Cheung Y K, Chappell R
Department of Statistics and Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin 53706, USA.
Biometrics. 2000 Dec;56(4):1177-82. doi: 10.1111/j.0006-341x.2000.01177.x.
Traditional designs for phase I clinical trials require each patient (or small group of patients) to be completely followed before the next patient or group is assigned. In situations such as when evaluating late-onset effects of radiation or toxicities from chemopreventive agents, this may result in trials of impractically long duration. We propose a new method, called the time-to-event continual reassessment method (TITE-CRM), that allows patients to be entered in a staggered fashion. It is an extension of the continual reassessment method (CRM; O'Quigley, Pepe, and Fisher, 1990, Biometrics 46, 33-48). We also note that this time-to-toxicity approach can be applied to extend other designs for studies of short-term toxicities. We prove that the recommended dose given by the TITE-CRM converges to the correct level under certain conditions. A simulation study shows our method's accuracy and safety are comparable with CRM's while the former takes a much shorter trial duration: a trial that would take up to 12 years to complete by the CRM could be reduced to 2-4 years by our method.
传统的I期临床试验设计要求在分配下一位患者或患者组之前，对每位患者（或一小群患者）进行完整的随访。在评估辐射的迟发效应或化学预防剂的毒性等情况下，这可能导致试验持续时间长得不切实际。我们提出了一种新方法，称为事件发生时间连续重新评估方法（TITE-CRM），该方法允许患者以交错方式入组。它是连续重新评估方法（CRM；O'Quigley、Pepe和Fisher，1990年，《生物统计学》46卷，33 - 48页）的扩展。我们还指出，这种针对毒性发生时间的方法可用于扩展其他短期毒性研究的设计。我们证明，在某些条件下，TITE-CRM给出的推荐剂量会收敛到正确水平。一项模拟研究表明，我们方法的准确性和安全性与CRM相当，而前者的试验持续时间要短得多：一项使用CRM需要长达12年才能完成的试验，采用我们的方法可缩短至2 - 4年。
