Special Issue Paper
Multiple testing of treatment-effect-modifying biomarkers in a randomized clinical trial with a survival endpoint
Article first published online: 23 FEB 2011
Copyright © 2011 John Wiley & Sons, Ltd.
Statistics in Medicine
Special Issue: Sixth International French Society of Statistics meeting on statistical methods in biopharmacy: Recent advances and trends in statistics as applied to clinical trials
Volume 30, Issue 13, pages 1502–1518, 15 June 2011
How to Cite
Michiels, S., Potthoff, R. F. and George, S. L. (2011), Multiple testing of treatment-effect-modifying biomarkers in a randomized clinical trial with a survival endpoint. Statist. Med., 30: 1502–1518. doi: 10.1002/sim.4022
- Issue published online: 19 MAY 2011
- Article first published online: 23 FEB 2011
- Manuscript Accepted: 16 JUN 2010
- Manuscript Received: 28 DEC 2009
- treatment-effect modifier;
- permutation test
The recent revolution in genomics and the advent of targeted therapies have increased interest in biomarker-defined subgroups of patients who respond to therapy or exhibit specific toxicities. Such biomarker-defined subgroups are also being investigated for non-targeted therapies (e.g. chemotherapy and statins). However, even when the targeting pathway has been identified, a broadly available test to identify the appropriate subgroup will rarely exist prior to the launch of the pivotal phase III trial.
Our aim in this paper is to provide guidance for the analysis of a phase III clinical trial with a survival endpoint, in order to ascertain whether a therapy is more effective in the biomarker-positive patients as compared with biomarker-negative patients, when the trial is conducted on the entire population and when there are multiple candidate biomarkers. We studied treatment-by-biomarker interactions in a Weibull regression model. Different permutation procedures, using single-biomarker statistics and novel composite statistics, are proposed in order to control the family-wise error rate accounting for dependence structures among the biomarkers. A simulation study was performed to compare the operational characteristics of the permutation tests under different scenarios. The tests were applied to a phase III trial of adjuvant chemotherapy in early breast cancer, for which 10 biomarkers were measured in tumor samples from 798 patients.
These permutation tests can be applied to retrospective biomarker studies and to prospective phase III trials of new drugs for which a few clues are known about the targeting pathway at the start of the trial. Copyright © 2011 John Wiley & Sons, Ltd.