Pharmaceuticals and Medical Devices Agency,...

Pharmaceuticals and Medical Devices Agency, Japan

Profile of ServicesFiscal Year 2010Fiscal Year 2010

Our Philosophy

PMDA continues to improve the public health and safety of our nation by reviewing applications for marketing approval of pharmaceuticals and medical devices, conducting safety measures, and providing relief to people who have suffered from adverse drug reactions.

We conduct our mission in accordance with the following principles:

● We pursue the development of medical science while performing our duty with greater transparency based on our mission to protect public health and the lives of our citizens.

● We will be the bridge between the patients and their wishes for faster access to safer and more effective drugs and medical devices.

● We make science-based judgments on quality, safety, and efficacy of medical products by training personnel to have the latest technical knowledge and wisdom in their field of expertise.

● We play an active role within the international community by promoting international harmonization.

● We conduct services in a way that is trusted by the public based on our experiences from the past.

Table of Contents

Greetings ………………………………………………………………………………………………… 5

Outline of the Pharmaceuticals and Medical Devices Agency (PMDA) …………… 6

Services of PMDA ……………………………………………………………………………………… 9

Relief Services for Adverse Health Effects ……………………………………………………………… 10

Relief Services ……………………………………………………………………………………… 12

Healthcare Allowances for SMON Patients ………………………………………………………… 16

Healthcare Allowances for HIV-positive and AIDS Patients ……………………………………… 16

Financial assistance under the “Act on Special Measures concerning the Payment of Benefi ts

to Assist the Individuals Affected by Hepatitis C through Specifi ed Fibrinogen Products and

Specifi ed Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus” …………… 17

Reviews and Related Services …………………………………………………………………………… 18

Post-marketing Safety Measures ………………………………………………………………………… 26

International Activities ………………………………………………………………………………… 33

Promoting Regulatory Science ………………………………………………………………………… 34

Contact & Map ……………………………………………………………………………………… 35

4

Greetings

Since its establishment in April 2004, the Pharmaceuticals and Medical Devices Agency (PMDA) has focused on the three key areas of relief services for adverse health effects, reviews, and post-marketing safety measures, encompassing the entire life cycle of drugs and medical devices from development through post-marketing surveillance. This so-called “safety triangle” system is unique to Japan. While providing relief services swiftly, PMDA is also striving to resolve the issues of drug lag and device lag and to enhance safety measures by increasing the number of its reviewers and safety staff and by building their expertise.

　To further improve public health services and respond to growing demands for more effective and safer drugs and medical devices, we are determined to make utmost efforts to be a leader in advanced medicine. How can we translate innovative academic science into clinical practice, thereby contributing to society? To this end, PMDA is committed to promoting regulatory science and broadening its links and personnel exchanges with academia, healthcare organizations and industry.

　The globalization of the pharmaceutical and medical device industries will accelerate the international regulatory harmonization of drugs and medical devices through both reviews and safety measures. PMDA has therefore established the Offi ce of International Programs to engage in international activities.

　PMDA will continue to work hard in line with its Philosophy and to serve as one of the world’s leading regulatory agencies.

April 2010

Tatsuya Kondo, M.D., Ph.D.Chief Executive

Pharmaceuticals and Medical Devices Agency

5

Outline of the Pharmaceuticals andMedical Devices Agency (PMDA)

Safety Triangle― Comprehensive Risk Management through the Three Functions ―

Adverse Health Ef fects), of fer ing guidance and

conducting reviews on the quality, effi cacy and safety of

drugs and medical devices through a system that

integrates the entire process from pre-clinical research

to approval (Reviews), and by collecting, analyzing and

providing post-market safety information (Safety

Measures).

Name: Pharmaceuticals and Medical Devices Agency (PMDA)Established: April 1, 2004Legal classification: Incorporated administrative agency with non-civil servant status

Following the Reorganization and Rationalization Plan

for Special Public Corporations, which was approved at

a Cabinet meeting in 2001, the Pharmaceuticals and

Medical Devices Agency (PMDA) was established and

came into service on April 1, 2004, under the Act on the

Pharmaceuticals and Medical Devices Agency, which

consolidated the services of the Pharmaceuticals and

Medical Devices Evaluation Center of the National Institute

of Health Sciences (PMDEC), the Organization for

Pharmaceutical Safety and Research (OPSR/Kiko), and

part of the Japan Association for the Advancement of

Medical Equipment (JAAME).

　PMDA's mission is to help improve public health in Japan

by providing swift relief to people who have suffered

health damage caused by adverse drug reactions or

infections from biological products (Relief Services for

Japanesecitizens

ReviewReduction in risk

ReliefRelief measures

for health damage caused by risk factors

SafetyContinuous risk mitigation efforts

Securing Safety and Efficacy

Three-pillar System Unique to Japan

6

SERVICES

Relief Services for Adverse Health Effects・ Benefits in the form of medical expenses, disability

pensions, bereaved family pensions, etc. for people who have suffered health damage such as diseases and disabilities resulting from adverse drug reactions and infections acquired through biological products

・ Benefits such as healthcare allowances to subacute myelo-optico-neuropathy (SMON) patients, and commissioned benefits services to HIV-positive and AIDS patients

・ Financial assistance under the “Act on Special Measures concerning the Payment of Benefi ts to Assist Individuals Affected by Hepatitis C through Specifi ed Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus”

Reviews and Related Services・ Regulatory reviews of drug and medical device

applications in accordance with the Pharmaceutical Affairs Act

・ Guidance and advice relating to clinical trials, etc.

・ Inspections conducted to assess compliance with GCP, GLP and other s tandards in relat ion to applications for marketing approval, re-examinations and re-evaluations

・ Inspections of manufacturing sites, manufacturing processes and quality controls for assessing GMP/QMS compliance

・ Re-examinations and re-evaluations in accordance with the Pharmaceutical Affairs Act

Safety Measures・ Collection, analysis and provision of information on

the quality, efficacy and safety of drugs and medical devices

・ Consultation services for consumers concerning drugs and medical devices

・ Guidance and advice for marketing authorization holders to enhance the safety of drugs and medical devices

・ Research relating to the development of standards for drugs and medical devices

The Fund for AdverseDrug ReactionsSuffering Relief

established

The Fund reorganizedinto the Fund for AdverseDrug Reaction Relief and

R&D Promotion

The Fund reorganized intothe Organization for

Pharmaceutical Safety andResearch (OPSR/Kiko)

Part of review activitiestransferred to the Japan

Association for the Advancementof Medical Equipment (JAAME)

Product applicationreview activities

started

R&D promotion services started

1979

1987

1994

1995

1997

2004

2005

Safety measures

The Pharmaceuticals and Medical Devices Agency (PMDA) established

Bureaus in the former Ministry ofHealth and Welfare (Government)

Services concerning clinical trials and inspections started

R&D promotion services transferred to the National Institute of Biomedical Innovation (NiBio)

Equivalence review for medical devices started

History of PMDA

The Pharmaceuticals and MedicalDevices Evaluation Center of the

National Institute of HealthSciences (PMDEC) established

7

April 1, 2005 April 1, 2006 April 1, 2007 April 1, 2008 April 1, 2009 April 1, 2010

Total (including executives)1 291 319 341 426 521 605

Review Department2 178 197 206 277 350 389

Safety Department3 43 49 57 65 82 123

Number of Executives and Regular Employees

Notes: 1. The total number includes 6 executives (including one part-time executive). (Five executives were included as of April 1, 2006.) 2. The Review Department consists of the Director of the Center for Product Evaluation, Associate Executive Directors (excluding the Associate Executive Director

responsible for the Offi ce of Regulatory Science Operations), Associate Center Directors, Offi ce of International Programs, International Liaison Offi cers, Offi ce of Review Administration, Offi ce of Review Management, Offi ces of New Drug I to V, Offi ces of Biologics I and II, Offi ce of OTC/Generic Drugs, Offi ces of Medical Devices I and II, Offi ce of Conformity Audit and senior scientists.

3. The Safety Department consists of the Chief Safety Offi cer, Offi ces of Safety I and II and Offi ce of Compliance and Standards.

Information Technology Promotion Group

Office of Safety I

Office of Safety II

Office of Compliance and Standards

Office of General Affairs

Office of Financial Management

Office of Planning and Coordination

Chief Actuary

Office of Relief Funds

Office of Regulatory Science Operations

Office of International Programs

International Liaison Officers

Office of Review Administration

Office of Review Management

Office of New Drug I

Office of New Drug II

Office of New Drug III

Office of New Drug IV

Office of New Drug V

Office of Biologics I

Office of Biologics II

Office of OTC/Generic Drugs

Office of Medical Devices I

Office of Medical Devices II

Office of Conformity Audit

Senior Scientists

Chief Safety Officer

Chief ManagementOfficer

Chief Relief Officer

Associate ExecutiveDirector

Associate CenterDirector


Chief Executive


Auditor

Auditor

AuditOffice



SeniorExecutiveDirector

ExecutiveDirector

ExecutiveDirector

Director ofCenter forProduct

Evaluation

Organization Chart (As of April 1, 2010)

8

Services of PMDA

●Relief for Adverse Drug Reaction●Relief for Infections Acquired through Biological Products●Health Allowances for SMON Patients●Health Allowances for HIV-Positive and AIDS Patients●Relief for Individuals Affected by Hepatitis C through Specified Products

●Consultations●Drug Reviews●Medical Device Reviews●GMP/QMS Inspections●GLP/GCP/GPSP Inspections

●Information Collection/Organization●Research and Reviews●Consultations●Information Provision●Standards Development

Relief

ReviewPost-marketingSafety

Measures

Services of PMDA

9

Relief Services for Adverse Health EffectsPMDA is dedicated to providing swift relief for adverse health effects by actively conducting public relations and providing information, and by expanding its consultation services.

10

Five Relief Services for Adverse Health Effects

The Organization for Pharmaceutical Safety and Research, the predecessor of PMDA, was

established in 1979 as the “Fund for Relief Services for Adverse Drug Reactions,” and started

providing such services in May of the following year.

　The Organization also provided healthcare allowances to SMON patients under commission from

the Japanese government and pharmaceutical companies, as well as to HIV-positive and AIDS

patients under commission from the Yu-ai Welfare Foundation.

　In April 2004, PMDA began “Relief Services for Infections Acquired through Biological Products”

to provide relief benefits to people suffering from adverse health effects such as infections acquired

through drug products or medical devices manufactured using ingredients and materials of biological

origin.

　Also, in January 2008, PMDA started to provide benefits under the “Act on Special Measures

concerning the Payment of Benefits to Assist Individuals Affected by Hepatitis C through Specified

Fibrinogen Products and Specified Blood Coagulation Factor IX Products Contaminated by

Hepatitis C Virus.”

Benefits for:Health allowances

forSMON patientsPatients suffering

from adversedrug reactions

Health allowancesfor HIV-positive

and AIDS patients

Benefits forindividuals affected

by hepatitis Cthrough specified

products

Patientssuffering

from infectionsacquired through

biologicalproducts

Relief Servicesfor Adverse

Health Effects

11

Relief Services for Adverse Health Effects

PMDA provides relief benefi ts relating to health damage

such as diseases and disabilities requiring hospitalization

that were caused by adverse reactions to drugs

prescribed at hospitals or clinics as well as drugs

purchased at pharmacies, etc., even if such drugs were

properly used.

　These relief benefits cover health damage caused

by adverse reactions to drugs that were used properly

on or after May 1, 1980. However, health damage caused

by adverse reactions to certain drugs such as anticancer

and immunosuppressant drugs is not eligible for these

benefi ts.

　In addition to providing relief benefi ts, PMDA, as part

of its health and welfare services, conducts investigative

research on serious and rare cases of adverse health

effects caused by drugs.

Relief System for Adverse Drug Reactions

Cases of Relief Services for Adverse Drug Reactions

Payment of Relief Benefi ts for Adverse Drug Reactions

Drug products and medical devices are indispensable for human health and welfare, but their efficacy and safety must be ensured before they can be marketed. It is equally important that drugs and medical devices are used properly in order to ensure their effi cacy and safety. And yet even if great care is taken in all these respects, it is almost impossible to completely prevent adverse drug reactions or infections from biological products.　Therefore, when drugs used to treat illnesses cause health damage such as infectious diseases or adverse reactions, it is vital to provide relief immediately. The Relief System for Adverse Drug Reactions and the Relief System for Infections Acquired through Biological Products have been established for this purpose.

Relief Services

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Number of claims 760 788 908 926 1,052

Number of judged cases 1,035 845 855 919 990

Of which: Withdrawn 4 0 2 1 2

Number of cases in progress* 681 624 677 684 746

Median processing time 11.2 months 6.6 months 6.4 months 6.5 months 6.8 months

Types of benefi tsFY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Number of cases Amount paid Number

of cases Amount paid Number of cases Amount paid Number

of cases Amount paid Number of cases Amount paid

Medical expenses 717 78,527 572 67,502 603 67,603 659 75,339 763 86,666

Medical allowances 757 70,073 624 60,034 651 62,668 711 62,055 813 70,963

Disability pension 33 653,143 35 692,446 42 730,007 27 747,362 26 804,251

Pension for raising handicapped children 17 40,639 6 30,131 7 35,760 7 40,127 7 50,804

Bereaved family pension 44 502,468 22 493,010 20 501,454 22 523,455 18 545,843

Lump-sum benefi ts for bereaved family 32 228,708 34 229,446 39 286,373 47 335,977 30 215,342

Funeral expenses 74 14,010 53 10,386 63 12,661 72 14,391 46 9,914

Total 1,674 1,587,567 1,346 1,582,956 1,425 1,696,525 1,545 1,798,706 1,703 1,783,783

*“Number of cases in progress” indicates the value at the end of each fi scal year.

Note: The number of cases indicates the cases newly judged as eligible for benefi ts in each fi scal year. The paid amount includes payments for both new and existing cases.

(Unit: Thousands of yen)

12


Since drugs or medical devices using ingredients and

materials of biological origin, such as humans and

animals, may contain organisms such as viruses that can

cause infections, various measures are taken to ensure

product safety. However, even safety measures based on

the latest scientifi c knowledge cannot completely eliminate

the risk of infections acquired through biological

products.

　A system for providing relief services for infections

acquired through biological products was therefore

established in April 2004. In this system, relief benefi ts

are provided to patients who have suffered health

damage such as diseases and disabilities requiring

hospitalization caused by infections acquired through

biological products, even i f such products were

properly used. Treatment to prevent the onset of disease

following infections and cases of patients with secondary

infection are also eligible for these relief benefi ts.

　Relief is provided for cases of infections acquired

through biological products that were used on or after

April 1, 2004.

Relief System for Infections Acquired through Biological Products

③ Consultation

① Claimfor benefits

⑥ Paymentof benefits

Subsidy(administrative fees)

② Request for judgment

④ Advice

⑤ Notice of judgment

Purchase/Prescription

Dosage/Usage

Adverse Drug Reaction Fund(general contribution/additional contribution)

Distribution

Infection Contributions(general contribution/additional contribution)

PharmaceuticalAffairs and

Food SanitationCouncil

Adverse healtheffects sufferers

Government(Ministry of Health,Labour and Welfare)

Pharmaceuticalmarketing

authorizationholders

Biologicalproduct

marketingauthorization

holders

Minister ofHealth, Labour

and Welfare

Medicalinstitutions and

pharmacies

PMDA

Relief System forAdverse Drug Reactions

Relief Systemfor Infections Acquired

through Biological Products

Flowchart of Relief Services


13


Cases of Relief Services for Infections Acquired through Biological Products

There are seven types of benefits: medical expenses,

medical allowances, disability pension, pension for raising

handicapped children, bereaved family pension, lump-

sum benefi ts for bereaved family and funeral expenses.

Types of Benefi ts

Documents Required for Claims for Relief Benefi ts

Claims for relief benefi ts must be submitted directly to

PMDA by the patient who has suffered health damage

caused by adverse drug reactions or infections, or by his

or her bereaved family.

　When claiming relief benefi ts, it is necessary to prove

the pathogeny and symptoms/progress of the adverse

reaction or infection, and the causal relationship

between the health damage and the use of the drug.

This requires a medical certificate issued by the doctor

who treated the adverse reaction or infection as well as

proof of prescription. A claimant for relief benefits

should request the doctor to issue the certificates and

submit them to PMDA together with the claim form

fi lled out by the claimant.

　All necessary forms, including claim forms and medical

certifi cate forms, are available from PMDA, and can be

obtained free of charge upon request by the patient

suffering from adverse health effects or by his or her

family.

　The necessary documents can also be downloaded

from the PMDA website: http://www.pmda.go.jp

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Number of applications 5 6 9 13 6

Number of judged cases 6 7 5 11 10


Number of cases in progress* 2 1 5 7 3

Median processing time 5.6 months 3.8 months 3.8 months 5.2 months 5.4 months

*“Number of cases in progress” indicates the value at the end of each fi scal year.

Payment of Relief Benefi ts for Infections Acquired through Biological Products

Types of benefi tsFY 2005 FY 2006 FY 2007 FY 2008 FY 2009

No. of cases

Amount paid

No. of cases

Amount paid

No. of cases

Amount paid

No. of cases

Amount paid

No. of cases

Amount paid

Medical expenses 3 475 6 473 3 102 5 204 6 375

Medical allowances 3 249 6 497 3 352 6 386 8 567

Disability pension －－－－－－－－－－Pension for raising handicapped children －－－－－－－－－－

Bereaved family pension －－ 1 1,387 － 2,378 － 2,378 － 2,378

Lump-sum benefi ts for bereaved family －－－－－－ 1 7,135 －－

Funeral expenses －－ 1 199 －－ 1 199 －－Total 6 724 14 2,556 6 2,833 13 10,302 14 3,320

Types of Benefi ts

In case of disease (requiring hospitalization)

In case of disability (causing serious impairment in daily life)

In case of death

Medical Expenses Medical Allowances Disability Pension Pension for RaisingHandicapped Children

Bereaved FamilyPension

Lump-sum Benefi t forBereaved Family Funeral Expenses

Compensation will refl ect the actual costs of treatment borne by the patient

Financial assistance is provided for costs other than medical costs for disease treatment

Financial assistance is provided to compensate living costs of patients over 18 years old, who suffer from a certain degree of disability

Financial assistance is provided for those who are responsible for raising patients under 18 years old who suffer from a certain degree of disability

Financial assistance is provided for bereaved families in rebuilding their life following the death of their main provider

Financial assistance is provided for bereaved families as a gesture of sympathy following the death of their family member who is not the main provider

Financial assistance is provided for costs in holding a funeral

(Unit: Thousands of yen)

14


The following cases are not eligible for relief benefits

under either the Relief System for Adverse Drug

Reactions or the Relief System for Infections Acquired

through Biological Products:

1. Cases of adverse health effects resulting from statutory

vaccinations (a different public relief system is available

for such cases). However, cases of adverse health

effects resulting from voluntary vaccinations are

eligible for the relief benefi ts.

2. Cases where it is apparent that the marketing authorization

holder is liable for the adverse health effects caused

by its drug or biological product.

3. Cases where it was necessary to use the drug or

biological product in an amount exceeding the regular

dosage for the purpose of saving the patient’s life,

even if it was acknowledged beforehand that adverse

health effects may occur.

4. Cases of adverse drug reactions, infections acquired

through biological products, etc., where the extent

of adverse health effects is minor, or where the

eligibility period for claiming relief benefi ts has passed.

5. Cases where the drug or biological product was not

used properly.

6. Cases of adverse health effects caused by drugs that

are not covered by the relief system (this applies only

to the Relief System for Adverse Drug Reactions).

The funds that are required for relief services come

from contributions made by marketing authorization

holders of drugs and biological products. When adverse

health effects occur due to a marketing authorization

holder’s own product and relief benefi ts must be paid,

the holder is liable for additional contributions in

addition to the general contributions.

　Meanwhile, half of the administrative fees for the

Relief System for Adverse Drug Reactions and the

Rel ie f System for In fect ions Acqui red through

Biological Products are subsidized by the Japanese

government.

Cases Not Eligible for Relief Benefi ts Contributions to the Relief System

If a claimant is not satisfied with the judgment on

eligibility for relief benefits, the claimant may file a

request for reconsideration with the Minister of Health,

Labour and Welfare within two months after the day on

which the claimant is informed of the judgment.

　In such a case, the petitioner may give a statement of

opinions.

Appeals against Judgments

Contributions to Relief System for Adverse Drug Reactions

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Marketing authorization holders (MAHs) of approved drug products［Number of MAHs］

2,923 3,240 3,049 3,722 3,783

［787］［778］［762］［752］［742］

MAHs of pharmacy-compounded drug products［Number of MAHs］

10 9 8 8 8

［9,993］［8,968］［8,309］［8,015］［7,598］Total contributions 2,933 3,249 3,057 3,730 3,790Contribution rate 0.3/1000 0.3/1000 0.3/1000 0.35/1000 0.35/1000

(Unit: Millions of yen)

Contributions to Relief System for Infections Acquired from Biological Products

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

MAHs of approved biological products［Number of MAHs］

553 556 574 620 631

［105］［101］［98］［96］［97］Contribution rate 1.0/1000 1.0/1000 1.0/1000 1.0/1000 1.0/1000

(Unit: Millions of yen)

15


Since December 1979, PMDA or its predecessor has

been providing nursing care expenses to patients with

grade III SMON who have very severe or extremely

severe symptoms, under commission from drug

manufacturers liable for causing SMON in such patients.

　Since FY 1982, PMDA or its predecessor has also been

providing nursing care expenses to patients with grade

III SMON who have severe symptoms (excluding

pat ients with ver y severe or extremely severe

symptoms), under commission from the Japanese

government.

Since December 1979, PMDA or its predecessor has

been providing healthcare allowances to SMON patients

under commission from drug manufacturers liable for

causing SMON in such patients.

Nursing Care Expenses

Healthcare Allowances

PMDA provides healthcare allowances and nursing care expenses to subacute myelo-optico-neuropathy (SMON) patients for whom a settlement has been reached in court.

Healthcare Allowances for SMON Patients

Healthcare Allowances for HIV-positive and AIDS Patients

PMDA provides healthcare allowances to AIDS patients

who have been infected with HIV through blood

coagulation factor products and for whom a settlement

has been reached in court. The purpose of these

healthcare allowances is to improve the welfare of AIDS

patients by reducing the cost of monitoring their health.

Patients with secondary and tertiary infections are also

eligible for these benefi ts.

To help prevent the development of AIDS, PMDA

provides healthcare expenses to HIV-positive patients

who have not yet developed AIDS and who were infected

through HIV-tainted blood products, in exchange for

reports on their health condition. Patients with secondary

and tertiary infections are also eligible for these

benefi ts.

Healthcare Support Services

Investigative Research

PMDA, under commission from the Yu-ai Welfare Foundation, provides the following services to patients who have become infected with HIV through blood products.

16


Flowchart of Claiming for Benefi ts

PMDA provides benefits under the “Act on Special

Measures concerning the Payment of Benefi ts to Assist

Individuals Affected by Hepatitis C through Specifi ed

Fibrinogen Products and Specified Blood Coagulation

Factor IX Products Contaminated by Hepatitis C Virus.”

Provision of Financial Assistance

Financial assistance under the “Act on Special Measures concerning the Payment of Benefi ts to Assist Individuals Affected by Hepatitis C through Specifi ed Fibrinogen Products and Specifi ed Blood Coagulation Factor IX Products Contaminated by Hepatitis C Virus”

Flowchart of Claiming for Additional Benefi ts

Court PMDA

④Payment

③Claim for benefits based on the　settlement, judgment, etc.①Filing a case

②Successful settlement/arbitration or　definitive judgment (the facts of drug　administration, a causal relationship, 　and symptoms are recognized)

Individualsaffected byhepatitis C

(or theirsuccessors)

Doctors PMDA

①Request for a medical certificate in the　case where the symptom worsens

②Preparation of a medical certificate　stating the symptom

③Claim for additional benefits based　on the medical certificate

④Payment of additional benefits

Individualsaffected byhepatitis C

(or theirsuccessors)

17

PMDA is committed to conducting appropriate reviews of applications for drugs and medical devices.

Reviews and Related Services

18

Consolidated Structure Allowing Greater Cooperation and Speed

In addition to reinforcing the review system by increasing the number of expert reviewers and

inspectors, PMDA is striving to enable patients and healthcare professionals to have faster access

to drugs and medical devices by using a team review system. In the review system, the same

review team is responsible for each step of the review process, from clinical trial consultations to

product application reviews to ensure that precise guidance and advice are provided and appropriate

reviews and inspections are conducted. In particular, to resolve the issue of the “drug lag,” whereby

drugs approved in the US and EU have not yet been approved in Japan and cannot be provided to

Japanese citizens, by FY 2011, PMDA is making the review process faster and more efficient by

increasing the number of review staff, shortening the period from the start of clinical trials to

approval of new drug applications, and training human resources.

　In FY 2009, PMDA also took various initiatives to reduce the “device lag,” which is the lag in

permitting the use of medical devices, by FY 2013 similarly to the measures taken for the “drug lag.”

Consultationsregarding drugs/medical devices

Reviews of drug/medicaldevice applications

Equivalence reviews,GLP/GCP inspections,GMP/QMS inspections

for drugs/medicaldevices

Safety measures fordrugs/medical devices

Post-marketingsurveillance and

GPSP inspections

Ministry of Health,Labour and Welfare

PMDA

Application ApprovalReviewDevelopment Post-marketing

19


Upon request, PMDA offers consultations to give guidance and advice on clinical trials for new drugs and medical devices as well as on clinical studies relating to re-examinations and re-evaluations of approved drug products and medical devices.　In clinical trial consultations, PMDA checks whether a proposed c l i n ica l t r i a l proper l y meet s t he requirements for regulatory submission, taking into consideration the ethical and scientific aspects and reliability of the clinical trial as well as the safety of trial subjects, and also gives guidance and advice on improving the quality of the clinical trial.　In FY 2009, PMDA started a pilot scheme for prior assessment consultations in which data such as on quality, efficacy and safety are evaluated before a new drug application is fi led.　In order to promote development and speed up application reviews by providing detailed advice as required at each stage of the product development process, PMDA expanded the categories of clinical trial consu ltat ions on medica l dev ices and in v it ro diagnostics in FY 2007 so as to provide specifi c advice for each development stage. For cell- and tissue-based products that are developed using state-of-the-art technology such as pharmacogenomics or regenerative medicine, there is a very strong need for advice on product development and regulatory submission, as there are only a few precedents. PMDA therefore established new categories of consultation services: consu ltat ions on submission documentation for cel l - and tissue-based products in FY 2 0 07, a nd consultations on pharmacogenomics/biomarkers in FY 2009.　In addition, simple consultations on generic drugs, OTC drugs and quasi -drugs are avai lable to give guidance and advice in face-to-face meetings with applicants.　For pr ior ity review products, PMDA provides consultations on GLP/GCP compliance of study data to be submitted.

Consultations

PMDA’s reviews and related services include evaluating

the quality, effi cacy and safety of drugs and medical

devices intended for use in clinical practice, as well as

over-the-counter (OTC) drugs and quasi-drugs used

in everyday life.

　As part of the reviews and related services, PMDA

conducts the following: consultations including those

prior to clinical trials, where guidance and advice on

clinical trials in relation to regulatory submission are

given; GLP/GCP/GPSP inspections and audits as to

whether the submitted application complies with ethical

and scientifi c standards; application reviews to evaluate

the quality, effi cacy and safety of the product submitted

for approval, taking the result of the GLP/GCP/GPSP

inspections into account and in the light of current

scientific and technological standards; and GMP/

QMS inspections to determine whether the applicant

is sufficiently capable of manufacturing the product

submitted for approval.

　In PMDA, the same review team handles the entire

review process from the stage before clinical trials

until approval is granted, including clinical trial

consultations and product application reviews. This

approach makes the reviews faster and more reliable.

　In accordance with the recommendations of the

Council for Science and Technology Policy, PMDA

has been improving its review system for new drugs

in order to reduce the drug lag by 2.5 years (consisting

of 1.5 years for development and 1 year for new drug

application review) by FY 2011.

　Measures being taken to achieve this goal include:

(1) increasing the number of reviewers, (2) improving

training, (3) reducing the development period by

signifi cantly expanding and improving the consultations,

(4) reinforcing and improving the transparency of the

progress management of reviews, (5) facilitating global

clinical trials, (6) clarifying review standards, (7)

developing a guidance document for the introduction

of a system of prior assessment consultation and (8)

implementing a project management system. Through

these efforts, PMDA will improve the reviews and

related services.

　Meanwhile, the Ministry of Health, Labour and

Welfare drew up the Action Program to Accelerate

Reviews of Medical Devices in December 2008, and

instructed PMDA to reduce the device lag by 19

months (consisting of 12 months for development and

7 months for new medical device application review)

by FY 2013. Following this instruction, PMDA has taken

measures to speed up and improve reviews, such as

(1) increasing the number of medical device reviewers,

(2) improving training, (3) introducing a 3-track review

system and prior assessment consultation system, (4)

clarifying review standards, and (5) ensuring thorough

progress management.


20


Flow of Drugs and Medical Devices: from Development to Marketing

Researchand

developmentNon-clinical

testsClinicaltrials

Filing ofapplication

Approval Marketing

Clinical trials consultation

MHLW

Non-clinical tests. Animal test

Phase I trials. Conducted in healthy volunteers

. Mainly for safety assessment

Phase II trials (First stage). Conducted in small group of patients

. Initial assessment of efficacy

. Conducted in patients. Determine the dosage with which efficacy

and safety will be assessed in the next phase

Phase II trials (Late stage)

. Conducted in larger group of patients. Controlled and uncontrolled trials to confirm

the efficacy and safety in actual clinical use

Phase III trials

From clinical trials to new drug application

Review Post-marketingsafety

measures

Relief foradverse health

effects

External experts

MHLW

PMDA Clinical trial

consultation/Review(Team review)

Applicant

Review of applications for drugs and medical devices

Application

Approval

Reviewreport

Expert discussion

New drug application

Inquiry/response

21


In the regulatory review of drug applications, PMDA reviewers, who have degrees in pharmaceutical science, medicine, veterinary medicine, physical science, biostatistics or other specialties, form a team to evaluate the quality, pharmacology, pharmacokinetics, toxicology, clinical implications, and biostatistics of the particular drug product under review. During the review process, the reviewers exchange opinions with external experts (Expert Discussions) to ensure that reviews are conducted by using advanced expertise.　In particular, for drugs developed with the latest technology such as biotechnology, PMDA reinforces the review system by inviting additional reviewers specialized in particular fi elds to participate in the review.　To provide healthcare professionals and patients with faster access to improved drugs, PMDA is also speeding up the review process, such as by setting target review times and conducting priority reviews for products designated as such.　While participating in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), which is intended to achieve consistency in regulations related to new drug application data and establish harmonized technical requirements leading to greater mutual acceptance of research and development data between Japan, the US and the EU, PMDA has actively incorporated the guidelines agreed upon in the ICH into its reviews.　A document on the principles of reviews entitled, “Points to Be Considered by the Review Staff Involved in the Evaluation Process of New Drug” was created and explained to the personnel who are responsible for new drug reviews. The principles are published on the PMDA website and help clarify the standards for review.　Drug reviews encompass not only new drugs but also generic drugs that are acknowledged as being equivalent to previously approved drugs, OTC drugs which can be purchased at pharmacies and drug stores without a doctor’s prescription, and quasi-drugs.　PMDA also conducts re-examinations and re-evaluations of approved drug products as well as reviews of confi rmation applications prior to clinical trial notifi cations for genetically modifi ed biological entities, regenerative medicine (cell- and tissue-based products) and gene therapy products.　In FY 2009, a total of 8,328 drugs were approved, of which 3,737 were prescription drugs (including

466 new drugs), 2,171 were OTC drugs, 199 were in vitro diagnostics and 2,221 were quasi-drugs.Drug Reviews

Number of Clinical Trial Consultations (Drugs)

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Number of consultations 232 295 302 338 393


●What Are Clinical Trials?A clinical trial refers to a research study conducted to verify the efficacy of a drug or medical device and potential adverse reactions when it is used in humans. The data col lected f rom such studies are then submitted for regulatory reviews.

Number of Clinical Trial Consultations Conducted in FY 2008 by Category (Drugs)

CTC Category Consultations

Category 1 (Gastrointestinal drugs) 35

Category 6-2 (Hormone drugs) 35

Category 2 (Cardiovascular drugs) 52

Category 5 (Drugs for urogenital system) 19

In vivo diagnostics 1

Radiopharmaceuticals 5

Category 3-1 (Central/peripheral nervous system drugs) 42

Category 3-2 (Anestheteic drugs) 22

Category 4 (Antibacterial agents) 35

AIDS drugs 0

Category 6-1 (Respiratory tract drugs) 32

Anti-cancer drugs 54

Blood products 8

Bio-CMC 11

Biological products 16

Cell- and tissue-based products 1

［Re-listed］ Prior assessment (pre-NDA review) 33

Pharmacogenomics and biomarkers 1

GLP/GCP compliance (for priority reviews) 1

Total 370

Withdrawn 23

Grand total 393

Note: 1. A consultation covering several categories is counted according to its main category.

2. Prior assessment consultations for drugs are conducted for the categories of qual i t y, non-cl inical : tox icology, non-cl inical : pharmacology, non-clinical: pharmacokinetics, phase I study and phase II study.

3. The numbers of pr ior assessment consul t a t ions for drugs and consultations on pharmacogenomics/biomarkers were counted on the basis of delivery dates of consultation documents to PMDA.

4. Consultations on pharmacogenomics/biomarkers are conducted by the Omics Project Team.

5. Consultations on GLP/GCP compliance (for priority reviews) are all conducted by the Offi ce of Conformity Audit, regardless of category.

22


technology and materials used in each medical device differ according to the type of product, from surgical instruments to MRI and pacemakers. It is therefore necessary to rationally regulate medical devices depending on various product characteristics, such as the usage method and level of risk.　From among the many types of medical devices, PMDA review staff mainly review applications for high-risk medical devices, such as artificial hearts, pacemakers, coronary stents, artificial blood vessels, artificial joints and artificial kidneys.　In order to enable healthcare professionals and patients to have faster access to these medical devices which are necessary in clinical practice, PMDA has set target review times and is working hard to achieve these targets.　Specifi cally, PMDA has greatly increased the number of reviewers who possess expertise in medical engineering, biological engineering and biomaterials to conduct professional reviews across a wide range of specialties. In addition to such engineering experts, the reviewers include experts with degrees in medicine, dentistry, pharmaceutical science, veterinary medicine, physical science and biostatistics, who participate in non-clinical, clinical and biostatistical reviews. During the review process, the reviewers exchange opinions with external experts (Expert Discussions) to enable more efficient and professional reviews.　In order to develop a globally harmonized review system for medical devices, PMDA participates in the Global Harmonization Task Force (GHTF) formed by Japan, the US, the EU, Australia and Canada. PMDA has actively incorporated the guidelines agreed upon in GHTF into its reviews, and its regulatory review system adopts standards such as those of the International Organization for Standardization (ISO) and the International Electrotechnical Commission (IEC).　Since April 2009, application categories for medical devices have been re-classifi ed as follows:

• New medical devices• Improved medical devices (with clinical data)• Improved medical devices (without clinical data)• Generic medical devices (with no applicable approval standards)

• Generic medical devices (with applicable approval standards)

　Meanwhile, low-risk medical devices for which certifi cation standards have been established need to be certified by a third-party certifi cation body under the current regulatory system, instead of receiving the Minister’s approval.　In the case of general medical devices, marketing notifi cation should be submitted to PMDA.

Medical devices, as with drugs, are products that are used for the diagnosis, treatment and prevention of diseases. The

Medical Device Reviews

Median Total Review Time for New Drugs (Priority Review Products)

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Total review time

[Months]4.9 13.7 12.3 15.4 11.9

Regulatory review time

[Months]2.8 6.4 4.9 7.3 3.6

Applicant's time

[Months] 2.2 6.0 6.5 6.8 6.4

Number of approved

applications9 20 20 24 15

Note: Values indicate the data for approved applications that were fi led in or after April 2004.

Median Total Review Time for New Drugs (Standard Review Products)

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Total review time

[Months] 18.1 20.3 20.7 22.0 19.2


[Months]10.3 12.8 12.9 11.3 10.5

Applicant's time

[Months] 7.2 6.9 7.9 7.4 6.7

Number of approved


Note: Values indicate the data for approved applications that were fi led in or after April 2004.

●What Are Priority Review Products?

Priority review products refer to orphan drugs (expected to be used by less than 50,000 patients) and products designated for priority review by the Ministry of Health, Labour and Welfare in consideration of their clinical usefulness and the seriousness of the diseases for which they are indicated.

●What Are Generic Drugs?

Generic drugs are drug products that are approved without clinical trials for confirming their efficacy and safety because their ingredients and specifi cations are equivalent to those of an off-patent brand drug that has already been approved as a new active ingredient or for which a new indication, etc. has been verifi ed through clinical trials, etc.

23


PMDA conducts inspections and reliability assessment

in relation to applications for marketing approval, re-

examination, or re-evaluation to assess whether the

tests and clinical trials have been conducted in an

ethically and scientifi cally appropriate way in compliance

with Good Laboratory Practice (GLP), Good Clinical

Practice (GCP) and Good Post-Marketing Surveillance

Practice (GPMSP) or Good Post-marketing Study Practice

(GPSP), and whether the submitted data comply with

the reliability standards for regulatory submission

documentation. PMDA also provides GLP compliance

certification to testing laboratories.

Conformity Audits (GLP/GCP/GPSP inspections

and data reliability assessment)

Number of Approved Medical Devices

FY 2005 FY2006 FY 2007 FY 2008 FY 2009

1,827 1,342 2,222 2,459 2,035

Note: 1. Values for GLP, GCP and GPSP inspections in or after FY 2005 are the number of notifi cations after the evaluation was conducted.

2. The numbers of inspections from FY 2005 to FY 2008 indicate those conducted as GPMSP inspections, while the number for FY 2009 includes GPMSP or GPSP inspections.

3. GLP: Good Laboratory Practice4. GCP: Good Clinical Practice5. GPMSP: Good Post-marketing Surveillance Practice6. GPSP: Good Post-marketing Study Practice

Number of GLP/GCP/GPSP Inspections

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Document-based inspections/reliability assessment

136 426 774 942 1,136

Drugs 135 251 234 293 246

Medical devices 1 175 540 649 890

GLP inspections 39 31 27 43 26

Drugs 37 23 23 32 18


GCP inspections 131 149 132 198 175

New drugs 120 137 122 182 164

Generic drugs 11 12 9 15 10


GPSP inspections 82 103 107 79 65

(Number of Products)

Median Total Review Time for New Medical Devices (Priority Review Products)

Note: 1. Values indicate the data for approved applications that were fi led in or after April 2004.

2. Since the target for applicant's time was set up beginning in FY 2009, no previous values were available.

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Total review time

[Months]－ 14.2 15.7 28.8 13.9


[Months]－ 5.7 8.6 5.8 6.0

Applicant's time

[Months] －－－－ 7.7

Number of approved


Median Total Review Time for New Medical Devices (Standard Review Products)

Note: 1. Values indicate the data for approved applications that were fi led in or after April 2004.

2. Since the target for applicant's time was set up beginning in FY 2009, no previous values were available.

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Total review time

[Months] 10.3 15.7 15.1 14.4 11.0


[Months]1.8 3.2 7.7 9.8 6.8

Applicant's time

[Months]－－－－ 7.1

Number of approved


Number of Clinical Trial Consultations (Medical Devices and In Vitro Diagnostics)

FY 2005 FY2006 FY 2007 FY 2008 FY 2009


In vitro diagnostics 1 3 1 2 6

Total 30 42 72 76 110

24


When manufacturing a drug or a medical device, all

products should be of the same quality as that of the

product which was approved. To ensure this, the

manufacturing site should have appropriate manufacturing

facilities, and the manufacturing process and quality

management system should be maintained and controlled

properly.

　PMDA conducts on - s ite and document-based

inspections of manufacturing sites that require a license

from the Minister of Health, Labour and Welfare,

such as manufacturing sites of new drugs, new medical

devices or vaccines, as well as those of high-risk (Class IV)

medical devices, in order to ascertain whether their

manufacturing facilities and manufacturing controls

comply with standards such as the Good Manufacturing

Practice/Quality Management System (GMP/QMS), and

whether the manufacturing sites have a system for

manufacturing products of adequate quality.

　PMDA also conducts inspections of the licensing of

manufacturing sites located in Japan that require a

license from the Minister and inspections relating to

accreditation of foreign manufacturers.

GMP/QMS Inspections

● Improvement of the Clinical Trial Environment

PMDA carries out GCP inspections as part of its services. GCP is a standard for the conduct of clinical trials to protect the human rights, safety and welfare of trial subjects, as well as to ensure the scientifi c quality of clinical trials and the reliability of the study results. GCP inspections at medical institutions where the clinical trials took place are conducted to verify how the safety of subjects was ensured and how the trials were managed.　In conducting GCP inspections, PMDA inspectors a lso g ive f i r s t-hand adv ice to the phys ic ians, pharmacists and nurses at the medical institutions, thus improving the clinical trial environment in Japan.

Number of GMP/QMS Inspections

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Drugs*53

(35)

783

(180)

893

(233)

738

(214)

2,000

(297)

In vitro diagnostics9

(0)

32

(4)

84

(1)

78

(1)

107

(3)

Quasi-drugs0

(0)

5

(0)

0

(0)

3

(0)

3

(0)

Medical devices32

(4)

300

(20)

1,021

(12)

915

(42)

1,285

(66)

Total94

(39)

1,120

(204)

1,998

(246)

1,734

(257)

3,395

(366)

*Excludes in vitro diagnosticsNote: 1. Figures in parentheses indicate the number of on-site inspections.

2. GMP: Good Manufacturing Pratice3. QMS: Quality Management System

25

In cooperation with the Ministry of Health, Labour and Welfare, PMDA is dedicated to improving the safety and reliability of drugs and medical devices.

Post-marketing Safety Measures

26

Flowchart of Safety Measures

PMDA collects information on the quality, efficacy and safety of drugs and medical devices from

marketing authorization holders and medical institutions in an integrated manner, which it then uses

for scientific research and reviews in order to accurately implement safety measures in conjunction

with the Ministry of Health, Labour and Welfare. PMDA also provides appropriate information to

healthcare professionals, drug manufacturers, and users of drug products and medical devices.

　Through such activities, PMDA is committed to improving the quality, safety and reliability of the

medical environment by integrating the entire process, from clinical trial consultations to post-

marketing safety measures.

Analysis

Considering safety measures

Reporting

Input and maintenance of information

Hearing

Notification regarding issue under consideration/

opinion exchange

Collection/confirmation of information regarding quality, efficacy, and safety of drugs and medical devices

Receipt of information regarding quality, efficacy, and safety of drugs and medical devices

Corporate hearing

Database

Data collection/analysis

Results of review/analysis

Consultation on drugs and medical devices

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

Discussionwith experts

Report

Broad dissemination of information

Broad dissemination of information

Broad disseminationof information

Reporting of safety information

Collection of safety information

Report

PMDAMinistry of Health,Labour and Welfare

(MHLW)

Marketing Authorization Holders

Keeping track of all theinformation

Planning/development of safety measures

Implementing safety measures

Implementation ofsafety measures

General publicMedical institutions

Medical institutions

Pharmaceutical Affairs and Food Sanitation Council

Reporting

Immediatelyaccessible

Information regarding overseas regulatory actions and medical literature

27


It is important to collect the necessary safety information on drugs and medical devices at appropriate times and from a wide range of sources.　PMDA collects safety information promptly and effi ciently by using information technology; safety staff electronically receive reports from companies when cases of adverse drug reactions (ADRs) and infections caused by drugs as well as malfunctions of medical devices are detected during the development and post-marketing periods.　PMDA also consolidates all essential safety information from a broad range of fields, such as information on ADRs, infections, or malfunctions as reported by healthcare professionals to MHLW, information from international sources, such as ICH, and conference papers and research reports related to medical and pharmaceutical sciences. The collected information is then promptly compiled into a database and shared with MHLW.

Collecting, Organizing, and Consolidating Safety

Information

Drugs and medical devices are essential for a healthy,

happy life.

　Thanks to advancements in science and technology,

humans have conquered many difficulties over the

years; the drugs and medical devices created by

human ingenuity have allowed us to overcome many

diseases.

　However, the drugs and medical devices used for

diagnosing or treating diseases may also cause

unexpected adverse reactions, so they should be

used considering the balance between risk and benefi t.

It is extremely important that healthcare professionals

use drugs and medical devices properly at all times;

safety is achieved through the ceaseless efforts of

people who are involved in all stages of the life cycle

of drugs and medical devices. And it is this safety that

gives users peace of mind.

　In cooperation with the Ministry of Health, Labour

and Welfare (MHLW), PMDA is dedicated to improving

the safety and reliability of drugs and medical

devices.


Number of Adverse Drug Reaction Reports

From FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Companies (Japanese) 24,751 26,560 28,257 32,306 30,928

Companies (foreign) 65,316 77,346 95,036 116,622 141,386

Healthcare professionals 3,992 3,669 3,891 3,816 3,721

Number of Medical Device Malfunction Reports

From FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Companies (Japanese) 6,222 9,310 13,842 4,301 4,116

Companies (foreign) 5,012 2,880 2,708 2,014 2,332

Healthcare professionals 445 424 434 444 363

28


In research and reviews of safety information, it is important to scientifically evaluate the collected information promptly and thoroughly. PMDA therefore strives to improve the quality of safety measures by using the latest scientific evaluation methods, such as epidemiological analysis, and by building the expertise of its safety staff through training.　PMDA conducts research and reviews of the collected information through scientific analyses by its highly specialized staff, interviews with companies, and discussions with experts as necessary, to determine whether any cases require urgent measures, whether the risk/benefit profile is favorable, and the optimum safety measures to be taken. All these efforts help increase the safety of drugs and medical devices.　To establish effective safety measures, the safety staff work together with the review and relief divisions as needed, as well as with MHLW.

Scientifi c Research and Reviews

In order for drugs and medical devices to be used safely and with a sense of trust, companies need to establish a system for collecting and evaluating information and taking appropriate measures on a daily basis without fail, as well as a risk-management system.　PMDA offers a broad range of consultations to companies on how to improve the safety of drugs and medical devices, such as how to revise package inserts accompanying drug products and medical devices, how to properly use them for preventing serious ADRs, and other medical safety issues. In such consultations, PMDA gives specifi c advice and guidance to companies to help them increase the safety of each drug product and medical device, while also raising corporate awareness of safety measures.　PMDA’s consultation services are also available for the general public to obtain advice and safety information on drugs and medical devices.

Appropriate Advice - Consultation Services

The Necessary Information at the Right Time -

Information Services

In order for drugs and medical devices to be used safely and with a sense of trust, it is important to provide the required information whenever needed.　PMDA actively provides the following information on the quality, efficacy and safety of drugs and medical devices on the Medical Product Information page of its website: http://www.info.pmda.go.jp

•Package inserts of drug products and medical devices•Recalls• Urgent safety information issued by manufacturers (“Dear Healthcare Professional” Letters)

•Ministry of Health, Labour and Welfare press releases•Approval of new drugs• Quality information for prescription drugs• Pharmaceuticals and Medical Devices Safety Information• PMDA Medical Safety Information

The funds necessary for safety measures carried out by PMDA come from contributions made by the marketing authorization holders of drugs and medical devices.　In accordance with the Act on the Pharmaceuticals and Medical Devices Agency, marketing authorization holders of drugs or medica l dev ices under the Pharmaceutical Affairs Act as of April 1 in any given year are required to make a declaration and pay a contribution to PMDA by July 31 of the same year based on the total quantity of their products shipped in the previous fi scal year.

Contributions to Post-marketing Safety Measures

Contributions to Safety Measures

FY 2005 FY 2006 FY 2007 FY 2008 FY 2009

Marketing authorization holders

(MAHs) of approved drug

products and medical devices

［Number of MAHs］

1,143 1,211 1,219 1,284 2,354

[2,982] [3,180] [3,094] [3,053] [3,019]

MAHs of pharmacy-compounded

drug products

［Number of MAHs］

10 9 8 8 8

[9,987] [8,960] [8,297] [8,013] [7,594]

Total contributions 1,153 1,220 1,227 1,292 2,362

Contribution rate 0.11/1000 0.11/1000 0.11/1000 0.11/10000.22/1000*

0.11/1000**

(Unit: Millions of yens)

*For drug products (excluding in vitro diagnostics)**For medical devices and in vitro diagnostics

29


Safety measures for drugs and medical devices are grounded in various standards, such as the Japanese Pharmacopoeia, which are set forth in the Pharmaceutical Affairs Act.　PMDA collects, organizes and investigates information on those standards which are relevant to the quality, efficacy and safety of drugs and medical devices, and submits its fi ndings to MHLW.　For the Japanese Pharmacopoeia in particular, PMDA has established expert committees on individual fi elds such as chemical drugs, biological drugs and general test methods. These committees mainly evaluate the quality of drugs and develop drafts for the Japanese Pharmacopoeia. Public comments are sought regarding items nominated for entry into the Japanese Pharmacopoeia and its draft monographs on the PMDA website: http://www.pmda.go.jp

Fundamentals of Safety Measures - Standards

Development

1. Decide the basic policy

3. Finalize the candidate drug list

PharmaceuticalAffairs and FoodSanitation Council

7. Prepare the English edition

5. Editing and correction6. Announcement

2. List the candidate drugs4. Prepare the draft monographs

Final draftsEnglishedition of JP

JapanesePharmacopoeia

Companies'drafts

PMDA

Pharmaceuticalcompanies

MHLW

①Request for drafts

②Submission of the drafts

③Inquiry and request for reconsideration

④Response

Seek publiccomments

(on the web)

Seek publiccomments

(on the web)

Expertcommittees by

fields (JapanesePharmacopoeia

DraftCommittees)

In FY 2008, PMDA established a safety measures operation support system incorporating data mining methods. This computer-based system conducts statistical analyses of information on adverse drug reactions as reported by companies and detects signals for which safety measures may be required.　The new operational flow with data mining allows the staff to analyze safety information not only from pharmacological aspects but also from quantitative aspects.　In line with the Mid-term Plan, PMDA intends to proactively make use of the data mining methods in organizing, evaluating, and analyzing information on adverse drug reactions and make improvements on an as-needed basis, in order to detect any adverse drug reaction at an early stage and take measures to prevent further events.　In FY 2009, PMDA examined the detection method of duplicate reports so as to further enhance the accuracy and reliability of signal detection by data mining. The Agency also studied the method of capturing time-series changes in the number of adverse drug reaction reports. The method has been adopted on a trial basis to verify the effectiveness of the safety measures taken in some cases.

Post-marketing Safety Measures by Data Mining

Line list(Weekly, daily)

Case cards

Database ofadverse reaction

reports

Case analysis

Analysisoperations

Consideration on the need of hearing with companies

and experts

All Adverse reactions

information

Adverse reactions information which needs

further investigations

Adverse reactions information which needs

response/measures

Line list analysis

Signaldetection

Detection results by data mining (signal detection technique)

Application of Data Mining to Safety Measures

Revision of Japanese Pharmacopoeia

30


Application of Electronic Medical Records to

Safety Measures

In l ine with the Mid-term Plan, PMDA intends to develop the access infrastructure for the medical record databases by FY 2013 so as to per form pharmacoepidemiological analyses and quantitatively evaluate pharmaceutical risk.　In July 2009, PMDA established the “Study committee on the application of electronic medical records to safety measures,” which is composed of external experts, under the initiative called the MIHARI Project. The project involves a series of investigations on advantages and disadvantages, etc. of data, such as health insurance claim data and hospital information system data, according to the data type.　PMDA investigated the characteristics of claim data and what analysis is applicable to safety evaluation by using a commercial ly-avai lable database of claims, and conducted a pilot study on anaphylaxis in FY 2009. The results of the study were posted on the PMDA website. The Agency continues to undertake pilot studies on different themes and to investigate analysis methods.　With regard to hospital information systems, PMDA conducted a pilot study on the detection of information on adverse drug reactions, in line with more than one theme such as “rhabdomyolysis caused by statin drugs,” from 5 medical institutions that are equipped with the standard storage based on the SS-MIX (Standardized Structured Medical Information Exchange project by the MHLW) standards. In this study, PMDA identified technical challenges for the secondary use of data from more than one hospital information system in terms of differences in data among institutions, potential for integration of retrieved and detected data, and preparation of data sets for analysis, which served as a basic investigation to make improvements in the future.　PMDA continuously examines the usability of other electronic medical records.

Study on Introduction of New Databases (DBs) to Drug Safety Evaluation Process

Medicalbill DB DPC DB

Hospitalinformation

DB

Drug useresult

survey DB

From FY 2013 onwards

Currently

DBs of various electronic medical records The Study Committeewas established in FY 2009to review various electronic

medical records.

Topics studied (examples)- How to obtain data- Characteristics and limitations

of various DBs- Method of safety analysis- How to use various DBs

Safety measures

Detectionof signals

Intensificationof signals

Verificationof signals

Study Committee on Application ofElectronic Medical Records toSafety Measures

PMDA

ADR reportdatabase

Universities, etc.Medical institutions

Participation ascommittee membersCooperation

All cases of adverse drug reactions and malfunctions reported by companies on or after April 1, 2004 (the date that PMDA was established) are posted on the Medical Product Information web page. PMDA has published the “Reported year,” “Sex,” “Age,” “Primary disease, etc.,” “Suspected drug,” “Adverse event,” “Suspected concomitant medication” and “Outcome” of ADR reports since January 2006, and the “Reported year,” “Sex,” “Age,” “Outcome,” “Generic name,” “Condition of medical device” and “Adverse event on patients” of malfunction reports since March 2006.　The publication has continuously been revised to make the website easier to understand and more user-friendly.

Publication of Adverse Drug Reactions and

Medical Device Malfunctions

31


As a safety measure for medical devices, PMDA is developing scientific evaluation methods by analyzing the incidence, etc. of medical device malfunctions that may unavoidably occur at a certain rate due to the nature of the device rather than to structural defects (for example, malfunctions resulting from handling or the usage period of the medical device, or from the patient’s pathological condition).　A study on coronary stents (a prospective five-year follow-up study of over 16,000 patients as a target number, in 26 institutions) has been conducted since February 2008 to collect data. In December 2009, the second interim analysis was performed using some of the data collected.　In line with the Mid-term Plan, PMDA intends to build a system for gathering and evaluating data on the operation status of medical devices such as the incidence of malfunctions over t ime, regard ing h igh -r i sk implantable medical devices subject to tracking, in order to properly use such a system for safety measures.　The first release of a web-based entry system called J-MACS for the registry of implantable artifi cial heart assist systems was finished at the end of March 2010, based on the implementation structures/protocols that were considered in detail under the industry-government-academia collaboration. The preparation for post-marketing registry of patients at 6 participating medical institutions was completed.

PMDA distributes the latest safety information by e-mail, including the urgent safety information, to registered healthcare professionals.

Information provided:• Urgent safety information (“Dear Healthcare Professional” Letters)

• Pharmaceuticals and Medical Devices Safety Information• Instructions for revision of precautions in package insert

• Drug safety update (DSU)

• Notifi cation for self-check and recalls (Class I)• PMDA Medical Safety Information

For details, please visit the Medical Product Information web page: http://www.info.pmda.go.jpRegistration for this e-mail service is free.

The “Drug Guide for Patients” is an explanation for patients, which helps them better understand prescription drugs, leading to earlier detection of serious adverse drug reactions. This guide is available on the Medical Product Information web page. It focuses on prescription drugs that contain warnings in their package inserts and that require special instructions relating to proper use by patients.

Publication of Drug Guide for Patients

Package Insert of Prescription Drugs and Drug Guide for Patients

InternetInternet

Explanatory& instructive materials forpatients

Package Insert

Properprescription

of drugs

.Described in technical terms

.Fully comprehensive description of ADRs

.Information that needs attention of doctors and pharmacists

Physicians, pharmacists, etc

.Can obtain accurate and comprehensive information on the drugs

.Can get necessary information for appropriate use of the drugs

Patients and their family

.Can detect serious ADRs early

.Can access to information on appropriate use of drugs including application and storage condition

Drug Guide for Patients

.Using clear and simple terms that a high school student can understand

.Showing subjective symptoms of serious ADRs and such ADRs by body parts

.Information that requires patients' attention on dosage or application of drugs and what should be done in case of missing to take them

Development of System for Evaluating Medical

Device Malfunctions

Pharmaceuticals and Medical Devices Information

E-mail Services

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The PMDA International Strategic Plan (finalized on February 6, 2009) was formulated as a basic policy for overall international activities during the period of the Second Mid-term Plan. PMDA actively carries out international activities in line with the strategic plan.　To build closer partnerships with the EU and the US, PMDA dispatched International Liaison Officers to the European Medicines Agency (EMA) in November 2009 and to the US Pharmacopeia in February 2010.　Regarding activities in East Asia, the Tripartite Health Ministers Meeting has been held annually since FY 2007 and the Director-General Meeting on Pharmaceutical Affairs since FY 2008, with the participation of the three health authorities from Japan, China and South Korea. As part of working-level talks, the Japan-China-Korea Working Group Meetings were held twice in FY 2009, in which the following plan was decided: MHLW/PMDA are responsible for coordinating the joint research project on ethnic factors in clinical data and the Korean Food and Drug Administration (KFDA) is responsible for coordinating the exchange of information on clinical trials of drugs.　PMDA has also been strengthening ties with regulatory agencies in the US, the EU and Asian countries with respect to reviews and safety measures through the exchange of trainees.　In addition to participating in the International Conference on Harmonization (ICH), Global Harmonization Task Force (GHTF) and International Organization for Standardization (ISO) to facilitate international harmonization of test methods as well as standards for preparing data for reviews, PMDA also takes part in the Pharmacopoeia Discussion Group (PDG) to promote international harmonization of the Japanese Pharmacopoeia. Moreover, the Agency is actively involved in the “Harmonization By Doing” activities and has launched the US-Japan Pilot Program regarding Medical Device Collaborative Consultation and Review of Pre-marketing Applications.　PMDA hosts international symposia every year. In October 2009, the 4th PMDA International Symposium on Biologics was held on the “Clinical evaluation of cell/tissue-based products,” with speakers from a regulatory agency in the EU and industry and medical institutions in Japan discussing the activities and trends in Japan and foreign countries. The 2010 China-Japan Symposium on Global Clinical Trials and Ethnic Factors 2010 was held in Beijing in May. Speakers from regulatory authorities,

International Activitiesacademia and the pharmaceutical industry in China and Japan were invited to discuss the current and future trends of global clinical trials in East Asia, and why and how ethnic factors should be clarifi ed.　PMDA continues to expand its English website to provide the latest information to an international audience.

Second Director-General Meeting on Pharmaceutical Affairs (December 2009, Beijing)

Fourth PMDA International Symposium on Biologics (October 2009, Tokyo)

China-Japan Symposium (May 2010, Beijing)

International Activities

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Promoting Regulatory Science

PMDA’s mission is to continually evaluate various confl icting issues and appropriately assess and balance the risks and benefi ts, in the most benefi cial manner for the public, based on the latest scientific knowledge. Regulatory decisions can then be made on a scientific basis.

　PMDA strives to enhance training programs for improving the expertise of its staff as well as to promote communication with external scientists in order to advance regulatory science. One such initiative is the Joint Graduate School Program, in which the Agency is actively promoting collaboration with educational institutions. PMDA has agreements with the Yokohama City University Graduate School of Medicine; the Graduate School of Life and Environmental Sciences, the University of Tsukuba; and the Yamagata University Graduate School of Medical Science as of July 2010.

Revised conventional training programs fundamentally by reference to FDA's training programs and put into practice stepwise from the latter half of FY 2007.

Training program for managerial staff (e.g., management skills)

General training program (e.g., English language and communication skills)

Specialized training program (case study, medical writing)

Facility visit (medical institutions which clinical trials take place, factories of drug manufacturers)

Participation in international conferences such as DIA (as speakers and attendees)Dispatching of lecturers to universities

Special training program (discussion on the latest technological topics with experts invited from Japan and foreign countries)Participation in and presentation at academic conferences in Japan and foreign countries

Mentoring system (established by reference to FDA's Orientation Mentoring Program)

Training at external institutions in Japan (medical institutions, research institutions)Long-term training at overseas organizations (such as overseas regulatory agencies)

Training program for mid-level employees

Training program for new recruits

First year Second year Third year onwards Management level

General training course

Specialized training course

Human Resource Training and Develofment

Promoting Regulatory Science

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独立行政法人医薬品医療機器総合機構

Shin-Kasumigaseki Building (Reception located on the 6th floor)

3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo 100-0013, Japan

●Website: http://www.pmda.go.jp

●Medical Product Information page (only in Japanese language): http://www.info.pmda.go.jp

Contact InformationOffice of International Programs

Telephone: +81-3-3506-9456

Facsimile: +81-3-3506-9572

E-mail: [email protected]

Pharmaceut ica ls and Medica l Dev ices Agency

Access Map

National Diet Building

Office of Prime Minister

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Marunouchi Line

Kasumigaseki

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2010.8

Pharmaceuticals and Medical Devices Agency, Japan

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