Sankoh Abdul J
Vertex Pharmaceuticals, Cambridge, MA 02139, USA.
Stat Med. 2008 Aug 30;27(19):3732-42. doi: 10.1002/sim.3256.
Compared with placebo-control clinical trials, the interpretation of efficacy results from active-control trials requires more caution. This is because efficacy results from such trials cannot be reliably interpreted without a thorough understanding of the efficacy evidence that formed the basis for the approval of the active control, especially when such drug efficacy is to be established on the basis of clinical evidence from the traditional two-arm active-control clinical equivalence studies as opposed to the multi-arm active control. This is because in addition to over-reliance on the quantification of a clinically irrelevant acceptable margin of inferiority from historical data, such interpretation also depends on cross-trial inference for demonstration of experimental drug effect. We provide a brief overview of some design issues with the traditional two-arm active-control clinical trial and discuss regulators' concern regarding Type I error rate control (with the two most popular methods for the quantification of the non-inferiority margin) in cross-trial demonstration of experimental drug effect. Simulation results are presented to show that the point estimate method provides adequate control of the Type I error rate with > or =75 per cent retention of known active-control effect and that the confidence interval approach is uniformly ultra-conservative. We also report (via a numerical example from real clinical trial data) a couple of potentially less stringent alternative approaches for establishing the non-inferiority of a test drug over a control, which have been used in the past to provide additional efficacy evidence in NDA submission.
与安慰剂对照临床试验相比，对活性对照试验的疗效结果进行解读需要更加谨慎。这是因为，如果没有透彻理解构成活性对照获批依据的疗效证据，就无法可靠地解读此类试验的疗效结果，尤其是当这种药物疗效要基于传统双臂活性对照临床等效性研究的临床证据而非多臂活性对照来确立时。这是因为，除了过度依赖从历史数据中量化临床上无关紧要的可接受劣势边际外，这种解读还依赖于跨试验推断来证明试验药物的效果。我们简要概述了传统双臂活性对照临床试验的一些设计问题，并讨论了监管机构在跨试验证明试验药物效果时对I型错误率控制的关注（以及两种最常用的量化非劣效性边际的方法）。给出的模拟结果表明，点估计法在已知活性对照效果保留率≥75%时能充分控制I型错误率，而置信区间法始终过于保守。我们还报告了（通过一个来自真实临床试验数据的数值示例）几种过去曾用于在新药申请中提供额外疗效证据的、用于确立试验药物相对于对照非劣效性的潜在不那么严格的替代方法。
