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Surrogate End Points in Clinical Trials: Are We Being Misled?

Thomas R. Fleming, PhD; and David L. DeMets, PhD
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From the University of Washington, Seattle, Washington; and the University of Wisconsin-Madison, Medical School, Madison, Wisconsin. Acknowledgments: The authors thank Robert Temple, Curt Furberg, and the reviewers for providing valuable suggestions. Grant Support: By research grants AI 29168 and CA 18332 from the National Institutes of Health. Requests for Reprints: Thomas R. Fleming, PhD, Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232. Current Author Addresses: Dr. Fleming: Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;125(7):605-613. doi:10.7326/0003-4819-125-7-199610010-00011
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Phase 3 clinical trials, which evaluate the effect that new interventions have on the clinical outcomes of particular relevance to the patient (such as death, loss of vision, or other major symptomatic event), often require many participants to be followed for a long time.There has recently been great interest in using surrogate end points, such as tumor shrinkage or changes in cholesterol level, blood pressure, CD4 cell count, or other laboratory measures, to reduce the cost and duration of clinical trials. In theory, for a surrogate end point to be an effective substitute for the clinical outcome, effects of the intervention on the surrogate must reliably predict the overall effect on the clinical outcome. In practice, this requirement frequently fails. Among several explanations for this failure is the possibility that the disease process could affect the clinical outcome through several causal pathways that are not mediated through the surrogate, with the intervention's effect on these pathways differing from its effect on the surrogate. Even more likely, the intervention might also affect the clinical outcome by unintended, unanticipated, and unrecognized mechanisms of action that operate independently of the disease process. We use examples from several disease areas to illustrate how surrogate end points have been misleading about the actual effects that treatments have on the health of patients.

Surrogate end points can be useful in phase 2 screening trials for identifying whether a new intervention is biologically active and for guiding decisions about whether the intervention is promising enough to justify a large definitive trial with clinically meaningful outcomes.In definitive phase 3 trials, except for rare circumstances in which the validity of the surrogate end point has already been rigorously established, the primary end point should be the true clinical outcome.


Grahic Jump Location
Figure 1. A. The surrogate is not in the causal pathway of the disease process. B. Of several causal pathways of disease, the intervention affects only the pathway mediated through the surrogate. C. The surrogate is not in the pathway of the intervention's effect or is insensitive to its effect. D. The intervention has mechanisms of action independent of the disease process. Dotted lines = mechanisms of action that might exist.
Reasons for failure of surrogate end points.
Grahic Jump Location
Grahic Jump Location
Figure 2.
The setting that provides the greatest potential for the surrogate end point to be valid.
Grahic Jump Location




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