Correcting for Missing Data When Evaluating Surrogate Markers in a Clinical Trial

TL;DR

This paper introduces new statistical methods to evaluate surrogate markers in clinical trials with missing data, improving accuracy and efficiency over traditional complete case analysis.

Contribution

It develops inverse probability weighting and semiparametric maximum likelihood methods to handle missing data in surrogate marker evaluation, implemented in the MissSurrogate R package.

Findings

Methods remain unbiased under various missing data mechanisms

Enhanced statistical precision compared to complete case analysis

Practical application demonstrated in a diabetes trial

Abstract

Evaluating treatment effects is critical in clinical trials but sometimes involves lengthy, invasive, or costly follow-up procedures. In these cases, surrogate markers, which provide intermediate measures of the long-term treatment effect, allow clinicians to obtain results faster and more efficiently than would have otherwise been possible. Prior to adoption, it is vital that the utility of surrogate markers (i.e., their ability to capture the treatment effect on the primary outcome) is statistically validated. Many frameworks for evaluating surrogate markers have been proposed, but they do not account for missing data. Instead, they rely on complete cases (the subset of patients without missing data), which can be inefficient and biased. To improve on this, we propose methods to accommodate missing data in nonparametric and parametric surrogate evaluation via inverse probability weighting (IPW) and semiparametric maximum likelihood estimation (SMLE). Through simulation studies, we demonstrate that the proposed methods remain unbiased under a broader range of missing data mechanisms than complete case analysis and can help retain the statistical precision of the full trial. We illustrate their practical utility through an application to a diabetes clinical trial. Moreover, our missing data corrections have complementary strengths with respect to computational ease, robustness, and statistical efficiency. All methods are implemented in the MissSurrogate R package.