Department of Medicine, University of Chicago, Chicago, IL 60637-1470, USA.
J Natl Cancer Inst. 2011 Jul 20;103(14):1093-100. doi: 10.1093/jnci/djr218. Epub 2011 Jun 27.
Given the multitude of novel anticancer drugs and the limited resources available to study them, phase II trials should identify drugs with the highest probability of succeeding in subsequent phase III trials. Currently, single-arm phase II trial results are interpreted relative to historical control subjects, introducing selection bias and confounding that may limit the validity of the conclusions. The rate of success (defined as a statistically significant difference between arms) in phase III oncology trials is only 40%, suggesting that current phase II trials are insufficiently informative. However, simulation studies suggest that randomized phase II trials would have lower error rates and greater predictive power for phase III results. Randomized phase II trials may also be more informative than single-arm phase II trials because of the hypotheses being tested, the variety of possible endpoints, and the opportunities for biomarker discovery. There are a wide variety of randomized phase II designs that can be used, including the randomized discontinuation design, the delayed-start design, adaptive (Bayesian) designs, selection designs, and phase II/III designs. The barriers to widespread adoption of randomized phase II trials include time to completion, sample size considerations, and ethical concerns, but none are insurmountable. We conclude that randomized phase II trials are a worthy investment considering finite patient and financial resources and should be the rule rather than the exception for evaluating novel therapies in oncology.
鉴于新型抗癌药物众多，而用于研究这些药物的资源有限，二期临床试验应确定最有可能在后续三期临床试验中取得成功的药物。目前，单臂二期临床试验结果相对于历史对照进行解读，引入了选择偏倚和混杂因素，可能限制结论的有效性。肿瘤学三期临床试验的成功率（定义为臂间具有统计学显著差异）仅为 40%，表明当前的二期临床试验信息量不足。然而，模拟研究表明，随机二期临床试验的错误率更低，对三期结果的预测能力更强。由于正在测试的假设、可能的终点的多样性以及生物标志物发现的机会，随机二期临床试验也可能比单臂二期临床试验更具信息量。有各种各样的随机二期设计可供使用，包括随机停药设计、延迟启动设计、适应性（贝叶斯）设计、选择设计和二期/三期设计。广泛采用随机二期临床试验的障碍包括完成时间、样本量考虑因素和伦理问题，但这些都不是不可逾越的。我们的结论是，考虑到有限的患者和财务资源，随机二期临床试验是一项值得的投资，应该成为评估肿瘤学新型疗法的常规做法，而不是例外。
