New designs for phase 2 clinical trials
New designs for phase 2 clinical trials
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DOI：
10.1182/blood-2002-09-2937
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发表时间：
2003-07-15
期刊：
影响因子：
20.3
通讯作者：
Thall, PF
中科院分区：
文献类型：
--
作者：
Estey, EH;Thall, PF
传统的2期临床试验通常是单臂实验，其结果特征在于一个二元“反应”变量。临床研究者很难用这种传统的方法。我们认为，2期试验本质上是比较性的，比较的结果决定了是否进行随后的3期试验。当在单独的单组试验中研究不同的治疗时，与治疗相关的应答率之间的实际差异（“治疗效应”）与试验之间的差异（“试验效应”）混淆。“因此，不可能分别估计这两种影响。因此，当比较不同治疗的单独单组试验的结果时，明显的治疗差异可能是由于试验效应。相反，治疗效果的明显缺乏可能是由于实际治疗效果被试验效果抵消。由于选择涉及比较，因此单臂II期试验无法提供可靠的方法来选择III期研究的治疗。此外，将复杂的临床现象（包括不良事件和期望事件）简化为单一结果浪费了重要信息。因此，传统的阶段2设计是低效和不可靠的。鉴于可用于II期试验的患者数量有限，并且必须评估的新疗法数量不断增加，因此有效地进行这些试验至关重要。这些问题促使随机选择试验的一般范式的发展，评价基于多种结局的几种疗法。三个说明性的应用程序使用这种方法的审判。(C)2003年，美国血液学会。
Conventional phase 2 clinical trials are typically single-arm experiments, with outcome characterized by one binary "response" variable. Clinical investigators are poorly served by such conventional methodology. We contend that phase 2 trials are inherently comparative, with the results of the comparison determining whether to conduct a subsequent phase 3 trial. When different treatments are studied in separate single-arm trials, actual differences between response rates associated with the treatments, "treatment effects," are confounded with differences between the trials, "trial effects." Thus, it is impossible to estimate either effect separately. Consequently, when the results of separate single-arm trials of different treatments are compared, an apparent treatment difference may be due to a trial effect. Conversely, the apparent absence of a treatment effect may be due to an actual treatment effect being cancelled out by a trial effect. Because selection involves comparison, single-arm phase 2 trials thus fail to provide a reliable means for selecting which therapies to investigate in phase 3. Moreover, reducing complex clinical phenomena, including both adverse and desirable events, to a single outcome wastes important information. Consequently, conventional phase 2 designs are inefficient and unreliable. Given the limited number of patients available for phase 2 trials and the increasing number of new therapies that must be evaluated, it is critically important to conduct these trials efficiently. These concerns motivated the development of a general paradigm for randomized selection trials evaluating several therapies based on multiple outcomes. Three illustrative applications of trials using this approach are presented. (C) 2003 by The American Society of Hematology.