Quantifying the feasibility of shortening clinical trial duration using surrogate markers

Stat Med. 2021 Dec 10;40(28):6321-6343. doi: 10.1002/sim.9185. Epub 2021 Sep 2.

Abstract

The potential benefit of using a surrogate marker in place of a long-term primary outcome is very attractive in terms of the impact on study length and cost. Many available methods for quantifying the effectiveness of a surrogate endpoint either rely on strict parametric modeling assumptions or require that the primary outcome and surrogate marker are fully observed that is, not subject to censoring. Moreover, available methods for quantifying surrogacy typically provide a proportion of treatment effect explained (PTE) measure and do not directly address the important questions of whether and how the trial can be ended earlier using the surrogate marker. In this article, we specifically address these important questions by proposing a PTE measure to quantify the feasibility of ending trials early based on endpoint information collected at an earlier landmark point t 0 in a time-to-event outcome setting. We provide a framework for deriving an optimally predicted outcome for individual patients at t 0 based on a combination of surrogate marker and event time information in the presence of censoring. We propose a non-parametric estimator for the PTE measure and derive the asymptotic properties of our estimators. Finite sample performance of our estimators are illustrated via extensive simulation studies and a real data application examining the potential of hemoglobin A1c and fasting plasma glucose to predict treatment effects on long term diabetes risk based on the Diabetes Prevention Program study.

Keywords: censored data; nonparametric estimation; proportion of treatment effect explained by the surrogate; surrogate marker.