Meta-Analytic Evalution of Surrogate Endpoints in Clinical Studies

• Activity Number: 468
• Type: Topic Contributed
• Date/Time: Wednesday, August 7, 2013 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Geert Molenberghs*+
• Companies: Universiteit Hasselt & Katholieke Universiteit Leuven
• Keywords: surrogate endpoint ; clinical trial ; mixed model

Abstract

Regulatory agencies are introducing provisions and policies relating to the use of surrogate endpoints in registration studies. But how can one establish the adequacy of a surrogate, in the sense that treatment effectiveness on the surrogate will accurately predict treatment effect on the intended, and more important, true outcome? What kind of evidence is needed, and what statistical methods portray that evidence most appropriately? A definition and criteria have been proposed, including use of the proportion explained, as well as other measures. In a multi-centre setting, these quantities can be generalized to individual- and trial-level measures of surrogacy: a meta-analytic framework. A number of variations of this theme have been developed, depending on the type of endpoint for the true and surrogate endpoint and on the focus of the evaluation exercise. At the same time, efforts have been made to converge to a common framework. This includes a so-called variance reduction factor and an information-theoretic approach. Further, work has been done to convert the evaluation methodology to sample size assessment methodology, leading to the surrogate threshold effect.