Calibration of clinical trial sample size based on design utility

Clinical trial design relies on both statistical and clinical considerations for pre-specification of potentially practice-changing target treatment effects. As larger trials tend to be associated with high power and modest minimal detectable benefit, trial sample size is typically calibrated with reference to relevant precedents to prevent overpowering. Albeit trial sponsors and regulators are accustomed to this practice, there is scope for simplification to enhance the robustness, transparency and cross-trial consistency of this aspect of the design process. To this end, a design utility index is proposed here as a formal basis for sample size calibration, balancing the increase in power at higher sample sizes against the corresponding reduction in the magnitude of minimum detectable treatment effects, without requiring additional statistical assumptions or bespoke software. Application of utility calibration to a broad range of designs demonstrates consistency with regulatory expectations for minimum power, particularly in confirmatory settings, and effective protection against overpowering and against overly aggressive interim analyses.