Statistical evaluation of surrogate endpoints with examples from cancer clinical trials

• Published in: Biometrical journal 2016-01, Vol.58 (1), p.104-132
• Main Authors: Buyse, Marc, Molenberghs, Geert, Paoletti, Xavier, Oba, Koji, Alonso, Ariel, Van der Elst, Wim, Burzykowski, Tomasz
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor - metabolism; Biometry - methods; Clinical outcomes; Clinical trials; Clinical Trials as Topic; Disease-Free Survival; Humans; Individual level association; Patients; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Surrogate endpoint; Surrogate threshold effect; Trial level association
• ISSN: 0323-3847; 1521-4036
• DOI: 10.1002/bimj.201400049

A surrogate endpoint is intended to replace a clinical endpoint for the evaluation of new treatments when it can be measured more cheaply, more conveniently, more frequently, or earlier than that clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these. Besides the biological plausibility of a surrogate, a quantitative assessment of the strength of evidence for surrogacy requires the demonstration of the prognostic value of the surrogate for the clinical outcome, and evidence that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome. We focus on these two conditions, and outline the statistical approaches that have been proposed to assess the extent to which these conditions are fulfilled. When data are available from a single trial, one can assess the “individual level association” between the surrogate and the true endpoint. When data are available from several trials, one can additionally assess the “trial level association” between the treatment effect on the surrogate and the treatment effect on the true endpoint. In the latter case, the “surrogate threshold effect” can be estimated as the minimum effect on the surrogate endpoint that predicts a statistically significant effect on the clinical endpoint. All these concepts are discussed in the context of randomized clinical trials in oncology, and illustrated with two meta‐analyses in gastric cancer.