Department of Biostatistics, Bioinformatics and Biomathematics, Lombardi Comprehensive Cancer Center, 12231Georgetown University Medical Center, Washington, DC, USA.
Division of Biostatistics, Department of Population Health, 12296New York University School of Medicine, New York, NY, USA.
Stat Methods Med Res. 2022 Jul;31(7):1207-1223. doi: 10.1177/09622802221091901. Epub 2022 Apr 11.
Basket trials pool histologic indications sharing molecular pathophysiology, improving development efficiency. Currently, basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power even with modest effect sizes, and provides nearly -fold increased efficiency for indications, but controls false positives for the pooled result only. Since family wise error rate by indications may sometimes be required, we now simulate a variant of this basket design controlling family wise error rate at 0.025, the total family wise error rate of separate randomized trials. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling family wise error rate and minimizing estimation bias were allowable. Optimal performance results when . We report efficiency (expected # true positives/expected sample size) relative to parallel studies, at 90% power ("uncorrected") or at the power achieved in the basket trial ("corrected," because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with a higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible. Even under family wise error rate control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical.
篮子试验汇集具有分子病理生理学相似性的组织学适应证，从而提高了研发效率。目前，篮子试验仅对特殊疗法具有确证性。我们之前的随机篮子设计可能在资源密集型的确证性阶段通常是适用的，即使效应量适中也能保持高功效，并且为适应证提供近 - 倍的效率提升，但仅对汇总结果进行假阳性控制。由于有时可能需要按适应证进行组间错误率控制，我们现在模拟了一种控制组间错误率为 0.025（单独随机试验的总组间错误率）的篮子设计变体。我们在多种设计参数变化的场景下模拟了这种修改后的设计。仅允许控制组间错误率和最小化估计偏差的设计。当 时，结果为最优性能。我们报告相对于平行研究的效率（预期的#真实阳性/预期样本量），在 90%功效（“未校正”）或在篮子试验中达到的功效（“校正”，因为常规设计也可以通过牺牲功效来提高效率）。效率和功效（识别出的有效适应证的百分比）随着初始适应证中活性适应证的比例增加而提高。未校正的效率提高可达 92%，校正的效率提高可达 38%。即使在组间错误率控制下，随机确证性篮子试验也能大大提高研发效率。初始适应证选择至关重要。
