Bayesian Two-Stage Design for Phase II Clinical Trials with Switching Hypothesis Tests

Abstract

Conventional phase II clinical trials use either a single-arm or a double-arm scheme to examine the treatment effect of an investigational drug. The hypotheses tests under these two schemes are different, as a single-arm study usually tests the response rate of the new drug against a set of fixed reference rates and a double-arm randomized trial compares the new drug with the standard treatment or placebo. To bridge the single- and double-arm schemes in one phase II clinical trial, we propose a Bayesian two-stage design with changing hypothesis tests. Stage 1 enrolls patients solely to the experimental arm to make a comparison with the reference rates, and stage 2 imposes a double-arm comparison of the experimental arm with the control arm. The design is calibrated with respect to error rates from both the frequentist and Bayesian perspectives. Moreover, we control the “type III error rate”, defined as the probability of prematurely stopping the trial at stage 1 when the trial is supposed to move on to stage 2. We conduct extensive simulations on the calculations of these error rates to examine the operational characteristics of our proposed method, and illustrate it with a non-small cell lung cancer trial.