Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions

Abstract

HEALTH CARE PRACTITIONERS AND PATIENTS SEEK safe and effective drugs. However, no drug is completely safe; all drugs have toxic effects that must be balanced with their benefits in deciding whether they should be marketed or used in any given person. To inform such decisions, the United States relies on a drug approval system whereby preclinical studies precede 3 phases of clinical studies. Collectively, these usually include 500 to 3000 exposed patients and 2 or more confirmatory trials, demonstrating before marketing that a drug is effective and reasonably safe for its recommended use. Thus, adverse reactions occurring in 1% or more of exposed patients are usually well described upon marketing. However, rarer adverse reactions are not well characterized until after marketing. This reflects a deliberate societal decision to balance delays in access to new drugs with delays in information about rare adverse reactions. To provide the missing information, the United States maintains a postmarketing surveillance system including passive collection of spontaneous reports of adverse drug reactions (ADRs) to generate signals of possible adverse drug events. This is supplemented by formal pharmacoepidemiology studies testing those hypotheses, confirming or disproving potential signals from the spontaneous reporting system (SRS). Cerivastatin uniquely challenged this system. It is now well known that cerivastatin, when combined with gemfibrozil, poses an increased risk of rhabdomyolysis. In fact, a rhabdomyolysis warning was included in the original cerivastatin label upon its US launch, along with a warning against use with fibrates, based on experiences with previously released statins. Postmarketing reports of rhabdomyolysis soon after marketing were therefore neither unexpected nor alarming. Thus, the normally difficult decision to act more aggressively on spontaneous reports, always subjective, was even more difficult here. I share the concern by Psaty et al that drug manufacturers have an inherent conflict of interest in making such decisions. However, cerivastatin presents a unique opportunity to highlight SRS limitations, and its potential misuse, and provides insights into how to improve the US drug monitoring program. This commentary will not consider issues of the ongoing litigation, including manufacturer conduct, timelines of company memos, the litany of legal exhibits, or the accusations made by Psaty et al regarding those issues. Rather, it will discuss the scientific and policy issues raised by Psaty et al, describe the SRS in some detail, and discuss appropriate uses of SRS data and organizational implications of its limitations. Cerivastatin serves as an instructive example. The company response addresses the cerivastatin legal issues elsewhere in this issue.