1. New Drug Safety Initiatives & the Drug Safety Oversight Board Drug Safety and Risk Management Advisory Committee, Gaithersburg, MD February 10 th, 2006 Susan K. Cummins, MD, MPH Executive Director, Drug Safety Oversight Board Center for Drug Evaluation and Research Food and Drug Administration

2. 2 Today’s Talk Drug Safety landscape New Drug Safety initiatives Dr. Crawford’s November 2004 announcement Secretary Leavitt’s February 2005 announcement Drug Safety Oversight Board & New drug risk communication outlets

3. 3 Drug Safety Landscape Drug Safety is a top priority for all of CDER at every stage of the product life cycle Pre-NDA phase New drugs Manufacturing/regulation of drug quality Generic drugs Regulation of clinical trials and promotional activities

4. 4 32% Pre-Market Safety Work Effort 18% Post-Market Safety Work Effort 50% Non-Safety Work Effort Half of all CDER Work Effort is Devoted to Drug Safety TM Mullin, PhD, Office of Planning, Office of Commissioner FDA Science Board Presentation April 15, 2005 2004 CDER Work Time Analysis

5. 5 Drug Safety Landscape Laws: FD& C Act requires safety evaluation before approval “All tests reasonably applicable” to safety FDA Drug Regulations: Information that “the product is safe…for recommended use.” Guidances: FDA & International guidance documents spell out level of evidence needed for safety evaluation. Bottom Line: Science plus judgment plus policy

6. 6 Drug Safety Landscape Despite the rules, there is lots of room for honest disagreement How safe is “safe”? There is no single, simple risk/benefit equation Tension between: Drive for innovation and new products VS. Greater assurance of safety through larger and longer studies

7. 7 “The Drug Approval Pendulum” by Anne Applebaum Washington Post Wednesday, April 13, 2005; Page A17 "It just breaks my heart when I think of American citizens having to go to Switzerland or Mexico to get the drugs and devices they need to stay alive because the Washington bureaucracy won't approve them." Rep. Thomas Bliley (R-Virginia), 1995 "When the FDA approves a drug, it should be a Good Housekeeping seal of approval.... Consumers shouldn't have to second-guess the safety of what's in their medicine cabinet." Sen. Chuck Grassley (R-Iowa), 2005

8. 8 November 2004: FDA Drug Safety Announcement FDA Acting Commissioner Crawford announced a 5-Point Plan to improve management of drug safety concerns: Sponsor an Institute of Medicine Study of the Drug Safety System UNDERWAY—Report due out July 2006 Implement a program for adjudicating differences of professional opinion Individual level–-Resolution through Ombudsman Organizational level—Drug Safety Oversight Board Appoint a permanent Director, Office of Drug Safety Gerald Dal Pan, MD, MHS appointed, October 2005 Conduct Drug Safety/Risk Management Consultations--UNDERWAY Publish Risk Management Guidances—DONE

9. 9 2005 Published Risk Management Guidance for Industry Pre-marketing Risk Assessment Development and Use of Risk Minimization Action Plans Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

10. 10 2005 Published FDA Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review Component of good review practice guidance for NDAs and BLAs Provides for standardization and consistency in format and content of safety reviews

11. 11 February 15 th 2005 HHS Secretary Mike Leavitt Announces Drug Safety Reforms "The public has spoken and they want more oversight and openness…We will address their concerns by cultivating openness and enhanced independence.“ "We will keep the promise of the FDA brand by putting in place more rigorous oversight and collecting and sharing important and emerging information about drug safety and effectiveness.“ HHS Secretary Mike Leavitt

12. 12 February 2005: HHS Secretary Leavitt Drug Safety Announcement Overall vision: Promote a culture of openness & Enhance oversight within the FDA Specific areas of change: More outside expert consultations Improve drug safety management practices Communicate emerging drug safety concerns early Continue to improve scientific methods of adverse event signal detection

13. 13 Drug Safety Initiative The initiative will: Give patients, healthcare professionals & consumers quick & easy access to the most up-to-date and accurate information on medicines.

14. 14 Drug Safety Initiative New drug safety information outlets Patient Information Sheets Healthcare Professional Sheets Proposed Drug Watch Program Drug Safety Oversight Board

15. 15 Definition: Important Drug Safety Issue A Drug Safety issue with the potential to: Significantly alter the risk-benefit analysis of a drug Affect physician’s decision to prescribe Affect patient’s decision to use Includes and is broader than regulatory definition of “serious and/or life-threatening” adverse event

16. 16 Drug Safety Oversight Board Charge Provide independent oversight and advice to Center Director on: Management of Important Drug Safety Issues Adjudication of organizational disputes Policies about management of drug safety issues Risk communication about important emerging drug safety concerns Development of HCP & patient information sheets

17. 17 Drug Safety Oversight Board Charge “Ensure that CDER decisions about a drug’s safety benefit from the input and perspective of 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 that drug.”

18. 18 Drug Safety Oversight Board Organizational Principles Voting members independent of primary decision- making for a drug with an important safety issue Federal employees Equal number of representatives from Offices of Drug Safety & New Drugs 25% of membership external to CDER Other FDA Centers with related activities NIH & Veterans Administration Expert, Consumer or Patient Consultants as needed

19. 19 Drug Safety Oversight Board Organizational Principles Fosters effective CDER management of important emerging drug safety concerns DOES NOT replace Public Advisory Committees DOES NOT replace current internal responsibility for Regulatory Decision-making

20. 20 Drug Safety Oversight Board Membership CDER Offices: Drug Safety (3) New Drugs (3) Counter-terrorism & Pediatrics Compliance Pharmaceutical Science Clinical Pharmacology & Biopharmaceutics Biostatistics Medical Policy (non-voting) External to CDER: Center for Biologic Evaluation & Research Center for Radiological Health Department of Veterans Affairs National Institute of Health (National Cancer Institute) Chair—Deputy Director, CDER (non-voting) Executive Secretary—Director, DSB (non-voting)

21. 21 Proposed Drug Watch: Definition, Goal and Status Definition: Web page on CDER Internet site about emerging important safety issues undergoing investigation Goal: Communicate emerging risk information to the public so that it can inform treatment decisions Status: Draft Guidance undergoing review and revision in response to public comment submitted during 2005 comment period

22. 22 When does FDA communicate about emerging risk? Factors that favor early communication: Risk is a “important drug safety concern” Affect prescribing or monitoring Whether measures can be taken in response to the information to prevent harm If unapproved (off-label) use poses a significant and/or yet undescribed risk If a specific and/or vulnerable subpopulation may be affected (children or the elderly)

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27. 27 Drug Safety HC Professional & Patient Information Sheets At least 44 drugs with safety postings through December 31, 2005 6 Product class issues 3 Market suspensions Palladone ( hydromorphone hydrochloride extended release) Tysabri (natalizumab) Neutrospec [Technetium (99m Tc) fanolesomab] 2 Product withdrawals Bextra (valdecoxib) Cylert (pemoline) 37 with added warnings to product label

28. 28 Drug Class Risks Described in HC Professional & Patient Information Sheets Antidepressants—suicidality in adults & children Atypical antipsychotics—increased risk of death in dementia (unapproved use) Non-steroidal anti-inflammatory drugs—increased cardiovascular risk Erectile dysfunction drugs—non-arteritic anterior ischemic optic neuropathy Topical Immunosuppressant calcineurin inhibitors—potential cancer risk Long-acting beta agonists—increased risk of severe asthma episodes that may lead to death

29. 29 Drug Safety HC Professional & Patient Information Sheets At least 44 drugs with safety postings through December 31, 2005 Examples: Accutane (isotretinoin)—new restricted access program to prevent pregnancy in treated women Paxil (paroxetine)—Pregnancy Category changed from C to D Strattera (atomoxetine)—increased pediatric suicidality risk Palladone (hydromorphone)— Withdrawn due to dose dumping with concomitant alcohol exposure Campath (alemtuzumab)—idiopathic thrombocytopenic purpura in patients with multiple sclerosis (unlabeled use) Neutrospec (99mTechnetium fanolesomab)—serious and life threatening cardiopulmonary events shortly after administration

30. 30 Summary Drug Safety Oversight Board established to: Improve public knowledge of emerging important drug safety concerns Strengthen internal drug safety management Foster practical policy development to improve consistency and timely resolution of important drug safety concerns Provide a standing venue for resolution of CDER organizational disputes Central component of CDER’s initiative to improve management of drug safety & inform the public about emerging medication risks