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An underrecognized challenge in evaluating postmarketing drug safety.

The withdrawal of the cyclooxygenase (COX)-2–specific inhibitor rofecoxib (Vioxx; Merck) has generated a high-profile debate in the medical and lay press over when a signal suggesting the potential for harm from this drug was first apparent and what steps the medical community, the US Food and Drug Administration, and the pharmaceutical sponsor took and should have taken to address this issue.1,2 This debate, however, has glossed over a fundamental problem that the withdrawal of the drug serves to highlight—not how best to deal with a potential signal once it is described, but rather how to identify such important and initially unanticipated effects after a drug is marketed.

The contemporary processes of drug discovery and marketing include both basic studies and drug exposure in humans, generally in no more than several thousand patients. These studies establish a putative mechanism of action of the new compound, although, as discussed below, new molecular mechanisms of actions often are discovered after a drug has been marketed. Efficacy must be established in rigorous controlled clinical trials, with well-defined patient populations, inclusion and exclusion criteria, predefined end points, and appropriate statistical analyses. Other important pieces of information include major mechanisms of drug metabolism and excretion and the potential for both pharmacokinetic and pharmacodynamic drug interactions. An important result of this premarketing workup is that adverse effects that commonly occur during the administration of a drug become well recognized. If these effects are common or serious, then the drug may in fact not be suitable for marketing.

The basic science and clinical trial experience that precedes the marketing of a new drug allows regulators to craft a label to guide use of the drug. Experience teaches that real-world use may result in a side effect profile quite different from that anticipated from the premarketing portfolio. Thus, …