Jung Sin-Ho, Sargent Daniel J
a Department of Biostatistics and Bioinformatics , Duke University , Durham , North Carolina , USA.
J Biopharm Stat. 2014;24(4):802-16. doi: 10.1080/10543406.2014.901343.
Traditionally, Phase II trials have been conducted as single-arm trials to compare the response probabilities between an experimental therapy and a historical control. Historical control data, however, often have a small sample size, are collected from a different patient population, or use a different response assessment method, so that a direct comparison between a historical control and an experimental therapy may be severely biased. Randomized Phase II trials entering patients prospectively to both experimental and control arms have been proposed to avoid any bias in such cases. The small sample sizes for typical Phase II clinical trials imply that the use of exact statistical methods for their design and analysis is appropriate. In this article, we propose two-stage randomized Phase II trials based on Fisher's exact test, which does not require specification of the response probability of the control arm for testing. Through numerical studies, we observe that the proposed method controls the type I error accurately and maintains a high power. If we specify the response probabilities of the two arms under the alternative hypothesis, we can identify good randomized Phase II trial designs by adopting the Simon's minimax and optimal design concepts that were developed for single-arm Phase II trials.
传统上，II期试验一直作为单臂试验进行，以比较实验性疗法与历史对照之间的反应概率。然而，历史对照数据往往样本量较小，是从不同的患者群体中收集的，或者使用不同的反应评估方法，因此历史对照与实验性疗法之间的直接比较可能会存在严重偏差。为避免此类情况出现偏差，已有人提出进行随机II期试验，让患者前瞻性地进入实验组和对照组。典型II期临床试验的样本量较小，这意味着使用精确的统计方法进行设计和分析是合适的。在本文中，我们基于费舍尔精确检验提出了两阶段随机II期试验，该检验在进行测试时不需要指定对照组的反应概率。通过数值研究，我们观察到所提出的方法能够准确控制I型错误并保持较高的检验效能。如果我们在备择假设下指定两组的反应概率，那么通过采用为单臂II期试验开发的西蒙极小极大和最优设计概念，我们可以识别出良好的随机II期试验设计。
