Sample Size Calculation and Timing of Dose Selection in a Multiple-Dose Clinical Trial

ABSTRACT

In a two-stage design for multiple-dose clinical trial, a dose that has the highest observed response rate is often chosen to carry to the next stage, then to compare against the control group. The observed response rate could overestimate the true response rate of the selected dose. If it is used to compare with the response rate of the control group without any adjustment, the Type I error of this statistical inference will not be controlled. In this article, the Stepwise Overcorrection method, which was shown to control the Type I error, is used to derive a formula to calculate the sample size needed for a two-stage multiple-dose design. A maximum-minimum strategy is proposed to ensure the sample size for each group will provide the desired statistical power of detecting the difference in response rates between the selected dose and the control group, assuming at least one of the experimental groups has the desired treatment effect versus the control group.

KEYWORDS:

• Adaptive design
• Dose selection
• Sample size calculation

Acknowledgments

The authors appreciate Liang Zhu for her contribution to simulations of some initial results.

Disclosure Statement

The authors are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

The author(s) reported there is no funding associated with the work featured in this article.