论文标题

多臂临床试验中的最佳患者分配

Optimal Patient Allocation in Multi-Arm Clinical Trials

论文作者

Law, Martin

论文摘要

多ARM多阶段试验是一项多ARM试验,其中包括临时分析 - 在某些指定点分析数据,通常停止使用的治疗方法,这些治疗方法是不起作用的,并继续进行剩余的处理。 通过考虑分配比率R:对于R:1分配比率,将多臂试验比单臂试验的优势进一步增强,RN患者被分配给对照组,并分配给每个主动治疗组的患者。在这项研究中,最佳分配比率将定义为分配比率,该分配比率最小,总样本量满足某些必需的功率和I型误差的可能性。在临床试验的背景下,这是一个直观的定义,因为一般而言,较小的试验将比满足相同错误率的较大的试验更具道德和便宜。本文的目的是研究在多个主动治疗组的情况下,最佳分配比率。 在第2节中描述了具有K主动治疗臂的单阶段试验的设置,并简要介绍了Dunnett在这种情况下关于最佳分配比率的声明。 I型误差和功率的方程是得出的,并描述了如何使用分配比例来研究如何最小化总样本量的方法。然后,使用相同的方法考虑了两阶段试验。图和表显示了第3节中给出了一系列I型误差和功率值的总样本量随分配比的变化(包括I型错误和功率值)。在第3节中还包括了更改分配比率(包括简单示例)的道德和财务收益。结果以及实际上含义的实践意义在第4节中。

A multi-arm multi-stage trial is a multi-arm trial which includes interim analyses - analysing the data at certain specified points, generally discontinuing treatments which are concluded to not work and proceeding with the remainder. It is possible that the advantages of multi-arm trials over single-arm trials may be enhanced further by considering the allocation ratio, R. For an R:1 allocation ratio, Rn patients are allocated to the control arm and n patients allocated to each active treatment arm. In this study, the optimal allocation ratio will be defined as the allocation ratio which results in the smallest total sample size satisfying some required power and probability of type I error. This is an intuitive definition in the context of clinical trials, as a smaller trial will in general be more ethical and less expensive than a larger one satisfying the same error rates. The purpose of this paper is to investigate the optimal allocation ratio in the case of multiple active treatment arms. The setup for a single stage trial with K active treatment arms is described in Section 2, along with a brief exposition of Dunnett's statement regarding the optimal allocation ratio in such circumstances. Equations for type I error and power are derived, and the methodology used to investigate how total sample size may be minimised using allocation ratio is described. A two-stage trial is then considered, using the same methodology. Figures and tables showing how total sample size changes with allocation ratio, for a range of type I error and power values, are given in Section 3. The possible ethical and financial benefits of changing allocation ratio, including a simple example, is also included in Section 3. The results, and what they could mean in practical terms, are discussed in Section 4.

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