Adaptive design for confirmatory clinical trials. Available at http://www.cytel.com/Learn/Publications.aspx

This paper discusses the benefits and limitations of adaptive sample size re-estimation for late stage confirmatory clinical trials. Comparisons are made with more traditional fixed sample and group sequential designs. It is seen that the real benefit of the adaptive approach arises through the ability to invest sample size resources into the trial in stages. The trial starts with a small up-front sample size commitment. Additional sample size resources are committed to the trial only if promising results are obtained at an interim analysis. This strategy is seen to be more advantageous than the fixed sample or group sequential approaches in certain settings. The discussion is illustrated through a case study of an actual adaptive trial. 1 The Setting Consider a two-arm trial to determine if there is an efficacy gain for an experimental drug relative to the industry standard treatment for negative symptoms schizophrenia. The primary endpoint is the improvement from baseline to week 26 in the Negative Symptoms Assessment (NSA), a 16-item clinician-rated instrument for measuring the negative symptomatology of schizophrenia. Let μt denote the difference between the mean NSA at baseline and the mea