Optimal design for inference on the threshold of a biomarker.

Abstract

Enrichment designs with a continuous biomarker require the estimation of a threshold to determine the subpopulation benefitting from the treatment. This article provides the optimal allocation for inference in a two-stage enrichment design for treatment comparisons when a continuous biomarker is suspected to affect patient response. Several design criteria, associated with different trial objectives, are optimized under balanced or Neyman allocation and under equality of the first two empirical biomarker's moments. Moreover, we propose a new covariate-adaptive randomization procedure that converges to the optimum with the fastest available rate. Theoretical and simulation results show that this strategy improves the efficiency of a two-stage enrichment clinical trial, especially with smaller sample sizes and under heterogeneous responses.