Rofecoxib, Merck, and the FDA.

The new england journal of medicine 2875 correspondence Rofecoxib, Merck, and the FDA to the editor: Merck has been proactive and conscientious in evaluating the cardiovascular profile of rofecoxib (Vioxx); Dr. Topol's remarks to the contrary in his Perspective article (Oct. 21 issue) 1 are false. First, his description of the time line obfus-cates the facts. The Food and Drug Administration (FDA) approved Vioxx in May 1999. The clinical data then existing on 5435 patients who had been treated for up to 22 months did not suggest an adverse car-diovascular effect. 2 Nevertheless, because the literature suggested a hypothetical possibility of both cardioprotective and prothrombotic effects of cy-clooxygenase-2 (COX-2) inhibitors, 1 Merck initiated adjudication of cardiovascular events by an external expert panel at the end of 1998 (i.e., before the Vioxx Gastrointestinal Outcomes Research [VIGOR] trial began) for future studies of Merck's COX-2 inhibitors. Merck learned the preliminary VIGOR results in March 2000, with more cardiovascular events over a period of one year in patients receiving Vioxx than in those receiving naproxen, and promptly disclosed this finding to the FDA, other regulators, and the media, beginning that month. Two months later, the VIGOR manuscript was submitted to the Journal, and it was published in November 2000. An application to include the results in the prescribing information was submitted to the FDA in June 2000, followed by a public Advisory Committee meeting in February 2001. In April 2002, the FDA approved the revised Vioxx prescribing information, reflecting the cardiovascular data from VIGOR (which lacked a placebo group) and interim data from long-term, placebo-controlled studies in elderly patients with Alzheimer's disease, which did not show an increased cardiovascular risk. 3 Second, Dr. Topol neglects to mention that beginning in 2000, Merck undertook three prospective , randomized, placebo-controlled trials of Vioxx in more than 24,000 patients with or without known cardiovascular disease. After deliberations with numerous consultants, Merck finalized a protocol in 2002, which prespecified the analysis of adjudi-cated cardiovascular-event data from these studies as a hypothesis-testing end point. Two of these studies, Adenomatous Polyp Prevention on Vioxx (APPROVe), with approximately 2600 patients, and Vioxx in Colorectal Therapy, Definition of Optimal Regimen (VICTOR), a study of 7000 patients with a history of colon cancer, had already begun, and the third, a study of 15,000 patients at risk for prostate cancer, was initiated after consultation with regulatory agencies. Third, before the results of the …