Regulatory Requirement on Dossier of Medicinal Products

WHO Workshop, October 2007

Sultan Ghani, Director Bureau of Pharmaceutical Sciences Therapeutic Products Directorate, Health Canada

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 1

Outline
 Common Technical Document (CTD ICH)  Quality Overall Summary (QOS)

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 2

An Overview of the CTD

 The CTD is not a Global Dossier !  It is an agreed-upon common format for the modular presentation of summaries, reports and data  Incorporates relevant ICH guidelines  It is organized into five sections:
 All modules harmonized except Module 1 regional specific  Raw data per regional requirements

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 3

Result was the CTD Triangle

Module 1 Regional Administrative Information Nonclinical Overview Nonclinical Summaries Clinical Overview

Not Part of CTD

Module 2

Quality Overall Summary

NDS Clinical Summary CTD

Module 3 Quality

Module 4 Nonclinical Study Reports

Module 5 Clinical Study Reports

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 4

CTD Structure
 Full dossier contains 5 Modules - - Only Modules 2-5 are CTD  Module 1 region-specific but always included in complete CTD structure  Module 2- All summaries / overviews  Module 3 CMC (Quality)  Module 4 Preclinical  Module 5 - Clinical

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 5

Module 2 - CTD Summaries

 2.1 Overall CTD ToC  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  2.7 Clinical Summary

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2.2 CTD Introduction

 General introduction to the pharmaceutical, including
 Pharmacologic class  Mode of action  Proposed clinical use

 Typically 1 page

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2.3 Quality Overall Summary - Content

 A Summary that follows the scope and outline of the Body of Data in Module 3  Emphasize and discuss critical key parameters of the product  Discuss key issues to integrate information from Module 3 and other modules  Typically 40 pages, excluding tables, figures

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2.3 Quality Overall Summary - Format

 2.3  2.3.S  2.3.P  2.3.A  2.3.R

Introduction Drug Substance Drug Product Appendices Regional Information

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007

2.4 Nonclinical Overview - Content

 An integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation  Discuss relevant guidance; any deviations from guidance should be discussed and justified  Nonclinical testing strategy should be justified, including GLP status of submitted studies  Discuss associations with quality characteristics, clinical trial results, effects with related products  Typically 30 pages
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2.4 Nonclinical Overview - Format

 2.4.1  2.4.2  2.4.3  2.4.4  2.4.5  2.4.6 Overview of Nonclinical Testing Strategy Pharmacology Pharmacokinetics Toxicology Integrated Overview and Conclusions List of Literature Citations

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2.5 Clinical Overview - Content

 Highest level summary and analysis of clinical data and overall clinical development plan  Overview of the clinical part of the dossier with succinct discussion and interpretation  Critical analysis of clinical data for efficacy and safety, as well as other relevant information (e.g. pertinent animal data or quality issues)  Typically 30 pages

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 12

2.5 Clinical Overview - Format

 2.5.1  2.5.2  2.5.3  2.5.4  2.5.5  2.5.6  2.5.7

Product development rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology Overview of Efficacy Overview of Safety Benefits and Risks Conclusions References

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2.6 Nonclinical Written and Tabulated Summaries - Content

 Integrate information across studies and across species  Primarily text, with examples of tables and figures  Exposure in test animals should be related to exposure in humans given maximum intended doses  Age, gender, and metabolite-related effects  In vitro studies first, then in vivo  Ordered by species, route, duration  Typically 100-150 pages
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2.6 Nonclinical Written and Tabulated Summaries - Format

 2.6.1  2.6.2  2.6.3  2.6.4  2.6.5  2.6.6  2.6.7 Introduction Written Summary of Pharmacology Tabulated Summary of Pharmacology Written Summary of Pharmacokinetics Tabulated Summary of Pharmacokinetics Written Summary of Toxicology Tabulated Summary of Toxicology

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2.7 Clinical Summary - Content

 Provides factual summary and support for conclusions and critical issues identified in the Clinical Overview  Comparison of results across studies with integration of clinical information  Analysis of all relevant information for dosing recommendations  Typically 50-400 pages (excluding tables)

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 16

2.7 Clinical Summary - Format

 2.7.1  2.7.2  2.7.3  2.7.4  2.7.5  2.7.6 Summary of biopharmaceutic studies and associated analytical methods Summary of clinical pharmacology (including clin micro characterization studies) Summary of clinical efficacy Summary of clinical safety References Synopses of individual studies

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Submission of CMC Information in CTD Format

3.2.S 3.2.S.1 3.2.S.2 3.2.S.3 3.2.S.4 3.2.S.5 3.2.S.6 3.2.S.7 DRUG SUBSTANCE General Information Manufacture Characterization Control of Drug Substance Reference Standards or Materials Container Closure System Stability

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Submission of CMC Information in CTD Format (contd)

3.2.P 3.2.P.1 3.2.P.2 3.2.P.3 3.2.P.4 3.2.P.5 3.2.P.6 3.2.P.7 3.2.P.8 DRUG PRODUCT Description and Composition of the Drug Product Pharmaceutical Development Manufacture Control of Excipients Control of Drug Product Reference Standards or Materials Container Closure System Stability

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 19

Submission of CMC Information in CTD Format (contd)

3.2.A 3.2.A.1 3.2.A.2 3.2.A.3 3.2.R APPENDICES Facilities and Equipment Adventitious Agents Safety Evaluation Excipients REGIONAL INFORMATION

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 20

Submission of CMC Information in CTD Format

 The CTD Quality Module is unique in that it is a combination of historical development and future commitments that apply to the commercial, postapproval production period.

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 21

Impact of the CTD

 The ICH CTD represents one of the most ambitious and successful international harmonization activities undertaken  It will significantly reduce time and resources needed by industry to compile applications for global registration

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Benefits of the 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

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Quality Overall Summary (QOS)

U.S.  information source not used for decision  Module M3 reviewed serves as a basis for decision and action EU  Same as above  Can be used for reviews

Training Workshop on Pharmaceutical Development | with a Focus on Paediatric Medicines / 15-19 October 2007 24

Quality Overall Summary (QOS)

Japan  Primary review document Canada  Basis for review template

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Quality Overall Summary (QOS)

The Quality Overall Summary (QOS):  Is part of a drug submission organized according to ICHs Common Technical Document (CTD) Guideline (i.e., Module 2.3)  ICHs CTD-Q structure (including the QOS) has been formally adopted by Canada for various drug submission types, e.g.:
 Clinical Trial Applications (CTAs) Phase I, Phase II/III, BA Studies

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Quality Overall Summary (QOS)

The Quality Overall Summary (QOS)  New Drug Submissions (NDSs)  Abbreviated New Drug Submissions (ANDSs)  Drug Master Files (DMFs)
 Provided the Open/Closed portions are submitted in separately bound dossiers
(contd)

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Quality Overall Summary Chemical Entities (QOS-CE) Template

Health Canadas (QOS-CE) Template:
 Was developed to manage the submission workload and to assist sponsors in the preparation of the Quality Summary  Promotes efficiencies in submission preparation and in the review process  Available for various submissions types (CTAs x3, NDSs and ANDSs, etc.)  Entirely compatible with ICHs QOS (e.g., can be considered an acceptable replacement for the QOS as defined by the CTD-Q)
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Thank you

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