Surrogate endpoints in clinical trials: Definition and operational criteria
Abstract
I discuss the idea of using surrogate endpoints in the context of clinical trials to compare two or more treatments or interventions in respect to some ‘true’ endpoint, typically a disease occurrence. In order that treatment comparison based on a surrogate response variable have a meaningful implication for the corresponding true endpoint treatment comparison, a rather restrictive criterion is proposed for use of the adjective ‘surrogate’. Specifically, I propose that a surrogate for a true endpoint yield a valid test of the null hypothesis of no association between treatment and the true response. This criterion essentially requires the surrogate variable to ‘capture’ any relationship between the treatment and the true endpoint, a notion that can be operationalized by requiring the true endpoint rate at any follow‐up time to be independent of treatment, given the preceding history of the surrogate variable. I then discuss this operational criterion in the examples of the accompanying papers 1–3 and in the setting of trials aimed at the primary and secondary prevention of cancer.
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Following the Prentice criteria, antibody measures were categorized as potential correlates of protection if they were significantly univariately predictive of log10 sgRNA as a measure of viral replication or if the addition of log10 dose to the linear model did not significantly improve prediction, as assessed by a likelihood ratio test.
“Following the Prentice criteria (47), we categorized antibody measures as potential correlates of protection if they were significantly univariately predictive of log10 sgRNA as a measure of viral replication or if the addition of log10 dose to the linear model did not significantly improve prediction, as assessed by a likelihood ratio test.”
From Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates (2021) · cites this paper as [47]
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- Authors
- Prentice, R. L.
- Affiliations
- Fred Hutch Cancer Center (US)
- Corresponding author
- Prentice, Ross L.
- ORCID
- Prentice, Ross L.
- Venue
- Statistics in Medicine
- Publisher
- Wiley
- Published
- 1989-04
- Volume
- 8
- Issue
- 4
- Pages
- 431-440
- ISSN
- 0277-6715 (ISSN-L)
- 1097-0258
- OpenAlex
- W2155949904
- Cited by
- 2,057
- References
- 6
- Citations by year
- 2026: 76 · 2025: 62 · 2024: 54 · 2023: 78 · 2022: 75 · 2021: 63 · 2020: 66 · 2019: 91 · 2018: 64 · 2017: 83 · 2016: 74 · 2015: 101 · 2014: 93 · 2013: 102 · 2012: 79
- FWCI
- 7.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Statistics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 24472)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Physical Sciences › Mathematics › Statistics and Probability › Probability and Statistical Research
- Keywords
- surrogate endpoints, surrogate validity, treatment comparison, null hypothesis testing, conditional independence, surrogate variables, cancer prevention trials
- MeSH terms
- Breast Neoplasms, Clinical Trials as Topic, Female, Humans, Mass Screening, Neoplasms, Research Design, Statistics as Topic
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