Improving safety of the continual reassessment method via a modified allocation rule
Improving safety of the continual reassessment method via a modified allocation rule
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DOI：
10.1002/sim.8450
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发表时间：
2019-12-20
影响因子：
2
通讯作者：
Jaki, Thomas
中科院分区：
文献类型：
--
作者：
Mozgunov, Pavel;Jaki, Thomas
本文提出了一种新的标准，用于分配患者在I期剂量递增临床试验，旨在找到最大耐受剂量（MTD）。通常，使用基于模型的方法，将下一个患者分配到毒性估计值最接近（就绝对或平方距离而言）最大可接受毒性的剂量。然而，这种方法忽略了点估计的不确定性和将大量患者分配给过度毒性剂量的伦理问题。事实上，平衡MTD估计的准确性和有多少患者会发生不良事件之间的权衡是I期研究的主要挑战之一。出于最近的讨论在理论上的估计在限制参数空间，我们提出了一个标准，允许明确地平衡这些。该标准只需要一个附加参数的规格，具有简单直观的解释。我们将建议的标准纳入单参数贝叶斯连续重新评估方法，并使用模拟，它可以导致类似的准确性平均为原始设计，但平均毒性反应较少。与其他基于模型的剂量递增设计（如采用过量控制的剂量递增及其修改）的比较表明，拟议的设计可以获得与替代品相同的平均准确度，但毒性反应较少，或者平均准确度较高，但毒性反应数量相同。因此，所提出的设计可以在准确性和发生不良事件的患者数量之间提供更好的权衡，使该设计成为I期试验中一些现有方法的更符合伦理的替代方案。
This article proposes a novel criterion for the allocation of patients in phase I dose-escalation clinical trials, aiming to find the maximum tolerated dose (MTD). Conventionally, using a model-based approach, the next patient is allocated to the dose with the toxicity estimate closest (in terms of the absolute or squared distance) to the maximum acceptable toxicity. This approach, however, ignores the uncertainty in point estimates and ethical concerns of assigning a lot of patients to overly toxic doses. In fact, balancing the trade-off between how accurately the MTD can be estimated and how many patients would experience adverse events is one of the primary challenges in phase I studies. Motivated by recent discussions in the theory of estimation in restricted parameter spaces, we propose a criterion that allows to balance these explicitly. The criterion requires a specification of one additional parameter only that has a simple and intuitive interpretation. We incorporate the proposed criterion into the one-parameter Bayesian continual reassessment method and show, using simulations, that it can result in similar accuracy on average as the original design, but with fewer toxic responses on average. A comparison with other model-based dose-escalation designs, such as escalation with overdose control and its modifications, demonstrates that the proposed design can result in either the same mean accuracy as alternatives but fewer toxic responses or in a higher mean accuracy but the same number of toxic responses. Therefore, the proposed design can provide a better trade-off between the accuracy and the number of patients experiencing adverse events, making the design a more ethical alternative over some of the existing methods for phase I trials.