AI 中文总结
研究针对适应性富集试验，开发路径全局校准的BOP2框架，通过联合校准全人群和生物标志物阳性阈值，推导精确有限状态递归枚举，控制全局I型错误率，优于单独校准的BOP2方法。
AI 中文摘要
适应性富集可使实验性治疗在全人群活性不足但在预设生物标志物阳性亚组中有前景时继续开展。然而，将分别校准的II期设计直接顺序应用于两个群体可能会增加假阳性疗效结论的概率。贝叶斯最优II期（BOP2）设计在单臂II期试验中使用后验概率阈值进行中期无效性监测和最终疗效决策。我们为分支适应性富集试验开发了一个路径全局校准的BOP2框架。在预设的全人群中期分析中，试验要么继续在全人群中招募，要么在越过全人群无效边界后，转向预设的生物标志物阳性富集路径。全人群和生物标志物阳性阈值针对两种可能疗效声明的联合进行校准，同时考虑富集开始时可用的随机生物标志物阳性样本量。所有决策规则在试验开始前预先设定。对于二元终点，我们推导了完整适应性程序的精确有限状态递归枚举，无需蒙特卡罗误差即可进行校准和操作特征评估。使用此精确程序，我们表明所提出的设计在预设的生物标志物患病率预设范围内控制了预设点全局零假设下的全局I型错误率，而单独校准的BOP2方法则没有。在替代方案下，疗效声明通过全人群和生物标志物阳性路径产生，其相对贡献取决于生物标志物患病率和亚组反应概率。
英文摘要
Adaptive enrichment allows development of an experimental treatment to continue when its activity is insufficient in an all-comer population but remains promising in a prespecified biomarker-positive subgroup. However, sequential application of separately calibrated phase II designs can inflate the probability of a false-positive efficacy conclusion. We develop a globally calibrated Bayesian optimal phase II (BOP2) design for branching adaptive enrichment trials. At prespecified all-comer interim analyses, the trial either continues all-comer enrollment or, after crossing the all-comer futility boundary, evaluates the accumulated biomarker-positive data. Enrichment is initiated only when a prespecified minimum number of biomarker-positive patients is available and the biomarker-positive futility boundary is not crossed; otherwise, the trial stops. The all-comer and biomarker-positive thresholds are jointly calibrated for the union of the two possible efficacy claims while accounting for the random subgroup sample size available when enrichment is considered. All decision rules are prespecified before trial initiation. For a binary endpoint, an exact finite-state recursive enumeration enables calibration and operating-characteristic evaluation without Monte Carlo error. Under the prespecified point global null, the proposed design controlled the global type I error rate over the prespecified set of biomarker-positive prevalence values while achieving higher power than the independently calibrated BOP2 comparator across the evaluated alternative scenarios. In the numerical study, the independently calibrated comparator exceeded the nominal global type I error level after its components were embedded in the branching procedure. The framework is also extended to complex categorical endpoints using a Dirichlet--multinomial formulation, with calibration and evaluation performed by simulation.
