Coherence principles in dose-finding studies
Coherence principles in dose-finding studies
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DOI：
10.1093/biomet/92.4.863
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发表时间：
2005-12-01
期刊：
影响因子：
2.7
通讯作者：
Cheung, YK
中科院分区：
文献类型：
--
作者：
Cheung, YK
本文在I期临床试验的背景下研究了剂量发现方法的一致性条件，其目的是估计未知剂量-毒性曲线的目标分位数。大多数I期方法是结果适应性的，因此根据先前的观察结果，为未来的患者增加或降低剂量。只有当之前的患者没有表现出毒性迹象时，新患者的病情升级才被认为是连贯的。同样，只有在刚刚看到有毒后果的情况下，缓和才是连贯的。出于试验中的伦理考虑，一致性条件被文献中的许多统计设计所满足，但不是通过对方法的一些常用修改来满足。这篇文章展示了违反一致性的例子，并讨论了如何应用一致性原则来校准两阶段设计和处理具有延迟毒性的情况。
This paper studies the coherence conditions of dose-finding methods in the context of phase I clinical trials, where the objective is to estimate a targeted quantile of the unknown dose-toxicity curve. Most phase I methods are outcome-adaptive, and thus escalate or de-escalate doses for future patients based on the previous observations. An escalation for a new patient is said to be coherent only when the previous patient does not show sign of toxicity. Likewise, a de-escalation is coherent only when a toxic outcome has just been seen. The coherence conditions, motivated by ethical concerns in trial conduct, are satisfied by many statistical designs in the literature, but not by some commonly used modifications of the methods. This paper shows examples in which coherence is violated, and discusses how the coherence principles may be applied to calibrate a two-stage design and to deal with situations with delayed toxicity.