Regulatory submission in Japan

Regulatory Submission in
Japan
Rohit Ashok Patil.
M. Pharmacy (QA)
Shree Santkrupa College Of
Pharmacy Ghogaon (Karad).
Email -rohitpharma3250@gmail.com
rohitpharma3250@gmail.com 1

 To make effective contribution to public health.
 To provide authoritative &accessible information.
 To influence international regulation.
 To minimise the cost of regulation.
 To support industry & scientific innovation.
 To provide an overview of the dossier requirements and Guidelines
used or referenced under the WHO Prequalification Program.
Objectives

 Population of 127 million, 2nd largest global economy.
 Japan’s medical market totals $27 billion.
 Expected to reach $39 billion by 2015.
 Japan’s population is aging at a faster rate than any other developed nation.
 Solid domestic device market, but huge importer.
Scope of DRA in Japan.

Japanese market characteristics
 Large, mature economy.
 Large target universe.
 Daimyo system.
 Socialized healthcare system.
 Heavy regulatory requirement.

 Japan is the world’s second largest market next to the US. With USD 52
billion drug market, it represents 11% of global sales.
 The Ministry of Health, Labour, and Welfare (MHLW) is in charge of
pharmaceutical regulatory affairs in Japan and the Pharmaceutical and
Medical Devices Agency (PMDA, KIKO) undertakes main duties and
functions of the Ministry: it handles clinical studies, approval reviews and
post-marketing safety measures i.e. approvals and licensing.
OVERVIEW
Japan history, healthcare structure, and economic status
History
 Application forms from both Japanese New Drug Application (J-NDA)
and Japanese Abbreviated New Drug Application (JANDA) for approval
to market drugs are usually submitted to the PMDA.

Past regulatory environment for importer and manufacturer
 Japan has medicinal regulations in place since 1960, when the
Pharmaceutical Affairs Law (PAL) was amended to include
medical devices and cosmetics.
 Prior to 2000, medicinal applications and approvals were
generally easy to understand, prepare, and obtain. Broad
categories of devices could be applied for and obtained, even if
data only existed for a small portion of these devices.
 Several factors led up to major regulatory changes that began
in 2000, with final regulations being adopted April 1, 2005.
 Implementation of these regulation changes will continue
through 2006 and beyond, some good for US manufacturers,
and some not.
 Lastly, there have been pressures, both within Japan and from abroad, for
harmonization with regulations from the US and Europe, and for
enhanced deregulation and competition laws which would speed the
approval process in Japan.rohitpharma3250@gmail.com 7

Language Used In Japan
 JAPANESE
 ENGLISH

Japan Health Authority (PMDA)
How do that specific Health Authority works?,
 No datasets are required but all data presented in CSR
should be listed because
• PMDA pays attention to data quality.
• PMDA is focused on data errors .
 PMDA conducts paper raw data review
CRF
Analysis plan.
Monitoring report, etc,…
 PMDA check consistency with CSR
• A 100 % check of Japanese patients can be expected.

 A Deliverables should be ready earlier.
 Delay in the review process should be avoided.
 Team has to be very reactive in answering the questions.
 Programming processes needs to be quicker but well
organized.

Format/type of Submission
Paper Submission.
CTD.
Electronic submission with
eCTD.

CTD

CTD Triangle
CTD Information

Benefits of CTD
 More “reviewable” applications.
 Complete, well-organized submissions.
 More predictable format.
 More consistent reviews.
 Easier analysis across applications.
 Easier exchange of information.
 Facilitates electronic submissions.

A common format for the technical documentation:
significantly reduces the time and resources needed to compile
applications for registration of human pharmaceuticals
 eases the preparation of electronic submissions
 Facilitates regulatory reviews and communication with
the applicant by a standard document of common
elements.
 Simplifies exchange of regulatory information between
Regulatory Authorities.
This guideline is not intended to indicate what studies are
required. It merely indicates an appropriate format for the data
that have been acquired.
CTD format (1)

GENERAL PRINCIPLES
 Text and tables should be prepared using margins that allow the
document to be printed on A4 paper.
 The left-hand margin should be sufficiently large that information is not
obscured by the method of binding.
 Font sizes for text and tables should be easily legible, even after
photocopying. Times New Roman, 12-point font, is recommended for
narrative text.
 Every page should be numbered.
 Acronyms and abbreviations should be defined the first time they are
used in each module.
 References should be cited in accordance with the current edition of the
Uniform Requirements for Manuscripts Submitted to Biomedical
Journals, International Committee of Medical Journal Editors
(ICMJE)1.
.
CTD format (2)

The CTD is organized into five modules:
 Module 1 is region specific.
 Modules 2, 3, 4, and 5 are intended to be common for all
regions.
CTD format (3)
Module 1. Administrative Information and Prescribing Information
Should contain documents specific to each region; e.g. application
forms or the proposed label for use in the region. The content and
format of this module can be specified by the relevant regulatory
authorities.
Module 1:
Administrative Information and Prescribing Information-
1.1 Table of Contents of the Submission Including Module 1
1.2 Documents Specific to Each Region (for example, application
forms, prescribing information)

Module 2. Common Technical Document Summaries
 Should begin with a general introduction to the pharmaceutical, including its
pharmacological class, mode of action, and proposed clinical use. In general,
the Introduction should not exceed one page.
 Should contain 7 sections in the following order :
2.1 Common Technical Document Table of Contents (Modules 2-5)
2.2 CTD Introduction
2.3 Quality Overall Summary
2.4 Non-clinical Overview
2.5 Clinical Overview
2.6 Non-clinical Written and Tabulated Summaries
Pharmacology
Pharmacokinetics
Toxicology
2.7 Clinical Summary
Biopharmaceutical Studies and Associated Analytical Methods
Clinical Pharmacology Studies
Clinical Efficacy
Clinical Safety
Literature References
Synopses of Individual Studies
CTD format (4)

Module 3. Quality
 Information on Quality should be presented in the structured format
described in Guideline M4Q
 Module 3: Quality
3.1 Table of Contents of Module 3
3.2 Body of Data
3.3 Literature References
CTD format (5)

CTD format: Numbering System: Module 3
Module 3
3.1 MODULE 3 TABLE OF CONTENTS
3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
3.2.S.2 Manufacture
3.2.S.3 Characterisation
3.2.S.4 Control of Drug Substance
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.2.P DRUG PRODUCT
3.2.P.1 Description and Composition of the Drug
Product
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.2.P.4 Control of Excipients
3.2.P.5 Control of Drug Product
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
3.2.P.8 Stability
Module 3 (Cont.)
3.2.A APPENDICES
3.2.A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Novel Excipients
3.2.R REGIONAL INFORMATION
3.3 LITERATURE REFERENCES

Module - 4: Non-clinical Study Reports
4.1 table of content
4.2 Study Reports
4 .2 .1 Pharmacology
4.2.1 Primary Pharmacodynamics
4.2.2 Secondary Pharmacodynamics
4.2.3 Safety pharmacology
4.2.4 Pharmacodynamics drug interactions
CTD format (6)

4.2.2 Pharmacokinetics
CTD format (7)
4.2.2.1 Analytical Methods and validation Reports
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions
4.2.2.7 Other Pharmacokinetic studies

4.2.3 Toxicology
4.2.3.1 Single-dose toxicity
4.2.3.2 Repeat-dose toxicity
4.2.3.3 Genotoxicity
4.2.3.4 Carcinogenicity
4.2.3.5 Reproductive and developmental toxicity
4.2.3.6 Local tolerance
4.2.3.7 Other toxicity studies
4.3 Literature References
CTD format (8)

Module - 5: Clinical Study Reports
5.1 Table of Contents
5.2 Tabular Listings of All Clinical Studies
5.3 Clinical Study Reports
5.3.1.1 Bioavailability (BA) study Reports
5.3.1.2 Comparative BA and Bioequivalence study reports
5.3.1.3 In-vitro In-vivo Correlation study reports
5.3.1.4 Reports of Bio analytical and Analytical methods
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic metabolism and Drug Interaction Studies and Drug
Interaction Studies
5.3.2.3 Reports of Studies Using human Biomaterials
CTD format (9)

Module – 5
5.3.3.1 Healthy Subject PK and Initial Tolerability study reports
5.3.3.2 Patient PK and Initial Tolerability study reports.
5.3.3.3 Intrinsic Factor PK study reports
5.3.3.4 Extrinsic Factor PK study reports
5.3.3.5 Population PK study reports
5.3.4.1 Healthy subject PD and PK/PD study reports
5.3.4.2 Patient PD and PK/PD study reports
5.3.5.1 Study reports of controlled clinical studies
5.4 List of Key Literature References
CTD format (10)

eCTD

Why eCTD
 Lesser and lesser space at Agencies.
 Handling paper an uphill task and quite subjective.
 Electronic submission give more accountability and ease
decision making process.
 eCTD is a superior technology.
 Establish a single application format for all applications.
 Avoids expensive internal processes and systems for receiving and
archiving applications.

eCTD FORMAT
 Module 1 : Administrative
 Module 2 : Summaries
 Module 3 : Quality (CMC)
 Module 4 : Non clinical study reports
 Module 5 : Clinical study reports

Module 1 : Administrative
•Required for Generic and New drug applications
•Specific for the agency like FDA , UK MHRA, CBG NL
•Regulatory information
Module 2 : Summaries
•CMC and Bioequivalence information
2.3 Quality Over all summary
2.7 Clinical Summary – Bioequivalence studies
Question based review
• In PDF and Word format
• Insert all questions
• Bioequivalence data summary Tables
- All 16 tables in MS word in Module 2.7rohitpharma3250@gmail.com 30

Module 3 : Quality (CMC)
• Details of Drug Substance
• Details of Drug Product
• Product development
• Regional information
Module 4 : Non-clinical data study reports
Not required for generic applications
Module 5 : Clinical Study Reports
• Tabular listing of all studies
• Clinical study reports
• Literature reports
• SAS files in main folder of Module 5

SRUCTURE OF eCTD
 XML backbone.
 Modules.
 Granules.

eCTD Submission Checklist
 eCTD Software .
 Software training and support from the
supplier.
 Compiling and eCTD.
 eCTD hyper linking.
 QC of eCTD.
 Submit eCTD on CD/DVD or Use electronic
gateway.rohitpharma3250@gmail.com 33

 PDF.
 XML.
 SAS.
 MSWord.
 JPG.
Format for regulatory submission

Format for regulatory submission,

 Clinical QC list.
 Medical Writing list.
 QA reports.
 Publishing work practice.
 CLINICAL SUMMARY REPORTS PUBLISING.
 Work practice.
 CSR Appendix list.
 Electronic PDF list.
 Guide for eSub ready Docs.
 Scanned Document list.
Checklist/Requirements of Registration
documents-

 Name, address and table of contents.
 Description of the device form and function.
 Practices and procedures – what device is used for.
 Foreign and domestic market history of the device, if any.
 Details about manufacturing process in making the device.
 Summary of clinical and non-clinical studies.
 Conclusion of studies, include safety and effectiveness of device.
Requirements

 Financial certification and disclosure statement.
 Bibliography of reports about safety/effectiveness of
device.
 Reference to any performance standards followed.
 Labeling and advertising literature (Ex: pamphlets).
 Results of non-clinical lab studies.
 Results of clinical studies on human patients.

FDA Requirements for Approval Generic Drug
To gain FDA approval, a generic drug must:
 contain same active ingredients as the innovator drug.
 be identical in strenght,dosage form, and route of administration.
 have same use/indications.
 have same batch requirements for Identity, Safety, Purity and Quality.
 follow strict standards of FDA’s GMPs.

Drug Development Process/Overall Timeline

Timeline

 In your timelines input from the Japanese team on the
request and translation of documents should be considered
 Japanese colleagues define specifications and programming .
 Conventions because they have a better overview of the Japanese
Submission requirements-
• Japanese team needs time to make their own validation.
• Japanese medical writer has to translate all the tables and the text
delivered to the PMDA.
 Deliverables should be ready earlier.

Application Form of ANDA

Approval procedure in Japan.

The flow chart illustrates the various authorities function on the approval of
drug applications.

New Drug Development &Approval

Continue…..

 Organization of CTD
 http://www.fda.gov/cder/guidance/45390.pdf
 http://www.pmda.go.jp/english/service/pdf
/points.pdf/ (English)
 http://www.fda.gov/downloads/Drugs/Develop
mentApprovalProcess/HowDrugsareDeveloped
andApproved/ApprovalApplications/Abbreviate
dNewDrugApplicationANDAGenerics/UCM1209
57.pdf
 http://www.info.pmda.go.jp/
 http://www.jpo.go.jp/index.htm
 http://www.pmda.go.jp/english/services/re
views/others.html
Reference

 Consultation items and fees:
http://www.pmda.go.jp/operations/sho
nin/info/consult/file/8_tesuryo.pdf
*
 Application procedures:
http://www.pmda.go.jp/operations/sho
nin/info/consult/taimen.html

Regards,
Rohit Ashok Patil.
Shree Santkrupa College Of
Pharmacy Ghogaon(Karad).
Email –rohitpharma3250@gmail.com

Thank You

Regulatory submission in Japan

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