Statistical testing strategies for assessing treatment efficacy and marker accuracy in phase III trials

When a candidate predictive marker is available, but evidence on its predictive ability is not sufficiently reliable, all-comers trials with marker stratification are frequently conducted. We propose a framework for planning and evaluating prospective testing strategies in confirmatory, phase III marker-stratified clinical trials based on a natural assumption on heterogeneity of treatment effects across marker-defined subpopulations, where weak rather than strong control is permitted for multiple population tests. For phase III marker-stratified trials, it is expected that treatment efficacy is established in a particular patient population, possibly in a marker-defined subpopulation, and that the marker accuracy is assessed when the marker is used to restrict the indication or labelling of the treatment to a marker-based subpopulation, ie, assessment of the clinical validity of the marker. In this paper, we develop statistical testing strategies based on criteria that are explicitly designated to the marker assessment, including those examining treatment effects in marker-negative patients. As existing and developed statistical testing strategies can assert treatment efficacy for either the overall patient population or the marker-positive subpopulation, we also develop criteria for evaluating the operating characteristics of the statistical testing strategies based on the probabilities of asserting treatment efficacy across marker subpopulations. Numerical evaluations to compare the statistical testing strategies based on the developed criteria are provided.