On the three-arm non-inferiority trial including a placebo with a prespecified margin
Article first published online: 5 NOV 2010
Copyright © 2010 John Wiley & Sons, Ltd.
Statistics in Medicine
Volume 30, Issue 3, pages 224–231, 10 February 2011
How to Cite
Hida, E. and Tango, T. (2011), On the three-arm non-inferiority trial including a placebo with a prespecified margin. Statist. Med., 30: 224–231. doi: 10.1002/sim.4099
- Issue published online: 7 JAN 2011
- Article first published online: 5 NOV 2010
- Manuscript Accepted: 3 SEP 2010
- Manuscript Received: 15 JUL 2009
- three-arm design;
- non-inferiority trial;
- prespecified non-inferiority margin;
- assay sensitivity;
- optimal allocation;
- bivariate normal distribution
Three-arm trials including the experimental treatment, an active reference treatment and a placebo are recommended in the guidelines of the ICH and EMEA/CPMP as a useful approach to the assessment of assay sensitivity. Generally, the acceptable non-inferiority margin Δ has been defined as the maximum clinically irrelevant difference between treatments in many two-arm non-inferiority trials. However, many recent articles discussing three-arm trials have considered a design with unknown Δ which is the prespecified fraction f of unknown effect size of the reference drug, where the prespecified fraction f is treated as if it were a revised margin. Therefore, these methods cannot be applied to the case where the acceptable non-inferiority margin must be a prespecified difference between treatments.
In this paper, we propose a statistical test procedure for three-arm non-inferiority trials with the margin Δ defined as a prespecified difference between treatments under the situation that the primary endpoints are normally distributed with a common, but unknown, variance. In addition, we derive the optimal allocation that minimizes the total sample size. The proposed method is illustrated with data on a randomized controlled trial on major depressive disorder. Copyright © 2010 John Wiley & Sons, Ltd.