Issues in designing flexible trials.

We outline the general framework of adaptive combination tests and discuss their relationship to flexible group sequential designs. An important field of applications is sample size reassessment. We discuss reassessment rules based on conditional power arguments using either the observed or the prefixed effect size. These rules tend to lead to large expected sample sizes for small actual effects. However, the application of a maximal bound for the second stage sample size leads to more favourable properties. Additionally, we consider an optimized reassessment rule in terms of expected sample sizes. Since the adaptive design does not use the classical test statistics for some types of sample size reassessments, the adaptive test may reject the null hypothesis while the classical one-sample test does not. We characterize sample size reassessment rules, where such inconsistencies are avoided. Finally, the extension of flexibility to the number of stages is explored. In the first interim analysis a second interim analysis is only planned if the chance to achieve a decision there is high. This leads to savings in the average number of interim analysis performed, without paying a noticeable price in terms of expected sample size. Copyright 2003 John Wiley & Sons, Ltd.