Rogatko André, Schoeneck David, Jonas William, Tighiouart Mourad, Khuri Fadlo R, Porter Alan
Winship Cancer Institute at Emory University, Atlanta, GA 30322, USA.
J Clin Oncol. 2007 Nov 1;25(31):4982-6. doi: 10.1200/JCO.2007.12.1012.
Phase I clinical trials of new anticancer therapies determine suitable doses for further testing. Optimization of their design is vital in that they enroll cancer patients whose well-being is distinctly at risk. This study examines the effectiveness of knowledge transfer about more effective statistical designs to clinical practice.
We examined abstract records of cancer phase I trials from the Science Citation Index database between 1991 and 2006 and classified them into clinical (dose-finding trials) and statistical trials (methodologic studies of dose-escalation designs). We then mapped these two sets by tracking which trials adopted new statistical designs.
One thousand two hundred thirty-five clinical and 90 statistical studies were identified. Only 1.6% of the phase I cancer trials (20 of 1,235 trials) followed a design proposed in one of the statistical studies. These 20 clinical studies showed extensive lags between publication of the statistical paper and its translation into a clinical paper. These 20 clinical trials followed Bayesian adaptive designs. The remainder used variations of the standard up-and-down method.
A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. Simulation studies have shown that up-and-down designs treated only 35% of patients at optimal dose levels versus 55% for Bayesian adaptive designs. This implies needless loss of treatment efficacy and, possibly, lives. We suggest that regulatory agencies (eg, US Food and Drug Administration) should proactively encourage the adoption of statistical designs that would allow more patients to be treated at near-optimal doses while controlling for excessive toxicity.
新型抗癌疗法的I期临床试验旨在确定适合进一步试验的剂量。优化试验设计至关重要，因为参与试验的癌症患者的健康明显面临风险。本研究考察了将更有效的统计设计相关知识传授到临床实践中的效果。
我们查阅了科学引文索引数据库1991年至2006年间癌症I期试验的摘要记录，并将其分为临床（剂量探索试验）和统计试验（剂量递增设计的方法学研究）。然后，通过追踪哪些试验采用了新的统计设计，对这两组试验进行映射分析。
共识别出1235项临床研究和90项统计研究。只有1.6%的I期癌症试验（1235项试验中的20项）采用了统计研究中提出的设计。这20项临床研究表明，统计论文发表与其转化为临床论文之间存在很长的时间间隔。这二十项临床试验采用了贝叶斯适应性设计。其余试验采用了标准上下法的变体。
使用效果较差的设计的一个后果是，更多患者接受了超出治疗窗的剂量治疗。模拟研究表明，上下法仅使35%的患者接受最佳剂量水平的治疗，而贝叶斯适应性设计为55%。这意味着治疗效果的不必要损失，甚至可能是生命损失。我们建议监管机构（如美国食品药品监督管理局）应积极鼓励采用统计设计，以便在控制过度毒性的同时，让更多患者接受接近最佳剂量的治疗。
