drug approval system of japan

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Drug Approval System of Japan

December 2015

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Abbreviation

MHLW: Ministry of Health, Labour, and Welfare

PMDA: Pharmaceuticals and Medical Devices Agency

PAFSC: Pharmaceutical Affairs and Food Sanitation Council

PFSB: Pharmaceutical and Food Safety Bureau

NIBIO: National Institute of Biomedical Innovation

JPMA: Japan Pharmaceutical Manufacturers Association

Notice

1. Due to the purpose of this document, most of the information was quoted

directly from the website or related guidelines of each country‟s drug

regulatory agencies and, reviewed by the agencies.

2. This document is limited only to pharmaceutical products, no applicable to

biological and herbal products.

3. When referring to the contents of this document, check the up-to-date

information including related laws and regulations, and revision of

guidelines.

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Table of Contents

I. Drug Regulatory Agency ·································································· 7

1. Ministry of Health, Labour and Welfare (MHLW) ································· 7

1.1 Organization ······································································· 7

1.2 Task of Pharmaceutical and Food Safety Bureau and its related Organization ··· 9

1.3 Website ············································································ 10

2. Pharmaceuticals and Medical Devices Agency (PMDA) ························ 10

2.1 Organization ······································································ 10

2.2 Tasks ·············································································· 12

2.3 Website ············································································ 14

II. Related Laws ·············································································· 15

1. Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical

Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products,

and Cosmetics ········································································· 15

1.1 Brief overview of revision of PAL ············································ 15

1.2 Related regulations······························································· 15

2. Guidance and guidelines ······························································ 15

III. Classification of Pharmaceutical Products ········································ 16

1. New drug ················································································ 16

2. Generic drug ············································································ 16

3. Orphan drug ············································································ 17

3.1 Number of patients ······························································ 17

3.2 Medial needs ····································································· 18

3.3 Possibility of development ····················································· 18

IV. Drug Approval System ································································· 19

1. Clinical trial (IND) notification ······················································ 19

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1.1 Overview ······································································· 19

1.2 Interview advice meeting ····················································· 20

1.3 Review period ·································································· 21

1.4 Required documents ·························································· 22

2. New drug approval (NDA) application ············································· 24

2.1 Procedure ······································································· 24

2.2 PMDA evaluation process ···················································· 26

2.3 PAFSC consultation ··························································· 26

2.4 Review period ·································································· 26

2.5 Required documents ·························································· 27

3. Generic drug approval application ··················································· 31

3.1 Procedure ······································································· 31

3.2 Review period ·································································· 31

3.3 Required documents ······························································· 31

3.4 Patent-approval linkage system ·············································· 33

4. Orphan drug ············································································ 34

4.1 Organization that designates orphan drugs ································· 34

4.2 Orphan drug designation procedure ········································· 35

4.3 Required documents for designation ········································ 35

4.4 Review period ·································································· 36

4.5 Incentives ······································································· 36

5. Priority review ·········································································· 37

5.1 Pharmaceutical products for priority review ······························· 37

5.2 Procedure ······································································· 37

5.3 Priority review meeting ······················································· 38

5.4 Review period ·································································· 38

V. Others ······················································································· 39

1. Good Manufacturing Practice (GMP) ··············································· 39

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1.1 GMP compliance inspection concerning pharmaceuticals (including APIs)

of foreign manufacturers ······················································· 39

2. Drug Master File (DMF) ······························································ 43

2.1 Overview ·········································································· 43

2.2 Items targeted for Drug Master File registration ···························· 44

3. Labeling and package inserts ························································· 44

3.1 Overview ·········································································· 44

3.2 Headings and their sequence in package inserts that are required in the

labeling ··········································································· 45

4. Requirements for Certificate of a Pharmaceutical Product (CPP) ··············· 48

5. Approval of manufacturing/marketing of medicinal products ··················· 49

5.1 Manufacturing/marketing business license ··································· 50

5.2 Efficacy and Safety of medicinal products ··································· 50

5.3 Accreditation of foreign manufacturers ······································· 50

6. Fees for regulatory approval ·························································· 51

VI. References ················································································ 52

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List of Figures

Figure 1 Organization of Ministry of Health, Labour and Welfare (MHLW)

Figure 2 Organization of Pharmaceuticals and Medical Devices Agency (PMDA)

Figure 3 Procedure of Interview Advice Meeting

Figure 4 New Drug Marketing Approval Process

Figure 5 Flowchart of New Drug Development and Approval

Figure 6 Organizations that Designate Orphan Drug/Medical Device

Figure 7. Flow Chart for Orphan Drug/Medical Device Designation

Figure 8 Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (1)

Figure 9 Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (2)

Figure 10 Layout of a Package Insert for a Prescription Drug (with "Warning")

Figure 11 Flow of Drug Manufacturing/Marketing Approvals

List of Appendices

Appendix 1. Instructions for Filling Out the IND Application Form

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I. Drug Regulatory Agency

1. Ministry of Health, Labour and Welfare (MHLW)

The Ministry of Health, Labour, and Welfare (MHLW) is responsible for medical care,

long-term care, pensions, labour, childcare, and public assistance of Japanese. It has its

mission to „enable people to live fulfilling lives with a greater sense of security.‟1 Therefore,

the MHLW is also in charge of pharmaceutical regulatory affairs in Japan (except veterinary

drugs which are under the jurisdiction of the Ministry of Agriculture, Forestry and Fisheries).

1.1 Organization

The MHLW consists of headquarters, affiliated institutions, councils, regional bureaus, and

external bureaus. The headquarters includes the Minister's Secretariat, 11 bureaus including

Pharmaceutical and Food Safety Bureau, 6 departments and the Director-General for Policy

Planning and Evaluation. Affiliated institutions include quarantine stations, National

Hansen‟s Disease Sanatoriums, research institutions including National Institute of Health

Sciences, and social welfare facilities. There are 14 Councils, including the Social Security

Council and Pharmaceutical Affairs and Food Sanitation Council (PAFSC). Moreover, there

are regional bureaus such as Regional Bureaus of Health and Welfare and Prefectural Labor

Bureaus; and external bureaus including the Central Labor Relations Commission. The

detailed organization is shown in Figure 1 as below:

1 Ministry of Health, Labour and Welfare Service Guide 2014, For people, for life, for the future (pamphlet of

MHLW)

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Figure 1. Organization of Ministry of Health, Labour and Welfare (MHLW)

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1.2 Task of Pharmaceutical and Food Safety Bureau and its related organization2

The Pharmaceutical and Food Safety Bureau (PFSB) undertakes main duties and functions

to ensure the quality, efficacy, and safety of drugs, medical devices, and food. It handles

clinical studies, approval and post-marketing safety measures, i.e., approvals and licensing.

The PFSB consists of Secretary-General, Councilor in charge of drugs, five divisions

(General Affairs Division, Evaluation and Licensing Division, Safety Division, Compliance

and Narcotics Division, and Blood and Blood Products Division), and one office.

Especially, tasks of the Evaluation and Licensing Division are as follows:

- Technical guidance and supervision concerning the production of drugs, quasi-drugs,

cosmetics, and medical devices (“drugs, etc.”)

- Manufacturing/marketing business licenses and approvals to manufacture and market

drugs, etc.

- Re-examination and re-evaluation of drugs and medical devices

- Business license and approvals to market, rental, or repair medical devices (excluding

areas under the control of the Health Policy Bureau)

- Issues related to the Japanese Pharmacopoeia (JP)

- Standards and specific precautions concerning drugs, etc.

- Designation of orphan drugs and orphan medical devices

- Enforcement of laws pertaining to poisonous and deleterious substances (excluding

areas under the control of the Compliance and Narcotics Division)

2 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association,

March, 2014. (http://www.jpma.or.jp/english/parj/whole.html)

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- Regulations related to evaluation of chemicals that might cause damage to the health of

humans, animals, and plants in living environment from the standpoint of the

environment and public health, as well as regulations concerning the manufacture,

import, use, and other handling of such chemicals

- Control of household products containing harmful substances

- Establishment of tolerable daily intake (TDI) of dioxins and related compounds

- Work related to the PMDA (limited to approval and license to manufacture and market

drugs, medical devices, etc.)

- Control and dissemination of industrial standards for medical devices and other hygiene

products and other industrial standards

The Pharmaceutical Affairs and Food Sanitation Council (PAFSC) is an advisory body to

the MHLW, the PAFSC reviews and discusses important pharmaceutical and food sanitation-

related matters.

1.3 Website

www.mhlw.go.jp

2 Pharmaceuticals and Medical Devices Agency (PMDA)

The PMDA was established in April 2004 in order to serve in areas of review of drugs and

medical devices, post-marketing safety measures, relief services for adverse health effects.

2.1 Organization

Under the Chief Executive, the PMDA consists of 27 offices, including Office of

Regulatory Science, Office of Review Administration, Office of Review Management, Office

of Standards and Guidelines Development, Office of International Programs, 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 Cellular and Tissue-based Products, Office of Vaccines and Blood

Products, Office of OTC/Quasi-drugs, Office of Generic Drugs, Office of Non-clinical and

Clinical Compliance, Office of Safety I, Office of Safety II, Office of Medical Informatics

and Epidemiology, Office of Manufacturing/Quality and Compliance, Office of Relief Funds,

Office of General Affairs, Office of Financial Management, and Office of Planning and

Coordination. The organization structure is shown in Figure 2 as below:

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Figure 2. Organization of Pharmaceuticals and Medical Devices Agency (PMDA)3

3 About PMDA>Organization (www.pmda.go.jp)

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2.2 Tasks4

The service of the PMDA is divided into three main categories: 1) Relief service for

adverse health effects, 2) review, and 3) post-marketing safety measures.

The role of each office related to drug approval is as follows:

- Office of Review Administration: This office handles tasks related to the receipt and

processing of license and other applications, drug master file (MF) registrations and

modifications, clinical trial notifications, simple consultation applications on generic

drugs and the issuance of manufacturing/marketing authorization letters, etc.

- Office of Review Management: This office handles tasks related to the publication

(disclosure) of approval review results, receipt and processing of clinical trial

consultations on new drugs, and receipt of processing of reports including basic

protocols for post-marketing surveillance, and periodic safety update reports (PMS,

reevaluation, GVP). The office also handles pharmaceutical affairs consultation on

R&D strategy on drugs and medical devices mainly for universities, research institutes,

and venture companies.

- Office of Standards and Guidelines Development: This office handles tasks related to

the preparation of draft Japanese Pharmacopoeia, standards on medical devices,

standards on drugs, master file systems, and generic names (JAN).

- Office of International Programs: This office represents PMDA at bilateral talks with

foreign regulatory agencies and plays a central role in international communication such

as the sharing of public and non-public information with foreign regulatory agencies

and organizations. The main services rendered are the promotion of international

harmonization of regulatory standards/practices, planning of international activities,

foreign public relations campaign, and expansion of human exchange.

- Office of New Drug I: This office confirms clinical trial notifications and adverse drug

reactions and conducts reviews required for approval, re-examinations, and re-

evaluation of gastrointestinal drugs, dermatologic drugs, hormone preparations, and

metabolic disease drugs (e.g., anti-diabetic, osteoporosis, gout, and congenital

metabolic disorder drugs)

- Office of New Drug II: This office confirms clinical trial notifications and adverse drug

reactions and conducts reviews required for approval, re-examinations and re-evaluation

of new cardiovascular drugs, drugs to treat Parkinson‟s disease, drugs to treat

Alzheimer‟s disease, urogenital and anal drugs, combination drugs,

radiopharmaceuticals, and contrast media.


July, 2015. (http://www.jpma.or.jp/english/parj/whole.html)

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- Office of New Drug III: This office confirms clinical trial notifications and adverse drug


evaluation of new central nervous system drugs, peripheral nervous system drugs,

anesthetic agents, sensory organ drugs (other than drugs for inflammatory diseases), and

narcotics.

- Office of New Drug IV: This office confirms clinical trial notifications and adverse drug

reactions and conducts reviews required for approval, reexaminations, and reevaluation

of antibacterial drugs, antiviral agents (except for anti-HIV/AIDS agents), new

respiratory tract drugs, anti-allergy drugs, sensory organ drugs (limited to drugs for

inflammatory diseases), and anti-HIV/AIDS agents.

- Office of New Drug V: This office confirms clinical trial notifications and adverse drug


evaluations of antineoplastic drugs.

- Office of Cellular and Tissue-based Products: This office confirms clinical trial

notifications and adverse drug reactions and conducts reviews required for approval,

reexaminations, and reevaluations of regenerative medical products (cellular and tissue-

based products and gene therapy products), preliminary reviews for approval or

verification based on the Cartagena Protocol, and quality review of antibody

preparations.

- Office of Vaccines and Blood Products: This office confirms clinical trial notifications

and adverse drug reactions of globulins, blood coagulation-factor products, vaccines,

and antidotes and performs the reviews required for approval, reexamination, or

reevaluation.

- Office of OTC/Quasi-Drugs: This office conducts reviews required for the approval,

export certification, and quality reevaluations of guidance-mandatory drugs non-

prescription drugs, quasi-drugs, and cosmetics.

- Office of Generics: This office conducts reviews required for the approval, export

certification, and quality reevaluations of generic drugs, etc. (ethical drugs excluding

new drugs and extracorporeal diagnostic medicines).

- Office of Compliance and Standards: This office reviews the documentation included

with applications for approval, reexamination, or reevaluation of drugs, medical devices,

and regenerative medicine products to assure that the studies on which the data is based

comply with GLP, GCP, GPSP, study protocol, etc. both ethically and scientifically to

determine if the documents have been prepared appropriately and accurately based on

the study results in accordance with the Criteria for Reliability of Application Data

(Article 43 of the Enforcement Regulations, Pharmaceutical Affairs Law) (hereinafter

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“Reliability Criteria”) and examined on site and on paper. Compliance of facilities

performing GLP-based studies is also examined and certified.

- Office of Safety I: This office undertakes centralized collection and compilation of

information related to the quality, efficacy, and safety of drugs and medical devices,

conducts surveys and guidance on the application of such information in medical

institutions, and conducts scientific analysis and evaluation of such safety information

using pharmaceutical and epidemiological procedures. It also undertakes consultations

and information dissemination work.

- Office of Safety II: This office undertakes analysis and evaluation of adverse reactions

of drugs and medical devices.

2.3 Website

www.pmda.go.jp

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II. Related Laws5

1. Act on Securing Quality, Efficacy and Safety of Pharmaceuticals,

Medical Devices, Regenerative and Cellular Therapy Products, Gene

Therapy Products, and Cosmetics6

The name of the “Pharmaceutical Affairs Law (PAL)” was be revised to the “Act on

Securing Quality Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and

Cellular Therapy products, Gene Therapy Products, and Cosmetics”. Revision of the

Pharmaceutical Affairs Law (PAL) was adopted by the Diet and announced on 27 November,

2013. The amendment was enforced on November 27, 2014.

1.1. The Brief overview of revision of PAL7

Points of the amendment of the law are to:

- Strengthen safety measures regarding drugs and medical devices

- Revise medical device regulations based on its characteristics

- Introduce Regenerative and Cellular Therapy Products (RCTP) & Gene Therapy

Products (GTP) regulations based on their characteristics

1.2. Related regulations

- Enforcement Ordinance on Securing Quality, Efficacy and Safety of Pharmaceuticals,

Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products,

and Cosmetics (医薬品、医療機器等の品質、有効性及び安全性の確保等に関する

法律施行令): Jan. 9, 2015 (No. 2 of Japan government ordinance)

- Enforcement Regulation on Securing Quality, Efficacy and Safety of Pharmaceuticals,

Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products,

and Cosmetics (医薬品、医療機器等の品質、有効性及び安全性の確保等に関する

法律施行規則): Jun. 16, 2015 (No. 82 of MHLW)8

2. Guidance and guidelines

Guidelines on drug approval are available at the PMDA website (few English versions are

available): http://www.pmda.go.jp/rs-std-jp/standards-development/guidance-guideline/0001.html)

5 http://law.e-gov.go.jp/cgi-bin/idxsearch.cgi

6 http://law.e-gov.go.jp/htmldata/S35/S35HO145.html 7 http://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/dl/150407-01.pdf

8 http://law.e-gov.go.jp/htmldata/S35/S35HO145.html

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III. Classification of Pharmaceutical Products

1. New drug

“New drugs are defined as drugs with ingredients, dosage, administration route, or

indications, which are clearly different from those of drugs, which have already been

approved for manufacture and marketing or those listed in the JP.”9

● Classification of a new prescription drug

(1) Prescription drugs with new active ingredients

(2) New combination prescription drugs

(3) Prescription drugs with new administration routes

(4) Prescription drugs with new indications

(5) Prescription drugs with new dosage forms

(6) Prescription drugs with new doses

(7) Biosimilar products

(8) Prescription drugs with additional dosage forms

(9) Combination prescription drugs with similar formulations

2. Generic drug

According to the Guideline for bioequivalence studies of generic products, “Generic

product” means the products of which active ingredients, strengths, dosage forms, and dosage

regimens are the same as those of innovator‟s products.

9 薬事法医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律』, No 14-4 (JPMA)

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3. Orphan drug

In Japan, drugs and medical devices can be designated as orphan drugs or medical devices

based on the Article 77-2* of the Act on Securing Quality, Efficacy and Safety of

Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene

Therapy Products, and Cosmetics. The Minister of Health, Labour and Welfare (MHLW)

may designate drugs and medical devices satisfying the following criteria as orphan

drugs/medical devices after receiving applications for orphan designation from the applicants.

*Article 77-2 (1) When an application has been made by a person who engages in

marketing a drug or medical device which fall under any and all of the following

items (including those engaging in manufacturing, etc. in foreign countries of those

which are intended to be exported to Japan), the Minister of Health, Labour and

Welfare may designate the drug or medical device in the application as an orphan

drug or medical device, after hearing the opinion of the Pharmaceutical Affairs and

Food Sanitation Council.

(i) The number of subjects for whom the drug or medical device used does not

satisfy the requirement of number laid down by the Ordinance of the Ministry of

Health, Labour and Welfare in Japan;

(ii) The drug or medical device in the application, if approved for manufacturing

and sales, is expected to prove especially valuable when applied in medical

practice in terms of the usage.

3.1 Number of patients

In order to be designated as orphan drug, the number of patients who may use the drug or

medical device should be less than 50,000 in Japan.

The number of patients could be estimated based on the report of the Health and Labour

Science Research or the data published by reliable scientific societies. The number of patients

with a difficult-to-treat disease is sometimes difficult to estimate accurately due to lack of

research on the patient population. Therefore, estimates from a variety of statistical data are

generally used to indicate that the number of those patients is less than 50,000 in Japan.

Submission of an estimate based on multiple statistical methods is recommended.

Since financial year 2006, applicants may apply for orphan drug designation with the

following new drugs if the estimated number of patients who may use the drug at the time of

application is less than 50,000 in Japan.

- A vaccine to prevent an infectious disease rarely reported in Japan or that only reported

overseas and the use of which is limited to a specific population, such as people who

have visited the endemic area.

- A vaccine to prevent an emerging or re-emerging infectious disease associated with

genetic mutation, of which an outbreak has not been reported at the time of designation

but which may significantly affect the lives and health of Japanese people, and of which

the time and size of epidemic are unpredictable.

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3.2 Medical needs

The drugs or medical devices should be indicated for the treatment of serious diseases,

including difficult-to-treat diseases. In addition, they must be drugs or medical devices for

which there are high un-met medical needs satisfying one of the following criteria:

- There is no appropriate alternative drug/medical device or treatment option.

- Better efficacy or safety is expected compared with existing products.

3.3 Possibility of development

There should be a theoretical rationale for the use of the product for the target disease, and

the development plan should be appropriate. For example, in the case of application of an

orphan drug, the possibility of development should be explained based on existing non-

clinical and clinical data in the late stage of the phase I study or in the early stage of the phase

II study except when the product has already been approved overseas or sufficient clinical

study data are available.

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IV. Drug Approval System

1. Clinical trial notification for new drug development

1.1 Overview10

In order to conduct clinical studies to collect data to be submitted with approval

applications for new drug manufacturing and marketing, the Act on Securing Quality,

Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy

Products, Gene Therapy Products, and Cosmetics and the GCP require that the MHLW be

notified of the study protocol beforehand and provide various requirements to be met by the

sponsor when requesting medical institutions to perform clinical studies.

From April 1st, 2011, attachments to the clinical trial notification are required to be

submitted in electronic format as well as in paper format.

The range of the GCP covers not only clinical studies on patients, but also Phase I studies

in healthy volunteers, bioequivalence studies on humans, studies for additional indications for

an approved drug and post-marketing clinical trials after marketing.

At the time of the clinical trial protocol notification, a system by which the PMDA

reviews the contents of the initial notification at the request of the MHLW is now specified

by law, and a "clinical trial consultation system" in which the PMDA gives guidance and

advice concerning study protocols has also been established

1.1.1 Type of clinical trial notification1112

- Industry Sponsored Clinical Trial

- Investigator Initiated Clinical Trial: The term "sponsor-investigator" as used in the

Ministerial Ordinance on Good Clinical Practice for Drugs means an investigator who has

submitted a clinical trial notification pursuant to the Act on Securing Quality, Efficacy and

Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products,

Gene Therapy Products, and Cosmetics, (the Act) in order to conduct a clinical trial at the

medical institution etc. to which the investigator belongs (including a coordinating

investigator who has submitted a clinical trial notification pursuant to the Act, on behalf of all

participating investigators, for a clinical trial conducted according to a single protocol but at

more than one medical institution).


March, 2014. (http://www.jpma.or.jp/english/parj/whole.html) 11治験の依頼をしようとする者による薬物に係る治験の計画の届出等に関する取扱いについて, 平成 25 年 5 月 31 日,

薬食審査発0531 第8 号, (Notification for clinical trial plan, Notification 0531 No. 8 of PFSB)

12 『自ら治験を実施しようとする者による薬物に係る治験の計画の届出等に関する取扱いについて,

平成25年5月31日, 薬食審査発0531第4号, (Notification for clinical trial plan by investigator sponsor,

Notification 0531 No. 4 of PFSB)

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1.1.2 Products required for clinical trial notification 13

The following products are required to submit clinical trial (protocol) notifications:

1) Drugs with new active ingredients

2) Drugs with new administration routes(excluding bioequivalence studies)

3) New combination drugs, drugs with new indications or new dosage and

administration (excluding bioequivalence studies)

4) Drugs containing the same active ingredients with the drugs with new active

ingredients, for which the reexamination period has not been completed yet

(excluding bioequivalence studies)

5) Drugs considered to be biological products [excluding 1) to 4)] (excluding

bioequivalence studies)

6) Drugs manufactured using gene recombinant technology [excluding 1) to 5)]

(excluding bioequivalence studies)

1.2 Interview advice meeting14

The PMDA has established a consultation system for clinical study protocols to improve

and reinforce the quality of clinical studies.

The procedure of interview advice meeting is as below:

Figure 3 Procedure of Interview Advice Meeting


July, 2015. (http://www.jpma.or.jp/english/parj/whole.html) 14 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association,

July, 2015. (http://www.jpma.or.jp/english/parj/whole.html)

21

Key consultation items and fees are as table below15

:

Contents Fee (¥)

1. consultations on procedure 143,800

2. consultations on bioequivalence studies 571,900

3. consultations on safety 1,833,700

4. consultations on quality 1,520,500

5. consultations before start of Phase I studies Non-orphan 4,360,500

Orphan 3,277,200

6. consultations before start of early phase II studies Non-orphan 1,669,400

Orphan 1,257,400

7. consultations before start of late phase II studies Non-orphan 3,114,900

Orphan 2,339,200

8. consultations after completion of phase II studies Non-orphan 6,183,300

Orphan 4,644,800

9. consultations before application Non-orphan 6,183,200

Orphan 4,642,000

10. Consultations when planning clinical studies for reevaluation and

reexamination 1,664,800

11. Consultations on completion of

clinical studies for reevaluation and

reexamination

re-evaluation and

re-examination 1,664,800

reviewing the approval condition

(evaluate the propriety quickly) 826,800

12. Additional consultations on drugs Non-orphan 2,752,100

Orphan 2,067,900

1.3 Review period

According to the new GCP, when a clinical study is requested, a contract for clinical trials

can be concluded only when 30 days have passed from the initial notification of the study

protocol received by the PMDA (at least 2 weeks have passed for subsequent notifications, as

a rule).

For drugs required in emergencies to prevent diseases that have a major effect on the life

or health of the patient or to prevent other damage to the health, clinical study protocols may

be submitted within 30 days after the start of the study (MHLW Ordinance No. 89, dated

May 2003)

15

Clinical trial consultations, etc. (new drugs) (http://www.pmda.go.jp/review-services/f2f-pre/

consultations/0007.html)

22

1.4 Required documents161718

1.4.1 Form of clinical trial notification

(Attachment Form 2)

ID:

Type of documents: Clinical trial notification

and attached documents Document title:

Clinical trial ingredient code: Number of notification:

Clinical trial notification date: Number of amendment:

Reporter:

Generic name (Japanese):

Generic name (English):

Dosage form (Japanese):

Drug classification (Japanese):

Expected dose and dosage:

Route of administration (Japanese):

Notes

(1) Please complete Attachment Form 2 in the format of Text or MS-Word.

(2) Please complete each section consistent with the clinical trial protocol notification.

(3) Rather than the first notification date, clinical trial notification date indicates the submission date of the

clinical trial notification. Keep the first notification date in case of suspension of the notification.

(4) Please write the number of revision for every clinical trial protocol revision notification and leave blank

in other cases.

(5) Please leave [ID] and [Document title] sections blank.

(6) If the generic name is not determined, please leave the section blank.

For instructions for filling out the application form, refer to Appendix 1.

1.4.2 Documents to be attached for the first notification

- Documents that give the reason why the request for the clinical study was judged to

be scientifically appropriate

- Clinical study protocol

- Explanatory materials and consent form used for obtaining informed consent

16

“治験の依頼をしようとする者による薬物に係る治験の計画の届出等に関する取扱いについて, 平成25年5月 31 日,

薬食審査発0531第8号 , (Notification for clinical trial plan, Notification 0531 No. 8 of PFSB

17 自ら治験を実施しようとする者による薬物に係る治験の計画の届出等に関する取扱いについて平

成25年5月31日, 薬食審査発0531第4号 (Notification for clinical trial plan by sponsor investigator,

Notification 0531 No. 4 of PFSB) 18

Clinical trial plan notification system of pharmaceutical (drug) (http://www.pmda.go.jp/review-

services/trials/0004.html)

23

- Sample of the case report form (CRF) (The sample is not required if information to

be contained in the CRF is explicitly stated in protocol.)

- Latest Investigator‟s Brochure

1.4.3 Documents to be attached from the second notification

- Documents that give the reason why the request for the clinical study was judged to

be scientifically appropriate (including a description of the results of new clinical

studies since the previous notification and a summary of information)

- Clinical study protocol

- Explanatory materials and consent form used for obtaining informed consent

- Sample of the case report form (CRF) (The sample is not required if information to

be contained in the CRF is explicitly stated in protocol.)

- Latest Investigator‟s Brochure

1.4.4 Format of documents submission

Effective on 1 Apr 2011, all attachments to be submitted along with the notification on

clinical study plan should be submitted in electronic format in addition to paper format. For

the paper format; stamp the printed papers with the company seal; and submit written report.

For the details of the notification, electronic files, such as electronic medical entry forms

and structure definition of XML documents are available from the website

(http://www.pmda.go.jp/).

In principle, follow the below for the number of notification copies depending on the type

of notification.

- For the applicable clinical study plan notification: two original copies and three copies

of the notification

- Five copies of the document to be attached to the notification; 1 electronic media for

XML file; and 1 PDF file for data management

- Report on clinical study plan other than the report under 30-day investigation

- One original copy and one copy of the notification; two documents to be attached to the

notification

- One copy of electronic media for XML file and 1 copy of PDF file for information

management.

http://www.pmda.go.jp/

24

2. New drug approval (NDA) application

2.1 Procedure1920

The entire process of approval review from review-related inspections and clinical trial

consultation to review works is undertaken by the PMDA (Figure 4, Figure 5). Application

forms for drug marketing authorization are submitted to the PMDA. When application forms

for new drugs marketing authorization are received by the PMDA, a compliance review of

the application data (certification from source data), GCP on-site inspection, and detailed

review are undertaken by review teams of the PMDA and the team prepares a review report.

The approval review process consists of expert meetings of review team members and

experts to discuss important problems. A general review conference attended by team

members, experts and representatives of the applicant is held after the expert meeting. It is

necessary to submit a “list of persons involved in compilation of attached data” and a “list of

competitive products and companies” in relation to persons who participated in clinical

studies submitted as application data immediately after application submission, prior to the

expert meeting, and prior to meeting of the Committee on Drugs.

Figure 4. New Drug Marketing Approval Process


March, 2014. (http://www.jpma.or.jp/english/parj/whole.html) 20

新医薬品の承認審査の進捗状況の確認について, 薬機発第１２２７００１号, 平成２２年１２月２７日

(Procedure for new drug review, Notification No. 1227001 of PMDA) (http://www.pmda.go.jp/files/000164140.pdf)

25

Figure 5. Flowchart of New Drug Development and Approval21



26

2.2 PMDA review process

The evaluation process followed by the PMDA is as follows:

1) Interview (presentation, inquiries, and replies)

2) Team review

3) Inquiries and replies

4) Application for GMP inspection (about 6 months before the meeting of the Committee

on Drugs)

5) Review report (1)

6) Expert meeting ()

9) Review report (2)

10) Report to MHLW for consultation to PAFSC

2.3 PAFSC consultation

After the PMDA review, the PAFSC is then consulted for discussions by the related

committees and the Pharmaceutical Affairs Committee as required on the basis of the review

report. After the PAFSC report is obtained and it is confirmed that the standards are met in a

separate GMP compliance review, the Minister grants the new drug manufacturing/marketing

approval.

2.4 Review period2223

In addition to the 1 year standard approval review time of the MHLW for approval of new

drugs from April 1, 2000 (dated March 28, 2000) (excluding the time taken by applicants to

prepare responses, etc.), the time allotted to the applicant is also 1 year so that the time from

the application to marketing approval is a maximum of 2 years. The applicant is requested by

the MHLW to withdraw the application in case a longer time is required for responding to

inquiries or conducting additional studies.

In June 2010, “Points to consider in applications for shortening the PMDA review period

for new drugs”24

was issued. This document includes points to consider from the applicant‟s

side to achieve the target PMDA review periods of 12 months for ordinary reviews and 9

months for priority reviews by 2013.

Further, the standard review timeline for new drug applications has been shown by the

Ministry to achieve a median total review time of 12 months for new drugs (It is shown by

22

標準的事務処理期間の設定等について, 昭和六〇年一〇月一日, 薬発第九六〇号 (Standard review

time, Notification No. 60 of PSB, 1985) 23

新医薬品等の承認申請に係る取下げ依頼について薬食審査発第０６０４００１号平成１６年６月４日 (New drug

application, Notification No. 0604001 of the Evaluation and Licensing Division, PFSB dated June 4, 2004) 24

日本の薬事行政省医薬食品局審査管理課・監視指導・麻薬対策課事務連絡 2010 年 6 月 9 日付厚生労働 Office

Communication of the Evaluation and Licensing Division and Compliance and Narcotics Division, PFSB dated

June 9, 2010

27

the Minister in 2012 that the median standard review timeline for new drug approval is 12

months).25

The median review time for new drugs is found in the website of PMDA.

2.5 Required documents

2.5.1 Form of documentation

With the agreement reached on the Common Technical Document (CTD) guidelines of the

International Conference on Harmonization (ICH), new guidelines for preparation of

approval application data were issued. Applications using the CTD became obligatory for

new products in applications filed on or after July 1, 2003. In Japan, submission of e-CTD is

not obligatory, but recommended. It is no longer necessary to submit paper data for approval

applications if an e-CTD is submitted as the original.

25

新医薬品に係る承認審査の標準的プロセスにおけるタイムラインについて事務連絡平成 24 年 3

月 30 日 (Standard process for new drug review, Administrative Notice of the Evaluation and Licensing

Division, PFSB dated March 30, 2012

28

2.5.2 Details for documents required to the regulatory agency26

- Prescription drugs

a. Origin or background of

discovery, conditions of use in

foreign countries

1. Origin or background of discovery

2. Conditions of use in foreign countries

3. Special characteristics, comparisons with other drugs, etc.

b. Manufacturing methods,

standards and test methods

1. Chemical structure and physicochemical properties, etc.

2. Manufacturing methods

3. Standards and test methods

c. Stability 1. Long-term storage tests

2. Tests under severe conditions (stress tests)

3. Accelerated tests

d. Pharmacological action 1. Tests to support efficacy

2. Secondary pharmacology, Safety pharmacology

3. Other pharmacology

e. Absorption, distribution,

metabolism, and excretion

1. Absorption 2. Distribution 3. Metabolism

4. Excretion 5. Bioequivalence 6. Other Pharmacokinetics

f. Acute, subacute, and chronic

toxicity, teratogenicity, and

other types of toxicity

1. Single dose toxicity 2. Repeated dose toxicity

3. Genotoxicity 4. Carcinogenicity

5. Reproductive toxicity 6. Local irritation 7. Other toxicity

g. Clinical studies Clinical trial results

26

医薬品の承認申請について, 平成 17 年 3 月 31 日, 薬食発第 0331015 号, (Application for drug,

Notification No. 0331015 of the PFSB dated March 31, 2005)

30

2.5.3 Use of foreign clinical data27

Japan has taken various measures in keeping with this change in the international

environment, and data from nonclinical studies such as physicochemical studies, stability

studies and animal studies performed in foreign countries are accepted, in principle, if their

study designs comply with the Japanese guidelines.

Two notifications were issued in relation to the acceptance of foreign clinical data:

- “Handling of Data on Clinical trials on Drugs Performed in Foreign Countries”28

- “Ethnic Factors to be Considered in the Acceptance of Foreign Clinical Trial Data”

and its Q & A29

According to these notifications, when data from clinical studies performed in foreign

countries are used for new drug application in Japan, the data is firstly checked to assure that

it complies with legal requirements in Japan. Whether or not the drug is apt to be affected by

ethnic factors (intrinsic or extrinsic factors) is then evaluated. When necessary, a bridging

study is performed, and when it is concluded that the clinical study outcome in a foreign

population can be extrapolated to the Japanese population, the foreign data can be accepted.

Since the possibility of acceptance is actually left up to the authorities concerned, it is

recommended that the requirements for bridging studies are confirmed as acceptable for the

regulatory agencies through consultations with PMDA.

It is mandatory to conduct pharmacokinetic studies in Japanese people as the bridging

study. With the intent to promote global clinical trials to achieve more efficient and rapid

development of new drugs and to eliminate drug lag in which the approval timing of new

drugs is several years behind that in other countries, basic concepts related to global clinical

trials have been compiled.30

In addition, the notice “Basic Principles on Global Clinical

Trials (Reference Cases)” was issued based on achievements of mutual cooperation and latest

knowledge obtained relating to multinational clinical trials among Japanese, Chinese, and

South Korean regulatory authorities with an objective of a smooth and appropriate conduct of

global clinical trials, especially in East Asia.

3. Generic drug approval application



外国で実施された医薬品の臨床試験データの取扱いについて平成 10 年 08 月 11 日

医薬発第 739 号 (Handling for foreign clinical trial, Notification No.739 of the PMSB dated August 11, 1998) 29

データを受け入れる際に考慮すべき民族的要因について, 平成 10 年 08 月 11 日医薬審第 672 号

(Ethnic difference on foreign clinical trial, Notification No. 672 of the Evaluation and Licensing Division,

Pharmaceutical and Medical Safety Bureau dated August 11, 1998 and partial revision by Office

Communication dated January 4, 1999) 30

国際共同治験に関する基本的考え方について , 平成 19 年 09 月 28 日薬食審査発第 928010 号,

(Multinational clinical study, Notification No. 0928010 of the Evaluation and Licensing Division, PFSB dated

September 28, 2007

31

3.1 Procedure31

Applications for generic drugs cannot be filed until completion of the reexamination.

Branded products are protected from patent and reexamination period during this period.

The PMDA reviews submitted data such as 1) specification and test methods, 2) stability

tests, 3) and bioequivalence study and determines the equivalence (quality, efficacy, and

safety) of generic drugs to the original drugs. The MHLW then approves

manufacturing/marketing business of the applied drugs.

Integrity of the submitted data including raw data must be checked.

3.2 Review period32

There was no difference between new drugs and generic drugs. (Drugs for prescription: 1

year, drugs for non-prescription: 10 months)

3.3 Required documents33

Specification and test methods, stability data, and bioequivalence data are required to

determine whether they are the same to the originator.

3.3.1 Specification and test methods

Section Raw material Preparation

1. Name ○ ○

2. Structural formula and rational formula △ ☓

3. Molecular formula and molecular weight ○ ☓

4. Origin △ △

5. Strength ○ ○

6. Appearance ○ ○

7. Identity test ○ ○

8. Property value (physical and chemical properties, etc.) △ △

31 ジェネリック医薬品(後発医薬品)の使用促進について(http://www.mhlw.go.jp/seisaku/2012/03/01.htm)

医療用医薬品の承認申請の際に添付すべき資料の取扱いについて薬食審査発第0109005号, 平成20年

1月9日 (Documentation for drug approval, Notification No.0109005 of PMDA dated January 9, 2008) 32

標準的事務処理期間の設定等について, 昭和六〇年一〇月一日, 薬発第九六〇号 (Standard review

time, Notification No. 60 of PSB, 1985) 33 ジェネリック医薬品(後発医薬品)の使用促進について (Promotion on use of generic drugs)

(http://www.mhlw.go.jp/seisaku/2012/03/01.html)

32

9. Purity test ○ △

10. Moisture content (moisture and loss on dry) △ △

11. Ignition residue, ash and acid-insoluble ash △ ☓

12. Formulation test ☓ ○

13. Special test △ △

14. Other test items (including microbial limit test and

particle diameter of bulk) △ △

15. Assay ○ ○

16. Reference substance △ △

17. Reagent and test solution △ △

Dosage form Details of “12 preparation test”

powder, granule preparation uniformity test, particle size test, elution Test and

collapse test

tablet, compressed pill,

capsule, troche preparation uniformity test, elution Test and collapse test

injection

insoluble foreign substance test, collected dose test, agent

uniformity test, endotoxin test and pyogen Test, emission test,

and particle diameter test

aerosol (requiring

quantitativeness)

relation between the spray time and amount of spray, particle

diameter test (if for suspension type)

elixirs, spirits, tincture,

fluid extract measurement of alcohol number

ophthalmic ointment metallic foreign substance test, sterility test, emission test,

particle diameter test, and plasticity test

percutaneous absorption,

such as PLASTERS adhesion test, emission test

suppository melting temperature test, emission test, softening point

eye drop insoluble foreign material test, sterility test, emission test,

particle diameter test

3.3.2 Stability data

For generic drugs, accelerated test data (at 40 (±1) degree, RH 75% (±5%), 3 lots, for 6

months) should be conducted and submitted for review.

3.3.3 Bioequivalence study

33

For bioequivalence study, refer to following guidelines for bioequivalence studies of

generic products that are published in Japanese34

and English.35

- Guideline for Bioequivalence Studies of Generic Products

- Guideline for Bioequivalence Studies of Generic Products for Different Strengths of

Oral Solid Dosage Forms

- Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage

Forms

- Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms

- Guidelines for the Design and Evaluation of Oral Prolonged Release Dosage Forms

3.4 Patent-approval linkage system

3.4.1 Patent system36

The patent term is 20 years from the time of application as a rule. However, if the patent

cannot be implemented because of laws and regulations to ensure safety of drugs, etc. the

patent term can be extended for a maximum of 5 years. The extension is for the period that

the patented invention cannot be utilized, such as the period from the date of the start of

clinical trials or date of patent registration, whichever is later, until one day prior to the date

on which the patentee receives approval for the drug.

Patentees who want an extension of the patent term must submit an application to the

Patent Office for extension of registration including the required items such as the requested

extension period before the patent rights become invalid within 3 months from the date of

receipt of drug approval.

In cases where it is anticipated that it will not be possible to obtain approval as specified

by government ordinance by the day before 6 months prior to the date on which the patent

expires, a document showing necessary information including the patent number must be

submitted. If an application for an extension is submitted, it can be considered that the patent

term has been extended until it is finally rejected or the extension is registered.

3.4.2 Manufacturing/marketing authorization on generic drugs and patent

Generic drugs will not be approved until the substance (application) patent has expired.

Branded products are protected from generics entry during this period. However, in the past if

some of the indications or dosage and administration of branded products were patented,

partial approvals were not granted because of patent protection, but with Notification, partial

approvals of indications or dosage and administration not covered by the patent are permitted.

4. Orphan drug3738

34

後発医薬品の生物学的同等性試験ガイドライン等の一部改正について平成 24 年 2 月 29 日,

薬食審査発 0229 第 10 号 (Partial amendment of bioequivalence study for generic drugs) English translation

of Attachment 1 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau, dated

February 29, 2012, page 5 (http://www.nihs.go.jp/drug/be-guide(e)/Generic/GL-E_120229_BE_rev140409.pdf) 35

Division of Drugs (http://www.nihs.go.jp/drug/DrugDiv-E.html)



34

4.1 Organization that designates orphan drugs

The responsibilities of major regulatory authorities involved in the designation system are

described as below:

4.1.1 MHLW

- Review and designation of orphan drugs/medical devices

- Review and approval of orphan drugs/medical devices

- Pre-designation consultation for orphan drugs/medical devices

- Payment for the operational cost of the National Institute of Biomedical Innovation

(NIBIO)

4.1.2 PMDA

- Priority scientific consultation for clinical trials and dossiers for marketing

authorization of orphan drugs/medical devices

4.1.3 National Institute of Biomedical Innovation (NIBIO)

- Subsidy payment to the applicant

- Accreditation for research expenses to be used by the applicant

- Provision of guidance and consultation to the applicant

Figure 6 Organizations that Designate Orphan Drug/Medical Device


March, 2014. (http://www.jpma.or.jp/english/parj/whole.html) 38Overview of Orphan drug/medical device designation system (http://www.mhlw.go.jp/english/policy/health-

medical/pharmaceuticals/orphan_drug.html)

35

4.2 Orphan drug designation procedure

After the consultation, the applicant should submit an original and a copy of the

application for designation to the Evaluation and Licensing Division under the

Pharmaceutical and Food Safety Bureau (PFSB) of MHLW. The application of orphan

designation should be submitted in Japanese.

The submitted application will be reviewed by the Evaluation and Licensing Division, and

if a designation can be determined, PAFSC will be consulted. A designation will be granted

in principle if the First or Second Committee on New Drugs of PAFSC (or the Committee on

Medical Devices and In-vitro Diagnostics for orphan medical devices) approves of the

designation.

The designation notice will be sent to the applicant after all the procedures are completed.

The designation [the name of drug (ingredient), expected indication(s), name and address of

applicant and date of designation] will be published in a government gazette as a MHLW

Ministerial Notification.

Figure 7. Flow Chart for Orphan Drug/Medical Device Designation

4.3 Required documents for designation39

The following documents are required for the orphan drug designation:

1) Data on the number of patients

2) Objective statistical data on the number of patients in Japan for whom the drug or

medical device will be indicated

3) Data on medical needs

- Data on the diseases such as etiology and symptoms

- Data on the current status such as availability of similar drugs/medical devices and

treatment

4) Data on the theoretical rationale for the use of the drugs/medical devices

39 薬事法及び医薬品副作用被害救済・研究振興基金法の一部を改正する法律の施行について , 平成五年八月二五日,

薬発第七二五号 (Partial amendment on compensation for adverse drug reaction and research support fund,

Notification No. 72 of PSB, dated August 25, 1993)

36

5) Related data in a draft dossier of application for marketing authorization, which is

available at the time of application for orphan drug/medical device

6) Development plan (data on the possibility of development)

7) Data on the outline of the development plan, including the current development status,

expected test items, duration of the study and necessary expenses

8) Preparation of Summary of the Orphan Drug/Medical Device: the Summary of the

Orphan Drug/Medical Device should be prepared for Committee meetings and

publication.

4.4 Review period

Orphan drug is subject to the priority review and the review period takes about 9 months.

4.5 Incentives40

For designated orphan drugs and medical devices, measures to support the research and

development activities described below are taken:

- Subsidy payment:

Orphan drug/medical device applicants can receive subsidies through the National

Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product

development. (The total budget for financial year 2010 was 650 million yen.)

- Guidance and consultation:

Orphan drug/medical device applicants can receive guidance and consultation from

the Ministry of Health, Labour and Welfare (MHLW), the Pharmaceuticals and

Medical Devices Agency (PMDA), and NIBIO on research and development

activities. The PMDA provides a priority consultation system for designated orphan

drug/medical device. Lower user fee categories for PMDA‟s consultation are

applicable to designated orphan drugs.

- Preferential tax treatment:

Twelve percent of study expenses for orphan drug/medical device incurred during the

NIBIO subsidy payment period (not including subsidies granted by NIBIO) can be

reported as a tax credit.

- Priority review:

Designated orphan drugs and medical devices will be subject to priority review for

marketing authorization to ensure that they are supplied to clinical settings at the

earliest possible opportunity. Categories of lower user fees are applicable to review

for marketing authorization of designated orphan drugs.

- Extension of re-examination period:

After orphan drug/medical device designation and approval, the re-examination period

for the concerned products will be extended up to 10 years for drugs and up to 7 years

for medical devices.

40

Overview of the designation system of orphan drugs and rare diseases for medical devices

(http://www.mhlw.go.jp/general/seido/iyaku/kisyo/)

37

5. Priority review4142

5.1 Pharmaceutical products for priority review

Drug approval reviews are normally processed in the order that the application forms are

received. However, for drugs designated as orphan drugs, and other drugs considered to be

especially important from a medical standpoint such as new drugs to treat serious diseases, a

decision must be made whether or not to specify an overall evaluation of (1) the seriousness

of the targeted disease and (2) the clinical effetiveness

With this system, applications for specified drugs of the following criteria are reviewed on

a priority basis:43

Priority review criteria

1) Seriousness of indicated diseases

• Diseases with important effects on patient‟s survival (fatal diseases)

• Progressive and irreversible diseases with marked effects on daily life

• Others

2) Overall assessment of therapeutic usefulness

• There is no existing method of treatment, prophylaxis, or diagnosis.

• Therapeutic usefulness with respect to existing treatment

- Standpoint of efficacy

- Standpoint of safety

- Reduction of physical and psychological burden on the patient

5.2 Procedure

When drugs are designated for priority reviews, opinions of experts on such designations

are compiled by the PMDA immediately after the application and reported to the MHLW.

Based on this report, the Evaluation and Licensing Division decides whether or not to apply

the priority review. The Evaluation and Licensing Division notifies this decision to the

applicant and the PMDA. The Evaluation and Licensing Division reports this application to

the next meeting of the review committee concerned of the PAFSC and obtains their approval.

Products for priority review are given priority at each stage of the review process as much

as possible. When products subject to priority review are approved as new drugs, this fact is

made public.

5.3 Priority review consultation

41Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association,


the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and

Cellular Therapy Products, Gene Therapy Products, and Cosmetics 43

優先審査等の取扱いについ平成 23 年 9 月 1 日, 薬食審査発 0901 第 1 号 (Handling of Priority

Review, Notification No. 0901-(1) of the Evaluation and Licensing Division, PFSB dated February 27, 2004)

38

When a product has been designated for priority review at the development stage, it is

possible to obtain priority interview advice on indications and other items concerning the

designated product. Products are designated on the basis of an overall evaluation of the

seriousness of indicated disease and clinical usefulness using the propriety review selection

criteria.

Applicants are requested to submit results of clinical studies up to late Phase II as a rule as

data for estimating the clinical usefulness assessment. Hearings and inquiries are undertaken

for the applicant as required and the designation is decided after hearing opinions of experts

in the field. The results, including reasons, are notified to the applicant in writing.

Orphan drugs are all handled as products for priority interview advice and an application

is not required.

5.4 Review period

Period for the priority review is about 9 months.

39

V. Others

1. Good Manufacturing Practice (GMP)4445

1.1 GMP compliance inspection concerning pharmaceuticals (including APIs) of

foreign manufacturers46

1.1.1 General

GMP compliance inspections include the following: 1) Inspections that are conducted at

the point of application for new marketing approval or of application for partial changes of

approved information, and 2) inspections that are conducted every five years following the

obtainment of marketing approval.

In the case of ethical drugs, packaging, labeling and storage facilities and external testing

laboratories are included in the scope of GMP Inspection, in addition to the manufacturing

sites of drug products, APIs (Active Pharmaceutical Ingredients) and intermediates.

In the case of application for partial change approval, GMP Compliance Inspection is not

required if the partial change is addition, change, or deletion etc. of dosage and

administration, or indication that will not affect the methods for manufacturing control or

quality control.

While drug products for over-the-counter drugs are included in the scope of GMP

compliance inspection, APIs for over-the-counter drugs are excluded from the inspection

(however APIs of over-the-counter for new marketing approval are in the scope of GMP

compliance inspection).

A marketing authorization holder that applies for the marketing approval of

pharmaceutical, or an appointed marketing authorization holder designated by a manufacturer

that seeks to obtain foreign restrictive approval, shall file an application with the PMDA for

GMP compliance inspection of foreign manufacturing sites.

Following the application for GMP compliance inspection, the applicant shall submit

“documents pertaining to manufacturing control and quality control of product(s) concerning

the compliance inspection” and “documents pertaining to manufacturing control and quality

control of manufacturing sites concerning the compliance inspection”, at request of the

PMDA.

Even applications and attached documents are concerning foreign manufacturing sites, it

should be prepared in Japanese. If the attachment includes a large volume of documents

written in a foreign language, it is acceptable to prepare only an overview of such documents

in Japanese.

44

Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association,


治験薬の製造管理、品質管理等に関する基準（治験薬ＧＭＰ）について , 平成 20 年 07 月 09 日

薬食発第 709002 号, (GMP for investigational drug for clinical trial, Notification No. 0709002 of the PFSB)”』

“治験薬の製造管理、品質管理等に関する基準（治験薬ＧＭＰ）に関するＱ＆Ａについて,平成 21 年 0

7 月 02 日事務連絡 (Q&A on GMP for investigational drug for clinical trial) 46

GMP Compliance Inspection Concerning Pharmaceuticals (including APIs) of Foreign Manufacturers

(Overview Guideance for Foreign Manufacturers), Sep.1, 2008, tentative translation (as of Oct. 7, 2008)

(http://www.pmda.go.jp/files/000152964.pdf)

40

1.1.2 Scope of the drugs subject to GMP compliance inspection

The scope of the drugs subject to GMP compliance inspection are drugs and APIs. The

products shown as below from a. through g. and APIs for over-the-counter drugs do not

require GMP compliance inspection

a. Drugs that are intended to be used for the extermination or prevention of rats, flies, mosquitoes,

fleas and other similar creatures, which are not used directly on human bodies.

b. Drugs that are intended to be used mainly for disinfection and sanitization, which are

not used directly on human bodies.

c. Drugs that are, APIs, intended to be mainly used for the manufacturing of drugs indicated in a.

or b.

d. Drugs that are manufactured at manufacturing sites that only conduct processes of

powdering and/or cutting crude drugs.

e. Drugs that are manufactured and/or marketed by pharmacies.

f. Of gases used for medical purposes, 1) nitrous oxide, 2) oxygen, 3) nitrogen, 4) carbon

dioxide, 5) compound of nitrous oxide and oxygen.

g. In addition to a. through f., drugs included in the Japanese Pharmacopoeia, which are

designated by the Minister of Health, Labour and Welfare as causing mild action to

human bodies (107 items including gum arabic).

1.1.3 Facilities subject to inspection

All manufacturing sites (including external testing laboratories) listed in the marketing

approval application or authorization.

1.1.4 Flow of GMP compliance inspection

A marketing authorization holder that is applying for the marketing approval, or a

marketing authorization holder that has obtained marketing approval, shall file an application

with the PMDA for GMP compliance inspection of foreign manufacturing sites. The PMDA

shall conduct the inspection.

In principle, GMP compliance inspection shall be onsite inspection by the PMDA.

However, inspection may be conducted on documents only (hereinafter “document

inspection”), by the PMDA‟s judgment on GMP compliance etc. based on the product‟s risk,

the country‟s GMP standards and their operation, and documents submitted for the inspection.

The PMDA shall report the inspection results to the Ministry of Health, Labour and Welfare,

using the form of “GMP Compliance Inspection Result Notification”. The PMDA shall issue

a copy of the GMP Compliance Inspection Result Notification to the marketing approval

holder that applied for the inspection, and a copy of the “GMP Compliance Inspection Result

Report” to the foreign manufacturer on which the onsite inspection was conducted. In the

case of document inspection only, a copy of the GMP Compliance Inspection Result Report

is not issued.

41

Figure 8. Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (1)47

Figure 9. Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (2) 47

1.1.5 Attached documents for an inspection application

47 GMP compliance inspection concerning pharmaceuticals (including APIS) of foreign manufacturers

(Overview guidance for foreign manufacturers), Sep.1,2008, Office of Compliance and Standards,

Pharmaceuticals and Medical Devices Agency

42

Below are the attached documents for an application for manufacturing/marketing

approval and an application for some amendment approval.

- Copy of compliance inspection result notification or report conducted for the past two

years from the application date of the applicable compliance inspection (including the

inspection conducted by other inspectors )

- For manufacturing sites in countries where MOU has been executed for the inspection

on overseas manufacturing sites, a copy of compliance certificate of other countries

based upon the applicable MRA, or a copy of GMP inspection report; for

manufacturing sites in the countries having executed an MOU etc., a copy of the other

country‟s certificate or a copy of GMP inspection report based upon the applicable

MOU; and for manufacturing sites in other countries, WHO certificate and

Compliance Certificate of the applicable government agency.

- A copy of an application for manufacturing/marketing approval for the product under

application

- Data requiring other compliance inspection

The following documents are required for the compliance inspection conducted every five

years after manufacturing/marketing approval

- Copy of compliance inspection result notification or report according to GMP

inspection conducted for the past two years from the application date of the applicable

compliance inspection (the inspection conducted by other inspectors )

- For manufacturing sites in countries where MRA has been executed for the inspection

into overseas manufactories, a copy of compliance certificate of other countries based

upon the applicable MRA, or a copy of GMP inspection report; for manufacturing

sites in the countries having executed an MOU etc., a copy of the other country‟s

certificate or a copy of GMP inspection report based upon the applicable MOU; and

for manufacturing sites in other countries, WHO certificate and compliance certificate

of the applicable government agency.

- Copy of manufacturing/sales approval letter

- Copy of some amendment approval letter for the last five years

- Copy of minor amendment report for the last five years

- When submitting an application for two or more products, a workplace, a workroom,

an area, and facilities are categorized and then a representative product is selected

from each category. The data indicating the rationale for categorization and selection

should be submitted.

- Presence or absence of recall of the product for the last five years from application (if

yes, provide the summary)

- Written pledge (prepared by an applicant)

- Other documents that compliance inspection need

1.1.6 Costs for inspection

The costs shall be paid by the manufacturer/marketing business who submitted an

application for manufacturing/marketing approval or obtained the approval.

If the same manufacturing site had GMP compliance inspection for the same product by

other manufacturer/marketing business; and provided a copy of compliance inspection result

notification to the applicable manufacturer/marketing business (within the past two years of

43

the dispensing date, in principle), the applicable manufacturer/marketing business does not

need to get GMP compliance inspection for the applicable manufacturing site.

1.1.7 Applicable laws

- Article 14, Paragraph 1 of Pharmaceutical Affairs Law (Approval for Manufacturing

and Approval for Drugs)

- Article 14, Paragraph 6 of Pharmaceutical Affairs Law

- Article 14-2, Paragraph 1 of Pharmaceutical Affairs Law (PMDA inspection conduct)

- Article 21 of Enforcement Ordinance of Pharmaceutical Affairs Law (Inspection period

according to manufacturing management or quality control method)

- Article 50, Paragraph 1 of Enforcement Regulation of Pharmaceutical Affairs Law

(Application for Compliance Inspection): #25 PDF format template (PDF format):

Template for Compliance Survey Application



- Article 51 of Enforcement Regulation of Pharmaceutical Affairs Law (Notification for

Compliance inspection Result): PDF format template #26 (PDF format): Notification

for Compliance inspection Result

1.1.8 Others

Japan has been registered as PIC/S GMP member on 1 July, 2014.

2. Drug Master File (DMF)

2.1 Overview48

With the amendment of the Pharmaceutical Affairs Act (now the Act on Securing Quality,

Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy

Products, Gene Therapy Products, and Cosmetics) enforced in April 2005, approvals for drug

substances that had been necessary in the past were no longer required.

Instead of that, the information of quality and manufacturing method of drug substance are

required to be included in the application document of finished product.

The DMF system aims at protecting intellectual property of relevant information at the

time of license application and facilitating review work by allowing a registrant (master file

registrant) of drug substances other than an applicant of finished product to separately submit

information on quality and the manufacturing method of drug substances to be used in drug

products.49

2.2 Items targeted for Drug Master File registration

48



原薬等登録原簿の利用に関する指針について, 平成 17 年 02 月 10 日薬食審査発第 210004 号 (Drug master file,

Notification No. 0210004 of the Evaluation and Licensing Division, PFSB dated February 10, 2005)

44

- Drug substances, intermediates

- Pharmaceutical product materials (materials of pharmaceutical products with special

dosage form, etc.)

- Excipients (new excipients , new pre-mix excipients)

- Materials for medical devices

- Containers, packaging materials

When an overseas drug substance manufacturer submits a DMF registration application, it

is necessary to appoint an in-country caretaker to handle the activities of the MF registrant in

Japan. When the registered contents of the DMF are changed, an application to change the

DMF or a minor DMF modification notification must be submitted.

Detailed information is found in the PMDA website.

3. Labeling and package inserts

3.1 Overview5051

Specified items must be entered on the immediate container of drugs. The package inserts

must contain indications, dosage/administration, precautions, and precautions for handling. In

addition, all ingredients used as excipients must be included in the package inserts of

products.

According to the Pharmaceutical Affairs Act (now the Act on Securing Quality, Efficacy

and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy

Products, Gene Therapy Products, and Cosmetics) amended on April 1, 2005, a new

regulatory category for prescription drug labeling “Caution: Use only with a prescription

from a physician” and a labeling item for manufacturer/marketing business instead of

manufacturer or importer were added.

The Law for Partial Amendment of the Pharmaceutical Affairs Act (now the Act on

Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative

and Cellular Therapy Products, Gene Therapy Products, and Cosmetics) issued on June 14,

2006 requires the manufacturer of non-prescription drugs to prescribe labeling contents

specified in the Law according to the level of potential risks.

To prevent medical accidents due to misunderstandings, assure traceability, and improve

the efficiency in prescription drug distribution, the implementation of barcode labeling for

prescription drugs (excluding in vitro diagnostics)52

and preparation of medication guides for

patients are being promoted so that the patient understands the prescription drug correctly and

serious adverse drug reactions can be discovered at an early stage.53

50

医薬品、医療機器等の品質、有効性及び安全性の確保等に関する法律』 No. 50-54 51



医療用医薬品へのバーコード表示の実施要項の一部改正について平成 24 年 06 月 29 日医政経発第 629001 号

(Bar code for pharmaceutical products, Notification No. 1 of the Economic Affairs Division, HPB and No. 1 of

the Safety Division, PFSB both dated June 29, 2012) 53

患者向医薬品ガイドの運用について平成 18 年 2 月 28 日付け薬食安発第 0228001 号、薬食監麻発第 0228002 号,

(Medication guides for patients, Notification No. 0228001 of the Safety Division, PFSB and No. 0228002 of the

Compliance and Narcotics Division, PFSB both dated February 28, 2006)

45

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 bioequivalence

test and other results (in accordance with improving the supply of Information on Generic

Drugs, Notification No. 0324006 of the Safety Division, issued by PFSB, March 24, 2006).54

This notification specifies to include the bioequivalence study data in the “Pharmacokinetics”

section of the package insert.

In accordance with the issue of the Law for Partial Amendment of the Pharmaceutical

Affairs Act (now the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals,

Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and

Cosmetics), a new package insert notification system was introduced to strengthen measures

for safety assurance. The manufacturing/marketing authorization holder is required to prepare

package insert based on latest scientific knowledge and information and notify the contents of

the package insert to the PMDA prior to marketing and upon every amendment.

3.2 Headings and their sequence in package inserts that are required in the

labeling

1) Date of preparation and/or revision(s) of the package insert

2) Standard Commodity Classification No. of Japan, etc.

- Standard Commodity Classification No. of Japan (SCCJ)

- Approval number

- Date of listing in the National Health Insurance (NHI) Reimbursement Price List

- Date of initial marketing in Japan

- Date(s) of latest reexamination

- Date(s) of latest reevaluation

- Date(s) of latest approval of additional indication(s)

- International birth date

- Storage conditions, etc. (storage, expiration date, shelf-life, etc.)

3) Therapeutic category

4) Regulatory classification (specified biological product, biological product, poisonous

substance, deleterious substance, habit-forming drug, prescription drug, etc.)

5) Name(s) [brand name, non-proprietary name, Japanese Accepted Name (JAN), etc.]

* At the beginning of the package insert Precautions concerning specified biological products (encased in

black)

6) Warning(s) (in red letters encased in red)

7) Contraindications (in black letters encased in red)

- Contraindications

- Relative contraindications

8) Compositions and description

- Compositions

- Product description

9) Indication(s)

- Indication(s)

54

後発医薬品に係る情報提供の充実について, 平成 18 年 3 月 24 日, 薬食安発第 0324006 号,

(Information on generic drugs, Notification No. 0324006 of the Safety Division, PFSB dated March 24, 2006)

46

- Precautions related to Indications

10) Dosage and administration

- Dosage and administration

- Precautions related to dosage and administration

11) Precautions: Refer to the following box.55

■ Headings used with precautions

① "Warning" (in red letters and encased in red at beginning of "Precautions")

② "Contraindications" (in black letters and encased in red following "Warning" in

principle. However, at the beginning of Precautions when there is no "Warning")

- Contraindications ("This product is contraindicated in the following patients.")

- Relative contraindications ("As a general rule, this product is contraindicated in

the following patients. If the use of this product is considered essential, it

should be administered with care.")

③ Precaution related to indications (In the event of such precautions, they are

indicated as "Indications" under the heading "Precautions" in the package insert)

④ Precaution related to dosage and administration (In the event of such

precautions, they are indicated as "Dosage and Administration" under the

heading "Precautions" in the package insert.)

⑤ Careful administration ("This product should be administered with care to the

following patients“)

⑥ Important precautions

⑦ Drug interactions

- Contraindications for co-administration ("This product should not be co-

administered with the following drugs") (in black letters and encased in red,

with simple explanation provided under "Contraindications" above)

- Precautions for co-administration: The MHLW issued an office communication

stressing that the Drug Interaction section must be based on the latest scientific

findings.

⑧ Adverse drug reaction (incidence indicated in numerical values whenever

possible)

* A key to the frequency of adverse reactions should be provided at the beginning.

55 医療用医薬品添付文書の記載要領について平成九年四月二五日, 薬発第六〇六号,

医療用医薬品添付文書の記載要領について平成九年四月二五日, 薬安第五九号

医療用医薬品の使用上の注意記載要領について , 平成九年四月二五日, 薬発第六〇七号

生物由来製品の添付文書の記載要領について, 平成 15 年 05 月 20 日医薬安発第 520004 号

生物由来製品の添付文書に記載すべき事項について, 平成 15 年 05 月 15 日医薬発第 515005 号

(Preparation on insert paper, Notifications No. 606 of PAB, No. 59 of the Safety Division, PAB, No. 607 of PAB, No.

0515005 of PFSB, and No. 0520004 of the Safety Division, PMSB)

47

- Clinical significant adverse drug reactions

- Other adverse drug reactions

⑨ Use in the elderly

⑩ Use during pregnancy, delivery, or lactation

⑪ Pediatric use (low-birth weight infants, newborns, infants, small children, children)

Reference: Age classification for pediatric use (basic standards)

• Children: under 15 years of age

• Small children: under 7 years of age

• Infants: under 1 year of age

• Newborns (neonates): under 4 weeks of age

• Low birth weight infants (premature infants): body weight of less than

2500g (according to the WHO recommendation)

⑫ Effects on the laboratory test

⑬ Overdosage

⑭ Precaution concerning use

⑮ Other precautions (Toxicity obtained in animal studies requiring particular

caution, etc.)

12) Pharmacokinetics

13) Clinical studies

14) Clinical pharmacology

15) Physicochemistry (active ingredient)

16) Precautions for handling

17) Conditions for approval

18) Packaging

19) References and reference requests

* Information of drugs with limited administration periods

20) Manufactured and/or marketed by: (name and address)

48

Figure 10. Layout of a Package Insert for a Prescription Drug (with "Warning")56

4. Requirements for Certificate of a Pharmaceutical Product (CPP)

CPP is not required in the approval application.



49

5. Approval of manufacturing/marketing of medicinal products5758

To get the manufacture/marketing approval on drugs, the following three reviews by

regulatory agency were required.

- Qualification of company: Licensing for Manufacturing/Marketing Businesses

- Efficacy and safety of medicinal products: Licensing for Manufacturing/Marketing on

drugs

- Qualification on manufacturing system and management: Licensing for Manufacturing

Businesses (domestic manufacturing), Accreditation of manufacturing business of

overseas manufacturers

Figure 11. Flow of Drug Manufacturing/Marketing Approvals

57

医薬品の製造販売手順について(Procedure for manufacturing and marketing for pharmaceutical products)

(http://www.pmda.go.jp/review-services/drug-reviews/foreign-mfr/0009.html,

http://www.pmda.go.jp/files/000161301.pdf 58

Accreditation of Foreign Manufacturers (http://www.pmda.go.jp/english/review-services/reviews/foreign-

mfr/0001.html)

50

5.1 Manufacturing/marketing business license

A person wishing to start manufacturing/marketing business for drugs, quasi-drugs,

cosmetics, or medical devices must obtain a manufacturing/marketing business license of the

prefectural governor depending on the type of business.

The licensing requirements for drug manufacturing/marketing businesses include the

appointment of a general marketing compliance officer, who is a pharmacist, and compliance

with Good Quality Practice (GQP) for quality control and Good Vigilance Practice (GVP) for

postmarketing safety surveillance.

Manufacturing/marketing business license is valid for a period of 5 years after every

renewal.

5.2 Efficacy and safety of medicinal products

Formal approvals are required for individual formulations of drugs in order to market the

drugs in Japan. Formal approval must be obtained prior to market launch from the Minister of

the MHLW or prefectural governor by submitting data and documents for required review on

product quality, efficacy, and safety. The approval and licensing system has been revised in

the amended Law and manufacturing (import) approvals became marketing approvals from

April 2005. Product licenses have been abolished and GMP compliance for each product has

been specified as an approval condition.

5.3 Accreditation of foreign manufacturers

A person wishing to manufacture drugs, quasi-drugs, cosmetics, or medical devices

exported to Japan from overseas (overseas manufacturers) must receive accreditation from

the Minister (enforced from April 1, 2005). The specifications for accreditation are the same

as those for manufacturing licenses for domestic manufacturers. The application should be

submitted by the time of the marketing approval application. When accreditation is not

obtained beforehand, “under application” should be entered in the marketing approval

application form (Marketing approval cannot be obtained - without accreditation approval).

The examination fees for accreditation of foreign manufacturers are shown in the table

below and detailed explanation was indicated in the PMDA website:59

Category of examination fees for foreign

manufacturing establishment

Fee

Gov't

(MHLW) PMDA

New Accreditation (On-site) 90,000 133,300

New Accreditation (Document) 90,000 58,100

Renewal of accreditation (On-site) 23,400 64,600

Renewal of accreditation (Document) 23,400 39,700

Addition of accreditation category (On-site) 90,000 64.600

59

http://www.pmda.go.jp/english/review-services/reviews/foreign-mfr/0001.html

51

Addition of accreditation category (Document) 90,000 39,700

Change in accreditation category (On-site) 23,400 64.600

Change in accreditation category (Document) 23,400 39,700

Issue of accreditation certificate 19,700 -

Reissue of accreditation certificate 19,700 -

Examination Fees for Accreditation of Foreign Manufacturers (Unit: JPY)

6. Fees for regulatory approval

According to the Pharmaceutical Ordinance on Fees for Regulatory Approval dated April

1st, 2014: 60

- For approval of new product manufacturing/marketing approval, following fees should

be paid: ¥533,800 to MHLW and ¥30,535,100 to PMDA

- For approval of generic product manufacturing/marketing, Licence of

manufacturing/marketing business for generic prescription drugs (required for GMP

inspection) is required and following fees should be paid: ¥28,100 to MHLW and

¥632,200 to PMDA

- Licence of manufacturing/marketing business for other drugs: ¥28,100 to MHLW,

¥110,300 to PMDA

60 http://web.fd-shinsei.go.jp/application/list_drug.html

52

VI. References

1. PMDA website: www.pmda.go.jp

2. Act on Securing Quality Efficacy and Safety of Pharmaceuticals, Medical Devices,

Regenerative and Cellular Therapy products, Gene Therapy Products, and Cosmetics』

(http://law.e-gov.go.jp/htmldata/S35/S35HO145.html)

3. Enforcement Regulation of Pharmaceutical Affairs Law 『the Act on Securing Quality

Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular

Therapy products, Gene Therapy Products, and Cosmetics』 (http://law.e-

gov.go.jp/htmldata/S36/S36F03601000001.html)

4. Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical

Manufacturers Association, March 2014 (JPMA, 2014)

- http://www.jpma.or.jp/about/issue/gratis/index2.html (Japanese)

- http://www.jpma.or.jp/english/parj/whole.html (English)

http://www.pmda.go.jp/

http://law.e-gov.go.jp/htmldata/S35/S35HO145.html

http://law.e-gov.go.jp/htmldata/S36/S36F03601000001.html

http://law.e-gov.go.jp/htmldata/S36/S36F03601000001.html

53

Appendix 1. Instructions for filling out the IND application form

I. Common sections for clinical trial protocol notification

① Clinical trial ingredient code

- Enter the clinical study ingredient code defined by the company in half-with forms

(about 20 characters in total combining alphabets and numbers).

- If there are changes in the clinical study ingredient codes of the first notification,

please provide the type of amendment, date of amendment, and reason for the

amendment.

- Use the different code for clinical study drug using different route of the

administration.

- Use one clinical study ingredient code for the clinical study to be added.

② Type of clinical study

- Enter “1” in the half-width form.

③ Receipt number of first notification

- Enter the receipt number of the first clinical study notification of same clinical study

ingredient code. In this case, please use the half-width form and half-width hyphen,

e.g. [Review #OO-OOOO] → [OO-OOOO] and [OOOO-OOOO].

- In addition, if there is no receipt number since the first notification was submitted

before April, Heisei 9 (1997), write the receipt number assigned initially in the

reporting of the applicable clinical study ingredient code.

- Leave the report blank if the applicable clinical study notification is the first.

④ First notification date

- Write the date of the first clinical study plan notification for the same clinical study

ingredient code.

⑤ Number of notification

- Write the total number of notification for the clinical study plan of the same clinical

study ingredient code (not including amendment report, etc.).

- Write the serial number (e.g. please enter 11 in half-width numbers if 10 reports were

submitted in total before) if the clinical study plan notification for the applicable study

drug had been submitted previously, e.g. in case of some amendments to previously

approved items, such as addition of efficacy and effectiveness of approved drug.

⑥ Receipt number of the applicable clinical study plan notification

- For protocol, please leave the applicable section blank.

- For clinical study plan amendment report, clinical study close out report and clinical

study discontinuation report, enter the receipt number of the applicable clinical study

plan notification in half-width numbers and half-width hyphen..

- In addition, if there is no receipt number since the applicable clinical study plan

notification was submitted before April, Heisei 9 (1997), enter the first assigned

receipt number from the clinical study plan amendment notification. If there is no

54

clinical study plan amendment notification since April, Heisei 9 (1997), please leave

this section blank.

⑦ Date of the applicable clinical study plan notification

- Enter the date of the applicable clinical study plan notification, the clinical study plan

amendment notification, clinical study close out notification and clinical study

discontinuation notification

II. Sections to be notified

① Notification date

- Enter the date of the applicable notification.

② Notification classification

- Fill in the applicable sections in the clinical study plan notification, the clinical study

plan amendment notification, clinical study close out notification, clinical study

discontinuation notification and development discontinuation notification.

③ Number of amendment

- For amendment reports, write the number of the clinical study plan amendment

notification in half-width form for each clinical study plan notification.

④ Classification of study drug under 30-day investigation

- If the clinical study plan for the applicable report is under 30-day investigation, enter

[new active substances], [new route of administration], and [new medical

compounding agents] depending on the type of the study drug under the clinical study

to be notified.

- For applicable drugs notified newly since 1 April Heisei 9 (1997), if the clinical study

was ongoing after the first notification and it is not the first time for human use, leave

the section blank and write the purpose in the section “Remark”.

⑤ Discontinuation information

- When the discontinuation of clinical study is notified, please write the period of

clinical study discontinuation (date of discontinuation determination), the reason for

discontinuation (provide specific information), and the actions taken thereafter

(provide details for action taken after the discontinuation is determined).

⑥ Name or location of manufacturer and business office

- Write the name or location of business office in case of import, and manufacturer in

case of manufacturing.

- Write the business code (9 digits) in half-width form. In addition, if the drug is

produced at the place without code, please write 3 digit [999] for the license holder in

compliance with the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals,

Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy

Products, and Cosmetics and if not, enter [999999999].

⑦ Ingredient and quantity

- Enter non-proprietary name (JAN and INN) as the ingredient name (English name and

Japanese name). If non-proprietary name is not determined, please write the clinical

55

study ingredient code. Please write the quantity to see the contents of active

substances per dosage form.

- Write the dosage form code (4 characters) including the first 2 characters in

English/Number using half-width forms in compliance with the code defined by

Japanese Pharmacopeia.

⑧ Manufacturing method

- Specify the type such as chemical synthesis, extraction, culture, or genetic

recombination with regards to the manufacturing method of bulk.

- Enter the dosage form of the agent clearly (“OOO with chemical synthesis shall be

produced in compliance with the sections of Japanese Pharmacopeia and provide the

description for special dosage form, such as sustained-release agent (drug) etc.

- In addition, enter the classification of the manufacturing/import and clarify the import

approval if it is imported. Please enter the originating country of the importer, name

and title of the manufacturer, or the product name used at the importer.

⑨ Expected indication

- Enter the expected indication based on efficacy/pharmacology of similar drugs

- Enter the drug classification number (3 digits) in half-width forms. In addition, please

write the main classification number of active ingredient if the number of drug

classification has two or more.

⑩ Expected dose and dosage

- Enter the expected dose and dosage.

- Enter the code of the route of administration (2 digits) in half-width forms.

⑪ Summary of clinical study plan

- Protocol identification code

- Development phase

- Study type: Write with “Clinical pharmacology”, “Exploratory study”, and

“Confirmatory study”.

- Objective

- Information on the expected number of subjects: For multinational studies, enter the

number of subjects in Japan. Furthermore, when the clinical study close-out and the

discontinuation of the clinical study are notified, please enter the number of all

subjects who participate in the applicable clinical study.

- Indication: Specify the disease name. For healthy individuals, please write the purpose.

- Dose and dosage information

- Institution: Write the period from the expected date of the clinical study agreement

execution (whichever occurs earliest) for each institution to the expected date of

observation completion at the institution (whichever occurs last) in the format of

Year/Month/Day.

- Reason for compensation etc: Please leave blank if it is not compensated. In principle,

the clinical study should be no compensation.

- Clinical study budget provider

- Information on the coordinating investigator and the investigators belong to clinical

study coordinating committee.

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- Name, address and scope of the delegated work of Contract Research Organization

(CRO) who is delegated to assume the whole or part of the work in connection with

contract and management of clinical study.

⑫ Remark

For the following sections, please write in Section [Remark].

1) For multinational clinical studies, please specify “Multinational clinical study”.

- To the best of knowledge, please provide the names of countries participating in the

applicable multinational clinical study, the regional information, the expected

number of subjects in the applicable multinational clinical study, and the ratio of the

number of subjects in your country to the expected number of subjects in the

applicable multinational clinical study.

- In case of multinational clinical study, it is not necessary to notify the clinical study

plan amendment of that study, and it would be OK to notify later with other clinical

study plan amendments notification.

2) Clinical study involving gene test

Please provide the purpose for [clinical study involving genome testing etc.] (including

the test involving biomarker relevant to expression of other genes and protein derived

from specific genes, the same hereinafter) if the clinical study uses a gene test in

connection with the mechanism of action of the drug.

Clinical study using a drug that is subject to the Cartagena Law in Japan

- If the clinical study is conducted using drugs, including living modified organisms

that are subject to Law concerning the Conservation and Sustainable Use of

Biological Diversity through Regulations on the Use of Living Modified Organisms

(hereinafter called “Cartagena Law”), please write the status of approval

[(application date) on the approval application)] and [Approval Completion

(Approval date and notification number)] under Type 1 Use Regulations of

Cartagena Law.

- For clinical studies using the drugs under Cartagena Law, please provide

Containment Measures to Be Taken in Type 2 Use of Living Modified Organisms

for Research and Development ([under Confirmation application], [confirmation

completion (confirmation date and notification number), [not necessary]) and

expected work level ([GILSP], [Category 1], and [Others]) per facility if there are

many facilities.

Clinical study using the drugs that are expected to be designated as biologics

- For clinical studies using the drugs to be expected (or designated) as biologics,

please indicate “to be expected (or designated) to be designated as biologics” and “to

be expected (or designated) as specific biologics”

Product to be developed in a microdose clinical trial

- If the applicable clinical study is the microdose clinical study and the prior

microdose clinical study was conducted for the development of the applicable

product, please describe the meaning.

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Description of machine and device used together in the clinical study to be

reported

- If clinical study used the equipment (e.g. machine/device) that does not require

clinical study plan notification, please write the classification of clinical study device,

general name, class classification, and other required sections and quantity to

identify the clinical study device on the section “Remark” of clinical study plan

notification (including clinical study plan amendment notification) in compliance

with the full provisions under Article 80-2, Paragraph 2 of the Act.

- In above case, incorporating the protocol, clinical study device summary,

information sheet and other documents required by GCP for medical device into the

document of clinical study for drug would not pose a problem.

- Others: Please provide any comments, if present.

⑬ Documents attached to notification

- Please indicate the title of the data attached to the notification.

- In addition, for the section “Remark” on attached documents to the notification,

please write comments, if applicable.

⑭ Information on person conducting the clinical study plan notification

- Please write the type of business (classification of the sponsor and local CRO), name

(its name and the name of the representative, if there is the local corporation), address

(location of the main branch office, if there is the local corporation), business code (9

characters), and the name, department, telephone number and fax number of the staff

in charge of notification.

⑮ Information on overseas manufacturer

- Please write the name of the overseas manufacturer (it name and the representative

name if there is the local corporation), address (location of the main branch office, if

there is the local corporation) of the overseas manufacturer in Japanese and English.

III. Sections for each institution

① Name, department, location and representative telephone number of the institution

- Write the name, department, location and representative telephone number of the

institution.

② Name and title of the principal investigator

- Write the name the title at the institution, university number (See Attachment 4), year

of graduation, name, the pronunciation of the name. In addition, it would be ok to

write simply “doctor” etc. as the title.

③ Name of the sub-investigators

- Write the name and its pronunciation.

④ Information on the quantity to be dispensed (obtained) of the study drug

- Write the quantity to be dispensed (obtained) of the study drug (study drug and

comparator) by type (formulation, contents). In addition, please dispense appropriate

amount depending on the dose and dosage or the expected number of subjects.

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- Write the amount of study drugs that were dispensed, used, returned and discarded on

an actual basis by type (formulation, contents) on the study close out report and

clinical study discontinuation report.

- If the unit is to be allocated in pairs in a double blinded clinical study or comparative

clinical study, write the quantity assigned per pair on the footnote, followed by the

number of pairs.

- In addition, if there is any change in the quantity of study drugs to be dispensed

according to the conduct of the clinical study, it is not necessary to report the change

according to the applicable section.

⑤ Expected number of subjects at institutions

- Write the expected number of subjects for each institution (including study group and

control group) on the clinical study plan report and clinical study plan amendment

report.

- In addition, if there is any change in the number of study drug to be dispensed

according to the conduct of the clinical study, it is not necessary to report the change

according to the applicable section.

⑥ Number of subjects at institutions

- Write the number of subjects for each institution (*including study group and control

group) on the study close out notification and clinical study discontinuation

notification.

⑦ Name and address of the party that received outsourcing from the institution with

regards to the clinical study (Site Management Organization (SMO) etc.) and the

scope of the outsourced works

- If the institution outsources some works of the clinical study, please write the name

and address of the outsourcing party and the scope of the outsourced works for each

institution.

⑧ Name and address of the IRB Organizer

- Write the name (name of the local corporation and representative name) of the IRB

and the address for each institution. Furthermore, if the IRB organized by the head of

the applicable institution (except if the IRB was co-established by the head of the

applicable institution and the head of other institution) is requested to review the

investigation, please write “in-hospital IRB”; it is not necessary to write the name of

the IRB organizer (name of the local corporation and representative name) and the

address. In addition, if the IRB co-established by the heads of multiple institutions is

requested to review the investigation, please write the name of the IRB co-established

instead of the name of the IRB organizer, and the address of the applicable IRB

administrative office.

- If the IRB to be requested to review the investigation is not established at the time of

reporting, the report can be replaced with amendment report at later point.

⑨ Miscellaneous

- Write any remarks in connection with each institution.

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⑩ Footnotes

- Write common sections for all institutions, such as the quantity allocated per pair, if

any.

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Drug Approval System of Japan

Publication date December 2015

Published by APEC Harmonization Center

※ If there is any inquiry or comment on this document, please

contact the APEC Harmonization Center.

• Tel. 043-719-2875~2877

• Fax. 043-719-2870