PSURs – How They Should Be Used

1. PSURs – How They Should Be Used E. Stewart Geary, M.D. Eisai Co., Ltd. National Regulatory Conference 2005 Subang Jaya, Selangor, Malaysia 6-7 September, 2005

2. Outline • History of the PSUR • Non-ICH PSURs • Content and Use of PSUR • Future Developments: DSUR National Regulatory Conference 2005

3. History of PSUR

4. History of ICH PSUR • CIOMS II Working Group • Began work in November 1989 after completing CIOMS I • Harmonize report format for aggregated safety information • Published Report in 1992 • ICH Topic E2C • Step 4 November 1996 • ICH E2C Addendum • Step 4 February 2003 National Regulatory Conference 2005

5. Non-ICH PSURs

6. Types of PSUR • FDA: Postmarketing Periodic Adverse Drug Experience Report • Japan: Anzenteikihoukoku • ICH: PSUR National Regulatory Conference 2005

7. FDA: Postmarketing Periodic Adverse Drug Experience Report • Described in • 21 CFR 314.80 (c) (2) • 21 CFR 600.80 (c) (2) • Submit quarterly for first 3 years then yearly forever • 30 days to prepare quarterly report, 60 days to prepare annual report National Regulatory Conference 2005

8. FDA: Postmarketing Periodic Adverse Drug Experience Report • Contains • An analysis of safety issues • A history of actions taken (PI changes) • Scientific literature • MedWatch forms: all individual AE reports which were received during that period and have not already been submitted to FDA as 15 day reports • No line listings • No cumulative tabulations National Regulatory Conference 2005

9. FDA: Postmarketing Periodic Adverse Drug Experience Report • Proposal to change to the ICH PSUR format in the “tome” • Proposed Rule of March 14, 2003 • Unclear when or if this Rule will be implemented National Regulatory Conference 2005

10. Japan: Anzenteikihoukoku • Periodic report focused on local safety experience • The PSUR is to be included as an appendix to this report • Only produced in Japanese • Limited/No use outside of Japan National Regulatory Conference 2005

11. Content and Use of PSUR

12. Content and Use of PSUR • Principles • Content • CIOMS V Recommendations • E2C Addendum • Use? National Regulatory Conference 2005

13. PSUR Principles • One PSUR for one active substance • Multiple indications, doses and even formulations will usually be covered in one PSUR • Interval data for the period covered • Except for cumulative tabulations and table of worldwide regulatory status • Create as a “stand alone” report • Interval covered changes as product matures • Every 6 months for first 2 years • Every 1 year for next 3 years • Every 5 years subsequently (changing to every 3 years) National Regulatory Conference 2005

14. PSUR Content (1) • Introduction • Worldwide Market Authorization Status • Dates of authorization and launch by country • Regulatory actions taken for safety • During the time interval • For safety: withdrawal, restrictions, failure to renew • Changes to CCDS/CCSI • Patient Exposure • Data available on exposure vary internationally • An estimate National Regulatory Conference 2005

15. PSUR Content (2) • Presentation of Cases • Select individual case series for discussion as needed • For a mature product with no new safety issues, there might be no cases or issues selected for individual discussion • Frequently highlighted issues • Deaths • Liver disorders • Renal disorders • Cardiac arrhythmias or other cardiovascular events National Regulatory Conference 2005

16. PSUR Content (3) • Line listings • Determine “listed” or “unlisted” according to the CCDS, not the locally approved label • A single line for each case • Line Listings • Spontaneous, Serious, Unlisted Reports • Spontaneous, Serious, Listed Reports • Spontaneous, Non-serious, Unlisted Reports • Clinical Trial, Serious, Reactions • Literature Serious and Unlisted Non-serious reactions • Regulatory Serious Reactions National Regulatory Conference 2005

17. PSUR Content (4) • Tabulations • Summary Tabs: Numbers of all reports for the interval period • Cumulative Tabs: Numbers of serious & unexpected reports since international birthdate • Studies • Newly analyzed company-sponsored studies (i.e. completed) • Targeted safety studies ongoing during reporting period National Regulatory Conference 2005

18. PSUR Content (5) • Other Information • Efficacy-related information for products used to treat serious or life-threatening diseases (lack of effect) • Late-breaking information (after data-lock period) • Overall safety evaluation • Drug-drug interactions, pregnancy exposure, overdose, abuse • Conclusion • Has the overall safety profile changed? • CCDS/CCSI as an appendix National Regulatory Conference 2005

19. CIOMS V PSUR recommendations • Company choose the International Birthdate • Summary Bridging Reports • Concise document integrating two or more PSURs • Addendum report • Update to most recent PSUR when a regulatory authority requests a PSUR outside usual reporting cycle • 5 year PSUR • Submit 5 one-year PSURs with bridging document • Simplification of PSUR • Abbreviated PSUR prepared when only a small number of AEs are received during the reporting period • Eliminate line listings for very large PSUR National Regulatory Conference 2005

20. E2C Addendum (1) • Followed CIOMS V • When a PSUR is needed outside IBD cycle, submit the already prepared PSUR plus: • Line listing + summary tabulation for periods up to 6 months • Addendum report for periods > 6 months • Summary Bridging Report • “Bridges” 2 or more PSURs • Does not contain new safety information • 10 x 6 month PSUR + Bridging Report = 5 yr PSUR National Regulatory Conference 2005

21. E2C Addendum (2) • Addendum Report • Summarize safety information between most recent PSUR and Regulatory Authority’s requested cut-off date • May follow a simplified presentation • 30 day extension to 60 day preparation period • Use latest CCSI to determine “listedness” for PSURs covering > 1 year • Present non-healthcare professional (consumer) reports in separate line-listings National Regulatory Conference 2005

22. PSUR: Use • Opportunity for re-assessment of safety profile • Not the only time • Assessment and rationale for updating CCDS/CCSI • Driving updates of Package Inserts worldwide • Rationale for why events have not been added to CCDS/CCSI • Opportunity to open discussions on label changes National Regulatory Conference 2005

23. PSUR: Use • Background on total exposure (denominator) • Interim snapshot of safety reports • Cumulative numbers of safety reports • CCDS/CCSI National Regulatory Conference 2005

24. PSUR Use: Caution! • Confidential information • Does not explain all prior safety issues • CCDS/CCSI does give company’s view of safety profile • Line-listings provide limited information for assessing a case • Very difficult to change format of line listings • Validated computer outputs • Causality for events cannot be determined based on information in a PSUR • Central problem for PV: what events are really due to use of the medicinal product? National Regulatory Conference 2005

25. PSUR Use: Unofficial Feedback • Original CIOMS group thought PSUR would be very short (<10 pages) • In fact they are very long for major products • “Line-listings not very useful” • Exposure calculations are very rough estimates • Data available does not exactly match PSUR periods National Regulatory Conference 2005

26. Development Safety Update Report

27. DSUR • The PSUR is designed to report on cumulative safety information after product launch • There are requirements in the US and EU for annual reports during drug development • “IND Annual Report” • “EU Annual Safety Report” • Harmonize the format and content of a periodic safety report to be used during development National Regulatory Conference 2005

28. DSUR Issues • Similar to PSUR • Periodicity? • Line listings? • Tabulations? • Events or reactions? • Handling of blinded reports? National Regulatory Conference 2005

29. Thank you for your kind attention!