Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial

Stat Med. 2015 Oct 15;34(23):3104-15. doi: 10.1002/sim.6567. Epub 2015 Jun 26.

Abstract

Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease.

Keywords: adaptive design; conditional error; error rate control; multiple testing; sequential clinical trial.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease
  • Clinical Trials, Phase II as Topic / methods
  • Clinical Trials, Phase II as Topic / statistics & numerical data*
  • Clinical Trials, Phase III as Topic / methods
  • Clinical Trials, Phase III as Topic / statistics & numerical data*
  • Computer Simulation
  • Endpoint Determination / methods
  • Endpoint Determination / statistics & numerical data*
  • Humans
  • Research Design