论文标题

在临床试验中使用内部和外部控制测试两次治疗效果

Testing for Treatment Effect Twice Using Internal and External Controls in Clinical Trials

论文作者

Yi, Yanyao, Zhang, Ying, Du, Yu, Ye, Ting

论文摘要

利用外部控制 - 从外部试验或现实世界数据中控制的相关个人患者数据 - 有可能降低随机对照试验(RCT)的成本,同时增加允许获得新治疗的试验患者的比例。但是,由于缺乏随机化,RCT患者和外部对照可能会在可能已经或可能无法测量的协变量方面有所不同。因此,在控制测得的协变量之后,通过匹配,使用外部控制对治疗效果进行测试仍然可能存在未测量的偏见。在本文中,我们提出了一种敏感性分析方法,以量化未测量偏差的幅度,以改变研究结论,即通过使用外部控制,假定没有引入未经测量的偏见。利用外部控制是否会增加功率,取决于样本量之间的相互作用以及治疗效果的大小和未测量的偏见,这可能很难预期。这激发了一项组合的测试程序,该程序执行了两个高度相关的分析,一个分析,一个没有外部控制,使用两个测试统计的联合分布进行多次测试的较小校正。合并的测试提供了一种针对数据融合问题设计的灵敏度分析的新方法,该方法仅基于RCT固定在公正的分析上,并花费了一小部分I类误差以使用外部控件进行测试。这样,如果利用外部控制会增加功率,那么与基于RCT的分析相比,功率增益可能是很大的。如果没有,功率损失很小。提出的方法在理论和权力计算中评估,并应用于实际试验。

Leveraging external controls -- relevant individual patient data under control from external trials or real-world data -- has the potential to reduce the cost of randomized controlled trials (RCTs) while increasing the proportion of trial patients given access to novel treatments. However, due to lack of randomization, RCT patients and external controls may differ with respect to covariates that may or may not have been measured. Hence, after controlling for measured covariates, for instance by matching, testing for treatment effect using external controls may still be subject to unmeasured biases. In this paper, we propose a sensitivity analysis approach to quantify the magnitude of unmeasured bias that would be needed to alter the study conclusion that presumed no unmeasured biases are introduced by employing external controls. Whether leveraging external controls increases power or not depends on the interplay between sample sizes and the magnitude of treatment effect and unmeasured biases, which may be difficult to anticipate. This motivates a combined testing procedure that performs two highly correlated analyses, one with and one without external controls, with a small correction for multiple testing using the joint distribution of the two test statistics. The combined test provides a new method of sensitivity analysis designed for data fusion problems, which anchors at the unbiased analysis based on RCT only and spends a small proportion of the type I error to also test using the external controls. In this way, if leveraging external controls increases power, the power gain compared to the analysis based on RCT only can be substantial; if not, the power loss is small. The proposed method is evaluated in theory and power calculations, and applied to a real trial.

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