Advisory Committee Presentation on Vioxx (Rofecoxib) Discussion on the meta analyses for cardiovascular risk assessment Qian Li, Sc. D.

February 8,2001VIOXX Confirmed Serious CV Thrombotic Events Observed in VIGOR 50 mg

February 8,2001VIOXX Key Features of the Meta Analysis  Meta analysis of 25 studies –pooling different dose levels of rofecoxib (12.5, 25, and 50 mg) –pooling studies of different duration (4 weeks to one year) –combining different indication by stratified analyses (RA, OA, Alzheimer and back pain)

February 8,2001VIOXX Issue of the Meta Analysis  Does the meta analysis adequately address the role of rofecoxib 50 mg in relation to CV event?

February 8,2001VIOXX Concerns of the Meta Analysis 1. The risk ratios between rofecoxib & comparator may not be constant over time, –short term studies may not be able to demonstrate the treatment difference

February 8,2001VIOXX Concerns of the Meta Analysis 2. The risks may not be the same for different dose levels of rofecoxib, pooling may obscure the risk associated with a high dose group. Complication occurs if –different lengths of follow-up for different dose levels –different sample sizes for different dose levels

February 8,2001VIOXX Rofecoxib Exposure Data from Meta Analysis Data Sets

February 8,2001VIOXX Summary of Limitations  Risk ratio is not constant over time,  Not enough data over 6 month  Inadequate sample size outside VIGOR for rofecoxib 50 mg …...  Pooling different dose levels is problematic for an evaluation of rofecoxib 50 mg

February 8,2001VIOXX Conclusions  The meta analysis does not resolve the role of rofecoxib 50 mg in relation to the risk of CV events observed in the VIGOR trial.

February 8,2001VIOXX Three Comparisons  Rofecoxib vs. naproxen: –include indications of RA and OA –driven by the VIGOR trial  Rofecoxib vs. non-naproxen NSAIDs: –include only OA indications  Rofecoxib vs. placebo: –include ALZ and BP indication –driven by the ALZ tirals

February 8,2001VIOXX Sample Sizes for Studies at Least 6-month Duration 12.5 mg25 mg50 mg Comparator

February 8,2001VIOXX The Assessment of CV Risk on Lower Doses of Rofecoxib  Did not show increased risk of CV events of low doses of rofecoxib in this meta analysis, –due to lack of power –due to special populations  It is not possible to draw conclusion based on this meta analysis.

February 8,2001VIOXX Preliminary Dose-response Assessment provided by sponsor including studies with duration longer than 6 months This assessment suggested a trend to increase risk with rofecoxib 50 mg.