Design and analysis of factorial clinical trials: The impact of one treatment's effectiveness on the statistical power and required sample size of the other

• Published in: Statistical methods in medical research Vol. 32; no. 6; pp. 1124 - 1144
• Main Authors: Walter, Stephen D., Belo, Ian J.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-06-2023; Sage Publications Ltd
• Subjects: Analytical chemistry; Binary system; Clinical research; Clinical trials; Control Groups; Effectiveness; Humans; Maximum power; Medical research; Odds Ratio; Original s; Research Design; Sample Size; Statistical power; Thresholds; clinical trials; power; Factorial studies; study design; sample size
• ISSN: 0962-2802; 1477-0334
• DOI: 10.1177/09622802231163332

Factorial allow for the simultaneous evaluation of more than one treatment, by randomizing patients to their possible combinations, including control. However, the statistical power of one treatment can be influenced by the effectiveness of the other, a matter that has not been widely recognized. In this paper, we evaluate the relationship between the observed effectiveness of one treatment and the implied power for a second treatment in the same trial, under a range of conditions. We provide analytic and numerical solutions for a binary outcome, under the additive, multiplicative, and odds ratio scales for treatment interaction. We demonstrate how the minimum required sample size for a trial depends on the two treatment effects. Relevant factors include the event rate in the control group, sample size, treatment effect sizes, and Type-I error rate thresholds. We show that that power for one treatment decreases as a function of the observed effectiveness of the other treatment if there is no multiplicative interaction. A similar pattern is observed with the odds ratio scale at low control rates, but at high control rates, power may increase if the first treatment is moderately more effective than its planned value. When treatments do not interact additively, power may either increase or decrease, depending on the control event rate. We also determine where the maximum power occurs for the second treatment. We illustrate these ideas with data from two actual factorial trials. These results can benefit investigators in planning the analysis of factorial clinical trials, in particular, to alert them to the potential for losses in power when one observed treatment effect differs from its originally postulated value. Updating the power calculation and modifying the associated required sample size can then ensure sufficient power for both treatments.