1. CDER Drug Safety Oversight Board Douglas C. Throckmorton, M.D. Deputy Director, CDER Food and Drug Administration November 5, 2005

2. Outline Drug Safety Oversight Board (DSOB, Board) membership and charge Summary of Board meetings Topics discussed Challenges for the Board Ongoing assessments of Board function and activity

3. DSOB Membership Chair – Deputy Director, CDER Executive Director –Susan Cummins, MD, MPH Membership - representatives from CDER offices, CBER, CDRH, NIH, VAH Consumer or patient representatives and advisory committee members as consultants

4. DSOB Charge Will provide independent oversight and advice to the CDER Center Director on management of: Important drug safety issues and policies Dissemination of certain safety information through FDA’s website to healthcare professionals and patients

5. DSOB Activities (from MaPP) Identify, track and oversee management of important drug safety issues Adjudicated organizational disputes concerning management of drug safety issues Select drugs to be placed on Drug Watch and update their status as appropriate Establish policies regarding management of drug safety issues in CDER

6. DSOB Activities (from MaPP) (cont) Oversee the development of patient and professional information sheets in CDER Track important emerging safety issues and ensure they are resolved in a timely manner Ensure CDER decisions about a drug’s safety benefit from the input and perspective or experts within and outside FDA who have not conducted the primary review or served as a deciding official in the ongoing pre-market evaluation or post-market surveillance activities with respect to the drug

7. DSOB Staff Mary Mease, RPh, MPH Toni Marie Nearing-Crowley Lee Zwanziger, PhD Work with the CDER Divisions to write the Public Health Advisories, and write the Patient and Professionals Information Sheets

8. Themes from the Four DSOB Meetings to Date Didactic sessions on drug safety Oversight of CDER safety issues Pre-decisional Make recommendations for ongoing CDER activities Post-decisional Review of decisions about safety communications Policy development Discussion today limited by commercial confidential nature of the data used in many of the discussions

9. Didactic Sessions Familiarize members from outside CDER with extensive safety activities ongoing in CDER Sessions on: Detection, assessment and management of safety issues in Office of Drug Safety (ODS) and Office of New Drugs (OND) Newly-issued Guidances related to safety: Guidance on risk management programs (ODS)

10. Oversight of CDER Safety Issues: Predecisional Intent: Provide full picture of the data as we know it Extensive background data in advance Presentations by knowledgeable CDER review staff Solicit specific suggestions for actions Reality: Many safety issues are time-sensitive May limit DSOB role here to complex, evolving issues Board has asked for fuller discussion of ongoing work in the Center about safety

11. Predecisional Oversight of CDER Safety Issues: Transdermal Patches Containing Fentanyl Issue: ODS report of patient deaths and possible fentanyl overdoses when using patch CDER Actions: Review of safety data Initial evaluation of manufacturing and pharmacokinetic data for sources of variability Patient/ HCP sheets highlighting need to follow label carefully Issue for Board: Additional Risk Management

12. FDA ALERT [7/2005]: Narcotic Overdose and Death FDA is looking into reports of death and other serious side effects from overdoses of the narcotic fentanyl in patients using the fentanyl transdermal skin patches for pain control. Directions for using the fentanyl skin patch must be followed exactly to prevent death or other severe side effects that can happen from using too much (overdosing) fentanyl. These directions are provided in the patient package insert.patient package insert

13. Predecisional Oversight of CDER Safety Issues: Transdermal Patches Containing Fentanyl (cont) Board Recommendation: Need to more evaluate fully the sources of variability of drug delivery for these complex drug delivery systems, especially for drugs with narrow therapeutic windows Risk Management strategies should be developed with this evaluation in mind, including the use of Medication Guides Action Item for CDER: After evaluation bring issue back to Board for fu discussion and questions

14. Oversight of CDER safety issues: Postdecisional Many of the safety issues time-sensitive Post-decisional oversight important part of DSOB role DSOB meetings include: Review of all postings on proposed Drug Watch web page Postings sent to all members via MedWatch Each action summarized at meeting Members asked about action taken, whether other steps need to be considered Feedback has been variable, but frank

15. Postdecisional Oversight of CDER Safety Issues: Withdrawal of Palladone Issue: decision to withdraw palladone from the market for ‘dose-dumping’ in EtOH CDER Actions: Reviewed in vitro and in vivo data on dose-dumping Discussed alternative therapies, concluded withdrawal of product best Started evaluation of other products for similar effect Board Recommendation: Agreed with appropriateness of withdrawal Recommended standard chemistry review of similar products prior to approval Action Item for CDER: FU on chemistry review process

16. Policy Discussions DSOB and the new forms of safety communication (e.g., Patient Information Sheets) are new ways for CDER to address safety: Need to define its role in the larger effort to address safety in CDER Avoid duplication of efforts

17. Policy Discussions: Issues ‘Threshold’ for communication: When should the DSOB recommend communicating publicly about an emerging safety issue? Board has identified set of circumstances that could influence the need to say something public, including: Gross credibility of data Plausibility (model) Other relevant data from related drugs Severity/reversability of adverse effect Public health impact of adverse effect

18. Policy Discussions: Issue & Challenge for the Board ‘Oversight’ function of the Board What is effective oversight? How to conduct effective oversight? New group within CDER with unique mix of expertise Need to conduct oversight over many diverse groups in CDER at work on safety Need to assure timely implementation of recommendation once accepted by Dr. Galson First step: need to understand breadth of safety issues in CDER and how they are handled

19. Policy Discussions: Issue & Challenge (cont) ‘Oversight’ Function Action Items: Board review of ways CDER identifies and handles safety issues, including canvassing by Board staff to understand full scope of safety activities Complimentary to ongoing safety tracking in CDER Board discussion to translate this review into clearer vision of how to conduct safety oversight Implementation of a Quality Assurance program to develop and track metrics of success for the Board Two meetings have been held Look for additional comments at upcoming Part 15 Hearing

20. Summary DSOB has broad set of challenges it is tasked with managing: All important Providing effective and timely oversight a critical task identified by the Board Board members are taking their responsibility very seriously, and have provided feedback to CDER that has: Added new, fresh voice on safety in CDER Changed the tone of the safety discussions in CDER Changed the approaches taken by CDER on specific safety issues

21. douglas.throckmorton@fda.gov 301-594-5400

22. Question for Science Board Based on your understanding of the safety system in CDER, how would you prioritize the 7 goals identified for the DSOB?

23. Board Activities (from MaPP) Identify, track and oversee management of important drug safety issues Adjudicated organizational disputes concerning management of drug safety issues Select drugs to be placed on Drug Watch and update their status as appropriate Establish policies regarding management of drug safety issues in CDER Oversee the development of patient and professional information sheets in CDER Track important emerging safety issues and ensure they are resolved in a timely manner Ensure CDER decisions about a drug’s safety benefit from the input and perspective or experts within and outside FDA who have not conducted the primary review or served as a deciding official in the ongoing pre-market evaluation or post-market surveillance activities with respect to the drug