2. ICH Public Meeting January 21, 2003 5630 Fishers Lane, Room 1066 FDA PERSPECTIVE IMPLEMENTATION STATUS OF THE CTD Justina A. Molzon, M.S. Pharm., J.D. Associate Director for International Programs Center for Drug Evaluation and Research/USFDA CDER ICH Steering Committee Representative

3. Practical Issues of Implementation  Finalized CTD presented at ICH-5  9-11 November 2000, San Diego  Three separate groups working in isolation to get the documents done on time  Had to edit for consistency  Numbering systems  Style  Format

4. Reality of Implementation  Once regulators started preparing documents for publication, realized how complicated they are  Faced with the enormous task of making them consistent  Regulators have different systems  No matter how closely we work together will still have some minor inconsistencies

5. I C H INTERNATIONAL CONFERENCE ON HARMONIS/ZATION of Technical Requirements for the Registration of Pharmaceuticals for Human Use

6. Reality of Implementation  Complications and minor inconsistencies don’t detract from the enormous work that has been done  We want the CTD to be the best it can be  Must work hard to do away with ambiguities and inconsistencies  An evolving process

7. The CTD Triangle Module 1 Regional Admin Information Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Quality Overall Summary Nonclinical Summary Nonclinical Overview Clinical Summary Clinical Overview Module 2 NOT Part of the CTD The CTD

8. Numbering System Module 1 Module 3Module 4Module 5 2.1 2.2 2.3 2.4 2.5 2.6 2.7 1.0 Quality 3.0 Nonclinical Study Reports 4.0 Clinical Study Reports 5.0 1.0Regional Administrative Information 1.1ToC of Module 1 or overall ToC, including Module 1 2.1ToC of the CTD (Mod 2,3,4,5) 2.2Introduction 2.3Quality Overall Summary 2.4Nonclinical Overview 2.5Clinical Overview 2.7Clinical Summary 2.6Nonclinical Summary Module 2 Source: ICH Implementation Coordination Group May 2001 Steering Committee

9. Practical Issues of Implementation  Need to work with other regions  Need experience with documents  Meetings a big help in pointing out areas which can be improved  Submissions will help industry and regulators gain familiarity with the new format  Reason voluntary submission phase extended from 2002 to July 2003

10. An Overview of the CTD  The CTD is not a “Global Dossier”!  Content different for US, EU and Japan based on individual regulations  Some regulations never covered in ICH  It is an agreed upon common format for the “modular” presentation of summaries, reports and data  Incorporates relevant ICH guidelines as building blocks and puts them in the same order for submission to ICH regions

11. CTD General Questions and Answers  Question #1  Will a dossier using the CTD format (Modules 2 to 5) be identical for all regions?  Answer #1  Not necessarily

12. Answer  The CTD provides a common format for the submission of information to regulatory authorities in the three ICH regions.  However, the CTD does not address the content of submissions.  Regional requirements  Applicants preferences

13. DRAFT Guidance Publication  Submitting Marketing Applications According to the ICH/CTD Format: General Considerations (DRAFT)  Posted September 5, 2001  Comment period until November 5, 2001  12 sets of comments submitted  Comments always welcome  In process of reopening docket  Will incorporate comments from SC/EWG and outreach meetings into final draft this spring

14. CTD General Considerations Guidance  What we expect to be submitted  Description of Module 1  Administrative/Prescribing Information  Physical description of submission  CTD requirements addressed  Obsolete guidances listed  Logistics of submission described  Timeframe for submission

15. Electronic Submission  The General Considerations Guidance describes the organization of an application provided entirely in paper  Also describes how to adapt the CTD to our current process for electronic submissions  May provide documents electronically (in PDF format) instead of on paper

16. CTD Guidance Publication  M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use  Posted October 15, 2001  Kept in review discipline format for ease of printing and navigating  Safety appendices split off because of size  Posted in WORD so companies can populate tables with data

17. CTD Guidance Publication  M4: Organization of the CTD  M4: The CTD -- Quality  M4: The CTD -- Efficacy  M4: The CTD -- Safety  M4: The CTD -- Safety Appendices  POSTED ON CDER WEB http://www.fda.gov/cder/guidance/index.htm

18. CDER CTD Submissions  11 submissions in CTD Format  7 different Review Divisions  All 5 Offices (ODE 1-->5)  Several CTDs for new dosage forms  Several rolling submissions  Hybrids (Safety or Quality Modules)  Paper and electronic submissions

19. Office of Drug Evaluation I Division of Oncology Drug Products HReceived: August 1, 2001 HCTD: Pharmtox section submitted electronically HFast track rollingsubmission

20. Office of Drug Evaluation IV Division of Special Pathogen and Immunologic Drug Products HReceived:October 22, 2001 HCTD: Uses CTD table of contents HStructure is not as recommended but close

21. Office of Drug Evaluation V Division of Anti-Inflammatory Analgesic, and Ophthalmologic Drug Products HReceived: Dec 27, 2001 HDifferent dosage form HCTD:Pharmtox, presubmission in CTDformat HThe application consists of a paper copy and electronic copy

22. Office of Drug Evaluation III Division of Reproductive and Urologic Drug Products HReceived: December 31, 2001 HCTD: Only the chemistry section is in the CTD format HSubmitted on paper HElectronic sections not in CTD format.

23. CDER CTD Submissions  No refuse to files  Not perfect submissions but could be reviewed  Flexible during voluntary submission phase  Through July 2003  July 2003--Mandatory in EU, Japan, highly recommended in US.  Further training based on practical experience  Encouraged to submit in CTD format  Hybrid submissions acceptable

24. CTD Pre-submission Experience  Submission should exactly match CTD  3.2.S.1.2 -- The structural formula, including relative and absolute stereochemistry, the molecular formula and the relative molecular mass should be provided.  Provide all information under CTD ICH negotiated headings and numbers  Do not create new headings or numbers

25. CTD Pre-submission Experience  DO NOT modifiy CTD TOC numbering system by adding additional levels  3.2.S.1.2 Structure  3.2.S.1.2.1Molecular Formula  3.2.S.1.2.2Molecular Weight  Provide all information under CTD designated headings  May use subheaders or bullets

26. CTD General Questions and Answers  Question #5 Sub-Heading Numbering or Numbering within Sections  How should sub-numbering within a document be organized? Some documents can be up to 50 pages in length with no defined CTD guideline heading and potentially no TOC entries or bookmarks

27. Answer  Within the document, the applicant can use section numbers at a lower level than those specified in the CTD guideline. However, there should be no other headings appearing in the overall TOC going below the numbering given in the CTD guideline

28. CTD Pre-submission Experience  If you don’t have information for a section provide:  ICH CTD Number and Header  NA (not applicable) or other language  Don’t skip or delete section  Never renumber sections  See CTD Safety Q&A #2

29. CTD Pre-submission Experience  CTD-Q 3.2.R -- Regional information is for unique regional information  Unique=Information that does not have a general topic designation in Module 3  Adhere to examples Listed in 3.2.R  Even though requested information may be unique to FDA, insert information in appropriate CTD-Q topic section  DO NOT place in Regional Information

30. CTD IWG/EWG Meetings 9-12 September 2002  Main topic for discussion  LOCATION-LOCATION-LOCATION  Especially for CTD-Q  Comparing to FDA DRAFT Drug Product and Drug Substance Guidances for Chemistry, Manufacturing and Controls Information  Location of information in CTD will be detailed by DRAFT Guidances  See CTD-Quality Q&A’s

31. CTD IWG/EWG Meetings 9-12 September 2002  Revised--Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use  Numbering and section headers have been edited for consistency and use in the e-CTD  Granularity document provides guidance on document location and pagination  Q&A’s for each Module (S, E, Q) posted on ICH web for clarification

32. CTD IWG/EWG Meetings 9-12 September 2002 DISCLAIMER  The final ICH CTD adopted version is published on the ICH website.  At regional level a local version is published.  The wording of the core CTD may be slightly different from one region to another due to specific editing and local regulation.  It does not affect the common understanding by the six parties of the CTD published on the ICH website.

33. eCTD  Six months behind CTD  The eCTD will be a transport format to be moved into an agency’s review environment  Step 4 reached in Washington DC September 2002  Biggest Payoff--eliminate controversy  A4 vs. 8  by 11 inch paper

34. The CTD Triangle Module 1 Regional Admin Information Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Quality Overall Summary Nonclinical Summary Nonclinical Overview Clinical Summary Clinical Overview Module 2 NOT Part of the CTD The CTD

35. CTD Major Issue Integrated Summary of Safety Integrated Summary of Efficacy  The name”summary” has caused great confusion  Not a summary but an integrated analysis  Critical components of the safety and efficacy review and expected to be part of FDA submission.

36. FDA’s ISS/ISE  Clarifying what remains of the Guideline for the Format and Content of the Clinical and Statistical Sections of an Application, July 1988  Integrated summary of safety section page 32 to 46  Integrated summary of efficacy section page 28 to 32  Likely to be updated as part of PDUFA- 3 risk management initiative

37. FDA’s ISS/ISE  If what is called for in the FDA Guidances can be incorporated into the CTD, it will be a complete substitute for the analysis  If not, it will need to be submitted as a separate document  If ISS is volumes  a summary  If ISE >200 pages  a summary  Concerns should be raised with FDA staff prior to submission

38. CTD Next Steps--Training  Prior to ICH-5 CDER rolled out CTD documents with review disciplines  Met with senior project managers to provide updates  Waiting for submissions for the next phase of training  Reviewers with CTD experience will provide practical training

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

40. Benefits of the CTD FDA Perspective  More “reviewable” applications  Complete, well-organized submissions  More predictable format  More consistent reviews  Easier analysis across applications  Easier exchange of information  Facilitates electronic submissions  BETTER DRUGS TO PATIENTS FASTER

41. Domo Arigato Thank You Danke Merci