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 argument¹: in the context of discussing the association between appetite suppressant drugs and primary pulmonary hypertension,² 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 dexfenfluramine³ 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 argument⁴: "the potential health benefits of anorectic drugs outweigh their risk when considered against the health hazards of obesity."⁵ When, after the drug was approved, the adverse effects were found to be greater than estimated on the basis of preapproval trials,^6- 7 the drug was withdrawn.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?