Exact inference for adaptive group sequential designs.

Methods for controlling the type-1 error of an adaptive group sequential trial were developed in seminal papers by Cui, Hung, and Wang (Biometrics, 1999), Lehmacher and Wassmer (Biometrics, 1999), and Müller and Schäfer (Biometrics, 2001). However, corresponding solutions for the equally important and related problem of parameter estimation at the end of the adaptive trial have not been completely satisfactory. In this paper, a method is provided for computing a two-sided confidence interval having exact coverage, along with a point estimate that is median unbiased for the primary efficacy parameter in a two-arm adaptive group sequential design. The possible adaptations are not only confined to sample size alterations but also include data-dependent changes in the number and spacing of interim looks and changes in the error spending function. The procedure is based on mapping the final test statistic obtained in the modified trial into a corresponding backward image in the original trial. This is an advance on previously available methods, which either produced conservative coverage and no point estimates or provided exact coverage for one-sided intervals only.