Towards More Flexible False Positive Control in Phase III Randomized Clinical Trials

Phase III randomized clinical trials play a monumentally critical role in the evaluation of new medical products. Because of the intrinsic nature of uncertainty embedded in our capability in assessing the efficacy of a medical product, interpretation of trial results relies on statistical principles to control the error of false positives below desirable level. The well-established statistical hypothesis testing procedure suffers from two major limitations, namely, the lack of flexibility in the thresholds to claim success and the lack of capability of controlling the total number of false positives that could be yielded by the large volume of trials. We propose two general theoretical frameworks based on the conventional frequentist paradigm and Bayesian perspectives, which offer realistic, flexible and effective solutions to these limitations. Our methods are based on the distribution of the effect sizes of the population of trials of interest. The estimation of this distribution is practically feasible as clinicaltrials.gov provides a centralized data repository with unbiased coverage of clinical trials. We provide a detailed development of the two frameworks with numerical results obtained for industry sponsored Phase III randomized clinical trials.