Evaluation of Surrogate Endpoints Based on Meta-Analysis with Surrogate Indices

Abstract

The meta-analytic (MA) framework is the gold standard for evaluating putative surrogate endpoints but it is not well-suited for complex surrogates. We address this limitation by considering real-valued summaries of complex surrogates as alternative, univariate putative surrogates. We focus on the surrogate index as a specific summary measure with desirable properties. We first formalize the data-generating mechanism underlying the MA framework, making explicit the assumptions required for valid inferences in any evaluation of trial-level surrogacy. These assumptions are often left implicit in the MA framework. Building on this formalization, we show that, under certain conditions, the surrogate index maximizes the trial-level surrogacy among all real-valued summaries. When the surrogate index is estimated, we show that valid inference about the trial-level surrogacy of this estimated surrogate index is possible. The proposed approach can be implemented using standard software and is illustrated using COVID-19 vaccine efficacy trials, where antibody markers are evaluated as candidate surrogate endpoints.

73 pages, 23 figures. v2: additional theory and improved paper organization; no changes to analysis/results