007), and the Optimization Plan for Operations and Systems was publicized on March 28, 2008. Moreover, at the Committee on Investment in Information Systems, which is under the Headquarters, the Agency appraised the appropriateness of the investment in the development of new systems and the modification of existing systems from the perspectives of cost-benefit performance and technical difficulties and selected systematic and effective investment decisions according to the Chief Executive’s business judgment (three meetings were held during FY 2007). In order to maintain sound financial performance and adequate operations, the Financial Management Committee, headed by the Chief Executive, was established, and has been holding regular meetings (12 meetings in FY 2007), during which reports on the monthly application status for user fees for each review division, reports on the monthly cash flow analysis, and reports on the declared amount of contributions were made. The Agency organized meetings with the Japan Pharmaceutical Manufacturers Association (JPMA), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the European Federation of Pharmaceutical Industries and Associations (EFPIA) twice (in July and December). Further, the Agency convened task force meetings six times, starting in February 2007, concerning medical devices and in vitro diagnostics. The Agency also convened meetings of four working groups, established under the task force, a total of 63 times. The Agency continues a study that aims to formulate the second phase Mid-term plan on the basis of the issues indicated in the Reorganization and Rationalization Plan for Independent Administrative Institutions. In order to ensure proper risk management of the overall organization, the Agency has established and operated a Risk Management Committee pursuant to the Risk Management Policy. At the Committee meeting held in FY 2007, we discussed the rule concerning taking important documents out of the Agency and established necessary regulations. Moreover, the Agency revised the operation policy of the Committee and decided to hold the Committee meeting once a month in order to increase awareness of risk management at the Agency. The Agency executives and employees have also continued to be familiarized with the risk management manual. The Audit Office, which is structured directly under the Chief Executive, has continued to conduct management of internal audit and internal reporting systems. To respond to disaster risks resulting from fires and earthquakes, the Agency informed all executives and employees of the disaster preparedness plan.

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PMDA Risk Management System Minister of Health, Labour and Welfare Indication of Midterm Targets Assessment by Evaluation Committee Appointment and dismissal of Chief Executive and Auditor

Submission of opinion reports

Auditor

Chief Executive

Notice of improvement results Manager audit

Coordination

Audit Office Internal audit

Advisory Council Risk Management Committee

Discussion on the important matters related to the operations and management of the Agency

System Advisor

Handling of lawsuits/ Legal consultation Information security measures

Risk management administrative personnel in each department

Legal Advisor (Labour, Appeals, Patent)

Audit of financial statements

Internal reporting system

Risk Management Guidelines

Risk Management Countermeasures Headquarters

Risk management supervisor in each department

Audit Corporation

Secretariat (Office of Planning and Coordination)

Employment regulations Code of ethics Sexual harassment regulations etc. Risk management training

General consultation Information service system Information service through website, etc.

Implementation guidelines for Health and risk management, etc. SOP

Information management regulations Disaster prevention plan

Note: Risks the Agency may face: a. Risks to the organization Possibility of an event that damages or may damage the reputation of the Agency in society Possibility of an event that significantly hinders or may damage the Agency’s execution of operations Possibility of an event that financially damages or may damage the Agency b. Risks that the Agency should address as part of its tasks Risks relating to the Agency’s operations and that have the possibility of causing or expanding critical adverse health effects due to pharmaceuticals, medical devices, etc. (pharmaceuticals, medical devices, quasi-drugs, and cosmetics, as well as agents and equipment subject to clinical trials). 3.1.(3) Advisory council meetings To create opportunities for exchanges of opinions between academic experts of diverse fields, the Agency established the Advisory Council (chaired by Masaaki Hirobe, Professor Emeritus at the University of Tokyo) consisting of academic experts, healthcare professionals, representatives from relevant industries, consumer representatives, representatives of people who have suffered from adverse drug reactions caused by pharmaceuticals, etc. By providing recommendations and improvement measures for operations and the management system, the Council works to secure fairness and transparency of the Agency’s operations, in addition to contributing to the streamlining of operations. Under the Advisory Council, the Committee on Relief Services (chaired by Hideaki - 18 -

Mizoguchi, Director of the Saitama Prefecture Red Cross Blood Center) and the Committee on Reviews and Post-marketing Safety Operations (chaired by Masaaki Hirobe, Professor Emeritus at the University of Tokyo) were also formed to discuss specialized issues relating to operations, and the dates of the meetings and specific agendas for FY 2007 are shown below. Advisory Council—FY 2007 Agenda for the 1st Meeting (June 22, 2007) (1) (2) (3) (4) (5) (6) (7)

PMDA Annual Report for FY 2006 Financial Report for FY 2006 Priority issues in FY 2007 operations Report on the employment status of personnel from the private sector Report on the status of problems caused by the anti-influenza drug Tamiflu Report on the measures against the problem of conflict of interests involving an outside expert Others

Agenda for the 2nd Meeting (September 18, 2007) (1) (2) (3) (4)

Results of the evaluation of operations performance for FY 2006 Original plan for the review of overall organization/services Restrictions with respect to employing personnel from the private sector Others

Agenda for the 3rd Meeting (December 26, 2007) (1) Review of overall organization/services (2) Principal achievements up to the end of October 2007 and priority issues in the latter half of FY 2007 (3) Restrictions with respect to employing personnel from the private sector (4) Rate of contribution to the adverse drug reaction fund in FY 2008 and onward (draft) (5) Others Request for approval (January 11, 2008) (1) Amendments to the Mid-term target and Mid-term plan of Pharmaceuticals and Medical Devices Agency (2) Amendments to the FY 2007 Plan of the Pharmaceuticals and Medical Devices Agency (3) Amendments to the operation manual concerning relief services of the Pharmaceuticals and Medical Devices Agency Agenda for the 4th Meeting (March 13, 2008) (1) Payment of benefits based on the Law on Special Measures concerning the Payment of Benefits to Assist the Individuals Affected by Hepatitis C through Specified Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus (2) Fiscal year 2008 plan (draft) (3) Budget for FY 2008 (draft) (4) Report on the employment status of personnel from the private sector (5) Others Committee on Review and Safety Operations—FY 2007 Agenda for the 1st Meeting (June 6, 2007)

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(1) Operating Report for FY 2006 (2) Fiscal year 2007 plan (3) Others Agenda for 2nd Meeting (December 13, 2007) (1) Principal achievements up to the end of October 2007 (between April and October) and the issues to be addressed hereafter. (2) Rate of contribution to the adverse drug reaction fund in FY 2008 and onward (draft) (3) Others Request for approval (January 11, 2008) (1) Amendment to the Mid-term target and Mid-term plan of the Pharmaceuticals and Medical Devices Agency (2) Amendment to the FY 2007 Plan of the Pharmaceuticals and Medical Devices Agency (3) Amendment to the operation manual concerning relief services of the Pharmaceuticals and Medical Devices Agency Committee on Review and Safety Operations—FY 2007 Agenda for the 1st Meeting (June 8, 2007) (1) (2) (3) (4) (5) (6) (7) (8)

Operating Report for FY 2006 Amendment to the Mid-term plan Future structure of the Agency Fiscal year 2007 plan Report on the employment status of personnel from the private sector Report on the problems caused by the anti-influenza drug Tamiflu Report on the measures against the problem of conflict of interests involving an outside expert Others

Agenda for the 2nd Meeting (August 27, 2007) (1) Review of services at the Pharmaceuticals and Medical Devices Agency (2) Restrictions with respect to employing personnel from the private sector (3) Others Agenda for the 3rd meeting (December 11, 2007) (1) (2) (3) (4)

Principal achievements up to the end of October 2007 and the issues to be addressed hereafter. Review of overall organization/services of the Pharmaceutical and Medical Devices Agency Restrictions with respect to employing personnel from the private sector Others

In order to ensure the transparency of the Advisory Council, Committee on Relief Services, and Committee on Review and Safety Operations, meetings held by these committees are generally open to the public and the minutes, materials, etc. relating to the meetings are disclosed on PMDA website. At the second Advisory Council meeting organized on September 18, 2007, discussion was made on the subject of restrictions with respect to employing personnel from the private sector and it was decided to revise the rule concerning the restrictions on employment of personnel from the private sector on the condition that the following measures are implemented in addition to the existing ones in order to secure fairness/transparency. - 20 -

(i)

The scope of report to the Advisory Council with regard to the status of allocation of personnel recruited from the private sector shall be widened so that the report is produced on an office basis instead of a functional basis. (ii) The audit office which is directly under the Chief Executive shall periodically check the status of compliance with the rule concerned and report the results to the Advisory Council semi-annually. (iii) The status of compliance with the rule concerned shall be included in the subjects of the annual audit conducted by the Auditor. Note: Information on the Advisory Council is available at: http://www.pmda.go.jp/guide/hyogikaikankei.html 3.1.(4) Approaches for an efficient operation system The Agency aims to establish an efficient operation system through flexible personnel allocation tailored to situations, as well as through effective use of outside experts. In review divisions that required flexible approaches in particular, the Agency continued to adopt a structure where, in addition to adopting a group system, Review Directors are placed underneath the division head, and the Review Directors are in charge of each review team. The Agency also invites commissioned outside experts to ask for their professional opinions relating to scientifically significant matters at specialized discussions on reviews and safety measures (896 such commissioned outside experts as of March 31, 2008). Similarly, the Agency invites commissioned outside experts to ask for their opinions on adverse drug reactions and adverse health effects caused by infections from biological products (63 such commissioned outside experts as of March 31, 2008 [14 of which are also commissioned as outside experts for reviews and safety measures as described above]). The names of the commissioned outside experts are listed on PMDA website. In progressing with operations, the Agency has also commissioned lawyers and accountants as advisors in order to handle operations that require specialized knowledge of laws and taxes. In addition, upon undertaking operational management of information systems and introducing a personnel evaluation system, the Agency made use of private companies to minimize increasing the number of permanent staff in the Agency. Assistance services for the development of the Optimization Plan for Operations and Systems were also commissioned to private companies. The Agency has continued to appoint people who have advanced professional expertise regarding information systems in general as well as knowledge of pharmaceutical affairs as information system advisors, in order to ensure consistency and coordination of operations relating to the Agency’s information systems. 3.1.(5) Standardization of operating procedures In order to effectively utilize part-time staff and limit the number of permanent staff through standardizing various operating procedures, the Agency 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. The Agency also used part-time employees for routine operations.

- 21 -

3.1.(6) Development of databases In FY 2007 as well, meetings of the Management Committee on Information Systems and Committee on Investment in Information Systems were held. In addition, discussions regarding the operational status of each information system, upgrades for the shared LAN system that serves as the common infrastructure system of the Agency, and improvements in the security of the e-mail system were carried out. Also, the Agency promoted establishment of databases in order to systematically organize and store documents as well as to enable easy collection and analysis of information. This effort includes creating a database that compiles inquiries from the general public regarding the Agency’s relief fund operations. The Agency has also upgraded existing databases on information relating to new drugs, adverse drug reactions, and malfunctions in order to apply such information widely to its operations. The notifications issued by MHLW and the Agency that are relevant to the Agency’s operations or that require broad dissemination of information to the public are posted on the following website: http://www.pmda.go.jp/operations/notice.html 3.1.(7) Approaches to developing the optimization plan for operations and systems The Agency developed the Optimization Plan for Operations and Systems with the assistance of the deputy CIO, an outside expert, and publicized it on March 28, 2008. The plan was 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 Independent Administrative Institutions (decided at the Liaison Meeting of the Chief Information Officers of the Ministries and Agencies held on June 29, 2005). In the course of the above, the Agency deployed external consultants and maintained a close collaboration with relevant offices in charge of services. In FY 2007 as well, the Agency further promoted reform of services in accordance with the results of diagnosis of services conducted in the previous year.

3.2 Cost Control by Increased Efficiency of Operations 3.2.(1) Retrenchment of general administrative expenses In addition to improving operations and endeavoring to increase efficiency of management, the Agency is expected to make the following cutbacks in the budget in the Mid-term plan relating to general administrative expenses (excluding retirement allowance) at the end of the effective period for the Mid-term targets, through suppressing personnel expenses by reviewing the pay standard and through the reduction of procurement costs. 1) 2)

3)

Approximately 15% cutback in comparison with FY 2003 The general administrative expenses that are incurred starting in FY 2004 in connection with revisions to laws and systems, etc., are to be cut back by approximately 12% in comparison with FY 2004. The general administrative expenses that are incurred starting in FY 2005 in connection with the enforcement of the amended Pharmaceutical Affairs Law in FY 2005 are to be cut back by approximately 9% in comparison with FY 2005.

- 22 -

4)

The administrative expenses that are incurred starting in FY 2007 in connection with efforts aimed at expediting reviews, according to the report issued by the Council for Science and Technology Policy titled, “Revision of structures aimed at the promotion of science and technology and the return of achievement to society” (dated December 25, 2006; hereinafter, referred to as the “Report of the Council for Science and Technology Policy”) are to be cut back by approximately 3% in comparison with FY 2007.

The budget in the Mid-term plan relating to general administrative expenses is based on the Mid-term targets for cost control as directed by the Minister of Health, Labour and Welfare. The Agency is to develop a fiscal budget plan based on the Mid-term plan and achieve the Mid-term targets by appropriately operating within the planned budget. In FY 2007, in order to execute the annual plan budget efficiently, the Agency strived to curve personnel expenses by introducing a new pay policy based on the structural reform of the pay system of national government employees. Moreover, the Agency formulated and publicized the Plan for the Review of Optional Contracts in December 2007 as per the Basic Policy for the Establishment of Reorganization and Rationalization Plan for Independent Administrative Institutions, approved at the cabinet meeting in August 2007. On the basis of this Plan, the Agency promoted general competitive bids and strived to reduce procurement costs arising from the purchase of expendables such as copy papers, the outsourcing of printed materials and so on, and the purchase of additional office furniture as well as the rental contract of additional PCs necessitated by the increase in employees. Consequently, the Agency successfully reduced general administrative expenses, excluding unused personnel expenses for vacant positions by 3.3% of the size of the budget; this reflects the target of efficient execution. 3.2.(2) Cost control of operating expenses By increasing efficiency of operations through promoting computerization, the Agency is expected to make the following cutbacks in the budget in the Mid-term plan relating to operating expenses (excluding expenses related to payment of benefits and single-year expenses due to new project launches) at the end of the effective period for the Mid-term targets. 1) 2) 3)

4)

Approximately 5% cutback in comparison with FY 2003 The operating expenses that were incurred starting in FY 2004 in connection with revisions to laws and systems are to be cut back by approximately 4% in comparison with F Y2004 The operating expenses that were incurred starting in FY 2005 in connection with the enforcement of the revised Pharmaceutical Affairs Law in FY 2005 are to be cut back by approximately 3% in comparison with FY 2005 The operating expenses that were incurred starting in FY 2007 in connection with the efforts to expedite reviews, in line with the Report of the Council for Science and Technology Policy, are to be cut back by approximately 1% in comparison with FY 2007

The budget in the Mid-term plan relating to project expenses is based on the Mid-term targets for cost control as directed by the Minister of Health, Labour and Welfare. The Agency is to develop a fiscal budget plan based on the Mid-term plan and achieve the Mid-term targets by appropriately operating within the planned budget. In FY 2007, the Agency progressively promoted the introduction of open competitive bidding for the contract of the clinical trial coordinator development project as per the Plan for the Review of Optional Contracts, which constitutes the target of the review. Moreover, the Agency commissioned outside

- 23 -

experts to assess expenses required for the development of various systems and tried to reduce cost. In the meantime, the Agency steadily managed the execution of operations, appraising the trend of commissions and contributions, which are the financial resources of operations, and securing necessary operations. Consequently, the Agency successfully reduced operating expenses, excluding the expenses for overseas GMP on-site inspections that were not used because the number of inspections was less than expected, by 13.1% compared with the budget amount, which is considered to be the target of efficient execution. Number of Open Competitive Bids Based on Disclosure Standards FY 2007: 55 bids (of which 21 were regarding general administrative expenses) FY 2006: 21 bids (of which 5 were regarding general administrative expenses) FY 2005: 18 bids (of which 7 were regarding general administrative expenses) FY 2004: 9 bids (of which 6 were regarding general administrative expenses) Reduction in General Administrative Expense and Operating Expenses in the Mid-term Plan (Expense Outlook Chart)

a. General Administrative Expenses Ex penses related to the increase of employees in FY 2008

Approx imately -3% Approx imately -9% Approx imately -12%

Approx imately -15%

Retirement Allow ance

Retirement Allow ance

Retirement Allow ance

Retirement Allow ance

Retirement Allow ance

Retirement Allow ance

FY 2003

FY 2004

FY 2005

FY 2006

FY 2007

FY 2008

- 24 -

b. Operating Expenses Expenses related to the increase of employees in FY 2008

Approx imately -1% Approx imately -3% Approx imately -4%

Approx imately -5%

Ex penses related to

Ex penses related to

Ex penses related to

Ex penses related to

Ex penses related to

Ex penses related to

the payment of

the payment of

the payment of

the payment of

the payment of

the payment of

benefits and a

benefits and a

benefits and a

benefits and a

benefits and a

benefits and a

competitive fund

competitive fund

competitive fund

competitive fund

competitive fund

competitive fund

FY 2003

FY 2004

FY 2005

FY 2006

FY 2007

FY 2008

3.2.(3) Collection and management of contributions Contributions from marketing authorization holders of the industry enable the Agency to secure financial resources for relief for adverse health effects such as adverse drug reactions and infections derived from biological products and other operations to improve the quality, efficacy, and safety of pharmaceuticals and medical devices. Specifically, contributions for the adverse drug reaction fund are declared and made by marketing authorization holders of approved drugs, contributions for relief for infections derived from biological products are declared and made by marketing authorization holders of approved biological products, and contributions to safety measures are declared and made by marketing authorization holders of pharmaceuticals and medical devices. The Agency automatically processed basic data such as those concerning newly approved items (pharmaceuticals and medical devices) and money transfer, using the contribution collection management system, which is able to manage contributions to the adverse drug reaction fund, infections fund, and safety measures fund in an integrated fashion. Consequently, the Agency efficiently conducted the operations of contribution collection management, such as the calculation of transaction value which constitutes the basis of the contribution amount and the management of the data concerning unpaid contributions. The Agency was also able to ensure convenience for contributors through continuing consignment contracts with four major banks and the Postal Savings Operation Centers (post offices) for receipt of contributions, resulting in prompt transfer of funds. In the Mid-term plan, the Agency sets the contribution collection rate for the adverse drug reaction fund and infection contributions to be no less than 99% by the end of the effective period for the Midterm targets. In FY 2007, the resulting contribution collection rate for the adverse drug reaction fund was 99.6%, and the rate for infection contributions was 100%.

- 25 -

Similarly, the Agency sets the contribution collection rate for contributions to safety measures to be no less than 99% by the end of the effective period of the Mid-term targets in the Mid-term plan. In FY 2007, the resulting contribution collection rate for contributions to safety measures was 97.6%. FY 2007 Contribution Collection Results Subjects (cases)

Category

ADR contributions Infection contributions

Safety measures contributions

Number of payers who made contributions (cases)

Collection rate (%)

Contribution amount (Million yen)

MAH Pharmacy

762 8,346

762 8,309

100% 99.6%

3,049 8

Total

9,108

9,071

99.6%

3,057

MAH

98

98

100%

574

673

670

99.6%

529

2,454

2,226

90.7%

186

Pharmaceutical manufacturers/traders Medical device manufacturers/traders Pharmaceutical & medical device manufacturers/traders Pharmacy

199

198

99.5%

504

8,346

8,297

99.4%

8

Total

11,672

11,391

97.6%

1,227

To efficiently improve contribution collection rates, 1)

The Agency continued to commission the Japan Pharmaceutical Association (JPA) to collect contributions from marketing authorization holders of pharmacy-compounded drugs. The Agency continued to call for requests to declare and make contributions to safety measures through industry associations and lectures, as well as through advertisements on websites and relevant trade journals. The Agency also created and distributed a handbook on the procedure for declaring and making contributions in order to make the procedure known to all the parties obligated to make contributions. Also, written requests for making contributions were sent to all contributors who have not yet made contributions, with the exception of marketing authorization holders of pharmacy-compounded drugs.

2)

(i)

Collected contributions for adverse drug reaction fund and shifts in the liability reserve a.

Adverse drug reaction fund To fund the adverse drug reaction relief service, the Agency has collected adverse drug reaction funds from marketing authorization holders of approved drugs. In FY 2007, the contribution rate applied to such marketing authorization holders was 0.3/1000 and the collected amount was 3,057 million yen.

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(Million yen) Fiscal year MAH of approved drugs MAH of pharmacycompounded drugs Total amount Contribution rate

FY 2003 (number of MAHs) 2,596 (842) 11 (11,175) 2,607 0.3/1000

FY 2004 (number of MAHs) 2,844 (833) 11 (10,550) 2,855 0.3/1000

FY 2005 (number of MAHs) 2,923 (787) 10 (9,993) 2,933 0.3/1000

FY 2006 (number of MAHs) 3,240 (778) 9 (8,968) 3,249 0.3/1000

FY 2007 (number of MAHs) 3,049 (762) 8 (8,309) 3,057 0.3/1000

The amount of adverse drug reaction funds and the contribution rate since the establishment of this service are shown below. Collected Amount

Trends in ADR Relief Contribution Income

Contribution Rate

Collected Amount (Million Yen)

Contribution Rate (per thousand)

4,000

1

3,000

0.8

2,000

0.6 0.4

1,000

0.2

0

0 1979

1982

1985

1988

1991

1994

1997

2000

2003

2006

Fiscal Year

b.

1.2

Liability reserve To cover the estimated relief benefit service costs that eligible persons will receive in the future, the Agency calculates the amount that they should possess at the end of every fiscal year and accumulates funds accordingly. The liability reserve at the end of FY 2007 was 15,912 million yen. (Million Yen)

Trends of Liability Resesrve

20,000 15,000 10,000 5,000 0 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 * This calculation is based on expected annual interest rate for investment of 4.0 % up to FY 2002, and 1.5 % from FY 2003 .

(ii) Collected contributions for relief for infections derived from biological products To fund the relief service for infections derived from biological products, the Agency has collected - 27 -

infection contributions from marketing authorization holders of approved biological products. In FY 2007, the contribution rate applied to such marketing authorization holders was 1/1000 and the collected amount was 574 million yen. (Million yen) Fiscal year FY 2004 FY 2005 FY 2006 FY 2007 MAH of 574 553 556 554 (108 companies) (105 companies) (101 companies) (98 companies) approved biological products Contribution rate 1/1000 1/1000 1/1000 1/1000 (iii) Collected contributions for safety measures To fund services for improvements in quality, efficacy, and safety of pharmaceuticals, etc., the Agency has collected contributions to safety measures from marketing authorization holders of pharmaceuticals and medical devices. In FY 2007, the contribution rate applied to such marketing authorization holders was 0.11/1000 and the collected amount was ¥1,227 million. (Million yen) FY 2004 FY 2005 FY 2006 FY 2007 Fiscal year (number of (number of (number of (number of MAHs) MAHs) MAHs) MAHs) MAH of drugs/medical 1,091 1,143 1,211 1,219 devices (3,076) (2,982) (3,180) (3,094) MAH of pharmacy10 10 9 8 compounded drugs (10,541) (9,987) (8,960) (8,297) Total amount 1,101 1,153 1,220 1,227 Contribution rate 0.11/1000 0.11/1000 0.11/1000 0.11/1000 3.2.(4) Reduction in personnel expenses and overhaul of the pay system In line with the policy stating that “fundamentally, personnel expenses should be reduced by at least 5% within the next 5 years, in accordance with the Mid-term targets. In addition, the pay system for Agency staff should be reconsidered taking the structural reform of the national civil servant pay system into account,” which is included in the Major Policies of Administrative Reform (approved at the Cabinet meeting on December 24, 2005), and based on the directive from MHLW dated March 31, 2006, the Mid-term plan was revised to specify that within the 5 years after FY 2006, the Agency will reduce personnel expenses by at least 5%, and that by FY 2008, which is the final year of the primary period for the Mid-term targets, the Agency will reduce personnel expenses by at least 3%. Along with the introduction of the personnel evaluation system established in April 2007, the Agency introduced a new pay policy as per the reform of the pay structure of national government employees. The introduction of the new pay policy allowed the Agency to successfully reduce personnel expenses by approximately 3.3% (compared with the planned amount of FY 2005).

- 28 -

3.3 Improvement of Services to the Public 3.3.(1) General consultation service Based on the General Consultation Guidelines that specifies how to handle inquiries directed toward the Agency and how to reflect comments and opinions to improve operations, the Agency manages a general consultation service and makes questionnaires available at its reception counter, enabling the collection of comments and opinions of visiting customers regarding the Agency’s overall operations. From June, 2007, the Agency has begun to receive comments and opinions via its website in addition to FAX so that citizens can transmit their opinions/requests more easily. Further, to provide increased convenience to visitors, the Agency is also implementing the consultation service all day, including during lunch breaks. Among the 2,821 inquiries that the Agency received in FY 2007, 1,402, or approximately 50% of the total inquiries received, were those relating to applications and consultations for pharmaceuticals and medical devices. Inquiry/consultation Complaint Opinion/request Other Total 2,711 56 45 9 2,821 FY 2007 (1,381) (5) (16) (0) (1,402) Note 1: Numbers in parentheses indicate the cases related to consultations and applications for drugs and medical devices approval. They are included in the total numbers above. Note 2: The Office of Review Administration also accepts inquiries on consultations and applications for drugs and medical devices approval, separately from this general consultation service.

3.3.(2) Responses to consultations, complaints, and claims of dissatisfaction from the private sector regarding reviews and safety operations In addition to responding to consultations and complaints from general consumers, the Agency also handles complaints from the private sector regarding reviews and safety operations. For inquiries relating to progress on reviews of new drugs, new medical devices, and improved medical devices, meetings are set up with the office director of the Agency in charge of the applicable review case. During these meetings, the office director explains the estimated time required to reach the next review stage. In FY 2007, the Agency handled consultations in such a way for 114 cases regarding new drugs and 3 cases each for new medical devices and improved medical devices.

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Number of Inquiries from Companies on Review Progress of New Drugs Therapeutic category Category 1 Gastrointestinal drugs, dermatologic medicines Antibacterial agents, vermifuge, antifungal agents, Category 4 Office of New antiviral agents except anti-HIV agents Drug I Oncology drugs Antineoplastic agents Anti-AIDS drugs Anti-HIV agents Cardiovascular drugs, antiparkinsonian drugs, Category 2 antithrombotics, anti-Alzheimer’s drugs Reproductive system drugs, genitourinary system Category 5 Office of New drugs, combination drugs Drug II RadioRadiopharmaceuticals pharmaceuticals In vivo diagnostics Contrast media Central/peripheral nervous system drugs, sensory Office of New Category 3 organ drugs (except drugs classified in category 6Drug III 1), narcotics Respiratory tract drugs, anti-allergy drugs, sensory Category 6-1 organ drugs for inflammatory diseases Office of New Drug IV Hormone drugs, drugs for metabolic disorders Category 6-2 (excluding combination drugs) Blood coagulation factor products, confirmation of Blood products Office of gene therapy, confirmation of Cartagena Biologics I Bio-quality Quality of antibody products Biological products Vaccines, antitoxin Office of Cellular and tissueBiologics II Cell therapy drugs derived products Total Division

Total cases 5 1 18 0 9 4 0 0 30 38 5 1 0 3 0 114

In FY 2004, the Agency established a system where, if an applicant files claims of dissatisfaction, etc., regarding reviews and safety measures, the office director (or the Director of the Center for Product Evaluation or Chief Safety Officer if claims of dissatisfaction have been filed more than once) is to directly conduct an investigation and respond to the applicant within 15 working days. The Agency continues to operate the system in FY 2007 as well. In addition, the Agency developed a consultation manual to handle complaints, etc., from relevant companies. From among the complaints received from relevant companies, the Agency is reviewing those that would be helpful in improving its operations. 3.3.(3) Improvement in PMDA website The Agency has prepared and posted on its website the Annual Report in FY 2006, which concerns the operation results of FY 2006, and Principal Achievements up to the End of October 2007 (between April and October) and Future Undertakings, which concerns the operation results between April and October 2007. In addition, materials used in Advisory Council meetings were also posted on the website sequentially. On the basis of the request from relevant offices, the Agency has posted on its website the procedures for and the flow of application for QMS audit, the document forms necessary for the application concerned, and the checklist concerning items required to be entered on the application form for approval for marketing.

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The Agency has posted information regarding information disclosure as a banner on the front page of our website so that it is more easily accessible. The Agency has revised the pages concerning recruitment information fundamentally and also considerably increased the information available to applicants. 3.3.(4) National forum on pharmaceuticals and medical devices The Agency held the National Forum on Pharmaceuticals and Medical Devices at the Enkei Hall of the Osaka Business Park on Saturday, October 20, 2007 with the aim of helping citizens understand the Agency’s operations and activities as well as diffusing among citizens the significance of pharmaceuticals and medical devices and the necessity of proper use. The forum, the theme of which was “Correct understanding protects you. Talk of pharmaceuticals. Talk of medical devices,” focused not only on pharmaceuticals but also medical devices as in the previous year and the keynote speeches and the panel discussions were conducted. In part I of the forum, Dr. Teruhiko Higuchi (President of National Center of Neurology and Psychiatry) and Dr. Yoshiyuki Taenaka (Deputy Director of the Research Institute, National Cardiovascular Center) made keynote speeches. Part II of the forum consisted of a panel discussion led by Ms. Rie Kouchi, a former NHK announcer, who served as the facilitator. Over 300 participants attended the forum, including healthcare professionals, students, and the general public.

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Part I Keynote Lectures Speech I “Let’s understand correctly. Efficacy and risk associated with pharmaceuticals” Dr. Teruhiko Higuchi (President of National Center of Neurology and Psychiatry) Speech II “Let’s learn more about latest medical devices” Dr. Yoshiyuki Taenaka (Deputy Director of Research Institute, National Cardiovascular Center) Part II Panel Discussion “Let’s deal with pharmaceuticals and medical devices cleverly” Panelists Dr. Hatsuo Aoki (President of Japan Pharmaceutical Manufacturers Association) Ms. Kuruyo Ima (manzai comedian) Dr. Yoshiyuki Taenaka (Deputy Director of Research Institute, National Cardiovascular Center) Dr. Teruhiko Higuchi (President of National Center of Neurology and Psychiatry) Mr. Kiyoshi Mamiya (Deputy Chief Caretaker, Japan Confederation of Druginduced Sufferers Organizations) Mr. Takashi Wachi (Chairman, Japan Federation of Medical Devices Associations) Mr. Akira Miyajima (Chief Executive, Pharmaceuticals and Medical Devices Agency) Facilitator Ms. Rie Kouchi (former NHK announcer) 3.3.(5) Disclosure request for corporate documents The status of requests for information disclosure is shown below. The petition of objection concerning requests for disclosure of corporate documents was filed twice in FY 2007. These petitions are expected to be discussed at the Information Disclosure and Personal Information Protection Review

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Board. Number of Requests for Disclosure of Corporate Documents Decisions Total requests

FY 2004 FY 2005 FY 2006

50 104 248

Refusal to answer on CarryRequests existence/ Objections over into Full Partial NonDocuments withdrawn nonnext FY disclosure disclosure disclosure not existing existence of the document 2 9 37 0 2 0 0 0 11 13 70 4 6 0 4 0 56 15 147 9 21 0 6 0

FY 2007

233

21

7

167

0

17

0

2

21

Total

635

90

44

421

13

46

0

12

21

250

Total requests 200

Cases of disclosure Cases of non-disclosure

150

Requests withdrawn 100

Carry-ov er into next FY 50

0

FY 2004

FY 2005

FY 2006

FY 2006 Carry-ov er

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.

Number of Requests for Disclosure of Corporate Documents by Requester Requester FY 2004 FY 2005 FY 2006 FY 2007 Aggregate Individuals 35 74 113 86 308 Corporates (e.g., drug manufacturers) 14 25 132 143 314 Press 3 4 13 Total 50 104 248 233 635 Note: The category “Individuals” includes requests made under an individual name, even if it substantially represents a corporation.

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Number of Requests for Disclosure of Corporate Documents by Operational Category Operational category FY 2004 FY 2005 FY 2006 FY 2007 Examples Marketing authorization application Approval review 8 22 90 115 for drugs not subject to approval GLP/GCP/GMP/QMS 32 69 117 74 Notice of GCP audit results etc. conformity audits Post-marketing safety 8 13 40 44 ADR report Others 2 — 1 — Business trip order forms Total 50 104 248 233 Note: The numbers include requests that were withdrawn or decided not to be disclosed, and those for non-existing documents. 3.3.(6) Auditing and related matters In addition to implementing audits through an external accounting firm in accordance with the system for incorporated administrative agencies and through the Agency’s Auditor, the Agency 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 2007, the Agency conducted internal audits on the management status of corporate documents in possession of the Agency, the status of bids and contracts, and the status of compliance with the rule restricting the employment of personnel from the private sector. 3.3.(7) Report on the financial standing To ensure the transparency of its expenditures, the Agency disclosed its financial standing, including the use of contributions and user fees from reviews, in government gazettes and on PMDA website. 3.3.(8) Official announcement of the plan for the review of optional contracts The Agency devised the Plan for the Review of Optional Contracts and publicized it on our website in December, 2007.

3.4 Personnel Issues 3.4.(1) Review of a personnel evaluation system According to the Mid-term target of the Agency, it is required to conduct proper personnel evaluation taking individual performance of full-time employees into consideration, and the Mid-term Plan of the Agency requests it to introduce a personnel evaluation system which enhances the morale of employees so that the results of the evaluation and the attainment of individual goals are properly reflected in remuneration, pay raise, and promotion. In line with the above, the Agency introduced the personnel evaluation system in April 2007 after conducting trials targeting at all full-time employees between April 2006 and September 2006. In order to ensure proper implementation of the personnel evaluation system, the Agency provided training courses for all employees, taking advantage of the personnel evaluation system as a subject of the training course for new recruits.

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3.4.(2) Systematic implementation of staff training In the operations for reviews, post-marketing safety measures, and relief service conducted by the Agency, an extremely high level of expertise is required. In addition, rapid strides are constantly in the advancement of scientific technology for developing pharmaceuticals and medical devices. Under such circumstances, it is necessary for the Agency to appropriately implement capacity development to enhance the level of expertise of the staff. Therefore, in FY 2007, the Agency revised the training policy on October 1, 2007 and reorganized the existing training course into two training courses: the general training course and the specialized training course. Consequently, employees can attend programs systematically. Furthermore, in order to provide efficient and effective training tailored to the abilities and standards of individual employees, the Agency actively deployed external institutions and experts, striving to reinforce training. The Agency also facilitated the participation of employees in academic conferences both at home and overseas to improve their knowledge and technological expertise. Specifically, the Training Committee formulated plans for beginner training, internal training, and external training based on the needs of each division. Various training programs, as introduced below, were implemented. (i)

(ii) (iii)

(iv)

(v)

(vi)

(vii)

The Agency conducted a training course for new recruits in April and October of 2007 and fully implemented new programs, which were referred to those of FDA, in October, 2007 after introducing the programs from April 2007 on a trial basis. The Agency dispatched an aggregate of 57 employees to universities both at home and overseas as well as foreign drug regulatory authorities for the purpose of training. As special training programs, the Agency also held 20 training sessions on technical issues, inviting experts belonging to domestic or foreign regulatory authorities, corporations, and universities. As general training, the Agency conducted basic business communication training in April and September 2007 and advanced business communication training in October, which was focused on addressing complaints. Moreover, the Agency also conducted e-learning training in IT literacy, communication training, business writing training, and finance training for career-track employees, deploying external institutions once for each training. As general training, the Agency conducted English conversation training between August and December 2007. The Agency also conducted TOEIC examinations in May and June 2007 and January 2008, for the purpose of assessing the effect of English conversation training as well as improving the linguistic ability of employees. The Agency conducted one training program aimed at acquiring basic knowledge on the protection of personal information. The Agency also conducted one training program, inviting lecturers from organizations of adverse drug reaction sufferers and organizations of patients. The training was intended to provide employees with the opportunity to listen to the requests to the Agency from respective standpoints. The Agency dispatched employees to technical training courses conducted by external institutions (e.g., training course for experts of pharmaceutical affairs, a visit to Showa University IRB)

The Agency provided new recruits with the opportunity to visit various facilities between June 2007 and January 2008: five plants where pharmaceuticals are manufactured, five where medical devices are manufactured, six medical institutions, one research institution, and the Japanese Red Cross Society. In addition, the status of participation in academic societies from each division were tracked and - 35 -

checked every fiscal quarter (1,023 participants in total as of the end of March 2008).

Human resource training and development Revised conventional training program fundamentally with reference to FDA’s training program and put into practice stepwise from the latter half of FY 2007.

Specialized training course

General training course

First year First year

Third year and onward

Second year Second year

Training course for mid-level employees

Training course for new recruits

Managerial staff Training course for managerial staff (management skill etc.)

General training course (communication skill, language, and so on.) Specialized training course (case study, medical writing)

Participation in international Training Associations such as the DIA (dispatching lecturers, attending a lecture). Dispatching of lecturers to universities

Visit to facilities (medical institutions which conduct clinical trials, factories of pharmaceuticals manufacture)

Special training course (discussion with experts invited from both Japan and overseas concerning latest technological topics) Active participation in academic conferences both in Japan and overseas and presentation at conferences

Mentor system

(with reference to FDA’s orientation mentoring program)

Training at external institutions in Japan (medical institutions, research institutions) Long-term training at overseas institutions (overseas reviews organization etc.)

3.4.(3) Appropriate personnel allocation To maintain the expertise of the staff members and operational continuity, the Agency aims to conduct appropriate personnel allocation. To achieve this target, the Agency conducted personnel allocation taking the knowledge and work experience of staff members into consideration. The Agency fundamentally avoids short-term rotation of personnel with the exception of cases such as health-related issues and special reasons related to operations. 3.4.(4) Securing human resources through open recruitment At the Agency, it is an important task to recruit, while paying due attention to the neutrality and fairness of the Agency, capable persons with professional expertise so that the Agency can conduct its operation of reviews and safety measures expeditiously and properly. According to the Mid-term plan before the revision made at the end of FY 2006, it was decided that although the number of permanent employees at the start of the Mid-term plan (April 2004) was 317, by the end of the Mid-term plan (March, 2009), it would be 346. The number of permanent employees in April 2007 was 341, and the number of permanent employees was almost reached as planned. On the other hand, as the Mid-term plan after the revision made at the end of FY 2006 set the number of permanent employees at the end of Mid-term plan is 484, the Agency was required to recruit capable persons based on the recruitment plan for each job category. Under such circumstances, the Agency conducted four times of open recruitment of technical permanent employees, in 2007, by utilizing our website as well as job information website and decided to recruit, formally or informally, as shown below. Note: Due to the revision of the Mid-term plan made at the end of FY 2006, the Agency plans to recruit 236 persons during the period of three years between FY 2007 and FY 2009 (58 persons in FY 2007, 80 persons in FY 2008, and 98 persons in FY 2009).

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Recruitment Activities (FY 2007) Schedule of briefing sessions on the Agency June: Two sessions in Tokyo (total participants, 131 persons) September: Two sessions in Tokyo and one in Osaka (total participants, 273 persons) December: Two sessions in Tokyo and one session in Osaka (total participants, 175 persons) March: One session in Tokyo and one session in Osaka (total participants, 51 persons) In-person visits to universities/hospitals by directors/employees and active approachs making use of opportunities at academic conferences The academic societies to be approached: The Japan Pediatric Society, the Japan College of Rheumatology, the Japanese Diabetes Society, the Pharmaceutical Society of Japan, the Japanese Joint Statistical Meeting, the Joint Medical Meeting of National Hospitals; requests to dispatch employees to the Agency from national centers, the National Hospital Organization, and core hospitals engaging in clinical trials; briefing at conferences for deans of medical faculties of national/public/private universities, university visits, lectures, and so on. Tools for recruitment activities Brochures for recruitment have been sent out to approximately 900 institutions including medical faculties of universities, medical institutions such as university hospitals, pharmacy faculties of universities, pharmacy departments of hospitals, faculties relevant to biostatistics and veterinary science, and research institutions. The brochures were also utilized at briefing sessions on the Agency. Renewal of websites and the production of a DVD introducing the Agency Posters for recruitment sent out to medical faculties of universities (80), distributed individually, and used in conjunction with other tools Information to be posted on job information websites (the websites NIKKEI NAVI and NIKKEI CAREER NET were chosen via a planning competition) Information to be posted on the following: Website presenting job offers for 2008 graduates (NIKKEI NAVI 2008) Pre-website presenting job offers for 2009 graduates (NIKKEI NAVI 2009—Special feature of pharmaceuticals/biotech industry) Website presenting job offers for 2009 new graduates (NIKKEI NAVI 2009) Website presenting job information for those seeking a career change (NIKKEI CAREER NET. For 1 month from September 7 and for 1 month from December 7) Recruitment advertising via academic journals The Japanese Biochemical Society (website), the Japanese Pharmacological Society (website), the Academy of Pharmaceutical Science and Technology, Japan (Journal of Pharmaceutical Science and Technology, Japan), the Japanese Society for the Study of Xenobiotics (Website), the Japanese Society of Clinical Pharmacology and Therapeutics (Clinical Pharmacology), the Japanese Society of Toxicology (website), the Pharmaceutical Society Japan (FARUMASHIA), the Journal of Japanese Society of Hospital Pharmacists, the Japan Medical Journal, the Nikkei Medical, Thorough study on Pharmaceuticals/biotech industry (job information journal for the postgraduates of pharmacy), the Japanese Joint Statistical Meeting (collected report of lectures), the Journal of Japanese Society of Pharmaceutical HealthCare and Sciences, Nature, and the 128th conference of the Pharmaceutical Society Japan (display advertising) Advertising via booth displays at academic conferences The 61st Joint Medical Conference of National Hospitals and the 128th conference of the Pharmaceutical Society Japan

- 37 -

Employment through Open Recruitment in FY 2007—as of April 1, 2008 1)

Technical employees (4 times of public recruitment) Number of applicants About 1,070 Number of employment 77 Number of prospective staff 74

2)

Administrative employees (twice of public recruitment) Number of applicants 190 Number of employment 14

Under extremely difficult circumstances for the recruitment of personnel who are qualified for GMP conformity audits and biostatistics, the Agency had set, with paying due attention to the fairness and transparency of the Agency, temporary exception to the Rule for operation concerning the restriction of employee’s engagement in jobs. However, since April 1, 2007, there was no recruit based on this exception until the revised Rule for operation concerning the restriction of employee’s engagement in jobs took effect (October 1, 2007). Numbers of the Agency’s Permanent Staff April 1, April 1, April 1, April 1, Numbers at the end of FY 2008 2005 2006 2007 (in the Mid-term plan) 2008 Total 256 291 319 341 426 484 Review divisions 154 178 197 206 277 Safety divisions 29 43 49 57 65 Notes 1. The expected number of the staff including executives at the beginning of the effective Mid-term period when the Agency was established, April 2004, was 317 (The number includes 11 staff members engaged in the R&D promotion service of the Agency). 2. The “Total” includes 6 executives, except for April 1, 2006, which includes 5 executives. 3. The “Total” as of April 1, 2004 includes 11 staff members engaged in the R&D promotion service. Before the service was transferred to the National Institute of Biomedical Innovation (NIBIO) in FY 2005, the planned total number at the end of the Mid-term plan (at the end of FY 2008) was 357. Before the Mid-term plan was revised at the end of FY 2006, the planned total number at the end of the Mid-term plan (at the end of FY 2008) was 346 4. The review divisions include the Director (Center for Product Evaluation), Associate Executive Director, Deputy Director, Associate Center Director, Office of Review Administration, Officse of New Drug I to IV, Office of Biologics I and II, Priority Reviews Director, Office of OTC/Generic Drugs, Office of Medical Devices, and Office of Conformity Audit (Office of New Drug IV was established on July 1, 2007 and the former Office of Biologics were divided into two on October 1, 2007). 5. The safety divisions consist of the Chief Safety Officer, Office of Safety, and Office of Compliance and Standards. April 1, 2004

3.4.(5) Appropriate personnel management based on work regulations The Agency is careful in conducting appropriate personnel management so that suspicions about inappropriate ties with pharmaceutical companies do not arise, by imposing certain restraints on recruitment and allocation of executives and employees as well as on reemployment after retirement from the Agency. For this purpose, the Agency conducts appropriate personnel management by prescribing, in the work regulations, restrictions for newly-employed staff members regarding the submission of a written oath, personnel allocation and reemployment after retirement, as well as work restrictions for employees whose family members work in the pharmaceutical industry. The Agency also strives to keep its staff

- 38 -

members informed of these regulations. More specifically, the Agency created summaries and a Q & A list concerning relevant regulations, and makes sure to keep the staff informed through the intranet and during beginner training. In addition, from the perspective of further informing the staff about service-related regulations, the Agency has created a handbook that includes service disciplines that should be followed by the staff and a Q & A list, and has distributed this handbook to all of the staff members.

3.5 Ensuring Security 3.5.(1) Management of entries and exits To ensure security and protect confidential information, the Agency has installed entrance/exit control equipment for each office to reinforce the internal security control system. Specifically, by introducing a security control system where access to each office is limited only to staff members through using unique ID cards and by recording the history of when each staff member enters or leaves each office, outsiders are not able to enter the rooms unaccompanied. In order to ensure further strict access control, the Agency has also prescribed restrictions on the entrance/exit control relating to operational management of the security control system, and has made maximum efforts to inform staff members about these restrictions through the intranet and during beginner training. 3.5.(2) Security measures for information systems Based on the FY 2007 plan, the Agency has strived to ensure the security of the information relating to information systems. By abolishing the Information Security Policy and amending the Information Management/Use Policy, the Agency established a security structure headed by CIO and consisted of owners of each system. In order to reinforce the backup function of information data, the Agency selected a storing company through competitive bids and commenced storing back-up data of information systems at remote locations in January 2008. In order to spread the use of secure e-mail to the services of medical device reviews, clinical trial consultations, and quality management, the Agency revised relevant policies and notified relevant institutions to that effect on March 31, 2008 so that the use of secure e-mail in relation to those services became available from FY 2008. Numbers of Users/Issued Certificates Using the Secure e-mail System as of the End of March 2008 Number of registered companies Number of issued certificates Outside the Agency 43 218 Within the Agency 223 Note: The numbers of registered companies and issued certificates as of the end of March 2008.

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PART 4

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

4.1 Relief Fund Services To widely inform the public on the Adverse Drug Reaction Relief System and the Relief System for Infections derived from Biological Products (hereinafter collectively referred to as “relief systems”), and to operate these relief systems appropriately, the Agency, through relief fund services, takes the following measures to provide adequate and prompt relief for those suffering from adverse drug reactions and infections derived from biological products. 4.1.(1) Expansion and reconsideration of the provision of Information (iv) Disclosure of cases of payment of benefits on the website To enrich the contents of the provision of information relating to the relief systems and to make the administration of the systems more transparent, the Agency plans to disclose information about actual performance of operations achieved in FY 2007 on PMDA website. In addition, the Agency has finished posting cases of approval/rejection up to the fourth quarter of FY 2006 on the website with due consideration to protecting personal information. The Agency also plans to provide information on cases in and after FY 2007 successively on the website. Cases of approval/rejection: http://pmda.go.jp/kenkouhigai/help/information2.html (v) Improvement of brochures, etc. Improvements were made to brochures and instruction manuals about applying for relief benefit payments so that the contents can be easily used and understood by doctors and patients. To reduce the amount of time required for administrative processing because of incomplete applications, and to make operations more efficient, the Agency carried out the following: a) Prepared and distributed brochures describing the relief systems in an understandable manner, and also posted the brochures on PMDA website (in PDF format) together with animations summarizing the brochure. b) Prepared an application sample and made improvements so that patients, etc., could fill out the forms more easily. c) Applications, which used to be mailed upon request, are now available for download on PMDA website, and the URL from which applications can be downloaded are included in brochures for easier use. Application forms are available at: http://search.pmda.go.jp/fukusayo_dl/ 4.1.(2) Active implementation of public relations activities To widely inform the public of the relief systems, the Agency reviewed methods for effective publicity and carried out the following: (i)

Publicity through a brochure entitled “Do You Know about Relief Systems?” explaining the relief systems in an understandable manner (this brochure is included in magazines published by the Japan Medical Association and the Japan Pharmaceutical Association; the brochure is also distributed on PMDA website in the form of an abridged animation version and a full-text PDF version), publicity via the Internet (banner advertisement on four websites aimed exclusively at

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(ii) (iii) (iv)

(v)

(vi)

medical professionals, keyword-linked advertisements on seven general websites, and promotion on So-net m3, a site aimed at doctors), and publicity by Prefectural Governments. Publicity on the infection relief system in six specialized magazines and publicity on commissioned payment services for HIV-positive patients, etc., in five specialized magazines Introduction of the relief systems in four programs and abstract journals of the Japan Municipal Hospital Association and other associations Participation in medical conventions (e.g., General Assembly of the Japanese Dermatological Association, the Spring Meeting of the Japanese Society of Allergology, the general assembly of the East Japan Branch of the Japan Society of Chemotherapy) and distribution of brochures about and presentations on the relief systems at 10 different events Explanation of the relief systems at seven different domestic medical institutions, workshops for vaccination specialists, the general assembly of the Society of National Hospital Pharmacists, and the Tokyo Transfusion Therapy Workshop Implementation of publicity for the 21st Annual Meeting of the Japanese Society for AIDS Research, such as through poster displays, articles in journals, and distribution of materials relating to the relief systems overall.

With the help of concerned bodies, the following were carried out as individual PR activities: (i)

Publicity in a magazine on drug safety updates (DSU) published by the Federation of Pharmaceutical Manufacturers’ Association of Japan and distribution of these magazines to all medical institutions (ii) Distribution of the brochure introducing the system to pharmacies by the Japan Pharmaceutical Association (iii) Distribution of the brochures introducing the relief systems to medical institutions by the Japanese Red Cross Society Blood Center (iv) Introduction of the relief systems in the drug handbook published by the Japan Pharmaceuticals Association. Publicity through the Brochure

- 41 -

To convey the concepts of the relief systems in an understandable manner to healthcare professionals, the brochure titled “Do You Know about Relief Systems?” (8 pages in total including the cover) and posters were distributed as attachments to the Japan Medical Association (about 150,000 copies) and Japan Pharmaceutical Association journals (about 100,000 copies). In addition, animations summarizing the brochure (14 minutes) and the brochure itself (in PDF format) were made available on PMDA website. 4.1.(3) Expansion of the consultation service In the FY 2007 plan, the Agency’s goal is to increase the number of consultations and accesses to PMDA website, both by 20% in comparison to FY 2003, but the actual number of consultations in FY 2007 increased by 36% as compared to FY 2003. This was due to the creation of a brochure understandably explaining the relief systems, publicity from enclosing copies of the brochure with magazines published by Japan Medical Association and Japan Pharmaceutical Association, publication of animations summarizing this brochure on PMDA website, and publicity via the Internet. Also, the number of accesses to PMDA website in FY 2007 increased by 79% as compared to FY 2003. Moreover, after five months of publicity through the Internet and prefectural governments’ websites, there were 101,720 accesses to the web pages used exclusively for publicity and containing overviews of the relief systems.

Fiscal Year

FY 2003

FY 2004

FY 2005

FY 2006

FY 2007

Number of consultations Number of web accesses

5,338 35,726

3,911 41,947

4,307 37,655

6,427 51,810

7,257 63,843

Toll-free number: 0120-149-931 Phone: 03-3506-9411 e-mail for relief system consultation: [email protected]

- 42 -

Compared with FY 2003 36% increase 79% increase

Number of Consultations 70,000 63,843

60,000 51,810

50,000 Number of consultations

41,947

40,000

37,655

35,726

Number of accesses to the w ebsite

30,000 20,000 10,000 5,338

0

FY 2003

6,427 3,911

FY 2004

7,257

4,307

FY 2005

FY 2006

FY 2007

4.1.(4) Central management of information through databases To make operations more efficient and swift, the Agency checks and properly understands the progress and accumulates data on the relief benefit services for adverse drug reactions and relief benefit services for infections (particularly information related to offending drugs and names of illnesses from adverse drug reactions). Further, in August 2007, it completed the first phase of the development of the Integration and Analysis System for Databases on Relief Benefit Services that can analyze the accumulated data from various angles and utilize them for service standardization. 4.1.(5) Prompt processing of relief benfit claims In order to conduct prompt administrative processing of relief benefit services, the Agency investigates and organizes the facts given in the contents of claims upon receiving a claim for relief benefit services, 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: i) ii) iii)

Fact-finding investigations, etc., of the relevant incident included in the claim Creation of a summary chart tracing the case over time Creation of investigation reports.

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Flow of Adverse Health Effect Relief Services Pharmaceutical Affairs and Food Sanitation Council (PAFSC), MHLW Dual Judgment Committee on Adverse Health Effect is held 6 times a year Request for judgment (Investigation report)

Pharmaceuticals and Medical Devices Agency (PMDA)

Claim for benefits Request for claim data Submission of claim data Payment of benefits

Submission of claim data

Request for claim data

Issue of medical certificate

Request for issue of medical certificate

Claimants for Benefits (Adverse health effect sufferers)

Request for claim data

Notice of judgment

(1) Improvement in quality of investigation reports through preliminary survey and discussion with outside experts (2) Promotion of operational efficiency by developing database system (3) Dissemination of the relief service by improving its information service and publicity

Submission of claim data

Medical Institutions

Payment of Relief Benefit

Cases

Unit: Million yen

1,000

1,800

900

1,600

# of claims accepted

800 700

# of newly paid cases

600

Amount of payment

1,400 1,200 1,000

500

800

400

600

300 200

400

100

200

0 80

82

84

86

88

90

92

94

96

98

00

02

04

06

0 Year

FY 2007 Relief services for adverse drug reactions → Number of applications: 908 Number of cases of approval/rejection: 855 (of which 718 were judged approved) Relief services for infections → Number of applications: 9 Number of cases of approval/rejection: 5 (of which 3 were judged approved)

The Agency also sets the time period for standard administrative processing of claims from when they are submitted until approval or rejection judgments are made (including the time required for a medical and pharmaceutical judgment to be made by MHLW) at 8 months. Through collaborations with MHLW, the Agency plans to process applications for benefits smoothly and completing judgments within the standard administrative processing time for 60% or more of the cases filed in FY 2008, which is the last year of the effective period for the Mid-term targets. The Agency and MHLW worked together to develop a system for sharing the paperwork for medical and pharmaceutical judgment and decided to allocate 2 months to MHLW and 6 months to the

- 44 -

Agency (excluding the time periods when administrative processing is not possible because of additional or supplementary documents and investigations are required of claimants or medical institutes) and established a scheme wherein a list of pending matters is periodically prepared to determine the appropriate management of the processing time for paperwork. The achievement rate for FY 2007 was 74.2%, 8.9 point increase from 65.3% in FY 2006, as a result of the intensive processing of paperwork. (vi) Adverse drug reaction relief services The Agency implements payment of 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 illnesses, disabilities, and deaths that occurred on and after May 1, 1980, caused by ADRs even though pharmaceuticals were used properly. a.

Actual performance of adverse drug reaction relief The actual performance for FY 2007 is shown below: Fiscal Year FY 2003 FY 2004 FY 2005 FY 2006 FY 2007 Number of claims 793 769 760 788 908 Number of judged cases 566 633 1,035 845 855 Approved 465 513 836 676 718 Rejected 99 119 195 169 135 Withdrawn 2 1 4 0 2 Cases in progress* 820 956 681 624 677 † Achievement rate 17.6% 14.5% 12.7% 65.3% 74.2% Median processing time 10.6 months 12.4 months 11.2 months 6.6 months 6.4 months * The numbers obtained at the end of each fiscal year. † The percentages of the cases judged within 8 months of the standard administrative processing time out of the total number of the cases judged during the fiscal year. b.

Number of claims by type of benefits The numbers of claimants filed in FY 2007 by type of benefits are shown below:

Types of Benefits

Fiscal Year FY 2003 Number of claims 793 Medical expenses 640 Medical allowances 683 Disability pensions 68 Pension for raising handicapped 9 children Bereaved family pensions 56 Lump-sum benefits for bereaved 42 families Funeral expenses 98 Note: A claim could include more than one kind of benefits.

- 45 -

FY 2004 769 613 650 73

FY 2005 760 602 659 78

FY 2006 788 643 694 60

(Cases) FY 2007 908 730 786 70

14

5

14

10

54

41

31

33

47

48

51

72

101

84

88

105

c.

Judgment status according to types of benefits The status of judgments made in FY 2007 by type of benefits is shown below: (Thousand yen) FY 2003 Number of cases

Types Medical expenses Medical allowances Disability pensions Pension for raising handicapped children Bereaved family pensions Lump-sum benefits for bereaved families Funeral expenses Total

Amount of payment

FY 2004 Number of cases

FY 2005

Amount of payment

Number of cases

Amount of payment

FY 2006 Number of cases

Amount of payment

FY 2007 Number of cases

Amount of payment

367 408 22

34,813 35,388 552,869

448 472 24

51,722 42,711 592,028

717 757 33

78,527 70,073 653,143

572 624 35

67,502 60,034 692,446

603 651 42

67,603 62,668 730,007

2

16,991

4

17,810

17

40,639

6

30,131

7

35,760

32

335,829

31

412,167

44

502,468

22

493,010

20

501,454

30

217,148

19

137,041

32

228,708

34

229,446

39

286,373

61

11,205

48

9,167

74

14,010

53

10,386

63

12,661

922 1,204,243

1,046 1,262,647

1,674 1,587,567

1,346 1,582,956

1,425 1,696,525

Note 1: “Number of cases” means judged cases. “Amount of payment” means benefits paid for both new and continuing cases. Note 2: The amount of money was rounded off to the nearest thousand yen. Therefore, the total of the values does not necessarily match the sum of individual values.

(vii) Infections derived from biological products relief The Agency implements payment of 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 illnesses, disabilities, and deaths that occurred on and after April 1, 2004, caused by infections even though biological products* were used properly. * Biological products refer to pharmaceuticals, quasi-drugs, cosmetics, or medical devices that are manufactured using materials or ingredients derived from human beings or other living matter (excluding plants), which are designated as special products requiring extreme caution from the perspective of health care by the Minister of Health, Labour and Welfare upon hearing opinions from the Pharmaceutical Affairs and Food Sanitation Council. a.

Actual performance of relief for infections The actual performance for FY 2007 is shown below: Fiscal Year FY 2004 FY 2005 FY 2006 FY 2007 Number of claims 5 5 6 9 Number of judgments 2 6 7 5 Approved 2 3 7 3 Rejected 0 3 0 2 Withdrawn 0 0 0 0 Cases in progress* 3 2 1 5 Achievement rate† 100.0% 50.0% 100.0% 100.0% Median processing time 3.0 months 5.6 months 3.8 months 3.8 months * The numbers obtained at the end of each fiscal year. † The percentages of the cases judged within 8 months of the standard administrative processing time out of the total number of the cases judged during the fiscal year.

- 46 -

b.

Number of claims by type of benefits The numbers of claims filed in FY 2007 by type of benefits are shown below. FY 2006 6 5 5 0

Types of benefits

Fiscal Year FY 2004 FY 2005 Number of claims 5 5 Medical expenses 5 5 Medical allowances 5 5 Disability pensions 0 0 Pension for raising handicapped 0 0 children Bereaved family pensions 0 0 Lump-sum benefits for bereaved 1 0 families Funeral expenses 1 0 Note: A claim could include the payment of more than one benefit.

c.

(Cases) FY 2007 9 7 8 1

0

0

1

0

0

0

1

0

Judgment status by type of benefits The status of judgments made in FY 2007 by type of benefit is shown below: (Thousand yen) FY 2004

Type of benefits Medical expenses Medical allowances Disability pensions Pension for raising handicapped children Bereaved family pensions Lump-sum benefits for bereaved families Funeral expenses Total

FY 2005

FY 2006

FY 2007

Number of cases

Amount of payment

Number of cases

Amount of payment

Number of cases

Amount of payment

Number of cases

Amount of payment

2 2 —

161 142 —

3 3 —

475 249 —

6 6 —

473 497 —

3 3 —

102 352 —

























1

1,387



2,378

























1

199





4

302

6

724

14

2,556

6

2,833

Note: The amount of money was rounded off to the nearest thousand yen. Therefore, the total of the values does not necessarily match the sum of values.

4.1.(6) Promotion of appropriate communication of information through collaboration between divisions To plan for collaboration between divisions within the Agency, information on judged cases relating to eligibility for relief benefits for adverse drug reactions and relief benefits for infections in FY 2007 was provided to the Office of Safety after excluding personal information. 4.1.(7) Surveys on actual status of effects from adverse drug reactions (investigative research as part of health and welfare services) As it is deemed necessary for operations other than payments for relief benefits to be conducted in order to plan for prompt relief of adverse health effects stemming from adverse drug reactions, the Agency implements health and welfare services for sufferers from adverse health effects (Article 15, Paragraph 1, Item 1-b of the Law for the Pharmaceuticals and Medical Devices Agency). Investigative Research for Improvements in QOL of Sufferers of Severe and Rare Adverse Health Effects Caused by Pharmaceuticals

- 47 -

As part of health and welfare services, the Agency established an Investigative Research Team for Improvements in the Quality of Life of Sufferers from Severe and Rare Adverse Health Effects Caused by Pharmaceuticals in April 2006 based on the results of a survey (March, 2007) on the actual condition of adverse health effects stemming from adverse drug reactions conducted in FY 2005, and initiated investigative research to obtain materials for reviewing the ideal way to provide required services and measures for improving the QOL of sufferers from severe and rare adverse health effects for which general measures for disabled people do not necessarily provide sufficient support. The reports on the Investigative Research were provided by the leaders of the Investigative Research Team on November 14, 2007, and were publicly announced on the website after disclosure to the Relief Committee session held on December 13, 2007. Contents of the Research The Agency 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 (60 volunteers in FY 2007). Investigative Research Team Leader Kazuaki Miyata Takao Takahashi Kazuo Tsubota Chieko Matsunaga

President of Nihon Fukushi University Professor, School of Medicine, Keio University (Department of Pediatrics) Professor, School of Medicine, Keio University (Department of Ophthalmology) Independent Administrative Agency National Center for Persons with Severe Intellectual Disabilities, Nozominosono Senior Researcher

4.1.(8) Appropriate implementation of healthcare allowances for sMON patients and HIV-positive patients affected through blood products In order to appropriately provide healthcare allowances, etc., for SMON patients and HIV-positive patients affected through blood products, the Agency implemented appropriate operations based on the contents of consignment contracts, giving due consideration to the confidentiality of personal information. Services for SMON patients (healthcare allowances) The Agency provides healthcare allowances and nursing care allowances for SMON patients for whom a settlement has been reached in court. In FY 2007, the number of patients receiving such allowances was 2,269, and the total amount of payments was 1.601 billion yen. Fiscal Year Number of recipients

FY 2003 2,713

FY 2004 2,598

FY 2005 2,504

FY 2006 2,381

FY 2007 2,269

Amount paid (thousand yen) 1,901,829 1,829,332 1,757,774 1,683,500 1,601,134 Healthcare allowance 1,417,469 1,359,056 1,305,168 1,251,622 1,191,245 Nursing allowance 349,933 342,357 330,086 315,027 299,108 (from companies) Nursing allowance 134,427 127,920 122,520 116,850 110,781 (from the government) Note: Since the numbers are rounded off to the nearest thousand yen, the amount paid does not always match the sum of the amounts for the breakdown categories. Breakdown

(i)

- 48 -

Amount (Million yen)

Payment of Healthcare Allowance to SMON patients # of recipients 4,000

3,000 2,500

3,000 2,000 2,000

1,500 1,000

1,000 500 0

0 98

99

00

01

02

03

He althcare allowance Nursing allowance (from companies)

04

05

06

07

Year

Nursing allowance (from g overnmen t) Number of recipients

(ii) AIDS-related services (healthcare allowances) The Agency provides the three services below for HIV-positive patients afected through blood products. Of the HIV-positive patients who received benefits in FY 2007, 604 patients received allowances relating to investigative research, 117 patients received allowances for healthcare support services and 3 patients received healthcare allowances. The total number of patients receiving allowances was 724 patients, and the total amount of payments was 561 million yen. a. Payment of healthcare allowances for HIV-positive patients, as services for investigative research. b. Payment of healthcare allowances for AIDS patients for whom a settlement has been reached in court, as healthcare support services. c. Payment of special allowances, etc., for AIDS patients for whom a settlement has not been reached in court, as healthcare allowances. Year

Relief Services for HIV Positive Patients Infected through Blood Products # of recipients

Cases 1,200

1,200

1,000

1,000

Investigative research Healthcare support services

800

800

600

600

400

400

Healthcare allowance

200

200

# of recipients

0

0 98

99

00

01

02

03

04

- 49 -

05

06

07

Year

FY 2003 FY 2004 FY 2005 FY 2006 FY 2007 Amount of Amount of Amount of Amount of Amount of Number of payment Number of payment Number of payment Number of payment Number of payment Recipients (Thousand Recipients (Thousand Recipients (Thousand Recipients (Thousand Recipients (Thousand yen) yen) yen) yen) yen)

Fiscal Year

Investigative research Healthcare support services Healthcare allowance Total

662

355,343

647

348,446

638

341,017

618

334,653

604

327,857

127

221,400

124

210,600

121

210,300

120

210,000

117

224,796

3

8,733

3

8,706

3

8,706

3

8,678

3

8,084

789

576,477

772

567,752

762

560,023

741

553,331

724

560,737

4.1.(9) Appropriate implementation of the service of the payment of benefits to assist the individuals affected by hepatitis C through specified fibrinogen products and specified blood coagulation factor IX products contaminated by hepatitis C virus The Agency also started the service of providing benefits to individuals affected by hepatitis C according to the Law on Special Measures concerning the Payment of Benefits to Assist the 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 108, with ¥2,360 million as the total amount paid in FY 2007.

4.2 Reviews and Related Services/Safety Measures To enable for the public to safely use pharmaceuticals and medical devices that have international standards, through reviews and related services and safety measures, the Agency is required to provide better pharmaceuticals and medical devices to clinical practice settings faster and with greater safety, ensure that pharmaceuticals and medical devices are used properly, prevent health hazards, and respond appropriately and promptly if hazards should occur, so that pharmaceuticals and medical devices can fulfill their purpose over a longer period of time. Therefore, the Agency has taken the following operations to reinforce the systems for consultation/review and post-marketing safety measures, and to organically link the operations to achieve the Mid-term targets and FY 2007 plan. 4.2.(1) Faster access to the latest pharmaceuticals and medical devices (iii) Ensuring the benefits of pharmaceuticals and medical devices for the public and healthcare professionals The Agency is required to ensure that the public and healthcare professionals enjoy the benefits of the latest and safe pharmaceuticals and medical devices promptly and to the fullest extent, and to ensure that pharmaceutical companies benefit from this prompter access. a.

Implementation structure for clinical trial consultations and reviews The review system for pharmaceuticals and medical devices has improved significantly since 1997. In 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) was founded while leaving the authority for approval and final judgment on pharmaceuticals and medical devices to the Ministry of Health, Labour and Welfare (MHLW), allowing consolidation of review functions. By taking the following kinds of measures, further improvements in the system were able to be planned. 1) In order to provide consistency across the operations and improve their efficiency, a new incorporated administrative agency, the Pharmaceuticals and Medical Devices Agency

- 50 -

2) 3)

4)

(PMDA), was established through the integration of three separate organizations responsible for reviews and related services. The Agency decided to greatly increase the number of its staff by about 100, including reviewers, within the effective period for the Mid-term targets. Under the new system of the Agency, the entire review process from consultations regarding clinical trials until review operations is conducted by the same team with the same staff members for consistency and coordination. (As consultations on clinical trials and review operations were done by different organizations and different staff members under the previous system, there were discrepancies in opinions and policies between the different parties.) To respond to new needs in the future, the Agency is reinforcing its functions for reviewing medical devices, as well as enhancing reviews of biological and biotechnologyderived products.

- 51 -

Review System

(Consolidated Structure of Consultation and Review Team)

Approval

Applicant

Conformity Audit etc.

Advice MHLW (Ministry of Health, Labour Consultation and Welfare)

Clinical trial consultation Application for approval Inquiries/ Guidance Response

Review Report

Pharmaceuticals and Medical Devices Agency (PMDA) CT Consultation & Review (Review Team)

Expert Discussion on Review

Outside experts

- 52 -

Pharmaceutical Affairs and Food Sanitation Council

Actual Results of Review Services in FY 2007 Reviews: Pharmaceuticals (i) Number of Expert Discussions conducted: 231 (182 in written form, 49 through meetings) (ii) Applications discussed at the Drug Committees (PAFSC): 51 Review reports made to the Drug Committees (PAFSC): 29 Medical devices and in vitro diagnostics (i) Number of Expert Discussions conducted: 115 (98 in written form, 17 through meetings) (ii) Applications discussed at the Drug Committees (PAFSC): 10 Review reports made to the Drug Committees (PAFSC): 71 (60 cases for medical devices, 11 cases for in vitro diagnostics)

Reviews of new drugs were conducted by review teams consisting of experts under the guidance of an office director and a review director. In most cases, the team members had academic degrees in pharmaceutical science, medicine, veterinary medicine, biostatistics, or other specialized courses. The review team is fundamentally comprised of team leader(s), deputy team leader(s), and reviewers specialized in quality, toxicity, pharmacology, pharmacokinetics, clinical medicine, and biostatistics. Similarly, under the guidance of an office director and a review director, reviews of new medical devices were conducted by review teams consisting of experts who usually have academic degrees in engineering, pharmacology, medicine, dentistry, veterinary medicine, statistics, etc. The review team is fundamentally comprised of team leader(s), and reviewers specialized in biological evaluations, physicochemical/physical property evaluations, and clinical evaluations. Organization Chart for Reviews Structure of a Review Team for New Drugs

Office Director Review Director (Review Team)

(Review Team)

Team Leader

2 Team Leaders (Review/Consultation)

Pharmaceutical Science

Veterinary Science

Biostatistics

Medical Sciences

Specification/ Stability

Pharmacology

Pharmacokinetics

Toxicity

Clinical Medicine

Biostatistics

1 reviewer

1 reviewer

1 reviewer

2 reviewers

2 reviewers

1 reviewer

Veterinary Science

Medical Science

Biostatistics

Pharmaceutical Science

- 53 -

Structure of a Review Team for New Medical Devices Office Director

Review Director

(Review Team)

(Review Team)

Team Leader

Team Leader (Review/Consultation)

Pharmaceutical Science (Science)

Engineering

Medical Sciences (Dentistry, Biostatistics)

Biological Evaluation

Physicochemical Evaluation, Physical Property Evaluation

Clinical Evaluation

1 reviewer

2 reviewers

1 reviewer

Pharmaceutical Science, Science

Material, Electrical, and Mechanical, Optics

Medical Sciences, Dentistry, Biostatistics

Reviews of new drugs were implemented upon establishing a dedicated office and team to each therapeutic category as shown below:

Therapeutic Categories in the Offices of New Drugs Name Category 1 Office of New Drug I

Category 4 Anti-cancer drugs Anti-AIDS drugs Category 2

Office of New Drug II

Category 5 Radiopharmaceuticals In vivo diagnostics

Office of New Drug III Office of New Drug IV Office of Biologics I Office of Biologics II

Category 3 Category 6-1 Category 6-2 Blood products Biotechnological products Biological products Cellular and tissuederived products

Therapeutic Category Gastrointestinal drugs, dermatologic medicines Antibacterial agents, vermifuge, antifungal agents, antiviral agents except anti-HIV agents Antineoplastic drugs Anti-HIV agents Cardiovascular drugs, antiparkinsonian drugs, antithrombotics, antiAlzheimer’s drugs Reproductive system drugs, drugs for urogenital system, combination drugs Radiopharmaceuticals Contrast media Central/peripheral nervous system drugs, sensory organ drugs (except drugs classified in Category 6-1), narcotics Respiratory tract drugs, anti-allergy drugs for internal use, sensory organ drugs for inflammatory diseases Hormone drugs, drugs for metabolic disorders (including diabetes mellitus, osteoporosis, gout, and inborn errors of metabolism) Blood coagulation factor products, Gene therapy, Cartagena Protocol Antibody products Vaccines, antitoxic serum Cell therapy products

- 54 -

Review of new medical devices were implemented upon establishing a team to each therapeutic category as shown below: Therapeutic Categories in the Office of Medical Devices Therapeutic Category Category 1 Mainly for ophthalmology and otorhinolaryngology Category 2 Mainly for dentistry Mainly for cerebral, cardiovascular, respiratory, and psychoneurologic (materials) Category 3-1 areas (intervention devices) Mainly for cerebral, cardiovascular, respiratory, and psychoneurologic (materials) Category 3-2 areas (excluding intervention devices) Category 4 Mainly for cerebral, cardiovascular, respiratory, psychoneurologic (mechanical) Category 5 Mainly for gastrointestinal and urinary systems, obstetrics and gynecology Category 6 Mainly for orthopedic surgery, plastic surgery, dermatology Category 7 Mainly for laboratory tests (in vitro diagnostics) Mainly for multicategory medical devices, advanced electronic medical devices, Category 8 other uncategorized medical devices

The Agency conducted face-to-face consultations on clinical trials for new drugs based on the team-reviewed guidance plan made by the Review Director as well as the Chief Reviewer and the Deputy Reviewer in charge, who were appointed from a review team. The Agency conducted face-to-face consultations on new medical devices based on the team-reviewed guidance plan made by the Review Director as well as the Chief Reviewer and the Deputy Reviewer in charge, who were appointed from a review team. b.

Comprehension of the needs of the public and healthcare professionals

The Agency has actively exchanged opinions with healthcare professionals by participating in academic societies, etc., both in Japan and overseas, to comprehend their needs. Note: A total of 664 PMDA staff members participated in 296 domestic and international academic societies and seminars.

In order to periodically grasp the needs of academic societies and patients regarding pharmaceuticals approved in Europe and the U.S. but not yet in Japan, the Investigative Panel Study Group on the Problems Concerning Use of Unapproved Drugs (chaired by Dr. Tomomitsu Hotta, Director of National Hospital Organization Nagoya Medical Center) has been conducting investigations ever since its establishment under MHLW in January 2005. The Agency has applied results from investigations conducted by this panel when providing consultations on clinical trials and review applications. In FY 2007, in order to promote development and speed up approval reviews by providing detailed advice that meets various needs at each stage, the clinical trial consultations on medical devices and in vitro disgnostics were improved to provide specific advice for each development stage of medical devices.

- 55 -

Expansion of the consultation menu by development stage

Pre-application consultation

Preparation of application documents Pre-application consultation

Confirmatory clinical trials Clinical trial consultation

Application preparation

Application procedures consultation

Exploratory clinical trials

Consideration of the need for clinical trials Clinical evaluation consultation

Consultation classification before revision (2)

Clinical trials

Exploratory clinical trial consultation

Performance testing

Electrical stability testing

Stability testing

Biological safety testing

Safety consultation

Performance testing consultation

After revision (9)

Non-clinical tests

Quality consultation

Pre-development consultation

Market and literature research

Predevelopment

Clinical trial consultation

Note: In addition to the consultation menu in the above diagram, other menu items such as additional consultation are also available.

For pharmaceuticals that use cellular tissue and that are developed with state-of-the-art technology such as pharmacogenomics and regenerative medicine, there is an extremely high need for advice on product development and approval application, as there are only a few precedents for development. In order to respond to these needs, the Agency established new categories for consultations on preparation of documents for pharmaceuticals using cellular tissue in 2007. (iv) Efforts for efficient and prompt reviews

With changes made to the Mid-term plan in response to the recommendations of the Council for Science and Technology Policy, the Agency decided to reduce the drug lag by 2.5 years (consisting of 1.5 years for development and 1.0 year for approval review) by FY 2011. To achieve this goal, measures are being taken, including i) increasing the number of personnel involved in the review process, ii) improving training, iii) reducing the development period by significant expansion of and improvement in consultation, iv) reinforcing and improving the transparency of the progress management of reviews, v) responding to international joint clinical trials and stateof-the-art technology, vi) clarifying review standards, vii) developing guidance toward the introduction of a system of preliminary review, and viii) a trial operation of a project management system. a.

Increasing personnel

A total of 236 employees are to be hired in the three years to FY 2009. In FY 2007,

- 56 -

applications were accepted four times on a routine basis. According to the recruitment results of FY 2007, 151 out of some 1,070 applicants were informally accepted (including 77 who were finally employed) and hired in technical positions. To increase the number of applicants, the Agency employed various measures including the holding of briefings to explain the services, visits by executives and employees to universities and hospitals, strengthened announcement of recruitment at academic meetings, revision of job posting brochures and webpages, placement of job postings on job information websites, and placement of job postings in academic journals (see 3.4.(4) Securing Human Resources through Open Recruitment). b.

Improvements in training

In April 2007, the Agency started a new training program on a trial basis that includes case studies, mainly at the Offices of New Drugs. Based on the lessons learned from the trial operation, the Agency launched the new training program on a full scale in October 2007. A mentoring system was also put in place to reinforce duty coaching, and the trial operation of the system began in October 2007. c.

Reducing the development period through large-scale improvements in consultation

In FY 2008, the Agency plans to develop a guidance system for the implementation of a new consultation and review system. The objectives of this new system are to substantially increase the number of consultations that are accepted, and to reduce the waiting time for consultations. Other efforts that will begin in FY 2009 include improvements to the consultation menu and the introduction of a consultation and review system including a preliminary evaluation of application descriptions. The Agency plans to increase the total number of consultations per year up to 1,200 for FY 2011. The number of consultations in FY 2007 was 281 (the target was 280) and 21 consultations were withdrawn. The average number of consultations per ingredient related to submitted items in FY 2007 was 2.0 relative to the target of 2.0. A working group (WG) assigned to handle technical matters pertaining to clinical consultation was established jointly with the Japan Pharmaceutical Manufacturers Association (JPMA), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This WG began reviews of actions to ensure large-scale improvements in consultation services, such as the abolition of the point system and improvements in the consultation menu with the intention of reducing the waiting time. As a result, a notification on improvement in the schedule adjustment method was issued on March 3, 2007. d.

Reinforcement and improvements in the transparency of the progress management of reviews

It was decided that by FY 2011 the median total review time for standard review items submitted for application in and after FY 2004 was to be 12 months (9 months for administration and 3 months for the applicant). The median total review time for priority items was to be 9 months (6 months for administration and 3 months for the applicant). The FY 2007 target for this goal was a median total review time of 21 months (13 months for

- 57 -

administration and 8 months for the applicant) for standard review items, and a median total review time of 12 months (6 for administration and 6 for the applicant) for priority review items. The median total review times for new drugs approved in FY 2007 are as follows: Median Total Review Time for New Drugs for which Applications Were Filed for Approval and Approved after FY 2004 FY 2005 FY 2006 FY 2007 20.7 months Total review time 18.1 months 20.3 months (29.5 months) Administrative review 12.9 months Standard 10.3 months 12.8 months time (17.7 months) review items 7.9 months Applicant review time 7.2 months 6.9 months (11.2 months) No. of applications 15 29 53 12.3 months Total review time 4.9 months 13.7 months (19.4 months) Administrative review 4.9 months Priority 2.8 months 6.4 months time (7.7 months) review items 6.5 months Applicant review time 2.2 months 6.0 months (12.0 months) No. of applications 9 20 20 Note: Values in parentheses are 80% of the reference values. Median Administrative TC Metrics for Standard Review From first From inquiries From application to consultation to about important first consultation inquiries about matters to Expert important matters Discussion 5.9 months 0.7 months 2.1 months FY 2007 (10.7 months) (1.4 months) (2.6 months) 50 48 44 Note: Values in parentheses are 80% of the reference values.

From Expert Discussion to approval 2.3 months (3.2 months) 51

The review time was slightly increased for standard items compared with that in FY 2006. This is because in FY 2006, the reviewers focused particularly on what are called “stockpiled items,” or applications submitted in and before FY 2003, and almost all of these reviews were completed. In FY 2007, the reviewers focused on items submitted in the fiscal year (FY 2004) when the Agency was established and almost all of these reviews were completed. The number of approvals in FY 2007 totaled 81, representing a small increase from the 77 approvals in FY 2006. e.

Responses to multi-national clinical trials, state-of-the-art technology, etc.

The Agency formulated a document titled “Basic Concept on Global Clinical Trials,” received public comments, and issued the document as a notification of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated September 28, 2007. Of 508 protocol applications submitted in FY 2007 (which represented the total number of initial protocol applications and protocol applications), 38 were for multi-national clinical trials. f.

Clarification of the review standards

The proposed basic concept for review was developed at the WG for reviews and other services reform set up under the Headquarters for PMDA Reform. The proposed concept was

- 58 -

verified with respect to its validity by each review team and incorporated the opinions of the people concerned. This information was then explained to personnel responsible for reviews in the form of “Points to Be Considered by the Review Staff Involved in the Evaluation Process of New Drug.” The concept was also put on PMDA website on April 17, 2008. g.

Development of the guidance for the introduction of a system by which preliminary evaluation (evaluation of efficacy and safety from the clinical Trial consultation stage) is conducted.

A working group assigned to handle technical matters of clinical trial consultation and review was established jointly with JPMA, PhRMA, and EFPIA. The working group reviewed the measures with the objective of evaluating efficacy and safety from the stage of clinical trial consultation. h.

Trial of the project management system

In October 2007, a review team implemented the project management system on a trial basis. Specifically, one member of the review team was assigned as progress coordinator. The coordinator comprehended the progress of reviews by and the review schedule of two subteams within that team as needed, and when the review progress began to fall behind schedule, the coordinator provided information to the review director of the review team. The sub-teams efficiently assigned or switched reviewers depending on the progress of reviews. Each sub-team comprehended and analyzed past review processes. (v) Implementation of approval review a.

Approval reviews for new drugs

For new drugs, the Agency aims to review 80% of all filed NDAs within a review time of 12 months. In order to reach this target, the Agency: 1) Reinforced the review system and improved its operational efficiency by increasing the number of reviewers for categories in which reviewing applications was considered to be difficult because of item bias in the approval applications for new drugs. 2) Regularly discussed its review policy with MHLW and managed the review process through the Progress Management Committee for Review-Related Operations within the Agency so that review operations can be conducted smoothly; 3) Made efforts to properly manage the review process by observing guidelines for implementing reviews and inspections, keeping reviewers informed about review-related information and developing standard operating procedures. With regard to new drugs (pharmaceuticals that are clearly different from approved pharmaceuticals in terms of active ingredients, quantities, administration, dosage, indications, efficacy, etc.) for which approval applications have been submitted, approval reviews were conducted by review teams consisting of experts in pharmaceutical science, medicine, veterinary medicine, biostatistics, etc. With regard to review services for new drugs, in order to ensure consistency among the review teams and carry out review work promptly and appropriately, the Agency developed the Implementation Manual for Approval Reviews of New Drugs regarding reviews and related procedures, and the Standard Operating Procedures (SOPs) for various operations.

- 59 -

In order to achieve the targets relating to time periods for administratively processing reviews as given in the Mid-term plan and to conduct review-related work promptly and appropriately, the Agency continued to have the Progress Management Committee for Review-Related Operations hold meetings to monitor and examine operational progress so that the Chief Executive and other executives of the Agency could accurately grasp the progress on approval review operations and plan for improvements in the progress. The directors of the review divisions assessed the operational progress on a routine basis. Based on the reports from these directors, the Director, Deputy Director, and Associate Center Director of the Center for Product Evaluation provided necessary guidance at liaison meetings for review-related divisions. The status of approval reviews for new drugs in FY 2007 is shown below: Number of Approved Pharmaceuticals etc. FY 2004 FY 2005 3,742 2,199 1,781 1,570 502 281 2,972 2,611 0 0 8,997 6,661

Prescription drugs OTC drugs In vitro diagnostics Quasi-drugs Cosmetics Total Breakdown New drugs (cases) Priority review items out of NDAs above (cases)

49 22

60 18

FY 2006 2,390 1,030 136 2,287 0 5,843

FY 2007 3,648 1,329 199 2,236 0 7,412

77 24

81 20

Note: The number of “cases” is obtained based on the number of applications discussed at and the number of review reports made to the Drug Committees of Pharmaceutical Affairs and Food Sanitation Council (PAFSC)

Number of Approved New Drugs FY 2005 FY 2004 All new drugs No. of approvals Median review time Median total review time Priority review items No. of approvals Median review time Median total review time Standard items No. of approvals Median review time Median total review time

FY 2006

Applications filed in and † after FY 2004

FY 2007

Applications filed in and † after FY 2004

Applications filed in and † after FY 2004

49 (8.6 months) [65%] 13.5 months

60 (12.0 months) [50%]* 22.4 months

24 (8.6 months) [83%] 16.2 months

77 (13.7 months) [39%]* 21.7 months

49 (10.5 months) [59%] 19.2 months

81 (11.6 months) [54%]* 20.1 months

73 (10.5 months) [60%] 19.2 months

22 (2.8 months) [86%] 4.5 months

18 (8.9 months) [28%]* 20.4 months

9 (2.8 months) [56%] 4.9 months

24 (7.3 months) [42%]* 15.6 months

20 (6.4 months) [50%] 13.7 months

20 (4.9 months) [65%]* 12.3 months

20 (4.9 months) [65%] 12.3 months

27 (12.3 months) [41%] 23.4 months

42 (14.2 months) [41%]* 22.4 months

15 (10.3 months) [73%] 18.1 months

53 (15.5 months) [23%]* 27.4 months

29 (12.8 months) [41%] 20.3 months

61 (14.5 months) [41%]* 22.0 months

53 (12.9 months) [47%] 20.7 months

- 60 -

Note: Percentage in brackets indicates that of the number of applications reviewed within 12 months after application for all new drugs and standard items and within 6 months for priority review items. *Also include NDAs filed in and before March 2004, which are excluded from the targets in the Mid-term plan. † The data indicate the number of applications filed in and after April 2004 among those filed in FY 2005, 2006, and 2007.

Review Status of NDAs New drug (FY of application) Cases* Approved Withdrawn Under review Applications submitted on and before 139 104 (8) 25 (2) 10 [−10] March 31, 2004 FY 2004 87 77 (13) 9 (0) 1 [−13] FY 2005 57 41 (21) 6 (2) 10 [−23] FY 2006 101 (−2)† 41 (35) 7 (7) 53 [−44] FY 2007 91 4 (4) 0 87 [87] Total 475 267 (81) 47 (11) 161 [−3] * The number of “Cases*” is obtained based on the scheduled number of review reports discussed at and reported to the Drug Committees of Pharmaceutical Affairs and Food Sanitation Council (PAFSC) † The number of applications submitted in FY 2006 is two less than that shown in the previous annual report because the Agency integrated two separate applications for a single ingredient into one application and had such two dual applications. Note 1: Values in parentheses indicate those processed in FY 2007 (included in values on their left) Note 2: Values in brackets indicate difference from FY 2006

Number of Applications Processed and Time Consumed in Each Review Process 3. From 1. From 4. From 2. From first expert receipt of notification of consultation Review process discussion to applications review result to expert notification of to first to approval discussion review result consultation Number of processed cases/ 79 cases 54 cases 56 cases 49 cases FY Review process time 2006 83.0 days 397.5 days 44.5 days 25.0 days (median)* Number of processed cases/ 63 cases 65 cases 72 cases 72 cases FY Review process time 2007 85.0 days 381.0 days 20.5 days 57.0 days (median)* * The days shown in each review process are the median of total review process time (the sum of reviewers’ and applicants’ time clocks). Note: Values are of applications filed in and after April 2004. Review status of new drugs overall With respect to the approval status in FY 2007, the Agency attained an achievement level of 60% for the performance target within 12 months by reviewing 44 out of 73 applications for new drug approval submitted in and after April 2004. The median review time was 10.5 months. When the applications submitted in and before March 2004 were included, the achievement rate was 54% (44 out of 81), and the median review time was 11.6 months.

The number of new drugs approved in FY 2007 increased by 4 from the previous fiscal year because of progress in the development of the review system. The median review time for all new drugs filed was improved to 11.6 months from 13.7 months in 2006. As for the 139 applications submitted before the establishment of PMDA (in and before March 2004) and the 336 applications submitted after the establishment of PMDA (in and after April 2004), the Agency processed reviews in the order of their submission, giving full consideration to the target time for processing reviews. However, the Agency has called for

- 61 -

withdrawal of applications that were considered to be difficult to approve due to a lack of response by applicants to inquiries made by the Agency. As for the applications submitted in and before March 2004, the Agency was able to process 129 of those through approvals or withdrawals by FY 2007. In order to achieve the target for the review time earlier, the Agency is progressing with reviews of such applications vigorously so that it can strive to concentrate all resources on the applications submitted after its establishment. Status of priority reviews With regard to priority reviews for pharmaceuticals specified by the Minister of Health, Labour and Welfare, the Agency is aiming to process 50% of all such reviews within a review time of 6 months by the end of the effective period for the Mid-term targets.

Reviews of approval applications for orphan drugs and other pharmaceuticals that are regarded as having particularly high medical necessity (i.e., pharmaceuticals for serious diseases with distinctly superior efficacy or safety to existing pharmaceuticals or treatment methods) were conducted on a priority basis as priority review items, and 20 applications were approved in FY 2007. In FY 2007, there were 16 applications for priority reviews of pharmaceuticals regarded as having particularly high medical necessity. Five of these applications were accepted as priority review items, 3 were judged to be non-priority review items, and 8 are currently being reviewed. b.

Approval reviews for new medical devices

For new medical devices, the Agency aimed for an achievement level of 90% of applications for the target review time of 12 months. As with approval reviews of new drugs, in order to attain these goals, the Agency discussed and took specific measures to improve and accelerate reviews, such as by establishing operating procedures for reviews and inspections. Review teams consisting of reviewers with expertise in engineering, pharmaceutical science, medicine, dentistry, veterinary medicine, biostatistics, etc., conducted approval reviews of new medical devices (devices subject to re-examination [medical devices that have a clearly different structure, usage, indications, performance, etc., as compared to existing approved medical devices or certified medical devices]). To ensure consistency among review teams and to carry out reviews on new medical devices promptly and appropriately, the Agency prepared the Implementation Manual for Approval Reviews of New Medical Devices, which describes reviews and review-related procedures, and developed standard operating procedures (SOPs) relating to various operations. The Agency also collected monthly data on the achievement level of the target review time and informed the reviewers of the achievement status. With regard to the progress of reviews etc., the Progress Management Committee for Review-Related Operations (whose mission is to enable the Chief Executive and other Agency management to comprehend the progress of approval review services without fail and improve its progress), continued to monitor and examine operational progress in order to achieve the Midterm plan for review time and ensure rapid and accurate review processes. In the review divisions, the Director of the Office of Medical Devices monitors operational progress on a routine basis, and at liaison meetings for review-related divisions, the Director,

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Deputy Director, and Associate Center Directors of the Center for Product Evaluation provide necessary guidance. The status of approval reviews for new medical devices in FY 2007 is shown below:

Previous data

Number of Approved New Medical Devices FY 2004 FY 2005 Medical devices (total) 3,309 1,827 Priority review items (included in total) 2 0 New medical devices 8 11 With no approval standards; and clinical data 0 required With no approval standards; and no clinical data 16 required With approval standards; and no clinical data 3 required Controlled medical devices (with no approval 1 standard or certification standard; and no clinical data required) Improved medical devices 154 263 Generic medical devices 3,147 1,533

FY 2006 1,342 1 23

FY 2007 2,222 4 26

5

14

189

552

444

1,141

146

335

136 399

78 76

Approval Status of New Medical Devices FY 2005

All new medical devices No. of approvals Median review time Median total review time Priority review items No. of approvals Median review time Median total review time Standard items No. of approvals Median review time Median total review time

FY 2006

Applications filed in and † after FY 2004

FY 2004

FY 2007

Applications filed in and † after FY 2004

Applications filed in and † after FY 2004

8 (12.7 months) [50%]* 35.8 months

11 (7.7 months) [82%]* 22.4 months

5 (1.8 months) [100%] 10.3 months

23 (6.0 months) [83%]* 19.7 months

15 (3.4 months) [100%] 15.3 months

26 (8.6 months) [73%]* 17.1 months

23 (8.2 months) [83%] 15.1 months

2 (9.3 months) [50%]* 24.0 months

0

0

1 (5.7 months) [100%]* 14.2 months

1 (5.7 months) [100%] 14.2 months

4 (8.6 months) [75%]* 15.7 months

4 (8.6 months) [75%] 15.7 months

6 (15.0 months) [33%]* 43.3 months

11 (7.7 months) [82%]* 22.4 months

5 (1.8 months) [100%] 10.3 months

22 (6.3 months) [82%]* 19.8 months

14 (3.2 months) [100%] 15.7 months

22 (8.7 months) [73%]* 18.9 months

19 (7.7 months) [84%] 15.1 months

Note: Percentage in brackets indicates that of the number of applications reviewed within 12 months after application for all medical devices and standard items and within 9 months for priority review items. * Also includes the applications filed in and before March 2004, which are excluded from the targets in the Midterm plan. † The data indicate the number of applications filed in and after April, 2004 among those filed in FY 2005, 2006, and 2007.

- 63 -

Review Status of New Medical Devices New medical devices Withdrawn Under review Cases* Approved† (FY of application) Applications submitted in and before 132 51 (8) 75 (3) 6 [−11] March 31, 2004 FY 2004 56 28 (13) 16 (0) 12 [−13] FY 2005 7 6 (3) 0 1 [−3] FY 2006 24 13 (11) 1 (0) 10 [−11] FY 2007 37 4 (4) 1 (1) 32 [32] Total 256 (37) 102 (39) 93 (4) 61 [−6] * Values in the Cases column are the numbers of applications for new medical devices. † The number of approved items includes improved medical devices. Note 1. Values in parentheses indicate those processed in FY 2007 (included in values on their left) Note 2. Values in brackets indicate difference from FY 2006 Number of Applications Processed and Time Consumed in Each Review Process 3. From 1. From 4. From 2. From first Dxpert receipt of notification of consultation Review process Discussion to applications review result to Expert notification of to first to approval Discussion review result consultation Number of processed cases/ 14 cases 17 cases 10 cases 15 cases FY 2006 Review process time 46.5 days 484.0 days 101.0 days 9.0 days (median)* Number of processed cases/ 8 cases 15 cases 15 cases 23 cases FY 2007 Review process time 53.0 days 402.0 days 151.0 days 9.0 days (median)* * The days shown in each review process are the median of total review process time (the sum of reviewers’ and applicants’ time clocks). Note 1: Expert Discussions were held several times as needed. Note 2: Values are of applications filed in and after April 2004. Review status of new medical devices overall In FY 2007, the Agency approved all applications for new medical devices submitted in and after April 2004 (19 out of 23 cases) within 12 months, reaching an achievement level of 83% for the target review time. The median review time was 8.2 months. However, when applications submitted in and before March 2004 are included, the achievement ratio decreases to 73% (19 out of 26 applications), and the median review time becomes 8.6 months.

For the 132 applications submitted before the establishment of PMDA (in and before March 2004) and the 124 applications submitted after the establishment of PMDA (in and after April 2004), the Agency processed reviews taking the target review time sufficiently into consideration. However, the Agency has called for withdrawal of applications that were considered difficult to approve due to a lack of response from applicants to inquiries made by the Agency. As to the applications submitted in and before March 2004, the Agency was able to process 126 of these applications through approvals or withdrawals by FY 2007. However, in order to achieve the target for the review time earlier, the Agency is progressing with reviews of such application vigorously so that it can strive to concentrate all resources on the applications submitted after its establishment.

- 64 -

Status of priority reviews With regard to priority reviews for new medical devices specified by the Minister of Health, Labour and Welfare, the Agency is aiming to process 70% of all such reviews within a review time of 9 months by the end of the effective period for the Mid-term targets.

Approval reviews for applications for orphan medical devices and other devices that are regarded as having particularly high medical necessity (medical devices for severe diseases and with distinctly superior efficacy or safety as compared to existing medical devices or treatment methods) were conducted on a priority basis as priority items. In FY 2007, there was four approvals. There was one new application for priority review, and its validity is currently being investigated. Status of development of approval standards In order to support MHLW in developing approval standards for medical devices, the Committee on Medical Device Approval Standards held three meetings, and the Expert Committee on Medical Device Review Guidelines held one meeting in FY 2007. The numbers of established standards for approval and certification reported to MHLW in FY 2007 were as follows: FY of report Approval standards Certification standards Review guidelines

FY 2006 6 0 0

FY 2007 7 14 1

Total 13 14 1

The number of standards established by MHLW in FY 2007 based on the reports from the Agency is shown below:

Numbers of Established Approval Standards, Certification Standards, and Review Guidelinesfor Medical Devices and In Vitro Diagnostics Established in: FY 2004 FY 2005 FY 2006 FY 2007 Total Approval standards 0 17 8 10 35 Certification standards 363 9 24 0 396 Review guidelines 0 0 0 0 0

The Agency established a database system of medical device approval standards and began to provide outside organizations with information on the certification and approval standards (including the review guidelines) and the Japanese Industrial Standards (JIS) on which those standards are based. c.

Document conformity audit of application documents, GLP conformity audits, GCP conformity audits, and GPMSP conformity audits

The Agency conducted efficient on-site and document inspections of approval application dossiers for new drugs and medical devices as well as on the tests on which these application documents are based, to determine whether such documents were gathered in accordance with Good Laboratory Practice (GLP; standards indicated in ministerial ordinances relating to standards for implementing non-clinical tests relating to the safety of pharmaceuticals), Good Clinical Practice (GCP; standards indicated in ministerial ordinances relating to standards for implementing clinical trials for pharmaceuticals), Good Post-

- 65 -

Marketing Surveillance Practice (GPMSP; standards indicated in ministerial ordinances relating to standards for post-marketing surveys on pharmaceuticals) and the conformity standards for the application documents. Numbers of Conducted Conformity Audits FY 2004 FY 2005 FY 2006 FY 2007 Document conformity audits 161 136 426 774 Pharmaceuticals 161 135 251 234 Medical devices — 1 175 540 GLP conformity audits 20 39 31 27 Pharmaceuticals 20 37 23 23 Medical devices — 2 8 4 GCP conformity audits* 73 131 149 132 New drugs 68 120 137 122 Generic drugs 5 11 12 9 Medical devices — 0 0 1 GPSP conformity audits† 27 82 103 107 * Values for GCP and GPMSP conformity audits in and after FY 2004 are notification values after evaluation were conducted. † All audits performed in and after FY 2005 were conducted as GPMSP conformity audits. Note 1: GLP: Good Laboratory Practice Note 2: GCP: Good Clinical Practice Note 3: GPMSP: Good Post-Marketing Surveillance Practice Note 4: GPSP: Good Post-marketing Study Practice

In order to efficiently carry out document conformity audits and on-site inspections for application documents, the Agency took the following measures: 1)

Review of the conformity audit system The Agency began a review of the conformity audit system further to the 2nd Midterm plan by, for example, shifting from the current document conformity audit method, where the relevant data and materials are delivered to the Agency for audit, to the auditor visit method, where the Agency staff directly visit the applicant company for audit.

2)

Diffusion of the knowledge of the interpretation of GCP operations The Agency conducted consultations with medical institutions which were subjected to onsite inspection on matters related to GCP after audit completion. The Agency also made an effort to improve the explanation of case examples by highlighting points to consider in conducting clinical trials through the Conformity Audit page on the Agency’s website. To deepen understanding regarding GCP, the Agency held GCP Workshops in Tokyo and Osaka for people in charge of drug development and pharmaceutical affairs at pharmaceutical companies, auditors, site management organizations (SMOs) and healthcare professionals, and in addition, PMDA staff members made lectures at academic societies, etc., for healthcare professionals. Number of GCP Workshop Participants Place FY 2006 FY 2007 Tokyo 1,303 1,212 Osaka 454 495 Total 1,757 1,707

- 66 -

3)

Enhancement and reinforcement of GCP on-site inspections

The Agency increased the number of GCP on-site inspections for medical institutions while giving consideration to the allocation of PMDA staff servicing the division in charge. The Agency shifted GCP inspection system from the division chief system to the inspection director system as part of the effort to reinforce the linkage between document inspection and GCP on-site inspection in July 2007. Although a standard administrative processing time for conformity audit services has not been set, the Agency made efforts so that the review time for approval reviews for relevant items were not affected, resulting in no delays in the approval reviews for these audit services in FY 2007. d.

Approval reviews for generic drugs, over-the-counter (OTC) drugs and quasi-drugs

In accordance with the Standard Administrative Process Time for Approval Review, Notification No. 960 of the Director-General of the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare dated October 1, 1985, the Agency set the standard administrative processing time of applications for generic drugs and other drugs submitted in and after April 2004 as follows. 1) Generic drugs: 12 months 2) OTC drugs: 10 months 3) Quasi-drugs: 6 months With regard to reviews of generic drugs, etc., in order to carry out review operations promptly and accurately, the Agency developed the Implementation Manual for Approval Review of Generic Drugs, Implementation Manual for Approval Review of OTC Drugs, Implementation Manual for Approval Review of Insecticides/Rodenticides, and Implementation Manual for Approval Review of Quasi-drugs as well as standard operating procedures for various operations. In addition to collecting data on the achievement level of the target review time each month and informing the reviewers of these levels, monthly meetings of the Progress Management Committee for Review-Related Operations were continuously held to monitor and examine operational progress.

- 67 -

The approval status of generic drugs, OTC drugs and quasi-drugs in FY 2007 are as follows: Number of Approved Generic Drugs and Others FY 2004 FY 2005 FY 2006 FY 2007 Generic drugs 3,476 1,919 2,152 3,278 Number of approved applications filed in and after 1,468 1,782 2,029 3,228 April 2004 (breakdown) Median review time 3.3 7.3 4.0 4.5 (for the applications filed in and after April 2004) months months months months Achievement rates on the target time 100% 98% 93% 95% (for the applications filed in and after April 2004) OTC drugs 1,781 1,570 1,030 1,329 Number of approved applications filed in and after 270 1,163 923 1,309 April 2004 (breakdown) Median review time 8.7 7.8 6.3 4.0 (for the applications filed in and after April 2004) months months months months Achievement rates on the target time 83% 84% 85% 90% (for the applications filed in and after April 2004) Quasi-drugs 2,972 2,611 2,287 2,236 Number of approved applications filed in and after 1,431 2,575 2,275 2,230 April 2004 (breakdown) Median review time 5.6 5.3 5.5 5.2 (for the applications filed in and after April 2004) months months months months Achievement rates on the target time 89% 86% 67% 83% (for the applications filed in and after April 2004) Total 8,229 6,100 5,469 6,843 Number of approved applications filed in and 3,169 5,520 5,227 6,767 after April 2004 (breakdown) Note: The median and TC achievement rate for OTC drugs and quasi-drugs in FY 2007 were calculated using data from the period from the completion of the audit to the notification of GMP results by prefectures. Application and Approval of OTC Drugs and Quasi-Drugs by Category of Application OTC drugs OTC test Insecticide, Category of Total 1 2 3 4-1 4-2 drugs rodenticide application Applied in FY 2007 2 96 68 97 1,093 0 21 1,377 Approved in FY 2007 0 59 36 142 1,089 0 3 1,329 Quasi-drugs Category of 1 and 3 2 Total application Filed in FY 2007 119 2,308 2,427 Approved in FY 2007 76 2,160 2,236 Note 1: Categories of application OTC drugs 1: Direct OTC drugs 2: Switch OTC drugs 3: Relatively innovative drugs excluding 1 and 2 4-1: Relatively less innovative drugs 4-2: Drugs that are not innovative Quasi-drugs 1: Products that include new active ingredient 2: Products that are not innovative 3: Innovative products excluding 1 Note 2: Each application belongs to the category for which it was submitted. Note 3: Each approval belongs to the category in which it was granted. Note 4: The number of quasi-drugs includes that of insecticides and rodenticides for which an application for approval as quasi-drugs was filed.

- 68 -

Reviews Conducted for Generic Drugs by Fiscal Year No. of No. of Withdrawal, Classification Fiscal year Under review applications approvals etc.† FY 2004 2,992 (2,966)* 3,476 12 2,470 FY 2005 1,829 1,919 221 2,159 Generic drugs FY 2006 2,631 2,152 173 2,465 FY 2007 3,729 3,278 160 2,756 FY 2004 1,955 (2,622)* 1,781 6 2,790 FY 2005 1,131 1,570 144 2,207 OTC drugs FY 2006 1,236 1,030 181 2,232 FY 2007 1,377 1,329 113 2,167 FY 2004 3,068 (1,865)* 2,972 23 1,938 FY 2005 2,286 2,611 118 1,495 Quasi-drugs FY 2006 2,503 2,287 96 1,615 FY 2007 2,427 2,236 118 1,688 * Values in parentheses show applications not yet reviewed as of March 31, 2004 (taken over from the Center for Product Evaluation) † Values in the column Withdrawal, etc. include the number of items switched to other review categories during the review.

With regard to achievement levels in FY 2007 of the target standard administrative processing time for applications submitted in and after April 1, 2004, the Agency attained an achievement level of 95% by reviewing 3,067 out of 3,228 applications for generic drugs within 12 months, 90% by reviewing 1,177 out of 1,309 applications for OTC drugs within 10 months and 83% by reviewing 1,840 out of 2,230 applications for quasi-drugs within 6 months. As a result, the Agency was able to adhere to the median for the administrative processing time indicated in the Notification No. 960 issued by Director-General of the Pharmaceutical Affairs Bureau, the Ministry of Health and Welfare, dated October 1, 1985. Document Conformity Audit Conducted for Generic Drugs by Fiscal Year FY 2004 FY 2005 FY 2006 FY 2007 Number of audits 1,090 941 628 1,135

For generic drugs, the Agency implemented surveys to confirm the compliance with the conformity criteria for approval application dossiers, by collating them with raw data such as test records, experiment notes, case report forms, etc. In FY 2007, the Japanese Pharmacopoeia Draft Committee held a total of 67 meetings and finalized 62 new monographs and 85 amendments for the second supplement of the 15th edition of the Japanese Pharmacopoeia (JP) (to be published in September 2009). The draft was posted on the Agency’s website for public comment. The Agency also called for comments on 41 reference ultraviolet visible absorption spectra and reference infrared absorption spectra in FY 2007. Drafts for the Japanese Pharmacopoeia reported to MHLW thus far are as follows: Month and year reported September 2005 March 2007 New monographs 102 90 Amendments 276 171 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. The Agency provided a report on those drafts to MHLW 6 months before the normal publication timing.

- 69 -

Public Announcement on the Japanese Pharmacopoeia by MHLW 1st supplement to the 15th edition of Public announcement of the 15th edition of the Japanese the Japanese Pharmacopoeia as Pharmacopoeia Pharmacopoeia as amended amended (month and year (March 2006) (September 2007) announced) New monographs 102 90 Amendments 272 170 Deletion 8 6 Total 1,483 1,567

The Agency opened a web page to provide information on the Japanese Pharmacopoeia and started to provide relevant information such as the condition of the JP draft review or international harmonization of pharmacopoeial standards, in addition to calling for comments on drafts.

Pharmaceutical Affairs and Food Sanitation Council

MHLW

PMDA

1. Decide the basic policy 3. Finalize the candidate drug list

2. List the candidate drugs 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 (on the web) Request for drafts Submission of the drafts Inquiry and Request for Reconsideration Response

Pharmaceutical companies

Flow of Revision of Japanese Pharmacopoeia

Seek public comments (on the web)

English edition of JP

(vi) Improvement of clinical trial consultations

In addition to improving pre-application consultations, the Agency is required to give priority to conducting consultations on clinical trials for pharmaceuticals and medical devices expected to have high medical benefits, in order to shorten the time period for their approval. a.

Conducting priority clinical trial consultations

With the priority clinical trial consultation system, the Agency succeeded in conducting clinical trial consultations in a prioritized manner as well as consultations on compliance with conformity criteria, allowing an increase in opportunities to provide advice on approval applications before they are submitted. With regard to the priority clinical trial consultation system for pharmaceuticals considered to be of particularly high medical necessity, the Agency received applications for six ingredients in FY 2007 and designated four ingredients (all applications filed in FY 2007) as being applicable to priority clinical trial consultation (a review is under way for the remaining two ingredients). None were rejected as inapplicable. The Agency conducted a total of 22 clinical trial consultations related to the designated ingredients. - 70 -

For medical devices, there were no applications for priority clinical trial consultations. For both pharmaceuticals and medical devices, there were no applications for consultations on conformity for items designated as priority consultation items. b.

Acceleration of clinical trial consultations for pharmaceuticals

The Agency worked to expedite clinical trial consultations for pharmaceuticals by shortening the duration from when application for a clinical trial consultation is submitted until a face-toface consultation is conducted, as well as until the first face-to-face consultation for priority clinical trial consultations is conducted. This was made possible through properly managing operations by implementing appropriate improvement measures for such operations, and by developing an operational manual. Clinical Trial Consultation (CTC) for New Drugs FY 2004 FY 2005 FY 2006 339 473 Applications for CTC 334 (243)* (327)* Conducted CTC 193 218 288 Withdrawn 23 14 7 Total 216 232 295 * Values in parentheses do not include reapplications caused by rejection.

FY 2007 435 (325)* 281 21 302

In FY 2007, the Agency conducted 302 clinical trial consultations (including 21 withdrawals) in relation to a goal of 280 clinical trial consultations. The Agency established goals for efficient consultation, that is, that the process from a faceto-face consultation to the settlement of records should be completed in 30 business days for 10% of all applications submitted. The established goals also require that the process to the first face-to-face clinical trial consultation should be completed in 30 business days for 50% of all applications submitted. In FY 2007, 186 (62.2%) out of 299 applications were processed within 30 days from the face-to-face consultation to the settlement of records, and 11 (75.0%) out of 16 were processed within 30 business days to the first face-to-face consultation (with respect to priority clinical trial consultation). The Agency promoted simple clinical trial consultations and support for Multi-national clinical trials. In FY 2007, it received 62 applications for consultations on Multi-national clinical trials for new active ingredients, of which 56 were carried out. In order to improve the quality of consultations, the Agency introduced a system in January 2007 in which the Agency’s outlook for the consultation is presented to the applicant beforehand (PMDA preliminary outlook disclosure system).

- 71 -

Number of Face-to-face Clinical Trial Consultations Conducted for Drugs by Category in FY 2007 Category Category 1 (Gastrointestinal drugs etc.) Category 2 (Cardiovascular drugs) In vivo diagnostics Radiopharmaceuticals Category 3 (Central / peripheral nervous system drugs etc.) Category 4 (Antibacterial agents etc.) Anti-AIDS drugs Category 5 (Drugs for the urogenital system etc.) Category 6-1 (Respiratory tract drugs etc.) Category 6-2 (Hormone drugs) Antineoplastic drugs Biologics Cellular and tissuederived products* Blood products Compliance to conformity criteria Total Withdrawn Grand Total

Apr

May

Jun

July

Aug

Sep

Oct

Nov

Dec

Jan

Feb

Mar

Total

1

2

3

2

2

2

1

1

3

3

4

3

27

5

4

4

3

2

4

2

5

4

5

4

4

46

0 0

0 0

1 0

0 0

1 0

0 0

0 0

0 0

0 0

1 1

0 1

0 0

3 2

4

3

4

4

4

4

2

4

2

3

3

2

39

1

3

3

2

2

0

1

1

1

0

2

0

16

0

0

0

0

0

0

0

0

0

0

0

0

0

1

0

1

2

2

2

1

0

1

1

2

1

14

1

2

1

0

2

2

3

4

4

2

2

3

26

2

1

3

3

2

2

3

2

4

3

3

3

31

4 3

5 1

2 1

4 0

4 0

5 2

4 2

5 1

3 2

3 1

4 0

7 0

50 13

0

1

1

0

0

1

1

1

1

0

2

1

9

0

1

0

1

0

1

1

0

0

0

0

1

5

0

0

0

0

0

0

0

0

0

0

0

0

0

22 0 22

23 2 25

24 1 25

21 3 24

21 0 21

25 2 27

21 6 27

24 2 26

25 2 27

23 0 23

27 0 27

25 3 28

281 21 302

Note 1: Consultation covering several categories was counted in terms of its main category. Note 2: Consultations on compliance with conformity criteria were all conducted by the Office of Conformity Audit regardless of category.

Number of Clinical Trial Consultations for New Medical Devices Applications for CT consultation* Medical devices In vitro diagnostics Conducted CT consultations Medical devices In vitro diagnostics Withdrawn Medical devices In vitro diagnostics Total (Conducted consultations and withdrawals) Medical devices In vitro diagnostics

FY 2004 9 7 2 8 6 2 0 0 0 8 6 2

* Applications submitted after arrangement of schedule.

- 72 -

FY 2005 33 32 1 30 29 1 0 0 0 30 29 1

FY 2006 46 43 3 42 39 3 0 0 0 42 39 3

FY 2007 76 75 1 72 71 1 0 0 0 72 71 1

Number of Clinical Trial Consultations for New Medical Devices by Category Conducted in FY 2007 Consultation category

Applications for CTC

Conducted CTC

Withdrawals

Total (Conducted consultations and withdrawals)

1

1

0

1

Consultation for preparation of documents for pharmaceuticals that are cellular and tissuederived CT/Pre- application consultations for medical devices or in vitro diagnostics Reliability standard compliance consultation for medical devices or in vitro diagnostics Pre-development consultation for medical devices Application procedure consultation for medical devices or in vitro diagnostics Safety consultation for medical devices (excluding biological ones) Quality consultation for medical devices (excluding biological ones) Performance testing consultation for medical devices Clinical evaluation consultation for medical devices Exploratory clinical trial consultation Safety consultation for biological medical devices Quality consultation for biological medical devices Additional consultation for medical devices and in vitro diagnostics Total

38 (1)*

44 (1)*

0

44 (1)*

0

0

0

0

5

2

0

2

3

2

0

2

1

1

0

1

0

0

0

0

1

1

0

1

20

15

0

15

1

1

0

1

0

0

0

0

1

0

0

0

5

5

0

5

76

72

0

72

* Numbers in parentheses indicate the number of in vitro diagnostics included.

(vii) Promotion of international harmonization The Agency is required to make efforts to accelerate the review process for new drug approvals, taking international trends into account, so that a target time for the total review time (the sum of the processing time on the reviewer side and the processing time on the applicant side for items approved in a particular year) can also be established by the end of the effective period for the Mid-term targets. a.

Approaches toward international harmonization such as through ICH

In FY 2007, the Agency continued to actively participate in ICH Steering Committee Meetings and Expert Working Group Meetings, and promoted further international harmonization by planning for the consistency of Japanese standards with international standards such as for developing review data, which were agreed upon among Japan, the U.S., and EU in ICH Meetings. Specifically, the Agency actively cooperated in efforts toward the consistency and harmonization of international standards through participation in Steering Committee Meetings and Expert Working Group Meetings of ICH, GHTF, etc., as well as in PDG. Note: ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use GHTF: Global Harmonization Task Force for Medical Devices - 73 -

PDG: Pharmacopoeial Discussion Group International conferences on pharmaceuticals in which the Agency participated (relating to reviews and safety measures) ICH Expert Working Groups ICH Meeting in Brussels ICH Meeting in Yokohama ICH Tokyo Symposium Topics discussed in FY 2007 Specifications for Electronic Submission of Pharmaceutical Regulatory Information (M2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials (M3 [R3]) Data Elements for Transmission of Individual Case Safety Reports (E2B [R3]) Development Safety Update Report (E2F) Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals (S2 [R1]) Non-clinical Safety Studies of Anti-cancer Agents (S9) Pharmaceutical Development (addendum)(Q8 [R1]) GMP Quality Systems (Q10) Regulatory Acceptance of Pharmacopoeial Interchangeability (Q4B) Data Elements and Standards for Drug Dictionaries (M5) Pharmacopoeial Discussion Group (PDG) MedDRA (Medical Dictionary for Regulatory Activities) Steering Committee Meeting OECD Pharmacogenetics workshop WHO INN meeting WHO meeting on new influenza vaccine WHO Workshop on Monitoring and Preparation of Pharmaceuticals In order to build a specific system for exchanging information, etc., relating to consultations, reviews, and safety measures in cooperation with the U.S. and EU, the Agency held discussions with FDA of the U.S. and EMEA of EU while collaborating with MHLW. International conferences on medical devices that the Agency participated in (relating to reviews and safety measures) IEC/TC/87 (Ultrasonics) ISO/TC/121 (Anesthetic and respiratory equipment) ISO/TC/150 (Implants for surgery, artificial heart) ISO/TC/194 (Biological evaluation of medical devices) ISO/TC/198 (Sterilization of health care products) GHTF SG1 (Regulatory systems) GHTF SG3 (Quality systems) GFTF SG4 (Regulatory auditing) GFTF SG5 (Clinical evidence) Regulatory Affairs Professionals Society (RAPS) IVD Conference (IVD regulation) b.

Efforts to introduce a total review time

In working toward introducing the concept of a total review time, the Agency is monitoring and

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managing the total review process time while taking international trends into account. The number of new drugs that were approved in FY 2007 was 81, and the median review time (PMDA review time) for these applications was 11.6 months, whereas the median total review time was 20.1 months. Applications for 73 of these approved drugs were submitted in and after April 2004, of which the median review time (PMDA review time) was 10.5 months and the median total review time was 19.2 months. (Refer to the Number of Approved New Drugs.) The number of new medical devices that were approved in FY 2007 was 26, and the median review time (PMDA review time) for these applications was 8.6 months, whereas the median total review time was 17.1 months. Applications for 23 of these approved medical devices were submitted in and after April 2004, of which the median review time (PMDA review time) was 8.2 months and the median total review time was 15.1 months. (Refer to the Number of Approved New Medical Devices.) As approaches directed toward implementing the total review time, the Agency continued to improve clinical trial consultations and solve as many fundamental problems as possible before the submission of applications. In addition, for applications whose reviews were suspended for reasons of their applicants, the Agency conducted consultations with the applicants and advised them to withdraw their applications. 4.2.(2) Improvement in reliability of operations (i)

Planned recruitment of staff with advanced expertise and systematic provision of training opportunities a.

Staff recruitment

In order to ensure smooth enforcement of the amended Pharmaceutical Affairs Law enacted in 2005, and to conduct operations for reviews and safety measures promptly and appropriately, the Agency recruited competent human resources with high expertise, mainly through open recruitment, while ensuring its neutrality and impartiality as an incorporated administrative agency (refer to II-PART 3.4.(4), Securing Human Resources through Open Recruitment). b.

Systematic training

In order to implement systematic training adapted to the purpose of operations, as well as to provide training suited to the qualifications and capabilities of individual staff members, the Agency worked to improve the skills and knowledge of its staff members by providing them with training opportunities using external training organizations and outside experts (refer to II-PART 3.4.(2), Systematic Implementation of Staff Training). (ii) Development of a GMP/QMS audit system Based on the amended Pharmaceutical Affairs Law that came into effect on April 1, 2005, conformance of methods for manufacturing control and quality control at manufacturing sites for pharmaceuticals, etc., with requirements specified in GMP Ministerial Ordinance on Drugs and Quasi-drugs*, and/or QMS Ministerial Ordinance on Medical Devices and In Vitro Diagnostics† is a pre-requisite for approval. Therefore, in addition to the manufacturing sites already licensed by the

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Minister of Health, Labour and Welfare, the following manufacturing sites became subject to investigations by the Agency: 1) foreign manufacturing sites related to all products that require regulatory approval; 2) domestic manufacturing sites for new pharmaceuticals, new medical devices and Class IV medical devices (high-risk medical devices such as pacemakers). * GMP Ministerial Ordinance on Drugs and Quasi-drugs: Standards for Manufacturing Control and Quality Control of Drugs and Quasi-drugs (MHLW Ministerial Ordinance No. 179 in 2004 † QMS Ministerial Ordinance on Medical Devices and In Vitro Diagnostics: Standards for Manufacturing Control and Quality Control of Medical Devices and In Vitro Diagnostics, MHLW Ministerial Ordinance No. 169 in 2004 Note 1: GMP = Good Manufacturing Practice, standards for manufacturing control and quality control Note 2: QMS = Quality Management System Therefore, the Agency continued to recruit GMP/QMS auditors to form a system of 37 inspectors as of April 1, 2008. At the same time, the Agency is also promoting educational training for GMP/QMS auditors as well as training programs, both domestic and overseas, including seminars hosted by the Pharmaceutical Inspection Cooperation Scheme (PIC/S), a European-based international organization for GMP audits. GMP/QMS Audits Conducted According to the Amended Pharmaceutical Affairs Law Applied Drugs* 203 In vitro diagnostics 22 Quasi-drugs 5 Medical devices 101 Total 331

Pharmaceuticals* In vitro diagnostics Quasi-drugs Medical devices Total

FY 2005 Completed Withdrawn In progress Applied 53 (35) 1 149 1,039 9 (0) 0 13 63 0 (0) 0 5 0 32 (4) 0 69 638 94 (39) 1 236 1,740

Applied 1,011 85 3 1,006 2,105

FY 2006 Completed Withdrawn In progress 783 (180) 24 381 32 (4) 1 43 5 (0) 0 0 300 (20) 29 378 1,120 (204) 54 802

FY 2007 Completed Withdrawn In progress 893 (233) 55 444 84 (1) 0 44 0 (0) 0 3 1,021 (12) 15 348 1,998 (246) 70 839

* Excluding In vitro diagnostics. Note: Values in parentheses show the number of on-site inspectionss.

The actual performance of on-site inspections that were initiated in FY 2005 is shown below: On-site Inspections of Overseas Manufacturing Sites of Drugs by Region North, Central Europe and South Asia Africa Total America FY 2005 2 8 2 0 12 FY 2006 13 20 2 1 36 FY 2007 22 22 8 0 52 Note: FY 2006: France, Netherlands, Ireland, Denmark, Finland, Austria, USA, South Korea, Indonesia, and South Africa FY 2007: France, UK, Denmark, Spain, Ireland, Belgium, Italy, Netherlands, USA, Puerto Rico, China, Singapore, and India

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On-site inspections of Overseas Manufacturing Sites of Medical Devices by Region North, Central Europe Asia Africa Total and South America FY 2005 1 1 0 0 2 FY 2006 5 10 0 0 15 FY 2007 1 10 0 0 11 Note: FY 2006: Ireland, Switzerland, USA, and Puerto Rico FY 2007: France, USA, and Puerto Rico

The administrative processing times of GMP/QMS audits in FY 2007 are shown below: Processing Time of GMP/QMS Audits According to the Amended Pharmaceutical Affairs Law FY 2005 FY 2006 FY 2007 Total PMDA Total PMDA Total PMDA processing processing processing processing processing processing time time time time time time (median) (median) (median) (median) (median) (median) Drugs * 78 days 59.5 days 161 days 117 days 170 days 111 days In vitro diagnostics 101 days 101 days 149 days 100 days 158 days 88 days Quasi-drugs — — 142 days 72 days — — Medical devices 131 days 104 days 161 days 110 days 157 days 88 days * Excluding in vitro diagnostics.

The processing status of audits of manufacturing facilities conducted in FY 2007 at domestic manufacturing sites under authorization from the Minister, as based on the Regulations for Buildings and Facilities for Pharmacies and Manufacturing Sites, is shown below: Number of Audits of Buildings and Facilities for Domestic Manufacturing Sites FY 2005 FY 2006 FY 2007 Drugs* 12 (8) 30 (23) 16 (14) In vitro diagnostics 1 (1) 6 (6) 2 (2) Medical devices 2 (1) 1 (0) 0 (0) Total 15 (10) 37 (29) 18 (16) * Excluding In vitro diagnostics. Note: Values include withdrawn cases. Values in parentheses show the number of on-site inspections.

The processing status of audits of manufacturing facilities conducted in FY 2007 at overseas manufacturing sites under authorization from the Minister, as based on the Regulations for Buildings and Facilities for Pharmacies and Manufacturing Establishments is shown below: Number of Audits of Buildings and Facilities for Overseas Manufacturing Sites FY 2005 FY 2006 FY 2007 Drugs* 69 614 387 In vitro diagnostics 9 85 69 Quasi-drugs 29 73 57 Medical devices 127 971 1,682 Total 234 1,743 2,195 * Excluding In vitro diagnostics. Note: Values include withdrawn cases. All cases were document audits.

The Agency conducts on-the-spot inspections, questioning, and sampling with regard to manufacturers, etc., under instructions from MHLW. The number of on-the-spot inspections - 77 -

conducted in FY 2007 is shown below: Number of On-the-spot Inspections FY 2005 FY 2006 Drugs* 15 11 Domestic In vitro diagnostics 0 0 manufacturers Medical devices 0 0 Drugs* 2 3 Foreign In vitro diagnostics 0 0 manufacturers Medical devices 0 2 Total 17 16 * Excluding In vitro diagnostics

FY 2007 27 1 2 5 0 0 35

The Agency conducts simple consultations on GMP/QMS audits. The number of simple consultations on GMP/QMS audits conducted in 2007 is shown below: Number of Simple Consultations Conducted for GMP/QMS Inspections FY 2007 Pharmaceuticals* 28 In vitro diagnostics 3 Quasi-drugs 0 Medical devices 10 Total 41 * Excluding In vitro diagnostics. (iii) Use of outside experts

The Agency continued with procedures to commission external professionals as outside experts for the Agency in order to obtain specialized opinions relating to scientifically important matters during Expert Discussions, etc., for reviews and safety measures. (As of March 31, 2008, the number of commissioned experts is 896 including outside experts commissioned for matters relating to safety measures.) (iv) System development for more efficient review services

In addition to a new application/review system used by the Agency, Pharmaceutical and Food Safety Bureau in MHLW, Regional Bureau of Health and Welfare, prefectural governments, pharmaceutical companies, etc, the system for review operations used by the Agency is comprised of the following individual systems necessary for executing reviews, audits, and management of commission: (i) support system for surveys on pharmaceuticals, etc., (ii) new drug database system, (iii) device system, (iv) conformity audit support system, (v) medical device survey support system, (vi) clinical trial database system, (vii) eCTD viewer system, (viii) medical device malfunction reporting system, and (ix) management system for information on adverse drug reactions*. *(viii) and (ix) are for reference only. With this new application/review system, the Agency is able to manage the progress for the entire process, from acceptance of applications and notifications for marketing approval and business license on pharmaceuticals, quasi-drugs, cosmetics and medical devices, until their enforcement. In addition, the Agency uses this system for operations related to official licenses, such as the development of application data (application software), acceptance of the application data, data

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exchange among review and audit authorities, recording of review memorandums, preparation of approval certificates and management of the approval registration list. In FY 2007, the Agency reviewed the structure and procurement method of the new application/review system in order to achieve the Mid-term targets and the Mid-term plan. At the same time, the Agency conducted the following system developments to promptly and efficiently perform review and audit services. 1)

Transition to the integrated database environment of the device system

Upon expiration of the lease period of the medical device review system, the Agency shifted to the existing database environment (integration with the new application/review system). Database integration resulted in a reduction in operational management workload and achieved smooth monitoring and coordination of the linkages between systems. Associated with database integration, the Agency repaired the new application/review system to successfully achieve a remarkable reduction in the number of errors in the new application/review system. Prior to the repair, over 200 errors were reported each day. 2)

Repair of the support system for surveys on pharmaceuticals, etc.

Resulting from the change to JAN codes, changes were made to ingredient codes and ingredient specifications. The Agency responded to those changes by making appropriate repairs to the support system. System functions were also reinforced for improved efficiency of reviews and audits, including improvement in fax transmission capability for inquiries or replacement instructions, and the enhancement of slip preparation capability for audit-related services. 3)

Outsourcing of the service to support requirement definition, etc. related to review function for eCTD

In order to further improve the efficiency of review services for the diffusion of applications for approval in eCTD format, the Agency outsourced the service to support requirement definition, etc. for the review comment management function to eliminate the need for the provision of paper documents in the review procedure. (v) Reinforcement of partnerships with foreign regulatory authorities

In order to reinforce the structure for international operations, the Agency divided the Training and International Division into the Human Resources Development Division and the International Affairs Division to enhance the processes of information gathering and provision. Also, the Agency promoted reinforcement of partnerships with regulatory authorities in the U.S. and Europe relating to operations for reviews and post-marketing safety measures, as well as with those of Asian countries where more clinical trials are conducted, through dispatching and welcoming trainees. In order to promote reinforcement of partnerships with the regulatory authorities of the U.S. and Europe as well as with those of Asian countries where clinical trials are conducted, the Agency participated in international conferences such as for ICH, GHTF and PDG, as well as in meetings of for OECD and WHO, and promoted cooperation with relevant countries with regard to developing international guidelines. The Agency also provided lectures on its review services and

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safety measures at DIA Annual Meeting in the U.S., at DIA EURO Meeting in Spain, at APEC Network Meeting in Taiwan, and at IFPMA Asian Regulatory Conference in Malaysia, etc. to improve the international recognition of the Agency. The Agency also made efforts to expand its cooperative framework with Asian countries by visiting China, South Korea, and other countries (refer to II-Part 4.2.(1)-(v)-a., Approaches Toward International Harmonization such as Through ICH). The Agency also implemented the following measures to further strengthen its partnerships with foreign regulatory authorities. 1) The Agency collected information on the review system and safety measures at FDA (Food and Drug Administration), EMEA (European Medicines Evaluation Agency), etc. The Agency also exchanged information with FDA and EMEA on methods for conducting operations, etc. The Agency also participated in the 2nd Meeting of Regulatory Officials in Europe, USA, and Asia held in Ireland in December 2007, and exchanged notes with regulators in various countries including FDA. 2) It was decided that the 2008 East Asian Pharmaceutical Regulatory Symposium, which aims to establish a cooperative relationship in East Asian countries centering on Japan, China, and South Korea, would be held in Tokyo in April 2008. The Agency served as a liaison for the countries involved and made preparations for the symposium. 3) Based on the Administrative Rules on Overseas Training on a Long-term Basis, the Agency dispatched one employee each to EMEA and OECD after recruiting personnel who were interested in being dispatched and screening the applicants. 4) The Agency received foreign trainees, including four from Indonesia, one from the U.S. (Mansfield trainee), and four from China. (vi) Evaluation of the latest technologies, such as biotechnology and genomics and cooperation in developing national guidelines

As the Agency is required to raise the standards for guidance and review techniques for the latest technologies such as biotechnology and genomics, the Agency utilized outside experts with a high level of knowledge and cooperated in developing national guidelines for reviewing products to which new technology has been applied (notification regarding applications for type 1 use under the Cartagena Law, notification regarding products derived from cellular and tissue, evaluation guidelines regarding biosimilars/follow-on biologics, and guidelines for clinical vaccine research). Recombinant human serum albumin (HSA), which is important in preventing infections, requires caution for yeast allergy, but has been approved for the first time worldwide. Autologous cultured epidermis has become the first-approved regenerative medicine product in Japan. In addition, the precipitated H5N1 influenza vaccine has been approved as a measure against the spread of the new influenza virus (H5N1 strain). In order to study effects on the safety and efficacy of pharmaceuticals by genetic factors of individual patients, and to administer pharmaceuticals to each patient in more appropriate conditions, there are expectations for applications towards pharmaceutical development of pharmacogenomics. However, since there are still many aspects to be considered, such as how pharmacogenomics should be used in clinical trials and approval reviews, the Pharmacogenomics Discussion Group (PDG) was established within the Agency to collect information from a scientific standpoint while cooperating with MHLW and commencing reviews directed toward developing specific guidelines. In FY 2007, PDG held seven unofficial meetings with the private sector to share information on pharmacogenomics and exchange opinions.

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In January 2008, the 2nd PMDA Biologics Symposium was held by PMDA with reviewers participating from South Korea and Canada, in addition to FDA and EU nations. The purpose of the symposium was to conduct international exchange of up-to-date information relating to review items on biologics, such as cellular and tissue-derived products and genetically-modified proteins, so that such information can be applied to consultations and review services. The Agency held five meetings for specialized discussions on pharmaceutical names and reported 29 Japanese accepted names (JAN) to MHLW. Five application consultations for international nonproprietary names (INN) were also conducted. The Agency participated in the WHO-hosted conference on INN in May and November. Note: JAN = Japanese Accepted Names INN = International Non-proprietary Names (vii) Promotion of appropriate clinical trials

To improve the quality of clinical trials in Japan, the Agency informed healthcare professionals and patients of appropriate clinical trials through its website and public relations, taking into consideration the results of field research at medical institutions, etc. For the purpose of contributing to the promotion of the development of clinical trial systems at medical institutions (from which trainees are dispatched), the Agency implemented Training for Clinical Research Coordinators (beginner training, lectures in September 2007 and practical training from October 2007 to February 2008; advanced training, lectures from November 2007 to January 2008; data management training, lectures and practical training in February 2008) to pharmacists and nurses from medical institutions. Trainees in FY 2007 Beginner training Advanced training Data management training

137 94 146

On the Agency’s website, the Agency disclosed case examples of GCP audits that it is implementing and for which there have been many suggestions. (viii) Prompt provision of information such as review reports

In promoting appropriate use of pharmaceuticals and ensuring transparency of approval reviews, the Agency has, with the understanding and cooperation of relevant companies, and also with the cooperation of MHLW, posted information on the approval of new drugs, etc., on the Postmarketing Safety Information site of the Agency’s website, as follows: Review reports on new drugs

Based on the contents of the submitted applications, new drugs are classified into two categories: those that are to be discussed in the Drug Committees of the Pharmaceutical Affairs and Food Sanitation Council (PAFSC) (hereinafter referred to as “discussion items”) and those that are to be reported to the Drug Committees of PAFSC (hereinafter referred to as “reported items”). From among the information on newly approved drugs, Review Reports that describe the status and results of reviews, and Summaries of Application Dossiers that contain overviews of application dossiers, are subject to provision of information for discussion items, whereas Review Reports are

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considered subject to provision of information for reported items. Information provision is implemented upon conferring with the relevant companies regarding the contents for disclosure for each item and based on the Notification Issued by the Director of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW. In FY 2007, the Agency finalized 77 review reports and 30 summaries of application dossiers to be officially disclosed. Review reports on new medical devices

It was decided that the Agency should publish review reports on medical devices in response to the issuance of the Notification by the Director of the Office of Medical Devices Evaluation, Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated September 21, 2005, which specifies the publication procedures, etc. In FY 2007, the Agency disclosed review reports for 7 applications. Review reports on OTC drugs and quasi-drugs

It was decided that the Agency should sequentially publish review reports on OTC drugs and quasi-drugs in response to the issuance of the Notification by the Director of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, MHLW, dated March 31, 2006, which specifies the publication procedures, etc. In FY 2007, the Agency disclosed 9 review reports for OTC drugs and 2 for quasi-drugs. (ix) Preparation and publication of the english version of review reports

In order to provide information on the Agency’s review services and post-marketing safety measures to overseas countries, the Agency decided to post the English version of the review reports on the Agency’s website. In FY 2007, the Agency prepared and published the English version of two review reports. 4.2.(3) Enhancement/reinforcement of post-marketing safety measures (reinforcement of information management and risk management system) (i)

Basic direction of post-marketing safety measures

In order to improve the safety of marketed pharmaceuticals and medical devices, and to enable patients and healthcare professionals to use them properly, the Agency has been progressing with operations so that reviews and safety measures function in such a way that they are inseparable, by collecting and examining safety information efficiently, processing the information speedily and providing appropriate and accurate plans for safety measures and easily understandable safety information promptly. There are approximately 126,000 reports on adverse drug reactions submitted to PMDA from within and outside of Japan each year, and approximately 17,000 reports on malfunctions of medical devices from within and outside of Japan are submitted to PMDA yearly. The Agency inputs this information into a database and promotes the sharing of this information with MHLW. In addition, the Agency is making efforts to take effective safety measures for pharmaceuticals and medical devices in the post-marketing stage by enhancing cooperation between the review

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divisions and safety divisions, as well as between the relief divisions and safety divisions. In addition to reviewing such adverse reaction reports and malfunction reports with representatives from MHLW every week based on daily reviews conducted by the supervising team in PMDA, the Agency gathers opinions from professionals once every 5 weeks and proposes necessary safety measures, such as for revision of precautions in package inserts. Issues that require particular urgency are responded to immediately. The Agency distributes important safety information, such as on revision of precautions in package inserts, to healthcare professionals and people in the private sector by e-mail whenever such information is issued, and is also making efforts to enhance and reinforce the provision of information by posting various safety information regarding package inserts, labeling, etc., on the Post-marketing Safety Information site of the Agency’s website: http://www.info.pmda.go.jp/. The Agency is in the process of implementing a method for detecting and analyzing new safety information by finding relevance with different kinds of information on adverse drug reactions (data mining method) during the effective period for the Mid-term plan in order to establish measures to prevent adverse drug reactions from occurring. In addition, the Agency plans to enhance safety measures by working on those that are capable of “predicting and preventing” through active scientific evaluation and analysis, and by building a sentinel medical institution network and applying the data mining technique to detect signals. Collection of adverse reaction reports, etc. 1)

Number of reports relating to pharmaceuticals Reports from companies (cases of adverse drug reactions, Japanese) (cases of infections caused by pharmaceuticals, Japanese) (cases of adverse drug reactions, foreign) (cases of infections caused by pharmaceuticals, foreign) (research reports) (foreign corrective action reports) (periodic infection reports)

Reports from medical professionals Total

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FY 2004

FY 2005

FY 2006

FY 2007

82,624 (25,142)

92,678 (24,523)

106,285 (26,309)

125,938 (27,988)

(306)

(228)

(251)

(269)

(54,312) (111) (1,311) (420) (1,022)

(64,650) (666) (971) (563) (1,077)

(77,314) (32) (818) (485) (1,076)

(95,015) (21) (858) (695) (1,092)

4,594

3,992

3,669

3,891

87,218

96,670

109,954

129,829

Changes in the Number of Reports on Adverse Drug Reactions/Infections 100,000

95,036

from companies (domestic reports) from companies (foreign reports) from medical institutions 77,346

80,000 65,316 60,000

54,423

40,000 25,448

28,257

26,560

24,751

20,000 4,681

3,992

3,891

3,669

0 FY 2004

2)

FY 2005

FY 2006

FY 2007

Number of reports relating to medical devices FY 2004

FY 2005

FY 2006

FY 2007

16,264 (11,515) (4,210) (157) (287) (95)

11,802 (6,222) (5,012) (37) (436) (95)

12,770 (9,310) (2,880) (36) (482) (62)

17,142 (13,842) (2,708) (15) (525) (52)

Reports from companies (cases of malfunctions of medical devices, Japanese*) (cases of malfunctions of medical devices, foreign*) (research reports) (foreign corrective action reports) (periodic infection reports) Reports from medical professionals Total

622

445

424

434

16,886

12,247

13,194

17,576

* There was no report of infection cases by medical devices.

Changes in the Number of Reports on Medical Device Malfunctions 16,000

14,000

from companies (domestic reports) from companies (foreign reports) from medical institutions

12,000

11,515

13,842

10,000

9,310

8,000 6,222 6,000

5,012 4,210

4,000 2,880

2,708

2,000 622

445

434

424

0 FY 2004

FY 2005

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FY 2006

FY 2007

Flowchart for Processing Adverse Reaction Reports Healthcare professional

Information regarding overseas regulations and publications Marketing Authorization Holders Collection, confirmation, analysis of ADR information Considering safety measures

PMDA Reporting

Data maintenance

Receipt of ADR Reports Daily confirmation in a team

Hearing

Corporate hearing Research and analysis of necessary data

Further considering safety measures A/N

Notifying considered issues /exchanging opinions

Contact and meeting with MHLW A/N

Contact and meeting with MHLW every week

Urgent response to issue with high probability of inflicting heavy damage on the nation

Discussion with experts

Information provision via Internet,etc.

Dissemination of information Implementing safety measures

All info sharing

Database

Cases difficult to judge medical significance

Results of review/analyses

Requesting revision of package insert, giving guidance for product improvement, requesting recall, etc.

Reporting

Ministry of Health, Labour and Welfare (MHLW)

Compiling information every 5weeks and notifying

Planning /development of safety measures

Notifying the results

Pharmaceutical Affairs and Food Sanitation Council Implementing safety measures

(ii) Introduction of a new method (review of the data mining method)

The Agency is aiming to implement a method for detecting and analyzing new safety information by finding relevancy in different kinds of information on adverse drug reactions (data mining method) in order to establish measures for preventing adverse drug reactions. Reference: What Is the Data Mining Method? The data mining method is technology that extracts, from among a large amount of data accumulated in the database, highly correlative events that occur frequently and simultaneously. The term “data mining” refers to the activity of retrieving, or “mining,” only useful information from the database. Specifically, the data mining method is a method for detecting combinations (signals) of pharmaceuticals and adverse drug reactions that are likely to have a causal relationship from the database of individual cases of adverse drug reactions.

Regarding the basic signal extraction techniques (i.e., six techniques including those introduced in foreign countries) that were subjected to detailed review in FY 2005 (in terms of the number of detections, increase or decrease in the number of detections, or quality of detection), the Agency narrowed them to three (ROR, GPS, and BCPNN) as a result of sensitivity and specificity analysis and correlation analysis conducted together with advanced review (stratified analysis, analysis of interaction with coadministred drugs, and adverse-reaction grouping) by the end of FY 2006. In FY 2007, the Agency conducted surveys on how the data mining technique was used by regulators in foreign countries and interviewed personnel in charge of adverse-reaction evaluation on the subject of operations processes. The Agency prepared the specifications of a new database system that could utilize the data mining method as a support tool that matches the operations flow of a new safety measures operation, and also launched the development of an operations support system supporting all aspects of safety measures. The Agency also conducted an

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experiment to evaluate the amount and contents of combinations of drugs and adverse drug reactions with respect to the function of primary screening, and to ascertain whether a signal is detected. In addition, the Agency developed a tool based on correlation analysis to support nonroutine analytical operations. This tool will be used as a means to advance data mining, and the Agency has started reviewing its utility. In FY 2008, the Agency plans to introduce the system to safety measures operations by the end of the year (upon completion of the Midterm target period) after a trial operation. The status of reviews relating to the implementation of safety measures for the data mining method is posted on the following website: http://www.info.pmda.go.jp/kyoten/dm.html Introducing the Data Mining Method into Safety Measures

Schedule for Introducing the Data Mining Method (Planned)

Study Group

End of FY 2006

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Introduction to Operation

Development of Work System

FY2008 Trial Operation

FY2007 Establishment of Technique

Examination of Signal detection Methods

FY2006

Trial Operation

FY2005

End of FY 2008

(iii) Building a sentinel medical institution network

As the Agency plans to emphasize safety measures in the post-marketing stage in accordance with the Midterm-plan, it is aiming to establish a sentinel medical institution network (a network of medical institutions organized according to specific therapeutic categories, products and diseases, of which the purpose is to collect information intensively within a certain period of time from the medical institutions in order to improve the accuracy of analysis of information on adverse drug reactions). The Agency has also continued to conduct the survey on anti-cancer combination therapies (22 therapies). After finishing follow-up of all relevant patients at the end of June 2007, the Agency studied data entry and analysis techniques, and in February 2008 completed final analysis on 3,505 registered patients and a total of 563 reported cases of adverse drug reactions from 75 participating institutions. The final report is to be posted on PMDA website in June 2008 (a target date). Survey on Anti-cancer Combination Therapies Institution C

Sentinel medical institution A

Inform, request

Academic societies

Examining patients in each institution for a year Grasping actual situation of prescribing and the number of ADR cases Occurrence rate of ADR Cooperation

Reference:

Information

Grasping Number of conducted treatment Actual situations Serious ADRs that seem to be related to the treatment

Request for cooperation on survey

Institution B

Institution D Institution

E Investigation of ADRs

Feedback of Liaison analysis results etc.

Relevant companies Relevant

Detailed investigation & case analysis

PMDA Case report

Analysis and evaluation of accumulated information

Therapies Subject to Survey on Anti-cancer Combination Therapies (22 Therapies*) *The numbering for the 22 therapies is unique to PMDA as therapies were categorized based on the implementation methods of the survey. 1. AC therapy (Breast cancer) 2. Pamidronate Disodium (Breast cancer) 3. (1) Ifosfamide single therapy (Bone and soft tissue tumor) (2) Doxorubicin single therapy (Bone and soft tissue tumor) (3) Ifosfamide and doxorubicin combination therapy (Bone and soft tissue tumor) 4. (1) Ifosfamide (Pediatric solid tumor) (2) Doxorubicin (Pediatric solid tumor) (3) Etoposide (Pediatric solid tumor) 5. AP therapy (Uterin corpus cancer) 6. Cisplatin (Malignant bone tumors) 7. VAD therapy (Myeloma) 8. Fluorouracil (Head and neck cancer) 9. Procarbazine/vincristine (Brain tumor) 10. Fluorouracil/leucovorin (Colon cancer)

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11. (1) ESHAP (Malignant lymphoma) (2) DHAP (Malignant lymphoma) 12. (1) Cisplatin (Pediatric solid tumor) (2) Carboplatin (Pediatric solid tumor) (3) Cisplatin (Medulloblastoma) 13. Actinomycin (Ewing’s sarcoma family of tumors) 14. (1) EC therapy (Breast cancer) (2) CEF therapy (Breast cancer)

In collaboration with MHLW’s evidence collection for pediatric pharmacotherapy, the Agency conducted studies to obtain pediatric safety data for pharmaceuticals whose package inserts note that safety in pediatric patients has not been established, if their revisions are requested by academic societies, or if pediatric safety data from multiple companies is considered necessary, in order to understand problems associated with collecting pediatric safety data. In 2007, additional patient data for the retrospective cohort study on hyponatremia caused by the administration of maintenance fluid using electronic medical records (conducted in 2006 as a pediatric trial study using 1,291 case data from three institutions) was obtained from one institution, and the data was analyzed. Subjects, whose serum sodium levels decreased from 136 mEq/L or higher at baseline to below 136 mEq/L after administration, were defined as hyponatremia cases. In the group of 487 cases in which serum sodium values were available before and after administration of the maintenance solution, 91 cases of hyponatremia were found. Three of these cases were classified as grade 2 according to the severity of adverse drug reactions. This study, which was conducted based on the secondary use of electronic medical records of medical institutions, revealed many problems such as those associated with data extraction and processing, and with the use of laboratory and diagnosis (disease name) data. The results of the study were published as a report on the Agency’s website in March 2008. (iv) Review of the system for comprehending and evaluating medical device malfunctions

The implementation status of surveys and the status of reviews in the sectional committee in charge in FY 2006 regarding coronary stents and implantable central venous access port system (hereinafter referred to as “implantable ports”) were reported to the Discussion Group for the System for Evaluating Medical Device Malfunctions in 2007. The status of implementation in FY 2007 was as follows: a) Implantable ports: In 2007, malfunctions were classified by category in order to evaluate malfunctions that were not considered to be due to structural defects. A survey was conducted for the purpose of evaluation, in which registered patients were followed up for one year and preliminary data up to August 2007 was tabulated. In 13 of the 112 patients from 12 institutions who received the implant, 21 problems including subcutaneous leakage of the drug solution, phlebitis, infection of the implant site, changes in catheter position, and resistance during insertion were reported. These reports were examined at the port subcommittee in October 2007. The results of the examination will be published on the Agency’s website in April 2008. b) Coronary stents: In FY 2007, a study protocol was written for the implementation of a survey expected to involve 26 institutions, and have a target patient number of 10,000, and a fiveyear follow-up period. In June 2007, the Agency selected parties to commission work such as collection of survey slips; and in February 2008, it commenced data collection efforts for 22 institutions that agreed to participate in the study.

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Cardiac pacemakers and other tracking medical devices: In FY 2007, a Discussion Group for the Collection and Evaluation of Data for Tracking Medical Devices, comprising specialists, was established. In February 2008, discussions aiming toward the establishment of a tracking system for ventricular assist devices were held.

Reference: Tracking Medical Devices Medical devices for which it is obligatory for a marketing authorization holder, etc., to create and store records on contact information of the users so that prompt and appropriate responses can be taken easily if a malfunction occurs with the medical device, etc. Under the Pharmaceutical Affairs Law, such devices are categorized as designated medical devices.

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Targeted System for Scientific Evaluation

MHLW Relevant Companies

Information provision, etc.

Information provision electronically on occurrence rate, evidence, etc.

Participants (Medical institutions) Provision of raw data, etc.

Medical device manufacturers/ Medical institutions Report Electronic dissemination of evaluated results

PMDA Improvement in evaluation and analysis Study Meeting of Mid-term plan

Sectional committee

Experts

Data Registration Center Information provision on safety and efficacy

Public

(v) Proper implementation of surveys on reports on adverse drug reactions and medical device malfunctions

Adverse drug reaction reports, medical device malfunction reports, infection reports, and research reports etc., from marketing authorization holders of pharmaceuticals and medical devices under the Pharmaceutical Affairs Law have been required to be submitted directly to PMDA starting in April 2004. These reports are input into PMDA database and managed so that information can be shared with MHLW. In addition, adverse drug reaction reports, reports on infections, etc., that are submitted by healthcare professionals (doctors, pharmacists, etc.) to MHLW are input into PMDA database and managed so that information can be shared with MHLW. In conducting surveys on reports on adverse drug reaction and medical device malfunctions, the

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Agency has been closely working with the Safety Division of the Pharmaceutical and Food Safety Bureau at MHLW to hold weekly reviews on both pharmaceuticals and medical devices, gather opinions from experts approximately once every 5 weeks, and report on proposals for necessary safety measures, such as for revision of precautions in package inserts. Issues that require particular urgency are responded to immediately. The number of reports made to MHLW on items for which measures were necessary (such as for revision of package inserts) in FY 2007 is as follows: FY 2004 FY 2005 FY 2006 FY 2007 Pharmaceuticals 133 240 131 204 Medical devices 15 18 4 10 Medical safety* 2 2 2 1 * “Medical safety” indicates the number of reports on near- incident cases, which are collected by the Japan Council for Quality Health Care. The Agency analyzes the data in the light of pharmaceuticals and medical devices expertise, after hearing opinions from experts, and reports the analysis results for safe use of pharmaceuticals and medical devices to MHLW.

Safety measures taken by MHLW in FY 2007 based on reports from PMDA are as follows (includes overlapping measures): FY 2004

FY 2005

FY 2006

FY 2007

Instructions for revision to 149 212 131 202 precautions in package insert Pharmaceuticals Posting articles and cases on the Safety Information on 33 26 24 86 Pharmaceuticals and Medical Devices Instructions for revision to precautions in package insert or 7 7 0 8 notifications to instruct selfMedical Devices inspection Posting articles on the Safety 6 7 0 3 Information of Pharmaceuticals and Medical Devices Note: These numbers indicates those of safety measures taken by MHLW based on the report from PMDA.

With regard to cooperation with review divisions within PMDA, approaches such as participation of personnel from the Office of Safety in the review process (Expert Discussions, etc.) of new drugs and new medical devices, and cooperation in adverse drug reaction case evaluations for early post-marketing stage vigilance (EPPV) are being implemented. As for cooperation with the Office of Relief Fund, information such as names of pharmaceuticals and adverse drug reactions in judged cases for payment/rejection of payment of benefits has been provided and is reflected in safety measures. In FY 2007, the Agency took the following approaches to appropriately collect, organize, and examine the adverse drug reaction reports and medical device malfunction reports submitted by the private sector and medical institutions. a. Improved the efficiency in receiving adverse drug reaction reports by using data input tools b. Increased the staff members specialized in data input c. Updated the master files consisting of pharmaceutical and company names d. Encouraged staff members to attend academic societies (total of 22 participants) and

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gathered information through the academic societies that they participated in Regularly held liaison meetings on both pharmaceuticals and medical devices every week with MHLW

e.

(vi) Digitization of adverse drug reaction reports and medical device malfunction reports

In FY 2007, as part of effectively and efficiently collecting safety information through utilizing IT, the Agency developed an environment that allows for easy online reporting in order to promote transmission of information on adverse drug reactions, infections, etc. through the Internet. In addition, the Agency requested for cooperation from the private sector and aimed to secure an online reporting rate of 80%. For this purpose, in addition to releasing data input tools on the Web and developing an environment that allows for easy data transmission, the Agency monitored the electronic reporting rate monthly and directly asked major companies that had not yet implemented online reporting to implement such a system. The Agency also made efforts to encourage implementation of online reporting by making use of opportunities such as lectures at academic conferences. As a result, a reporting rate of 91.1% on a full-year basis was achieved in FY 2007, exceeding the target of 80%. Status of Online Reporting for Adverse Drug Reaction Reports, etc. FY 2004 FY 2005 FY 2006 FY 2007 Electronic reporting rate (full year) 69.1% 86.4% 90.4% 91.1% * Online reporting started from October, 2003. As of April 2004, the electronic reporting rate was 50%. The target of the Mid-term plan: 80% or more of average annual electronic reporting rate by the end of effective period of the Mid-term target The target of FY 2007 plan: Ensuring the 80% of electronic reporting rate Status of Online Reporting for Malfunction Reports FY 2004 FY 2005 FY 2006 FY 2007 Electronic reporting rate (full year) 36.8% 86.9% 53.6% 22.1% Note: In FY 2007, the administrative organ in charge was changed from MHLW to the Ministry of Internal Affairs and Communications (MIC). Online reporting was suspended for approximately one month to facilitate the system switch. No target was established in the Mid-term plan for electronic reporting of malfunctions. (vii) Establishment of post-marketing safety system based on seedback of information a.

Feedback to the private sector 1)

Access to information on adverse drug reactions relating to a company’s own products

In order to contribute to enhancing the risk management system in the private sector, the Agency is building and enhancing a system that enables a company to access information relating to its own products from among the information on adverse drug reactions reported by medical institutions and other companies. In FY 2005, the Agency disclosed all of the information on adverse drug reactions reported by the private sector after FY 2004, and subsequently started to release information as line lists in January 2006. At the end of March 2008, the agency disclosed 84,094 adverse drug reaction reports and 34,226 medical device malfunction reports that had been submitted up to the end of

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March 2007. 2)

Responses to consultations from the private sector

In order to contribute to the improvement of safety measures in the private sector, the Agency responded to various consultations (on pharmaceuticals, medical devices, and medical safety) from the private sector. Specifically, these medical safety consultations related to revisions to package inserts, post-marketing risk management plans, creation of drug guides for patients, naming and labeling of pharmaceuticals to prevent medical accidents, and improvements in products to prevent medical accidents based on analyses of near-incident cases. The number of consultations by category for FY 2007 is shown below: FY 2004 FY 2005 FY 2006 Pharmaceuticals 513 557 567 Medical devices 722 553 292 Medical safety 46 46 44

FY 2007 486 260 166

One reason for the reduction in the number of consultations on medical devices is considered to be the improvements in knowledge and understanding on the part of the consulting party as a result of the consultation services provided from FY 2004. On the other hand, the increase in the number of consultations on medical safety is attributed to the sudden rise in the number of pre-application consultations for name substitution of pharmaceuticals in 2007, as a preventive measure against medical accidents for pharmaceuticals whose names are similar to those of other products, or whose labels do not contain the name or quantity of the active ingredient. The Agency handled all cases in an appropriate and speedy manner. b.

Feedback to healthcare professionals During FY 2007, the Agency took the following approaches to provide safety information on pharmaceuticals and medical devices to the public as well as healthcare professionals by using the Internet. 1)

Prompt posting of information on the agency’s website

The Agency posted information on revisions to package inserts of prescription drugs, etc., on its website within two days after receiving such information. To improve the supply of information on generic drugs, the Agency is asking for revisions to include bioloequivalence test and other results (in accordance with Improving the Supply of Information on Generic Drugs, Notification No. 0324006 of the Safety Division, issued by Director of the Pharmaceutical and Food Safety Bureau [PFSB], dated March 24, 2006) by the end of March 2008. All package insert information on the Agency’s website designed to provide information was revised before the end of January 2008. 2)

Provision of information relating to package inserts of OTC drugs

Following the revision of the Pharmaceutical Affairs Law in June 2006, the Agency commenced posting package inserts of OTC drugs on the Agency’s website in March 2007, and there were 7,437 package inserts posted on the site as of the end of March 2008. The pupose of this is to ensure that information supply and consultation systems

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are adapted to the degree of risk associated with the pharmaceuticals, and that experts engaged in selling pharmaceuticals have qualifications, and to develop and maintain an environment that can respond appropriately to consultations as well as provide appropriate information. 3)

Preparation of information on in vitro diagnositics package inserts for posting it on the agency’s website

Information on package inserts of prescription drugs, medical devices, and OTC drugs are provided on the Post-marketing Safety Information site of the Agency’s website to ensure their correct usage. Package insert information for in vitro diagnostics is targeted to be available within FY 2008. Through cooperation with industry groups, the Agency has conducted pilot tests to view the information on the website under test conditions, and developed tools and systems to convert the package inserts into electronic format. 4)

Provision of manuals for management of individual serious adverse drug reactions

The manuals for management of individual serious adverse drug reactions made by MHLW have been made available on the Agency’s website since November 2006. In FY 2007, manuals for 16 new items were added to the website (total number of items, 25). These manuals contain information on methods of early detection of serious adverse drug reactions based on symptoms for patients and their family members, and methods of their diagnosis and management for healthcare professionals. 5)

Implementation of the information delivery service for pharmaceuticals and medical devices

The information delivery service for pharmaceuticals and medical devices, a service providing safety information such as revisions to package inserts and Class I recalls, is provided via e-mail to healthcare professionals who subscribe to the service. A total of 11,965 e-mail addresses were registered as of March 2008. Approximately 30% of these subscribers were hospitals and clinics, approx. 20% were pharmacies, approx. 10% were dentist clinics or other medical facilities, approx. 20% were marketing authorization holders, approx. 10% were distributors, and approx. 10% were classified as other.

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E-mail Information Service on Pharmaceuticals and Medical Devices

Number of Push E-mail Service Subscribers by Subscription Content in FY 2007 Subscription content Number Recalls (Class I) 43 Pharmaceuticals and Medical Devices Safety information 11 Drug Safety Update (DSU) 10 Revision of PRECAUTIONS of pharmaceuticals 15 Revision of PRECAUTIONS of medical devices 5 Other 3 Total 87 6)

Provision of medical safety information

The Agency has been extracting, evaluating, and examining near-incident cases associated with pharmaceuticals and medical devices from the Project to Collect Information on Medical Incident Reports published by the Japan Council for Quality Health Care. In FY 2007, 412 cases associated with pharmaceuticals and 308 cases associated with medical devices were evaluated, and the results were reported to MHLW. For 292 cases for which deliberations by MHLW were completed, the details of the cases were posted on the Post-marketing Safety Information site of the Agency’s website. Items

Pharmaceuticals

Medical devices

Total subject cases: 292 cases 1) Cases in which safety measures for the use of pharmaceuticals/medical devices by the marketing authorization holders etc. were considered necessary or possible. 2) Cases in which measures have already been taken, or are currently being investigated, by the marketing authorization holder etc.

170

122

4

7

18

25

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3) Cases in which a lack of information is considered to hinder the marketing authorization holder’s investigations for measures, or cases that were considered to be a result of human error or human factors.

148

90

In addition, in November 2007, the Agency started to provide medical safety information, which use charts and other tools so that healthcare professionals can easily understand precautions for safe use based on collected near-incident cases and adverse drug reaction and manfunction reports stating much the same events repeatedly or notifying revisions to package inserts repeatedly, while referring to opinions given by healthcare professionals such as physicians, pharmacists, nurses, and clinical engineers and specialists in fields such as ergonomics. In FY 2007, the following three pieces of PMDA Medical Safety Information were posted on the Post-marketing Safety Information site of the Agency’s website.

7)

No.1 No.2

Month and year published Nobember 2007 November 2007

No.3

January 2008

PMDA safety information titles Points to note in case of obstruction of feeding tube Recall of Resuscitators Precautions against improper connection of speech valves etc. to tracheostomy tubes

Disclosure of adverse drug reaction cases

From among the contents of all adverse reaction reports that have been submitted by the private sector since April 2004, the Agency has disclosed information on fiscal year reported, sex, age, primary disease, suspected drug, adverse event, suspected concomitant drug, and outcome on the Post-marketing Safety Information site of the Agency’s website, since January 2006. By the end of March 2008, the Agency posted 84,094 reports submitted up to September 2007. Reference: For cases with a fatal outcome, evaluations on the causality between the suspected drug and death is classified into the following three categories and disclosed on the website. A: Cases for which the causality between the suspected drug and death cannot be ruled out Cases for which the possibility that the adverse event alleged to be associated with the suspected drug caused the death cannot be ruled out, after comprehensive judgment from medical and pharmaceutical perspectives and in view of various factors such as the relationship between the primary disease and the death, its pharmacological viewpoint and the time that had elapsed. B: Cases for which no causality between the suspected drug and death can be found Cases for which it is not recognized that the adverse event alleged to be associated with the suspected drug caused the death, after comprehensive judgment from medical and pharmaceutical perspectives and in view of various factors such as the relationship between the primary disease and the death, its pharmacological viewpoint, and the time that had elapsed. C: Cases for which the causality between the suspected drug and death cannot be evaluated because of lack of information Cases for which the causality between the suspected drug and death cannot be evaluated because of insufficient information or inappropriateness of the intended use or usage method of the drug, etc.

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8)

Disclosure of medical device malfunction cases

From among the contents of all reports on medical device malfunctions that have been submitted by the private sector since April 2004, the Agency has disclosed information on fiscal year reported, sex, age, outcome, generic name, condition of the medical device, and patient adverse event on the Information Page of the Agency’s website designed to provide information on pharmaceuticals and medical devices, since March 2006. By the end of March 2008, the Agency posted 34,226 reports submitted up to September 2007. Reference: For cases with a fatal outcome, evaluations on the causality between the medical device used and death is classified into the following three categories and disclosed on the website. A: Cases for which the causality between the medical device used and death cannot be ruled out Cases for which the possibility that the adverse event alleged to be associated with the medical device used caused the death cannot be ruled out, after comprehensive judgment from medical, pharmaceutical, and engineering perspectives and in view of various factors such as the relationship between the primary disease and the death, the circumstances when the malfunction occurred, the status of maintenance and inspections, and the time that had elapsed. B: Cases for which no causality between the medical device used and death can be found Cases for which it is not recognized that the adverse event alleged to be associated with the medical device used caused the death, after comprehensive judgment from medical, pharmaceutical, and engineering perspectives and in view of various factors such as the relationship between the primary cause and the death, the circumstances when the malfunction occurred, the status of maintenance and inspections, and the time that had elapsed. C: Cases for which the causality between the medical device used and death cannot be evaluated because of lack of information Cases for which the causality between the medical device used and death cannot be evaluated because of insufficient information or inappropriateness of the intended use or usage method of the device, etc.

9)

Support for disclosing relevant information for companies

The Agency developed a new digitalization tool for medical device package inserts with advanced utility and made it available to companies for free. The Agency translated into English the safety information on pharmaceuticals and medical devices prepared by MHLW and posted the translations on the English website of PMDA. c.

Provision of information to general consumers and patients 1)

Implementation of consultations on drugs/medical devices

In order for general consumers and patients to use pharmaceuticals and medical devices safely and securely, the Agency implements a telephone consultation service for drugs and medical devices. Drug consultation services have been carried out since July 1994. Starting in February 2005, consultation services have been available even during lunch breaks. Counseling services for consumers and healthcare professionals regarding generic drugs were launched in May 2007, and 122 consultations have been conducted.

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Counseling services for consumers regarding medical devices were launched in July 2005. In FY 2007, there were 12,477 consultation requests for drugs and 824 requests for medical devices.

Number of phone calls Number of consultations

Number of Consultations on Drugs FY 2002 FY 2003 FY 2004 FY 2005 6,465 7,641 7,137 7,741 (26.4 (31.1 (29.6 (30.0 cases/day) cases/day) cases/day) cases/day) 8,770 9,906 8,790 10,505 (35.8 (40.4 (36.5 (43.4 cases/day) cases/day) cases/day) cases/day)

FY 2006 8,459 (34.5 cases/day) 11,696 (47.7 cases/day)

FY 2007 8,696 (35.5 cases/day) 12,477 (50.9 cases/day)

Contents of Consultations on Drugs Contents of Consultation (1) Safety (2) Indications (3) Administration and Dosage (4) Interaction (5) Active ingredients Other Total

FY 2004

FY 2005

FY 2006

FY 2007

4,211 (47.9%) 1,194 (13.6%)

5,968 (56.8%) 1,132 (10.8%)

5,697 (48.7%) 1,175 (10.0%)

5,731 (45.9%) 1,175 (9.4%)

669 (7.6%)

771 (7.3%)

828 (7.1%)

1,072 (8.6%)

611 (7.0%) 628 (6.0%) 691 (5.9%) 715 (5.7%) 205 (2.3%) 161 (1.5%) 219 (1.9%) 236 (1.9%) 1,900 (21.6%) 1,845 (17.6%) 3,086 (26.4%) 3,548 (28.4%) 8,790 (100.0%) 10,505 (100.0%) 11,696 (100.0%) 12,477 (100.0%)

Number of Consultations by Major Classification of Therapeutic Category (Total of Top 10 Categories) in FY 2007 Others, 2,440, 13.6% Hormone agents, 436, 2.4% Drugs for blood and body fluid, 529, 3.0% Drugs for allergy, 590, 3.3%

Drugs for central nerve system, 7,070, 39.5%

Other metabolic drugs, 603, 3.4% Dermatological agents, 622, 3.5% Drugs for respiratory organs, 844, 4.7% Preparations for antibiotics, 851, 4.7% Drugs for digestive organs, 2,352, 13.1%

Drugs for circulatory organs, 1,582, 8.8%

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Number of Patients (Receiving Counseling) by Age and by Sex in FY 2007 Cases

1600 1400 1200 1000 Unknown sex

800

Females Males

600 400 200 0

0-9

10 - 19

20 - 29

30 - 39

40 - 49

50 - 59

60 - 69

70 - 79

80 -

Unknown age years old

Age

Number of Consultations on Medical Devices with Consumers FY 2005* FY 2006 FY 2007 Number of phone calls 166 (1.0 case/day) 376 (1.5 case/day) 564 (2.3 case/day) Number of consultations 323 (1.9 case/day) 581 (2.4 case/day) 824 (3.4 case/day) * The consultation service has been provided since July 2005. Contents of Consultations on Medical Devices with Consumers Contents of consultation FY 2005 FY 2006 FY 2007 (1) Safety 32 (9.9%) 62 (10.7%) 91 (11.0%) (2) Indications 64 (19.8%) 101 (17.4%) 85 (10.3%) (3) Performance 25 (7.7%) 45 (7.7%) 37 (4.5%) (4) Directions for use 12 (3.7%) 16 (2.8%) 12 (1.5%) Other 190 (58.8%) 357 (61.4%) 599 (72.7%) Total 323 (100.0%) 581 (100.0%) 824 (100.0%) 2)

Publication of the drug guide for patients

The Drug Guide for Patients, the purpose of which is to make it possible for patients to properly understand prescription drugs and enable them to detect serious adverse reactions at an earlier stage, has been posted on the Agency’s website since January 2006. In FY 2007, the Guide contained an additional 33 ingredients in 327 items (which were designated or newly sold thereafter), and 270 ingredients in 1,567 items were posted by the end of March 2008. In accordance with the Guidelines for Developing the Drug Guide for Patients (Notification of the Director-General of the Pharmaceutical and Food Safety Bureau, MHLW dated June 30, 2005), the Agency has reviewed and revised the Drug Guide for Patients while continuously obtaining advice from experts (scientific research by MHLW [research on how to provide patients and people with drug safety information]).

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Package Inserts for Prescription Drugs and Drug Guide for Patients

Package Insert

Drug Guide for Patients

Described in technical terms Exhaustive description of ADRs Those that need attention of doctors and pharmacists are described

Using clear and simple terms that a high school student can understand Showing subjective symptoms of serious ADRs and such ADRs by body parts Such information that requires patients’ attention on how to take drugs and what should be done in case of missing to take them is described

Physicians, pharmacists, etc.

Patients and their family

Can obtain accurate and comprehensive information on the drugs Can get necessary information for appropriate use of the drugs

Explanatory & instructive materials for patients

Can detect serious ADRs early

Can access information on appropriate use of drugs including Proper prescription how to take and instruction for of drugs storage condition

Number of Drug Guide for Patients Published Group of target Pharmaceuticals Antidiabetic agents *

was posted by

Number of component

Number of package insert

Number of item

Jan. FY 2006

10

44

56

2

9

11

3

44

71

8

13

18

91

348

551

53

292

385

76

319

346

Mar. FY 2007

27

72

129

Total

270

1141

1567

Antirheumatic drug * Anticoagulant and antiplatelet agent *

Mar. FY 2006

Antiasthmatic drug * The 100s to 200s of Classification of drugs by Jul. FY 2006 efficacy * The 300s to 400s of Classification of drugs by Oct. FY 2007 efficacy * The 500s, 600s, 700s, 800s of Classification of Jan. FY 2007 drugs by efficacy * Injectable solution

* The numbers of items with asterisk are figures that have been published as of the end of March 2008.

3)

Upgrading Post-marketing Safety Information site of the Agency’s website

In FY 2007, referring to opinions given by the website users, the Agency added icons on the upper part of the top page for linking to content such as Information Related to Pharmaceuticals, Information Related to Medical Devices, and Information for the General Public, and also added icons for links on the information of package inserts, thereby improving the more purpose-oriented user interface.

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With respect to information for the general public, on its revised website, the Agency posted the Drug Guide for Patients, a manual which includes disease-specific countermeasures for serious adverse drug reactions, information on package inserts for OTC drugs, and contact information on the consultation service for pharmaceuticals and medical devices. It also includes Q & As about pharmaceuticals and medical devices, which are questions relatively frequently asked by general consumers in the consultation service for pharmaceuticals and medical devices and answers to them. Updated Post-marketing Safety Information site of the Agency’s website

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Q & As about Pharmaceuticals

Q & As about Medical Devices

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4)

Implementation of post-marketing safety measures workshops

In November 2007 and January 2008, workshops on the effective use of information on safety measures recommended by the Agency were held for healthcare professionals on the theme of “Information on Pharmaceuticals for Appropriate Use—What Information Is Useful for Clinical Settings?” Over 350 participants attended the workshops. The Agency also gave presentations on the recent revision of precautions in package inserts, the effective use of the Post-marketing Safety Information site of the Agency’s website, and the Agency’s consultation services at workshops held by others and at academic meetings.

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Number of Posted Items on the Post-marketing Safety Information Site of the Agency’s Website as of March 2008 Types of provided information

Number of posted information FY 2003 FY 2004 FY 2005

FY 2001

FY 2002

FY 2006

FY 2007

11,045 sheets

11,380 sheets

11,516 sheets

11,706 sheets

Medical devices

-

-

-

-

OTC drugs

-

-

-

-

-

-

-

-

153 cases

192 cases

231 cases

267 cases

294 cases

323 cases

20 cases

23 cases

23 cases

23 cases

24 cases

24 cases

-

1 cases

11 cases

21 cases

31 cases

41 cases

-

-

42 cases 10 cases 2 cases

-

-

-

-

-

-

45 cases 20 cases 33 cases 3,884 cases 1,750 cases

45 cases 21 cases 35 cases 48,584 cases 17,345 cases

45 cases 28 cases 54 cases 84,094 cases 34,226 cases

1 cases

11 cases

14 cases

18 cases

21 cases

26 cases

Package insert information *1 Prescription drugs

Drug guide for patients *1

Safety information issued by MHLW - Instruction of revisions of package inserts - Pharmaceuticals and medical devices 114 cases safety information - Press release Urgent safety information 13 cases (by pharmaceutical companies) Drug Safety Update (by Federation of Pharmaceutical Manufacturers’ Associations of Japan (FPMAJ)) Notification of safety measures for medical devices Notification of self-assessment Notification of revisions of labeling Notification related to medical devices Information about case reports on suspected ADR (provided in new form) Information about case reports on suspected malfunction Notification related to preventive measures 1 cases for medical accidents PMDA Medical Safety Information Manuals for management of individual serious adverse drug reactions Information about approved new drugs 119 - Review reports, summary of application ingredients materials (291 items) 158 A list of prescription drugs on which Quality ingredients/ formulation Information Package (Orange Book) was published (1,780 items) Information about withdrawals of 1,378 pharmaceuticals or medical devices *2 cases E-mail service of pharmaceuticals and medical devices information E-mails issued *3 Subscribers Number of visitors to the website *

*1 *2 *3 *4

4

11,819 sheets 1,524 sheets

12,341 13,090 sheets sheets 3,995 5,462 sheets sheets 3,306 7,437 sheets sheets 237 270 23 ingredients ingredients ingredients (1,240 (1,567 (150 items) items) items)

3 cases

127 ingredients (311 items) 190 ingredients/ formulation (1,971 items) 2,150 cases

114 ingredients (268 items) 358 ingredients/ formulation (3,083 items) 1,329 cases

137 ingredients (308 items) 427 ingredients/ formulation (3,513 items) 1,295 cases

-

-

-

-

-

76 million

87 million

203 ingredients (435 items) 481 ingredients/ formulation (3,737 items) 1,453 cases

25 cases

261 ingredients (559 items) 481 ingredients/ formulation (3,737 items) 2,128 cases

308 ingredients (642 items) 811 ingredients/ formulation (3,900 items) 2,777 cases

92 e-mails 93 e-mails 87 e-mails 2,892 6,762 11,965 addresses addresses addresses 107 million 233 million 289 million 391 million 497 million

When necessary, an addition or deletion was conducted. Addition was conducted when necessary, and the information is deleted after two years in principle. Accumulated total number of e-mails issued in each year Total number of viewed files in each year

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9 cases

III. SUPPLEMENTARY INFORMATION

Table 1. FY2007 List of Approved Products: New Drugs

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Table 2. FY2007 List of Approved Products: New Medical Devices

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Table 3. FY2007 List of Approved Products: Medical Devices Approved with Clinical Data (Other Than New Medical Devices)

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Table 4.

Safety Measures Implemented by MHLW and Revision of PRECAUTIONS for Pharmaceuticals, etc. in FY 2007

Safety measures implemented by MHLW in FY 2007 Pharmaceuticals

Medical devices

Instructions for Revision of PRECAUTIONS

132

6

Publishing information on the Phamaceuticals and Medical Devices Safety Information

24

5

Note: In FY 2007, no instructions for self-inspection of medical devices were issued.

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Revision to PRECAUTIONS in the Package Inserts of Pharmaceuticals, instructed by MHLW in FY 2007 Date

Drug name

Apr. 13, 2007

1.

Oseltamivir Phosphate

Apr. 19, 2007

1. 2.

Pergolide Mesilate Cabergoline

Apr. 27, 2007

1. 2. 3. 4. 5. 6.

Jun. 1, 2007

1. 2. 3. 4. 5.

Jul.6, 2007

1. 2. 3. 4.

Aug. 8, 2007

1.

Risperidone Gadodiamide Hydrate Ampiroxicam Piroxicam (oral dosage form, suppository dosage form) Nisoldipine Theophylline (extended-release oral dosage form) (including pediatric dosage and administration) 7. Oxaliplatin 8. Arsenic Trioxide 9. Miconazole 10. Ivermectin Zopiclone Zolpidem Tartrate Triazolam Mycophenolate Mofetil Carboplatin

Alteplase (genetical recombination) Meropenem Trihydrate Oxycodone Hydrochloride Hydrate Amobarbital Barbital Phenobarbital (oral dosage form) Bromovalerylurea Pentobarbital Calcium Chloral Hydrate (oral dosage form) 5. Estazolam Nitrazepam Nimetazepam Haloxazolam Flurazepam Hydrochloride Lormetazepam 6. Quazepam Flunitrazepam (oral dosage form) Brotizolam Rilmazafone Hydrochloride 7. Ambroxol Hydrochloride 8. Fluticasone Propionate (inhalant dosage form) 9. Infliximab (genetical recombination) 10. Etanercept (genetical recombination) 11. Ribavirin (tablet dosage form) Peginterferon Alfa-2a (genetical recombination) Telithromycin

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Date Aug. 10, 2007

Drug name 1. 2. 3. 4. 5. 6. 7.

Sep. 7, 2007

1. 2. 3.

4.

Sep. 21, 2007

Dried Thyroid Levothyroxine Sodium Hydrate Cyclofenil Silodosin Disulfiram Entecavir Hydrate Recombinant Adsorbed Hepatitis B Vaccine (yeast origin) Freeze-dried Live Attenuated Measles and Rubella Combined Vaccine Pralidoxime Iodide Accu-Chek Aviva Test Strips Cyclic GB Sensor LFS Quick Sensor Ascensia Easyfill Sensor Ascensia Autodisc Sensor Glutest Sensor Dia Sensor G Sensor Glutest Neo Sensor Blood Glucose Test Kit Blood Glucose Self-monitoring Kit (Excluding Accu-Chek Aviva Test Strips, Cyclic GB Sensor, LFS Quick Sensor, Ascensia Easyfill Sensor, Ascensia Autodisc Sensor, Glutest Sensor, Dia Sensor, G Sensor, Glutest Neo Sensor)

1. 2. 3. 4. 5. 6. 7. 8.

Amiodarone Hydrochloride (oral dosage form) Amiodarone Hydrochloride (injectable dosage form) Methylphenidate Hydrochloride Tiapride Hydrochloride Verteporfin Liothyronine Sodium Finasteride Pyridoxal Phosphate Pyridoxal Calcium Phosphate Pyridoxine Hydrochloride 9. Miglitol 10. Etidronate Disodium 11. Anastrozole 12. Ceftriaxone Sodium

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Date Oct. 31, 2007

Drug name 1. 2. 3. 4.

8. 9. 10. 11. 12. 13. 14. 15.

Tizanidine Hydrochloride Atorvastatin Calcium Hydrate Thiamazole Amitriptyline Hydrochloride Imipramine Hydrochloride Clomipramine Hydrochloride (oral dosage form) Dosulepin Hydrochloride Trazodone Hydrochloride Mianserin Hydrochloride Amoxapine Clomipramine Hydrochloride (injectable dosage form) Setiptiline Maleate Trimipramine Maleate Nortriptyline Hydrochloride Maprotiline Hydrochloride Lofepramine Hydrochloride Sertraline Hydrochloride Paroxetine Hydrochloride Hydrate Fluvoxamine Maleate Milnacipran Hydrochloride Gemeprost Idarubicin Hydrochloride Gadopentetate Dimeglumine Advantage Test Strips S

Nov. 30, 2007

1. 2. 3. 4. 5.

Flurbiprofen (oral dosage form) Flurbiprofen Axetil Botulinum Toxin Type A Everolimus Garenoxacin Mesilate Hydrate

Dec. 26, 2007

1.

Amantadine Hydrochloride

Dec. 26, 2007

1.

Zanamivir Hydrate

Jan. 10, 2008

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

5. 6. 7.

GEM-Premier 3000 PAK Ezetimibe L-Carbocisteine Goserelin Acetate (3.6 mg) Goserelin Acetate (10.8 mg) Doripenem Hydrate Oseltamivir Phosphate Terbinafine Hydrochloride (oral dosage form) Yellow Fever Vaccine Over-the-counter Drugs Containing L-Carbocisteine 11. Over-the-counter Drugs Polygoni Multiflori Radix

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Date

Drug name

Feb. 12, 2008

1. 2. 3. 4. 5. 6. 7.

Pramipexole Hydrochloride Hydrate Ropinirole Hydrochloride Cyclophosphamide (oral dosage form) Cyclophosphamide (injectable dosage form) Talipexole Hydrochloride Nicorandil (oral dosage form) Moxifloxacin Hydrochloride (oral dosage form)

Mar. 21, 2008

1.

Desmopressin Acetate (drug products with the indication for nocturnal enuresis) Desmopressin Acetate (drug products with the indication for central diabetes insipidus) Clopidogrel Sulfate Biapenem Garenoxacin Mesilate Hydrate

2. 3. 4. 5.

Note: Detailed information is available on the Agency’s Post-marketing Safety Information website on pharmaceuticals and medical devices.

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Table 5.

Revision of PRECAUTIONS for and Instructions for Self-inspection of Medical Devices in FY 2007

Revision of PRECAUTIONS for Medical Devices

Date

Title

Apr. 27, 2007

Provision of Guidelines on Standard Connection Procedures and Appropriate Safety Education for the Use of Artificial Heart-Lung Machines, and MHLWordered Revision of PRECAUTIONS regarding artificial heart-lung machines

Jun. 15, 2007

MHLW-ordered revisions to package insert regarding feeding tubes for enteral alimentation

Aug. 3, 2007

MHLW-ordered Revision of PRECAUTIONS regarding needleless devices

Sep. 7, 2007

MHLW-ordered Revision of PRECAUTIONS regarding blood glucose meters for self-monitoring

Sep. 21, 2007

MHLW-ordered Revision of PRECAUTIONS regarding the interaction between implantable cardioverter defibrillators and antiarrhythmic drugs

Feb. 27, 2008

MHLW-ordered revisions to package insert regarding drug-eluting coronary stents

Note: Detailed information is available on the Agency’s Post-marketing Safety Information website on pharmaceuticals and medical devices.

Instructions for Self-inspection of Medical Devices

In FY 2007, no instructions for self-inspection of medical devices were made.

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Table 6.

FY 2007 Pharmaceuticals and Medical Devices Safety Information (No. 235-245)

Date

No.

Contents 1. 2. 3.

Apr. 26, 2007

235

Uniformity in drop rate of infusion and transfusion sets Project for Japan Drug Information Institute in Pregnancy Safety information available on PMDA website designed to provide information on pharmaceuticals and medical devices 4. List of products subject to Early Post-marketing Phase Vigilance (Reference material) 1. Information on Oseltamivir Phosphate 2. The outlook for pharmacogenomics (Genetic polymorphisms and Warfarin therapy) 1. 2.

May 31, 2007

236 3. 4. 1. 2.

3. Jun. 27, 2007

237 4.

Information on post-marketing safety measures for Ticlopidine Hydrochloride and Taxus Express2 coronary stent systems Important Safety Information 1. Edaravone 2. Amiodarone (oral dosage form) 3. Cibenzoline Succinate (oral dosage form) Revision of PRECAUTIONS (No. 186) Oseltamivir Phosphate and 11 others List of products subject to Early Post-marketing Phase Vigilance The effect of UHF-band RFID devices and advanced-system mobile phones on cardiac pacemakers and other implantable devices Important Safety Information 1. Gadodiamide Hydrate 2. Cabergoline 3. Pergolide Mesilate 4. Risperidone Revision of PRECAUTIONS (No. 187) 1. Ampiroxicam and 7 others 2. Medical devices that are components of artificial heart-lung machines including oxygenators, blood pumps, blood circuits List of products subject to Early Post-marketing Phase Vigilance

(Reference material) 1. Manuals for management of individual serious adverse drug reactions 2. Guidelines on standard connection procedures and appropriate safety education for the use of artificial heart-lung machines 1.

Jul. 31, 2007

238

2.

3. 1. Aug. 30, 2007

239 2. 3.

Important Safety Information 1. Zolpidem Tartrate 2. Zopiclone Revision of PRECAUTIONS (No. 188) 1. Triazolam and 2 others 2. Enteral tubes and gastric feeding tubes for enteral alimentation (only components with a stylet or guidewire) and 2 others List of products subject to Early Post-marketing Phase Vigilance Important Safety Information 1. Alteplase (genetical recombination) 2. Oxycodone Hydrochloride Hydrate 3. Meropenem Trihydrate Revision of PRECAUTIONS (No. 189) 1. Amobarbital and 7 others List of products subject to Early Post-marketing Phase Vigilance

- 126 -

Date

No.

Contents 1. 2.

Sep. 27, 2007

240 3. 1. 2.

Nov. 29, 2007

241 3. 4. 1.

Dec. 26, 2007

242 2. 3. 1. 2.

Jan. 29, 2008

243

Feb. 28, 2008

244

“PMDA medical safety information” is new posted on the Pharmaceuticals and Medical Devices Information Website Important Safety Information 1. Amiodarone Hydrochloride (oral dosage form), Amiodarone Hydrochloride (injectable dosage form) Revision of PRECAUTIONS (No. 191) (1) Drugs: Pralidoxime Iodide and 13 others (2) Medical Devices: Glucose meters for self-monitoring and 5 others List of products subject to Early Post-marketing Phase Vigilance Important Safety Information 1. Atorvastatin Calcium Hydrate 2. Tizanidine Hydrochloride 3. Thiamazole Revision of PRECAUTIONS (No. 192) 1. Amitriptyline Hydrochloride and 11 others List of products subject to Early Post-marketing Phase Vigilance Revision of PRECAUTIONS (No. 193) Flurbiprofen (oral dosage form) and 6 others List of products subject to Early Post-marketing Phase Vigilance

(Reference Material) 1. About Oseltamivir Phosphate (Tamiflu) 1. 2. 1. 2. 3.

Mar. 27, 2008

Reports of the adverse effects of influenza vaccines in FY 2006 Revision of PRECAUTIONS (No. 190) 1. Telithromycin and 7 others 2. Needleless devices that connect to internal fluid flow channels and 1 other List of products subject to Early Post-marketing Phase Vigilance

245 4. 5.

Revision of PRECAUTIONS (No. 194) GEM-Premier 3000 PAK and 10 others List of products subject to Early Post-marketing Phase Vigilance Treatment of hepatitis viral with interferon products Sudden onset of sleep, etc. associated with non-ergoline dopamine agonists (patients must be advised to refrain from driving, etc.) Important Safety Information 1. Cyclophosphamide (oral dosage form), Cyclophosphamide (injectable dosage form) Revision of PRECAUTIONS (No. 195) Nicorandil (oral dosage form) and 1 other List of products subject to Early Post-marketing Phase Vigilance

Note: Detailed information is available at the Agency’s Post-marketing Safety Information website on pharmaceuticals and medical devices.

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Table 7.

PMDA Medical Safety Information

No.

Date published

Title

1

Nov. 2007

Points to note in case of obstruction of feeding tube

2

Nov. 2007

Recall of Resuscitators

3

Jan. 2008

Precautions against improper connection of speech valves etc. to tracheostomy tubes

* Detailed information is available at the Agency’s Post-marketing Safety Information website on pharmaceuticals and medical devices.

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Table 8.

Lists of User Fees (partially revised on April 1, 2007; refer to the Attachment revised on April 1, 2008 for a comparison of former and revised fees.)

List of user fees for reviews etc. of pharmaceuticals, quasi-drugs, and cosmetics based on the Pharmaceutical Affairs Law (Law No. 145, 1960) Note: The lower rows in the User fees column indicate the articles on user fees to MHLW in the Cabinet Ordinance on Fees related to the Pharmaceutical Affairs Law. (Yen) Classification

Review

User fees Conformity

Total

Investigation for manufacturing license of drugs On-site

148,100

148,100

111,500

111,500

97,400

97,400

55,300

55,300

97,400

97,400

55,300

55,300

133,300 + travel expences Article 16 (2) 1-a 58,100 Article 16 (2) 1-b 64,600 + travel expences Article 16 (2) 2-a 39,700 Article 16 (2) 2-b 64,600 + travel expences Article 16 (2) 3-a 39,700 Article 16 (2) 3-b

133,300 + travel expences

6,559,600

30,347,700

1,639,800

4,103,800

3,286,000

23,220,100

818,100

2,879,600

2,463,200

13,816,300

615,900

1,790,200

1,232,500

10,578,200

310,100

1,314,200

214,000

626,100

Article 16 (1) 1-a

New license Document

Article 16 (1) 1-b

On-site

Article 16 (1) 2-a

Change/Addition of classification Document

Article 16 (1) 2-b

On-site

Article 16 (1) 3-a

Renewal of existing license Document

Article 16 (1) 3-b

Investigation for foreign manufacturers accreditation of drugs On-site New accreditation Document On-site Change/Addition of classification Document On-site Renewal of existing accreditation Document

58,100 64,600 + travel expences 39,700 64,600 + travel expences 39,700

Drug review (new approval) New drug 1 (non-orphan drugs) New drug 1 (orphan drugs) New drug 2 (non-orphan drugs) New drug 2 (orphan drugs)

First application items Applications with different dosage etc. First application items Applications with different dosage etc. First application items Applications with different dosage etc. First application items

Applications with different dosage etc. Generic prescription drugs (with conformity audits) OTC drugs

In vitro diagnostics (without approval standards) In vitro diagnostics (with approval standards)

Basic Addition of series

Quasi-drugs/cosmetics New application of change or replacement of brand name

23,788,100 Article 17 (1) 1-a (1) 2,464,000 Article 17 (1) 1-a (3) 19,934,100 Article 17 (1) 1-a (2) 2,061,500 Article 17 (1) 1-a (4) 11,353,100 Article 17 (1) 1-a (5) 1,174,300 Article 17 (1) 1-a (6) 9,345,700 Article 17 (1) 1-a (7) 1,004,100 Article 17 (1) 1-a (8) 412,100 Article 17 (1) 1-a (9) 110,300 Article 17 (1) 1-a (10) 584,100 Article 17 (1) 1-a (13) 282,900 Article 17 (1) 1-a (12) 60,300 Article 17 (1) 1-a (11) 63,500 Article 17 (1) 1-b, c 35,600 Article 17 (1) 1-e

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Article 17 (2) 1-a Article 17 (2) 1-c Article 17 (2) 1-b Article 17 (2) 1-d Article 17 (2) 1-e Article 17 (2) 1-f Article 17 (2) 1-g Article 17 (2) 1-h Article 17 (2) 1-i 110,300 584,100 282,900 60,300 63,500 35,600

Classification

Review

User fees Conformity

Total

(Approval for partial changes to approved matters) New drug 1 (other than orphan)

Changes in indications

First application items Applications with different dosage etc. Other

New drug 1 (orphan)

Changes in indications

First application items Applications with different dosage etc. Other

New drug 2 (other than orphan)

Changes in indications

First application items Applications with different dosage etc. Other

New drug 2 (orphan)

Changes in indications

First application items Applications with different dosage etc. Other

Generic drugs (with compliance audit)

Changes in indications

First application items Applications with different dosage etc. Other

OTC drugs In vitro diagnostics (without approval standards) In vitro diagnostics (with approval standards)

Basic Addition of series

Quasi-drugs and cosmetics

10,190,500 Article 17 (1) 2-a (1) 1,057,400 Article 17 (1) 2-a (2) 205,100 Article 17 (1) 2-a (3) 8,434,300 Article 17 (1) 2-a (4) 875,600 Article 17 (1) 2-a (5) 132,700 Article 17 (1) 2-a (6) 10,190,500 Article 17 (1) 2-a (1) 1,057,400 Article 17 (1) 2-a (2) 205,100 Article 17 (1) 2-a (3) 8,434,300 Article 17 (1) 2-a (4) 875,600 Article 17 (1) 2-a (5) 132,700 Article 17 (1) 2-a (6) 10,190,500 Article 17 (1) 2-a (1) 1,057,400 Article 17 (1) 2-a (2) 205,100 Article 17 (1) 2-a (3) 56,400 Article 17 (1) 2-a (7) 295,800 Article 17 (1) 2-a (10) 143,500 Article 17 (1) 2-a (9) 31,900 Article 17 (1) 2-a (8) 35,600 Article 17 (1) 2-b, c

2,463,200

12,653,700

615,900

1,673,300

120,700

325,800

1,232,500

9,666,800

310,100

1,185,700

109,800

242,500

2,463,200

12,653,700

615,900

1,673,300

120,700

325,800

1,232,500

9,666,800

310,100

1,185,700

109,800

242,500

2,463,200

12,653,700

615,900

1,673,300

120,700

325,800

Article 17 (2) 2-a Article 17 (2) 2-b Article 17 (2) 2-c Article 17 (2) 2-d Article 17 (2) 2-e Article 17 (2) 2-f Article 17 (2) 2-a Article 17 (2) 2-b Article 17 (2) 2-c Article 17 (2) 2-d Article 17 (2) 2-e Article 17 (2) 2-f Article 17 (2) 2-a Article 17 (2) 2-b Article 17 (2) 2-c 56,400 295,800 143,500 31,900 35,600

GMP audit of drugs 739,800 Article 17 (4) 1-b (1) 933,500 + travel expences Article 17 (4) 1-b (2) 666,100 Article 17 (4) 1-a (1) 844,400 + travel expences Article 17 (4) 1-a (2) 201,300 Article 17 (4) 1-c (1) 229,800 + travel expences Article 17 (4) 1-c (2) 141,200 Article 17 (4) 1-d (1) 155,400 + travel expences Article 17 (4) 1-d (2) 63,800 Article 17 (4) 2-a, Article 17 (5) 1-a 84,800 + travel expences Article 17 (4) 2-b, Article 17 (5) 1-b

Approval, partial change and manufacture for export

Domestic New drugs Overseas Biological drugs/ Radiopharmaceuticals Sterilized drugs/ sterilized quasi-drugs Drugs and quasi-drugs other than the above Package, labeling, storage, external testing etc.

Domestic Overseas Domestic Overseas Domestic Overseas Domestic Overseas

- 130 -

739,800 933,500 + travel expences 666,100 844,400 + travel expences 201,300 229,800 + travel expences 141,200 155,400 + travel expences 63,800 84,800 + travel expences

Classification

Review

Article 17 (4) 3-a(1) 554,200 + travel expences Article 17 (4) 3-a (2) 30,500 Article 17 (4) 3-a (1) 30,500 Article 17 (4) 3-a (2) 380,000 Article 17 (4) 3-b (1) 480,000 + travel expences Article 17 (4) 3-b (2) 12,400 Article 17 (4) 3-b (1) 12,400 Article 17 (4) 3-b (2) 336,500 Article 17 (4) 3-c (1) 409,400 + travel expences Article 17 (4) 3-c (2) 9,600 Article 17 (4) 3-c (1) 9,600 Article 17 (4) 3-c (2) 258,500 Article 17 (4) 3-d (1), Article 17 (5) 2-a 338,100 + travel expences Article 17 (4) 3-d (2), Article 17 (5) 2-b 6,700 Article 17 (4) 3-d (1), Article 17 (5) 2-a 6,700 Article 17 (4) 3-d (2), Article 17 (5) 2-b

Basic Overseas Addition of items

Domestic Overseas Domestic

Renewal of the above

Basic Sterilized drugs/ sterilized quasidrugs

Overseas Addition of items

Domestic Overseas Domestic

Drugs and quasi-drugs other than the above

Basic Overseas Addition of items

Domestic Overseas Domestic

Package, labeling, storage, external testing etc.

Basic Overseas Addition of items

Total 436,000

Domestic Biological drugs/Radiopharmaceuticals

User fees Conformity

Domestic Overseas

436,000 554,200 + travel expences 30,500 30,500 380,000 480,000 + travel expences 12,400 12,400 336,500 409,400 + travel expences 9,600 9,600 258,500 338,100 + travel expences 6,700 6,700

GLP audit of drugs 2,062,400 Article 17 (3) 1-a, Article 17 (9) 2-a (1) 2,282,600 + travel expences Article 17 (3) 1-b, Article 17 (9) 2-a (2)

Domestic GLP Overseas

2,062,400 2,282,600 + travel expences

GCP audit of drugs First application items New GCP

Applications with different dosage etc.

2,723,200 Article 17 (3) 2-a 3,011,900 + travel expences Article 17 (3) 2-b 720,800 Article 17 (3) 2-c 751,800 + travel expences Article 17 (3) 2-d 645,200 Article 17 (3) 2-e 950,200 + travel expences Article 17 (3) 2-f

Domestic Overseas Domestic Overseas Domestic

GCP audit of generic drugs Overseas

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2,723,200 3,011,900 + travel expences 720,800 751,800 + travel expences 645,200 950,200 + travel expences

Classification

Review

User fees Conformity

Total

Re-examination of drugs Confirmation/ examination

First application items Application with different dosage etc. First application items

GPSP

Application with different dosage etc.

806,600 Article 17 (8) 1-a 271,500 Article 17 (8) 1-b

2,673,700

3,480,300

892,100

1,163,600

Article 17 (9) 1-a Article 17 (9) 1-b 2,193,300 2,193,300 Article 17 (9) 2-b (1) 2,409,600 + travel expences 2,409,600 + travel expences Article 17 (9) 2-b (2) 752,600 752,600 Article 17 (9) 2-b (3) 772,300 + travel expences 772,300 + travel expences Article 17 (9) 2-b (4)

Domestic Overseas Domestic Overseas

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List of User Fees for Reviews etc. of Medical Devices under the Pharmaceutical Affairs Law (Law No. 145 of 1960) Note:

The lower rows in the User fees column indicate the articles on user fees to MHLW in the Cabinet Ordinance on Fees related to the Pharmaceutical Affairs Law. (Yen) Classification

Review

User fees Conformity

Total

Investigation for manufacturing license of medical devices On-site

148,100

148,100

111,500

111,500

97,400

97,400

55,300

55,300

97,400

97,400

55,300

55,300

133,300 + travel expences Article 16 (2) 1-a 58,100 Article 16 (2) 1-b 64,600 + travel expences Article 16 (2) 2-a 39,700 Article 16 (2) 2-b 64,600 + travel expences Article 16 (2) 3-a 39,700 Article 16 (2) 3-b

133,300 + travel expences

664,500

3,741,500

68,500

1,232,800

68,500

351,400

Article 16 (1) 1-a

New license Document

Article 16 (1) 1-b

On-site

Article 16 (1) 2-a

Change/Addition of classification Document

Article 16 (1) 2-b

On-site

Article 16 (1) 3-a

Renewal of existing license Document

Article 16 (1) 3-b

Investigation for foreign manufacturing accreditation of medical devices On-site New accreditation Document On-site Change/Addition of classification Document On-site Renewal of existing accreditation Document

58,100 64,600 + travel expences 39,700 64,600 + travel expences 39,700

Approval review of medical devices (new approval) Medical devices (without approval standards/with clinical data) Medical devices (without approval standards/without clinical data) Specially controlled medical devices (with approval standards/without clinical data) Controlled medical devices (with certification standards/without clinical data) Change of brand name

3,077,000 Article 17 (1) 1-d (1) 1,164,300 Article 17 (1) 1-d (3) 282,900 Article 17 (1) 1-d (2) 282,900 Article 17 (1) 1-d (2) 35,600 Article 17 (1) 1-e

Article 17 (2) 1-j Article 17 (2) 1-l Article 17 (2) 1-k 282,900 35,600

Approval review of medical devices (approval for partial changes to approved matters) Medical devices (without approval standards/with clinical data) Medical devices (without approval standards/without clinical data) Specially controlled medical devices (with approval standards/without clinical data) Controlled medical devices (with certification standards/without clinical data)

1,538,000 Article 17 (1) 2-d (1) 584,100 Article 17 (1) 2-d (3) 143,500 Article 17 (1) 2-d (2) 143,500 Article 17 (1) 2-d (2)

- 133 -

664,500

2,202,500

37,100

621,200

37,100

180,600

Article 17 (2) 2-g Article 17 (2) 2-i Article 17 (2) 2-h 143,500

Classification

Review

User fees Conformity

Total

QMS review (audit) of medical devices 739,800 Article 17 (4) 1-b (1) 933,500 + travel expences Article 17 (4) 1-b (2) 666,100 Article 17 (4) 1-a (1) 844,400 + travel expences Article 17 (4) 1-a (2) 201,300 Article 17 (4) 1-c (1) 229,800 + travel expences Article 17 (4) 1-c (2) 141,200 Article 17 (4) 1-d (1) 155,400 + travel expences Article 17 (4) 1-d (2) 63,800 Article 17 (4) 2-a, Article 17 (5) 1-a 84,800 + travel expences Article 17 (4) 2-b, Article 17 (5) 1-b 436,000 Article 17 (4) 3-a (1) 554,200 + travel expences Article 17 (4) 3-a (2) 30,500 Article 17 (4) 3-a (1) 30,500 Article 17 (4) 3-a (2) 380,000 Article 17 (4) 3-b (1) 480,000 + travel expences Article 17 (4) 3-b (2) 12,400 Article 17 (4) 3-b (1) 12,400 Article 17 (4) 3-b (2) 336,500 Article 17 (4) 3-c (1) 409,400 + travel expences Article 17 (4) 3-c (2) 9,600 Article 17 (4) 3-c (1) 9,600 Article 17 (4) 3-c (2) 258,500 Article 17 (4) 3-d (1), Article 17 (5) 2-a 338,100 + travel expences Article 17 (4) 3-d (2), Article 17 (5) 2-b 6,700 Article 17 (4) 3-d (1), Article 17 (5) 2-a 6,700 Article 17 (4) 3-d (2), Article 17 (5) 2-b

Domestic New medical devices Approval, partial change and manufacture for export

Overseas Domestic

Biological medical devices, specially controlled medical devices (class IV), etc

Overseas Domestic

Sterilized medical devices Overseas

Medical devices other than the above

Domestic Overseas Domestic

Package, labeling, storage, external testing, etc.

Overseas

Biological Basic medical devices, specially controlled medical devices Addition of items (class IV), etc

Domestic Overseas Domestic Overseas Domestic

Basic Overseas

Renewal of the above

Sterilized medical devices

Domestic Addition of items Overseas Domestic Basic Overseas

Medical devices other than the above

Domestic Addition of items Overseas Domestic

Package, labeling, storage, external testing etc.

Basic Overseas Domestic Addition of items Overseas

739,800 933,500 + travel expences 666,100 844,400 + travel expences 201,300 229,800 + travel expences 141,200 155,400 + travel expences 63,800 84,800 + travel expences 436,000 554,200 + travel expences 30,500 30,500 380,000 480,000 + travel expences 12,400 12,400 336,500 409,400 + travel expences 9,600 9,600 258,500

338,100 + travel expences 6,700 6,700

GLP audit of medical devices 2,062,400 Article 17 (3) 1-a, Article 17 (9) 2-a (1) 2,282,600 + travel expences Article 17 (3) 1-b, Article 17 (9) 2-a (2)

Domestic GLP Overseas

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2,062,400 2,282,600 + travel expences

Classification

Review

User fees Conformity

Total

GCP audit of medical devices 635,300 Article 17 (3) 3-a 918,400 + travel expences Article 17 (3) 3-b

Domestic GCP Overseas

635,300 918,400 + travel expences

Re-examination of medical devices New medical devices Medical devices other than new ones

502,600 Article 17 (8) 2-a 51,600 Article 17 (8) 2-b

624,600

51,600 610,700 Article 17 (9) 2-b (5) 949,000 + travel expences Article 17 (9) 2-b (6)

Domestic GPSP Overseas

- 135 -

1,127,200

Article 17 (9) 1-c

610,700 949,000 + travel expences

List of User Fees under the Article 3 of the Administrative Instructions for Review and Other Services of the Independent Administrative Agency Pharmaceuticals and Medical Devices Agency (Yen)

Devices and in vitro diagnostics

Simple consultations

Clinical trial consultations

Drugs

Classification Face-to-face consultations Consultation on compliance with conformity criteria for drugs Procedural consultation for drugs Consultation on biological equivalence testing etc. for drugs Quality consultation for drugs Safety consultation for drugs Consultation before initiation of phase I study for drugs Consultation before initiation of the first stage of phase II study for drugs Consultation before initiation of the second stage of phase II study for drugs Consultation after completion of phase II study for drugs Pre-application consultation for drugs Additional consultation for drugs Consultation on the protocols of clinical trials for reevaluation and reexamination of drugs Consultation at completion of clinical trials for reevaluation and re-examination of drugs Pre-application consultation for new OTC drugs Clinical trial/Pre-application consultation for medical devices or in vitro diagnostics Consultation on compliance with conformity criteria for medical devices Pre-development consultation for medical devices Safety consultation for medical devices (excluding biological devices) Safety consultation for biological medical devices Quality consultation for medical devices (excluding biological devices) Quality consultation for biological medical devices Performance testing consultation for medical devices Clinical evaluation consultation for medical devices Exploratory clinical trial consultation for medical devices Application procedure consultation for medical devices or in vitro diagnostics Additional consultation for medical devices and in vitro diagnostics Consultation on preparation of documents for cell- and tissue-based products Generic drugs OTC drugs Quasi-drugs (Including pesticides and rodenticides) Medical devices or in vitro diagnostics Writing applications for new drugs GMP/QMS audit Review for designation of priority face-to-face consultation Review for designation of priority face-to-face consultation on drugs Review for designation of priority face-to-face consultation on medical devices or in vitro diagnostics GLP inspection of test facilities All test items (for drugs and medical devices) Domestic All test items (for drugs or medical devices) Overseas Limited test items Additional compliance accreditation Confirmation of certification on drugs etc. Certification of drug products Other certifications Use of document storage rooms

User fees

Timing of Payment

2,875,500 yen per consultation 139,800 yen per consultation 556,000 yen per consultation 1,478,300 yen per consultation 1,782,800 yen per consultation 4,239,400 yen per consultation 1,623,000 yen per consultation 3,028,400 yen per consultation 6,011,500 yen per consultation 6,011,400 yen per consultation 2,675,600 yen per consultation 3,320,600 yen per consultation 3,319,400 yen per consultation 445,100 yen per consultation

Payment by the date of application after arrangement of the date of the face-to-face consultation

1,594,700 ye per consultation 650,300 yen per consultation 135,200 yen per consultation 675,100 yen per consultation 754,400 yen per consultation 650,500 yen per consultation 753,500 yen per consultation 690,900 yen per consultation 854,100 yen per consultation 903,700 yen per consultation 135,200 yen per consultation 927,500 yen per consultation 223,500 yen per consultation 21,000 yen per consultation 21,000 yen per consultation 21,000 yen per consultation 34,300 yen per consultation 21,000 yen per consultation 24,700 yen per consultation 818,800 yen per application

Request to the Agency after advance payment

818,800 yen per application 3,023,800 yen per facility 2,062,400 yen per facility 2,282,600 yen + travel expenses per facility

Request to the Agency after advance payment

995,200 yen per facility 932,600 yen per facility 15,100 yen per item 8,400 yen per matter of one item 3,000 yen per day per room

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Request to the Agency after advance payment Pay invoice sent from the Agency after the end of use period

Attachment

Comparison of Former and Revised User Fees (revision implemented on April 1, 2008) (Yen)

Classification

Former user fees

Revised user fees

Drug review (new approval) 1,291,600

Switch to OTC status, etc.

Article 17 (1)1-a (10)

OTC drugs Others

110,300

110,300

Article 17 (1) 1-a (10)

Article 17 (1) 1-a (11)

10,190,500

10,190,500

Article 17 (1) 2-a (1)

Article 17 (1) 2-a (1)

1,057,400

1,057,400

Article 17 (1) 2-a (2)

Article 17 (1) 2-a (2)

Drug review (approval for partial changes in approved matters)

Generic drugs

First application Changes in items indications (different from Applications those for with different approved drugs) dosage, etc.

35,600

Changes based on guidelines

Others

Changes in indications (e.g., direct OTC use) OTC drugs

First application items Product with different specifications

Article 17 (1) 2-a (7) 205,100

205,100

Article 17 (1) 2-a (3)

Article 17 (1) 2-a (3)

10,190,500

10,190,500

Article 17 (1) 2-a (1)

Article 17 (1) 2-a (1)

1,057,400

1,057,400

Article 17 (1) 2-a (2)

Article 17 (1) 2-a (2) 35,600

Changes based on guidelines

Others

Article 17 (1) 2-a (7) 56,400

56,400

Article 17 (1) 2-a (7)

Article 17 (1) 2-a (7)

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