The New England Journal of Statistics in Data Science

The high cost of drug development and the relatively low success rates of phase III clinical trials highlight the need for improved and reasonably sized phase II trial designs, especially when responses observed in treatment and control could not lead to a clear-cut decision warranting further studies. To this end, we propose a three-outcome dual-criterion randomized (TDR) trial design, which implements inconclusive region sculpting using boundaries defined by both statistically significant differences between treatment and control as well as the clinical relevance of treatment responses. We provide statistical justifications for the TDR design in both one-stage and two-stage trial settings. Additionally, we evaluate its operating characteristics through a comparison with existing designs. The proposed design is shown able to achieve sample size saving and type II error reduction while controlling the type I error at a marginal cost of power reduction. Lastly, robustness under various deviations from the assumed control response rate is also demonstrated.