Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim
Article first published online: 6 APR 2010
Copyright © 2010 John Wiley & Sons, Ltd.
Volume 10, Issue 2, pages 96–104, March/April 2011
How to Cite
Posch, M., Maurer, W. and Bretz, F. (2011), Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim. Pharmaceut. Statist., 10: 96–104. doi: 10.1002/pst.413
- Issue published online: 29 MAR 2011
- Article first published online: 6 APR 2010
- familywise error rate;
- conditional error rate;
- adaptive designs;
- sample size reallocation;
Interest in confirmatory adaptive combined phase II/III studies with treatment selection has increased in the past few years. These studies start comparing several treatments with a control. One (or more) treatment(s) is then selected after the first stage based on the available information at an interim analysis, including interim data from the ongoing trial, external information and expert knowledge. Recruitment continues, but now only for the selected treatment(s) and the control, possibly in combination with a sample size reassessment. The final analysis of the selected treatment(s) includes the patients from both stages and is performed such that the overall Type I error rate is strictly controlled, thus providing confirmatory evidence of efficacy at the final analysis. In this paper we describe two approaches to control the Type I error rate in adaptive designs with sample size reassessment and/or treatment selection. The first method adjusts the critical value using a simulation-based approach, which incorporates the number of patients at an interim analysis, the true response rates, the treatment selection rule, etc. We discuss the underlying assumptions of simulation-based procedures and give several examples where the Type I error rate is not controlled if some of the assumptions are violated. The second method is an adaptive Bonferroni–Holm test procedure based on conditional error rates of the individual treatment–control comparisons. We show that this procedure controls the Type I error rate, even if a deviation from a pre-planned adaptation rule or the time point of such a decision is necessary. Copyright © 2010 John Wiley & Sons, Ltd.