Marker Sequential Test (MaST) design
Marker Sequential Test (MaST) design
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DOI：
10.1177/1740774513503739
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发表时间：
2014-02-01
期刊：
影响因子：
2.7
通讯作者：
Gray, Robert
中科院分区：
文献类型：
--
作者：
Freidlin, Boris;Korn, Edward L.;Gray, Robert
新的靶向抗癌疗法通常只对特定癌症患者的一小部分患者有益。对这些药物的最终评估可能需要III期随机临床试验设计，将新治疗的评估和生物标志物的预测能力结合起来，这些生物标志物推定地决定了敏感亚群。我们提出了一种新的综合生物标志物设计，标记序列测试（MaST）设计，允许在生物标志物亚组和总体人群中进行治疗效果的序列测试，同时控制相关的I型错误率。方法在定义了综合生物标志物设计的测试和误差框架后，回顾了常用的综合生物标志物测试方法。然后，我们提出了MaST设计的一般形式，并描述了如何使用它来适当控制生物标志物阳性和生物标志物阴性亚群的假阳性错误率。通过分析方法和模拟将MaST设计的操作特性与序列亚组特异性设计进行比较，序列亚组特异性设计依次评估生物标志物亚组的治疗效果。讨论了桅杆设计实施的实际问题。结果表明，在治疗效果跨生物标志物亚组均匀的情况下，相对于序列亚组特定设计，MaST设计具有更高的功效，而在治疗益处仅限于生物标志物阳性亚组的情况下，MaST设计仍具有较高的功效。例如，在考虑30%生物标志物阳性患病率的事件时间设置中，当治疗对所有患者都有同等益处时，MaST设计在生物标志物阳性和生物标志物阴性亚组中提供了高达30%的功效增加，而在生物标志物阳性亚组中，与替代方案相比，功效损失不到2%。建议的设计适用于合理假设治疗对生物标志物阴性患者无效，除非对生物标志物阳性患者有效的情况。结论当需要考虑生物标志物阳性和阴性亚组的治疗效果时，MaST试验设计可替代序列亚组特异性设计。
Background New targeted anticancer therapies often benefit only a subset of patients with a given cancer. Definitive evaluation of these agents may require phase III randomized clinical trial designs that integrate evaluation of the new treatment and the predictive ability of the biomarker that putatively determines the sensitive subset.Purpose We propose a new integrated biomarker design, the Marker Sequential Test (MaST) design, that allows sequential testing of the treatment effect in the biomarker subgroups and overall population while controlling the relevant type I error rates.Methods After defining the testing and error framework for integrated biomarker designs, we review the commonly used approaches to integrated biomarker testing. We then present a general form of the MaST design and describe how it can be used to provide proper control of false-positive error rates for biomarker-positive and biomarker-negative subgroups. The operating characteristics of the MaST design are compared by analytical methods and simulations to the sequential subgroup-specific design that sequentially assesses the treatment effect in the biomarker subgroups. Practical aspects of MaST design implementation are discussed.Results The MaST design is shown to have higher power relative to the sequential subgroup-specific design in situations where the treatment effect is homogeneous across biomarker subgroups, while preserving the power for settings where treatment benefit is limited to biomarker-positive subgroup. For example, in the time-to-event setting considered with 30% biomarker-positive prevalence, the MaST design provides up to a 30% increase in power in the biomarker-positive and biomarker-negative subgroups when the treatment benefits all patients equally, while sustaining less than a 2% loss of power against alternatives where the benefit is limited to the biomarker-positive subgroup.Limitations The proposed design is appropriate for settings where it is reasonable to assume that the treatment will not be effective in the biomarker-negative patients unless it is effective in the biomarker-positive patients.Conclusion The MaST trial design is a useful alternative to the sequential subgroup-specific design when it is important to consider the treatment effect in the biomarker-positive and biomarker-negative subgroups.