The US Food and Drug Administration approves most drugs based on rigorous randomized clinical trials showing that the drug is “efficacious,” which is operationally defined as statistically superior to placebo. However, a number of critically important knowledge gaps exist long after a drug is approved. For example, many drugs are approved based on studies of a surrogate end point, which is a biological marker or event observable earlier than the clinical end points that are actually of primary interest. For instance, antihypertensive drugs are usually approved on the basis of their ability to reduce blood pressure rather than on their ability to reduce the risk of the clinically important consequences of high blood pressure such as stroke. Unfortunately, reliance on surrogate end points can sometimes produce disastrous results. Encainide hydrochloride and flecainide acetate, 2 antiarrhythmic drugs approved in the early 1980s based on their ability to suppress premature ventricular contractions, which was considered a surrogate end point for reducing cardiac mortality, serve as illustrative examples. Nearly a decade after these drugs were approved, a large randomized trial1 showed that, in direct opposition to expectation, they actually increased mortality in the patient population in whom they were thought to reduce mortality.
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