Surrogate endpoints in clinical trials: Definition and operational criteria

TLDR

Surrogate endpoints are used in clinical trials to compare treatments relative to a true endpoint such as disease occurrence. The study proposes a restrictive criterion that a surrogate must allow a valid test of the null hypothesis of no association between treatment and the true endpoint. This criterion requires the surrogate to capture all treatment–endpoint relationships, operationalized by demanding that the true endpoint rate at any follow‑up time be independent of treatment given the prior history of the surrogate variable, and is illustrated in several example trials.

Abstract

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.