Pooled analysis of rofecoxib placebo-controlled clinical trial data: lessons for postmarket pharmaceutical safety surveillance.
BACKGROUND
In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket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; 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).


CONCLUSIONS
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 3(1/2) years before the manufacturer's voluntary market withdrawal.
Ross
Joseph S
JS
Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1070, New York, NY 10029, USA. joseph.ross@mssm.edu
Madigan
David
D
Hill
Kevin P
KP
Egilman
David S
DS
Wang
Yongfei
Y
Krumholz
Harlan M
HM
D016907:Adverse Drug Reaction Reporting Systems; D002319:Cardiovascular System / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004345:Drug Industry / Q000592:standards; D006801:Humans; D015994:Incidence; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects*; D009203:Myocardial Infarction / Q000139:chemically induced* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D056737:Safety-Based Drug Withdrawals; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib