1. ICH V1 An FDA Update Min Chen, M.S., RPh Office of Drug Safety Center for Drug Evaluation and Research FDA January 21, 2003

2. ICH E2C V1 Expert Working Group Need of an Addendum to E2C was defined as topic V1 in early 2002 in Brussels Interim meeting held in June 2002 in London- First draft Step 2 document or Addendum completed in September 2002 in Washington DC

3. Status of V1 Addendum ICH Steering Committee signed off the Step 2 document in September 2002 3 regional regulatory agencies to publish for comments –EMEA published for comments on EU website in September 2002, comments collected (http://www.ich.org/ich5e.html) –MHLW published in Japanese November 2002, comments deadline Jan. 10, 2003 –U.S. published in FR on December 31, 2002, comments deadline Jan. 24, 2003

4. PSURs (Periodic Safety Update Reports) Present Situation in U.S. Adopted ICH E2C Guideline published in FR May 1997 Not required format for periodic reports yet Draft Reporting Guidance published 3/2001 allows companies through waiver request submitting periodic reports in E2C format

5. V1 Step 2 Document- Overview Synchronization of National Birthdates with the International Birthdates Use of the latest version of the reference safety information Submission of executive summaries as part of the PSUR Options to submit summary bridging reports and addendum reports Handling of solicited reports

6. Next Steps to the Addendum Step 3 - Collecting comments for further EWG discussions Reach Step 4 Each regulatory agency publication as final guideline

7. Current Postmarketing Periodic Reporting Requirement in U.S. 21 CFR 314.80 Reporting timeline –quarterly for first three years, then annually –upon written notice, FDA may extend or re- establish the cycle at different times, e.g., new major supplement approvals or other conditions

8. Current Postmarketing Periodic Reporting Requirement in US (Cont’d) Required Components –narrative summary and analysis of interval expedited reports –FDA Form 3500A with an index consisting of a line listing of all non-expedited reports for interval –history of actions taken

9. Current Draft Reporting Guidance re: Periodic Reports Information required and contained within a report should be divided into 4 sections: –1. Narrative summary and analysis –2. Narrative discussion of actions taken –3. Index line listing –4. FDA Form 3500As or VAERS forms

10. Summary of Content in the Addendum Introduction- –provides further clarifications, guidance or increased flexibility beyond that provided in E2C –Addendum to be used with E2C

11. 1.1 Objectives PSURs contain proprietary information Confidentiality of the data and conclusions stated in Title page A more comprehensive safety or risk- benefit analysis can be prepared and submitted as a “stand alone” document –in addition to the usual safety analysis in PSUR –results of the risk-benefit analysis be included in the next PSUR

12. 1.4 General Principles 1.4.1 One report for one active substance All indications, dosage forms and regimens Separate PSURs –fixed combinations –two or more different formulations, e.g., systemic vs topical

13. 1.4.4 IBD and frequency of review and reporting When use local approval date, may submit prepared IBD-based PSUR plus: –line-listings and/or summary tabulations covering the additional period (<3 mo for 6 month PSUR, <6 mo for a longer duration PSUR), or –and Addendum Report (>3 mo for 6 mo PSUR, >6 mo for a longer duration PSUR)

14. 1.4.4.1 Synchronization of national birthdates with the IBD IBD unknown, MAH can designate the IBD and notify the Regulatory Authorities Different approval dates in regions, MAH may negotiate a mutually acceptable birth month and day

15. 1.4.4.2 Summary Bridging Reports CIOMS V - p. 154-6 Concise document that integrates two or more PSURs to cover a specified period –format identical to the usual PSUR –summary highlights and overview of data

16. 1.4.4.3 Addendum Reports An update to the most recently completed PSUR, requested by Regulatory Authorities outside of the usual IBD cycle Summarize the safety data between interval: –Introduction –Changes to the CCSI –Significant regulatory actions –Line listing and summary tabulations –Conclusions

17. 1.4.4.4 Restart the Clock Decision should be discussed with the Regulatory Authority –A new clinically dissimilar indication –A previously unapproved use in a special patient population –A new formulation and/or new route of administration

18. 1.4.4.5 Time Interval between the Data Lock Point and the Submission RA sends comments to the MAH on: –non-compliance –safety issues need further evaluation –additional analysis or issues of content identified Additional time for Submission –Large number of reports –Issues raised by RA or MAH for further analysis

19. 1.4.5 Reference Safety Information CCSI at the beginning of the period used for 6 month and 1 year reports The latest CCSI at the end of the period used for longer period of reports

20. 2.1 Executive Summary Overview of PSUR when needed At the beginning of the PSUR Example in CIOMS V p.333

21. 2.5 Patient Exposure Difficulty in estimating patient exposure data is discussed Consistent in methods of calculation Extrapolations may be used based on information from a period that does not fully cover the period Avoid patient exposure data that overlap time periods in a summary bridging report

22. 2.6 Presentation of Individual Case Histories Contain a description and analysis of “selected” cases containing new or relevant information and grouped by SOCs Describe criteria used to select cases for presentation Consumer and other non-healthcare professional reports in separate listings and analysis Solicited reports are handled as from clinical trials, clearly identified in analysis

23. 2.9 Overall Safety Evaluation Discussion and analysis should be organized by SOC Related terms should be reviewed together for clinical relevance