1. ICH and CTD November 19, 2002 Kimberly Stranick, Ph.D. Worldwide Regulatory Affairs The Common Technical Document

2. Topics  What is ICH?  Who is ICH?  ICH Guidelines  What is CTD?  Applicability and Implementation of CTD  CTD Structure  What’s New with CTD?  FDA Experience with CTD  What is e-CTD?  WRA’s CTD Initiatives

3. What is ICH?  Agreement between EU, Japan, and US  Joint Initiative between HA Regulators and Industry  System of Steering Committee and Expert Working Groups  Defined Process for Implementation of agreements in ICH regions

4. ICH Mission (International Conference on Harmonization)  “A more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.”

5. ICH Parties  European Commission - European Union  European Federation of Pharmaceutical Industries and Associations (EFPIA)  Ministry of Health, Labor and Welfare (MHLW) - Japan  Japan Pharmaceutical Manufacturers Association (JPMA)  US FDA  Pharmaceutical Research and Manufacturers of America (PhRMA)

6. ICH Observers  WHO  European Free Trade Area (EFTA) –represented at ICH by Switzerland  Canada –represented at ICH by Health Canada  ICH Secretariat managed by International Federation of Pharmaceutical Manufacturers Associations (IFPMA) to ensure contact with industry outside ICH region

7. ICH Topics  Q = QUALITY Topics –those relating to chemical and pharmaceutical Quality Assurance  S = SAFETY Topics –those relating to in vitro and in vivo preclinical studies  E = EFFICACY Topics –those relating to clinical studies in human subjects  M = Multidisciplinary Topics

8. Multidisciplinary ICH Topics  M1 = Medical Terminology  M2 = Electronic Standards for Transmission of Regulatory Information  M3 = Timing of Preclinical Studies in Relation to Clinical Trials  M4 = The Common Technical Document

9. ICH Guidelines  E1: The Extent of Population Exposure to Assess Clinical Safety  E3: Structure and Content of Clinical Study Reports  E5: Ethnic Factors in the Acceptability of Foreign Clinical Data  E6: Good Clinical Practice (GCP)  Q7: GMP for Active Pharmaceutical Ingredients

10. ICH Process  Step 1 - Consensus Building –Sign off by Expert Working Group members  Step 2 - Start of Regulatory Action (and testing)  Step 3 - Regulatory Consultation (Draft guidance)  Step 4 - Adoption of a Tripartite Harmonized Text  Step 5 - Implementation

11. What is the Common Technical Document?  CTD is –an agreed format for common organization of documents in regulatory applications.  CTD is not –a common content for all markets.  As always, content is data and label driven for a given market.

12. What does CTD specify?  The intention of the CTD format is to save time and resources and to facilitated regulatory review and communication  CTD guidance gives no information about the content of a dossier and does not indicate which studies and data are required for a successful application.  Content guidelines distinct from CTD

13. Why a common format?  CTD concept provides a common format to: –allow each HA to find supporting information they need for their assessment (consistency of scientific content) –show approach to scientific development plan and assess quality of design, study performance, and compliance

14. Applicability of CTD  The CTD was designed to apply to all categories of medicinal products, including –drugs –biologics –generics –herbals –radiopharmaceuticals –vaccines  Applies to all types of applications (stand alone and abridged)

15. CTD through the ICH Process  Step 1: Consensus Building –presented to ICH Steering Committee March 1996  Step 4: Adoption –Endorsed by the ICH Steering Committee October 2000  Step 5: Implementation –Ongoing in ICH regions

16. Implementation of CTD (ICH Step 5)  July, 2001OptionalEU Japan US  July, 2003MandatoryEU Japan Highly Recom.US

17. US Requirement for CTD  CTD is highly recommended in US after July ‘03, not required  Likely CTD will never be “mandatory” in US  Would require change in US law  FDA “expects” rather than “requires”

18. CTD Implementation Issues  At national level for each ICH party, a local version of ICH approved guidance is published.  Wording in the core CTD may be slightly different among regions due to specific editing for local regulations.  Does not affect common understanding by the parties of the ICH CTD.  However, some region-specific expectations and requirements exist.

19. Region-specific requirements  Module 1 (all) –regional administrative information (forms), labeling, Environmental Risk Assessment, signature of experts...  Module 3 (3.2R and 2.3R summary) –US: Method validation package, comparability protocols –US and Canada: Executed batch records –EU: Process validation scheme for drug product, medical device  Module 5 (no location specified) –ISE, ISS and case report forms if required by FDA –tabulated list of trial subjects if required by MHLW

20. Implementation in EU for MRPs  CPMP has clarified CTD implementation requirements for ongoing MRPs. –For submissions made to RMS in old format before July ‘03, where MRP starts after July ‘03, the CMSs will accept old EU format until Dec 31, 2004. SPRI example: Ezetimibe –After July ‘03, CTD is mandatory for all initial submissions under MRP.

21. SPRI’s CTD Implementation recommendations for ongoing procedures  Line extensions –EU: DS reformatted to CTD with identical content –US: cross reference to approved DS application IF electronic –DP in CTD format  EU Variation –All new data in CTD format  US Supplement –Follow format of original NDA

22. CTD Implementation by SPRI Source Areas  DevOps –Document Quality Initiative for report templates and sample reports according to CTD  DSM –Tabular formats and summary document templates revised for CTD  Clinical –No content change required to CSRs –Different summary documents required

23. Making a CTD Submission  Submission format as defined by M4 is paper  Electronic applications before July ‘03 must be hybrid based on “old” electronic guidelines with CTD pieces mapped in  Electronic CTD guidance is separate and lags behind CTD for definition and implementation

24. 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

25. Non-clinical Summary Module 1 Regional Administrative Information Non-clinical Overview Quality Overall Summary Clinical Summary Clinical Overview Module 2 Not part of the CTD CTD Module 3 Quality Module 4 Non-clinical Study Reports Module 5 Clinical Study Reports 2.1 ToC of the CTD (Mod 2, 3, 4, 5) 2.2 CTD Introduction 1.1 Overall ToC inc. Mod 1-5 3.1 ToC for Mod 3 4.1 ToC for Mod 4 5.1 ToC for Mod 5 2.32.42.5 4.05.03.0 2.62.7

26. 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

27. 2.2 CTD Introduction  General introduction to the pharmaceutical, including –pharmacologic class –mode of action –proposed clinical use  Typically 1 page

28. 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

29. 2. 3 Quality Overall Summary - Format  2.3Introduction  2.3.SDrug Substance  2.3.PDrug Product  2.3.A Appendices  2.3.RRegional Information

30. 2. 4 Nonclinical Overview - Content  An integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation  Discuss relevant guidance, and 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

31. 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

32. 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

33. 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

34. 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

35. 2.6 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

36. 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)

37. 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

38. Clinical Overview vs Clinical Summary  Clinical Overview (2.5): –critical analyses of efficacy, safety, and benefit/risk –links the dossier with the label –links all aspects of the development program  Clinical Summary (2.7): –comprehensive factual summary of all relevant data, including cross study analyses and post-marketing experience –includes references and synopses of clinical studies

39. What’s New with CTD?  Granularity and pagination of documents within modules and study reports  Definition of discrete header information for documents within modules  Cross referencing between modules  Confusion about ISS requirement for US

40. Cross references between modules  Quality and Nonclinical/Clinical: –Quality module should include appropriate reference to modules 4 and 5 for drug substance and drug product batch information and formulation development issues –Process change information should cross reference reports in modules 4 or 5 that demonstrate comparability after the process changes

41. Cross references between modules  Nonclinical and Quality: –Nonclinical overview should address: relevance of analytical methods used quality characteristics of human drug as relates to nonclinical findings impurities and degradants present in drug substance and product and what is known of their potential pharmacologic and toxicologic effects

42. Cross references between modules  Nonclinical and Clinical –Nonclinical overview should include: Assessment of limitations and utility of nonclinical studies for prediction of potential AEs in humans associations between nonclinical data and results of clinical trials relevance of pharmacokinetic and nonclinical models, including derived parameters effects seen with related products, metabolites, excipients

43. US Need for ISS?  FDA to reissue guideline to clarify what should be included as ISS for CTD submissions  ISS should be integrated analysis, not summary  Lengthy integrated analyses unlikely to be fully captured in shorter Module 2 documents  Integrated safety analysis in Module 5 for US  FDA recommends early discussion with review division for agreement or questions

44. FDA Experience with CTD  FDA reviewer training ongoing  10 CTD submissions to CDER (across 7 review divisions)  No RTFs  Most have been supplements, not full NDAs  Several rolling submissions in CTD  Several hybrids (CTD/NDA, paper/elec)

45. Problems noted by FDA  Deletion or renumbering/renaming of CTD sections  Additional decimal points in numbering - won’t match e-CTD structure  Incorrect regional sections in Quality module  Advise to strictly follow guidance and examples

46. Next step: What is e-CTD?  Guidelines and technical specifications for submission of CTD dossier electronically  Reached step 4 (adoption of final) Sept 12, 2002  Designed to support full life cycle of regulatory submission  Facilitate electronic viewing, navigation, searching, updating

47. eCTD Impact  Technological: –XML format for identifying individual files and creating ToC –requires new tools to create, manage, review  Procedural: –eCTD specification will have significant impact on company processes from authoring to archiving –Document granularity and metadata must be defined up front

48. eCTD Implementation Activities  Step 4 - September, 2002  Step 5 - To be Implemented in all regions  Under development –eCTD Viewer for review –XML tools –Training, Training, Training

49. 21 CFR Part 11 Considerations  Electronic submissions include electronic records  Electronic records are subject to 21 CFR Part 11 according to predicate rules  Examples of impact: –Versions of documents included in submissions and xml attributes assigned to each submission file must include audit trail for changes –Lifecycle management tool(s) and strategy must comply with records requirements

50. WRA’s CTD Initiatives CTD Task Force established within WRA  Identify and track submissions that will be in CTD format  Establish Cross Functional Task Force with representatives from across SPRI to advise and coordinate CTD implementation issues  Initiate Scoping Project for new technology and processes required to support eCTD  Establish Working Groups to ensure implementation of CTD format submissions in a timely and efficient manner

51. CTD Working Groups in WRA  CTD Publishing Working Group: –Purpose: define publishing/template standards and processes for CTD submissions, including future electronic CTD requirements –Representatives from WRA, Source areas, Publishing groups, RIS  WRA Implementation Working Group: –Purpose: provide communication and training on CTD guidance and SPRI implementation strategies –Communication teams available using WRA representatives and experts

52. CTD Working Groups in WRA  Subsidiary Communication: –Purpose: provide communication to subsidiaries on SPRI's implementation of CTD guidance –Periodic communications as information becomes available, including e-CTD information  Global Dossier Support: –Purpose: define requirements and processes necessary to ensure SPRI's CTD format submissions will be adequate for global subsidiary submission needs –Communicate with subsidiaries to identify additional support/processes required with CTD dossiers (including regional and module 1 requirements)

53. CTD Working Groups in WRA  Frequently Asked Questions Working Group: –Purpose: provide coordinated responses to CTD related questions from members of WRA and SPRI, as well as subsidiaries –Q & As on WRA CTD web site for reference

54. QUESTIONS?