Bersimis S, Sachlas A, Papaioannou T
Department of Statistics & Insurance Science, University of Piraeus, Piraeus, Greece.
Stat Med. 2015 Jan 30;34(2):197-214. doi: 10.1002/sim.6317. Epub 2014 Oct 2.
The aim of phase II clinical trials is to determine whether an experimental treatment is sufficiently promising and safe to justify further testing. The need for reduced sample size arises naturally in phase II clinical trials owing to both technical and ethical reasons, motivating a significant part of research in the field during recent years, while another significant part of the research effort is aimed at more complex therapeutic schemes that demand the consideration of multiple endpoints to make decisions. In this paper, our attention is restricted to phase II clinical trials in which two treatments are compared with respect to two dependent dichotomous responses proposing some flexible designs. These designs permit the researcher to terminate the clinical trial when high rates of favorable or unfavorable outcomes are observed early enough requiring in this way a small number of patients. From the mathematical point of view, the proposed designs are defined on bivariate sequences of multi-state trials, and the corresponding stopping rules are based on various distributions related to the waiting time until a certain number of events appear in these sequences. The exact distributions of interest, under a unified framework, are studied using the Markov chain embedding technique, which appears to be very useful in clinical trials for the sample size determination. Tables of expected sample size and power are presented. The numerical illustration showed a very good performance for these new designs.
II期临床试验的目的是确定一种实验性治疗方法是否具有足够的前景和安全性，从而有理由进行进一步测试。由于技术和伦理原因，在II期临床试验中自然会出现减少样本量的需求，这推动了近年来该领域的大量研究，而另一部分重要的研究工作则针对更复杂的治疗方案，这些方案需要考虑多个终点来做出决策。在本文中，我们将注意力限制在II期临床试验上，在这类试验中，针对两个相关的二分反应比较两种治疗方法，并提出一些灵活的设计。这些设计允许研究人员在早期观察到高比例的有利或不利结果时终止临床试验，从而只需少量患者。从数学角度来看，所提出的设计是在多状态试验的二元序列上定义的，相应的停止规则基于与这些序列中出现一定数量事件之前的等待时间相关的各种分布。在一个统一的框架下，使用马尔可夫链嵌入技术研究了感兴趣的精确分布，该技术在临床试验中确定样本量时似乎非常有用。给出了预期样本量和检验效能的表格。数值例证表明这些新设计具有非常好的性能。
