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Control Clin Trials. 2002 Dec;23(6):607-25.

Statistical challenges in the evaluation of surrogate endpoints in randomized trials.

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  • 1Limburgs Universitair Centrum, tUL, Center for Statistics, Biostatistics, Diepenbeek, Belgium.


The validation of surrogate endpoints has been studied by Prentice, who presented a definition as well as a set of criteria that are equivalent if the surrogate and true endpoints are binary. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs 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 a multiunit setting, these quantities can be generalized to a trial-level measure of surrogacy and an individual-level measure of surrogacy. In this paper, we argue that such a multiunit approach should be adopted because it overcomes difficulties that necessarily surround validation efforts based on a single trial. These difficulties are highlighted.

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