Regulatory History

1. Regulatory History JOINT MEETING OF THE ARTHRITIS AND THE DRUG SAFETY AND RISK MANAGEMENT ADVISORY COMMITTEE Jonca Bull, M.D. Office of New Drugs February 16, 2005

2. Overview of NSAID Class NSAIDS : Large class of marketed products with both OTC and Rx indications and use; wide range of products with varying risk to benefit profiles Short term use Dysmennorhea, acute pain Chronic Use: osteoarthritis, rheumatoid arthritis; FAP (celebrex) Other proposed uses: ankylosing spondylitis, Alzheimers, sporadic polyp prevention

3. NSAIDs/COX-2 and FDA(Arthritis Advisory Committee Meetings) • December 2, 1986 • “GI paragraph” databases discussed • October 11-12, 1995 • Revisions for NSAID class label • Citizen’s Petition-piroxicam • March 24, 1998 • NSAID/COX-2 Safety Issues: Potential GI benefit • December 1, 1998 Celebrex Advisory Committee • December 31, 1998 (Celebrex approval) • April 20, 1999 (Vioxx Advisory Committee) • May 20, 1999 Vioxx approval • February 7-8, 2001 (long-term safety)

4. Timeline of IND/NDA Filings PENDING NDAs Bextra IM/IV NDA Filed Bextra IM/IV IND Filed Arcoxia NDA Originally Filed Arcoxia IND Filed Prexige IND Filed Prexige NDA Filed 94 95 97 98 99 00 01 02 03 04 05 96 Bextra IND Filed Bextra NDA Approved 11/01 Celebrex IND Filed Celebrex NDA Filed/approved 12/98 Vioxx IND Filed Vioxx NDA Filed/approved 5/99 APPROVED NDAs

5. COX-2 Agents: Different? • Risk to Benefit • How do these agents differ from traditional NSAIDS? • Can a population of greater benefit (clinically meaningful GI safety) and less risk (CV risk, renal, hepatic, allergy) be characterized? • What additional study is needed to better understand the science of COX 2 inhibition? • Label/Risk Management • What risk management options are appropriate, i.e., ranging from withdrawal to labeling changes?

6. Lessons Learned Drug Development • “No improvements can completely eliminate the risk of unexpected events” • Temple and Himmel, JAMA, May 1, 2002 • Large NDA databases helpful but continued monitoring is essential to assess evolving risk profile for a new product • Impact of aggressive marketing and unknowns of drug safety

7. Day 1 Morning • Dr. Byron Cryer – Gastrointestinal Effects of NSAIDs and COX-2 Specific Inhibitors • Dr. Garrett Fitzgerald -- Mechanisms for Cardiovascular Risk from Inhibition of COXs • Merck -- Rofecoxib • FDA – Vioxx Cardiovascular Safety

8. Day 1 Afternoon • Pfizer – Review of Cardiovascular Safety and Risk/Benefit Assessment of Celecoxib • FDA – COX-2 CV Safety -- Celecoxib • NIH sponsored Colon Polyp Prevention Trials • Pfizer – Cardiovascular Safety and Risk/Benefit Assessment of Valdecoxib and Parecoxib • FDA – COX-2 CV Safety -- Valdecoxib • Bayer & Roche — Joint Presentation on Naproxen

9. Day 2 Morning • Dr. Richard Platt -- Interpretation of Observational Studies of Cardiovascular Risk of Non-steroidal Drugs • Dr. David Graham – Review of Epidemiological Studies on Cardiovascular Risk with Selected NSAIDs • Merck – Etoricoxib • FDA –Analysis of Cardiovascular Thromboembolic Events With Etoricoxib • Novartis – Gastrointestinal and Cardiovascular Safety of Lumiracoxib, Ibuprofen, and Naproxen • FDA – Lumiracoxib Cardiovascular Safety

10. Day 2 Afternoon • Open Public Hearing • Committee Discussion

11. Day 3 Morning • Dr. Constantine G. Lyketsos – Alzheimer’s Prevention Study: ADAPT • Dr. Milton Packer – Interpretation of CV events • Dr. Robert Temple -- Clinical Trial Design and Patient Safety: Future Directions for COX-2 Selective NSAIDs • Dr. Robert O’Neill – Issues in Projecting Increased Risk of Cardiovascular Events to the Exposed Population • Dr. Sharon Hertz – Summary of Meeting Presentations

12. Day 3 Afternoon • Advisory Committee Discussion of Questions • Meeting Wrap-up • Adjourn