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Mr. TANAKA Katsuya(田中 克哉)
Section Chief, Pharmaceutical Evaluation Division,
Pharmaceutical Safety and Environmental Health Bureau,
Ministry of Health, Labour and Welfare (MHLW)
Feb 5th, 2020
4th India -Japan Medical Products Regulatory Symposium
Regulatory system on Generic drugs in Japan
4th India - Japan Medical Products Regulation Symposium 2019 1
Contents
• Introduction of Review Points and BE Guidelines
• Overview of Japan’s Strategy for promoting the use of Generic Drugs
24th India - Japan Medical Products Regulation Symposium 2019
Contents
• Introduction of Review Points and BE Guidelines
• Overview of Japan’s Strategy for promoting the use of Generic Drugs
34th India - Japan Medical Products Regulation Symposium 2019
・Expiration of re-examination period of the original product
・No valid patent (substance/utility patent for the active ingredient) at the time of
approval
・Warranty of equivalent quality and bioequivalence to the original product
Requirements for application/approval of generic drugs
Comparing with the original, brand drug, generic drug have the same:
・API (active pharmaceutical ingredients)
・Strengths
・Route of administration
・Dosage form
・Dose and administration and Indications
What are generic drugs?
About generic drugs
44th India - Japan Medical Products Regulation Symposium 2019
Documents Originator Generic
a. Origin or background of discovery, condition of use in foreign countries
1 Origin or background of discovery ○ ×
2 Conditions of use overseas ○ ×
3 Special characteristics, comparisons with other drugs etc. ○ ×
b. Manufacturing methods, specification and test methods
1 Chemical/physical characteristics and structure property ○ ×
2 Manufacturing methods ○ △
3 Specification and test methods ○ ○
c. Stability1 Long-term storage tests ○ ×
2 Tests under severe conditions ○ ×
3 Accelerated tests ○ ○
d. Pharmacological action1 Tests to support efficacy ○ ×
2 Secondary pharmacology, safety pharmacology ○ ×
3 Other pharmacology △ ×
e. Absorption, distribution, metabolism, and excretion
1 Absorption ○ ×
2 Distribution ○ ×
3 Metabolism ○ ×
4 Excretion ○ ×
5 Bioequivalency × ○
6 Other pharmacokinetics △ ×
f. Acute/sub acute/chronic toxicity, teratogenicity, and other type of toxicity
1 Single dose toxicity ○ ×
2 Repeated dose toxicity ○ ×
3 Genotoxicity ○ ×
4 Carcinogenecity △ ×
5 Reproductive toxicity ○ ×
6 Local irritation △ ×
7 Other toxicity △ ×
g. Clinical trials 1 Results of clinical trials ○ ×
h. Package inserts 1 Points to consider of package inserts ○ ○
Note) ○ means necessary, × means not necessary, and △ means to depend on each product
Requirements of data in application in Japan
54th India - Japan Medical Products Regulation Symposium 2019
1. Specifications and analytical procedures
• Specifications are one part of a total control strategy for the drug substance and drug product designed to ensure product quality and consistency (ICH Q6A guideline).
• The following tests are also considered generally applicable to generic drugs.
- Limits of the content of the ingredient(s) and/or the unit of potency, Description, Identification tests, Specific physical and/or chemical values, Purity tests, Water or loss on drying, Residue on ignition, Assay, and so on.
Points of quality review
4th India - Japan Medical Products Regulation Symposium 2019 6
1. Specifications and analytical procedures (continued)
• Assay
• Set acceptance criteria assuring the equal efficacy and safety based on the batch data and stability data, etc.
• Impurities
• Equal or tighter acceptance criteria than that of
the original drug in principle.
• Review based on ICH guidelines (Q3A, Q3B, Q3C) about impurities which are not detected in the original drug.
Points of quality review
74th India - Japan Medical Products Regulation Symposium 2019
2. Manufacturing processes
The Marketing Approval Document includes all processes from starting material(s) to packaging process.
• Starting materials
• Intermediates
• Critical steps
• In-process control
• Container closure system, and so on
• An applicant should demonstrate that the manufacturing process is capable of consistently producing drug substance and drug product of the intended quality.
Points of quality review
84th India - Japan Medical Products Regulation Symposium 2019
3. Stability
• An applicant should submit 6 months of accelerated stability data.
- at 40 ℃, RH 75%, 3 lots, for 6 months
• In some cases, the applicant should also submit the following stability data at the time of submission.
Long-term storage tests
- at 25 ℃, RH 60%, 3 lots, for 12 months at least
Tests under severe conditions
- photostability, etc.
Points of quality review
94th India - Japan Medical Products Regulation Symposium 2019
4.Bioequivalence
• Assure therapeutic equivalence of a generic drug to the original drug.
• Compare the bioavailability between a generic drug and the original drug.
TimeP
lasm
a level of
dru
g
Points of quality review
104th India - Japan Medical Products Regulation Symposium 2019
• Guideline for Bioequivalence Studies of Generic Products + Q&A (February 29, 2012)
– Q&A has not been denied the possibility of acceptance of foreign subjects BE data.
– Japanese research group has summarized the consideration from the scientific view point to cope with BE study (including acceptance of foreign subjects data).
Summary:
− The target of BE studies is to detect differences between formulations, and the influence that the racial difference bring to the result could be considered to be small.
− Foreign BE studies are acceptable as a rule in light of the current guideline concept.
− However, if there is a significant difference between the dissolution rates of the standard formulation and the investigational formulation, it is necessary to conduct BE studies for Japanese who are subject to administration.
− The standard formulation should be the brand name product that is approved and distributed in the Japanese domestic market.
Foreign subjects BE study data
114th India - Japan Medical Products Regulation Symposium 2019
1. Pre-Consultation (free)
2. Face to Face Consultation (charge):
• On Bioequivalence
• On Quality
(URL) PMDA Websites (Japanese only)
1: https://www.pmda.go.jp/review-services/f2f-pre/consultations/0001.html
2: https://www.pmda.go.jp/review-services/f2f-pre/consultations/0018.html
PMDA’s Consultation
124th India - Japan Medical Products Regulation Symposium 2019
New Application
First inquires (major discussion points)
Notification of the application result
Marketing Approval
1 - 5 Months
4 Months
12 Months
-2 Months
1 Months
Review of equivalence
Replies
Additional inquiries
1-2 Weeks
Conformity to
reliable criterial, GLP
and GCP
Compliance of
manufacturers with GMP
(GMP Inspection)
Twice a year
In February/August
Timeline of Newly Applied Generic Products
134th India - Japan Medical Products Regulation Symposium 2019
Contents
• Introduction of Review Points and BE Guidelines
• Overview of Japan’s Strategy for promoting the use of Generic Drugs
144th India - Japan Medical Products Regulation Symposium 2019
Transition of Generic Drugs Market Share in Volume and its Goal
Goal of share in volume(Gov’s Policy in 2017)
By September 2020, the ratio of generic drugs use in volume should be 80% and
further promoting measures are studied to enable the goal as early as possible
32.5%34.9% 35.8%
39.9%
46.9%
56.2%
65.8%
72.6%
20%
40%
60%
80%Target 80%
(Source: MHLW survey) Volume share means ratio of quantity of “generics” against quantities of “branded drugs with generics” and “generics”15
Stable supplyEnsure the reliability of
quality
Information provision/Environmental Improvement
Matters on medical insurance system
Stable supply• Marketing authorization holder is
instructed to investigate cause and prevent recurrence in case of hindrance to stable supply.
• industry groups/companies are instructed to establish manuals for stable supply.
Provide information to medical personnel
• MHLW publishes information brochure on the quality of generic drugs.
• In each prefecture, medical institutions are encouraged to promote the use of generic drugs.
• The list of commonly used generic drugs is made and shared among local medical institutions.
Evaluation on medical treatment fee etc.
【medical institutions】• The requirement for incentives for use of
generic drugs has been enhanced.• Incentive of common name prescription has
been enhanced.【Pharmacy】• The requirement for incentives for dispensing
generic drugs has been enhanced. etc.
Ensure the reliability of quality
• National Institute of Health Science implements quality inspections and discloses information.
• companies hold seminars for medical personnel, factory tours etc.
Environmental Improvement• Government promotes dissemination and awareness
through government public relations, posters, leaflets, etc.• Medical insurance insurers inform insured about
differences in burden amount when using generic drugs• Designate priority areas from prefectures where
incomplete use of generic drugs is not sufficient, conduct research and analysis of problem points, implement model projects
• Promotion of use promotion in each prefecture based on the Third Medical Cost Optimization Plan (FY 2018 to 2023)
etc.
Drug price revision / calculation
• As a general rule, one price range is set for generic drugs that have been 12 years since launch
Main measures for promoting generic drugs
164th India - Japan Medical Products Regulation Symposium 2019
○Quality revaluation(1997~)
■For solid pharmaceutical products for internal use applied before April 1995, standards for
dissolution of pharmaceuticals have been set.
→Conducted on 4,590 items (638 active ingredient). Results have been published in Orange Book.
○Action program for promoting the use of generic drugs without anxiety(2007~)
■Expansion of collection inspection items, implementation of on-site inspection, active publication of
inspection results
■Implementation of impurity test etc. in injections of generic drugs.
■Collect research papers on the quality of generic drugs and conduct tests as necessary.
○Roadmap for further promotion of use of generic drugs(2013 ~)
*Continuation of the above measures
○Comprehensive strategy to strengthen the pharmaceutical industry(2015~)
■Promoting centralized quality assurance by linking accelerated academic evaluation and
examination inspection for quality assurance
■Disseminating information that organizes data on quality. (Blue Book)
Recent efforts on securing the quality of generic drugs
174th India - Japan Medical Products Regulation Symposium 2019
MHLW implements two main projects:
• Promoting information provision in collaboration with academia
• Certifying quality in the market as a part of inspection
Joint Projects of Strengthening Quality Certification in Collaboration with Academia/Inspection
Project of Promoting Information Provision Project of Certifying Quality
Concerns from nationals/academia/medical
workers
PMDA
MHLW
Local Health
Centers
NIHSQuality Information
Committee
Local Prefectures
Products
under test
ResultsLocal Health
Centers
NIHSMHLW
Results
Marketing Authorization Holders
Consultation service
184th India - Japan Medical Products Regulation Symposium 2019
Test items Number of active ingredients
Number of products
Dissolution test 92 1261
Purity test 15 127
Quantitative test 2 27
Content uniformity test 3 64
Component content ratio test 1 13
Mass deviation test 1 8
Test results(Expert committee on quality of generic drug products) ;http://www.nihs.go.jp/drug/ecqaged/kentou-list.html
"Expert committee on quality of generic drug products" conducts inspections and evaluates products
in order to confirm that the quality of generic drugs is equal to or higher than that of original drugs.
Product evaluated by Expert committee on quality of generic drug products
194th India - Japan Medical Products Regulation Symposium 2019
• NIH starts publication of the Blue Book in March
2017.(URL) http://www.nihs.go.jp/drug/ecqaged/bluebook/list.html
• The blue book site publishes on quality-related
information such as similarity of dissolution
behavior, bioequivalency and collaborative
development of generic drugs
Information Package of Quality of Prescription Drugs (Blue Book)
204th India - Japan Medical Products Regulation Symposium 2019
Thank you for your attention
214th India - Japan Medical Products Regulation Symposium 2019