Surrogate Outcomes in Clinical Research
DOI:
https://doi.org/10.51987/Rev.Hosp.Ital.B.Aires.v46i2.1312Keywords:
surrogate outcomes, clinical research, clinical endpoints, health decision-makingAbstract
A surrogate endpoint is a biomarker or intermediate endpoint used as a substitute for a clinically relevant endpoint, such as survival or quality of life, and proposed to predict the benefits or harms of an intervention. Its use in clinical research may reduce the duration and sample size of clinical trials and expedite regulatory assessment and coverage decisions for new treatments. However, not every biomarker or intermediate endpoint constitutes a validated surrogate endpoint. Their use remains controversial because, in many cases, they have not been adequately validated as reliable predictors of clinically meaningful benefits for patients. This statistical note provides a critical review of the use of surrogate endpoints, examines their main conceptual and methodological limitations, and proposes an approach that prioritizes clinically relevant, patient-centered endpoints.
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Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676.
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-2122.
U.S. Food and Drug Administration. FDA facts: biomarkers and surrogate endpoints [Internet]. Silver Spring (MD): Food and Drug Administration; 2019 [citado 2025 nov 23]. Disponible en: https://www.fda.gov/about-fda/innovation-fda/fda-facts-biomarkers-and-surrogate-endpoints.
FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) [Internet]. Silver Spring (MD): Food and Drug Administration; Bethesda (MD): National Institutes of Health; 2016- [citado 2025 nov 23]. Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK326791/.
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89-95.
Lassere MN, Johnson KR, Boers M, et al. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol. 2007;34(3):607-615.
Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ. 2011;343:d7995.
Schuster DP. The opportunities and challenges of developing imaging biomarkers to study lung function and disease. Am J Respir Crit Care Med. 2007;176(3):224-230.
Ciani O, Buyse M, Drummond M, et al. Time to review the role of surrogate end points in health policy: state of the art and the way forward. Value Health. 2017;20(3):487-495.
U.S. Food and Drug Administration. Guidance, compliance, & regulatory information. [Internet]. Silver Spring (MD): Food and Drug Administration; 2023 Aug 21 [citado 2025 nov 23]. Disponible en: https://www.fda.gov/drugs/guidance-compliance-regulatory-information.
Christensen R, Ciani O, Manyara AM, et al. Surrogate endpoints: a key concept in clinical epidemiology. J Clin Epidemiol. 2024;167:111242.
Manyara AM, Davies P, Stewart D, et al. Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate): extension checklist with explanation and elaboration. BMJ. 2024;386:e078524.
Churruca K, Pomare C, Ellis LA, et al. Patient-reported outcome measures (PROMs): a review of generic and condition-specific measures and a discussion of trends and issues. Health Expect. 2021;24(4):1015-1024.
Williamson PR, Altman DG, Bagley H, et al. The COMET handbook: version 1.0. Trials. 2017;18(Suppl 3):280.
Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
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Copyright (c) 2026 Mariana A. Burgos, Silvana B. Soli, Habik A. Páez Alvarez, María F. Grande Ratti
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