Surrogate End Points, Health Outcomes, and the Drug-Approval Process for the Treatment of Risk Factors for Cardiovascular Disease

DATA ON SURROGATE END POINTS SUCH AS BLOOD pressure or body weight have often been used to support the approval of new pharmacologic treatments for cardiovascular risk factors. In small, short-term studies, a new drug reduces the level of a risk factor, and the changes in risk factor levels are interpreted as if the health benefits expected on the basis of those changes will necessarily follow. An editorial on the pharmacotherapy of obesity illustrates the argument: in the context of discussing the association between appetite suppressant drugs and primary pulmonary hypertension, the editorialists used observational evidence on the association of body mass index with mortality and translated data on weight loss in a small, short-term trial of dexfenfluramine into an estimate of lives that could be saved by long-term drug therapy for obesity. The US Food and Drug Administration (FDA) approved dexfenfluramine on the basis of this same surrogate end point argument: “the potential health benefits of anorectic drugs outweigh their risk when considered against the health hazards of obesity.” When, after the drug was approved, the adverse effects were found to be greater than estimated on the basis of preapproval trials, the drug was withdrawn. Is this an example of the drug-approval process working well, or does it point to a fundamental flaw in the way drugs are approved? Surrogate end points sometimes fail to serve as valid predictors of important health outcomes. One remedy would be to require, prior to approving new drug therapies for cardiovascular risk factors, large, long-term clinical trials to assess the drug’s effects on major disease end points. The historical precedent of having accepted surrogate end points and the current interest in minimizing the time to drug approval may make this approach impracticable. Alternatively, a regular requirement for phase 4 trials would perhaps be a practical and achievable strategy for drug approval, one that improves incrementally upon the current approach, which usually requires no other evaluation than the use of surrogate end points.