Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy of drug combinations
Article first published online: 17 MAY 2011
Copyright © 2011 John Wiley & Sons, Ltd.
Statistics in Medicine
Volume 30, Issue 16, pages 1952–1970, 20 July 2011
How to Cite
Whitehead, J., Thygesen, H. and Whitehead, A. (2011), Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy of drug combinations. Statist. Med., 30: 1952–1970. doi: 10.1002/sim.4267
- Issue published online: 15 JUN 2011
- Article first published online: 17 MAY 2011
- Manuscript Accepted: 21 MAR 2011
- Manuscript Received: 30 JUN 2010
- combination therapies;
- decision procedure;
- phase I/II clinical trials
Many formal statistical procedures for phase I dose-finding studies have been proposed. Most concern a single novel agent available at a number of doses and administered to subjects participating in a single treatment period and returning a single binary indicator of toxicity. Such a structure is common when evaluating cytotoxic drugs for cancer. This paper concerns studies of combinations of two agents, both available at several doses. Subjects participate in one treatment period and provide two binary responses: one an indicator of benefit and the other of harm. The word ‘benefit’ is used loosely here: the response might be an early indicator of physiological change which, if induced in patients, is of potential therapeutic value. The context need not be oncology, but might be any study intended to meet both the phase I aim of establishing which doses are safe and the phase II goal of exploring potential therapeutic activity. A Bayesian approach is used based on an assumption of monotonicity in the relationship between the strength of the dose-combination and the distribution of the bivariate outcome. Special cases are described, and the procedure is evaluated using simulation. The parameters that define the model have immediate and simple interpretation. Graphical representations of the posterior opinions about model parameters are shown, and these can be used to inform the discussions of the trial safety committee. Copyright © 2011 John Wiley & Sons, Ltd.