Multiplicity and flexibility in clinical trials

Flexible designs offer a large amount of flexibility in clinical trials with control of the type I error rate. This allows the combination of trials from different clinical phases of a drug development process. Such combinations require designs where hypotheses are selected and/or added at interim analysis without knowing the selection rule in advance so that both flexibility and multiplicity issues arise. The paper reviews the basic principles and some of the common methods for reaching flexibility while controlling the family-wise error rate in the strong sense. Flexible designs have been criticized because they may, lead to different weights for the patients from the different stages when reassessing sample sizes. Analyzing the data in a conventional way avoids such unequal weighting but may inflate the multiple type I error rate. In cases where the conditional type I error rates of the new design (and conventional analysis) are below the conditional type I error rates of the initial design the conventional analysis may, however, be done without inflating the type I error rate. Focusing on a parallel group design with two treatments and a common control, we use this principle to investigate when we can select one treatment, reassess sample sizes and test the corresponding null hypotheses by the conventional level alpha z-test without compromising on the multiple type I error rate. Copyright (C) 2007 John Wiley & Sons, Ltd.