BOP2-ENR：一种用于自适应富集设计的贝叶斯最优II期设计，控制家系错误率并限制联合声明功效
BOP2-ENR: a Bayesian optimal phase II design for adaptive enrichment with family-wise error rate control and a bound on joint-claim power
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中文总结 AI 辅助
提出BOP2-ENR贝叶斯最优II期设计，用于自适应富集，通过分别监测生物标志物阴性和阳性队列控制家系错误率并限制联合声明功效，扩展了BOP2框架。
中文摘要 AI 辅助
贝叶斯最优II期（BOP2）设计可容纳简单和复杂的终点，但不处理生物标志物引导的富集或合并与亚组声明之间的多重性控制。我们提出BOP2-ENR，该设计分别监测生物标志物阴性（NG）和生物标志物阳性（PG）队列，允许中期富集至PG，并校准合并及PG限制的声明。强家系错误率（FWER）控制在预先指定的单调活性参数空间上定义。在NG无活性而PG有活性的混合配置下，虚假联合声明的概率受限于NG通过无效性监测的概率。这一精确的单队列界限不涉及最终疗效截断值，同时也为联合声明功效设定了上限。对于疗效-毒性监测，亚组无活性通过联合零假设定义，安全性在每个亚组内单独确定。在所考虑的场景以及二元、共同主要和疗效-毒性终点中，所有选定的设计均满足预先指定的精确界限和蒙特卡洛验证标准；在针对校准中假设独立的组分结局之间的比值比进行的敏感性分析中，误差控制量的点估计保持在名义水平以下，尽管功效对关联性敏感。当PG疗效接近干扰空间边界时，该界限几乎达到，而禁用富集则使混合配置误差率接近一。因此，BOP2-ENR将BOP2框架扩展至自适应富集，同时阐明NG无效性门控控制强误差控制的混合配置部分以及联合声明的可达功效。
英文摘要
The Bayesian optimal phase II (BOP2) design accommodates simple and complex endpoints but does not address biomarker-guided enrichment or multiplicity control across pooled and subgroup claims. We propose BOP2-ENR, which monitors biomarker-negative (NG) and biomarker-positive (PG) cohorts separately, permits interim enrichment to PG, and calibrates pooled and PG-restricted claims. Strong family-wise error rate (FWER) control is defined over a prespecified monotone-activity parameter space. Under the mixed configuration in which NG is inactive and PG is active, the probability of a false joint claim is bounded by the probability that NG survives futility monitoring. This exact single-cohort bound does not involve the final efficacy cutoff and also yields a ceiling on joint-claim power. For efficacy-toxicity monitoring, subgroup inactivity is defined by a union null and safety is established separately within each subgroup. Across the scenarios considered and binary, co-primary and efficacy-toxicity endpoints, all selected designs met the prespecified exact-bound and Monte Carlo verification criteria; in sensitivity analyses over odds ratios between component outcomes assumed independent in calibration, point estimates of the error-control quantities remained below the nominal level, although power was association-sensitive. The bound was nearly attained as PG efficacy approached the boundary of the nuisance space, whereas disabling enrichment produced mixed-configuration error rates near one. BOP2-ENR therefore extends the BOP2 framework to adaptive enrichment while clarifying that the NG futility gate governs the mixed-configuration component of strong error control and the attainable power of a joint claim.
发表机构
- Astellas Pharma Global Development Inc.（安斯泰来全球开发公司）
- Astellas Pharma Europe Ltd.（安斯泰来欧洲有限公司）
- Chuo University（中央大学）
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