Robust inference for responder analysis: Innovative clinical trial design using a minimum p-value approach

Responder analysis is in common use in clinical trials, and has been described and endorsed in regulatory guidance documents, especially in trials where “soft” clinical endpoints such as rating scales are used. The procedure is useful, because responder rates can be understood more intuitively than a difference in means of rating scales. However, two major issues arise: 1) such dichotomized outcomes are inefficient in terms of using the information available and can seriously reduce the power of the study; and 2) the results of clinical trials depend considerably on the response cutoff chosen, yet in many disease areas there is no consensus as to what is the most appropriate cutoff. This article addresses these two issues, offering a novel approach for responder analysis that could both improve the power of responder analysis and explore different responder cutoffs if an agreed-upon common cutoff is not present. Specifically, we propose a statistically rigorous clinical trial design that pre-specifies multiple tests of responder rates between treatment groups based on a range of pre-specified responder cutoffs, and uses the minimum of the p-values for formal inference. The critical value for hypothesis testing comes from permutation distributions. Simulation studies are carried out to examine the finite sample performance of the proposed method. We demonstrate that the new method substantially improves the power of responder analysis, and in certain cases, yields power that is approaching the analysis using the original continuous (or ordinal) measure.