Designing multi-arm multi-stage clinical trials using a risk-benefit criterion for treatment selection.
Designing multi-arm multi-stage clinical trials using a risk-benefit criterion for treatment selection.
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DOI：
10.1002/sim.6760
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发表时间：
2016-02-20
影响因子：
2
通讯作者：
Hampson LV
中科院分区：
文献类型：
--
作者：
Jaki T;Hampson LV
多组临床试验将几种有效的治疗方法与普通对照进行比较，这是一种有效的方法，可以在确认性研究中对几种治疗方法中的哪一种进行进一步评估。通过结合中期分析，特别是II/III阶段的无缝设计已成为最近研究的重点，从而获得了额外的效率。这项工作的共同点是选择和正式测试应该基于单一疗效终点的约束，尽管在实践中，安全性考虑通常在决定选择决策中起中心作用。在这里，我们开发了一个具有疗效和安全性终点的多臂多阶段试验设计。在问题的表述、实验臂的选择和假设检验中都明确考虑了安全终点。该设计扩展了组序思想，并考虑了要满足最低安全要求的情况，并选择了满足此约束的最佳综合安全性和有效性权衡的治疗方法进行进一步测试。在第一次中期分析中选择具有最佳权衡的处理，而整个试验允许由J分析组成。结果表明，该设计在较强意义上控制了家族误差率，并通过实例和仿真说明了该方法。我们发现，该设计对于终点之间相关性的错误描述具有稳健性，并且需要与仅基于中度相关终点的疗效的试验相似数量的受试者。©2015作者。医学统计由约翰威利和儿子有限公司出版。
Multi‐arm clinical trials that compare several active treatments to a common control have been proposed as an efficient means of making an informed decision about which of several treatments should be evaluated further in a confirmatory study. Additional efficiency is gained by incorporating interim analyses and, in particular, seamless Phase II/III designs have been the focus of recent research. Common to much of this work is the constraint that selection and formal testing should be based on a single efficacy endpoint, despite the fact that in practice, safety considerations will often play a central role in determining selection decisions. Here, we develop a multi‐arm multi‐stage design for a trial with an efficacy and safety endpoint. The safety endpoint is explicitly considered in the formulation of the problem, selection of experimental arm and hypothesis testing. The design extends group‐sequential ideas and considers the scenario where a minimal safety requirement is to be fulfilled and the treatment yielding the best combined safety and efficacy trade‐off satisfying this constraint is selected for further testing. The treatment with the best trade‐off is selected at the first interim analysis, while the whole trial is allowed to compose of J analyses. We show that the design controls the familywise error rate in the strong sense and illustrate the method through an example and simulation. We find that the design is robust to misspecification of the correlation between the endpoints and requires similar numbers of subjects to a trial based on efficacy alone for moderately correlated endpoints. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.