ADAPT: the wrong way to stop a clinical trial.

In an accompanying article published in PLoS Clinical Trials, the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) Research Group report the cardiovascular outcomes from their study [1]. The circumstances surrounding the termination of ADAPT were unusual and provide an important lesson for all clinical trialists, demonstrating the importance of following rigorous procedures for prematurely stopping clinical trials. In this case, stopping the trial before its intended completion resulted in data that cannot be reliably interpreted. On September 30, 2004, Merck withdrew rofecoxib (Vioxx) from the market after the trial's data safety and monitoring board (DSMB) recommended termination of a placebo-controlled study of this agent in the prevention of colon polyps [2]. The reason for study termination was a statistically significant increase in adverse cardiovascular outcomes. On December 17, 2004, Pfizer announced that termination of a trial of celecoxib (Celebrex) in colon polyp prevention, because it also showed statistically significant evidence for increased cardiovascular event rates [3]. The results of these two trials were subsequently published in February 2005 in the New England Journal of Medicine [4,5]. The revelations about increased cardiovascular events with these “coxibs” generated enormous public attention and concern. However, in both cases, the decision-making leading to trial discontinuation was handled appropriately through the regular reviews conducted by an independent DSMB. Three days following the announcement of the termination of the celecoxib colon polyp prevention study, the National Institute of Health (NIH), issued a press release entitled “Use of Non-Steroid Anti-Inflammatory Drugs Suspended in Large Alzheimer's Disease Prevention Trial” [6]. The NIH press release stated that “data from the ADAPT trial indicated an apparent increase in cardiovascular and cerebrovascular events among participants taking naproxen when compared to placebo.” In the press release, NIH Director Dr. Elias Zerhouni stated that “this step is being taken as a precautionary measure to ensure the safety of the study's participants” and that “the investigators made their decision based on the risk/benefit analysis specific to this trial.” Shortly following the NIH announcement, the Food and Drug Administration (FDA) issued a public statement that “based on emerging information from a long-term prevention trial, the risk of cardiovascular and cerebrovascular events may increase among patients taking naproxen” [7]. These announcements generated front-page headlines such as “Heart Risk Seen in Naproxen” (Wall Street Journal), “Tough Choice: Pain or Risk” (USA Today), and “Patients, Doctors Agonize over Risks of Painkiller (Los Angeles Times) [8]. Occurring immediately following the revelations about rofecoxib and celecoxib, the naproxen announcement generated considerable public apprehension [8]. Physicians received many urgent calls from worried patients. However, there was a major problem with the naproxen warning: it was not based upon the application of standard procedures for stopping an ongoing clinical trial. During the subsequent FDA hearings to set policy on nonsteroidal anti-inflammatory agents (NSAIDs) and COX-2 inhibitors, I described the warnings about naproxen as “the medical equivalent of yelling ‘fire' in a crowded auditorium” [9].