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April 12, 2007

Testimony of Sidney M. Wolfe M.D. Director, Health Research Group of Public Citizen FDA Arthritis Advisory Committee Meeting on Etoricoxib (Arcoxia) for Treatment of Osteoarthritis. April 12, 2007. Introduction. The consideration of approval of etoricoxib involves three outcome variables:

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April 12, 2007

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  1. Testimony of Sidney M. Wolfe M.D.Director, Health Research Group of Public Citizen FDA Arthritis Advisory Committee Meeting on Etoricoxib (Arcoxia) for Treatment of Osteoarthritis April 12, 2007

  2. Introduction The consideration of approval of etoricoxib involves three outcome variables: • Relative efficacy for osteoarthritis • Relative cardiovascular risk • Relative gastrointestinal toxicity (serious complications such as perforation, bleed and obstruction)

  3. Merck Conclusions of Etoricoxib Efficacy (Page 66 of Merck Advisory Committee Briefing package) “Once daily treatment with etoricoxib 60 mg shows comparable efficacy to naproxen 1000 mg (500 mg 2 times daily) and to diclofenac 150 mg (50 mg 3 times daily) in patients with OA.” “Once daily treatment with etoricoxib 30 mg shows comparable efficacy to ibuprofen 2400 mg (800 mg 3 times daily) and to celecoxib 200 mg once daily in patients with OA.

  4. Sponsors need incentives to evaluate drugs in a manner that highlights potential clinical value, not marketing potential. NSAID Trials and the Choice of Comparators--Questions of Public Health Importance. Psaty and Weiss. NEJM, January, 2007

  5. RCTs: COX-2 vs Placebo Favors Placebo MIs with COX-2/ Placebo Kearney, et al 2006, BMJ. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials

  6. RCTs: COX-2 Drugs vs Older NSAIDs Ratio favoring older NSAIDs: COX-2 MI/Older NSIAD MI Kearney, et al 2006, BMJ

  7. AHA Recommendations: Antman, et al Circulation. March 2007

  8. Non-Selective NSAIDs and Cardiovascular Risk (cont’d) AHA Recommendations: Antman, et al Circulation. March 2007

  9. NDA/Deaths(rates are per 100 PYR) FDA Presentation at 2/05 Meeting

  10. NDA/Absolute Rate & Relative Risk FDA Presentation at 2/05 Meeting

  11. NDA/Naproxen FDA Presentation at 2/05 AAC Meeting

  12. NDA/Naproxen FDA Presentation at 2/05 AAC Meeting

  13. EDGE/Hypertension FDA Presentation at 2/05 AAC Meeting

  14. EDGE/CHF FDA Presentation at 2/05 AAC Meeting

  15. Summary • In NDA, etoricoxib trends worse in terms of CV/TE particularly cardiac/MI • Comparisons of etoricoxib to naproxen for CV/TE events are similar to rofecoxib/naproxen comparisons • Trial design concerns in EDGE (2 ongoing trials of similar design) • Trends in EDGE for cardiac events worse for etoricoxib, mainly in non-ASA users FDA Presentation at 2/05 AAC Meeting

  16. Summary statistics for CV outcomes, pooled MEDAL Program Confirmed APTC (Antiplatelet Trialists’ Collaboration) Combined Endpoint (from Summary of FDA Medical Officer Review for this meeting 4/12/07)

  17. from Summary of FDA Medical Officer Review for this meeting 4/12/07

  18. from Summary of FDA Medical Officer Review for this meeting 4/12/07

  19. In Vitro Selectivity: COX-2/COX-1 Ratio lumiracoxib etoricoxib rofecoxib > 50-fold COX-2 selective valdecoxib etodolac nimesulide 5- 50-fold COX-2 selective diclofenac celecoxib meloxicam fenoprofen < 5-fold COX-2 selective ibuprofen tolmetin naproxen aspirin indomethacin ketoprofen flurbiprofen Warner et al. FASEB J. 2004:18:790-804 ketorolac -3 -2 -1 0 1 2 3 Increasingly COX-1 Selective Increasingly COX-2 Selective Range of COX Selectivity for COX-1 and COX-2 (log10 IC50 COX-2/COX-1)

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