CONTINUOUS AND GROUP SEQUENTIAL CONDITIONAL-PROBABILITY RATIO TESTS FOR PHASE-II CLINICAL-TRIALS

We present continuous and group sequential designs for phase II clinic al trials based on the sequential conditional probability ratio test ( SCPRT). The SCPRT is derived from a conditional likelihood ratio, wher e the conditioning is on what the corresponding (reference) fixed samp le size test (RFSST) would achieve. In other words, we obtain the sequ ential design by controlling the maximum probability that the SCPRT do es not agree with the RFSST. We shall discuss the difference between S CPRT and stochastic curtailment which also uses the concept of conditi onal distribution. We show that the power function of the SCPRT is vir tually the same as that of the RFSST and its average sample numbers (A SNs) are close to those of Wald's sequential probability ratio test (S PRT), whereas its maximum sample size is no greater than that of the R FSST. Thus the SCPRT has all the desirable properties, such as allowin g the use of the RFSST at the last analysis, of the Fleming procedure for phase II trials. The SCPRT, however, preserves the power function of the RFSST better and gives us the option for continuous monitoring. Our recommendation, therefore, is to use a group SCPRT boundary (for interim analyses performed as scheduled) embedded in a continuous SCPR T boundary (for unplanned interim analyses and analyses at times based on data trends). We provide as well a bias-adjusted estimator of the success rate after sequential stopping. We illustrate the method with several examples. The method applies to any single-arm clinical trial with binary endpoints, such as the classic paired design.