Regulatory Requirement on Dossier of Medicinal Products WHO Workshop, October 2007

1. Regulatory Requirement on Dossier of Medicinal ProductsWHO Workshop, October 2007 Sultan Ghani, Director Bureau of Pharmaceutical Sciences Therapeutic Products Directorate, Health Canada

2. Outline • Common Technical Document (CTD – ICH) • Quality Overall Summary (QOS)

3. 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

4. Module 1 Regional Administrative Information Not Part of CTD Nonclinical Overview Clinical Overview Quality Overall Summary Nonclinical Summaries Clinical Summary CTD Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Result was the CTD Triangle NDS Module 2

5. 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

6. 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

7. 2.2 CTD Introduction • General introduction to the pharmaceutical, including • Pharmacologic class • Mode of action • Proposed clinical use • Typically 1 page

8. 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

9. 2.3 Quality Overall Summary - Format • 2.3 Introduction • 2.3.S Drug Substance • 2.3.P Drug Product • 2.3.A Appendices • 2.3.R Regional Information

10. 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

11. 2.4 Nonclinical Overview - Format • 2.4.1 Overview of Nonclinical Testing Strategy • 2.4.2 Pharmacology • 2.4.3 Pharmacokinetics • 2.4.4 Toxicology • 2.4.5 Integrated Overview and Conclusions • 2.4.6 List of Literature Citations

12. 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

13. 2.5 Clinical Overview - Format • 2.5.1 Product development rationale • 2.5.2 Overview of Biopharmaceutics • 2.5.3 Overview of Clinical Pharmacology • 2.5.4 Overview of Efficacy • 2.5.5 Overview of Safety • 2.5.6 Benefits and Risks Conclusions • 2.5.7 References

14. 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

15. 2.6 Nonclinical Written and Tabulated Summaries - Format • 2.6.1 Introduction • 2.6.2 Written Summary of Pharmacology • 2.6.3 Tabulated Summary of Pharmacology • 2.6.4 Written Summary of Pharmacokinetics • 2.6.5 Tabulated Summary of Pharmacokinetics • 2.6.6 Written Summary of Toxicology • 2.6.7 Tabulated Summary of Toxicology

16. 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)

17. 2.7 Clinical Summary - Format • 2.7.1 Summary of biopharmaceutic studies and associated analytical methods • 2.7.2 Summary of clinical pharmacology (including clin micro characterization studies) • 2.7.3 Summary of clinical efficacy • 2.7.4 Summary of clinical safety • 2.7.5 References • 2.7.6 Synopses of individual studies

18. 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

19. Submission of CMC Information in CTD Format (cont’d) 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

20. Submission of CMC Information in CTD Format (cont’d) 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

21. 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, post-approval production period.

22. 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

23. 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

24. 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

25. Quality Overall Summary (QOS) Japan • Primary review document Canada • Basis for review template

26. Quality Overall Summary (QOS) The Quality Overall Summary (QOS): • Is part of a drug submission organized according to ICH’s Common Technical Document (CTD) Guideline (i.e., Module 2.3) • ICH’s 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

27. Quality Overall Summary (QOS) The Quality Overall Summary (QOS)(cont’d): • New Drug Submissions (NDSs) • Abbreviated New Drug Submissions (ANDSs) • Drug Master Files (DMFs) • Provided the ‘Open’/‘Closed’ portions are submitted in separately bound dossiers

28. Quality Overall Summary – Chemical Entities (QOS-CE) Template Health Canada’s (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 ICH’s QOS (e.g., can be considered an acceptable replacement for the QOS as defined by the CTD-Q)

29. Thank you