In clinical trials, a surrogate endpoint (or surrogate marker) is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of Health (USA) defines surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint".[1][2]
Surrogate markers are used when the primary endpoint is undesired (e.g., death), or when the number of events is very small, thus making it impractical to conduct a clinical trial to gather a statistically significant number of endpoints. The FDA and other regulatory agencies will often accept evidence from clinical trials that show a direct clinical benefit to surrogate markers.[3]
Surrogate endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or biomarkers from Electroencephalography (qEEG), MRI, PET, or biochemical biomarkers.
A correlate does not make a surrogate. It is a common misconception that if an outcome is a correlate (that is, correlated with the true clinical outcome) it can be used as a valid surrogate endpoint (that is, a replacement for the true clinical outcome). However, proper justification for such replacement requires that the effect of the intervention on the surrogate endpoint predicts the effect on the clinical outcome: a much stronger condition than correlation.[4][5] In this context, the term Prentice criteria is used.[6]
The term "surrogate" should not be used in describing endpoints. Instead, descriptions of results and interpretations should be formulated in terms that designate the specific nature and category of variable assessed.[7]
A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.[8]
^De Gruttola, Victor G; Clax, Pamela; DeMets, David L; Downing, Gregory J; Ellenberg, Susan S; Friedman, Lawrence; Gail, Mitchell H; Prentice, Ross; Wittes, Janet; Zeger, Scott L (2001). "Considerations in the Evaluation of Surrogate Endpoints in Clinical Trials". Controlled Clinical Trials. 22 (5): 485–502. doi:10.1016/S0197-2456(01)00153-2. ISSN 0197-2456. PMID 11578783.
^Alexandra Goho, "An Imperfect Substitute" CR Magazine, Spring 2009
^Fleming, Thomas R. (1996). "Surrogate End Points in Clinical Trials: Are We Being Misled?". Annals of Internal Medicine. 125 (7): 605–613. doi:10.7326/0003-4819-125-7-199610010-00011. PMID 8815760. S2CID 12267404.
^Prentice, Ross L. (1989). "Surrogate endpoints in clinical trials: Definition and operational criteria". Statistics in Medicine. 8 (4): 431–440. doi:10.1002/sim.4780080407. PMID 2727467.
^O'Quigley, John; Flandre, Philippe (March 2006). "Quantification of the Prentice Criteria for Surrogate Endpoints". Biometrics. 62 (1): 297–300. doi:10.1111/j.1541-0420.2006.00538.x. PMID 16542258. S2CID 19927364.
^Sobel, Burton E.; Furberg, Curt D. (1997). "Surrogates, Semantics, and Sensible Public Policy". Circulation. 95 (6): 1661–1663. doi:10.1161/01.CIR.95.6.1661. PMID 9118540.
^Temple RJ. A regulatory authority's opinion about surrogate endpoints. Clinical Measurement in Drug Evaluation. Edited by Nimmo WS, Tucker GT. New York: Wiley; 1995.
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