Group-Sequential and Adaptive Designs

As motivated in Part I of this book, a major difficulty when planning a clinical trial with a composite primary endpoint or, as an alternative, with a single component as primary efficacy measure is to make valid planning assumptions on the required parameters and the expected effect size. A common way to deal with planning uncertainties is the use of adaptive or classical group-sequential designs, which allow an early stop of the trial either for futility or, in case of an unexpectedly large effect, also for efficacy. It is intuitively clear that the option of an early termination of the trial can decrease the total required sample size by a relevant amount. In adaptive designs, it is moreover possible to change other trial settings such as the second-stage sample size or the test strategy. As repeated hypothesis tests are performed in group-sequential and adaptive designs, the local significance levels for each individual analysis have to be adjusted in order to maintain the global type I error rate. Therefore, under the correct parameter assumptions, the maximal required sample size of such a design is larger than the sample size for a standard single-stage design.