Author Affiliations: The Cardiovascular Health Research Unit, the Departments of Medicine (Drs Psaty, Koepsell, Siscovick, and Smith), Epidemiology (Drs Psaty, Weiss, Koepsell, Siscovick, and Heckbert, and Mr Kaplan), Health Services (Drs Psaty, Koepsell, and Wagner), and Biostatistics (Drs Lin and Fleming), University of Washington, Seattle; the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (Dr Furberg); the Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (Dr Rosendaal); and the Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle (Dr Wagner).
Controversies Section Editor: Phil B. Fontanarosa,
MD, Interim Coeditor.
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the drug was withdrawn.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?
Psaty BM, Weiss NS, Furberg CD, Koepsell TD, Siscovick DS, Rosendaal FR, Smith NL, Heckbert SR, Kaplan RC, Lin D, Fleming TR, Wagner EH. Surrogate End Points, Health Outcomes, and the Drug-Approval Process for the Treatment of Risk Factors for Cardiovascular Disease. JAMA. 1999;282(8):786-790. doi:10.1001/jama.282.8.786