Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data Lessons for Postmarket Pharmaceutical Safety Surveillance

Background: In September 2004, rofecoxib, was voluntarily withdrawn front the worldwide market, Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib, before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts. Methods: We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event. Results: We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects, Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000,21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35-1 95% CI 1.00-1.96) (P = .05). Analyzing data available as of April. 2002, we found a 39% increased risk (RR, 1.39; 95% CI 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR, 1.43; 95% CI 1.16-1.76) (P < .001). Conclusion: Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 31/2 years before the manufacturer's voluntary market withdrawal.