Adaptive patient enrichment designs in therapeutic trials
Adaptive patient enrichment designs in therapeutic trials
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DOI：
10.1002/bimj.200900003
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发表时间：
2009-04-01
影响因子：
1.7
通讯作者：
O'Neill, Robert T.
中科院分区：
文献类型：
--
作者：
Wang, Sue-Jane;Hung, H. M. James;O'Neill, Robert T.
在一个充分且良好对照的试验环境中，对具有适应性患者富集的临床试验设计的效用进行了研究。总体治疗效果是原计划的整个研究人群的互斥子集中治疗效果的加权平均值。适应性富集方法允许评估由于患者特征的异质性和/或对治疗的不同反应而可能适用于特定嵌套患者（子）集的治疗效果，例如在所有研究的患者（子）集中，有反应的患者子集与无受益的患者子集。所考虑的适应性富集方法包括三种适应性设计方案：（i）总样本量固定且有无效性终止，（ii）样本量调整且有无效性终止，以及（iii）样本量调整但无无效性终止。我们表明，无论最终评估的治疗效果是适用于最初研究的患者人群还是仅适用于嵌套的患者子集，都有可能设计出一种在统计学上优于一刀切的固定设计方法以及具有预先指定的多重检验程序的固定设计的适应性富集方法。我们强调需要进行额外的研究来重复在富集患者子集中治疗效果的发现。由于确定的治疗效果大小大于稀释后的总体效果大小，重复研究可能需要较少的患者数量。在适用的情况下，适应性设计符合药物开发项目中的效率考虑。
The utility of clinical trial designs with adaptive patient enrichment is investigated in an adequate and well-controlled trial setting. The overall treatment effect is the weighted average of the treatment effects in the mutually exclusive subsets of the originally intended entire study population. The adaptive enrichment approaches permit assessment of treatment effect that may be applicable to specific nested patient (sub)sets due to heterogeneous patient characteristics and/or differential response to treatment, e.g. a responsive patient subset versus a lack of beneficial patient subset, in all patient (sub)sets studied. The adaptive enrichment approaches considered include three adaptive design scenarios: (i) total sample size fixed and with futility stopping, (ii) sample size adaptation and futility stopping, and (iii) sample size adaptation without futility stopping. We show that regardless of whether the treatment effect eventually assessed is applicable to the originally studied patient population or only to the nested patient subsets; it is possible to devise an adaptive enrichment approach that statistically outperforms one-size-fits-all fixed design approach and the fixed design with a pre-specified multiple test procedure. We emphasize the need of additional studies to replicate the finding of a treatment effect in an enriched patient subset. The replication studies are likely to need fewer number of patients because of an identified treatment effect size that is larger than the diluted overall effect size. The adaptive designs, when applicable, are along the line of efficiency consideration in a drug development program.