Challenges in the methodology for the validation of surrogate endpoints in randomized trials

Abstract

The validation of surrogate endpoints has been studied by Prentice (1989). He presented a definition as well as a set of criteria that are equivalent if the surrogate and true endpoints are binary. Freedman (1992) supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs (1998) proposed to replace the proportion explained by two quantities: (1) the relative effect linking the effect of treatment on both endpoints and (2) the adjusted association, an individual-level measure of agreement between both endpoints. In this paper, we argue that a meta-analytic approach should be adopted because it overcomes difficulties which necessarily surround validation efforts based on a single trial.