Clinical trial designs based on sequential conditional probability ratio tests and reverse stochastic curtailing

Abstract

We propose a group sequential method based on the sequential conditional probability ratio test and show that it has the conservatism desired in practice. We also propose calculating the discordant probability, that is, the probability that the sequential test concludes differently from a fixed-sample test at the planned end of the trial, recognizing that this probability could be substantial, even if the sequential test has the same size and power as the fixed-sample size test at the planned end of the study. In addition, we show that the proposed method can be used as a stochastic curtailing tool. Thus, the method accommodates unplanned interim analyses as well as those deemed necessary based on data trends, virtually without inflating the type I error, but it is less conservative than the usual stochastic curtailing. The method is implemented through an interactive computer program.