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Regulatory Submission in
Japan
Rohit Ashok Patil. M. Pharmacy (QA)
Shree Santkrupa College Of Pharmacy Ghogaon (Karad).
Email [email protected]@gmail.com
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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
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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.
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Japanese market characteristics
Large, mature economy.
Large target universe.
Daimyo system.
Socialized healthcare system.
Heavy regulatory requirement.
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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.
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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 [email protected]
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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 CRFAnalysis plan. Monitoring report, etc,…
PMDA check consistency with CSR• A 100 % check of Japanese patients can be expected.
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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.
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Format/type of Submission
Paper Submission.
CTD.
Electronic submission with eCTD.
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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 [email protected]
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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)
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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)
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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)
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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)
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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)
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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
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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)
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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 [email protected]
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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)
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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)
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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)
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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.
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eCTD FORMAT
Module 1 : Administrative
Module 2 : Summaries
Module 3 : Quality (CMC)
Module 4 : Non clinical study reports
Module 5 : Clinical study reports
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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 [email protected]
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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 [email protected]
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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.
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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-
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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
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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.
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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.
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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.
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The flow chart illustrates the various authorities function on the approval of drug applications.
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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/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf
http://www.info.pmda.go.jp/
http://www.jpo.go.jp/index.htm
http://www.pmda.go.jp/english/services/reviews/others.html
Reference
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Consultation items and fees: http://www.pmda.go.jp/operations/shonin/info/consult/file/8_tesuryo.pdf * Application procedures: http://www.pmda.go.jp/operations/shonin/info/consult/taimen.html
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Regards, Rohit Ashok Patil. Shree Santkrupa College Of Pharmacy Ghogaon(Karad). Email –[email protected]
