1. VIOXX ™ Gastrointestinal Outcome Research (VIGOR) Arthritis Advisory Committee Meeting February 8, 2001 Lourdes Villalba, M.D. DAAODP, CDER, FDA

2. Rofecoxib Overall Safety  VIGOR - General safety  CV safety in other databases  Risk/benefit assessment - Co-use of ASA  Post-marketing safety  Conclusions

3. VIGOR General Safety  Evaluation of routine safety parameters  Deaths  Serious Clinical AE’s  Dropouts due to Clinical AE’s  Laboratory AE’s  Number of Hospitalizations  Pre-specified NSAID-related AE’s

4. VIGOR General Safety Deaths Rofecoxib (N=4047) 22 (0.5%) 9 cardiovascular 5 pneumonia 4 worsening ILD 2 GI bleeding 1 gastric malignancy 1 unknown (CHF?) Naproxen (N=4029) 15 (0.4 %) 7 cardiovascular 3 pneumonia 1 worsening ILD 1 GI bleeding 1 hepatic necrosis 2 malignant neoplasm

5. Definition of Serious AE’s  Death  Life threatening  Results in persistent or significant disability/incapacity  Results in or prolongs patient hospitalization  Is a congenital anomaly/birth defect  Cancer  The result of an overdose  Or event may jeopardize the patient and require medical or surgical intervention to prevent one of the outcomes listed above

6. VIGOR General Safety Serious AE’s (  >1%) Rofecoxib Naproxen N=4047 (%) N=4029 (%) Any * 378 (9.3) 315 (7.8) CV * 101 (2.5) 46 (1.1) Digestive * 48 (1.2) 97 (2.4 ) MS 1 83 (2.1) 70 (1.7) Resp 52 (1.3) 39 (1.0) * p < 0.05 1 MS: musculo-skeletal

7. VIGOR General Safety Dropouts due to AE’s (  >1%) Rofecoxib Naproxen N=4047 (%) N=4029 (%) Any 643 (15.9) 635 (15.8) CV* 109 (2.7) 33 (0.8) Digestive 292 (7.2) 392 (9.7) Nervous* 44 (1.1) 24 (0.6) Body 1 100 (2.5) 107 (2.7) * p < 0.05 1 Body: body as a whole

8. VIGOR General Safety Lab AE’s Rofecoxib Naproxen N=4047 (%) N=4029 (%) Any 418 (10.4) 368 (9.2) Dropouts 22 (0.6) 12 (0.3) Serious 3 (<0.1) 0

9. VIGOR General Safety Hospitalizations Rofecoxib Naproxen N=4047 N=4029 Any 338 265 CV 65 24 GI 29 49 Hematologic 7 6 Hepatobiliary 12 8 Renal 6 6 Other

10. VIGOR General Safety Pre-specified NSAID-related AE’s Rofecoxib Naproxen p-value N=4047 N=4029  Dropouts GI + abdom. pain 307 416 <0.001 Edema-related 25 13 0.057 HTN-related 28 6 <0.001 Liver-related 10 3 0.067 Renal-related 8 7 0.796  CHF-related 19 9 0.065

11. VIGOR General Safety Summary  GI safety favored rofecoxib  Overall, general safety parameters trended in favor of naproxen, particularly due to the excess in serious cardiovascular events in the rofecoxib group.

12. Rofecoxib Overall Safety  VIGOR - General Safety  CV safety in other databases  Risk/benefit assessment - Co-use of ASA  Post-marketing safety  Conclusions

13. Time to event plot. Adjudicated serious CV thrombotic events in VIGOR RR = 2.37 (R vs. N)

14. Serious CV/thrombotic Events Definitions 1) Investigator reported 2) Adjudicated: confirmed by the CV Case Review Committees (Pre-specified analysis in SOP)(excludes hemorrhagic stroke) 3) APTC: Anti-platelet Trialists’ Collaboration composite endpoint: cardiac death, non- fatal MI and stroke (includes hemorrhagic stroke and excludes peripheral events)

15. VIGOR Adjudicated Serious CV thrombotic Events Included for Analyses  Cardiac Event  Acute myocardial infarction  Unstable angina  Sudden cardiac death  Cerebrovascular Event  Ischemic CVA stroke with documentation  Transient ischemic attack (TIA)  Peripheral Vascular Event  Peripheral arterial thrombosis  Peripheral venous thrombosis

16. VIGOR Serious CV thrombotic events Three Different Endpoints 64 45 35 32 1918 0 20 40 60 80 InvestigatorAdjudicatedAPTC 1 # patients with events rofecoxib naproxen APTC 1: Anti-platelet Trialists’ Collaboration composite

17. VIGOR CV Safety Hypotheses  Pro-thrombotic effect with rofecoxib? (biological plausibility)  Cardio-protective effect of naproxen? (biological plausibility)  Unknown factors?

18. VIGOR CV Safety Hypotheses (2)  Cardio-protective effect of naproxen? – Adjudication criteria: RR = 0.42 N vs. R – APTC combined endpoint: RR = 0.51 N vs. R (8,000 patients, median f.u. 9 months, population of patients with no recent CV/thrombotic event)  No controlled studies of naproxen vs. placebo for CV prophylaxis.

19. Rofecoxib CV Safety Important Limitations to Sponsor’s Meta-analysis –Studies of different length (4 - 86 weeks)  Most patients exposed < 6 months –Different doses (rofecoxib 12.5, 25 and 50 mg)  Most patients exposed  25 mg –Multiple comparators which may be associated with different risk of CV events. –Different diseases that may be associated with different risk of CV events.

20. Rofecoxib Exposure Data from Meta Analysis Data Sets  Total number included in sponsor’s meta- analysis: 28,349 patients  Exposure to rofecoxib 50 mg/day for at least 6 months in studies other than VIGOR: 638 patients

21. Rofecoxib CV Safety Summary  Cardiovascular Safety in VIGOR favored naproxen (CV/thrombotic, HTN and CHF)  HTN/fluid retention/edema for rofecoxib: dose dependent (signal present in original NDA)  CV/thrombotic events: –Original NDA small database –Sponsor’s meta-analysis has serious methodological limitations to answer the question

22. Rofecoxib Overall Safety  VIGOR - General Safety  CV safety in other studies  Risk/benefit assessment - Co-use of ASA  Post-marketing safety  Conclusions

23. Rofecoxib Risk/benefit Assessment  Patients at increased risk of certain CV thrombotic events should be on concomitant low dose ASA  The effect of concomitant use of rofecoxib with low dose ASA on GI and CV risk is unknown. Studies that allowed ASA from the start were small and short in duration, except for study 102 (“Advantage” study)

24. Study 102 1 Preliminary safety data Rofecoxib* Naproxen* 25 mg 1000 mg N=2785 N=2771 Serious CV 2 10 7 Cardiac 7 1 MI 5 1 Sudden death 2 0 Ischemic CVA 0 6 Other events 3 3 0 Confirmed UGI 6 12 1 12- week 2 APTC terms 3 Arterial rupture, hemorrhagic CVA, unknown cause of death * 1 2 % low dose ASA

25. Rofecoxib Risk/benefit Assessment Co-use with low dose ASA Summary  Insufficient data on concomitant ASA use.

26. Rofecoxib Overall Safety  VIGOR - General Safety  CV safety in other studies  Risk/benefit assessment - Co-use of ASA  Post-marketing safety  Conclusions

27. Rofecoxib Overall Safety Post-marketing Surveillance  Post-marketing reports include: –GI –Renal –Liver –Anaphylactoid reactions –Prothrombin time prolongation with coumadin co-use

28. Rofecoxib Overall Safety  VIGOR - General Safety  CV Safety in other studies  Risk/benefit assessment - Co-use of ASA  Post-marketing safety  Conclusions

29. Rofecoxib Overall Safety Conclusions (1)  VIGOR: GI Safety favored rofecoxib vs. naproxen (in a population of patients not taking ASA)  VIGOR: Overall, no safety superiority of rofecoxib over naproxen due to an excess of serious CV events in the rofecoxib group compared to the naproxen group  Rofecoxib 50 mg is twice the upper dose labeled for chronic use in OA. The chronic use of the 50 mg dose is not recommended.

30. Rofecoxib Overall Safety Conclusions (2)  Post-marketing safety: risk of serious GI events still a concern in high risk population  Questions raised in VIGOR: –Is there a pro-thrombotic effect of rofecoxib? –What would be the impact of chronic co-use of low dose ASA in GI and CV events?