Clinical Trials in the Wake of Vioxx

Clinical trials have become the preeminent tool for investigating new diagnostic, therapeutic, and preventive treatment strategies. During these trials, periodic interim data analyses are conducted by data monitoring committees (DMCs) to ensure participant safety. If accumulated data indicate harm to participants, clear evidence of superior efficacy, or futility of collecting additional data, studies may be terminated before their planned conclusion.Editorial p 2173 These termination decisions are invariably complex and involve important subjective and ethical elements.1 Of greatest concern when studies are terminated because of clear benefit is the possibility that the superior intervention has toxicities that remain undiscovered. Early termination entails the abbreviation of clinical experience that would permit assessment of the longer-term safety profile. However, study continuation when treatments are not equally effective also means that some participants will continue to receive a less effective therapy.The tension between protecting both trial participants and future patients has been increasingly acute since rofecoxib (Vioxx [Merck]) and other cyclooxygenase-2 inhibitors were implicated in a greater risk of myocardial infarction. Thrombotic side effects of cyclooxygenase-2 inhibition were postulated as a result of the propensity for selective antagonists to decrease vascular prostacyclin production and possibly affect the balance between prothrombotic and antithrombotic eicosanoids.2 Little evidence of toxicity was evident in preapproval trials, however, and rofecoxib was approved in 1999 for relief of the signs and symptoms of osteoarthritis, the management of acute pain, and the treatment of primary dysmennorhea.3The possibility of cardiac toxicity in human trials was recognized in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial.4 Meta-analyses, database studies, and prospective trials further corroborated cardiac toxicity,5–8 and Merck voluntarily withdrew rofecoxib from the US market on September 30, 2004,9 amid widespread criticism of both Merck and the Food and Drug Administration.10,11In the wake …