1. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 1 |1 | Regulatory Requirement on Dossier of Medicinal Products WHO Workshop, October 2007 Sultan Ghani, Director Bureau of Pharmaceutical Sciences Therapeutic Products Directorate, Health Canada

2. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 2 |2 | Outline Common Technical Document (CTD – ICH) Quality Overall Summary (QOS)

3. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 3 |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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 4 |4 | Module 1 Regional Administrative Information Nonclinical Overview Quality Overall Summary Clinical Summary Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Clinical Overview Nonclinical Summaries Not Part of CTD CTD Module 2 NDS Result was the CTD Triangle

5. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 5 |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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 6 |6 | Module 2 - CTD Summaries 2.1Overall CTD ToC 2.2CTD Introduction 2.3Quality Overall Summary 2.4Non-Clinical Overview 2.5Clinical Overview 2.6Non-Clinical Written and Tabulated Summaries 2.7Clinical Summary

7. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 7 |7 | 2.2CTD Introduction General introduction to the pharmaceutical, including  Pharmacologic class  Mode of action  Proposed clinical use Typically 1 page

8. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 8 |8 | 2.3Quality 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 9 |9 | 2.3Quality Overall Summary - Format 2.3Introduction 2.3.SDrug Substance 2.3.PDrug Product 2.3.AAppendices 2.3.RRegional Information

10. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 10 | 2.4Nonclinical 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 11 | 2.4Nonclinical Overview - Format 2.4.1Overview of Nonclinical Testing Strategy 2.4.2Pharmacology 2.4.3Pharmacokinetics 2.4.4Toxicology 2.4.5Integrated Overview and Conclusions 2.4.6List of Literature Citations

12. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 12 | 2.5Clinical 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 13 | 2.5Clinical Overview - Format 2.5.1Product development rationale 2.5.2Overview of Biopharmaceutics 2.5.3Overview of Clinical Pharmacology 2.5.4Overview of Efficacy 2.5.5Overview of Safety 2.5.6Benefits and Risks Conclusions 2.5.7References

14. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 14 | 2.6Nonclinical 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 15 | 2.6Nonclinical Written and Tabulated Summaries - Format 2.6.1Introduction 2.6.2Written Summary of Pharmacology 2.6.3Tabulated Summary of Pharmacology 2.6.4Written Summary of Pharmacokinetics 2.6.5Tabulated Summary of Pharmacokinetics 2.6.6Written Summary of Toxicology 2.6.7Tabulated Summary of Toxicology

16. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 16 | 2.7Clinical 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 17 | 2.7Clinical Summary - Format 2.7.1Summary of biopharmaceutic studies and associated analytical methods 2.7.2Summary of clinical pharmacology (including clin micro characterization studies) 2.7.3Summary of clinical efficacy 2.7.4Summary of clinical safety 2.7.5References 2.7.6 Synopses of individual studies

18. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 25 | Quality Overall Summary (QOS) Japan Primary review document Canada Basis for review template

26. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 29 | Thank you