Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Pharmaceutical
Administration and
Regulations in Japan
2019
http://www.jpma.or.jp/about/issue/gratis/index2.html (Japanese)
http://www.jpma.or.jp/english/parj/whole.html (English)
Epidemiology ............................. 8
4.24 Office of International Cooperation ... 9
Table of Contents 4.25 Office of In Vitro Diagnostics .......... 9
4.26 Kansai Branch ............................ 9
4.27 Hokuriku Branch ......................... 9
5. NATIONAL INSTITUTE OF
BIOMEDICAL INNOVATION, HEALTH
CHAPTER 1 ........................................................... 1 AND NUTRITION (NIBIOHN) ................. 9
6. JAPAN AGENCY FOR MEDICAL
ORGANIZATION AND FUNCTION OF THE RESEARCH AND DEVELOPMENT
MINISTRY OF HEALTH, LABOUR AND (AMED) ............................................ 9
WELFARE .............................................. 1 7. PHARMACEUTICAL AFFAIRS AND
1. PHARMACEUTICAL SAFETY AND FOOD SANITATION COUNCIL (PAFSC) ... 9
ENVIRONMENTAL HEALTH BUREAU 8. NATIONAL INSTITUTE OF
(PSEHB) ........................................... 2 INFECTIOUS DISEASES .................... 10
1.1 General Affairs Division ................. 2
1.2 Pharmaceutical Evaluation Division .. 2
1.3 Medical Device Evaluation Division .. 2 CHAPTER 2 ..........................................................15
1.4 Pharmaceutical Safety Division ....... 3
1.5 Compliance and Narcotics Division... 3 PHARMACEUTICAL LAWS AND
1.6 Blood and Blood Products Division ... 4 REGULATIONS ..................................... 15
2. HEALTH POLICY BUREAU .................... 4
1. PHARMACEUTICAL LAWS ................. 15
2.1 Economic Affairs Division ............... 4
2. PHARMACEUTICAL AND MEDICAL
2.2 Research and Development
DEVICE ACT .................................... 15
Division ..................................... 4
3. OUTLINE OF PHARMACEUTICAL
3. NATIONAL INSTITUTE OF HEALTH
REGULATIONS ................................ 17
SCIENCES ........................................ 5
3.1 Definition of Drugs ..................... 17
4. PHARMACEUTICALS AND MEDICAL
3.2 Classification of Drugs ................ 17
DEVICES AGENCY, AN INDEPENDENT
3.3 License for
ADMINISTRATIVE ORGANIZATION ......... 5
Manufacturing/Marketing
4.1 Office of Review Administration ....... 6
Businesses .............................. 19
4.2 Office of Review Management......... 6
3.4 License for Manufacturing Business
4.3 Office of New Drug I ..................... 6
and Accreditation of Overseas
4.4 Office of New Drug II .................... 6
Manufacturers .......................... 20
4.5 Office of New Drug III.................... 6
3.5 Manufacturing/Marketing Approvals 22
4.6 Office of New Drug IV ................... 7
3.6 Good Manufacturing Practice
4.7 Office of New Drug V .................... 7
(GMP) .................................... 22
4.8 Office of Cellular and Tissue-based
3.7 Drug Master File (MF) ................ 23
Products .................................... 7
3.8 Drug Retail Seller Licensing ......... 23
4.9 Office of Vaccines and Blood
3.9 Labeling and Package Inserts ....... 24
Products .................................... 7
3.10 Proper Advertisement ................. 25
4.10 Office of OTC/Quasi-drugs ............. 7
3.11 Good Laboratory Practice (GLP) ... 26
4.11 Office of Generic Drugs ................. 7
3.12 Good Clinical Practice (GCP) ....... 26
4.12 Office of Medical Devices I ............. 7
3.13 Trial Conducted from a
4.13 Office of Medical Devices II ............ 7
Compassionate Viewpoint
4.14 Office of Standards and
(expanded trial) ......................... 27
Compliance for Medical Devices .... 7
3.14 Patient-requested Therapy System 28
4.15 Office of Non-clinical and Clinical
3.15 Good Post-marketing Study
Compliance .............................. 8
Practice (GPSP) ....................... 28
4.16 Office of Informatics and
3.16 Reexamination and Reevaluation .. 28
Management for Safety ................. 8
3.17 Reevaluation ............................ 29
4.17 Office of Pharmacovigilance I .......... 8
3.18 Adverse Drug Reaction (ADR) and
4.18 Office of Pharmacovigilance II ......... 8
Infection Reporting .................... 29
4.19 Office of Manufacturing Quality for
3.19 Risk Management Plan (RMP) ...... 29
Drugs ....................................... 8
3.20 Dissemination of Information ........ 30
4.20 Office of Manufacturing Quality and
3.21 Measures related to the Law
Vigilance for Medical Devices ......... 8
Concerning Access to Information
4.21 Office of International Programs ...... 8
Held by Administrative
4.22 Office of Advanced Evaluation with
Organizations ........................... 30
Electronic Data ........................... 8
3.22 Patent System .......................... 31
4.23 Office of Medical Informatics and
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(excluding items handled by the Guidance of in April 2004, through the integration of the
Medical Service Division of the HPB) Pharmaceutical and Medical Devices Evaluation
5) Matters related to the improvement of health Center in the National Institute of Health Sciences, the
care information-processing and management OPSR, and part of the Medical Devices Center, and
system the PMDA started handling all consultation and
review work from the preclinical stage to approvals
6) Matters related to the evaluation of medical
and post-marketing surveillance.
technology (excluding those handled by other
The work of the PMDA can be divided into three
bureaus of MHLW)
main categories: ADR relief work, review work and
Office of Clinical Trial Promotion safety measures.
Promotion of clinical trials specified in Article 2, The PMDA consists of 28 offices, 4 groups, and
Paragraph 16 of the Pharmaceutical Affairs Law the Kansai and Hokuriku branches as shown in Fig. 2,
(Law No. 145 issued in 1960) (other than those and, the duties are indicated below.
handled by PSEHB) The PMDA is currently working to achieve goals
under the Third Medium Range Plan
3. NATIONAL INSTITUTE OF HEALTH (FY2014-FY2018), including strengthening and
SCIENCES enhancing post-marketing safety measures to ensure
the quality of products and prevent the occurrence or
In July 1997, the name of the former National
escalation of health hazards and striving to speed up
Institute of Hygienic Sciences was changed to the
and improve the quality of reviews, in order to be the
National Institute of Health Sciences. In addition to
first in the world to facilitate practical use of innovative
its long-standing work related to testing and research
drugs, pharmaceutical medical devices and
on drugs, quasi-drugs, cosmetics, medical devices,
regenerative m relief systems are definitely used
foods, poisonous and deleterious substances, the
when necessary. medicine products, as well
Institute supervised the Pharmaceuticals and Medical
conducting publicity activities so that
Devices Evaluation Center to undertake the reviews
required for approval to manufacture or import drugs, 1) Drug ADR Relief Work
quasi-drugs, cosmetics and medical devices, as well Provision of medical benefits to cover
as the reexamination and the reevaluation of drugs, healthcare expenses, disability pensions,
and medical devices. Thereafter, the Evaluation and survivors pensions for individuals
Center was incorporated into the Pharmaceuticals suffering disease or disability due to adverse
and Medical Devices Agency (PMDA) in April 2004. drug reactions or bioderived infections
Provision of medical allowances for
4. PHARMACEUTICALS AND MEDICAL treatment of myelo-optico-neuropathy
DEVICES AGENCY, AN INDEPENDENT (SMON) patients and for HIV carriers and
ADMINISTRATIVE ORGANIZATION AIDS patients
Surveys on damage caused by drugs and
In accordance with the special corporation
research on treatment, etc. of adverse drug
rationalization plan passed by the Cabinet in
reactions as health and welfare work
December 2001, and enactment of the
Pharmaceuticals and Medical Devices Agency Law in Provision of medical allowances based on
December 2002, the PMDA (KIKO) was established the Special Measures Law for Provision of
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4.15 Office of Non-clinical and Clinical 4.19 Office of Manufacturing Quality for
Compliance Drugs
This office reviews the documentation included This office conducts works related to compliance
with applications for approval, reexamination, or inspections for GMP and GCTP, etc.
reevaluation of drugs and regenerative medicine
products to assure that the studies on which the data 4.20 Office of Manufacturing Quality and
is based comply with GLP, GCP, GPSP, study Vigilance for Medical Devices
protocol, etc. both ethically and scientifically to
This office conducts works related to compliance
determine if the documents have been prepared
inspections for QMS, etc., on-site inspection of
appropriately and accurately based on the study
manufacturing sites of medical devices, etc., and
results in accordance with the Criteria for Reliability of
face-to-face advice on QMS. This office also conducts
Application Data (hereinafter “Reliability Criteria”)
safety measures for medical devices and in vitro
and examined on site and on paper. Compliance of
diagnostics.
facilities performing GLP-based studies is also
examined and certified.
4.21 Office of International Programs
4.16 Office of Informatics and Management This office makes plans and proposals concerning
for Safety international activities and undertakes surveys and
coordinations associated with this, coordinates the
This office handles tasks related to contributions
matters related to international conferences,
for safety measures, tasks related to receipt and
international organizations, and foreign government
organization of reports of adverse reactions and
organizations and groups, and conducts works
publication of the results of organization, and tasks
related to the collection and analysis of overseas
related to provision of information for improvement of
information and foreign public relations campaign.
the quality, efficacy and safety of drugs and medical
devices, etc.
4.22 Office of Advanced Evaluation with
Electronic Data
4.17 Office of Pharmacovigilance I
This office conducts works related to collection of
This office conducts safety measures related to
information on the use of various data related to
drugs in the fields under the jurisdiction of Office of
application, planning, drafting, and investigation and
New Drug I, Office of New Drug II, and Office of New
analysis, etc. of the information regarding the quality,
Drug III (including generic drugs and OTC drugs),
efficacy and safety of drugs and medical devices, etc.
quasi-drugs, and cosmetics.
through the use of various data on planning, drafting,
and application. This office also makes plans for
4.18 Office of Pharmacovigilance II
education and training regarding access to and
This office conducts safety measures related to analysis of various data related to application.
drugs in the fields under the jurisdiction of Office of
New Drug IV, Office of New Drug V, and Office of 4.23 Office of Medical Informatics and
Vaccines and Blood Products (including generic drugs Epidemiology
and OTC drugs) and cellular and tissue-based
This office conducts works related to investigation
products.
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and analysis of the information regarding the quality, Research promotion and orphan drug
efficacy, and safety of drugs and medical devices, etc. development promotion, which had been conducted
using the technique of pharmacoepidemiology and by the PMDA, were transferred to the institute.
other scientic techniques, as well as the works related
to operation and management, etc. of MID-NET®.
6. JAPAN AGENCY FOR MEDICAL
RESEARCH AND DEVELOPMENT (AMED)
4.24 Office of International Cooperation
AMED was established on April 1, 2015 to
This office makes plans and proposals concerning
promote integrated research and development in the
the works conducted by Asia Training Center for
field of medicine (medical R&D), from basic research
Pharmaceuticals and Medical Devices Regulatory
to practical application; to ensure smooth application
Affairs and undertakes surveys and coordinations
of the R&D outcomes to practices; and to establish
associated with this.
and maintain an encouraging environment for
medical R&D comprehensively and effectively.
4.25 Office of In Vitro Diagnostics By supporting research activities of universities
This office conducts reviews required for approval and research institutions, AMED promotes R&D and
of in vitro diagnostics. furthermore establishes an encouraging environment
for R&D.
4.26 Kansai Branch
This branch undertakes regulatory science 7. PHARMACEUTICAL AFFAIRS AND FOOD
strategy consultations and GMP and QMS SANITATION COUNCIL (PAFSC)
inspections in the Kansai area. The Pharmaceutical Affairs and Food Sanitation
Council (PAFSC) serves as an advisory body to the
4.27 Hokuriku Branch MHLW, and reviews and discusses important
This branch provides training on GMP inspections pharmaceutical and food sanitation-related matters
at manufacturing sites in Toyama prefecture held by Fig. 3 Organization of the Pharmaceutical Affairs
Asia Training Center for Pharmaceuticals and Medical and Food Sanitation Council (PAFSC). This council
Devices Regulatory Affairs (PMDA-ATC). was created by merging of the Central
Pharmaceutical Affairs Council (CPAC) and the Food
Sanitation Investigation Council. It is divided into a
5. NATIONAL INSTITUTE OF BIOMEDICAL Pharmaceutical Affairs Committee and a Food
INNOVATION, HEALTH AND NUTRITION Sanitation Committee. The latter comes under the
(NIBIOHN) Food Sanitation Law and the former under other laws.
The National Institute of Biomedical Innovation The Council has as members experts in various
was established in April 2005 based on the Law for fields1) including the medical and pharmaceutical
the National Institute of Biomedical Innovation which sciences.
was approved by the 159th National Diet Session and The frequency of committee meetings differs.
promulgated in 2004 to make a major contribution to For example, the First Committee on New Drugs2) and
drug research and development by integrating basic the Second Committee on New Drugs2), which review
research, research on bioresources, and promotion of new drug applications, each meet approximately eight
research and development. times a year and the Committee on Non-prescription
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Drugs3) meets four times a year.4) New drugs are Infectious Diseases. The institute undertakes basic
then reviewed or reported and approved by the and applied research, reference and surveillance
Pharmaceutical Affairs Committee that meets four activities, and collection, analysis, and supply of
times a year.5) 6)
information pertaining to infectious diseases, performs
Note 1) Expert areas: Nursing, life sciences, research on the quality control of antibiotics and other
applied biochemistry, mathematics and biological products, and undertakes national
statistics, law, and economics certification/testing and activities related to
Note 2) Categories of drugs for the Second international cooperation.
Committee on New Drugs to review: Infectious Diseases Information Center
Antiviral drugs, chemotherapeutic agents,
This Center was established in April 1997 to
anti-malignant tumor agents, blood
undertake surveys and research, and collect and
products, and biological products. Those
supply information on infectious diseases, etc.
for the First Committee: Remaining
therapeutic categories AIDS Research Center
Note 3) Categories of drugs for the Committee on This Center was established in April 1988 to
Non-prescription Drugs to review: New undertake HIV basic research and to develop
non-prescription drugs which are methods of prevention and treatment of AIDS.
apparently different from existing
non-prescription drugs in active ingredient,
strength, dosage/administration,
indications, etc.
Note 4) The First and Second Committees on
New Drugs meet in January, February,
April, May, July, August, October, and
November in principle. The Committees
on Non-prescription Drugs meets in
February, May, August, and November in
principle.
Note 5) The Pharmaceutical Affairs Committee
meets in March, June, September, and
December in principle.
Note 6) For recent new drugs, refer to the
homepage on drug information.
(http://www.pmda.go.jp/english/review-services/revie
ws/approved-information/drugs/0002.html)
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Ministry Proper
Minister’s Secretariat
Employment
Environment and
Equal Employment
Bureau
Insurance Bureau
Pension Bureau
Director-General for
Policy Planning and
Evaluation
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Pharmaceutical Safety
and Environmental
Pharmaceutical and Medical Devices Agency
Health Bureau (except
(PMDA)
for the Department of
Food Safety)
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Committee on Guidance-Mandatory
Drugs and Non-prescription Drugs
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Fig. 3 Organization of the Pharmaceutical Affairs and Food Sanitation Council (PAFSC)
(17 Committees and 19 Subcommittees)
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potential risks (type 1: especially high risk, type 2: Businesses, etc. of Medical
relatively high risk, and type 3: relatively low risk) and Devices and in vitro Diagnostics
the systems of information dissemination and Section 1 Manufacturing/Marketing
consultation on drugs for each classification were Businesses of Medical Devices and
implemented. in vitro Diagnostics (Article 23-2 to
In 2013, the Law for Partial Amendment of the 23-2-22).
Pharmaceutical Affairs Law (Law No. 84 dated Section 2 Third-party Certification
November 27, 2013) was issued for strengthening Bodies (Article 23-2-23 to 23-19)
safety measures and for establishing regulations and Chapter 6: Manufacturing/Marketing
control on medical devices and regenerative medicine Businesses of Cellular and
products in view of their properties and Tissue-based Products (Article
characteristics. The Law was enacted on November 23-20 to 23-42)
25, 2014. In conjunction with this law, the Law for Chapter 7: Retail Sellers, etc. of Drugs,
Partial Amendment of the Pharmaceutical Affairs Law Medical Devices and Cellular and
and the Pharmacists Law (Law No. 103 dated Tissue-based Products
December 13, 2013) was issued in the same year for Section 1 Retail Sellers of drugs
clarifying the Internet retailing rules of non-prescription (Articles 24 to 38)
drugs and for tightening regulations on designated Section 2 Retail Sellers, Leasers
drugs/substances. The Law was enacted on June and Repairers of Medical Devices
12, 2014 (provisions strengthening regulation of (Articles 39 to 40-4)
designated substances were enacted on April 1, Section 3 Retail Sellers of Cellular
2014). and Tissue-based Products
In the revised Pharmaceutical Affairs Law enacted (Articles 40-5 to 40-7)
on November 25, 2014, regulations on drugs, medical Chapter 8: Standards and Government
devices and regenerative medicine products were Certification for Drugs (Article 41 to
divided into individual chapters to restructure the Article 43)
entire framework, as well as the Pharmaceutical Chapter 9: Handling of Drugs
Affairs Law was renamed to be the Law for Ensuring Section 1 Handling of Poisonous
Quality, Efficacy, and Safety of Drugs and Medical and Deleterious Substances
Devices (commonly-called the Pharmaceutical and (Articles 44 to 48)
Medical Device Act). Section 2 Handling of Drugs
The revised Law, Pharmaceutical and Medical (Articles 49 to 58)
Device Act, consists of 17 chapters and 91 articles as Section 3 Handling of Quasi-drugs
outlined below. (Articles 59 and 60)
Chapter 1: General Provisions (Articles 1 to 2) Section 4 Handling of Cosmetics
Chapter 2: Prefectural Pha rmaceutical (Articles 61 and 62)
Affairs Councils (Article 3) Section 5 Handling of Medical
Chapter 3: Pharmacies (Articles 4 to 11) Devices (Articles 63 to 65)
Chapter 4: Manufacturing/Marketing Section 6 Handling of Cellular and
Businesses of Drugs, Quasi-drugs Tissue-based Products (Articles
and Cosmetics (Articles 12 to 23) 65-2 to 65-6)
Chapter 5: Manufacturing/Marketing Chapter 10: Advertising of Drugs, etc. (Articles
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provided by a pharmacist, etc. Those are based on the definition by the regulations and risk
neither pharmacy drugs nor of infection as specified in Notification No.
guidance-mandatory drugs. Those are 0731011 of the PMSB dated July 31, 2002, from
classified into three types based on the degree the standpoint of augmentation of safety
of risks to humans: Type 1 (highly risky), Type 2 measures in keeping with advances in science
(moderately risky) and Type 3 (relatively low and technology including biotechnology and
risky). In the revised Pharmaceutical Affairs genomics.
Law enacted on June 12, 2014, (1) Biological products
non-prescription drugs may be retailed via the
Drugs, quasi-drugs, cosmetics, or medical
Internet in accordance with the proper rule.
devices using materials manufactured from
2) Classification according to handling humans or other organisms (excluding
regulations related to safety plants) as raw materials or packaging
Drugs include those that are highly poisonous, materials, which are designated as requiring
which have serious adverse reactions and which special precautions in terms of public health
are addictive or habit forming. They are and hygiene.
classified as follows in related laws such as the (2) Specified biological products
Pharmaceutical and Medical Device Act or the
Biological products designated as requiring
Stimulants Control Law (Table 1 List of Main
measures to prevent the onset or spread of
Controlled Substances).
risk to public health and hygiene due to the
(1) Poisonous substances (Article 44 of the biological product concerned after selling,
Law). leasing, or giving.
(2) Deleterious substances (Article 44 of the Biological products and specified biological
Law). products are specified by the Minister of Health,
(3) Drugs requiring a prescription (Article 49 of Labour and Welfare in its Ordinance No. 209
the Law). issued in 2003 and Notification No. 0520001 of the
PMSB dated May 20, 2003 that came into effect on
(4) Habit-forming drugs (Article 50 of the
July 30, 2003.
Law).
Based on the provisions in the Pharmaceutical
(5) Drugs for specially designated diseases
and Medical Device Act for biological products and
(Article 67 of the Law).
specified biological products, the “Manufacturing
(6) Narcotics (Narcotics and Psychotropics Supervisors and Import and Marketing Supervisors
Control Law). for Biological Products,” “Labeling on the Immediate
(7) Psychotropic drugs (Narcotics and Container or Packaging,” “Entries in the Package
Psychotropics Control Law). Inserts (Notification No. 0515005 of the PMSB
(8) Opium (Opium Law). dated May 15, 2003),” ”Periodic Infection Reporting
System (Notification No. 0515008 of the PMSB
(9) Cannabis (Cannabis Control Law).
dated May 15, 2003),” ”Records and Their
(10) Stimulants (Stimulant Control Law).
Retention,” “Outsourcing of Records and Their
3) Biological products and specified biological Retention,” “Dissemination of Information,” and
products “Manufacturing Control and Quality Control” are
Biological products were classified as follows specified in Notification No. 0515017 of the PMSB
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dated May 15, 2003 and Notification No. 0520004 business for drugs, medical devices and cellular and
of the PMSB dated May 20, 2003, etc. tissue-based products, etc. must obtain a
manufacturing/marketing business license of the
4) Regenerative medicine products
prefectural governor depending on the type of
The Pharmaceutical and Medical Device Act
business.
specifies a new definition for cellular and
These licenses are of the following nine types.
tissue-based products to be distinguished from
“drugs” and “medical devices”. These are (1) Type 1 drug manufacturing/marketing
specifically defined as products derived from business license: Marketing of prescription
human cells via cultures, etc., to be used for (1) drugs (Article 12 of the Law)
reconstruction, repair or formulation of structure or (2) Type 2 drug manufacturing/marketing
function of the body and (2) treatment or prevention business license: Marketing of drugs other
of disease, or to be induced into human cells for than prescription drugs (Article 12 of the
gene therapy. Law)
The basic technical requirements to assure the (3) Quasi-drug manufacturing/marketing
quality and safety of drugs and medical devices business license: Marketing of quasi-drugs
processed from human-derived (autologous) cells (Article 12 of the Law)
and tissues are specified on February 8, 2008
(4) Cosmetic drug manufacturing/marketing
(Notification No. 0208003 of the PFSB). On
business license: Marketing of cosmetics
March 27, 2008, the manufacturing control and
(Article 12 of the Law)
quality control of drugs and medical devices
(5) Type 1 medical device
processed from human-derived (autologous) cells
manufacturing/marketing business license:
and tissues (Notification No. 0327027 of the
Marketing of specially controlled medical
Compliance and Narcotics Division, PFSB) was
devices (Article 23-2 of the Law)
issued. The basic technical requirements to
assure the quality and safety of drugs and medical (6) Type 2 medical device
devices processed from human-derived manufacturing/marketing business license:
(homologous) cells and tissues are specified on Marketing of controlled medical devices
September 12, 2008 (Notification No. 0912006 of (Article 23-2 of the Law)
the PFSB). In addition, separate notifications were (7) Type 3 medical device
issued specifying the basic technical requirements manufacturing/marketing business license:
to assure the quality and safety of human-derived Marketing of general medical devices
(autologous) somatic stem cells, human-derived (Article 23-2 of the Law)
(homologous) somatic stem cells, human-derived (8) Manufacturing/marketing business license
(autologous) iPS (-like) cells, human-derived of in vitro diagnostics: Marketing of in vitro
(homologous) iPS (-like) cells, and human-derived diagnostics (Article 23-2 of the Law)
ES cells, (Notification Nos. 0907-(2) to (6) of the
(9) Manufacturing/marketing business license
PFSB dated September 7, 2012).
of cellular and tissue-based products:
Marketing of cellular and tissue-based
3.3 License for Manufacturing/Marketing products (Article 23-20 of the Law)
Businesses
The licensing requirements for drug
A person wishing to start manufacturing/marketing manufacturing/marketing businesses include the
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appointment of a general marketing compliance 3.4 License for Manufacturing Business and
officer of drugs, etc., who is a pharmacist, and Accreditation of Overseas
compliance with Good Quality Practice (GQP) for Manufacturers
quality control and Good Vigilance Practice (GVP) for
1) Licenses for manufacturing businesses
postmarketing safety surveillance.
A person wishing to start manufacturing business
The licensing requirements for
for drugs, quasi-drugs or cosmetics is required to
manufacturing/marketing businesses of medical
comply with the Regulations for Buildings and
devices include the appointment of a general
Equipment of Pharmacies, etc., that specify standards
marketing compliance officer of medical devices, etc.,
for structures and equipment in manufacturing plants
and compliance with the standards of manufacturing
for each manufacturing category specified by the
management and Quality Management System
applicable Ministerial ordinance and must obtain a
(QMS) and Good Vigilance Practice (GVP) for
manufacturing business license for individual
postmarketing safety surveillance. The licensing
manufacturing categories from the prefectural
requirements for manufacturing/marketing
governor. These licenses are of the following five
businesses of cellular and tissue-based products
categories:
include the appointment of a general marketing
(1) Category of biological products
compliance officer, and compliance with the Good
Quality Practice (GQP) for quality control and Good (2) Category of radioactive products
Vigilance Practice (GVP) for postmarketing safety (3) Category of sterile products
surveillance. (4) General category of products
Manufacturing/marketing business license is valid
(5) Category of packaging, labeling and
for a period of 5 years after every renewal.
storage
The general drug marketing compliance officer,
Manufacturing business license is valid for a
the quality assurance supervisor of the quality
period of 5 years after every renewal.
assurance unit in charge of GQP, and the safety
A person wishing to start manufacturing business
management supervisor of the general safety
for cellular and tissue-based products is required to
management division in charge of GVP are known as
comply with the Regulations for Buildings and
the “manufacturing/marketing triumvirate” and are at
Equipment of Pharmacies, etc., and must obtain a
the center of the marketing system. Appropriate
manufacturing business license for cellular and
implementation of the activities of the triumvirate is
tissue-based products in each manufacturing plant
required for the manufacturing/marketing business
from the prefectural governor.
license holder, and a notification covering the points to
After enforcement of the Law for Partial
consider to clarify the position and requirements of a
Amendment of the Pharmaceutical Affairs Law in
general drug marketing compliance officer as well as
November 2014, registration is required for
the chain of command, roles and authority of the
manufacturing business of medical devices and
triumvirate, to ensure the human resources
extracorporeal diagnostic medicines, instead of
necessary for notifying them in the company and
previously required business licenses. Each
carrying out the activities, and to conduct quality
manufacturing plant is required to register its
management activities and safety assurance
manufacturing business.
activities, etc. was issued (Notification No. 0626-(3) of
the PSEHB dated June 26, 2017). 2) Accreditation of manufacturing business of
overseas manufacturers
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manufacturing plant required for accreditation of The approval and licensing system has been
overseas manufacturers and attached revised in the amended Law and manufacturing
documentation (import) approvals became marketing approvals from
- The outline of the structure and facilities of April 2005. Product licenses have been abolished
the manufacturing plant should be based on and compliance with the criteria in GMP for each
that in the manufacturing business license product has been specified as an approval condition.
application in Japan. A list of the structures Marketing approvals require a review to determine
and facilities must be included. whether or not the product in the application is
suitable as a drug to be marketed by the marketing
- When Japanese cannot be used as the
authorization holder and confirmation that the product
language in the attached documentation
has been manufactured in a plant compliant with the
under special circumstances, a foreign
criteria in GMP.
language can be used, but a Japanese
Approval items specified in the approval certificate
translation must be attached in such cases.
are as follows: When a change is made on approval
If the foreign language is not English,
items except for brand name, a partial change
certification of the translator must be
application or slight modification notification has to be
attached.
submitted.
- For executive officers, if a corporation, prima
Brand name
facie documents should be submitted to
Ingredients and quantities, or nature
assure that they are not affected by
Manufacturing process
psychosomatic disorder or intoxicated with
Dosage and administration
narcotics, cannabinoids, opium or
Indications
psychostimulants (Article 35-2 of the
Storage condition and shelf life
Enforcement Regulations).
Specifications and testing methods
(4) On-site surveys for accreditation of overseas Manufacturing plant of item to be marketed
manufacturers Manufacturing plant of the drug substance
When a GMP compliance survey is performed
simultaneously with the accreditation, the 3.6 Good Manufacturing Practice (GMP)
structures and facilities are required for
accreditation to be confirmed in the GMP In manufacturing plants with manufacturing
compliance survey, as a rule. business license or overseas manufacturer
accredication, compliance with the criteria in GMP
3.5 Manufacturing/Marketing Approvals that specifies standards for structures and equipment
required for the product concerned as well as
Formal approvals are required for individual standards for manufacturing control and quality
formulations of drugs in order to market the drugs in control for each manufactured product is a condition
Japan. Formal approval must be obtained prior to for approval of the drug concerned (refer to Chapter
market launch from the Minister of the MHLW 3).
(prefectural governor for non-prescription drugs for In consideration of the characteristics of clinical
which approval standards are established) by trials including the early exploratory stage, the GMP
submitting data and documents for required review on for investigational products was amended on July 9,
product quality, efficacy, and safety. 2008 to make it possible to assure the quality of the
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Pharmaceutical Regulations in Japan:
investigational product at each stage of the clinical trial Items that may be registered through the MF
(Notification No. 0709002 of the PFSB). Thereafter, system are drug substances, intermediates, and
Q&A on the GMP for Investigational Products was additives, nevertheless raw materials of regenerative
published (Office Communication of the Inspection medicine products (e.g., cells, media, medium
and Guidance Division, Narcotics Division, PFSB additives or processing materials of cells) may also be
dated July 2, 2009). registered through the system.
MHLW, PMDA, and prefectures had submitted bid When an overseas drug substance manufacturer
for membership to the office of Pharmaceutical submits an MF registration application, it is necessary
Inspection Cooperation Scheme (PIC/S) in March to appoint a drug substance in-country caretaker to
2012, which guarantees a high level of the handle the activities of the MF registrant in Japan (MF
implementation of the internationally recognized GMP in-country caretaker). The MF in-country caretaker
rules, to further promote international standardization mediates communication between the MF registrant
and conformity in GMP inspection, and then became and the manufacturer or Japanese regulatory
members since July 1, 2014. The enforcement authority.
notification of the GMP was amended accordingly in When the registered contents of the MF are
August 2013 to meet criteria in the PIC/S. (Notification changed, an application to change the MF or a minor
No. 0830-(1) of the Compliance and Narcotics MF modification notification must be submitted.
Division dated August 30, 2013.) When an application to change of the MF is
submitted, the manufacturing/marketing authorization
3.7 Drug Master File (MF) holder also must submit a partial change application
or a slight modification notification for the MF
With the amendment of the Pharmaceutical Affairs
depending on the contents of the change. When a
Law enforced in April 2005, approvals for drug
minor MF modification notification is submitted,
substances that had been necessary in the past were
however, a procedure for changing the approval
no longer required and instead the information of
certificate is not required. In either case, the MF
quality and manufacturing method of drug substance
registrant must notify the manufacturing/marketing
are required to be included in the application
authorization holder of the change(s) in advance
document of finished product. The master file (MF)
through the MF in-country caretaker.
system aims at protecting intellectual property of the
Information of chemicals, drug substances, drug
manufacturer of drug substances, etc. from marketing
products, etc. registered under the MF system is
authorization houlders, etc. and facilitating review
publicly available at the following PMDA homepages.
work. Drug substance manufacturers, etc. (MF
http://www.pmda.go.jp/review-services/drug-reviews/
registrants) register the data on quality and the
master-files/0008.html
manufacturing method, etc. of drug substances, etc.
to be used in drug products with regulatory authorities
3.8 Drug Retail Seller Licensing
in the form of MF, thereby enabling applicants other
than MF registrants to quote the data in the approval A license must be obtained from the Prefectural
review (Notifications No. 1117-(3) of the Evaluation Governor or other specified officials for marketing or
and Licensing Division of PFSB and No. 1117-(1) of otherwise providing of drugs. Licenses for drug
the Director of Medical Devices Evaluation, retailers have been classified as follows based on
Evaluation and Licensing Division of PFSB dated amendment of the Pharmaceutical Affairs Law
November 17, 2014). MF registration is optional. enacted on June 1, 2009 (Law No. 69 dated from
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Pharmaceutical Regulations in Japan:
June 14, 2006): the PMSB dated May 15, 2003 and labeling on the
(1) Store-based drug sellers: Operations in immediate container or packaging of biological
which guidance-mandatory drugs or products is specified in Notification No. 0515017 of
non-prescription drugs are marketed or the PMSB dated May 15, 2003. These
provided at a store specifications came into effect from July 30, 2003.
According to the Pharmaceutical Affairs Law
(2) Drug sellers by household distribution:
amended on April 1, 2005, a new regulatory category
Operations in which non-prescription
for prescription drug labeling “Caution: Use only with a
drugs are marketed or provided through
prescription from a physician” and a labeling item for
distribution
manufacturer/marketing business instead of
(3) Drug sellers wholesale distribution:
manufacturer or importer were added.
Operations in which drugs are marketed or
The Law for Partial Amendment of the
provided to proprietors of pharmacy,
Pharmaceutical Affairs Law enforced on June 1, 2009
pharmaceutical manufacturing/marketing
(Law No. 69, June 14, 2006) mandates
authorization holders, manufacturers or
non-prescription drugs to be classified into one of type
distributors, or hospitals, clinics or other
1, type 2, and type 3 according to the risk and to bear
parties specified under the MHLW
a label indicating the type.
Ordinance
In addition, barcode labeling of prescription drugs
Marketing business license is valid for a period of (excluding extracorporeal diagnostic medicines) was
6 years. partially mandated in July 2015 to prevent medical
At pharmacies and store-based drug sellers, accidents due to misunderstandings, ensure
pharmacists can market guidance-mandatory drugs traceability, and improve the efficiency in prescription
or type 1 non-prescription drugs, and pharmacists or drug distribution (Notification No. 1 of the Economic
registered sellers can market type 2 and type 3 Affairs Division, HPB and No. 1 of the Safety Division,
non-prescription drugs.. PFSB both dated June 29, 2012). Moreover, it has
Non-prescription drugs may be marketed on the been requested to increase the range of essential
Internet since June 2014, only if these are also labeling, to take more rapid and reliable measures to
marketed in an actual store with an applicable identify and manage batch numbers, etc. in the
marketing business license. distribution process, and to carry out important
For drug sellers by wholesale distribution, a responsibilities in taking safety measures by April
pharmacist must be allocated to each sales office and 2021 (or by April 2023 in special circumstances)
thereby assigned to management of the office. (Notification No. 0830-(1) of the Economic Affairs
Division, HPB, Notification No. 0830-(1) of the Safety
3.9 Labeling and Package Inserts Division, PSEHB, and Notification No. 0830-(1) of the
Specified items must be entered on the immediate Compliance and Narcotics Division of PSEHB all
container of drugs. The package inserts must dated August 30, 2016)
contain indications, dosage/administration, Furthermore, preparation of medication guides for
precautions, and precautions for handling. In patients are being promoted so that the patient
addition, all ingredients used as excipients must be understands the prescription drug correctly, and
included. Entries in the package inserts of biological serious adverse drug reactions can be discovered at
products are specified in Notification No. 0515005 of an early stage (Notification No. 0630001 of the Safety
Division, PFSB dated June 30, and No. 0331-1 of the
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Pharmaceutical Regulations in Japan:
Safety Division, PFSB and No. 0331-8 of the to disseminate accurate information so that users
Compliance and Narcotics Division, PFSB both dated may use the drug, etc. properly. The standards
March 31, 2014). include interpretation of the Law about description of
In the revised Pharmaceutical Affairs Law enacted names, indications or dosage/administrations, etc. of
on November 25, 2014 (Law No. 84, November 27, the drug, etc. as well as matters to be adhered to
2013), the new package insert notification system otherwise misuse or abuse may be encouraged or
was introduced to enhance safety assurance confidence may be lost among general users
measures. Manufacturing/marketing authorization (Notification No. 0929(4) of the PSEHB dated
holders must prepare package inserts based on September 29, 2017, and Notification No. 0929(5) of
scientific knowledge and information obtained from the Compliance and Narcotics Division of PSEHB
latest literatures, etc. to provide related information. dated September 29, 2017).
Furthermore, before initiation of Appropriateness of advertisement of drugs shall
manufacturing/marketing or amendment, they must be judged based on the following requirements: the
submit to the PMDA the package insert that covers all advertisement clearly intend to attract customers
the required information such as precautions for use (enhances purchase motivation of customers); it
and handling. The package insert must be present the commercial name and class clearly such
published on the PMDA homepage immediately after as specified drug; and it be accessible to general
submission of the notification. public (Notification No. 148 of the Inspection and
The guidelines on preparation of package inserts Guidance Division, PMSB dated September 29,
have been revised into the guidelines which are 1998).
easier to understand and use. They will be applied With the increased awareness of the public
from April 1, 2019. The package inserts for the concerning health and the spread of the Internet,
drugs which have already been approved and the there have been cases of advertisement of
drugs for which application for approval has already unapproved drugs by persons acting as importers.
been filed as of this date must be revised as soon as Therefore, a notification has been issued concerning
possible according to the revised guidelines on guidance and control of individual importers including
preparation of package inserts by March 31, 2024 items related to drug advertising (Notification No.
(Notification No. 0608-(1) of the PSEHB dated June 8, 0828014 of the PMSB dated August 28, 2002).
2017) Furthermore, behaviors which are unlikely to leave
evidence (oral explanation, etc.), behaviors which are
3.10 Proper Advertisement not regarded as obviously false and deceptive but are
likely to facilitate inappropriate use, and behaviors to
The “Standards for Proper Advertisement of Drugs,
provide information for which it is difficult to
etc.” have been established for the purpose that
immediately detect involvement of the company and
advertisement of drugs, etc. should made properly
difficult to judge whether it should be regarded as
and should not include false information or
advertisement (such as research papers) are
exaggerated statement, so that harm caused by
conducted in activities to provide sales information on
drugs, etc. should be prevented in public health. The
prescription drugs, and their effects on the proper use
standards shall be applied to advertisements on all
of prescription drugs are concerned. Under such
media including newspapers, magazines, TV, radio,
circumstances, "Guidelines on Activities to Provide
website, and social network services. A person
Sales Information on Prescription Drugs" (Notification
intending to advertise drugs, etc. should make efforts
No. 0925-(1) of the PSEHB dated September 25,
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Pharmaceutical Regulations in Japan:
2018) was issued to improve public health by properly March 27, 1997) and Notification of the
conducting advertising or advertising-like behaviors in Pharmaceuticals and Cosmetics Division/Safety
the activities to provide sales information. Division, Pharmaceutical Affairs Bureau (Notification
No. 445 of PAB/PCD/Notification No. 68 of PAB/SD
3.11 Good Laboratory Practice (GLP) dated May 29, 1997).
Since then, standards intended to activate clinical
GLP specifies standards that must be met by
trials have been established for utilization of site
testing facilities for nonclinical safety tests on drugs
management organizations (SMOs), training of
from the viewpoint of the structure/equipment and the
clinical research coordinators (CRCs), and
operation/management of the facilities. The first
implementation of a site monitoring system. In 2003,
GLP guideline was issued as a PAB notification in
a system of investigator-initiated clinical trials was
1982, but was changed to a MHW ordinance on
officially introduced (Ministerial Ordinance No. 106
March 26, 1997 (Ordinance No. 21: GLP dated
dated June 12, 2003). Even after that, discussion
March 26, 1997) that was enforced on April 1, 1997 to
has been held for measures to ensure reliability of
assure greater reliability of application data.
clinical trials and safety of study subjects as well as
The GLP ordinance was partially revised by
smooth and transparent conduct of clinical studies.
MHLW Ordinance No. 114 entitled “MHLW
Consequently, the GCP has been often revised in
Ordinance to Partially Amend the MHLW Ordnance
addition to the ministerial ordinances and notifications
on Standards for Implementation of Nonclinical
for implementation.
Studies on Safety of Drugs” dated June 13, 2008 and
Other: Enforcement Notification of major changes
the amendment was enacted on August 15, 2008.
in GCP Ordinance, etc.:
Notification No. 0620059 of the PMDA entitled
● 2006
“ Establishment of Guidelines for Drug GLP and
On receiving results of discussion from the MHLW
Medical Device GLP On-site Inspections” was issued
Council of Ideal Registration-Directed Clinical Trials,
on June 20, 2008 and partially amended on
the requirements for designating IRB members have
November 21, 2014 (Notification No. 1121005 of the
been relaxed as measures for securing the reliability
PMDA).
of the IRB and improving the functions of the IRB
(MHLW Ordinance No. 72 dated March 31, 2006).
3.12 Good Clinical Practice (GCP)
● 2007
”Clinical trials” refer to studies with the objective of In accordance with a report compiled by the
collecting data on clinical trial results from among the Council of Ideal Registration-Directed Clinical Trials,
data attached to drug approval application forms. In the Notification entitled “the Common Application
Japan, clinical trials are conducted in accordance with Form for Clinical Trial Notification” was jointly issued
the GCP which was implemented to assure scientific by the Research and Development Division of HPB
quality and reliability of clinical study data. This GCP (Notification No. 1221002 of the Research and
was replaced by the Standards for the Conduct of Development Division of HPB dated December 21,
Clinical Studies (MHW Ordinance No. 28, dated 2007; revised by Notification No. 0326-(1) of the
March 27, 1997) based on the ICH-GCP Guidelines Research and Development Division of HPB and
(E6) (see Chapter 3 for details). Operating Notification No. 0326-(1) of the Evaluation and
procedures of the implementation of the New GCP Licensing Division of PFSB dated March 26, 2013,
were issued as Notification of the Pharmaceutical and Notification No. 0710-(4) of the Research and
Affairs Bureau (Notification No. 430 of the PAB dated Development Division of HPB, Notification No.
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Pharmaceutical Regulations in Japan:
0710-(2) of the Pharmaceutical Evaluation Division, “the coordinating investigator” who submitted trial
PSEHB, and Notification No. 0710-(2) of the Medical notification to the regulatory body to “a person” who
Device Evaluation Division, PSEHB dated July 10, submitted trial notification to the regulatory body in
2018) was issued to reevaluate and rationalize the multicenter investigator-initiated trial.
type and scope of documents necessary for the ● 2016
conduct of clinical trials. The GCP Ordinance was revised on January 22,
● 2008 2016 according to the "Ministerial Ordinance to
The GCP ordinance (MHLW Ordinance No. 24 Partially Revise the Ordinance on Standards for
dated February 29, 2008) made public disclosure of Conduct of Clinical Trials (GCP)" (MHLW Ordinance
IRB review results in summary format compulsory. No. 9). The major points of revision were associated
Then, “the Registration of IRB Information (Request)” with the implementation of expanded trials (see 3.13
(Notification No. 1001013 of the Evaluation and Trial Conducted from a Compassionate Viewpoint
Licensing Division, PFSB dated October 1, 2008) was (expanded trial)).
issued to provide an environment for trial-related
people to easily access IRB information and to inform 3.13 Trial Conducted from a Compassionate
the public of such information. Viewpoint (expanded trial)
Further, limitations for selecting the IRB were
For “unapproved drugs and drugs of off-label use
reviewed and currently the director of medical
with high medical needs,” discussion was held on
institution is permitted to select the IRB from among
introduction of a program for enhanced access of
IRBs available inside and outside the institution
patients not eligible for ongoing trials of these drugs to
(MHLW Ordinance No. 24 dated February 29, 2008).
a trial (trial conducted from a compassionate
● 2011
viewpoint or expanded access trial), while the
Notifications for GCP operating procedures were
development and process for approval are continued.
revised to include changes in procedures made with
The program came into operation on January 25,
the intent of enhancing efficiency in the conduct of
2016 (Notification No. 0122-7 of the Evaluation and
clinical trials and the requirement of precision controls
Licensing Division, PSEHB, dated January 22, 2016).
in laboratory tests in global clinical trials, etc.
An expanded access trial is conducted after
● 2012
conduct of a trial at the final development phase in
The latest amendment to the GCP was a partial
Japan (pivotal trial) in which patients are highly likely
revision entitled “Ordinance for Partially Modifying the
to benefit from an unapproved drug or off-label use as
Pharmaceutical Affairs Law Enforcement Regulations,
expected, or while such trial is ongoing (after
Etc.” (the Ministerial Ordinance No. 161) issued on
completion of the enrollment). Applicable
December 28, 2012. The main objectives of the
investigational products have to be used for serious
amendment were to improve the efficiency of trial
life-threatening diseases for which no effective
procedures, accelerate trial processes, reduce burden
conventional treatment is available.
on study personnel in investigator-initiated trials, and
To enforce expanded access trials, the GCP
promote industrial-academic cooperation in order to
Ordinance was revised (MHLW Ordinance No. 9
fulfill unmet medical needs while promoting global
dated January 22, 2016). More specifically, the
harmonization on the conduct of clinical trials.
revisions included: (1) a trial conducted from a
Specific points of revision included removal of trial
compassionate viewpoint is defined as an “expanded
parameters of low significance (e.g., target number of
access trial”; (2) a part of matters to be described on
subjects) from clinical trial contract and change from
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Pharmaceutical Regulations in Japan:
the investigational product are to be exempted if it is of the consideration, patient-requested therapy should
an investigational product used outside of Japan or a be considered.
commercially available approved drug; and (3) a drug
to be used in the expanded access trial is required to 3.15 Good Post-marketing Study Practice
be quarantined from the other drugs appropriately (GPSP)
(investigational product control/accountability)
The GPMSP ordinance was enacted to specify
(Notification No. 0122-2 of thePSEHB, dated January
the system and scope of activities of pharmaceutical
22, 2016).
companies to assure proper implementation of
Information on the clinical trials being conducted
post-marketing surveillance of drugs and reliability of
as pivotal trials and expanded access trials is placed
the data obtained after marketing. (Ordinance No.
on the homepage of the PMDA.
10 of the MHW dated March 10, 1997) Thereafter, the
http://www.pmda.go.jp/review-services/trials/0019.html
GPMSP was divided into Good Vigilance Practice
(GVP) and Good Post-marketing Study Practice
3.14 Patient-requested Therapy System
(GPSP). The GPSP ordinance was enforced from
This system was enforced in April 2016 to allow April 1, 2005. The ordinance was revised on
patients to receive an unapproved drug as an October 26, 2017 to add the "post-marketing
uninsured concomitant therapy at a local medical database survey" to the "drug use-results survey" and
institution as accessible to him or her as possible with the "post-marketing clinical study," which had been
the safety and efficacy being monitored. It is prescribed as the surveys to be conducted after
intended to collect data that may lead to application of marketing. The ordinance was enforced on April 1,
insurance and scientific evidences. 2018 (refer to Chapter 4).
Medical care potentially supported by the Data submitted with applications for reexamination
patient-requested therapy system is one that is or reevaluation must be collected and compiled in
expanded from “advanced medical care” under the accordance with the GPSP.
uninsured concomitant therapy expense system and
is intended to be covered by insurance in the future. 3.16 Reexamination
In addition, it has to be originated by the request from
Manufacturing/marketing authorization holders
a patient to the MHLW. If the medical care has not
must perform post-marketing surveys on new drugs
been used as a patient-requested therapy, a clinical
so that efficacy and safety can be reconfirmed by
research central hospital shall judge the feasibility,
reexamination by the MHLW for a specified period
and submit an application form to the MHLW with
after marketing approval.
attached documents such as protocol. If it has been
The drugs to be reexamined are the drugs which
used previously, a clinical central hospital shall review
have been designated by the Minister of Health,
the application, and judge whether it can be used or
Labour and Welfare at the time of marketing approval
not before the clinical use.
as the drugs obviously different from existing
When a patient requests for use of an unapproved
approved drugs in terms of active components,
drug that has been already used in clinical trials or in
contents, administration method, dose levels,
advanced medical care, firstly participation in a clinical
indications, and so on.
trial, and if there is no relevant clinical trial,
The concept of the risk management plan has
participation in advanced medical care should be
been incorporated in reexamination. At the same
considered. If no relevant trial can be found in spite
time, a notification regarding the documents to be
2019 - 28 -
Pharmaceutical Regulations in Japan:
attached to application for reexamination was revised expected from the investigator’s brochure of the
in 2017 to cope with the above-described revision of currently ongoing trial should be reported, whenever it
the GPSP ordinance (Notification No. 1128-(2) of the occurs. In addition, adverse drug reactions must be
Evaluation and Licensing Division, PSEHB, dated periodically reported through Development Safety
November 28, 2017). Update Report (DSUR) on an annual basis.
Refer to Designation for Reexamination in As of December 28, 1999, the use of the
Chapter 4 for the timing of reexamination. Japanese version of ICH MedDRA (MedDRA/J) was
In this connection, applications for generic drugs authorized for reporting of adverse drug reactions and
cannot be filed until completion of the reexamination. infectious diseases and its use was enforced on April
Branded products are protected from generics during 1, 2004 (Notification No. 0325001 of the Safety
this period. Division and Notification No. 0325032 of the
Evaluation and Licensing Division, PFSB dated
3.17 Reevaluation March 25, 2004).
Since October 27, 2003, electronic adverse drug
All drugs, including those that have completed
reaction reports have been accepted (Notification No.
reexamination must undergo reevaluation to recheck
0828010 of the PFSB dated August 28, 2003.). The
their efficacy, safety, and quality in accordance with
reports are required to be sent to the PMDA from April
progress in medical and pharmaceutical sciences.
1, 2004. (Notification No. 0325013 of PFSB dated
The Minister of Health, Labour and Welfare will
March 25, 2004)
hear the opinions of the Pharmaceutical Affairs and
Food Sanitation Council regarding the drugs to be
3.19 Risk Management Plan (RMP)
reevaluated, and publicly announce the drugs which
are judged to necessitate reevaluation. In public The basic requirement to ensure the safety of
announcement, the scope of the drugs to be drugs in clinical practice is to develop and implement
reevaluated, documents to be submitted, and due appropriate measures to manage potential risks of
date for submission of documents will be presented. drug-related events based on information collected
If necessary documents are not submitted before the during the development to post-marketing phases of
due date, the approval of the drug will be cancelled or a new drug’s life cycle. The Ministry issued the Risk
other necessary measures will be taken according to Management (RMP) Guidance (Notification No.
the provision in Article 74-2, Paragraph 3 of the Law. 0411-(1) of the Safety Division of PFSB and No.
0411-(2) of the Evaluation and Licensing Division of
3.18 Adverse Drug Reaction (ADR) and PFSB both dated April 11, 2012) to support the
Infection Reporting manufacturing/marketing authorization holder in
developing risk minimization plans for the reduction of
When manufacturing/marketing authorization
treatment-related risks in addition to conventional
holders of drugs are informed of any adverse
pharmacovigilance plans following drug approval.
reactions, infections, etc. as specified by MHLW
The RMP Guidance has applied to new drugs and
ordinance for trial products or their marketed products,
biosimilar products for which manufacturing/marketing
they must report them to the Minister within the
approval application is made on or after April 1, 2013
specified period (Notification No. 0317006 of the
and to generic drugs for which
PFSB dated March 17, 2005). Handling of safety
manufacturing/marketing approval application is
reporting is described in CHAPTER 4.
made on or after August 26, 2014.
Any serious adverse drug reaction that cannot be
2019 - 29 -
Pharmaceutical Regulations in Japan:
2019 - 30 -
Pharmaceutical Regulations in Japan:
Reaction Report Forms were revised by Notification it is anticipated that it will not be possible to obtain
No. 4 of the Federation of Pharmaceutical approval as specified by government ordinance by
Manufacturers' Associations of Japan (FPMAJ) dated the day before 6 months prior to the date on which the
January 6, 2004. Notification No. 0330011 of the patent expires, a document showing necessary
PMDA dated March 30, 2011 specifies points to information including the patent number must be
consider in the disclosure of information related to submitted to the Commissioner of Patents. If an
new drug approval reviews and subsequently issued application for an extension is submitted, it can be
Notification No. 0325-(1) of the Evaluation and considered that the patent term has been extended
Licensing Division, PFSB dated March 25, 2013 until rejection becomes final or the extension is
partially modified the procedures for public disclosure. registered (Fig. 4 Flowchart of Patent-Life
Review reports and summaries of data for Extension).
applications are placed in the homepage of the Generic drugs will not be approved until the
PMDA. substance (application) patent has expired. Branded
Japanese HP: products are protected from generics during this
http://www.pmda.go.jp/PmdaSearch/iyakuSearch/ period. However, in the past if some of the
English HP: indications or dosage and administration of branded
https://www.pmda.go.jp/english/review-services/revie products were patented, partial approvals were not
ws/approved-information/drugs/0001.html granted because of patent protection, but with
Notification No. 065001 of the Economic Affairs
3.22 Patent System Division, HPB and No. 0605014 of the Evaluation and
Licensing Division, PFSB dated June 5, 2009, partial
The patent term is 20 years from the time of
approvals of indications or dosage and administration
application as a rule. However, if the patent cannot
not covered by the patent are permitted.
be implemented because of laws and regulations to
Japanese HP of the Patent Office:
ensure safety of drugs and regenerative medicine
https://www.jpo.go.jp/index.html
products, etc. the patent term can be extended for a
English HP:
maximum of 5 years. The extension is for the period
https://www.jpo.go.jp/e/index.html
that the patented invention cannot be used, such as
the period from the date of the start of clinical trials
3.23 Drug Abuse Control
(submission date of clinical trial plan) or date of patent
registration, whichever is later, until one day prior to Japan has become signatory to the following three
the date on which the patentee receives approval for conventions: the Single Convention on Narcotic
the drug (For regenerative medicine products, the Drugs of 1961, the Convention on Psychotropic
term may be extended until acquisition of conditional Substances of 1971, and the United Nations
approval and the extension does not cover the Convention against Illicit Traffic in Narcotic Drugs and
subsequent period to acquisition of approval). Psychotropic Substances of 1988, and has ratified all
Patentees who want an extension of the patent of these conventions. In addition, Japan has
term must submit an application to the Patent Office enacted five laws of its own: the Narcotics and
for extension of registration including the required Psychotropics Control Law, the Opium Law, the
items such as the requested extension period before Cannabis Control Law, the Stimulants Control Law,
the patent rights become invalid within 3 months from and the Law Concerning Special Provisions for the
the date of receipt of drug approval. In cases where Narcotics and Psychotropics Control Law, etc., and
2019 - 31 -
Pharmaceutical Regulations in Japan:
Other Matters for the Prevention of Activities of the PSEHB dated February 18, 2016). On
Encouraging Illicit Conduct or Involving Controlled February 20, 2013, MHLW Ordinance No. 19 was
Substances through International Cooperation. revised and issued to implement comprehensive
June 26, the final day of the International Narcotics control of controlled drugs/substances.
Conference held in 1987, was designated as In the Law for Partial Amendment of the
“International Drug Abuse Eradication Day.” At a Pharmaceutical Affairs Law enacted on April 1, 2014
special United Nations meeting on narcotics in 1998, (Law No. 103 dated December 13, 2013), new
the “Declaration on Guidance to Prevent Drug Abuse” provisions have been added for possessing, using,
was adopted. purchasing and receiving such designated drugs.
The problem of drug abuse, including narcotics, Furthermore, in the Law for Partial Amendment of
stimulants, and hemp, has spread worldwide at the Law enacted on December 17, 2014 (Law No.
present and it is one of the most serious social 122 dated November 27, 2014), additional measures
problems affecting the human race not only in terms were established for prevention of public health risk
of survival but also as a threat to safe and stable caused by “dangerous illegal drugs”, i.e., the
societies and nations. Japan is now facing a serious inspection order and the sales-suspension order
situation of stimulant abuse with feelings of resistance should apply more widely, goods subjected to the
and alarm concerning drug abuse waning among sales-suspension order must not be sold in a wide
young people such as middle and high school area, and advertisement should be restricted more
students. strictly.
One aim of the Law for Partial Amendment of the In August 2018, the Fifth Five-Year Drug Abuse
Pharmaceutical Affairs Law (Law No. 69) issued on Prevention Strategy was formulated to reinforce the
June 14, 2006 was to strengthen control of measures for coping with smuggling, to intensify the
“dangerous drugs” because such drugs are being counter measures for smuggling crimes which are
sold in a disguised form suggesting they are not becoming more and more shrewd and latent, to cope
intended for human consumption even though they with the drugs which are not regulated in Japan or the
can cause health damage due to abuse and risk drugs which are used in different forms, and to carry
leading to the use of other illegal drugs such as out monitoring and crackdown to prevent vicious
narcotics and stimulants. crimes improperly using psychotropic drug.
Measures for the regulation of designated drugs
(drugs with a high probability of such actions as 3.24 Countermeasures for Counterfeit
excitation of the central nervous system that present a Prescription Drug
risk to public health and hygiene) have been added to
Safety, stability, and efficiency are required in
the Pharmaceutical and Medical Device Act as
distribution of drugs because shortage of the products
countermeasures against “dangerous illegal drugs”.
can directly endanger life. Under such circumstances,
In particular, importing, manufacturing, marketing,
it was found in 2017 that a counterfeit drug was
giving and storing for selling, etc. of such designated
distributed and dispensed at a pharmacy. In response
drugs with intended use other than healthcare have
to this event, "Ordinance for Partially Modifying the
been prohibited (MHLW Ordinance No. 14 dated
Enforcement Regulations for the Law for Ensuring
February 28, 2007). On February 28, 2007, the
Quality, Efficacy, and Safety of Drugs and Medical
Guidelines on Monitoring of Import of Designated
Devices" (MHLW Ordinance No. 106 of 2017),
Drugs were issued (Notification No. 0228009 of the
"Ordinance for Partially Modifying Regulations for
PFSB, partially amended by Notification No, 0218-5
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Pharmaceutical Regulations in Japan:
Buildings and Equipment of Pharmacies, etc." manufacturing control and quality control standards.
(MHLW Ordinance No. 107 of 2017), and "Ordinance Marketing approval is granted to products meeting
for Partially Modifying the Ministerial Order to these standards. This approval system is the
Determine the System for Pharmacies, Store-Based essential basis for ensuring good quality, efficacy, and
Distribution, and Household Distribution" (MHLW safety of drugs and related products, which is the
Ordinance No. 108 of 2017) were promulgated on principal objective of the Pharmaceutical and Medical
October 5, 2017 and enforced on January 31, 2018 (a Device Act.
part of them on July 31, 2018) to take necessary
measures for the matters which need to be coped 4.2 Marketing Approval Reviews
with immediately to prevent distribution of the
The entire process of approval review from
counterfeit drug. At the same time, "Handling of
review-related inspections and clinical trial
Sealing of Drugs" (Notification No. 0801-(1) of the
consultation to review works for the drugs approved
PSEHB dated August 1, 2018) was issued from the
by the Minister of Health, Labour and Welfare is
point of view of prevention, etc. of recurrence of
undertaken by the PMDA.
distribution of counterfeit drugs, etc., and "Guidelines
Application forms for approval to market drugs are
on Good Distribution Practice (GDP)" (Office
usually submitted to the PMDA. When application
communication dated December 28, 2018) was
forms for new drugs are received by the PMDA, a
formulated in the Health , Labour and Welfare Policy
compliance review of the application data (certification
Research.
from source data), GCP on-site inspection, and
detailed review are undertaken by review teams of
4. MARKETING APPROVALS the PMDA and the team prepares a review report.
The approval review process consists of expert
4.1 Drug Marketing Approvals meetings of review team members and experts to
discuss important problems. A general review
Drug marketing approval refers to governmental
conference attended by team members, experts and
permission for a drug with the quality, efficacy, and
representatives of the applicant is held after the expert
safety or a drug that is manufactured by a method in
meeting.
compliance with manufacturing control and quality
The ordinary evaluation process followed by the
control standards based on an appropriate quality and
PMDA is as follows (see the PMDA homepage). The
safety management system, generally distributed,
applicant can confirm the status of review progress for
and used for healthcare in Japan. Whether or not a
each product applied for with the manager of the
substance under application is appropriate for human
PMDA review team (Notification No. 1227001 of the
health care is objectively determined in light of state of
PMDA dated December 27, 2010, Notification No.
the art medical and pharmaceutical technology.
1003001 of the PMDA dated October 3, 2016).
Specifically, the Minister or (prefectural governor for
http://www.pmda.go.jp/review-services/drug-revi
non-prescription drugs for which approval standards
ews/0001.html
are established) reviews the name, quality, dosage
(1) Interview (presentation, inquiries, and
and administration, indications, ADRs, etc. of the
replies)
product in an application submitted by a person with a
(2) Team review
marketing business license. A GMP compliance
(3) Inquiries and replies
review is performed to assure that the plant
(4) Application for GMP inspection (until 6
manufacturing the product complies with the
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Pharmaceutical Regulations in Japan:
months before the anticipated date of (3) Drugs with new routes of administration
approval) (4) Drugs with new indications
(5) Review report (1)
(5) Prescription drugs with new dosage forms
(6) Expert review meeting (includes at least
(6) Drugs with new dosages
three clinical specialists as experts)
(7) Review report (2) (7) Biosimilar Products
(8) Report to the Pharmaceutical Evaluation (8) Prescription drugs with additional dosage
and Licensing Division, PFSB forms
The PAFSC is then consulted for discussions by (9) Prescription combination drugs with similar
the related committees and the Pharmaceutical formulations
Affairs Committee as required on the basis of the
(10) Other prescription drugs
review report. After the report of the PAFSC report is
With the agreement reached on the common
obtained and it is confirmed that the standards are
technical document (CTD) guidelines of the
met in a separate GMP compliance review, the
International Conference on Harmonization (ICH),
Minister grants the new drug
new guidelines for preparation of approval application
manufacturing/marketing approval (Fig. 5 Flowchart
data were issued (Notification No. 899 of the
of Approval Review). “Information Concerning New
Evaluation and Licensing Division, PMSB dated June
Drug Approval” prepared from the review data is
21, 2001). Applications using the CTD became
placed on the homepage of the PMDA so that
obligatory for new products in applications filed on or
accurate information concerning the quality, efficacy,
after July 1, 2003.
and safety obtained during the approval review
These guidelines consist of five parts: Module 1
process is supplied to medical institutions, etc.
(Regulatory Information Such as Application Forms
In reviews of new drugs prepared from vaccine or
and Information Concerning Attached
blood, the specifications and test methods are
Documentation), Module 2 (Data Summary), Module
examined on site by the National Institute of Infectious
3 (Data on Quality), Module 4 (Nonclinical Study
Diseases prior to approval, as necessary.
Reports), and Module 5 (Clinical Study Reports).
When active ingredients, dosage, administration
Modules 2 to 5 should be prepared on the basis of the
route, and indications are the same as those of
CTD guidelines. Part 1 consists of documents
approved drugs (so-called “generic drugs”), a review
requested by each regulatory authority. Detailed
by the PMDA is undertaken after reviews on drug
standards are shown in the Appendix (organization
equivalence and compliance, and approval is
and format) of the CTD guidelines.
granted.
For the generic products, their application has
A basic notification concerning drug approval
come to require submission of CTD, in principle, since
reviews was issued on April 8, 1999 and came into
March 1, 2017 (Notification No. 0311-3 of the
force for approval reviews of drugs from April 1, 2000.
Evaluation and Licensing Division, PSEHB dated
Later, following repeated revisions and with the
March 11, 2016).
enactment of the Pharmaceutical and Medical Device
Regarding the total review time for new drugs, it
Act, “On Drug Approval Applications” (PFSB
was decided to raise the percentile of the standard
Notification No. 1121-(2) dated November 21, 2014)
total review time in stages starting from FY2014,
was issued. The current categories are as follows:
aiming to reach a review time of 9 months for priority
(1) Drugs containing new active ingredients
review products and 12 months for ordinary review
(2) New prescription combination drugs
2019 - 34 -
Pharmaceutical Regulations in Japan:
products at 80th percentile by FY2018. In view of this, For products for which marketing application will be
“On the Handling of Approval Applications for made since October 1, 2016, clinical trial data should
Improvement of the Predictability, etc. of New Drug be submitted in accordance with the specifications in
Approvals and Approach to Total Review Time” the Clinical Data Interchange Standards Consortium
Notification No. 1006-(1) of PFSB and Notification No. (the CDISC standards), so that PMDA itself may
1006-(1) of Compliance and Narcotics Division dated proceed with analyses or investigation with clinical
October 6, 2014” was issued, setting out the policy of data, etc. and establishment of more reasonable and
conducting preliminary interviews for planned reviews efficient evaluation and assessment process in review
and indicating procedures, etc. for contacting and consultation.
applicants in case of difficult approval reviews, with a When clinical study data are submitted as
view to improving the predictability of reviews and the electronic data at the time of application for approval,
transparency of the review process. A timeline for the a consultation with PMDA should be held in advance
standard process of new drug approval reviews was to check submission of the electronic data for
also indicated (Administrative Notice of the Evaluation application. The consultation will cover the contents of
and Licensing Division dated January 30, 2015). On the electronic data to be submitted (including the
April 17, 2008, “Points to Consider for Reviewers specification, etc., definition file, and the program for
Related to New Drug Approval Review Work” was preparation of data set). As a rule, final confirmation
issued. This showed the basic conditions related to with PMDA regarding the scope of the electronic data
new drug review activities in the PMDA and was to be submitted is made in a preliminary interview for
intended to clarify the main points to consider in planned reviews for approval of a new drug
reviews and to assure uniform awareness of PMDA (Attachment to Notification No. 0427-(1) issued by
reviewers concerning review work. Office of Next Generation Review System, PMDA
Japanese HP: dated April 27, 2015).
http://www.pmda.go.jp/review-services/outline/0002.h In line with submission of electronic data of clinical
tml studies, application documents are required to be
English HP: submitted in the form of eCTD. (Notification No.
http://www.pmda.go.jp/english/review-services/review 0620-(6) of the Evaluation and Licensing Division,
s/0001.html PFSB dated June 20, 2014)
Documents for manufacturing/marketing approval
4.3 Manufacturing/Marketing Approval application are to be submitted via gateway system, in
Application with Electronic Data principle, to improve efficiency of information
processing between the applicant and PMDA, share
The specifications of the electronic CTD (eCTD)
information between them, and manage progress of
have been published for electronic application
review-related paperwork. (the conventional
documents submitted since April 1, 2005.
submission will be accepted by March 31, 2020)
(Notification No. 0527-(4) of the Evaluation and
(Notification No. 0427-(1) of the Evaluation and
Licensing Division, PFSB) (Partially modified by
Licensing Division, PFSB dated April 27, 2015)
Notification No. 0825-(1) of the Evaluation and
Licensing Division, PFSB dated August 25, 2008, and
Notification No. 0707-(3) of the Evaluation and
Licensing Division, PFSB dated July 7, 2009).
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Pharmaceutical Regulations in Japan:
4.4 Priority Review System and Designation (2) Designation of drug products for priority
of Drug Products for Priority Reviews reviews
1) Priority review system When drugs are designated for priority reviews,
Drug approval reviews are normally processed in opinions of experts on such designations are
the order that the application forms are received, but compiled by the PMDA immediately after the
for drugs designated as orphan drugs, ones covered application and reported to the MHLW. Based on
by the SAKIGAKE Designation System and the other this report, the Pharmaceutical Evaluation Division
ones considered to be especially important from a decides whether or not to apply the priority review.
medical standpoint such as new drugs to treat serious The Pharmaceutical Evaluation Division notifies this
diseases, a decision must be made whether or not to decision to the applicant and the PMDA. The
specify an overall evaluation of (1) the seriousness of Pharmaceutical Evaluation Division reports this
the targeted disease and (2) the clinical usefulness, application to the next meeting of the review
as stipulated in Article 14-(7) of the Pharmaceutical committee concerned of the PAFSC and obtains
Affairs Law. This system is also applied to the drugs their approval. Products for priority review are
subjected to the Conditional Accelerated Approval given priority at each stage of the review process as
System. With this system, applications for specified much as possible. When products subject to
drugs are reviewed on a priority basis (Notification No. priority review are approved as new drugs, this fact
0122-(12) of the Evaluation and Licensing Division, is made public.
PSEHB / Notification No. 0122-(2) of the Medical 2) Review of products designated for priority
Device Evaluation Division entitled “Handling of interview advice
Priority Review” dated January 22, 2016). It is possible to obtain priority interview advice on
indications and other items concerning the products
(1) Priority review criteria
designated for priority interview advice. Orphan
(A) Seriousness of indicated diseases
drugs and drugs covered by the SAKIGAKE
(i) Diseases with important effects on Designation System are handled as the products
patient’s survival (fatal diseases) designated for priority interview advice. Consultation
(ii) Progressive and irreversible diseases regarding eligibility for the Conditional Accelerated
with marked effects on daily life Approval System for Pharmaceuticals will be
(iii) Other subjected to the products designated for priority
interview advice, but it will not apply if characteristics
(B) Overall assessment of therapeutic
of the disease and the results of clinical trials
usefulness
conducted suggest that the requirements for
(i) There is no existing method of
Conditional Accelerated Approval System for
treatment, prophylaxis, or diagnosis.
Pharmaceuticals are not satisfied.
(ii) Therapeutic usefulness with respect to
existing treatment
4.5 Restrictive Approval System
a) Standpoint of efficacy
The drugs to which this system applies are those
b) Standpoint of safety
used in emergencies to prevent the spread of
c) Standpoint of physical and mental
diseases that might have a major effect on the public
burden on the patient
health. It also applies to drugs for diseases for which
the drug concerned is the only method of treatment
2019 - 36 -
Pharmaceutical Regulations in Japan:
and which are marketed overseas. Such products 4.7 Drugs for Pediatric Use
may be granted a restrictive approval by the Minister
Drugs used in pediatric clinics are often
without going through ordinary approval review
considered as “therapeutic orphans” throughout the
procedures after hearing the opinion of the PAFSC
world because they are difficult to develop and are not
(Article 14-3 of the law).
provided with sufficient information. This also
applies in Japan and very few drug products are
4.6 Orphan Drugs indicated for pediatric use. The number of clinical
Policies to promote research and development on trials performed in children is not sufficient, the
orphan drugs were adopted in 1993, and a notification number of products that can be used for children is
was issued by the MHW concerning designation insufficient, and information contained in package
criteria and measures to promote research. The insert (dosage, efficacy, safety, etc.) in relation to
criteria for designation include less than 50,000 applications in children is also insufficient. Therefore,
patients (except for intractable diseases specified by “off-label use” of drugs basically intended for adults,
the national agency) indicated for the drug concerned use of in-hospital products without adequately verified
and excellent usefulness of the drug from the medical stability, and use of drugs for pediatric use obtained
standpoint. The designation is conducted after by individual import are common.
deliberation by PAFSC. At present, laws and regulations aimed at drug
Drugs designated as orphan drugs are entitled to development and direct promotion of information
certain priority measures such as financial aid, tax dissemination in the pediatric field such as those in
relief on research expenses, reduction of application the EU and United States do not exist in Japan.
and consultation expenses, guidance and advice, When clinical trials are planned for dose setting, etc.
priority interview advice, priority review, and extension in children during approval applications or after
of the reexamination period from the conventional 8 approval of drugs intended for use in children to
years to a maximum of 10 years for drugs. When a collect information on experience of use in pediatric
drug designated as an orphan drug has obtained a populations, the reexamination period can be now
marketing approval, new drug creation premium will extended for a set period not exceeding 10 years in
be applied at the time of calculation of drug price for consideration of the results of special drug use-results
the product. surveys or post-marketing clinical studies during the
A list of the products designated as orphan drugs reexamination period (Notification No. 1324 of the
is published on the homepage of the National PMSB dated December 27, 2000).
Institutes of Biomedical Innovation, Health and Guidance on Clinical studies on Drugs in Pediatric
Nutrition. Populations was issued as a guideline for
http://www.nibiohn.go.jp/en/activities/research-develo implementation of clinical studies in the pediatric
pment.html population (Notification No. 1334 of the Evaluation
A list of specified intractable diseases is available and Licensing Division, PMSB dated December 15,
on the homepage of MHLW. 2000). PMDA consultations include those on clinical
http://www.mhlw.go.jp/stf/seisakunitsuite/bunya/000 development of drug in pediatric populations and
0084783.html development of pediatric formulations.
A supplement was issued to supplement the
contents of the guidance, and to propose a new way
of thinking necessary for development of pediatric
2019 - 37 -
Pharmaceutical Regulations in Japan:
drugs (Notification No. 1227-5 of the Evaluation and 4.8 Unapproved Drugs and Drugs of
Licensing Division, PSEHB dated December 27, Off-label Use
2017).
In May 2010, “a List of Drugs for Which
Requests for the addition of indications by related
Developing Companies are Being Recruited or
academic societies can be handled by an application
Requests for Development Made” was issued based
for partial changes in approved items such as
on the results of discussions by the Special
indications or dosage/administration on the basis of
Committee on Unapproved Drugs and Drugs of
clinical studies or clinical results in accordance with
Off-label Use Urgently Required for Healthcare. As
notifications (No. 4 of the Research and Development
a result of the first recruitment, the development
Division, Health Policy Bureau and No. 104 of the
request was issued for 165 items, and the clinical
Evaluation and Licensing Division, PMSB dated
development of 20 unapproved items or those of
February 1, 1999), when the necessity of additional
off-label use requested for development was started.
indications in healthcare are confirmed and requests
In the second recruitment, the development request
to study are made by the Research and Development
was issued for 88 items, and the clinical development
Division of the Health Policy Bureau. This can also
of 15 unapproved items or those off-label use was
be applied to drugs intended for use in the pediatric
started in sequence one after the other. In the third
field. In these notifications, it states that whole or part
recruitment, the development request was issued for
of the clinical studies do not have to be performed
50 items, and developing companies were recruited
again and when the indications related to off-label use
for the 5 items. In the fourth recruitment, the
are public knowledge in medicine or pharmacology,
development request was issued for 10 items, and
this can be applied to judgments on whether or not to
developing companies were recruited for 2 items (the
approve indications.
latest version of the drug list is available at the
The Special Committee on Unapproved Drugs
following site). The fourth recruitment of requests for
was founded in December 2004 to study drugs not
unapproved or off-label use drugs was started in July
approved in Japan for which efficacy was established
2015, and requests have been received as needed.
and approvals granted in the West and perform
Recruitment is still ongoing. From July 2015 and
periodic surveys and scientific evaluations of requests
onward, not only development requests for
of academic societies and patients. Separately, in
unapproved drugs in Japan but also those for
March 2006, the Special Committee on Pediatric
unapproved drugs overseas are discussed.
Drug Treatment was established to collect and
Development of unapproved drugs and those of
evaluate evidence on the efficacy and safety of
off-label use in requests is discussed within the
unapproved pediatric drugs. Thereafter, both special
Scheme for prompt practical use of unapproved
committees were developmentally reorganized into a
drugs under the Packaging Strategy for World-first
new “Special Committee to Investigate Unapproved
Products (Strategy of Sakigake). (Notification No.
Drugs and Off-Label Use of Drugs Urgently Required
0701-2 of the Evaluation and Licensing Division,
for Healthcare” in February 2010. The committee
PFSB and Notification No. 0701-2 of the Research
started wide-ranging discussions on off-label drugs
and Development Division, HPB both dated July 1,
including unapproved drugs and pediatric drugs.
2015)
Contents of previous discussion meetings are
available on homepage of the MHLW.
2019 - 38 -
Pharmaceutical Regulations in Japan:
2019 - 39 -
Pharmaceutical Regulations in Japan:
2019 - 40 -
Pharmaceutical Regulations in Japan:
Promote the Application of Regenerative the efficacy and safety become a condition for
Medicine Including Cellular and approval. Medical information databases and
Tissue-Based Products for patient registries, etc. can be used for such surveys.
Commercialization (Approval with If it is appropriate to define the requirements for
Conditions and Time Limit) institutions, etc. from the point of view of ensuring
Following enforcement of the Law for Partial proper use of the drugs, implementation of the
Amendment of the Pharmaceutical Affairs Law (Law measures, etc., necessary for ensuring the
No. 84, November 27, 2013), a new approval system requirements may be included in the conditions for
was introduced for regenerative medicine: approval.
non-homogenous quality tissue-engineered medical The drugs covered by this system will be subject
products can be approved earlier than with the routine to the priority review.
approval system with conditions and time limit if they
are assumed to be effective and proven to be safe in 4.13 Guidelines for Promoting Optimal Use
humans. The applicant is required to verify the A drug with a new innovative mechanism of
efficacy and safety and resubmit the application within action may have obviously different pharmacological
seven years after the conditioned approval. actions or safety profiles as compared with existing
drugs. Thus, it is important that the drug is used at
4.12 Conditional Accelerated Approval medical institutions satisfying certain requirements
System for Pharmaceuticals and having the ability to promptly take necessary
measures for coping with any adverse drug
For the drugs for treating serious diseases which
reactions for a period until sufficient efficacy and
occur in a small number of patients and for which
safety information is accumulated. Therefore, it is
effective treatment methods are limited, a conditional
necessary to formulate the guidelines for promoting
accelerated approval system was established in
the optimal use at the same time with the reviews
which the results of confirmatory clinical trials are not
related to the approval for innovative drugs with new
required, but the conduct of necessary post-marketing
mechanisms of action from the point of view of
surveys, etc. is required as a condition for marketing
promoting the optimal use on the basis of the latest
approval. (Notification No. 1020(1) of Pharmaceutical
scientific findings with the aim of presenting the
Evaluation Division, PSEHB entitled "Implementation
requirements for the patients and medical
of conditional accelerated approval system for
institutions, etc. that are to use the drug as well as
pharmaceuticals" dated October 20, 2017).
the points to consider. (Notification No. 0915(1) of
The drugs to be subjected to this system must
Pharmaceutical Evaluation Division, PSEHB,
meet all of the following conditions from (i) to (iv).
Notification No. 0915(1) of Medical Economics
(i) The drug is indicated for serious diseases.
Division, HIB entitled "Handling of Guidelines for
(ii) The medical usefulness is high.
Promoting Optimal Use" dated September 15,
(iii) Confirmatory clinical trials are difficult to
2017).
conduct.
The drugs to be subjected to the guidelines must
(iv) The results of clinical trials, etc. other than
meet any of the following conditions from (i) to (iii).
confirmatory clinical trials suggest some
(i) The drugs that have a mechanism of action
efficacy and safety.
different from that of existing drugs
For the approval of the drugs subjected to this
available for treatment of the disease
system, surveys, etc. necessary for reconfirmation of
2019 - 41 -
Pharmaceutical Regulations in Japan:
(ii) The drugs that have the same mechanism dated March 4, 2009) were formulated in Japan.
of action as a drug which has already been "Biosimilar products" were established as a new
subjected to the guidelines application category for prescription drugs
(iii) The drugs that meet the condition (i) or (ii) (Notification No. 0304004 of the Evaluation and
and have already been subjected to the Licensing Division, PFSB dated March 4, 2009).
guidelines, and for which new indications Documents on points to consider in approval
are added applications (Notification No. 0304015 of the
Concerning the drugs falling under (i), eligibility Evaluation and Licensing Division, PFSB dated
for the target drug will be judged globally considering March 4, 2009) and handling of non-proprietary and
the following points. brand names (Notification No. 0304011 of the
The pharmacological action differs Evaluation and Licensing Division, PFSB dated
significantly from that of existing drugs. March 4, 2009, Notification No. 0214-(1) of the
The safety profile differs significantly from Evaluation and Licensing Division, PFSB, Office
that of existing drugs, and special communication dated February 14, 2013), and
precautions are required for the use. Questions and Answers on Policies to Verify the
The efficacy is significantly higher than that Quality, Efficacy, and Safety of Biosimilar Products
of existing drugs. (Office communication dated July 21, 2009, Office
The clinical positioning differs from that of communication dated March 31, and Office
existing drugs, and the drug may be usable communication dated December 15, 2015) were
for a wider range of patients. issued.
It may be possible to increase the users
through development for other diseases 4.15 Combination Products
(addition of indications, etc.).
A “combination product” is defined as a drug that
The guidelines for promoting the optimal use are
was approved to be manufactured/marketed with
available on the homephage of the PMDA.
other components including devices or equipments in
http://www.pmda.go.jp/review-services/drug-reviews/r
an integrated fashion. It would be categorized as a
eview-information/p-drugs/0028.html
medical device, if distributed alone. Handling of
combination products are specified in “Handling of
4.14 Biosimilar Products
Approval Application for Combination Products”
For biological products, it is difficult to prove the (Notification No. 1024-(2) of the Evaluation and
equivalence of active ingredients with those of Licensing Division, PFSB, Notification No. 1024-(1) of
existing drugs unlike with chemically synthesized the Director of Medical Devices Evaluation,
drugs, but with the advances made in technology, Evaluation and Licensing Division, PFSB, Notification
biosimilars (or follow-on biologics) have been No. 1024-(9) of the Safety Division, PFSB, and
developed in foreign countries as products with Notification No. 1024-(15) of the Compliance and
equivalence to and the same quality as existing Narcotics Division, PFSB, dated October 24, 2014)
biological products. WHO and major countries and has been applied since November 25, 2014.
established new legal systems and specified Subsequently, it was revised by Notification No.
technological policies. In March 2009, policies for 0915-(1) of the Pharmaceutical Evaluation Division,
the assurance of the quality, safety and efficacy of PSEHB / Notification No. 0915-(1) of the Medical
biosimilar products (Notification No. 0304007 of PFSB Device Evaluation Division, PSEHB / Notification No.
2019 - 42 -
Pharmaceutical Regulations in Japan:
0915-(3) of the Safety Division, PSEHB / Notification guidelines for drug approval applications issued on
No. 0915-(3) of the Compliance and Narcotics April 8, 1999.
Division of PSEHB dated September 15, 2016, and The main points of this deregulation included
Notification No. 1122-(4) of the Pharmaceutical cancellation of the requirement that the group had to
Evaluation Division, PSEHB / Notification No. include members with previous experience in
1122-(10) of the Medical Device Evaluation Division, receiving a new drug approval. Among the
PSEHB / Notification No. 1122-(7) of the Safety requirements for those preparing the data, it was
Division, PSEHB / Notification No. 1122-(4) of the previously required that when the codevelopment
Compliance and Narcotics Division of PSEHB dated group performed a clinical trial, group members had
November 22, 2016. After this revision, a medical to be joint sponsors of the trial, but currently other
device which cannot be separated from the drug and members in the group can use data in applications
which is generally referred to as a container according from clinical trials performed by any member of the
to the definition of the general term for the medical group.
device has come to be regarded as a container, and If clinical trials performed by other companies in
is no longer regarded as a combination product. the group meet certain requirements, data prepared
However, the category of the "prefilling syringe," by persons other than the applicant can be accepted
which used to be regarded as a container according as approval application data and reviews of
to the definition of general terms of medical devices, applications submitted by several members of the
was changed to an ordinary medical device. codevelopment group can apply the same application
Therefore, a "prefilled syringe product" will data. Requirements for data submitted for approval
continuously be handled as a combination product. applications have been simplified.
Though a combination product is deemed a drug,
when the device or equipment constituting the 4.17 Transfer of Marketing Approvals
product caused a defect, the
Marketing approvals can be transferred to legally
manufacturing/marketing authorization holder of the
authorized marketing authorization holders through
combination product should report the defect in
succession, merger, contracts, etc. provided that all
accordance with the defect reporting of medical
data and related information are transferred from the
devices. Handling of defect reporting is specified in
original approval holders.
“Reporting of Adverse Drug Reactions to Drugs, etc.”
Transfer of marketing approvals of products that
(Notification No. 1002-(20) of the PFSB, October 2,
have been marketed only for shorter than 1 year
2014).
since the approval is not accepted except for that due
to business merger. For transfer in association with
4.16 Codevelopment
disposition of the business unit, however, whether or
The objective of codevelopment is to reduce the not it is acceptable will be judged as an evaluation
risk of development of new drugs and to promote result of the individual content, if the specified
more efficient development. Codevelopment requirements are met. Consultation with the
regulations, including requirements for composition of regulatory authority to which the notification is to be
the codevelopment group and requirements for those submitted should be done in advance to obtain the
preparing the data, had been specified in the past, but acceptance (Office Communication from the
codevelopment was deregulated by the basic Evaluation and Licensing Division / Compliance and
Narcotics Division dated March 29, 2016).
2019 - 43 -
Pharmaceutical Regulations in Japan:
4.18 Approval Applications for Drugs Pharmaceutical and Food Safety Bureau in Charge of
Manufactured Overseas Certification Work). Export certificates on drugs,
quasi-drugs, etc, are issued using the specified format
Pharmaceutical manufacturers outside Japan can
via the PMDA. The notification of export
apply directly under their own name for marketing
certifications requires the applicant of certification to
approval if they perform the studies regarding quality,
inquire the Ministry of availability of certification in
efficacy, and safety required for the drugs they intend
advance, if the form of certificate designated by the
to export to Japan and undertake the necessary
requesting country is different from that specified in
procedures (Fig. 6 Procedure for manufacturing
the notification (Notification No. 1125-(12) of the
and marketing approval of drugs for overseas
PFSB dated November 25, 2014, Partial revision of
manufacturers in Japan). In such cases, the
Notification No. 1011-(1) of the PSEHB dated
overseas manufacturer appoints a marketing
October 1, 2015).
authorization holder in Japan among those that have
The certificates are also issued, when final
received a marketing business license of the type
products manufactured in an oversea plant are
corresponding to approved product. The appointed
exported to a third country (Notification No. 0604-(3)
marketing authorization holder takes measures
of the Evaluation and Licensing Division, PFSB dated
required to prevent the onset of health and
June 4, 2014).
hygiene-related hazards caused by the approved
In October 2013, the issue of GMP certificate
drug in Japan and can also undertake manufacturing
based on the mutual recognition system for drug
and marketing in Japan.
GMP (MRA) with the EU countries was terminated
and replaced with product registration in the
4.19 Issuing of Certificates for Exported
EudraGMDP database that was provided by the
Drugs by MHLW
European Medicines Agency (EMA) for aseptic
Upon request, the MHLW issues a certificate chemical pharmaceuticals (such as tablets, capsules,
indicating to the effect that a drug, quasi drug, or and external preparations). The countries to which
medical device to be exported has been the certification system is applied are required to be
manufactured in compliance with provisions of the those with which the mutual agreements for GMP
Pharmaceutical and Medical Device Act in the format were exchanged with Japan. In April 2016,
designated by the destination country requesting the Japan-Europe certification system became applicable
certificate. to all the EU countries (Notification No. 0426-3 of the
Currently, the MHLW issues the following Compliance and Narcotics Division of PSEHB dated
certificates upon request: business licenses for April 26, 2016). From July 17, 2018, the drugs
marketing and manufacturing of drugs, etc., subject to GMP mutual recognition system were
marketing approvals for drugs, etc., attached expanded to the drug substances (active ingredients),
documentation for new drug marketing applications, aseptic drugs, biological products including vaccines
GLP compliance for drugs, notifications of clinical trial (except for the products originating from the samples
for investigational products, certifications of collected from a large number of unspecified donors,
pharmaceutical formulations based on the WHO such as human blood, cells, and tissues), and most
certification system, statements of approval and drug products came to be covered. The contents to
licensing status of pharmaceutical products, and be certified are prepared and registered by the PMDA
GMP compliance for drugs, and GMP compliance for in the EudraGMDP database based on information
investigational drugs. (Table 2 Divisions of the submitted by the manufacturer. Registered
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
those expected to have high medical needs, preparation of the JP draft. The draft is reviewed
“first-in-class” drugs approved by priority review, those by the JP Expert Committee and then, after
with no alternative drugs available, and those already collecting public comments, by the Committee on
entered in the US Pharmacopoeia (USP) and JP. After the review and approval by the
European Pharmacopoeia (EP) and are globally in Committee on JP, public comments are collected
wide use. Approved drugs which are important from again and then listed in the JP (Fig. 7 Flowchart
the point of view of insurance and the drugs approved of Drug Listing in Japanese Pharmacopoeia).
as generic drugs are examined for entry as soon as
possible. New drugs to be approved in the future will 5.2 Standards Based on Article 42 of the
be entered after a certain period has passed after Pharmaceutical and Medical Device Ac
approval. For example, entry of such drugs will be
For drugs that require special precautions with
considered as soon as it becomes possible to collect
respect to public health and sanitation, several
a certain amount of information about quality, safety
necessary standards have been established
and efficacy.
concerning the methods of manufacture, properties,
• Date of enforcement
quality, storage methods, etc. based on Article 42 of
The 18th edition of the JP is expected to be the Law. The following standards exist at present:
enacted in April, 2021. Revision of Supplement Radiopharmaceutical Standards
and partial revision of the 17th edition of JP will be
Minimum Requirements for Biological Products
made as needed, considering the situation of
review, etc. Minimum Requirements for Blood Grouping
Antibodies
• The compilation review organization for
Standards for Biological Materials
the JP
Revisions of the JP had been initiated by the Standards for in vitro Diagnostics
Councils of the MHLW, but at present, the draft is
prepared by the PMDA’s JP Expert Committees 5.3 Standards for Biological Materials
and is approved by the MHLW’s Committee on The Standards for Biological Materials were
JP. The JP Expert Committees are headed by specified in Notice No. 210 issued by the MHLW in
the Expert Committee and include Committee on 2003 for quality and safety assurance of raw materials
Chemicals, Committee on Biologicals, etc. for a and packaging materials manufactured from
review of draft text. The committees may biological materials and used in the manufacturing
organize working groups to discuss and make process for drugs, quasi-drugs, cosmetics, and
recommendations on specific issues, as needed. medical devices based on the provisions of Article 42,
The technical research committees of the Paragraph 1 (Standards of Drugs, etc.) of the Law.
Kansai Pharmaceutical Manufacturers Association These standards including interim measures came
and Pharmaceutical Manufacturers Association of into effect from July 30, 2003. They consist of
Tokyo, and many other organizations every time General Notices, General Rules for Blood Products,
cooperate in preparation of new versions of the General Rules for Human-derived Biological
JP. Products, and General Rules for Animal-Derived
The draft JP monograph of a candidate item to Biological Products. The Standards for Cell and
be listed in the JP is first developed by the Tissue-Derived Drugs and Medical Devices were
applicant on the basis of the guidelines for abolished on July 29, 2003. With the specification of
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Pharmaceutical Regulations in Japan:
the Standards for Biological Materials, the Minimum materials used in the preparation of master cell banks
Requirements for Biological Products were partially or master seed banks that do not comply with the
revised by MHLW Notice No. 211 in 2003 and the specifications in the standards for raw materials of
General Rules for Blood Products were abolished by biological origin are specified in Office
the Minimum Requirements for Biological Products. Communication of the Evaluation and Licensing
Notice No. 262 issued by the MHLW on July 5, Division dated March 27, 2009.
2004 states that the standards for raw materials of In line with the revised Pharmaceutical Affairs Law
biological origin have been partially revised as enacted on November 25, 2014 (Law No. 84 dated
indicated below. These revisions, including interim November 27, 2013), the Standards for Biological
measures, came into effect on the day of notification. Materials were partially revised as for the standards
for human- or animal-derived materials to be used in
• Standards for raw materials of ruminant origin
drugs, medical devices or regenerative medicine
(1) The spine, skull, trigeminal ganglion, and
products, etc. based on reviews of such materials with
dorsal root ganglion of ruminants have
latest scientific knowledge and information (Notice
been added to the list of materials
No. 375 issued by MHLW of 2014. Gelatin
prohibited for use as raw materials in
(including collagen) derived from wool, milk, bone and
drugs, medical devices, quasi-drugs, and
skin was classified as “low-risk raw materials,” and the
cosmetics (hereafter drugs, medical
scope of countries of origin excepted from the
devices, etc.).
restriction was expanded. Previously, fatty acids,
(2) In conjunction with the confirmation of a
glycerin, fatty acid esters, amino acids, synthetic
cow infected with BSE in the United States
oligopeptides and materials processed by heat and
in December 2003, the United States was
alkali treatment were excluded from the scope of the
removed from the list of countries of origin
Standards for raw materials of ruminant origin. In
of raw materials originating from cows and
addition, with this notice, materials processed by
other ruminants that can be used as raw
appropriate treatment are to be excluded, such as
materials for drugs, medical devices, etc.
those that have been assessed to ensure the safety
(3) Gelatin and collagen used in drugs,
of the final products on the basis of clearance data of
medical devices, etc., which are
prion potentially present in raw materials.
manufactured from raw materials derived
from skin, have been removed from the list
of regulated items from countries of origin 5.4 Quality Standards Based on
with confirmed cases of BSE. Notifications
Based on Notice No. 310 of the MHLW dated In addition to quality standards specified on the
September 28, 2007, Chile was removed from the list basis of laws and ordinances, the quality
of countries of origin of raw materials originating from specifications have also been published as listed
cows and other ruminants. Based on Notice No. below based on notifications for administrative
343 of the MHLW dated July 1, 2009, the use of raw guidance.
materials of ruminant origin with Canada as the Japan Pharmaceutical Codex
country of origin was approved to be used within the Japan Crude Drug Codex
same range as that of materials from the United
Insecticide Standards
States as the country of origin.
Regulatory handling in application review of raw Standards for Raw Materials for in vitro
Diagnostics
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Pharmaceutical Regulations in Japan:
Japan Pharmaceutical Excipient Standards Improvement orders in cases where the buildings
Japan Standards of Quasi-drug Ingredients and equipment, etc. do not comply with
regulatory requirements
5.5 Government Batch Test
6.2 Product Recalls
Government supervision and certification based
on batch tests are specified for drugs that require A manufacturing/marketing authorization holder of
advanced and sophisticated manufacturing drugs or medical devices, etc. or a manufacturing
technology or testing methods. Such drugs are authorization holder of drugs or medical devices to be
tested in order to assure their quality in institutions exported, intending to recall its
designated by the MHLW, and the drugs cannot be manufactured/marketed or manufactured products
sold or otherwise marketed unless they pass these should report to the effect that it initiated recall, recall
tests (Article 43 of the Law). status, and to the effect that it has completed recall to
At present, a part of biological products is subject the prefectural governor. (Article 68-11 of the Law and
to such testing. The designated testing institution is Article 228-22 of the Regulation.)
the National Institute of Infectious Diseases. Such products should be recalled as having a
concern in safety or efficacy due to a failure or as
violating the Pharmaceutical and Medical Device Act
6. PHARMACEUTICAL SUPERVISION or approved condition, and all recall information is
6.1 Pharmaceutical Supervision published on the PMDA homepage by class as
below. Also depending on the class of the drug and
Based on the provisions of the Pharmaceuticals
whether or not it is exported overseas, a Rapid Alert
and Medical Devices Act, the Minister of the MHLW,
Notification of Quality Defect/Recall should be issued
prefectural governors, or other may appoint
to PIC/S member countries and countries of
"pharmaceutical inspectors" in connection with the
applicants, member companies of the European
rationalization of pharmaceutical manufacture, import,
Economic Area (EEA), cooperating global
labeling, advertisements or marketing. This
organization (World Health Organization; WHO), The
pharmaceutical inspection system covers falsely
European Directorate for the Quality of Medicines and
labeled drugs, drugs of poor quality, drugs that have
Healthcare (EDQM), and European Commission.
not been approved or licensed, and false or
Class I: Serious health damage or death may be
exaggerated advertising. Pharmaceutical inspectors
caused by use of the product.
perform on-site inspections as needed, and when
Class II: Transient or medically-curable health
violations are discovered, the inspectors may issue
damage may be caused by use of the
various orders including administrative measures.
product, or serious health damage may
The main measures are as follows:
not be caused by use of the product.
Revocation of approval or change orders in
Class III: Health damage may not be caused by
approved items
use of the product.
Revocation of licenses or business suspension
(Notification No. 1121-(10) of the PFSB dated
orders
November 21, 2014, partially revised by Notification
Temporary suspension of sales and disposal of No. 0208-(1) of the PSEHB dated February 8, 2018)
drugs, etc.
Recall orders 6.3 Prevention of Medical Accidents Caused
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
Patent
right 1
Patent
right 2
Patent Registration of Expiration
application establishment (20 years)
of patent right
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Pharmaceutical Regulations in Japan:
Special review
Review specialist and External expert
discussion II
(To be held as needed) Held after interview review.
Request for
withdrawal
Review report (2)
GMP compliance
survey results Review results
Notification of (Review result notification)
survey results
Approved/
Consultation
not approved
Minister of Health, Labour and Welfare Pharmaceutical Affairs and
Food Sanitation Council
Advice
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Pharmaceutical Regulations in Japan:
(3)
overseas
drugs manufactured
Restrictive approval of
Fig. 6 Procedure for manufacturing and marketing approval of drugs for overseas
manufacturers in Japan
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Pharmaceutical Regulations in Japan:
PMDA MHLW
Selection of candidate drug items for Doc preparation PAFSC’s review & entry in JP
entry
Committee’s review
Evaluation of
Letter of
request
Draft
Submission Submission Submission Reply Submission Reply
submission
Public comments
Public comments
confirmation
confirmation
Corrections
Draft after
Letter of
integrity
Items of
Candidate
Items of
request
Request
content
integrity
of draft
Reply
Draft
Draft
item
PMDA:
Division of
evaluation
Integrity
Standards
Approval Approval
Review by:
Committee Review Review Review
on Draft
Monograph
Public comments
Entry in JP
Review by Review by
PAFSC’s PAFSC’s
Approval
MHLW Committee Committee
on JP on JP
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
compliance with these standards are performed by At the time of the clinical trial protocol
the Pharmaceuticals and Medical Devices Agency notification, a system by which the PMDA reviews
(PMDA) at the request of the MHLW. the contents of the initial notification at the request
A flowchart from development to approval of of the MHLW is now specified by law, and a "clinical
new drugs is shown in Fig. 8 Flowchart of New trial consultation system" in which the PMDA gives
Drug Development and Approval. guidance and advice concerning study protocols
has also been established (refer to Section 1.4:
1.2 Procedures for Clinical Trials Interview Advice Meetings).
It is necessary to submit clinical trial (protocol)
For clinical studies (trials) to be conducted for
notifications in the following instances:
collection of data to be submitted in marketing
(1) Drugs with new active ingredients
approval application of a new drug, etc., the Law
(2) Drugs with new administration routes
and the GCP specified sponsor’s responsibility for
(excluding bioequivalence studies)
submitting a notification of the clinical trial plan in
(3) New combination drugs, drugs with new
advance and matters that a sponsor must comply
indications or new dosage and administration
with in requesting a medical institution to conduct a
(excluding bioequivalence studies)
clinical trial.
(4) Drugs containing the same active ingredients
Scope of GCP includes not only clinical trials in
with the drugs with new active ingredients, for
patients but also Phase I studies in healthy
which the reexamination period has not been
volunteers, bioequivalence studies in human,
completed yet (excluding bioequivalence
studies for additional indication of an approved drug
studies)
and post-marketing clinical trials after marketing.
(5) Drugs considered to be biological products
Furthermore, its partial amendment 2003 specifies
[excluding (1) to (4)] (excluding bioequivalence
investigator-initiated clinical trials as well.
studies)
According to the new GCP, when a clinical
(6) Drugs manufactured using gene recombinant
study is requested, a contract for clinical trials can
technology [excluding (1) to (5)] (excluding
be concluded only when 30 days have passed from
bioequivalence studies)
the initial notification of the study protocol is
The types of clinical trial protocol notifications
received by the PMDA (at least 2 weeks for
and documents to be submitted are shown below.
subsequent notifications, as a rule). The sponsor
(1) Clinical trial protocol notifications (when
must report to the authorities any severe adverse
notifications are first made for drugs with new
reactions or infections that occur during the study,
active ingredients or new routes of
and the authorities may undertake on-site
administration and new combination drugs,
inspections concerning GCP compliance in the
they must be submitted at least 31 days before
sponsor's facilities and the medical institution
the planned start date of the trial stated in the
performing the study when problems arise during
contract with the medical institution performing
the study. For drugs required in emergencies to
the clinical study. Otherwise, they must be
prevent diseases that have a major effect on the life
submitted at least 2 weeks before the planned
or health of the patient or to prevent other damage
date of the trial.)
to the health, clinical study protocols may be
a. Document that gives the reason why the
submitted within 30 days after the start of the study
request for the clinical study was judged to be
(MHLW Ordinance No. 89 dated May 15, 2003).
scientifically appropriate (from the 2nd
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
trial is required to include information concerning 227 of the Evaluation and Licensing Division, PAB
international clinical trials in the clinical trial dated March 20, 1995; ICH-E2A).
notification submitted on or after April 1, 2008 In the revision of the Enforcement Regulations
(Notification No. 0321001 of the Evaluation and of the Law in April 1997 for which the ICH
Licensing Division, PFSB dated March 21, 2008). guidelines served as a reference, the obligation to
Additionally, in view of a trend of development of report adverse reactions, etc. related to the
drugs with associated companion diagnostics investigational product, including those occurring in
relating to the individualized medicine, a sponsor is foreign countries, to the Minister was specified by
required to include whether a companion law. These provisions are outlined below.
diagnostics is being developed for the drug with its A: 7-Day reports (When either of the following
development status, if any, in the remarks in a events is suspected to be caused by an
clinical trial notification of a drug to be submitted adverse reaction of the investigational product
since February 1, 2014 (Notification No. 0701-(10) concerned or by an infection suspected of
of the Evaluation and Licensing Division, PFSB being caused by the investigational product
dated July 1, 2013). concerned, and the event is not expected
When the plan of a trial of a product deemed as a from the description in the investigator's
combination product at the time of marketing is brochure of the investigational product
submitted, a phrase, "trial of a combination product," concerned: the report must be made within 7
shall be stated on the space for remarks, and a plan days.)
of a clinical trial shall be submitted either as a drug, a) Death
device, processed cells, etc. (Notification No. b) Cases that might result in death
1024-(2) of the Evaluation and Licensing Division, B: 15-Day reports (For the following events: the
PFSB, Notification No. 1024-(1) of the Medical report must be made within 15 days.)
Devices Division, PFSB, Notification No. 1024-(9) of a) Any of the following events suspected to be
the Safety Division, PFSB, and Notification No. caused by an adverse reaction of the
1024-(15) of the Compliance and Narcotics Division, investigational product concerned or by an
PFSB all dated October 24, 2014, revised by infection suspected of being caused by the
Notification No. 1122-(4) of the Pharmaceutical investigational product concerned, which is
Evaluation Division, PSEHB, Notification of No. not expected from the description in the
1122-(10) of the Medical Device Evaluation Division, investigator's brochure of the investigational
PSEHB, Notification No. 1122-(7) of the Safety product concerned.
Division, PSEHB, and Notification No. 1122-(4) of the • Any case that requires hospitalization for
Compliance and Narcotics Division of PSEHB dated treatment or prolongs the duration of
November 22, 2016). hospitalization.
• Disability
1.3 Safety information on Adverse • Cases that might result in disability
Reactions and Infections during the • Other medically serious condition
Study • Congenital diseases or abnormalities in
the next generation
Safety information obtained during the study
b) Predicted deaths or events that might result
must be reported promptly, as is specified in
in death.
"Clinical Safety Data Management" (Notification No.
c) Measures related to safety problems of the
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Pharmaceutical Regulations in Japan:
investigational product concerned, including Notification No. 1122-(4) of the Compliance and
discontinuation of manufacture and/or Narcotics Division of PSEHB dated November 22,
marketing in a foreign country. 2016).
d) Research reports showing the possibility of
causing cancer or other serious diseases 1.4 Interview advice meetings
due to adverse reactions, etc. of the
The PMDA has established a consultation
investigational product concerned.
system for clinical study protocols to improve and
The Enforcement Regulation of the Law, which
reinforce the quality of clinical studies. The
was modified in February 2008 require the sponsor
consultations and review work have been united
to report to the MHLW cases of serious ADRs, etc.
under the same teams in the Review Department.
expected according to the IB periodically at 6-month
With the increasing demand for clinical trial
intervals. Later, this reporting period was changed
consultations, improvements have been made in
to 1-year intervals by further revising the
the quality of consultations with respect to
Enforcement Regulations (Ministerial Ordinance
preparation for consultations, implementation of
No. 161 entitled “Ordinance for Partially Modifying
consultations, preparation of records, etc. as
the Pharmaceutical Affairs Law Enforcement
measures to meet the demands for those
Regulations, etc.” dated December 28, 2012) to
requesting consultations (Notification No. 0302070
harmonize the period with relevant ICH guidelines.
of the PMDA dated March 2, 2012, partially revised
Basic standards for periodically reporting safety
on June 1, 2018). Main items of the interview
information during the development phase,
advice meeting handled by the PMDA are as
common to all drugs, etc., are available in
described below. Details of the consultation items,
“Development Safety Update Report (DSUR)”
the latest information on consultation fees, and
(Notification No. 1228-(1) of the Evaluation and
application procedures for interview advice meeting
Licensing Division, PFSB dated December 28,
are available at the following homepages of the
2012: ICH E2F)
PMDA.
Any manufacturer or marketing authorization
http://www.pmda.go.jp/review-services/f2f-pre/cons
holder who has submitted plan of a trial of a product
ultations/0007.html
deemed as a combination product at a market shall
Preparatory consultation is also available to
be obligated to report any malfunction of a part of
assure smooth interview advice.
device or equipment in the combination product as
(1) Clinical trial consultation
specified for malfunction reports of medical devices
• Consultations on procedures
(Notification No. 1024-(2) of the Evaluation and
• Consultations on bioequivalence studies
Licensing Division, PFSB, Notification No. 1024-(1)
• Consultations on safety
of the Medical Devices Division, PFSB, Notification
• Consultations on quality
No. 1024-(9) of the Safety Division, PFSB, and
• Consultations before start of Phase I studies
Notification No. 1024-(15) of the Compliance and
• Consultations before start of early Phase II
Narcotics Division, PFSB all dated October 24,
studies
2014, revised by Notification No. 1122-(4) of the
• Consultations before start of late Phase II
Pharmaceutical Evaluation Division, PSEHB,
studies
Notification of No. 1122-(10) of the Medical Device
• Consultations after completion of Phase II
Evaluation Division, PSEHB, Notification No.
studies
1122-(7) of the Safety Division, PSEHB, and
2019 - 61 -
Pharmaceutical Regulations in Japan:
• Consultations before license application the list of drug products for the designation of priority
• Consultations on plans of post-marketing review as the implementation of the SAKIGAKE
clinical studies of drugs, etc. designation system was started (Notification No.
• Consultation at completion of post-marketing 0122-(12) of the Evaluation and Licensing Division,
clinical studies of drugs, etc. PSEHB and Notification No. 0122-(2) of the Medical
• Additional consultations on drugs Device Evaluation Division, PSEHB dated January
• Consultations before start of expanded trials 22, 2016).
of drugs The consultation fee is different between the
(2) Consultations on preliminary assessment case of only priority assessment consultation and
of new drugs that in conjunction with the consultation before
Assessment of data in preparation for license license application.
application (preliminary assessment of data • Consultations on the applicability of priority
concerning the following areas planned to be review status
submitted for application in order to identify potential • Consultations on the applicability of priority
issues to be addressed during review): review status (consultation in conjunction with
• Quality that before license application)
• Nonclinical: Toxicology • Consultations on the applicability of conditional
• Nonclinical: Pharmacology accelerated approval status
• Nonclinical: Pharmacokinetics • Consultations on the applicability of conditional
• Phase I studies accelerated approval status (consultation in
• Phase II studies conjunction with that before license application)
• Phase II/III studies (4) Consultations on the applicability as
(3) Consultations on eligibility for priority pharmacogenomics markers or biomarkers
review and conditional accelerated • Assessment of applicability
approval for new drugs • Assessment of major aspects of clinical trial
In consultations on eligibility for priority review, design
eligibility for priority review is evaluated and a report • Additional consultation (on the applicability)
is prepared for new drugs other than the drugs • Additional consultation (on major aspects of
covered by the SAKIGAKE designation system or clinical trial design)
orphan drugs for which the applicant desires priority (5) Consultations on epidemiological surveys
review before application for approval. In • Consultations on the procedure of
consultations on eligibility for conditional epidemiological surveys of drugs
accelerated approval, eligibility for conditional • Consultations on the plan of epidemiological
accelerated approval is evaluated and a report is surveys of drugs
prepared for new drugs for which the applicant • Additional consultation on epidemiological
desires conditional accelerated approval before surveys of drugs
application for approval. (6) Consultations for preliminary confirmation
Procedures for handling priority review are of the revision of package inserts and
available in Notification No. 0901-(1) of the consultations on the revision of package
Evaluation and Licensing Division of PFSB dated inserts
September 1, 2011. Subsequently, the drugs (7) Consultations on generic drugs
subjected to SAKIGAKE designation were added to • Consultations on bioequivalence of generic
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
consultations," and individual consultations are held desires to use the system for changing approved
as "regulatory science general consultations." In matters using the Post-Approval Change
addition, guidance and advice for quality and safety Management Protocol (PACMP) based on the
may be provided from an early development phase notification entitled "Handling, etc. of Changes in
for regenerative medicine products or preventive Approved Matters Related to Drug Quality,"
products to be used for expressing transgenes in (Notification No. 0309-(1) of the Pharmaceutical
the human body (other than regenerative medicine Evaluation Division and Notification No. 0309-(1) of
products; e.g., recombinant live vaccine). The the Compliance and Narcotics Division, PSEHB
verification application system for products for gene dated March 9,2018).
therapy has been abolished. • Pharmaceutical PACMP quality consultation
(17) Consultations on SAKIGAKE • Generic drug PACMP quality consultation
comprehensive assessment • PACMP GMP consultation
Consultations on drugs covered by the
SAKIGAKE Designation System (prior data 1.5 Approval review
assessment of planned application documents on
The documents to be attached at the time of
the following fields to organize issues and tasks to
application are designated for each application
be addressed before the review)
category (PFSB Notification No. 1121-(2) entitled
• Quality data
"Approval Applications for Drugs" dated November
• Non-clinical data
21, 2014). See the "Points to Consider for Approval
• Clinical data
Application Data for New Drugs" (Notification No.
• Reliability
1121-(12) of the Evaluation and Licensing Division
• GMP/GCTP/QMS
of PFSB dated November 21, 2014), etc. for the
(18) Consultations on electronic data
matters to be kept in mind in preparation of the
submission for application for new drugs
documents. Related notifications are available on
Consultations to ensure smooth preparation of
the PMDA homepages.
approval application and subsequent review, in
Japanese HP:
which the following contents are investigated on a
http://www.pmda.go.jp/review-services/drug-review
specific product at a stage prior to approval
s/about-reviews/otc/0001.html
application: the contents are to be submitted in a
The recommended standard format for the
form of electronic data for approval application of a
quality and clinical safety information on CTD is
new drug, of which clinical data are planned to be
presented by PMDA (Office Communication
attached in an electronic form (including formats
entitled "Format for Preparing the Common
and programs for constructing definition files and
Technical Document for Submission of New Drug
data set).
Applications to Reduce Total Review Time" dated
(19) Preparatory consultation on minor change
January 17, 2011).
notification of drugs
PMDA is mainly in charge of the activities related
Consultation on issues that generally require
to an approval review of a new drug. Once the
prior data assessment for appropriateness of items
application form is received by PMDA, a detailed
to be included in a minor change notification
team review is performed by the review staff.
(20) Consultation on the system for changing
Moreover, compliance review (certification from
approved matters using PACMP for drugs
source data) and GCP on-site inspection are
Consultation will be held when an applicant
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
The reviews are generally performed in manufacturing and marketing approval of drugs,
the applicant’s offices and facilities and etc. (Article 14-2, Paragraph 4 of the
medical institutions performing the clinical Pharmaceutical Affairs Law).
study (approximately four facilities as a rule When a manufacturing plant does not conform
for ordinary review products; approximately to GMP standards, the MHLW minister or
two facilities for priority review products). In prefectural governor may not grant a license.
selection of review facilities, consideration
1.7.1 GMP Compliance Reviews
should be given to the number of subjects in
clinical trials and dates of GCP reviews When an application is submitted for a new drug
used by companies for document-based (GMP/QMS) of drugs and medical devices, etc. in
association with enforcement of the Law for partial
inspection and GCP on-site inspection was
officially published by PMDA. The companies amendment of the Pharmaceutical Affairs Law and
that wish to use it should submit it to PMDA the Blood Collection and Donation Service Control
Law” Notification No. 0330001 of the Compliance
as the document to be used immediately
before the inspection. and Narcotics Division, PFSB dated March 30,
http://www.pmda.go.jp/review-services/inspections/ 2005.)
First, a review is conducted for each product
gcp/0002.html#r=s&r=s
using the following criteria for GMP compliance as
to each article in the control regulations and building
1.7 GMP compliance inspection
and facility regulations.
Formal approvals are required for individual
formulations of drugs in order to market the drugs in Evaluation rank criteria
Japan. Formal approval must be obtained prior to A (Compliance): Manufacturing is
market launch from the Minister of the MHLW performed properly.
(prefectural governor for non-prescription drugs for B (Slightly defective): There is little effect on
which approval standards are established) by drug quality but improvement necessary
submitting data and documents for required review for complete compliance with control
on product quality, efficacy, and safety. regulations.
Marketing approvals require a review to C (Moderately defective): Effect on drug
determine whether or not the product in the quality cannot be ruled out and
application is suitable as a drug to be marketed by a improvement necessary for compliance
person who has obtained a marketing business with control regulations.
license (marketing authorization holder) for the type D (Seriously defective): Clear violation of
of drug concerned and confirmation that the product control regulations
has been manufactured in a plant compliant with Next, a review is undertaken for each product
GMP. Thus, GMP compliance is a requirement for using the following criteria on the basis of the results
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Pharmaceutical Regulations in Japan:
of the review of GMP compliance for each article in 2003, and in April 2016, Japan-Europe MRA
the control regulations and building and facility became applicable to all the 28 EU countries
regulations: (Notification No. 0426-(3) of the Compliance and
Compliance: Cases of A only. Narcotics Division of PSEHB dated April 26, 2016).
General compliance: Cases of A and B or B In July 2018, the scope of the drugs to be subjected
only. to mutual approval was expanded to newly include
Improvement required: Cases of C evaluated drug substances and aseptic preparations for
for half or less of all items and no D. chemical pharmaceuticals, and to newly include
Non-compliance: Cases not corresponding to drug substances and aseptic products (such as
any of the above. vaccines), other than the products for which
When GMP compliance by product is equivalence of GMP to be applied has not been
determined as "General compliance" or confirmed, for biological pharmaceuticals
"Improvement required," an order for (Notification No. 0718-(1) of the Compliance and
improvement(s) for the item(s) rated as B is issued Narcotics Division of PSEHB dated July 18, 2018).
in writing. Positive utilization of the internationally
In such cases, the applicant must submit a recognized GMP rules contained in Pharmaceutical
concrete plan of improvements. When Inspection Cooperation Scheme was
improvements are completed, a report on the recommended to secure closer international
improvement must be submitted. When the standardization and conformity in GMP inspections.
improvements have been confirmed, the rating of MHLW, PMDA, and prefectural governments bid
the corresponding item is changed to "Compliance." membership to the office of PIC/S in March 2012
The results of reviews or assessments at each and became a member on July 1, 2014. ("Concepts
of the above stages are compiled, and a report of of Utilization of GMP Guidelines of PIC/S," Office
the GMP compliance review is prepared for the Communication dated February 1, 2012, partially
plant in the application concerned. When the initial revised on August 9, 2017).
GMP compliance review results of a product The enforcement notification of the GMP
correspond to "General compliance" or (Notification No. 0330001 of the Compliance and
"Improvement required," the subsequent course is Narcotics Division, PFSB dated March 30, 2005)
entered in the GMP compliance review report. was amended in August 2013 in order to align with
the GMP guideline in PIC/S (Notification No.
1.7.2 Global Harmonization of GMP
0830-(1) of the Compliance and Narcotics Division,
Japan has concluded mutual agreements for PFSB dated August 30, 2013).
GMP (MOU) approvals with countries with
equivalent levels of GMP. These agreements are 1.7.3 Regulations for Imported Drug
meant to assure the quality of drugs imported into Management and Quality Control
Japan through mutual acceptance of GMP Since it is very important to assure the quality of
inspection results and exchange of information on imported drugs in the same way as drugs
drugs marketed in the two countries. These manufactured in Japan, items related to regulations
mutual agreements have been concluded with for manufacturing control and quality control, when
Germany, Sweden, Switzerland and Australia. importers and marketing authorization holders
Mutual recognition agreement of drug GMP (MRAs) import drugs, were specified in the Import Control
with the EU countries was firstly concluded in May and Quality Control of Drugs and Quasi-drugs
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Pharmaceutical Regulations in Japan:
(MHW Ordinance No.62, June 2, 1999), but since Detailed handling procedures are specified in
the import business license has been including in “Points to Consider in Drug Approval Applications”
the manufacturing/marketing business license, this (Notification No. 666 of the Evaluation and
was abolished on March 31, 2005. These Licensing Division, PMSB dated April 8, 1999). In
regulations included matters to be agreed upon with addition, in association with enforcement of the
the manufacturer in foreign country by the importer revised Pharmaceutical Affairs Law in April 2005,
in accordance with the agreement. The importer revised handling procedures of documents to be
must confirm that the drug to be imported is attached to manufacturing/marketing approval
manufactured under appropriate manufacturing application for drugs were specified in “Approval
control and quality control, and must import, store, Applications for Drugs” (Notification No. 0331015 of
and conduct testing in accordance with standards, PFSB dated March 31, 2005; Notification No.
etc. 1020001 of PFSB dated October 20, 2008 for
In addition, when a mutual agreement for GMP partial amendment on non-prescription drugs;
approvals has been concluded between the Notification No. 0304004 of PFSB dated March 4,
exporting country and Japan, part of the quality 2009 for partial amendment on biosimilar products;
control work may be omitted if the following two Notification No. 0701-(10) of the Evaluation and
conditions are met: that it is confirmed by the Licensing Division, PFSB dated July 1, 2013 for
government organization in the exporting country partial amendment on companion diagnostics and
that the plant where the imported drug was associated drugs; and PFSB Notification No.
manufactured complies with the GMP in the 0612-(6) dated June 12, 2014 for partial
country; and that the records of tests performed by amendment on guidance-mandatory drugs) with
the manufacturer of the drug are provided to the abolishment of Notification No. 481 of PFSB, as
importer in Japan. well as the handling procedures were detailed in
From April 1, 2005, a manufacturer/marketing “Points to Consider in Approval Application of
authorization holder or manufacturer had to submit Drugs” (Notification No. 0331009 of the Evaluation
an import certificate before custom clearance when and Licensing Division, PFSB dated March 31,
importing drugs as business, but this regulation was 2005 ; Notification No. 1020002 of the Evaluation
abolished in December 2015. No import certificate and Licensing Division, PFSB dated October 20,
is currently required. Instead, from January 2016, 2008 for partial amendment on non-prescription
the custom clearance procedure requires drugs; Notification No. 0304015 of the Evaluation
presentation of business license and marketing and Licensing Division, PFSB dated March 4, 2009
approval certificate of a product to be imported. for partial amendment on biosimilar products ;
Notification No.0701-(10) of the Evaluation and
Licensing Division, PFSB dated July 1, 2013 for
2. DATA REQUIRED FOR APPROVAL
partial amendment for companion diagnostics and
APPLICATIONS
associated drugs; and Notification No. 0612-(1) of
The data to be attached to approval applications the Evaluation and Licensing Division, PFSB dated
for drugs is specified in the basic notification entitled June 12, 2014 for partial amendment on
“Approval Applications for Drugs” (Notification No. guidance-mandatory drugs).
481 of PMSB dated April 8, 1999 and partial Later, with the enactment of the Pharmaceutical
revision: Notification No. 0525003 of the Evaluation and Medical Device Law, “Approval Application for
and Licensing Division, PFSB dated May 25, 2004). Drugs” (Notification No. 1121-(2) of the PFSB) and
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Pharmaceutical Regulations in Japan:
Applicable clinical trial data should be submitted in <3> Inquiries (copies) and responses to
the formats according to the specifications in inquiries (copies)
Clinical Data Interchange Standards Consortium. <4> Other data [data submitted to the
1) Module 1: Administrative information such PMDA (copies), data submitted to the
as application forms and prescribing MHLW (copies)]
information Laboratory target and set values to
be entered in the manufacturing
(1) Application documentation table of
method column of the application
contents (including Module 1)
form for drugs other than biological
(i) Table of contents of application
products should be tabulated and the
document including Part 1
list be attached to the application
(ii) Synopsis
document as directed in “CTD Format
(2) Approval application (copy) for Reducing Total Review Time for
(3) Certificates (Declarations of those New Drugs” (Office Communication
responsible for collection and of the Evaluation and Licensing
compilation of data for approval Division, PFSB dated January 17,
applications, GLP and GCP related 2011).
data, contracts for codevelopment Review data on new additives, if any,
[copies], and declarations required to should be included in the application
be attached in accordance with dossier (copies) as directed in the
Notification No. 0527004 of the “Submission of Review Data on New
Evaluation and Licensing Division, Additives” (Notice of the PMDA dated
PFSB dated May 27, 2004 entitled June 23, 2017).
“Handling of Computer Formatting of <5> Points to consider in formatting the
the Common Technical Document”). eCTD
(4) Patent status
2) Module 2: Data summaries or CTD
(5) Background of origin, discovery, and
“Gaiyo”
development
(1) Modules 2 to 5 (CTD) table of contents
(6) Data related to conditions of use in
(2) CTD introduction
foreign countries, etc.
(3) Quality overall summary
(7) List of related products
(4) Nonclinical overview
(8) Package insert (draft)
(5) Clinical overview
(9) Documents concerning non-proprietary
(6) Nonclinical summary (text and tables)
name
<1> Pharmacology
(10) Data for review of designation as
<2> Pharmacokinetics
poisons, deleterious substances, etc.
<3> Toxicity
(11) Risk management plan (RMP) (draft):
(7) Clinical summary
(12) List of attached documentation
<1> Summary of biopharmaceutics and
(13) Other
associated analytical methods
<1> Data related to approved drugs
<2> Summary of human pharmacology
<2> Clinical trial consultation records
<3> Summary of clinical efficacy
(copies)
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(1) Module 3 table of contents It was decided that the applicant should submit
(2) Data or reports the conversion factor, etc. for calculating the
(3) Literature references maximum daily use of drug additives during the
process of application for marketing approval
4) Module 4: Nonclinical study reports
(including application for a change) in order to
(1) Module 4 table of contents enable appropriate management of the maximum
(2) Study reports daily use of drug additives by the regulatory
(3) Literature references authority. (Notification No. 1007001 of the Office of
5) Module 5: Clinical study reports Review Management, PMDA dated October 7,
(1) Module 5 table of contents 2016, partially revised by Notification No. 0927001
(2) Tabular listing of all clinical studies of the Office of Review Management, PMDA dated
(3) Clinical study reports September 27, 2017).
(4) Literature references
(See Fig. 11 Organization of ICH Common 2.1 Data to be Attached to Approval
Technical Documents). Application of Drugs
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Pharmaceutical Regulations in Japan:
November 21, 2014). After complete enforcement to be Considered in the Acceptance of Foreign
of the CTD (from July 1, 2003), the present Clinical Trial Data” (Notification No. 672 of the
guidelines for preparation of data to be attached to Evaluation and Licensing Division, Pharmaceutical
approval applications can be applied to approval and Medical Safety Bureau dated August 11, 1998
applications for non-prescription drugs as in the and partial revision by Office Communication dated
past. For the time being, data on the manufacturing January 4, 1999) and its Q and A (Office
method and specifications and test methods for Communications dated February 25, 2004 and
non-prescription drugs with new active ingredients October 5, 2006). According to these notifications,
are prepared using the CTD only for reference when data from clinical studies performed in foreign
purpose. countries are used for new drug application in
Japan, the data is first checked to assure that it
complies with legal requirements in Japan.
3. GUIDELINES CONCERNING DRUG
Whether or not the drug is apt to be affected by
APPROVAL APPLICATIONS
ethnic factors (intrinsic or extrinsic factors) is then
Guidelines outlining standard test methods and evaluated. When necessary, a bridging study is
essential criteria for reference in the preparation of performed, and when it is concluded that the clinical
data for drug manufacturing and marketing study outcome in a foreign population can be
approval applications have been published in order extrapolated to the Japanese population, the
to assure efficient and appropriate research and foreign data can be accepted. Since the possibility
development. These guidelines have been of acceptance is actually left up to the authorities
prepared on the basis of results of studies concerned, it is recommended that the
undertaken by groups of experts in the field requirements for bridging studies be confirmed as
concerned. acceptable for the regulatory agencies through
Various standards and guidelines have been consultations with PMDA.
established and implemented according to ICH With the intent to promote global clinical trials to
harmonization and the reliability and amount of achieve more efficient and rapid development of
research data has been internationally harmonized. new drugs and to eliminate drug lag in which the
To meet demands for more efficient and less costly approval timing of new drugs is several years
development of new drugs, international utilization behind that in other countries, basic concepts
of data is on the increase. related to global clinical trials have been compiled
Japan has taken various measures in keeping (Notification No. 0928010 of the Evaluation and
with this change in the international environment, Licensing Division, PFSB dated September 28,
and data from nonclinical studies such as 2007). In addition, the notice “Basic Principles on
physicochemical studies, stability studies and Global Clinical Trials (Reference Cases)” (Office
animal studies performed in foreign countries are Communication dated September 5, 2012) was
accepted, in principle, if their study designs comply issued based on achievements of mutual
with the Japanese guidelines. cooperation and latest knowledge obtained relating
Two notifications were issued in relation to the to multinational clinical trials among Japanese,
acceptance of foreign clinical data: “Handling of Chinese, and South Korean regulatory authorities
Data on Clinical trials on Drugs Performed in with an objective of a smooth and appropriate
Foreign Countries” (Notification No. 739 of the conduct of global clinical trials, especially in East
PMSB dated August 11, 1998) and “Ethnic Factors Asia. In addition, “Basic Approach to Conduct of
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Pharmaceutical Regulations in Japan:
Phase I Clinical Trial in Japanese Before Start of is available, and data appended to the
Global Clinical Trial” (Office Communication of the application for the regulatory authorities can be
Evaluation and Licensing Division of the PFSB, obtained.
MHLW dated October 27, 2014) indicates points to (2) Cases where an official approval indication(s)
consider when examining whether or not a phase I unapproved in Japan has already been
clinical trial is necessary in the case where Japan granted overseas, sufficient experience of use
takes part in a global clinical trial. in medical practice is available, scientific
As globalization of drug development evidence has been published in internationally
progresses and numerous global joint clinical trials reputable scientific journals, or review articles,
have come to be planned and conducted, "General etc. of international organizations can be
Principles for Planning and Design of obtained.
Multi-Regional Clinical Trials" (Notification No. (3) Cases where there are clinical study results
0612-(1) of the Pharmaceutical Evaluation Division, that can be confirmed in terms of ethics,
PSEHB dated June 12, 2018: ICH-E17) was science, and reliability by such means as
notified. This notification shows the general contract research performed as part of public
principles for planning and design of global joint research projects.
clinical trials to make global joint clinical trials more The data attached to applications for approval to
acceptable in various regions in the world. manufacture and market drugs must be in
Marketed drugs that have been used for Japanese, but as part of the deregulation process, it
unapproved indications or dosage and was specified in Notifications No. 256 of the PMSB
administration in clinical practice (off-label use) and No. 265 of the Evaluation and Licensing
should be used appropriately by receiving Division, PMSB, both dated March 18, 1998, that
marketing approval based on the Law. But in the documents in English in Modules 3, 4, and 5 need
cases the indications and dosage and not be completely translated into Japanese as long
administration related to off-label use are confirmed as a Japanese summary is attached. In approval
by medical and pharmaceutical knowledge in the applications using the CTD format, a Japanese
public domain, a judgment is made of whether or summary is not required for entries in the original in
not the use can be approved without performing English.
whole or part of the clinical trials again (Notifications
No. 4 of the Research and Development Division, 3.1 Quality and Nonclinical Studies
Health Policy Bureau and No. 104 of the Evaluation
1) Guidelines on physicochemical
and Licensing Division, Pharmaceutical and
properties, specifications, and tests
Medical Safety Bureau dated February 1, 1999).
methods
After this notification was issued, applications based
The contents of specifications and test methods
on public knowledge have been filed and approved.
in approval applications must include required test
(1) Cases where an official approval of
items in reference to the specified test guidelines.
indication(s) unapproved in Japan has already
For drugs with new active ingredients manufactured
been granted overseas (countries with
by chemical synthesis, refer to “Setting of
approval systems confirmed to be on the same
Specifications and Test Methods of New Drugs”
level as the system in Japan or with
(ICH Q6A) (Notification No. 568 of the Evaluation
corresponding systems; the same hereinafter),
and Licensing Division, PMSB dated May 1, 2001)
sufficient experience of use in medical practice
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Pharmaceutical Regulations in Japan:
For new biological products (biotechnological necessary information may be obtained for
products/drug products derived from living establishing a period of retest of an active
organisms), refer to “Setting of Specifications and pharmaceutical ingredient, an available period of a
Test Methods of Biological Products formulation and storing conditions of a drug.
(biotechnological products/drug products derived The former guidelines for stability tests of
from living organisms)” (ICH Q6B) (Notification No. prescription drugs with new active ingredients
571 of the Evaluation and Licensing Division, (Notification No. 565 of the Evaluation and
PMSB dated May 1, 2001). These guidelines on Licensing Division, PMSB dated May 1, 2001) has
specifications and test methods were prepared been abolished and new stability guidelines based
based on ICH agreements. To achieve sufficient on ICH agreements have been established
utilization of ICH-Q6A and ICH-Q6B, it is necessary (Revision of Stability Test Guidelines (ICH
to harmonize the General Test, Processes and Q1A(R2)). Photostability tests for drugs with new
Apparatus of Pharmacopoeia among ICH regions, active ingredients and new combinations are
and hence the Guidelines on Evaluation and performed on the basis of the Guidelines for
Recommendation of Pharmacopoeial Texts for Use Photostability Tests of New Bulk Drugs and New
in the ICH Regions (Notification No. 0526001 of the Preparations (ICH Q1B) (Notification No. 422 of the
Evaluation and Licensing Division, PFSB dated Evaluation and Licensing Division, PAB dated May
May 26, 2009, No.1; ICH-Q4B) were issued. 28, 1997). For drugs with new routes of
Based on these guidelines, when it is judged that it administration, stability tests must be performed as
is possible to utilize the pharmacopoeial texts in the specified in the Guidelines for Handling Results of
ICH regions, these texts can be used mutually in Stability Tests of Drugs with New Routes of
accordance with the conditions set in annexes. Administration (ICH Q1C) (Notification No. 425 of
The guidelines shown in Table 6 have been the Evaluation and Licensing Division, PAB dated
revised or established concerning physicochemical May 28, 1997), and for biological products, stability
properties, specifications, and tests methods. tests must be performed as specified in the
The quality standards published in the Japanese Guidelines for Handling Results of Stability Tests of
Pharmacopoeia, Japan Pharmaceutical Codex, etc. Biological Products (biotechnological products/drug
serve as references for specifications and test products derived from living organisms) (ICH Q5C)
methods including content specifications, (Notification No. 6 of the Evaluation and Licensing
identification, purity and assay. Division, PMSB dated January 6, 1998).
For sustained-release drugs, refer to the Concepts concerning simplification of stability
Guidelines for Design and Evaluation of tests on a scientific basis have also been specified
Sustained-Release (Oral) Preparations (Notification in Application of Bracketing and Matrixing Methods
No. 5 of the First Evaluation and Registration in Stability Tests on Drug Substances and Drug
Division, PAB dated March 11, 1998) in addition to Products (ICH Q1D) (Notification No. 0731004 of
the above guidelines. the Evaluation and Licensing Division, PMSB dated
July 31, 2002, partially revised by Office
2) Guidelines for stability tests
Communication dated June 3, 2003).
Stability tests for approval application of drugs
For generic drugs, etc., standard methods for
are conducted to evaluate change in quality over
long-term stability studies, stress stability studies
time with various environment factors including
and accelerated stability studies are specified in the
temperature, humidity or light, through which
Guidelines for Stability Tests Attached to Approval
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
investigators must give scientific and ethical GCP for scientific and ethical conduct of clinical
consideration to the subjects' human rights to studies in three regions, the MHLW Ordinance on
minimize their risk relative to the expected benefits. Standards for Implementation of Clinical Studies on
Guidance concerning drug development Drugs (GCP) (MHW Ordinance No. 28 dated
strategies and evaluation processes has been March 27, 1997, partial revision by MHLW
issued in the three ICH regions. In 1998, General Ordinance No. 9 dated January 22, 2016) was
Considerations for Clinical Studies (Notification No. issued with the aims of specifying the requirements
380 of the Evaluation and Licensing Division, for the planning, conduct, monitoring, auditing,
PMSB dated April 21, 1998, ICH E8) was prepared records, analysis, and reports of clinical studies
as one aspect of MHLW’s efforts to promote performed to collect data to be submitted with
international harmonization of approval review data applications for approval to manufacture and
for new drugs. This notification consists of the market drugs; to protect the human rights, safety,
objective of the guidelines, general principles and welfare of study subjects; and to assure the
(protection of clinical trial subjects and scientific scientific quality of the study and the reliability of its
approach in design and analysis) and development results.
methods (points to consider for development plans The importance of precision control of laboratory
and for individual clinical studies). data in clinical trial to ensure the reliability of
In order to protect the study subjects these laboratory data and the trial is shown in “the Basic
Guidelines specify that, as a condition to start a Concept of Precision Control of Laboratory Data in
clinical study, the safety of the drug must be shown Clinical Trial” (Office Communication of the
from nonclinical studies or previous human studies. Evaluation and Licensing Division, PFSB dated July
Throughout drug development, qualified clinicians 1, 2013).
and other experts should review and evaluate all
2) Considerations for the development
newly obtained data from toxicity studies on animals
plan
and human studies to assess their implications for
the safety of the subjects. 2.1) Nonclinical studies
Clinical studies should be designed, conducted, Important considerations for determining
and analyzed in keeping with sound scientific the nature of nonclinical studies and their
principles in order to achieve their objectives, and timing with respect to clinical studies include:
they should be reported appropriately. The (1) Duration and total exposure (dose) in
essence of rational drug development is to pose individual patients
important questions and answer them with the (2) Characteristics of the drug
results of carefully controlled clinical studies. The (3) Disease or condition targeted for
primary objectives of any study should be clear and treatment
explicitly stated. (4) Use in special populations
Clinical studies can be classified by their (5) Route of administration
objectives. The basic logic behind serially The actual timing of each nonclinical safety
conducted studies of a drug is that the results of study is specified in the Guidelines on Nonclinical
prior studies should influence the protocols of later Safety Studies for the Conduct of Human Clinical
studies (Table 5 Classification of Clinical Studies Trials and Marketing Authorization for
According to Objectives). Pharmaceuticals (Notification No. 0219-(4) issued
Following an ICH agreement to issue common by the Evaluation and Licensing Division of PFSB
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Pharmaceutical Regulations in Japan:
dated February 19, 2010: ICH M3R(R2), and Office Investigational Product GMP was revised to allow
Communication (Q&A on the guidelines) dated the quality assurance of an investigational product
August 16, 2012). according to the phase of a clinical trial in
consideration of characteristics of the trial, including
(i) Safety studies
ones at an early exploratory stage (Notification No.
For the first studies in humans, the dose
0709002 of PFSB). Subsequently, the Q&A on the
used should be determined by careful
Investigational Product GMP was released (Office
examination of the prerequisite nonclinical
Communication of Compliance and Narcotics
pharmacological and toxicological
Division, PFSB dated July 2, 2009).
evaluations. Early nonclinical studies
should provide sufficient information to 2.3) Phases of clinical development
support selection of the initial human dose Clinical studies have been conventionally
and safe duration of exposure, to provide classified by phase of development (I to IV).
information about the physiological and The ICH conference proposed a new
toxicological effects of a new drug. classification system according to the
objective of studies as described in the
(ii) Pharmacological studies
General Considerations for Clinical Studies
The basis and direction of the clinical
(Notification No. 380 of the Evaluation and
exploration and development rests on the
Licensing Division, PMSB dated April 21,
nonclinical pharmacology profile, which
1998, ICH E8), and according to this system
includes the following information:
clinical studies are classified to the following
(1) Pharmacological basis of principal
four types:
effects (mechanism of action).
(1) Human pharmacology studies
(2) Dose-response or
(2) Therapeutic exploratory studies
concentration-response relationships
(3) Therapeutic confirmatory studies
and duration of action.
(4) Therapeutic use studies
(3) Study of the potential clinical routes of
Objectives and types of studies in these four
administration.
categories are listed in Table 5 (Classification of
(4) Systemic general pharmacology,
Clinical Studies According to Objectives) and the
including pharmacological effects on
close but variable correlations between the
major organ systems and physiological
development phase and study type are shown in
processes.
Fig. 12 Correlation between Development
(5) Absorption, distribution, metabolism, and
Phases and Types of Study).
excretion
The distribution of the circles, open circles and
2.2) Quality of investigational products shaded circles, in the figure shows that the types of
Products used in clinical studies should be well study do not automatically define the phases of
characterized, with information on bioavailability development.
wherever feasible. The product should be Clinical development is ideally a step-wise
appropriate for the stage of drug development. process in which information from small early
Ideally, the preparation should be adequate to allow studies is used to support and plan later larger,
testing in a series of studies that examine a range of more definitive studies. To develop new drugs
doses. efficiently, it is essential to identify characteristics of
For investigational products, on July 9, 2008, the
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Pharmaceutical Regulations in Japan:
the investigational product in the early stages of are entered into the study according to
development and to plan appropriate development clearly defined criteria and whose condition
based on this profile. The four clinical is monitored. An important goal for this
development phases are described below. phase is to determine the dose(s) and
regimen for Phase III studies. Dose
(i) Phase I (typical study: clinical
response designs should be used to assess
pharmacology)
and confirm the dose-response relation for
Phase I entails the initial administration of
the indication concerned. Additional
an investigational new drug to humans.
objectives of Phase II clinical studies include
The most typical study is that on clinical
evaluation of study endpoints, therapeutic
pharmacology. Although clinical
regimens (including concomitant medication)
pharmacology studies are typically identified
or target populations for further study in
with Phase I, they may also be indicated at
Phase II or III.
other points in the development sequence.
Studies conducted in Phase I typically (iii) Phase III (typical study: therapeutic
involve one or a combination of the following confirmatory)
aspects: The primary objective of Phase III studies
(1) Estimation of initial safety and tolerability is to confirm the therapeutic effects.
(2) Characterization of pharmacokinetics Studies in Phase III are designed to confirm
(3) Assessment of pharmacodynamics the preliminary evidence accumulated in
(4) Early assessment of efficacy Phase I and II that a drug is safe and
As a reference, the basic concepts effective for use in the proposed indication
concerning the study items and conduct of all and recipient population. These studies are
clinical pharmacokinetic studies for the intended to provide data to serve as an
purpose of drug development are given in adequate basis for manufacturing approval.
Clinical Pharmacokinetic Studies on Drugs “Arrangements for supplying and
(Notification No. 796 of the Evaluation and receiving of control drugs” were established
Licensing Division, PMSB dated June 1, as voluntary arrangements among member
2001) and Guidance on Ensuring Safety of companies of the JPMA in July 1981 for the
Human Subjects in the Initial Clinical Trial of smooth supply and receipt of control drugs
New Investigational Medicinal Product by the companies developing new drugs and
(Notification No. 0402-(1) of the Evaluation the manufacturing/marketing authorization
and Licensing Division, PFSB dated April 2, holders of control drugs when
2012). pharmaceutical companies developing new
drugs evaluate efficacy and safety of new
(ii) Phase II (typical study: therapeutic
drugs with approved drugs already on the
exploratory)
market as controls. After four subsequent
Phase II is usually considered to be the
revisions, the most recent version appeared
phase in which studies with the primary
on November 1, 2005.
objective of exploring therapeutic efficacy in
patients are initiated. The most typical (iv) Phase IV (various types of study:
Phase II study is the therapeutic exploratory therapeutic use)
study performed on a group of patients who
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
clinically used in consideration of balance between Notification No. 0709002 of the PFSB on July 9,
the relevant risk and expected therapeutic benefit; 2008 as a replacement of the old Investigational
and such use does not interfere with development Product GMP in order to assure the quality of
of the concerned drug. investigational products depending on development
By this system, an investigational product after phase. In addition to the protection of human
conduct of a trial at the final development phase in subjects and reliability assurance of clinical trials,
Japan (which is regularly intended to verify the the new regulations aim to ensure not only the
efficacy and safety after the indications as well as efficacy and safety of drug product but also
dosage and administration have been set through a adequateness of clinical studies themselves in the
series of development operations, or called as a post-marketing phase by securing pharmaceutical
pivotal trial) or while such trial is ongoing (but after consistency between the investigational product
completion of the enrollment) is made available in a and marketed product following the final selection of
framework of a trial in patients with the above research compound to be developed and by
diseases. assuring the equivalence between the two products
following the establishment of manufacturing
7) Investigational Product GMP
method and test methods of investigational product.
In Article 17, Supply of the Investigational
Q&A on the standards for manufacturing control
Product, in the GCP ordinance, it specifies that the
and quality control of investigational products
sponsor shall supply to the medical institution
(Investigational Product GMP) were published in
performing the study investigational product
Office Communication dated July 2, 2009.
manufactured in factories applying appropriate
The Investigational Product GMP is applied to all
manufacturing control and quality control methods
investigational products used in clinical studies
and with the buildings and facilities required to
conducted in accordance with the GCP ordinance.
assure the quality of the investigational product.
The GMP is a set of requirements to be followed by
To that end, requirements for manufacturing
the study sponsor and investigators and also
investigational products have been issued in the
applied to investigational products manufactured at
form of Notification No. 480 of the PAB dated March
foreign facilities. The system/procedure-related
31, 1997 entitled "Standards for Manufacturing
provisions of the Investigational Product GMP
Control and Quality Control of Investigational
require the sponsor to establish investigational
Products and Standards for Buildings and Facilities
product manufacturing division and investigational
of Plants Manufacturing Investigational Products" in
product quality control division at each
order to assure the reliability of clinical studies by
manufacturing facility. The release of
guaranteeing the quality of investigational products
investigational product from factory must be judged
and to protect subjects from poor quality
by personnel of the quality control division
investigational products. In light of the specificities
designated for individual investigational product
of the investigational product, such as the use in an
items. The provisions require the preparation and
early exploratory development phase, Standards for
retention of documents pertaining to
Manufacturing Control and Quality Control of
ingredients/quantities, specifications, test methods,
Investigational Products and Standards for
manufacturing procedures, etc. for each
Buildings and Facilities of Plants Manufacturing
investigational product item and those pertaining to
Investigational Products (“new” Investigational
manufacturing hygiene control procedures,
Product GMP) were issued in the form of
manufacturing control procedures, and
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Pharmaceutical Regulations in Japan:
manufacturing control procedures for each (Office Communication dated March 30, 2009) and
manufacturing facility. It is also required to prepare the procedures for requesting the issue of
and retain documents standardizing manufacturing investigational product GMP certificates are given in
and quality control. The GMP also contains the “Procedures for Issuing Investigational Product
provisions concerning the use of contract testing GMP Certificates” (Notification No. 0330023 dated
facilities, validation/verification, change control, March 30, 2009).
deviation control, quality test results, handling of
inferior quality products, recall, self-inspections,
4. OTHER
education/training, document/record control,
contracted manufacture, buildings/facilities
4.1 Biotechnological Products
manufacturing investigational products, etc.
The building/facility-related provisions of the The Guidelines for Manufacturing Drugs by
Investigational Product GMP specify requirements using Recombinant DNA Technology were
for individual facilities manufacturing investigational published to ensure manufacturing safety of
products other than bulk products, investigational products during the manufacture of
bulk products, investigational sterile preparations, pharmaceuticals with recombinant DNA
investigational sterile bulk product, investigational technology (Notification No. 1051 of the PAB
biological products and investigational blood dated December 11, 1986, partially revised by
products. Notification Nos. 434 and 769 of the PAB dated
The requirements for manufacturing control and May 21, 1987 and August 18, 1995, respectively).
quality control methods for drug substances are The guidelines specify methods of safety
specified in the Guidelines on GMP for Drug evaluation of recombinants (live cells), classify the
Substances (ICH Q7A, currently Q7) (Notification level of each working process into four levels, i.e.
No. 1200 dated November 2, 2001), which includes GILSP (Good Industrial Large Scale Practice),
20 requirements for drug substances including Category 1, Category 2, and Category 3, at the
quality management, buildings and facilities, and manufacturing stage based on the degree of
validation, as approved at ICH5 held in San Diego safety, identify the type of facilities and equipment
in November 2000. necessary for the manufacture, and also specify
Further, the adoption of the Pharmaceutical the requirements for the establishment of an
Inspection Convention and Pharmaceutical institutional biosafety committee, the appointment
Inspection Co-operation Scheme (jointly referred to of a biological safety officer (BSO), and
as PIC/S) Guidelines in Japan has been proposed supervision by a product security pharmacist.
by the Ministry in light of the need for international Thereafter, based on the Law for Securing
harmonization and other reasons (Office Multiplicity of Living Organisms under the Use
Communication dated February 1, 2012). Control of Genetically-Engineered Living
Since requests from overseas regulatory Organisms (so-called “Cartagena Law”) (Law No.
authorities to submit investigational product GMP 97 dated June 18, 2003), the MHLW Ordinance
certificates are made when a clinical study is on Measures to Prevent Spread of Industrial Use
performed overseas using an investigational among Secondary Uses of
product produced in Japan for a global clinical trial, Genetically-Engineered Living Organisms
the issue of such certificates is specified in the (Ordinance No. 1 of the Ministry of Finance,
“Supply of investigational product GMP certificates” MHLW, Ministry of Agriculture, Forestry and
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Pharmaceutical Regulations in Japan:
Fisheries, Ministry of Economy, Trade and 4.2 Drugs Using Materials of Human or
Industry and Ministry of Environment dated Animal Origin as Ingredients
January 29, 2004; partially revised in Ordinance (Biological Products)
No. 2 dated June 6, 2006) was enforced on It is necessary to take measures to assure
February 19, 2004 (the preceding guidelines were quality and safety based on current scientific levels
replaced by the Ordinance). for drugs manufactured using materials of human or
Separately, a notification entitled “Preparation animal origin as raw materials. Therefore, the
of Data Required for Approval Applications for Biotechnology Committee of the Pharmaceutical
Drugs Manufactured by Using Recombinant DNA Affairs and Food Sanitation Council established
Technology” was issued as Notification No. 243 of “Basic Concepts for Handling and Use of Drugs
the Evaluation and Regulation Division, PAB and Devices Utilizing Cells or Tissues” (December
dated March 30, 1984 for the evaluation of the 1, 2000) and “the Guidelines for Assurance of
quality, efficacy, and safety of drugs produced by Quality and Safety of Drugs and Devices
recombinant DNA technology, and then Processed from Cells and Tissues of Human
“Preparation of Data Required for Approvals Origin” (December 1, 2000) (Notification No. 1314
Applications for Drugs Manufactured by Cell of the PMSB dated December 26, 2000). In
Culture Technology” was issued as Notification addition, various notifications have been issued,
No. 10 of the First Evaluation and Regulation manufacturers have been requested to undertake
Division, PAB dated June 6, 1988. After that, the self-inspection and coordinate application
above notifications were reconsidered on the documents, and safety measures have been
basis of marked advancement of gene specified. For ingredients of bovine origin in
recombinant technology, cell culture technology particular, notifications have been issued as
and other scientific technology as well as the required in accordance with worldwide risk
knowledge of quality, safety and efficacy of conditions and measures to assure quality and
biological products accumulated to date, and safety have been strengthened (refer to “Safety
"Approval Application Category of Biotechnology Measures for Bovine Spongiform Encephalopathy
Products and Procedure for Preparation of [BSE]” in Section 6.4, Chapter 2). Biological
Attached Documents Necessary for Approval products and specified biological products were
Application" (Notification No. 0705-(5) of the newly defined in the revised Pharmaceutical Affairs
Pharmaceutical Evaluation Division, PSEHB Law dated July 31, 2002 and measures to assure
dated July 5, 2017) was issued. safety when there is a risk of infection have been
Various guidelines have been issued for designated. The Standards for Biological
biotechnology products on the basis of discussion Materials were specified in May 2003 and
at ICH (Table 12). There are other notifications specifications for raw materials and packaging
issued in relation to medicinal products to be materials used in the manufacture of biological
developed and manufactured by using cells and products or raw materials and packaging materials
tissues and those products for gene therapy manufactured from biological materials and used in
(Table 3-xx). the manufacturing process for drugs, quasi-drugs,
cosmetics and medical devices were designated
(Notice No. 210 issued by the MHLW in 2003).
In 2013, regenerative medicine products were
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Pharmaceutical Regulations in Japan:
characterized in the law separately from drugs or Biological Products Subject to Changes in their
medical devices, and biological materials used in Manufacturing Process.” It is also necessary to
regenerative medicine products have been evaluate the comparability of biosimilars using
discussed to be standardized. In conjunction with clinical studies.
global trends for the BSE risk in bovine-derived raw Q&A on the Guidelines on the Assurance of
materials or the like in addition to the above, the Quality, Efficacy, and Safety of Biosimilar Products
Standards for Biological Materials were partially were published (Office Communication dated July
amended (Notice No. 375, issued by MHLW in 21, 2009, Office Communication dated March 31,
2014). 2010, and Office Communication dated December
15, 2015). Views of the regulatory authorities on
4.3 Biosimilar Products timing, definitions of equivalent products,
evaluations of comparability, development of
With the advances made in biotechnological
formulations and test methods, and safety
products, the development of similar
evaluations for biosimilar applications are included.
biotechnological products (biosimilar products or
The application for a biosimilar product is
follow-on biologics) equivalent to and the same
required to contain detailed procedures and
quality as existing biotechnological products is
programs of postmarketing surveillance and risk
being promoted overseas. Based on such
management as directed in Appendix 9 of the
technological advances, a Health Sciences Council
Guidelines on the Assurance of Quality, Efficacy,
Research Project entitled “Research on Quality,
and Safety of Biosimilar Products (Notification No.
Efficacy, and Safety Evaluation Methods for
0304007 of the Evaluation and Licensing Division,
Biosimilars” was established with funding from
PFSB dated March 4, 2009). The Guidelines on
MHLW, and the Guidelines on the Assurance of
the Risk Management Plan (RMP) issued later
Quality, Efficacy, and Safety of Biosimilar Products
(Notification No. 0426-(2) of the Evaluation and
were formulated (Notification No. 0304007 of the
Licensing Division, PFSB dated April 26, 2012)
Evaluation and Licensing Division, PFSB dated
requires to attach an RMP draft in the application
March 4, 2009). Biosimilars are defined as drugs
dossier.
developed by different marketing authorization
holders as drugs with the same quality, efficacy,
4.4 Public Disclosure of Information on
and safety as biotechnological products already
New Drug Development
approved as drugs with new active ingredients in
Japan. “Biosimilar” does not mean that the drug A notification concerning publication of
has exactly the same quality with the original information on new drug approvals was issued
biotechnological product, but that they are highly (Notification No. 1651 of the Evaluation and
similar in quality and characteristics and even if Licensing Division, PMSB dated November 11,
there are differences in quality and characteristics, 1999), and New Drug Approval Information
the differences can be scientifically judged not Packages containing summary reviews prepared
leading to any unintended effects on the efficacy by the MHLW and nonclinical and clinical data
and safety profiles of the final product. To prove submitted by the applicant have been published.
the comparability, appropriate studies are Thereafter, the methods of submitting data for
necessary based on the concepts in the ICH Q5E application were changed as specified in
guidelines “Comparability of Biotechnological/ “Disclosure of Information Concerning Approval
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Pharmaceutical Regulations in Japan:
Japan, the United States, and Europe, with the aim Step 4: Sign-off and adoption of the
of promptly supplying safe and effective new drugs guidelines
to the patients who need them. The ICH Steering Step 5: Regulatory implementation of the
Committee consists of six original parties of EU, guidelines according to regional
EFPIA, MHLW, JPMA, FDA, PhRMA as well as requirements
Swissmedic and Health Canada. In addition, Currently, over 70 topics (guidelines), including
WHO and IFPMA participate as an observer and a revised versions, have been agreed and approved
member (without the vote), respectively. To (Step 4 or 5) based on ICH activities. As shown in
discuss issues on an individual basis, expert Table 13 (ICH topics and guidelines - Progress of
working groups (EWGs) consisting of specialists harmonization).
and government officials from organizations were Visit the following homepage for details of ICH
established. Furthermore, in an attempt to cope guidelines.
with increasingly globalized drug development and Japanese:
regulations, organizational reform took place in https://www.pmda.go.jp/int-activities/int-harmony/ich
October 2015, and a new ICH corporation was /0014.html
established as an international nonprofit corporation English:
under the SWISS ACT to enhance further http://www.ich.org/home.html
international harmonization of pharmaceutical
affairs.
At present, it is made up of the general assembly
which consists of all members and serves as the
main body of the organization, the management
committee responsible for preparation for
discussion in the general assembly as well as for
operation of the organization, and working groups in
which specialists discuss the guidelines.
New ICH harmonization is conducted by the
following five steps.
Step 1: Selection and analysis of topics to
be addressed, analysis of issues,
establishment of EWGs, and
preparation of draft ICH guidelines
Step 2a: Consensus of regulatory authorities
and industry groups regarding
technical documents
Step 2b: Consensus among regulatory
authorities regarding public
consultation in each ICH region
Step 3: Regulatory consultation in the three
regions, call for public comments,
and revision of the draft guidelines
based on comments received
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Pharmaceutical Regulations in Japan:
Basic investigation
Screening tests
Nonclinical studies
1. Physicochemistry
2. Toxicity on GLP Ministry proper PMDA
3. Pharmacology & pharmacokinetics
Clinical trial consultation
Evaluation of nonclinical studies
Handling of clinical Receipt of the
Clinical trial notification to PMDA trial notification notification
Clinical studies
(Studies based on GCP)
1. Phase 1 Guidance as Review of the
2. Phase 2 investigation notification
3. Phase 3 required
Approval
review Pharmaceutical Affairs PMDA
and Food Sanitation
Council (PAFSC) Consultation Approval Compliance review
review
Experts GMP review
Advice
Notice of
review results
Evaluation committees MHLW
Pharmaceutical Inquiry (Pharmaceutical
Affairs Sections Evaluation Div, Minister of MHLW
Response PFSB) (final evaluation)
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Pharmaceutical Regulations in Japan:
Timeline of the standard process of new drug approval (ordinary review products)
The following timeline shows a rough indication of review timeNote 1) for individual review process,
according to the past records of approval reviews, to achieve the target total review time of 12 months
(ordinary review products) from application to approval for new drugs for which applications are made
from FY2014, assuming that no specific time-consuming situation may occur during the review.
Manufacturing/marketing authorization
Expert review
Review report
Application
PMDA
Compliance review
GMP inspection
Evaluation by
MHLW
PAFSC
Note 1) Past records of approval reviews for new drugs in FY2013 were used to determine a rough
indication of review time. The number of individual processes from application to approval used
in the calculation were as follows: Initial interview meeting: 35, Questions on key issues: 31,
Expert review: 85, Evaluation by PAFSC: 83, Manufacturing/marketing authorization: 96.
Note 2) Questions on key issues: First questions issued following the initial interview
Fig. 9 Timeline of the standard process of new drug approval (ordinary review products)
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Pharmaceutical Regulations in Japan:
Timeline of the standard process of new drug approval (priority review products)
The following timeline shows a rough indication of review timeNote 1) for individual review process,
according to the past records of approval reviews, to achieve the target total review time of 9 months
(ordinary review products) from application to approval for new drugs for which applications are made
from FY2014, assuming that no specific time-consuming situation may occur during the review.
Manufacturing/marketing authorization
Expert review
Review report
Application
PMDA
Compliance review
GMP inspection
Evaluation by
MHLW
PAFSC
Note 1) Past records of approval reviews for new drugs in FY2013 were used to determine a rough
indication of review time. The number of individual processes from application to approval used in
the calculation were as follows: Initial interview meeting: 12, Questions on key issues: 12, Expert
review: 34, Evaluation by PAFSC: 30, Manufacturing/marketing authorization: 31.
Note 2) Questions on key issues: First questions issued following the initial interview
Fig. 10 Timeline of the standard process of new drug approval (priority review products)
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Pharmaceutical Regulations in Japan:
Note 1) The marks and numbers in the columns on the right indicate the marks and numbers of the data
specified in Attached Table 1, and the marks have the following meanings, in principle: ○: Data
required ×: Data not required △: Data required depending on individual cases
Note 2) Note 1) in column on the right signifies as follows.
1) Only for applications that do not involve any change to information contained in the attached data, including
change to the manufacturing method or change to the testing method, the attachment of data under H is not
required, in principle.
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Therapeutic Explore use for the targeted Earliest studies of relatively short duration
exploratory indication in well-defined narrow patient
studies populations, using surrogate or
Dose-response exploration studies
pharmacological endpoints or clinical
Provide basis for confirmatory measures
study design, endpoints,
methodologies
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Guidelines for Assessment and Control of DNA Reactive (mutagenic) Notification No. 1110-(3) of the Evaluation and
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Licensing Division, PSEHB dated November 10,
2015 (ICH-M7)
Partially revised by Notification No. 0627-(1) of
the Pharmaceutical Evaluation Division, PSEHB
dated June 27, 2018
Matters to be considered in assuring and evaluating quality of nucleic acid Notification No. 0927-(3) of the Pharmaceutical
drugs Evaluation Division, PSEHB dated September
27, 2018
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
Principles for Clinical Evaluation of New Antihypertensive Drugs Notification No. 0128001 of the Evaluation and
Licensing Division, PMSB dated January 28, 2002
(ICH E12A, currently E12)
Guidelines on Clinical Evaluation of Antiarrhythmic Drugs Notification No. 0325035 of the Evaluation and
Licensing Division, PFSB dated March 25, 2004
Guidelines on Clinical Evaluation of Antianginal Drugs Notification No. 0512001 of the Evaluation and
Licensing Division, PFSB dated May 12, 2004
Guidelines for Clinical Evaluation of Antimalignant Tumor Drugs Notification No. 1101001 of the Evaluation and
Licensing Division, PFSB dated November 1,
2005, partially revised by Office Communication
dated November 2, 2005
Guidelines for Clinical Evaluation of Antirheumatoid Drugs Notification No. 0217001 of the Evaluation and
Licensing Division, PFSB dated February 17,
2006
Guidelines for Clinical Evaluation of Drugs for Overactive Bladder or Notification No. 0628001 of the Evaluation and
Incontinence Licensing Division, PFSB dated June 28, 2006
Guidelines for Clinical Evaluation of Prophylactic Vaccines against Notification No. 0527-(5) of the Evaluation and
Infections Licensing Division, PFSB dated May 27, 2010
Guidelines for Clinical Evaluation of Oral Hypoglycemic Drug Notification No. 0709-(1) of the Evaluation and
Licensing Division, PFSB dated July 9, 2010.
The draft amendment was presented on May 19,
2014
Guidelines for Clinical Evaluation of Antidepressant Drugs Notification No. 1116-(1) of the Evaluation and
Licensing Division, PFSB dated November 16,
2010
Guidelines on Clinical Evaluation of Drugs to Treat Heart Failure Notification No. 0329-(18) of the Evaluation and
Licensing Division, PFSB dated March 29, 2011
Guidelines for Clinical Evaluation of Therapeutic Drugs for Renal Anemia Notification No. 0930-(1) of the Evaluation and
Licensing Division, PFSB dated September 30,
2011
Guidelines on Clinical Evaluation of Hypnotics Notification No. 1213-(1) of the Evaluation and
Licensing Division, PFSB dated December 13,
2011
Guidance for Clinical Evaluation Method of Anticancer Drugs in Pediatric Notification No. 0930-(1) of the Evaluation and
Patients With Malignant Cancer Licensing Division, PFSB dated September 30,
2015
Guidance on Clinical Evaluation of Travelers' Vaccine, etc. Notification No. 0407-(1) of the Evaluation and
Licensing Division, PSEHB dated April 7, 2016
[2] Common guidelines for clinical evaluation
Studies in Support of Special Populations: Geriatrics Notification No. 104 of the New Drugs Division,
PAB dated December 2, 1993 (ICH-E7) and Q&A
dated September 17, 2010
Questions and Answers for "Studies in Support of Special Populations: Office Communication dated September 17, 2010
Geriatrics"
Dose-Response Information to Support Drug Registration Notification No. 494 of the Evaluation and
Licensing Division, PAB dated July 25, 1994
(ICH-E4)
Extent of Population Exposure to Assess Clinical Safety for Drugs Intended Notification No. 592 of the Evaluation and
for Long-term Treatment of Non-Life-Threatening Conditions Licensing Division, PAB dated May 24, 1995
(ICH-E1)
Structure and Content of Clinical Study Reports Notification No. 335 of the Evaluation and
Licensing Division, PAB dated May 1, 1996
(ICH-E3)
General Considerations for Clinical Trials Notification No. 380 of the Evaluation and
Licensing Division, PMSB dated April 21, 1998
(ICH-E8)
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Pharmaceutical Regulations in Japan:
Ethnic Factors to be Considered in the Acceptance of Foreign Clinical Trial Notification No. 672 of the Evaluation and
Data Licensing Division, PMSB dated August 11, 1998
(ICH E5, currently E5(R1)) Q&A by Office
Communication dated February 25, 2004, and
Q&A-(2) by Office Communication dated October
5, 2006
Statistical Principles for Clinical Trials Notification No. 1047 of the Evaluation and
Licensing Division, PMSB dated November 30,
1998
(ICH-E9)
Clinical Investigation of Medicinal Products in the Pediatric Population Notification No. 1334 of the Evaluating and
Licensing Division, PMSB dated December 15,
2000
(ICH-E11)
Supplement to Clinical Investigation of Medicinal Products in the Pediatric Notification No. 1227-(5) of the Pharmaceutical
Population Evaluation Division, PSEHB dated December 27,
2017 (ICH-E11 (R1))
Choice of Control Group and Related Issues in Conducting Clinical Studies Notification No. 136 of the Evaluating and
Licensing Division, PMSB dated February 27,
2001, partially revised by Office Communication
dated April 10, 2001
Guidance for Conducting Microdose Clinical Studies Notification No. 0603001 of the Evaluating and
Licensing Division, PFSB dated June 3, 2008
Clinical Investigation of QT/QTc Interval Prolongation and Proarrhythmic Notification No. 1023-(1) of the Evaluating and
Potential for Non-antiarrhythmic Drugs Licensing Division, PFSB dated October 23, 2009,
Q&A by Office Communication dated October 23,
2009, and Q&A-(2) by Office Communication
dated July 3, 2012
Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Notification No. 0219-(4) of the Evaluation and
Trials and Marketing Authorization for Pharmaceuticals Licensing Division, PFSB dated February 19,
2010 (ICH-M3(R2)) and Q&A by Office
Communication dated August 16, 2012
General Principles for Planning and Design of Multi-Regional Clinical Trials Notification No. 0612-(1) of the Pharmaceutical
Evaluation Division, PSEHB dated June 12, 2018
(ICH-E17)
[3] Other guidelines for clinical evaluation
Research on Evaluation of Immunotherapeutic Agents for Malignant Iyakuhin Kenkyu 11(4), 1980
Tumors
Research on Evaluation of Blood Preparations, Especially Plasma Fraction Iyakuhin Kenkyu 15(2), 1984
Preparations
Research on Overall Evaluation of Interferon Preparations Iyakuhin Kenkyu 15(6), 1984
Guidelines on Clinical Evaluation of Anti-inflammatory Analgesic Drugs Iyakuhin Kenkyu 16(3), 1985
Guidelines on the Design and Evaluation of Sustained-release (Oral) Notification No. 5 of the First Evaluation and
Preparations Registration Division, PAB dated March 11, 1988
Guidance for Developing Prototype Vaccines in Preparation for Influenza Notification No. 1031-(1) of the Evaluation and
Pandemic Licensing Division, PFSB dated October 31, 2011
Guidance for Clinical Evaluation of Diagnostic Radiopharmaceuticals Notification No. 0611-(1) of the Evaluation and
Licensing Division, PFSB dated June 11, 2012
Points to Consider in Application of Companion Diagnostics and Related Notification No. 0701-(10) of the Evaluation and
Drug Products Licensing Division, PFSB dated July 1, 2013
Technical Guidance for Companion Diagnostics and Related Drug Products Office Communication dated December 26, 2013
Guideline for PK/PD of Antibacterial Agents Notification No. 1225-(10) of the Evaluation and
Licensing Division, PSEHB dated December 25,
2015
Guideline for Development of Liposomal Preparations Notification No. 0328-(19) of the Evaluation and
Licensing Division, PSEHB dated March 28, 2016
Reflection Paper on Nucleic Acid (siRNA)-Encapsulated Nanoparticle Office Communication dated March 28, 2016
Formulations
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N
o
n
Module 1 C
Administrative
T
information:
D
1.1: NDA TOC
2.1: TOC
2.2: Introduction
Module 2
2.4: Nonclinical 2.5: Clinical
Overview Overview
2.3: Quality
overall 2.6: Nonclinical
summary Written and
2.7:
C
Clinical
Tabulated
Summary
Summaries T
D
Module 3 Module 4 Module 5
Quality Safety Efficacy
3.1: TOC 4.1: TOC 5.1: TOC
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Pharmaceutical Regulations in Japan:
This matrix graph illustrates the relationship between the phases of development
and types of study by objective that may be conducted during each clinical development
of a new medicinal product. The shaded circles show the types of study most usually
conducted in a certain phase of development, the open circles show certain types of
study that may be conducted in that phase of development but are less usual. Each
circle represents an individual study. To illustrate the development of a single study, one
circle is joined by a dotted line to an inset column that depicts the elements and
sequence of an individual study.
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Pharmaceutical Regulations in Japan:
Quality
Code Topics
Step 5 Q1A(R2) Stability testing: New drug substances and products
Q1B Stability testing: Photostability
Q1C Stability testing: New & partially revised dosage forms
Q1D Stability testing: Bracketing and matrixing designs
Q1E Stability testing: Evaluation of stability data
Q2(R1) Validation of analytical procedures: Text and methodology
Q3A(R2) Impurities in new drug substances
Q3B(R2) Impurities in new drug products
Q3C(R5) Impurities: Residual solvents
Q3D Guideline for metal impurities
Q4B Pharmacopoeias: Harmonized texts for use in ICH regions
Q4B(Annex1)(R1) Test for residue on ignition
Q4B(Annex2)(R1) Test for extractable volume of parenteral preparations
Q4B(Annex3)(R1) Test for particulate contamination of parenteral preparations
Q4B(Annex4A, 4B, 4C) (R1) Microbial limit tests of non-sterile products
Q4B(Annex6)(R1) Uniformity of dosage units
Q4B(Annex5)(R1) Disintegration test
Q4B(Annex7)(R2) Dissolution test
Q4B(Annex8)(R1) Sterility test
Q4B(Annex9)(R1) Tablet friability test
Q4B(Annex10)(R1) Polyacrylamide gel electrophoresis
Q4B(Annex11) Capillary electrophoresis
Q4B(Annex12) Analytical sieving
Q4B(Annex13) Bulk density and tapped density of powders
Q4B(Annex14) Bacterial endotoxins test
Q5A(R1) Quality of biotechnology products: Viral bioburden
Q5B Quality of biotechnology products: Genetic stability
Q5C Quality of biotechnology products: Stability Testing of products
Q5D Quality of biotechnology products: Cell bank control (cell substrates)
Q5E Quality of Biotechnology Products: Comparability of products
Q6A Specifications/test methods: Chemicals/pharmacopoeial harmonization
Q6B Specifications/test methods: Biological products
Q7 GMP for active pharmaceutical ingredients
Q8(R2) Pharmaceutical development
Q9 Quality risk management
Q10 Pharmaceutical quality system
Q11 Manufacturing and development of active pharmaceutical ingredients
Step 4 Q3C(R5) Impurities: Residual solvents (Revision)
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Pharmaceutical Regulations in Japan:
Quality
Code Topics
Step 3
Step 2a/2b
Step 1
Pre-Step 1 Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management
Safety
Code Topics
Step 5 S1A Need for carcinogenicity studies
S1B Testing of carcinogenicity of pharmaceuticals
S1C(R2) Dose selection for carcinogenicity studies
S2(R1) Genotoxicity
S3A Toxicokinetics: Assessment of systemic exposure in toxicity studies
S3B Pharmacokinetics: Repeated-dose tissue distribution
S4 Single- and repeated-dose toxicity studies
S5(R2) Reproduction studies of medicinal products
S6(R1) Safety evaluation of biological products
S7A Safety pharmacology studies
S7B The non-clinical evaluation of QT interval prolongation potential
S8 Immunotoxicology studies
S9 Non-clinical evaluation of anticancer drugs
S10 Guidance on photosafety testing
Step 4
Step 3
Step 2a/2b
Step 1
Pre-Step 1 S1 Testing of carcinogenicity of pharmaceuticals (review of guideline)
S5(R3) Reproduction studies of medicinal products (Revision)
S11 Nonclinical safety testing in support of development of pediatric medicines
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Efficacy
Code Topics
Step 5 E1 The extent of population exposure to assess clinical safety for drugs intended for long-term treatment of non-life
threatening condition
E2A Clinical safety data management: Definitions and standards for expedited reporting in the clinical phase
Data elements for transmission of individual case safety reports
E2B(R2) Implementation guide – data elements and message specification in individual case safety reports (ICSR)
E2B(R3) Periodic Benefit-Risk Evaluation Report(PBRER)
Post-approval safety data management
E2C(R2) E2D Pharmacovigilance planning (PVP)
E2E E2F Development of safety update report (DSUR)
E3 Structure and content of clinical study reports
E4 Dose-response information to support drug registration
E5(R1) Ethnic factors in the acceptability of foreign clinical data
E6(R1) Guidance for good clinical practice
E7 Studies in support of special populations: Geriatrics
E8 General considerations for clinical trials
E9 Statistical principles for clinical trials
E10 Choice of control group and related issues in clinical trials
E11 Clinical investigation of medicinal products in the pediatric population
E12 Principles for clinical evaluation of new antihypertensive drugs
E14 The clinical evaluation of QT interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs
E15 Definitions for genomic biomarkers, pharmacogenomics, pharmaco- genetics, genomic data, and sample coding
categories
E16 Genomic biomarkers related to drug response: Context, structure and format of qualification submissions
Step 4 E6(R2) Guideline for good clinical practice (Supplement)
Step 3 E11(R1) Clinical investigation of medicinal products in the pediatric population
E17 General principle on planning/designing multi-regional clinical trials
E18 Gnomic sampling methodologies for future use
Step 2a/2b
Step 1
Pre-
E9(R1) Statistical principles for clinical trials (Supplement)
Step 1
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Multidisciplinary
Code Topics
Step 5 M1 Medical dictionary for regulatory activities (MedDRA)
M2 Electronic standards for transmission of regulatory information
M3(R2) Non-clinical safety studies for the conduct of human clinical trials
M4 Common Technical Document
M8 e-CTD specification (v. 3.2.2)
M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to reduce potential carcinogenic
risk
Step 4 M8 e-CTD specification (v.4.0)
M4E(R2) Guideline on enhancing the format and structure of benefit-risk information in CTD
Step 3 M7(R1) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to reduce potential carcinogenic
risk (Supplement)
Step 2a/2b
Step 1
Pre- M9 BCS-based biowaivers
Step 1 M10 Bioanalytical Method Validation
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data.
CHAPTER 4
Periodic reporting of safety information on new
drugs, etc. was agreed at the ICH in January 1996,
POST-MARKETING
and the periodic safety update report (PSUR)
SURVEILLANCE OF DRUGS system was introduced by Notification No. 32 of the
Safety Division, PMSB dated March 27, 1997 to
replace the previous annual reporting system with
the PSUR (MHW Ordinance No. 29 dated March
Post-marketing surveillance (PMS) to assure the
27, 1997) and the Guidelines on Methods for
quality, efficacy and safety of drugs after they go on
Surveillance of Results of Use of Prescription Drugs
the market and to establish proper methods of use
(Notification No. 34 of the Safety Division, PMSB
of drugs consists of three systems: the ADRs and
dated March 27, 1997) were specified for drug
infections collection and reporting system, the
use-result surveys to be intensively implemented
reexamination system, and the reevaluation system
after marketing. However, because of an increase
(Fig. 13 Pharmaceutical Post-marketing
in post-marketing ADRs not observed in the clinical
Surveillance System).
trial stage of drug development and implementation
The re-examination system for new drugs was
of safety measures, regulations on safety measured
introduced in the October 1979 amendment of the
for drugs (Notification No. 25 of the Safety Division,
Pharmaceutical Affairs Law, and Good
PMSB) and entries in case report forms for ADRs
Post-marketing Surveillance Practice (GPMSP)
and infections (Office Communication) were
came into effect from April 1993 to assure proper
specified in March 11, 1998. Furthermore,
implementation of PMS and also to assure the
additional guidelines, “Periodic Infection Reporting
reliability of such PMS data. Thereafter, major
System for Biological Products” (Notification No.
revisions were made in the Pharmaceutical Affairs
0515008 of the PMSB dated May 15, 2003) and
Law and its Enforcement Regulations in 1996 to
“Implementation of Early Post-marketing Phase
1997 to further strengthen post-marketing safety
Vigilance for Prescription Drugs” (Notification No.
measures, and the GPMSP, which had formerly
0324001, the Safety Division, PFSB dated March
been considered as an administrative notification,
24, 2006) were issued to further strengthen the
became law in “MHW Ordinance for Good
safety monitoring of medical products (Fig. 14
Post-Marketing Surveillance Practice of Drugs
Post-marketing Collection and Reporting of
(Drug GPMSP)” and came into effect in April 1997
Pharmaceutical Safety Information).
(MHW Ordinance No. 10 dated March 10, 1997).
In the revised Pharmaceutical Affairs Law
The Drug GPMSP was partially revised by MHW
enforced on April 1, 2005, the historical
Ordinance No. 151 dated December 27, 2000, and
manufacturing approval system was changed to the
“Early Post-marketing Phase Vigilance” for new
marketing (as well as manufacturing) authorization
drugs was newly established to reinforce safety
system to internationally harmonize the concept of
measures in an early phase of marketing (enforced
approval system, and the part that deals with the
from October 1, 2001).
collection, evaluation, and assessment of
The GPMSP is applied as standards requiring
information for appropriate use of post-marketing
compliance by manufacturers or importers when
safety measures of the MHLW Ordinance on
performing post-marketing surveillance or studies,
GPMSP related to the implementation of safety
and also as compliance criteria for preparation of
assurance measures was separated from the part
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that deals with tests and surveillance conducted to and Studies on Drugs (Related to MHLW Ordinance
collect and assess materials for reexamination and Related to Standards for Conducting
reevaluation. The former has been specified in the Post-Marketing Surveys and Studies on Drugs)"
MHLW Ordinance on GVP (MHLW Ordinance (Notification No. 1026-(1) of the Evaluation and
Related to Standards for Post-Marketing Safety Licensing Division, PSEHB dated October 26, 2017)
Management of Drugs, quasi-drugs, Cosmetics and was issued and enforced on April 1, 2018. In
Medical Devices, MHLW Ordinance No. 135 dated association with this revision, "Procedures for
September 22, 2004), and the latter in the MHLW Developing Post-marketing Database Survey Plan"
Ordinance on GPSP (MHLW Ordinance Related to was presented by PMDA in January 2018 as a
Standards for Conducting Post-Marketing Surveys reference for preparation of a post-marketing
and Studies on Drugs; MHLW Ordinance No. 171 database survey plan, and "Points to Consider for
issued by MHLW on December 20, 2004). The Ensuring Reliability in Post-marketing Database
MHLW Ordinance on GPMSP was abolished. Surveys of Drugs" (Notification No. 0221-(1) of the
The Guidelines on Pharmacovigilance Planning Pharmaceutical Evaluation Division, PSEHB dated
(ICH E2E guidelines) (Notification No. 0916001 of February 21, 2018) was issued in February 2018.
the Evaluation and Licensing Division, PFSB and Moreover, since this revision clarified the positioning
Notification No. 0916001 of the Safety Division, of post-marketing surveys using medical information
PFSB both dated September 16, 2005) were issued database as a technique of post-marketing surveys,
with an objective of guiding and assisting the and implementation of efficient and effective surveys
applicant in planning pharmacovigilance activities for with the choice of the scientific technique for the
new drug in the early post-marketing phase. Since objectives of the survey has come to be required,
the operation of the Medical Information Database "How to Proceed with Examination for Development
System (MID-NET) developed by PMDA is of Plans for Post-marketing Surveys, etc." was
expected to start on a full scale, and the proposed by PMDA on January 23, 2018 and the
environment for utilizing the medical information procedure of basic examination for development of
database in pharmacovigilance is being established, a plan for conducting post-marketing surveys, etc.
"Basic Concept of the Use of Medical Information was proposed.
Database in Post-marketing Pharmacovigilance " In 2012, the Risk Management (RMP) Guidance
(Notification No. 0609-(8) of the Pharmaceutical (Notification No. 0411-(1) of the Safety Division,
Evaluation Division, PSEHB / Notification No. PFSB and No. 0411-(2) of the Evaluation and
0609-(4) of the Safety Division, PSEHB dated June Licensing Division, PFSB both dated April 11, 2012)
9, 2017) was issued in June 2017. Thus, the basic was issued to support the manufacturing/marketing
concept to be applied when a marketing authorization holder in developing the RMP
authorization holder for drugs use the medical including risk minimization plans for the reduction of
information database in post-marketing treatment-related risks in addition to conventional
pharmacovigilance was presented. Subsequently, pharmacovigilance plans following drug approval.
the GPSP Ministerial Ordinance was revised on These Notifications are applicable to
October 26, 2017 to add "post-marketing database manufacturing/marketing approval application for
survey" as a type of post-marketing survey. new drugs and biosimilar products submitted on or
"Announcement of Ministerial Ordinance Partially after April 1, 2013 and August 26, 2014,
Revising Ministerial Ordinance Related to respectively. Further, the MHLW Ordinances on
Standards for Conducting Post-Marketing Surveys GVP and GPSP were revised on March 11, 2013 to
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ensure the development and subsequent the standards for post-marketing safety
implementation of risk management plan (RMP). In management of drugs, quasi-drugs, cosmetics,
March 2016, “Preparation and publication of drug medical devices and regenerative medicine
risk management plan” (Notification No. 0331-(13) products) was partially revised to be the standards
of the Evaluation and Licensing Division, PSEHB for licensing manufacturing/marketing business of
and Notification No. 0331-(13) of the Safety Division, regenerative medicine product and to include the
PSEHB both dated March 31, 2016) and “Points to provisions for subcontract of post-marketing safety
be considered in submission of publication management tasks specified in Article 18,
documents of drug risk management plan” Paragraph 3, etc. in the Law (Article 98 in the
(Notification No. 0331001 of the Office of Safety, Enforcement Regulations).
PMDA dated March 31, 2016) were issued. To Furthermore, the GPSP Ordinance for
promote use of RMPs in clinical practices, these regenerative medicine products was newly issued in
notifications presented points to be considered in response to the new approval system established in
preparation and publication of RMP synopsis as well consideration of characteristics of regenerative
as submission of publication documents to medicine products (the MHLW Ordinance for
PMDA."Description on Materials Prepared and standards for conducting post-marketing surveys
Distributed for Additional Risk Minimization Activities and studies on regenerative medicine products;
in Risk Management Plan (RMP)" (Office 2014 MHLW Ordinance No. 90, dated July 30,
Communication dated June 8, 2017) was issued. 2014). To conduct use-results survey or
It was decided to display RMP marks on the post-marketing clinical study of a regenerative
materials for health professionals and the materials medicine product, applicable documents have to be
for patients in order to enable health professionals to prepared under this ordinance. More specific
be aware that the materials such as the guide to handling procedures were shown in the notification
proper use are based on the drug risk minimization “Description methods of basic plan for evaluation of
activities in RMP. In addition, "Partial Revision of post-marketing approval conditions and basic plan
'Publication of Drug Risk Management Plan'" of post-marketing surveys for regenerative medicine
(Notification No. 1029-(1) of the Pharmaceutical products” (Notification No. 0826-(1) of the Medical
Evaluation Division, PSEHB and Notification No. Devices Division, PFSB dated August 26, 2015).
1029-(1) of the Safety Division, PSEHB dated Since the environment for using medical information
October 29, 2018) was issued, and placement of database for collection of post-marketing safety
the materials prepared based on RMP for health information, etc. for cellular and tissue-based
professionals and for patients on the website of products, etc. is being established, the GPSP
PMDA was decided. Ordinance was partially revised and enforced also
The Law for Partial Amendment of the for cellular and tissue-based products in the same
Pharmaceutical Affairs Law (Law No. 84, 2013) was way as drugs.
issued on November 27, 2013, in which Based on the Guidelines, Periodic Safety
regenerative medicine products were newly defined. Update Reports (PSUR) for Marketed Drugs which
In line with the provisions in Article 23-21, Item 2 in objective was the standardization of the format and
the revised Law, the “Law for Ensuring the Quality, time of safety reporting, the new Guidelines, the
Efficacy, and Safety of Drugs and Medical Devices” Periodic Benefit-Risk Evaluation Report (PBRER:
(Pharmaceutical and Medical Device Act), the ICH E2C (R2)) with the objective of assessing not
MHLW Ordinance on GVP (MHLW Ordinance for only risks but also integrated risk-benefit balance
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and a guidance for assisting safety report writing marketed drugs, etc., and to the implementation of
was issued (Notification No. 0517-(1) of the measures for safety assurance. On March 11,
Evaluation and Licensing Division, PFSB both dated 2013, the GVP was revised to incorporate the RMP
May 17, 2013). In August 2014, Q&A on PBRER in the GVP guidelines.
was also issued (Office Communication, August 25, The extent of duties of the manufacturing/market
2014). authorization holder in post-marketing safety
The use of the Medical Dictionary for Regulatory management to be entrusted to third parties is
Activities (MedDRA) as agreed by ICH is defined in the Ordinance for Enforcement of the
recommended to standardize international Pharmaceutical and Medical Device Act.
regulatory-related medical terminology (M1) use at This GVP consists of 17 articles. A summary is
all regulatory levels before and after marketing for provided below.
regulatory communication in registration, records,
(1) Purpose (Article 1)
and safety monitoring of drugs. Efforts are being
This Ministerial Ordinance establishes the
made to achieve international coordination of
standards established by the MHLW Ordinance
terminology related to pharmaceutical regulations
related to post-marketing safety management
(adverse reactions, signs and symptoms, diagnosis,
set forth in Article 12-2, Paragraph 2 of the
indications, laboratory tests, surgical and
Pharmaceutical and Medical Device Act.
conservative interventions and patient
characteristics). Since the end of March 2000, it (2) Definitions of terms (Article 2)
has been possible to use MedDRA for clinical trial [1] Safety management information refers to
data, reexamination and reevaluation data and material relating to the quality, efficacy or
package inserts. It is used in data input, retrieval, safety of drugs etc. and any other
evaluation, and presentation at both the pre- and information required for the proper use of
post-marketing regulatory stages for drugs. From drugs, etc.
October 27, 2003, it became obligatory to use [2] Quality assurance activities refers to any
MedDRA in individual case safety reports to be activity related to post-marketing quality
submitted to the PMDA in accordance with the control concerned with requisite
ADRs and Infections Reporting System. MedDRA measures based on the collection and
is maintained by the Maintenance and Support study of safety management information,
Service Organization (MSSO) and two new or on the results.
versions are generally published each year. [3] The RMP refers to safety assurance
activities including clinical information
collection, post-marketing surveys,
1. GVP clinical studies, and other activities for
Good Vigilance Practice (GVP) establishes minimizing potential risks inherent in the
standards for post-marketing safety management use of new drugs, etc. with an objective
related to the collection, evaluation, and assessment of adequate risk control of new drugs, etc.
of proper use information on the establishment of by analyzing safety and efficacy
appropriate safety-related organizations and information to be thus obtained and
systems as one of licensing requirements for the implementing necessary safety
manufacturing/marketing authorization holder, assurance measures. These activities
development and implementation of relevant SOPs, are undertaken by the
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procedures for post-marketing safety [3] Items required for proper and smooth
management must be prepared. implementation of safety assurance
Procedures for collection of safety activities must be specified in writing.
management information [4] When the procedures in [1] or the
Procedures for drafting of safety documents in [2] and [3] are prepared or
assurance measures based on revised, they must be dated and
examination of safety management retained.
information and the results thereof [5] The general marketing compliance
Procedures for implementation of safety officer shall make available the
assurance measures procedures in [1], the documents in [2]
Procedures for reporting from safety and [3] and other documents required for
management supervisors to general safety assurance work in the office
marketing compliance officer performing the work and also must make
Procedures for reporting from safety available copies of procedures and other
management implementation supervisor related documents in other offices
to safety management supervisors performing safety assurance work.
Procedures for implementing the RMP
(6) Duties of the safety management
(including procedures for early
supervisor (Article 6)
post-marketing phase vigilance) when
[1] The safety management supervisor shall
the RMP is required in practice
perform the following duties:
Procedures for in-house inspections
Overall supervision of safety assurance
Procedures for education and training
work
Procedures for retention of records
Confirmation that safety assurance work
Procedures for mutual cooperation with
is being performed properly and
quality assurance supervisors and other
smoothly and preparation and retention
supervisors engaged in work related to
of records of such confirmation
marketing of prescription drugs, highly
Offering of opinions in writing to general
controlled medical devices, or cellular
marketing compliance supervisor when
and tissue-based products
safety assurance work is required and
Procedures for collaborating with the
retention of copies of such opinions
supervisors on post-marketing
To closely collaborate with the supervisor
surveillance and other post-marketing
of post-marketing surveys, etc. in
obligations when the RMP is required in
implementing the RMP.
practice
Other procedures necessary for properly (7) Collection of safety management
and smoothly implementing safety information (Article 7)
assurance measures of post-marketing [1] The following safety management
surveillance information shall be collected by the
[2] The duties and management system for safety management supervisor and
persons employed for work related to safety management implementation
post-marketing safety management must supervisor and records thereof shall be
be specified in writing. prepared.
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records and make reports in writing. (10) Risk management plan (RMP) (Article
The copies shall be given to the safety 9-(2))
management supervisor. [1] The general marketing compliance
[2] The safety management supervisor shall officer or the safety management
perform the following duties: supervisor must undertake the following
Safety assurance measures shall be duties in implementing the RMP:
undertaken based on instructions from Preparation of protocol for individual
the general marketing compliance officer RMPs (“RMP protocol”) that contain the
and records thereof shall be prepared following information:
and retained. Specific safety and efficacy issues to be
When safety assurance measures are addressed
undertaken by safety management Outline of plans and procedures for
implementation supervisors, instructions information collection, survey, and study
shall be issued in writing and copies shall of safety and efficacy issues to be
be retained. Records shall be prepared, resolved
reported in writing and retained. Outline of risk minimization activities
The results of implementation of safety Time schedules of the RMP
assurance measures shall be reported in implementation status and evaluation
writing to the general marketing Other necessary items
compliance officer, and copies shall be Revision of the RMP protocol as
retained. situations may require
Copies of reports from the safety When the RMP protocol is prepared or
management implementation supervisor revised, the protocol shall be dated and
shall be retained. retained.
[3] Evaluation of drafts of safety assurance [2] The general marketing compliance
measures for which post-marketing officer must make available the RMP
safety management standard operating protocol in his/her office and also must
procedures have been specified make available copies of the RMP
beforehand, deciding on safety protocol specifying assigned activities
assurance measures to be taken, and and procedures in other offices
preparation and retention of records can performing the compliance activities.
be undertaken by the safety [3] The safety management supervisor must
management supervisor in place of the confirm that the RMP is being adequately
general manufacturing/marketing and smoothly implemented, and shall
supervisor. In this case, necessary retain records of such confirmation.
matters regarding the works prescribed [4] Whenever performing RMP-related
in [1] and [2] should be stipulated in the activities, the safety management
standard operating procedures for implementation supervisor must records
post-marketing safety management, etc. the activities performed and report the
activities in writing to the safety
management supervisor, and the safety
management supervisor must retain the
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shall undertake the specified measures mutandis with the exception of the following:
and prepare records thereof. The [1] Establishment of a safety management
safety management supervisor shall division is not specified.
retain these records. [2] No qualifications for safety management
supervisors are specified.
(13) Education and training (Article 12)
[3] No qualifications for a safety
[1] The general marketing compliance
management implementation supervisor
officer shall prepare and retain education
are specified.
and training protocols for employees
engaged in duties related to (15) Standards for post-marketing safety
post-marketing safety management management of type 3 marketing
[2] Education and training shall be authorization holders (Marketing
performed as planned by a person authorization holders of quasi-drugs,
appointed beforehand. cosmetics and ordinary medical
[3] When the person appointed beforehand devices) (Articles 15)
in [2] is the safety management The standards for type 1 marketing
supervisor, the safety management authorization holders shall apply mutatis
supervisor shall prepare and retain mutandis with the exception of the following:
records of education and training. [1] [1] to [3] in Article (14) above.
[4] When the person appointed beforehand [2] Standard operating procedures for
in [2] is a person other than the safety post-marketing safety management are
management supervisor, that person not specified.
shall prepare records of education and [3] Collection of safety information in (7) for
training and report in writing to the safety quasi-drugs and cosmetics is limited to
management supervisor. The safety research reports and other safety
management supervisor shall retain management information.
these reports. [4] In-house inspections and education and
[5] The safety management supervisor shall training are not specified.
report the results of the education and
(16) Retention of records related to safety
training in writing to the general
assurance (Article 16)
marketing compliance officer and shall
[1] The period of retention of 5 years from
retain a copy of the report.
the date when the records are no longer
(14) Standards for post-marketing safety utilized. However, the period shall be
management of type 2 marketing 10 years for biological products and
authorization holders (marketing cellular and tissue-based products, 30
authorization holders of drugs other years for specified biological products
than prescription drugs and controlled and specified cellular and tissue-based
medical devices, including marketing products, and 15 years for designated
authorization holders of in vitro controlled medical devices and highly
diagnostics) (Articles 13 and 14) controlled medical devices. Records
The standards for type 1 marketing related to in-house inspections and
authorization holders shall apply mutatis education and training shall be kept for 5
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In cases in which a person other than the are capable of properly and effectively carrying
supervisor of post-marketing surveys, etc. out these activities.
conducts an in-house inspection, the
(11) Preservation of records in connection
supervisor of post-marketing surveys, etc.
with post-marketing surveys, etc.
is to be notified in writing of the results of
(Article 11)
the inspection.
Records of reexamination and reevaluation
Records of the results of the in-house
data must be retained for 5 years from the date
inspection are prepared and preserved.
that reexamination or reevaluation is completed.
[2] Post-marketing surveillance supervisors
Other records must be preserved for 5 years
must report in writing the results of the
from the date they are no longer in actual use
self-inspections to the
or date of the final entry.
manufacturing/marketing authorization
holder. (12) Standards for Compliance of
[3] When it is found that improvements must Reexamination and Reevaluation Data
be made in the work based on the results in Connection with Post-marketing
of the self-inspection, the necessary Surveillance (Article 12)
measures must be taken, and records of In addition to provisions of the GCP MHLW
these measures must be prepared and Ordinance, the provisions of Article 3 through
retained. Article 8, Article 10, and Article 11 of this GPSP
MHLW apply mutatis mutandis to the collection
(9) Education and training (Article 9)
and preparation of data for reexamination and
[1] Planned education and training related to
reevaluation applications in connection with
post-marketing surveillance must be
post-marketing surveys, etc.
performed by the post-marketing
surveillance supervisors or other persons
designated by the 3. PAPER COMPLIANCE REVIEW AND
manufacturing/marketing authorization ON-SITE GPSP SURVEYS OF DATA FOR
holder for persons employed in REEXAMINATION AND REEVALUATION
post-marketing surveillance work. Documents and data submitted for
[2] In cases in which education and training reexamination and reevaluation of a drug are
are performed by a person other than the subject to paper compliance review and on-site
supervisor of post-marketing surveys, GPSP surveys in order to examine whether the
etc., the supervisor of post-marketing materials for evaluation have been collected in
surveys, etc., is notified in writing of the accordance with the standards specified by the
conditions of its implementation. MHLW minister. Detailed procedures for the
[3] Records of education and training are compliance review and on-site surveys are available
prepared and preserved. as “the Guidelines on Compliance Paper Reviews
(10) Delegation of duties of post-marketing on Approval Application Data for New Drugs”
surveys, etc, (Article 10) (Notification No. 1121-(5) of the Evaluation and
The manufacturing/marketing authorization Licensing Division, PFSB dated November 21,
holder may assign some of the duties of 2014), and “the Guidelines for Implementation of
post-marketing surveys, etc. to persons who GPSP On-site Surveys” (Notification No. 0330003
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quasi drugs and cosmetic products was also 4.2 Drug and Medical Device Safety
stipulated. Furthermore, "Q&As on ADR Reporting Information Reporting System by
in Post-marketing Surveillance and Clinical Trials in Medical Personnel
accordance with the Implementation Guide for
This is a MHLW reporting system that directly
Electronic Transmission of Individual Case Safety
collects safety information from health
Reports (ICSRs) (E2B (R3))" (Office
professionals. Because of the need for collection
Communication dated March 31, 2017) was
of further information required for post-marketing
published.
product safety strategies, the limitation on
Furthermore, the procedures including
reporting facilities was eliminated in July 1997.
precautions for reception and reporting of the
This system has been expanded and revised to
reports of post-marketing adverse reactions and
include all medical institutions and pharmacies,
adverse reactions in clinical studies were partially
and the reporting format has been simplified in
revised, and "Points to Consider in ADR Reporting
order to further increase the number of reports
in Post-marketing Surveillance and Clinical Trials in
from physicians, dentists, and pharmacists.
accordance with the Implementation Guide for
Furthermore, the need of report as the duty of
Electronic Transmission of Individual Case Safety
medical personnel was specified in the
Reports (ICSRs) (E2B (R3))" (Notification No.
Pharmaceutical Affairs Law in July 2003 (Article
0331001 of the Office of Review Management of
77-(4)-2-2).
PMDA / Notification No. 0331001 of the Office of
* The Pharmaceutical Affairs Law revised
Safety I of PMDA / Notification No. 0331002 of the
on June 14, 2006 also requests the
Office of Safety II of PMDA dated March 31, 2017)
registered manufacturing/marketing
was issued. As related notifications, "Corrections
authorization holder to report safety
on Implementation Guide for electronic
information.
Transmission of Individual Case Safety Reports"
The information subject to reporting includes
(Notification No. 0315-(6) of the Pharmaceutical
adverse reactions associated with the use of
Evaluation Division, PSEHB / Notification No.
prescription medicines, over-the-counter drugs,
0315-(1) of the Safety Division, PSEHB dated
medical devices, etc. with the exception of mild,
March 15, 2017) and "Q&A on Electronic
well-known adverse events, even though a causal
Transmission of Individual Case Safety Reports"
relationship with the drug concerned is unclear.
(Office Communication dated November 8, 2018)
When drugs and related products require
were published.
especially intensive investigation and collection of
From January 2006, access to all cases of
information, the MHLW selects medical
suspected adverse drug reactions reported by
institutions and, if necessary, performs "early
companies has been possible on the
post-marketing phase safety information collection
homepage of the PMDA.
program (fixed-point survey)" in collaboration with
http://www.pmda.go.jp/safety/info-services/drugs/
them.
adr-info/suspected-adr/0005.html
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view of the deformation scandal caused by Medicine Products and Biological Products" (Office
thalidomide in 1961, the World Health Organization Communication dated July 29, 2017) was issued in
(WHO) first implemented an international July 2017.
drug-monitoring program in 1968. Adverse drug
reaction data is collected from all participating
6. REEXAMINATION SYSTEM (ARTICLE 14-4
member states, and a summary of the results of
AND 23-29 OF THE PHARMACEUTICAL
evaluation of this information is sent back to each
AFFAIRS LAW)
country. Japan became a member of this program
in 1972. Information about adverse drug reactions The reexamination system is aimed at
that occur in Japan has been reported to WHO, and reconfirmation of the clinical usefulness of drugs by
likewise, WHO has provided any necessary performing GPSP or GVP as one aspect of PMS,
information to Japan. There is also information through collecting information on the efficacy and
exchange with countries including the United States, safety of the drug during a specified period of time
Great Britain, and Germany. after approval. This system was commenced in
April 1980. Based on the revision of October 1993,
the reexamination period for orphan drugs was
5. PERIODIC INFECTION REPORTS FOR
extended to a maximum of 10 years.
BIOLOGICAL PRODUCTS (ARTICLE 68-14
There are limitations on the quantity and quality
AND 68-24 IN THE LAW)
of data submitted for review at the time of approval
With the revision of the Pharmaceutical Affairs of a new drug. Examples of such limitations
Law in July 2002, drugs manufactured from include relatively small numbers of subjects in
materials derived from humans or other living clinical studies performed prior to approval, relatively
organisms (excluding plants) that require caution in short use data of the drug, and lack of experience
terms of public health and hygiene are designated using the drug under diverse conditions such as
as biological products by the MHLW, as a lesion concomitant medication, complications, and age.
from incidents of AIDS infection and There are limitations on confirmation of all of these
Creutzfeldt-Jacob disease due to contaminated aspects before approval.
blood coagulation factors. From July 30, 2003, the It is, therefore, obligatory for
system of periodic infection reports was introduced manufacturing/marketing companies to perform
by which manufacturers of such biological products postmarketing surveillance of their drugs after
must evaluate their products based on findings approval in order to determine if any problems have
obtained from the latest reports on infections caused arisen with efficacy when the drug is used in actual
by raw materials of the products and report the practice, or to see if the level of efficacy has not
results every 6 months to the Minister. been changed by factors such as dosage, duration
In April 2017, "Notification on the System of of administration, complications or concomitant
Periodic Infection Reports for Regenerative medication. In terms of safety, any marked
Medicine Products and Biological Products" increase in the incidence of ADRs and changes in
(Notification No. 00428-(1) of the PSEHB dated April the incidence of ADRs due to factors such as
28, 2017) was issued to change the format of dosage, duration of administration, complications, or
reports, and to require submission of the reports by concomitant medication should be detected and
electronic media. Moreover, "Q&A on the System assessed.
of Periodic Infection Reports for Regenerative When the revised Pharmaceutical Affairs Law
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was enforced from April 1997, the surveillance and (maximum reexamination period: 10 years).
studies required for reexamination applications must When an additional indication is obtained during
be performed in compliance with the GPMSP, GCP the reexamination period, the reexamination period
or GLP depending on their objective. It is also for the additional indication will be as described
obligatory to prepare application data in accordance below.
with these standards. Based on the revision of the • When the existing indication is a usual
Law in April 2005, the GPMSP has been abolished indication
and replaced with the GPSP and GVP. When the additional indication is a usual
indication: 4 years or the residual period of the
6.1 Designation for Reexamination of reexamination period for the existing
Drugs indication
When the additional indication is an indication
The drugs subject to reexamination include
of an orphan drug: 10 years
products designated by the MHLW at the time of
• When the existing indication is an indication of
marketing approval as drugs with, for example,
an orphan drug
active ingredients, quantities of ingredients, dosage
When the additional indication is a usual
and administration, and/or indications that are
indication: 5 years and 10 months
distinctly different from drugs that have already been
When the additional indication is an indication
approved (Article 14-4 of the Law).
of an orphan drug: 10 years
The timing when these drugs should be
reexamined is designated by the MHLW at the time
6.2 Periodic Safety Reports (Article 63 of
of their approval as new drugs. The times that
the Enforcement Regulations of the
reexaminations should generally be conducted for
Law)
specific products are given below.
(1) Reexamination 10 years after the date of On the basis of agreements at the ICH
approval: concerning the periodic safety update report
Orphan drugs (PSUR) system, however, a "periodic safety report
(2) Reexamination 8 years after the date of system" was enacted into law at the time of revision
approval: to the Pharmaceutical Affairs Law in April 1997. In
Drugs containing new active ingredients May 2013, the PSUR system was replaced with the
(3) Reexamination 6 years after the date of periodic benefit-risk evaluation report (PBRER)
approval: system following the release of ICH E2C (R2)
Drugs with new routes of administration guidelines.
(4) Reexamination from 4 to within 6 years As the base date for the reporting period of these
after the date of approval: reports, the concept of the international birth date in
New prescription combination drugs the PBRER system was introduced. Based on this
Drugs with new indications concept, the date designated by the MHLW at the
Drugs with new dosages time of approval is established as the base date.
When pharmacoepidemiological surveys or The frequency of reports is every 6 months during
clinical studies for setting pediatric doses performed, the first 2 years from this base date. Thereafter,
the study period can be prolonged before reports are to be submitted once each year during
completion of the reexamination period as required the remaining period of reexamination. The drugs
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for which these reports are applicable include drug use-results surveys, post-marketing database
prescription medicines designated for reexamination surveys, and post-marketing clinical trials, must be
(medical devices are subject to annual reporting as implemented in accordance with the GPSP. The
previously). In the event that a drug is marketed in data must also be collected and prepared in
a foreign country, reports must specify any adverse accordance with these standards (post-marketing
drug reactions that appeared in that country and clinical trials must be conducted also in compliance
information about any regulatory measures with the GCP).
adopted. In addition, when PBRER prepared by Applications for reexamination must be
foreign companies should be appended to the completed within 3 months from the time of the
Japanese Periodic Safety Report together with the designated base date. The data submitted and
information obtained in drug use-results survey in organization of this data should generally be as
the section "Future Safety Measures Planned on described below, with a focus on data from
the Basis of Surveillance Results" in the Periodic post-marketing surveys, etc. In addition, for any
Safety Report, and submitted, or the contents of the other research data acquired after drug approval
PBRER should be compiled and incorporated into related to indications and/or safety of the drug
the Japanese Periodic Safety Report and submitted. concerned, a Periodic Safety Report submitted near
Either method is acceptable. A summary of the the date of the reexamination application should be
report items to be submitted includes the following: attached.
Period of the survey (1) Summary of data for reexamination
Number of cases surveyed applications
Quantity of product shipped The data should include a summary of the drug
Status of implementation of drug specified in the application; specific details up to the
use-results survey time of reexamination application including the
Summary of the surveillance results and changes in quantity and value of product shipped
analysis of the data and the estimated number of patients who used the
Incidence of adverse drug reactions drug, the status of approval and sales overseas;
classified by type summary of post-marketing surveillance;
A list of cases in which adverse drug information about safety and efficacy; conclusion;
reactions occurred and references.
Measures adopted to ensure proper (2) Data Attached to Reexamination
product use such as revisions of the Applications
precautions This data should include summary of drug
Package inserts use-results surveys; post-marketing database
Future safety measures planned on the surveys, and post-marketing clinical trial reports;
basis of surveillance results data from patients who have developed adverse
drug reactions or infections; data from research
6.3 Data Required for Reexamination reports; reports of specific measures adopted in
Applications and Reexamination Japan and overseas; and reports of serious adverse
Procedures drug reactions.
(3) Compliance survey data
Post-marketing surveillance to acquire data
This includes data from GPSP compliance
required for reexamination applications, including
reviews as well as data from GCP and/or GLP
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* Designated Classifications
7. REEVALUATION SYSTEM (ARTICLES
[I] Approval refused (manufacturing and 14-6 AND 23-31 OF THE LAW)
marketing suspended, approval revoked)
[II] Changes in approval (modifications in The reevaluation of drugs is a system whereby
approved items as directed) the efficacy and safety of a drug, which has already
[III] Approved (as per application for been approved, is reconsidered on the basis of the
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Pharmaceutical Regulations in Japan:
Notification No. 610 of the PMSB dated July 7, guarantee the therapeutic equivalence of generic
1971. From January 1985, reevaluations were drugs to the original drugs.
based on the Pharmaceutical Affairs Law, and the For products with dissolution tests established
new reevaluation system came into effect from May after completion of quality reevaluation, "official
1988. dissolution tests" were included in the third section
of the Japanese Pharmaceutical Codex, which was
New Reevaluation System:
published on March 23, 1999.
This new reevaluation system aimed at
reevaluations of the efficacy and safety of all
prescription drugs was started in May 1988.
These reevaluations are at first performed by
means of a review by the PAFSC. When the
Council's decision requires further literature
surveys by the manufacturers, they are
required to perform such surveys according to
the provisions of the Pharmaceutical Affairs
Law (Fig. 17 Reevaluation System).
The new reevaluations were designated from
February 1990.
The MHLW has implemented various measures
related to generic drugs. In the final report of the
Council on the Pharmaceutical Sector in the 21st
Century issued on May 28, 1993, it was suggested
that manufacturing control and quality control must
be thoroughly implemented for all products including
original drugs. For this purpose the dissolution test
was proposed as a routine verification method. In
February 1997, "quality reevaluation" was started,
and dissolution test conditions and specifications
were set for original drugs that had no specified
dissolution test. This step was intended to assure
the quality of generic drugs by confirming their
equivalence to the original products.
Thereafter, a notification entitled the "Guidelines
for Bioequivalence Studies on Generic Drugs" was
issued in December 22, 1997 and partially revised
on May 31, 2001 (Notification No. 786 of the
Evaluation and Licensing Division, PMSB) and on
November 24, 2006 (Notification No. 1124004 of the
Evaluation and Licensing Division, PFSB) and
February 29, 2012 (Notification No. 0229-(10) of the
Evaluation and Licensing Division, PFSB) to
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Pharmaceutical Regulations in Japan:
Post-marketing
surveillance GVP, GPSP (GCP)
(PMS) system
Reexamination system
Reexamination application
Reevaluation system
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Pharmaceutical Regulations in Japan:
Visits of MRs to
physicians to provide
safety information
and to ask
cooperation
Early post-marketing
phase vigilance
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Pharmaceutical Regulations in Japan:
Information exchange
Ministry of Health,
Labour, and Welfare
• Medical assoc. Information (MHLW) Evaluation
Dissemination Pharmaceutical Affairs
• Dental assoc. and Food Sanitation
Pharmaceutical and
• Pharmaceutical assoc. Examination Council (PAFSC)
Medical Device Agency
(PMDA)
(Collection, analysis and
evaluation of reports
from industries)
Pharmaceutical safety
information reports
ADR & infection reports
Periodic safety reports
Reexamination
Administrative Reevaluation
measures/
guidance
Information Information
• Hospitals collection exchange
• Manufacturer/ Foreign
• Clinics
Marketing companies
• Dental clinics Dissemination ADR
authorization holder
• Pharmacies PBRER
Regulatory
information
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( MHLW ) (PMDA)
Submission
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Pharmaceutical Regulations in Japan:
(MHLW) (PMDA)
Submission
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Pharmaceutical Regulations in Japan:
To cope with this problem, the MHW (currently abolishment of the sections of “Relative
MHLW) established three special committees on the contraindications” and “Careful administration,” and
revision of pharmaceutical package inserts, which addition of a section of “Use in patients with special
completed their work and submitted reports in May backgrounds," and overall improvement of the
1996. Based on these reports, guidelines for information to be entered. The guidelines were
package inserts and for Precautions were completely applied from April 2019 (the transitional measure
revised (Notification No. 606 of PAB dated April period for approved products will be 5 years).
25, 1997, Notification No. 59 of the Safety Subsequently, Questions and Answers for the
Division, PAB dated April 25, 1997, and Guidelines on Preparation of Package Inserts for
Notification No. 607 of PAB dated April 25, Prescription Drugs (Office communication of the
1997). Pharmaceutical Safety Division of MHLW dated
Two notifications concerning package inserts for January 17, 2019, and Office Communication of
biological products were issued in May 2003: “Entries Office of Pharmacovigilance I and Office of
in Package Inserts for Biological Products” Pharmacovigilance II of PMDA dated January 17,
(Notification No. 0515005 of the PMSB dated May 15, 2019) were issued.
2003) and “the Guidelines for Entries in Package For generic drugs, "Improvement of Provision of
Inserts of Biological Products” (Notification No. Information in Package Inserts, etc. of Generic
0520004 of the Safety Division, PMSB dated May 20, Products" (Notification No. 0413-(2) of the
2003). These notifications came into effect from July Pharmaceutical Evaluation Division, PSEHB and
2003. Notification No. 0413-(1) of the Safety Division,
After that, the guidelines on preparation of package PSEHB dated April 13, 2018) was issued to improve
inserts were revised and the following notifications provision of information, and the notification requires
were issued to make the package inserts easier to that the same information as that provided in the
understand and easier to use reflecting the dramatic package inserts, etc. of the branded products should
changes in the situation surrounding medicine, be provided in the sections of "Pharmacokinetics,"
including advancement of medical care, aging of the "Clinical Studies" and "Pharmacology."
society, and advancement of IT technology, and The notification entitled “Enforcement of The Law
proposal of "Review of the Drug Administration for for Partial Amendment of the Pharmaceutical Affairs
Preventing Recurrence of Drug-induced Sufferings Law”(Notification No. 0806-(3) of PFSB dated August
(Final Proposal)" in 2010, and proposals made in 6, 2014) specified that precautions for usage and
Health and Labour Sciences Research from 2008 to handling based on the latest scientific knowledge
2013 and subsequent examination. and information should be prepared to promptly
(1) Guidelines on Preparation of Package Inserts reflect essential cautions, etc. based on outcome from
for Prescription Drugs (Notification No. 0608-(1) evaluation of safety information including adverse
of the PSEHB dated June 8, 2017) drug reactions collected according to the provisions in
(2) Points to Consider Regarding Guidelines on the Law and the MHLW Ordinance on GVP.
Preparation of Package Inserts for Prescription Package inserts must include the package insert
Drugs (Notification No. 0608-(1) of the Safety information based on latest findings, nonetheless
Division, PSEHB dated June 8, 2017) package inserts prior to amendment may be attached
in the following exceptional amendment case:
The major points of improvement are
(1) When the products had already been
reconsideration of the items and structure, including
manufactured and distributed prior to
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Pharmaceutical Regulations in Japan:
amendment of package insert information between the notification date and the amendment
(post-marketing products), date of package insert information, publication may be
(2) When the package insert includes all of the made in line with the scheduled amendment date.
information before amendment (that is, old Of note, it is possible that information provision of
package insert printed at the time of the amended package insert information may be
amendment), and all of the following initiated upon submission of the notification to the
requirements are met: PMDA, however it is recommended that such
i. The products are manufactured and distributed information is provided upon confirmation of PMDA’s
within 6 months after the amendment date acceptance, because some modification may be
(within 1 year in cases of amendment of needed when any inadequacy was found at
package insert information of products requiring confirmation from the PMDA (Office Communication
testing or multiple products, which cannot be of the Safety Division, PFSB dated September 1,
manufactured and marketed promptly with the 2014).
amended package insert information),
ii. The amended package insert information are 1.1 New Guidance on the Style and Format
published on the PMDA homepage, and of Package Inserts
iii. The manufacturing/marketing authorization
1) Basic Rules for Compilation of Package
holder of the product may promptly notify users
Inserts
including physicians or pharmacists of
(1) Package inserts and other relevant
information on amendment of package insert
documents for prescription drugs shall be
information.
prepared by the marketing authorization
For submission of notifications, it was specified in
holders of the drugs in accordance with
the “Points to consider for notification of package
the provisions set forth in each item of
insert information” (Notification No. 0901-(1) of the
Article 52, Paragraph 1 of the
Safety Division, PFSB dated September 1, 2014) that
Pharmaceutical and Medical Device Act
notifications should be submitted on the web page for
so that the necessary information is
notification via the PMDA homepage before initiation
provided to healthcare professionals such
of manufacturing/marketing in cases of notifications
as physicians, dentists, and pharmacists
for products to be newly manufactured/marketed
to ensure the safety of patients taking the
including new drugs (nonetheless, when information
drugs and to promote their proper use of
provision to medical institutions, etc. is started prior to
drugs.
initiation of manufacturing/marketing, the notification
should be submitted in advance preferably), or before (2) Information to be included in package
the initiation date of information provision of the inserts shall be that required for use of the
amendment or the initiation date of drugs within the scope of approval, as a
manufacturing/marketing of products with the rule. However, other information that is
amended package insert, whichever is earlier, in considered to be important and
cases of amendment of package insert information. particularly necessary shall be provided.
It was also specified that package insert information (3) Information shall be described in the
should be published on the PMDA homepage order specified in “Sections and their
promptly upon submission of the notification to the Order” with its section number
PMDA. Nonetheless, when there is a certain time concerned. When there is no information
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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0710-(5) of the Safety Division, PFSB dated July 10, conformance to evidence data for drug package
2014). The brand name of generic drugs is required insert revision" in which reliability of the data on
to be a name based on the Japanese Accepted clinical studies which serve as the rationale for the
Name as directed in Notification No. 0922001 of the package insert revision is verified.
Evaluation and Licensing Division, PFSB dated
September 22, 2005 and the brand name of
2. INFORMATION TO SUPPLEMENT
biosimilar products as directed in Notification No.
PACKAGE INSERTS
0214-(1) of the Evaluation and Licensing Division,
PFSB dated February 14, 2013. Because of space limitations in Japanese
For generic drugs of combination drugs, unified package inserts, the following main media are also of
brand names had been discussed, and since August use to provide more detailed information about
2013, these have been managed in accordance with pharmaceutical products.
voluntary consensus that unified brand names may • Outline of Prescription Pharmaceutical Product
be retained by Japanese Society of Generic and Information
Biosimilar Medicines as trade names and used by • Pharmaceutical Interview Forms
companies on a license basis. • Commentaries on "Precautions" in package
The application fee for revising brand name was inserts of new drugs
lowered in April 2005. The timing of brand name New drugs that are approved after October 2001
revision for prevention of medical accident is the time are marked with a logo commonly adopted by the
for NHI price listing twice a year. As a result, pharmaceutical industry indicating that the drug is
measures have been completed for a total of about subject to early post-marketing phase vigilance for
5,400 products as of the NHI price listing in such a period of time as specified in labeling (6
September 2009. months after the start of marketing).
Package inserts are updated whenever necessary The Outline of Prescription Pharmaceutical
based on collection and evaluation of the information Product Information is prepared by the
obtained from post-marketing use-results surveys of manufacturing/marketing authorization holders with
drugs, case reports in Japan and abroad, and the objective of providing accurate and appropriate
literature reports. information to health professionals to promote proper
In the meantime, PMDA newly established three use of their drugs. The material is available in two
consultations regarding package inserts of drugs on types: the general outline version showing the entire
December 25, 2017 to improve consultation works description of the product containing information
for those who desire revision based on the results of under all headings of package insert and
post-marketing clinical studies, etc.: "Consultation for property-specific version containing information under
preliminary confirmation of revision of drug package certain headings of package insert such as clinical
insert" and "Consultation for drug package insert studies and clinical pharmacology.
revision" in which appropriateness of the revision of The Outline of Prescription Pharmaceutical
the package insert is evaluated based on evaluation Product Information is prepared on the basis of the
including efficacy, and "Consultation for investigating “Guidelines for Preparation of Outlines of Prescription
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Pharmaceutical Regulations in Japan:
Pharmaceutical Product Information” (prepared by the "Guidelines for preparation of interview forms for
Japan Pharmaceutical Manufacturers Association generic products" was issued by the Japan Generic
[JPMA], developed in September 2015). To ensure medicines Association for generic products. The
consistency of the content with that of the package guidelines mainly introduce the examples of the
insert, attention should be paid to the JPMA Code of sections describing the data which are deemed to be
Practice. unique to generic products, such as the results of
In addition, the Outline of Prescription bioequivalence studies, elution studies, and stability
Pharmaceutical Product Information is internally studies, as well as the procedures for describing
reviewed by the pharmaceutical company and these issues. The guidelines are used as the
voluntarily reviewed by JPMA. Because standards for preparation of IF together with the
administrative disciplinary actions were taken in 2014 guidelines of the Japanese Association of Hospital
and 2015 against the advertisement violating the law Pharmacists.
(Article 66) that prohibits false or exaggerated Basically, IFs are provided in electronic media of
advertisements, the system to strengthen the internal PDF files, which are available on HP of PMDA.
review system of pharmaceutical companies was
introduced in 2016, such as placement of the 2.3 Commentaries on "Precautions" in
responsible organization of the internal review outside Package Inserts of New Drugs
of the sales division and involvement of a third party in
Commentaries are prepared by marketing
the internal review in principle. For the voluntarily
authorization holders of drugs for detailed explanation
review of JPMA, expansion of the scope and
of "Precaution " when a new drug is launched.
introduction of the electronic review system were
Reflecting the notification of revision of the
conducted in 2017.
instructions for package inserts and precautions in
April 1997, a guide to preparation of the
2.2 Pharmaceutical Interview Forms (IF)
commentaries was published (Notification No. 88 of
In medical settings, physicians and pharmacists, the Safety Division, PAB dated June 27, 1997) and
etc. collect detailed information about drugs through commentaries have been prepared for the new drugs
interviews with medical representatives (MR) of launched after that.
pharmaceutical companies and utilize such
information in daily works. Pharmaceutical Interview
3. SUPPLY AND DISSEMINATION OF SAFETY
Forms (IFs) used to specify questions to be asked for
MANAGEMENT INFORMATION
such purposes, but in order to reduce the burden on
pharmacists and MRs, the replies (detailed For the proper use of drugs, it is important that the
information) to the questions are already entered, and necessary information be supplied and disseminated
the IF are supplied to health professionals from in an appropriate and timely manner to health
pharmaceutical company as academic material to be professionals.
used in explanations and discussions concerning the Safety management information reported to the
product. MHLW, etc. is evaluated by the PMDA after hearing
The Japanese Association of Hospital opinions of experts. After the Committee on Safety
Pharmacists published new preparation guidelines in of Drugs of the Council on Drugs and Food Sanitation
November 2018, and IFs are being prepared in the approves the results, the necessary administrative
new format for new drugs approved from April 2019. measures based on the evaluation results are taken.
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
The information will also be placed in the safety information as noted above but more promptly
homepage of the PMDA together with the safety flash than routine revisions of “precautions for use” with an
report (blue letters) in the following section. intent to prevent the recurrence and spread of
Japanese: health-related harm or injury to the public. Practices
https://www.pmda.go.jp/safety/info-services/drugs/call for disseminating such information are specified in
ing-attention/esc-rsc/0001.html Notification No. 1031-(1) of the Safety Division, PFSB
English: dated October 31, 2014.
https://www.pmda.go.jp/english/safety/info-services/dr 2) Format and content
ugs/esc-rsc/0001.html Safety flash reports must be prepared in the style
Of note, for drugs of which package insert
and format specified in the guidelines, using blue
information are subjected to be notified,
paper, etc. Information contained in the reports may
manufacturing/marketing authorization holders must
be required to be arranged for the public (patients)
notify the PMDA of details of amendment in package
depending on the usage in practice.
inserts prior to publication on the homepage of
companies or the like. 3) Methods of information dissemination
(1) The staff (MRs) in charge of the drug
4) Distribution
information of the marketing authorization
The distribution of emergency safety information to
holder are to efficiently distribute the
medical institutions must be completed within 1 month
information to physicians, pharmacists,
of receipt of the government order, according to the
and other health professionals in medical
plan and method of distribution. The marketing
institutions by using multiple
authorization holder must submit a safety information
communication tools such as direct
dissemination report to the Director of the
handout, direct mail, fax, and e-mail to
Pharmaceutical Safety Division of Pharmaceutical
achieve prompt and widespread alert for
Safety and Environmental Health Bureau when
safety concerns. PMDA distributes safety
distribution has been completed as specified by the
flash reports, revisions of package inserts,
office.
etc. to medical personnel who have
registered their e-mail address with the
3.2 Safety Flash Report (Blue Letters) Agency via PMDA medi-navi.
1) Preparation criteria (2) The marketing authorization holder must
The safety flash report (“blue letter”) is prepared by transfer safety information to medical or
the marketing authorization holder on the basis of pharmaceutical organizations, as
discussion with the MHLW and PMDA following an appropriate, and requests them to
order or instruction from the MHLW, voluntary cooperate in collecting and disseminating
decision by the marketing authorization holder, or information through efficient
other requirements in cases where it is judged communication tools such as their
necessary to take the measures specified in Section homepages. If the marketing
3.1: 1-(2) above for drawing physician’s urgent and authorization holder knows patient groups
specialized attention to safety-related matters and that use products concerned, safety
measures necessary for optimal drug use (e.g., information should be distributed to such
efficient method of notification, laboratory tests, etc.) groups, as appropriate.
similarly to the procedures for handling important Of note, for drugs of which package insert
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Pharmaceutical Regulations in Japan:
2) Format and content Among the case reports and scientific reports on
The paper must be not yellow or blue. adverse reactions collected from the
manufacturer/marketing authorization holder, and
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Pharmaceutical Regulations in Japan:
ADR reports collected from or submitted by health including approximately 10,000 hospitals, 90,000
professionals, the MHLW compiles commentaries clinics and 60,000 dental clinics, as well as about and
and Notices of Revisions of Precautions concerning 50,000 pharmacies and dispensing facilities within
important ADRs. They are supplied in digest form one month after printing.
as "Pharmaceuticals and Medical Devices Safety The DSU of the OTC version has been edited and
Information" to health professionals who submitted published by the Japan Federation of Self-Medication
ADR reports, and also published in the media, on the Industries since November 2015.
PMDA homepage for information on drugs , and in These journals are available immediately after
various publications such as the Journal of the Japan publication at the following the PMDA homepage.
Medical Association and the Journal of the Japanese http://www.pmda.go.jp/safety/info-services/drugs/calli
Association of Hospital Pharmacists. An English ng-attention/dsu/0001.html
version is sent to WHO. http://www.pmda.go.jp/safety/info-services/drugs/calli
The digest has been published since June 1973 ng-attention/otc-dsu/0001.html
and is available and regularly updated at the following
PMDA homepage. 3.7 Commentaries on "Precautions" in
Japanese: Package Inserts of New Drugs
http://www.pmda.go.jp/safety/info-services/drugs/calli
As a rule, MRs distribute the commentaries to
ng-attention/safety-info/0043.html
medical institutions before new drugs are used in
English:
medical practice in order to assure proper use of new
https://www.pmda.go.jp/english/safety/info-services/dr
drugs.
ugs/medical-safety-information/0002.html
Drug Safety Update (DSU) is published for The MHLW received a report from its special
prescription drugs and the DSU of the OTC version committee on policies to supply drug information to
(Information of revisions of precautions for use for health professionals, etc. using the Internet, which
OTC drugs) is published for non-prescription drugs was established in 1997, and started operation of a
under the supervision of the Ministry of Health, Labour "Drug Information System” to supply such information
and Welfare as the information journals which via the Internet at the end of May 1999.
summarize and comprehensively and promptly The information supplied includes information
convey information on revisions of the Precautions regarding the proper use of drugs, information on
evaluated by the Ministry of Health, Labour and package inserts of prescription drugs, safety
Welfare. information disseminated by the MHLW, cases of
The Society of Japanese Pharmacopoeia and the suspected adverse reactions collected by the MHLW,
Federation of Pharmaceutical Manufacturers' as well as risk management plan (RMP), information
Associations of Japan (FPMAJ) have been jointly on Yellow Letters (formally-called Dear Doctor
editing and publishing the DSU, since September Letters)/Blue Letters, drug guide for patients, the
1992 (10 times per year) (published by the FPMAJ manual for handling disorders due to adverse drug
since Issue No. 128 dated April 2004). The journal is reactions, drug approval applications, drug recalls,
distributed by mail to medical institutions nationwide etc.
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Pharmaceutical Regulations in Japan:
The marketing authorization holder is required to for Precautions, and information that should be
discuss the necessity for issuance and publication of included on the outer containers. The style and
“PMDA requests on the proper use of drugs” among format of the description on the outer containers or
official notices on the proper use of drugs, if ADRs wrappers were revised to assist the purchase of
due to drug use or those due to improper drug use do suitable drugs based on labeling and issued as a
not decrease despite major revisions to labeling such notification of PFSB on October 14, 2011. The old
as an issue or revisions of warnings and precautions. notification of PMSB dated August 12, 1999 was
The marketing authorization holder is also required to abolished accordingly. For non-prescription Chinese
determine the necessity of disseminating such herbal preparations with the established approval
information through print media, as appropriate. criteria, items to be included in Precautions in
Standard Generalized Markup Language (SGML) package inserts, etc. were presented in Notification
was adopted as the basic format for information about No. 1014-(7) of the Safety Division, PFSB and No.
package inserts of prescription drugs, but was 1014-(8) of the Evaluation and Licensing Division,
changed to Extensible Markup Language (XML) from PFSB dated October 14, 2011, and partially amended
April 2019 to cope with the revised instructions for in Notification No. 0327-(1) of the Safety Division,
package inserts and to improve the convenience of PFSB and No. 0327-(1) of the Evaluation and
the package insert search system of PMDA's HP. Licensing Division, PFSB dated March 27, 2013.
The supply of package insert information for Labeling requirements of excipients of
non-prescription drugs was started from March 2007 non-prescription drugs are the same as those for
and supply of information on drug interview forms prescription drugs according to a voluntary agreement
from May 2009. of the JPMA (Notification No. 165 of the JPMA dated
The PMDA is providing services free (via PMDA March 27, 1991) and Office Communication of the
medi-navi) to distribute safety-related information Safety Division, PAB dated June 3, 1991. Based on
such as revisions to precautions in use of drugs, a voluntary agreement of the JPMA (Notification No.
which has been placed on the Agency’s homepage 170 of the JPMA dated March 13, 2002), all
for information on drugs, to medical personnel who ingredients must be included in package inserts by
have registered their e-mail address with the Agency. March 31, 2004 and the names of excipients including
http://www.pmda.go.jp/safety/info-services/medi-navi/ voluntarily designated ingredients must be included
0006.html on the outer container (or its equivalent).
Based on this voluntary agreement, Notification
No. 165 of the JPMA was canceled and the Office
5. PACKAGE INSERTS OF
Communication of the Safety Division, PAB dated
NON-PRESCRIPTION DRUGS
June 3, 1991 was canceled by Notification No.
The MHW established a special committee to 0409001 of the Safety Division, PMSB dated April 9,
improve package inserts of non-prescriptions drugs in 2002.
August 1996 following the revision of the guidelines For the background of labeling of excipients for
for package inserts of prescription drugs, and this prescription drugs, refer to Section 1.4 on excipients.
group issued its report in September 1998. The revised Law enacted on November 25, 2014
The PMSB of the MHLW issued notifications on specified that package insert information should be
August 12, 1999 on the type and format for based on scientific knowledge and information
non-prescriptions drugs to define items of information obtained in latest literatures, etc. as is the case for
to be included in the package insert, entry methods prescription drugs. Nonetheless, the exceptions for
2019 - 155 -
Pharmaceutical Regulations in Japan:
6. PACKAGE INSERTS OF
GUIDANCE-MANDATORY DRUGS
For guidance-mandatory drugs (refer to
CHAPTER 2, 3.2 Classification of Drugs), as is the
case for prescription drugs, package inserts should be
based on scientific knowledge and information
obtained in latest literatures, etc., and brand names
and precautions for usage and handling should be
noticed prior to initiation of manufacturing/marketing
or amendment followed by prompt publication on the
PMDA homepage (Notification No. 0806-(3) of PFSB
dated August 6, 2014).
For notification, the specified notification format
should be submitted to the PMDA with package insert
information (copy) attached (Notification No. 0901-(1)
of the Safety Division, PFSB dated September 1,
2014).
Nonetheless, the exceptions for package inserts to
be attached to products may be applicable also as is
the case in prescription drugs (refer to 1. PACKAGE
INSERTS).
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Pharmaceutical Regulations in Japan:
**
Revised: Month, 20XX (Version XX, ○ ○) Standard Commodity
Classification No. of Japan
Name of therapeutic category
Storage: Nonproprietary name, standard name, ●mg ▲mg
Expiration
date:
or name designated on Japanese Pharmacopoeia Approval No.
Date of initial
XX,
marketing in XX, 20XX
20XX
Regulatory classification Japan
2019 - 157 -
Pharmaceutical Regulations in Japan:
16.8 Others
17.3 Others
18. Pharmacology
18.1 Mechanism of action
18.2 ○○ action
19. Physicochemistry
22. Packaging
23. References
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Pharmaceutical Regulations in Japan:
Individual teams
Extraction of
noteworthy adverse
reactions
Sharing information
with the Ministry
Inquiries to
companies
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Pharmaceutical Regulations in Japan:
Emergency
Emergency safety cases (1 week)
information
Company's opinion
Consultation from
Safety flash Company for
reports revision
NO (Pending) YES (Policy for taking measures)
Interview
Primary screening as
noteworthy event
(discussion on the
measures to be taken)
(Necessity of expert discussion)
No Yes
(Within 2 weeks after
necessary documents have (Approximately
become available) 10 to 40 days)
Disclosure of risk information
Revision of package under evaluation
insert (1 week)
Expert discussion
(every 5 weeks as a rule)
(1 week)
(1 week)
2019 - 160 -
Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
The health-care insurance reform concurrently Thereafter, problems related to the burden on the
studied in 1997 brought a change in the coverage on elderly were pointed out and the government adopted
benefits by employee's health insurance to 80% and a policy of exemption of the elderly from outpatient
to introduce a partial cost-sharing for medication. partial cost sharing for medication as an extraordinary
Thereafter, in 2002 the revision of the Health measure in July 1999. In December 2000, the
Insurance Law containing the 30% copayment for the Health Insurance Law was promulgated and from
insured was passed by the Diet. The 30% burden January 1, 2001, it became possible to select a
for the insured was enforced from April 2003. copayment system with 10% of the medical expenses
The law to reform the health insurance system as the upper limit or a fixed copayment for the elderly.
was discussed from 2005 and was enacted in June From October 2002, the burden on elderly patients
2006. From October 2006, persons aged 70 years aged 70 years or older was set at 10% and at 20% for
or older with similar regular income as during their those with a certain level of income, latter of which
working years were subject to a copayment of 30% was revised to 30% from October 2006.
and limits on copayments and food/housing costs for For family members of insured persons,
inpatients of nursing home increased. From April regardless of type of health insurance program, at
2008, a healthcare system for very old people was least 70% of actual costs are covered by the
initiated. programs. Furthermore, when a patient's medical
payment reaches a certain limit, the patient is
refunded the excess. Supplementary programs are
2. MEDICAL BENEFITS OFFERED UNDER
also available to cover the costs of special treatments
HEALTH INSURANCE PROGRAMS
including highly advanced medical treatments and to
As mentioned above, there are various types of support specified medical care coverage system that
health insurance programs in Japan and medical permits selection of treatment by patients. These all
benefits available vary from one program to another. contribute to overall improvement in medical care.
Medical benefits available for the insured person can Under these health insurance programs, medical
also differ depending on the type of insurer, type of benefits are almost always provided to insured
insurance program, and presence of family members persons in the form of actual treatment rather than as
(non-working dependents). Under a cash reimbursement. In exceptional cases where
industry-managed health insurance programs, 90% of this rule is difficult to apply, money is provided to cover
medical costs of insured persons is covered by health treatment costs.
insurance programs according to the revision of the
Health Insurance Law in 1984 (the original coverage
3. REIMBURSEMENT OF MEDICAL FEES
was stipulated to be 80% in the law but it was 90%
until a notification of the Minister of Health and Medical institutions where patients are treated
Welfare issued on a day after April 1986 after under health insurance programs apply to respective
approval by the Diet). From September 1997, the health insurance associations, after treatment has
coverage was changed to 80% of medical costs to been rendered, for reimbursement of actual treatment
medical institutions where patients are treated under costs after subtracting the amount paid directly by
health insurance programs. A copayment by patients. Medical fees listed in the NHI system are
patients for outpatient medication fees was also set by the MHLW, which consults with the Central
introduced with children less than 6 years of age and Social Insurance Medical Council ("Chuikyo"). The
low-income elderly patients excluded. fees are calculated on the basis of Article 76, Item 2 of
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Pharmaceutical Regulations in Japan:
the Health Insurance Act (Act No. 70, 1918) and April 2018 and forecast of the application of this billing
Article 71, Item 1 of the Act on Assurance of Medical system has been extended to 1,730 hospitals
Care for Elderly People (Act No. 80, 1982), and (approximately 490,000 beds) in April 2018.
according to the Calculation Method of Medical Fees Medical procedures, such as medication and
(Public Notice No. 59 of the Ministry of Health, Labour injection, require the use of drugs, and the list of
and Welfare in 2008) (partially revised on March 5, reimbursement prices of drugs permitted under health
2018 by Public Notice No. 43 of the Ministry of Health, insurance programs is called the National Health
Labour and Welfare). Insurance (NHI) Price List.
Under these rules, a point value is assigned for
each of the thousands of medical procedures listed.
4. NATIONAL HEALTH INSURANCE PRICE
Fees (in Yen) are then calculated by multiplying
LIST
the number of points by 10. This system, in which
medical fees are paid to medical institutions for the The National Health Insurance (NHI) Price List is a
procedures performed, is called the “payment for list of drugs for which medical providers can be
services system” as the basis of the medical cost reimbursed under the health insurance programs as
reimbursement system in Japan. There are many specified in the regulations for hospitals and nursing
types of points set for “lump sum” payment for homes covered by health insurance. The rules used
hospitalized treatment, etc. of patients with chronic to calculate healthcare fees in accordance with the
disease. From April 2003, the Diagnosis Procedure Health Insurance Law state that the reimbursement
Combination (DPC) system was introduced by price of drugs for medical institutions is to be
university and other large hospitals (university determined separately by the Minister of the MHLW.
hospitals, National Cancer center, and National Thereby, the prices to be invoiced for drugs used in
Cardiovascular Center: 82 hospitals in total) for hospitals are set by the Minister and shown in the NHI
diagnosis-based assessment of lump sum payments Price List.
for emergency admissions and treatments. With this
system, medical bills per day per patient are
5. PRICING FORMULA FOR
determined using 1,860 DPC classifications. The
REIMBURSEMENT PRICE REVISIONS OF
medical bill includes basic admission fees, laboratory
DRUGS LISTED IN THE NHI PRICE LIST
test fees, imaging diagnosis fees, drug dispensing
fees, injection fees, and treatment fees of less than The difference in the purchase price by medical
1,000 points. The medical bill is calculated by the institutions and the NHI reimbursement price (price
following formula. discrepancy), which provides extra income for
Number of points per day for each DPC x medical institutions, has been a problem since the
coefficient by medical institution x number (days) of latter half of the 1980s, and various pricing formulas
admissions x ¥10 have been used to reduce this price discrepancy and
The coefficient by medical institution is set by the correct the fluctuations in purchase prices, but
function and past performance records of the hospital. improvements have not been adequate.
No. of points per day is set higher for cases of earlier Under these conditions, taking an opportunity of
discharge than the mean number of hospitalization an attempt to improve the distribution of drugs from
days of the DPC. April 1, 1991, the former bulk line method was
The number of DPC classifications was changed abolished and a pricing formula based on the
to 4,955 (number of payment classification: 2,462) in weighted average market price was adopted in
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Pharmaceutical Regulations in Japan:
anticipation that the NHI Price List would more conflicting topics of evaluation of innovative drugs and
accurately reflect market prices, unnatural fluctuations maintenance of nationwide comprehensive health
in prices would be corrected, and pricing would be insurance system were being discussed, repricing for
simplified. Based on a recommendation submitted market growth was applied in an exceptional manner
by Chuikyo to the MHLW on May 31, 1991, the as a measure of reconciliation when the annual sales
pricing formula used for drugs listed in the NHI Price exceeded 100 billion yen but not 150 billion yen and
List at the time of reimbursement price revisions was reached at least 1.5 times of the originally expected
revised, and the first overall price revision using the sales, and when the annual sales exceeded 150
new formula was conducted in 1992. billion yen and reached at least 1.3 times of the
In brief, the revised reimbursement prices are originally expected sales. Thus, special repricing of
determined by calculating weighted means of sales drugs was implemented.
prices of all existing package sizes by brand and Reflecting the issues of unapproved drugs and the
adding a certain percentage of the current time-lag in new drug approval, a new “premium
reimbursement prices (within a “specified price system for the promotion of innovative drug discovery
range”) to the weighted mean prices obtained and resolution of off-label use" was applied to the new
(however, the new reimbursement prices must never drugs without generic drugs as of 15 years after listing
be higher than the current prices). (discrepancy shown in the drug price survery is
The price range decreased gradually from 15% in smaller than the mean discrepancy for all products)
1992 to 13% in 1994, 11% in 1996, 10% (8% for after discussion at the Central Chuikyo, and the pilot
products listed for a long time) in 1997, and 5% (2% operation was continued until 2016. In April 2018, a
for high price products with relatively large margin) in rule was established to strictly select the target
1998. In 2000, the range was set at 2% to secure products in view of innovativeness and usefulness,
stable drug supply involved over the need of and to gradually set the premium according to the
reimbursement system reform. The pricing formula status of research and development by companies.
was changed to the weighted average market price On the other hand, the evaluation of
and range adjustment method. cost-effectiveness of drugs and medical devices was
At the same time, price increases of some introduced in April 2016 on a trial basis, and price
products presented problems, and a Chuikyo adjustment was conducted for the product subjected
recommendation was issued to deal with the to the trial. A conclusion on implementation on a full
problems on November 22, 1995. In addition to the scale was to be drawn by the end of FY2018.
usual price revision in April 1996, repricing was In addition, the rule of special lowering (Z2)
undertaken for products that showed a much greater adopted from 2014 was reconsidered for long-listed
market scale (at least double) than originally expected products (branded products with generic products),
at the time of listing and for which annual sales and a new rule was introduced to classify the
(converted to reimbursement prices) exceeded 15 products with the generic product replacement rate of
billion yen. Repricing was also undertaken for drugs 80% or more (G1 product) and those with the rate of
for which indications were added after the original less than 80% (G2 product) as of 10 years after the
listing. Later in 2014, a new rule for an additional first listing of a generic product and to gradually lower
indication of an orphan drug was added to ensure that each drug price to the level of the drug price of
repricing shall be considered when the sales of the generic products.
orphan drug increases at least 10 times than originally Furthermore, to ensure stable supply of drugs with
expected and exceeds 10 billion yen. In 2016, while high medical needs covered by health insurance, the
2019 - 164 -
Pharmaceutical Regulations in Japan:
drug price maintenance system for basic drugs was to 6. RECENT REVISIONS OF THE NHI PRICE
be implemented as a pilot operation. This system LIST
may be applied to drugs meeting all of the following
Based on the 1991 Chuikyo recommendation, the
requirements (except for sufficiently profitable drugs):
MHW undertook a complete revision of the
[1] The drug has an established position in clinical
reimbursement prices of all products already in the
settings and is clearly known to be widely used
NHI Price List using the weighted average pricing
in clinical practices.
formula from 1992.
[2] Of the concerned already listed drug as well as
The actual reimbursement price revisions covers
all similar drugs with the same composition
the drugs sold in the month of September of a
and dosage form category as those of the
previous year. A survey of all products in the NHI
former, at least one drug has been on a NHI
Price List is conducted on about 4,000 sellers, all
Price List for 25 years or longer.
first-class wholesalers, and about 3,400 purchasers
[3] If there are similar drugs with the same
consisting of hospitals, clinics and pharmacies
composition and dosage form category as
selected at random using specified sampling fractions
those of the concerned already listed drug, the
in each case. Supplemental price surveys including
mean discrepancy of the similar drugs
those on changes with time are performed six times.
including the concerned already listed drug
The new reimbursement price is calculated by adding
between the NHI price and current market
a reasonable adjustment zone (R) to the weighted
price does not exceed that of all the listed
average marketing price obtained from these surveys
drugs.
in consideration of the consumption tax (refer to the
[4] The discrepancy of the concerned already
calculation formula).
listed drug between the NHI price and current
< Formula >
market price does not exceed the mean
New drug price = weighted average value
discrepancy of all the already listed drugs.
of market price in survey x (1 +
The products previously subjected to repricing due
consumption tax rate) + current
to unprofitable sales and the drugs against pathogens
reimbursement price x R/100 (however,
serving the medical platform for years and medical
the new price shall not exceed the current
narcotics were added to the target products in the
reimbursement price).
revision of the NHI price list in 2016, and the drug
This pricing formula is applied to products that are
efficacy classifications, etc. which showed
sold in large quantities, and the prices for drugs sold
discrepancy of 2% or less 3 times in the past were
in lower quantities are adjusted using the revision rate
added in the revision in 2018. The pilot operation is
for drugs of the same class and same indication.
still continued.
From 1992, prices were revised at about every 2
The pricing formulas for drugs included in the list
years, but an adjustment was made for the increase
were specified in March 2000 to assure transparency
of the consumption tax rate in 1997, and as a result,
of drug pricing. The most recent revision is given in
reimbursement prices were reduced for 3 consecutive
Notification No. 0210-(1) of the Health Insurance
years: 1996, 1997, and 1998. The reimbursement
Bureau dated February 10, 2016, “Drug Pricing
prices were reduced 2% further by the
Standards.”
range-adjustment method in 2000. In 2002, the
adjustment range was kept at 2%, and an additional
reduction of an average of 5% was made for original
2019 - 165 -
Pharmaceutical Regulations in Japan:
drugs of generic drugs (excluding those in the JP) in reimbursement price of new drugs should be
the case of drugs entered in the NHI Price List for a determined on the basis of comparison with existing
long time. In 2004, a price range of 2% and drugs from the same category as before but marked
exceptions for long-listed products were applied. up using premiums for innovation, usefulness, and
Among JP products entered by brand name, original market size; and that requirements for each premium
products for which generic products are available on be clearly defined. The price of a daily dose of a
the market were subjected to an additional price new but non-innovative drug approved on or after
reduction of one half of the rate for non-JP products. April 1, 1996, for which several drugs with similar
In 2006, a further reduction of 2% was applied as an pharmacological action and indications are already
exception for long-listed products. listed and for which the efficacy and safety are
In order to deal with of the pending “drug lag” issue objectively evaluated to be about the same as these
(unavailability for use or longer approval time of new drugs (excluding drugs within 3 years from the launch
drugs), the Central Chuikyo discussed the issue and of the first drug or within three drugs with the same
proposed a new “premium for promoting new drug pharmacological action) was set at a lower price for a
research and resolving problems of treatment not daily dose. The rule for coordinating prices with
covered by insurance. In 2010, the premium was foreign reimbursement prices was also clarified
applied for prescription drugs that have been in the (maximally twice the foreign price).
reimbursement list within 15 years and not followed The seven premium rates as of February 2014
by generic drugs (for negative price divergence from were set at 70-120%, 35-60%, 5-30%, 5-20%,
average price of all drugs in class confirmed by price 10-20%, 5%, and 10-20% for innovation, usefulness I
surveys). This premium pricing system on trial still and II, pediatric use, market size I and II, and world’s
continues to be implemented in 2014. first registration in Japan, respectively.
Drug prices listed in the NHI Price List were Requirements for applying premiums are listed in
revised to include additional 3% consumption tax in Table 16 (Requirements for Applying Premiums).
April 2014 as the tax rate was raised from 5% to 8% Furthermore, it has been decided to apply
in the month. premium to the drug price itself from the point of view
The results of reimbursement price revisions from of evaluation of innovation in drug pricing by cost
1992 through 2018 are shown in Table 14 (Methods calculation although some adjustment is made
of Previous Reimbursement Price Revisions) and depending on the level of disclosure.
Table 15 (Revision Rates of Reimbursement Prices). A special calculation formula was introduced for
new combination drugs (oral preparations): as a rule,
the price is set at 80% of the total of prices of
7. DETERMINATION OF REIMBURSEMENT
individual drugs.
PRICES FOR NEW DRUGS
To assure transparency of the pricing system,
In view of trends in the new drug development drug pricing formulas were made public in March
environment in recent years, Chuikyo stated in their 2000 (the most recent revision is given in Notification
May 1991 recommendation concerning the No. 0207-(1) of the Health Insurance Bureau dated
reimbursement price of new drugs that a more February 7, 2018, “Drug Pricing Standards”).
appropriate premium system should be introduced Procedures for calculation of drug prices were issued
with a new premium for innovation that would be in detail in September 2000 (the most recent revision
applicable to only truly innovative new drugs. is given in Notification No. 0207-(7) of the Health
Specifically, it was recommended that the Policy Bureau dated February 7, 2018, “Handling of
2019 - 166 -
Pharmaceutical Regulations in Japan:
Entries of Prescription Drugs in the NHI Price List”). Economic Affairs Division, Health Policy Bureau
Methods for submission of requests for inclusion of dated February 7, 2018 “Method for Submission of
new drugs in the price list were most recently revised Requests for Entry in the NHI Price List for
in Notification No. 0207-(2) of the Economic Affairs Prescription Drugs”).
Division, Health Policy Bureau dated February 7, • When a generic drug identical to the brand
2018. drug is entered in the price list for the first
A drug pricing organization was established to time, the price of the generic drug is
undertake scientific surveys concerning selection of obtained by multiplying the brand drug
products for price comparison and the applicability of price by a factor of 0.5. The factor is 0.4 for
premiums by experts in the medical and “oral” preparations, in the case that more
pharmaceutical fields. This organization deals than 10 brands are already on the market.
especially with pricing and repricing of new drugs in When both the brand and generic drugs
the NHI Price List. are already entered, the price of a newly
With the establishment of the pricing organization, entered generic drug is the same as the
flowcharts of the process from new drug approval until lowest of the generic prices.
entry in the NHI Price List are shown in Fig. 21 A special formula was introduced for
(Reimbursement Pricing Flow-sheet for New Drugs). biosimilar products. A premium (maximally
(Entries of new drugs in the NHI Price List are 10/100 of the standard) is added to the
made as a rule four times a year.) standard price (the factors are 0.7 and 0.6,
respectively) depending on qualitative and
quantitative data obtained from clinical
8. ENTRY OF GENERIC DRUGS IN THE NHI
trials.
PRICE LIST
In the past, generic drugs have been entered in
9. ISSUES RELATED TO THE USE OF
the NHI Price List once every 2 years, but the entry
DETERMINATION OF UNAPPROVED
has been made once a year from 1994 and twice a
DRUGS AND OFF-LABEL USE
year since 2008 (entries in May and November from
2009). The reimbursement prices for the drugs There have been major issues related to the use
listed since 1996 are calculated as follows in principle. of unapproved drugs and the “time-lag” in new drug
As in the case of new drugs, the drug pricing approval. The Ministry of Health, Labour and Welfare
formulas were issued in March 2000 with the aim of formed “Special Committee on Unapproved Drugs” in
assuring transparency of the generic drug pricing 2005 to address these issues. In view of an
system. increasing need for regulatory and industry measures
(The most recent revision is given in Notification to lend greater support to the use of unapproved
No. 0207-(1) of the Health Insurance Bureau dated drugs and new indications, the Ministry and member
February 7, 2018, “Drug Pricing Standards.”) companies of the JPMA worked together and
Procedures for calculation of reimbursement prices established “Pharmaceutical Development Support
were specified in detail in September 2000 (most Center” in May 2009 to improve regulatory systems
recent revisions: Notification No. 0207-(7) of the and structures to support the development of such
Health Policy Bureau dated February 7, 2018, drugs and new indications by pharmaceutical
“Handling of Entries of Prescription Drugs in the NHI companies. The Chuikyo also joined the support and
Price List” and Notification No. 0207-(2) of the they discussed potential approaches and introduced
2019 - 167 -
Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
Pharmaceutical approval
(Note 1) The parts in the double box show parts involving the drug pricing
organization
(Note 2) Time clock (agreed on at MOSS conferences)
Entry in price list 4 times per year. Listing within 60 days as a rule or 90 days
at the longest provided that there are no further problems with the pricing
draft.
2019 - 169 -
Pharmaceutical Regulations in Japan:
(Month) 1 2 3 4 5 6 7 8 9 10 11 12 1
Approval #
products)
● Rule on the entry into the NHI Price List: Generally, within 60 days (or within 90 days at the latest) after approval
● New formulations of drugs approved after the reexamination period: Classified as generic drugs (time of entry: twice a
year)
● Drugs reported to but not reviewed by the Committee (PAFSC) are handled by the principle of “change on late notice.”
Approvals indicated with means those that do not require price listing (Approval indicated with means 4 times/year
of approval of drugs that requires price listing procedures).
#/#: Special entry in the year of NHI price revision (every 2 years)
# : The entry in February in the year of NHI price revision (year of “special entry”) is actually made in April (based on
the 90-day rule).
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
-8.5% 0.4% -
-6.8% 0.2% -
-7.0% 0.2% -
-9.7% 0.0% -
-7.5% 0.5% -
Since a new premium formula was introduced for the promotion of new drug research and resolution of
problems of treatment not covered by insurance on a trial basis after 2010, above data are not available.
The drug price revision implemented in 2018 is outlined below:
The revision rate is -7.48% on the drug price basis and -1.65% on the medical care expenditure basis.
Among them, the portion for revision of actual price, etc. accounted for 6.17% on the drug price basis and
1.36% on the medical care expenditure basis. The proportion attributable to the drug price system reform
accounted for 1.31% on the drug price basis and 0.29% on the medical care expenditure basis.
The numbers of products listed on the price list as of April 2018 are shown in the following table.
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Pharmaceutical Regulations in Japan:
iii. Listed drugs with replacement rate ≥60% and < 80%, 1.50%
(2) Lowering of drug price to the price of generic drugs for long-listed drugs 10 years or more after listing
of generic drugs
1) Among the original drugs (except for orphan drugs, etc.) 10 years or more after listing of the first
generic drug, the price of the drugs for which the rate of replacement with generic drugs reached
80% or more (except for the cases in which the indications of the original drug and the generic
drug are not identical; hereinafter referred to as G1 product) is lowered to the following amount.
i. Drugs subjected to drug price revision for the first time after falling under G1 product
2.5 times of the weighted mean of the price of generic drugs
ii. Drugs subjected to drug price revision for the first time after passage of 2 years after falling
under G1 product
2 times of the weighted mean of the price of generic drugs
iii. Drugs subjected to drug price revision for the first time after passage of 4 years after falling
under G1 product
1.5 times of the weighted mean of the price of generic drugs
iv. Drugs subjected to drug price revision for the first time after passage of 6 years after falling
under G1 product
Weighted mean of the price of generic drugs
2) Among the original drugs (except for orphan drugs, etc.) 10 years or more after listing of the first
generic drug, the price of the drugs other than G1 products (hereinafter referred to as G2 product)
will be lowered to the following price. The rules in 3) will be applied to biological products.
i. Drugs subjected to drug price revision for the first time after falling under G2 product
2.5 times of the weighted mean of the price of generic drugs
ii. Drugs subjected to drug price revision for the first time after passage of 2 years after falling
under G2 product
2.3 times of the weighted mean of the price of generic drugs
iii. Drugs subjected to drug price revision for the first time after passage of 4 years after falling
under G2 product
2.1 times of the weighted mean of the price of generic drugs
iv. Drugs subjected to drug price revision for the first time after passage of 6 years after falling
under G2 product
1.9 times of the weighted mean of the price of generic drugs
v. Drugs subjected to drug price revision for the first time after passage of 8 years after falling
under G2 product
1.7 times of the weighted mean of the price of generic drugs
vi. Drugs subjected to drug price revision for the first time after passage of 10 years after falling
under G2 product
1.5 times of the weighted mean of the price of generic drugs
3) For the products the amount calculated by the rules in 2) is higher than the amount lowered
according to the following classification, the price will be revised to the amount lowered according
to the following classification, regardless of the rules in 2) (C).
i. Replacement rate is <40%, 2.00%
ii. Replacement rate is ≥40% and < 60%, 1.75%
iii. Listed drugs with replacement rate ≥60% and < 80%, 1.50%
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Pharmaceutical Regulations in Japan:
i. Drug price lowering for original drugs with slow replacement with generic drugs (Z2)
Replacement rate of generic drugs
≥40% ≥60% Total
<40%
<60% <80%
Number of ingredients 30 34 21 85
Number of products 60 79 68 207
ii. Lowering of drug price to the price of generic drugs for long-listed drugs 10 years or more after
listing of generic drugs
Classification Number of ingredients Number of products
G1 38 85
G2 137 293
Replacement <40% 111 275
rate of generic
drugs ≥40% and <60% 98 189
C
≥60% and <80% 59 108
Total for C 268 572
Total 443 950
2. Premium for addition, etc. of indication of pediatric indication or rare disease and verification of true
clinical usefulness
Number of ingredients/ products subject to premium for addition, etc. of pediatric indication
Pediatric Verification of true
Rare disease Total
indication clinical usefulness
Number of ingredients 7 11 1 19
Number of products 27 19 3 49
3. Repricing for market growth and repricing for change of dosage and administration
Number of ingredients/ of products of target drugs
Repricing for market Special repricing for Repricing for change of dosage
growth growth and administration
Number of ingredients 9 2 3
Number of products 19 4 5
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Pharmaceutical Regulations in Japan:
5. Basic drugs
(1) For the drugs satisfying the following requirements, integrate the price to the brand with the largest
sales volume, and maintain the price.
i. It should be clear that the medical positioning has been established, and the drug is widely used
in clinical settings.
ii. Among all similar drugs for which the listed product, component, and dosage form are same,
identical, the time after the date of drug price listing is more than 25 years for some of the
products.
iii. If there is any similar drug for which the listed product, component, and dosage form are same,
the mean discrepancy rate for the similar drugs including the listed product is not larger than the
mean discrepancy rate for all listed drugs.
iv. The discrepancy rate of the listed drug from the actual market price is not larger than the mean
discrepancy rate for all listed drugs.
Classification Number of ingredients Number of products
Unprofitable 119 370
Pathogenic organisms 81 205
Narcotics 9 24
Crude drugs 48 55
Ointment base 3 3
Dental topical analgesics 1 3
Total 261 660
* Any drugs falling under multiple classifications should be included in the classification listed higher.
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Pharmaceutical Regulations in Japan:
7. Premium for promotion of innovative drug discovery and resolution of off-label use
(1) Target of premium
1) Target products
New drugs meeting all of the following requirements
I) 15 years or less after drug price listing without entry of generic drugs
II) Falling under any of the following requirments
i. Drugs approved for indications designated for orphan drugs
ii. Drugs for which development is requested publicly based on the results of examination by
the Unapproved Drug, etc. Review Committee
iii. Drugs for which plus correction for premium for innovativeness, premium for usefulness
(I), premium for usefulness (II) or operating margin was applied at the time of drug price
listing, or drugs for which special repricing associated with drug price revision for a listed
drug for which true clinical usefulness was verified after marketing at the time fo drug price
revision (hereinafter referred to as the product subject to premium)
iv. Drugs with new mechanism of action falling under the criteria for innovativeness and
usefulness
v. Drugs for which only one or two drug(s) with similar pharmacological action existed at the
time of drug price listing, listed within 3 years after listing of the first drug with similar
pharmacological action, and for which the drug with similar pharmacological action listed
first is a product subject to premium or satisfies the criteria for innovativeness and
usefulness
III) For any combination product for which drug price is calculated as an exceptional measure for
new medical combination products, an active ingredient of any listed product more than15
years after the date of drug price listing, or an active ingredient of any listed product for which
generic drugs have been listed on the drug price list must not be contained
IV) The drug is not subject to repricing
2) Target company
The target company for premium for new drug discovery must not be a company which showed
inappropriate behaviors, such as refusal of development and unreasonable delay in develoment,
for the products for which development is requested by the Ministry of Health, Labour and
Welfare, based on the results of examination in the Unapproved Drug, etc. Review Committee.
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Pharmaceutical Regulations in Japan:
(2) Products for which the amount equivalent to premium was returned
1) For new drugs who no longer satisfy the requirements in 1) i) or iii) or 2) in the previous section,
the total amount equivalent to the premium in the past drug price revision will be deducted from
the value calculated from the actual market price.
3) Total amount of innovative drug discovery premium, etc. deducted: 65 billion yen
8. Others
Drug price investigation result for 2017
(1) Mean discrepancy rate: 9.1%
* Mean discrepancy rate is calculated as {Total of (current drug price×sales volume)- total of (actual sales unit price×sales
volume) } / Total of (current drug price×sales volume).
(2) Percentage of generic drugs in volume: 65.8%
* Percentage of generic drugs in volume is calculated as (Volume of generic drug) / {(volume of original drug with generic drugs)+
(volume of generic drugs)}.
(3) Settlement rate (on the drug price basis) = 97.7%
* Settlement rate (on the drug price basis) is based on the results of the survey on the status of price settment (for September 2017).
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Pharmaceutical Regulations in Japan:
*1 "Other products" include products of Japanese Pharmacopoeia, herbal extracts, crude drugs, biological
products (vaccines and blood products, etc.) and drugs approved in 1967 or before.
*2 Number of products is the figure as of April 2018, and discrepancy rate, percentage against total on the drug
price basis, percentage of volume against total, and percentage of volume of generic drugs are based on the
volume and drug price as of investigation in September 2017.
*3 Since figures are rounded to the first decimal place, the total of the percentages may not be equal to
100.0%.
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
Index
Clinical study reports (FSR) ........................................... 83
1 Codevelopment of Drugs ............................................... 43
Combination Products .................................................... 42
15-Day reports (ADR)............................................. 60, 128
Commentaries on Precautions in package inserts ....... 154
Compliance and Narcotics Division .................................. 3
3
Compliance Reviews...................................................... 66
30-Day reports (ADR)................................................... 128 Countermeasures for Counterfeit Prescription Drug ...... 32
Common Technical Document (CTD) ........................... 107
7 CTD Module 1 ................................................................. 71
7-Day reports (ADR) ...................................................... 60 CTD Module 2: Data summaries....................................... 71
CTD Module 3: Quality ..................................................... 72
A CTD Module 4: Nonclinical study reports ........................... 72
CTD Module 5: Clinical study reports ................................ 72
ADR reporting system
Reporting by MHLW ................................................. 127 D
Reporting by pharmaceutical companies ................. 127
Development Of New Drugs .......................................... 57
Adverse Drug Reaction (ADR) and Infection Reporting . 29
Dissemination of drug information
AIDS Research Center ................................................... 10
General .................................................................... 141
Approval and licenses
Safety information .................................................... 149
Acceptance of foreign clinical trial data ...................... 73
Dissemination of information .......................................... 30
Data required for approval applications...................... 69
Dissemination of information on adverse reactions to
Data to be Attached to Approval Application................... 72
drugs ........................................................................ 153
Approval and Licenses
Drug Abuse Control ........................................................ 31
Approval Applications for Drugs Manufactured in Drug development
Foreign Countries .................................................. 44 Process from development to approval...................... 57
Approval and Licenses Drug Marketing Approvals .............................................. 33
Transfer of Approvals ................................................. 43 Drug pricing .................................................................. 161
Approval Review ............................................................ 64 Drug Retail Seller Licensing ........................................... 23
Approval System for Regenerative Medicine ................. 41 Drug Safety Update...................................................... 154
Article 42 of the Pharmaceutical Affairs Law .................. 46 Drugs
Classification .............................................................. 17
B Definition .................................................................... 17
Biological products ......................................................... 18 Quality Standards Based on Notifications .................. 47
Biosimilar products ......................................................... 42 Drugs for Pediatric Use .................................................. 37
Biosimilar Products ........................................................ 88 Drugs using materials of human or animal origin ........... 87
Biotechnological products .............................................. 86
Blood and Blood Products Division ..................................4 E
Brand Names of Prescriptions Drugs ........................... 147
Early post-marketing phase vigilance........................... 121
bridging studies .............................................................. 73
Economic Affairs Division ................................................. 4
Electronic information dissemination
C
Safety information .................................................... 154
Certificates Issued by MHLW ......................................... 44 Emergency safety information (Yellow letter) ............... 151
Classification of reexamination approval ...................... 134 Entry of generic drugs in the NHI price list ................... 167
Clinical Studies............................................................... 78 Evaluation and Licensing Division .................................... 2
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
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Pharmaceutical Regulations in Japan:
S U
Safety flash report ........................................................ 152 Unapproved drugs and drugs of off-label use ................ 38
Safety information
Reporting system by Medical Personnel .................. 130 W
Safety monitoring WHO safety monitoring program .................................. 130
During clinical studies ................................................ 60
Safety studies Y
Requirements............................................................. 80
Yellow letter .................................................................. 151
SOP for PMS ................................................................ 117
Specified biological products .......................................... 18
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Pharmaceutical Regulations in Japan:
Under the supervision of Ministry of Health Labour and Welfare Japan, this publication
has been updated regularly with the cooperation of the enthusiastic editors below.
Contact:
JAPAN PHARMACEUTICAL
Office of International Affairs
MANUFACTURERS ASSOCIATION
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