1. FDA Oversight Of Drug Safety: What Works, What Doesn’t Geoffrey Levitt Chief Counsel, Regulatory and Research Wyeth Pharmaceuticals August 24, 2006

2. 2 FDA Oversight of Drug Safety: The Stakes 100,000 deaths/year from ADEs; “huge” # of hospitalizations100,000 deaths/year from ADEs; “huge” # of hospitalizations Drug withdrawal rate about 2.5%Drug withdrawal rate about 2.5% –Unchanged over last 30 years Drug safety a core issue from preclinical research through postmarketingDrug safety a core issue from preclinical research through postmarketing Most recent attention focused on postmarketing phaseMost recent attention focused on postmarketing phase

3. 3 The Problem: Loss of Trust FDA taking too long to tell physicians and patients about new safety informationFDA taking too long to tell physicians and patients about new safety information FDA not acting quickly enough on evidence of safety risksFDA not acting quickly enough on evidence of safety risks Disagreements within FDA about how to address safety issuesDisagreements within FDA about how to address safety issues FDA organizational structure underweights postmarket safety considerationsFDA organizational structure underweights postmarket safety considerations

4. 4 The Problem: Loss of Trust FDA lacks clear, effective process for decisions about postmarketing drug safetyFDA lacks clear, effective process for decisions about postmarketing drug safety FDA lacks authority and funding for adequate oversight of postmarketing drug safetyFDA lacks authority and funding for adequate oversight of postmarketing drug safety Drug safety system has “broken down”Drug safety system has “broken down” “We are defenseless”“We are defenseless”

5. 5 Underlying Issues CommunicationCommunication –Not fast enough StructureStructure –Not clear enough AuthorityAuthority –Not strong enough

6. 6 Underlying Issues CommunicationCommunication –Not fast enough StructureStructure –Not clear enough AuthorityAuthority –Not strong enough

7. 7 Fixes: Communication Get emerging safety information out faster: DrugWatch (May 2005)Get emerging safety information out faster: DrugWatch (May 2005) Drugs for which FDA is “actively evaluating early safety signals”Drugs for which FDA is “actively evaluating early safety signals” –Newly observed SAEs –New risk minimization measures –Significant emerging risks that may be avoided by proper countermeasures

8. 8 DrugWatch: Concerns FDA imprimatur on unvalidated safety informationFDA imprimatur on unvalidated safety information –Potential for confusion, overreaction –Irreparable damage to drug’s reputation –No sponsor input –Undermines status of drug label as key source of safety information

9. 9 DrugWatch: FDA Response FDA heeds criticisms, puts DrugWatch on hold (Nov. 2005)FDA heeds criticisms, puts DrugWatch on hold (Nov. 2005) But continues lower-key communication of drug safety informationBut continues lower-key communication of drug safety information –Public Health Advisories –Patient, HCP Information Sheets –MedWatch

10. 10 Fixes: Communication Hearing on Risk Communication (Dec. 2005)Hearing on Risk Communication (Dec. 2005) Communication tools covered:Communication tools covered: –Patient and HCP info sheets –Safety-related Talk Papers –Public health advisories –MedWatch updates

11. 11 Hearing on Risk Communication Public comment requested on:Public comment requested on: –Strengths and weaknesses –Awareness and use by intended audiences –Right kind and amount of risk info –Acessibility and understandability –Special populations

12. 12 Hearing on Risk Communication Key messages:Key messages: –Simplify risk communications –Improve HCP and patient access –Develop consistent approaches –Engage HCP organizations –Address limited-literacy populations –Maintain risk-benefit balance

13. 13 Underlying Issues CommunicationCommunication –Not fast enough StructureStructure –Not clear enough AuthorityAuthority –Not strong enough

14. 14 Fixes: Structure Drug Safety Oversight BoardDrug Safety Oversight Board –Identify, track, and oversee important safety issues and establish policies –Adjudicate organizational disputes –Ensure that drug safety decisions receive input of experts not involved in primary review or pre-market evaluation –[Oversee DrugWatch]

15. 15 DSOB: Membership Fifteen voting membersFifteen voting members –Three each from OND and ODS –Five from other CDER offices –One each from CBER and CDRH –One from non-FDA HHS agency (NCI) –One from non-HHS health agency (VA) Deputy Director CDER is non-voting chairDeputy Director CDER is non-voting chair

16. 16 DSOB: Procedures DSOB decisions are recommendations to CDER DirectorDSOB decisions are recommendations to CDER Director Should be reached by consensus but if necessary vote will be taken; 2/3 majority of quorum (11 members)Should be reached by consensus but if necessary vote will be taken; 2/3 majority of quorum (11 members) Members involved in primary review of data or regulatory decision-making for drug at issue recused from votingMembers involved in primary review of data or regulatory decision-making for drug at issue recused from voting

17. 17 DSOB: Activities Meetings closed; brief written summaries posted to webMeetings closed; brief written summaries posted to web Relate mostly to selection of drugs for patient or HCP information sheets or public health advisoriesRelate mostly to selection of drugs for patient or HCP information sheets or public health advisories

18. 18 Proposed Fixes: Structure Raise profile of drug safety operationsRaise profile of drug safety operations –Enhance role of FDA drug safety office in premarket reviews and postmarket safety deliberations –Take drug safety office out of CDER, reporting directly to Commissioner –Take drug safety function out of FDA altogether (NTSB model)

19. 19 Proposed Fixes: Reaction So far FDA has taken no major steps to restructure drug safety operations (DSOB aside)So far FDA has taken no major steps to restructure drug safety operations (DSOB aside) IOM evaluating agency’s internal safety organization and operationsIOM evaluating agency’s internal safety organization and operations Some bills have called for independent drug safety boardSome bills have called for independent drug safety board Most recent major bill relies on DSOBMost recent major bill relies on DSOB

20. 20 Underlying Issues CommunicationCommunication –Not fast enough StructureStructure –Not clear enough AuthorityAuthority –Not strong enough

21. 21 Authority: Issues LabelingLabeling –authority to compel safety changes Postmarketing studiesPostmarketing studies –authority to enforce commitments –authority to require new studies IOM review: Consider FDA’s legal authorities for identifying and responding to drug safety issuesIOM review: Consider FDA’s legal authorities for identifying and responding to drug safety issues

22. 22 Authority: Is there an issue? Existing Authority Over LabelingExisting Authority Over Labeling –Power to issue patient/HCP information sheets, public health advisories, Talk Papers, etc. –Authority to declare drug misbranded for omitting material safety information –Ability to withdraw approval over safety concern, suspend marketing if “imminent hazard” –Not always easy or practical to utilize

23. 23 Authority Over Label: Proposed Fixes Basic idea: Give FDA power to order safety changes to drug label; avoid lengthy talks, sponsor foot-draggingBasic idea: Give FDA power to order safety changes to drug label; avoid lengthy talks, sponsor foot-dragging Sanctions for non-compliance may include misbranding charge, civil money penaltiesSanctions for non-compliance may include misbranding charge, civil money penalties

24. 24 Post Marketing Study Commitments Key element of drug approval process: 73% of drugs approved since 1998 carried PMCsKey element of drug approval process: 73% of drugs approved since 1998 carried PMCs FDAMA, FDA regs require annual sponsor status reportsFDAMA, FDA regs require annual sponsor status reports Enforcement of existing PMCs: Is there a problem?Enforcement of existing PMCs: Is there a problem? –FDA: Four percent of confirmatory studies for accelerated approval drugs are delayed; one percent of all pending postmarket studies for drugs

25. 25 Authority over PMCs: Is there a problem? Rep. Hinchey: “Conspiracy of silence;” majority of companies benefiting from accelerated approval are failing to complete PMCs on a timely basisRep. Hinchey: “Conspiracy of silence;” majority of companies benefiting from accelerated approval are failing to complete PMCs on a timely basis 68% of public companies failed to disclose PMCs in SEC filings68% of public companies failed to disclose PMCs in SEC filings

26. 26 Authority over PMCs: Proposed Fixes Little to no direct FDA authority over completion of PMCsLittle to no direct FDA authority over completion of PMCs Little to no direct FDA authority to impose new postmarketing study requirementsLittle to no direct FDA authority to impose new postmarketing study requirements Pending legislation would make failure to complete postmarketing studies a violation under FDCA, allow for civil money penaltiesPending legislation would make failure to complete postmarketing studies a violation under FDCA, allow for civil money penalties –Would also give FDA limited authority to require new postmarketing studies

27. 27 Net Result: Enhanced Drug Safety? Expedite risk communicationExpedite risk communication Clarify safety structureClarify safety structure Strengthen safety authorityStrengthen safety authority Trust restored?Trust restored? Better drug safety?Better drug safety? Healthier population?Healthier population?

28. 28 Drug Safety: A Different Perspective Drug safety concerns: “part real – part hype – part hysteria”Drug safety concerns: “part real – part hype – part hysteria” Risk vs. BenefitRisk vs. Benefit “Statistical myopia”“Statistical myopia” Patients are dying while waiting for approval of new treatmentsPatients are dying while waiting for approval of new treatments

29. 29 Drug Safety: How to Balance Pendulum has clearly swung toward caution/safetyPendulum has clearly swung toward caution/safety Some strengthening of safety tools a foregone conclusionSome strengthening of safety tools a foregone conclusion Harder part is to strike the right balance, not lose sight of benefit as well as riskHarder part is to strike the right balance, not lose sight of benefit as well as risk