Statistical Inference after an Adaptive Group Sequential Design: A Case Study

Abstract

The adaptive group sequential design of Lehmacher and Wassmer allows fully flexible redetermination of sample size after each of a predetermined number of interim looks. Study 02CLLIII, a large, randomized, multicenter trial in chronic lymphocytic leukemia, was based on this approach, with five planned analyses. The study terminated for efficacy at the third interim analysis. While it was clear how statistical significance was to be determined, calculations of proper P values as well as point and interval estimates turned out to be much less straightforward. We extend existing analysis approaches to the stratified binary and time-to-event data from this trial, investigate the properties of the estimators for the primary endpoint, and highlight remaining issues with full statistical inference after such a design. In conclusion, the flexibility offered by the adaptive features renders statistical inference more difficult and less precise. We believe that there are situations where it may be worth paying this price.