Bayesian inference for a principal stratum estimand to assess the treatment effect in a subgroup characterized by post-randomization events

TL;DR

This paper introduces a Bayesian approach to estimate treatment effects within a subgroup defined by post-randomization events, using principal stratification to address biases in clinical trial analysis.

Contribution

It develops a Bayesian framework for principal stratification to accurately assess treatment effects in subgroups characterized by post-randomization events in randomized trials.

Findings

Bayesian principal stratification provides unbiased subgroup treatment effect estimates.

Application to multiple sclerosis trial demonstrates the method's practical utility.

Sensitivity analyses confirm robustness of the estimates.

Abstract

The treatment effect in a specific subgroup is often of interest in randomized clinical trials. When the subgroup is characterized by the absence of certain post-randomization events, a naive analysis on the subset of patients without these events may be misleading. The principal stratification framework allows one to define an appropriate causal estimand in such settings. Statistical inference for the principal stratum estimand hinges on scientifically justified assumptions, which can be included with Bayesian methods through prior distributions. Our motivating example is a large randomized placebo-controlled trial of siponimod in patients with secondary progressive multiple sclerosis. The primary objective of this trial was to demonstrate the efficacy of siponimod relative to placebo in delaying disability progression for the whole study population. However, the treatment effect in the subgroup of patients who would not relapse during the trial is relevant from both a scientific and regulatory perspective. Assessing this subgroup treatment effect is challenging as there is strong evidence that siponimod reduces relapses. Aligned with the draft regulatory guidance ICH E9(R1), we describe in detail the scientific question of interest, the principal stratum estimand, the corresponding analysis method for binary endpoints and sensitivity analyses.