An adaptive clinical trials procedure for a sensitive subgroup examined in the multiple sclerosis context

Abstract

The biomarker-adaptive threshold design (BATD) allows researchers to simultaneously study the efficacy of treatment in the overall group and to investigate the relationship between a hypothesized predictive biomarker and the treatment effect on the primary outcome. It was originally developed for survival outcomes for Phase III clinical trials where the biomarker of interest is measured on a continuous scale. In this paper, generalizations of the BATD to accommodate count biomarkers and outcomes are developed and then studied in the multiple sclerosis (MS) context where the number of relapses is a commonly used outcome. Through simulation studies, we find that the BATD has increased power compared with a traditional fixed procedure under varying scenarios for which there exists a sensitive patient subgroup. As an illustration, we apply the procedure for two hypothesized markers, baseline enhancing lesion count and disease duration at baseline, using data from a previously completed trial. MS duration appears to be a predictive marker relationship for this dataset, and the procedure indicates that the treatment effect is strongest for patients who have had MS for less than 7.8 years. The procedure holds promise of enhanced statistical power when the treatment effect is greatest in a sensitive patient subgroup.