A BAYESIAN ADAPTIVE TWO-STAGE DESIGN FOR PEDIATRIC CLINICAL TRIALS

We develop a novel two-stage Bayesian adaptive trial design for pediatric settings which borrows information from previously completed trials in adults to support establishing substantial evidence of efficacy for the pediatric population in situations where information extrapolation from adults is justifiable. At the time of the stage I analysis, the extent of information borrowing from adult data is determined by assessing compatibility of the observed pediatric data with its prior predictive distribution, derived using the adult trial data. At this time, the trial may be stopped for futility, enrollment may be stopped (with ongoing patients followed up for primary outcome ascertainment), or enrollment may proceed into stage II to reach a prespecified maximum sample size. We provide guidance on how practitioners can approach answering the question “How much information should be borrowed?” through balancing use of the adult data (when compatible with the pediatric data) with the need to ensure the design leads to reasonable recommendations regarding key actions that might be taken regarding the trial (e.g., when to stop early for efficacy). Type I error control is considered secondary to these considerations as type I error rate inflation above typical levels is unavoidable in these settings. We illustrate how the method can be applied using the Pediatric Lupus Trial of Belimumab Plus Background Standard Therapy as motivation.

本研究针对儿科场景开发了一种新型两阶段贝叶斯自适应试验设计（two-stage Bayesian adaptive trial design），当成人数据的信息外推具备合理性时，该设计可借鉴既往成人已完成临床试验的信息，助力为儿科人群建立充分的疗效证据。在第一阶段分析阶段，基于成人试验数据推导得到的先验预测分布（prior predictive distribution），通过评估观测到的儿科数据与该先验预测分布的相容性，来确定从成人数据中借鉴信息的程度。在此阶段，试验可因无效性提前终止、停止入组（对仍在入组的患者进行随访以确定主要结局），或继续入组至第二阶段，直至达到预先设定的最大样本量。本研究为从业者提供了指导思路，以解答“应借鉴多少信息？”这一问题：需在合理使用成人数据（当儿科数据与成人数据相容时）与确保该设计能为试验关键决策（如何时因疗效提前终止试验）提供合理建议的需求之间取得平衡。I类错误（Type I error）控制在此类研究中属于次要考量因素，因为在此类场景下，I类错误率超出常规水平的情况不可避免。本研究以贝利尤单抗联合背景标准疗法儿科狼疮临床试验为示例，阐释了该方法的具体应用流程。