Chen Yeh-Fong, Zhang Xiangmin, Tamura Roy N, Chen Chiung M
Division of Biometrics I, Office of Biostatistics, Office of Translational Sciences, Center of Drug Evaluation and Research (CDER), US Food and Drug Administration, Silver Spring, MD, U.S.A.
Stat Med. 2014 Jul 30;33(17):2953-67. doi: 10.1002/sim.6116.
High placebo response is widely believed to be one major reason why many psychiatric clinical trials fail to demonstrate drug efficacy. In order to alleviate this problem, research has developed several enrichment designs, including the parallel design with a placebo lead-in phase, the sequential parallel design, and a recently proposed two-way enriched design. While these designs have been evaluated and discussed individually, their effectiveness against each other has not been rigorously compared. The current study examines the various enrichment designs simultaneously. Building on their strengths, we introduce a new improved design named' sequential enriched design' (SED) aimed at removing not only patients with high placebo response but also patients who do not respond to any treatment from the study. The SED begins with a double-blind placebo lead-in phase followed by a traditional parallel design in the first stage. Only patients who respond to the drug in the first stage are re-randomized to the drug or placebo at the second stage. We simulate data for a mixed population composed of four subgroups of patients who are predetermined as to whether they respond to drug or not as well as to placebo or not. By focusing on the target patients whose responses reflect the drug's efficacy,we evaluate the bias, mean squared error, and power for different designs. We demonstrate that the SED produces a less biased estimate for the target treatment effect and yields reasonably high power in general compared with the other designs.
高安慰剂反应被广泛认为是许多精神科临床试验未能证明药物疗效的一个主要原因。为了缓解这一问题，研究人员开发了几种富集设计，包括带有安慰剂导入期的平行设计、序贯平行设计以及最近提出的双向富集设计。虽然这些设计已分别进行了评估和讨论，但它们相互之间的有效性尚未得到严格比较。当前的研究同时考察了各种富集设计。基于它们的优势，我们引入了一种名为“序贯富集设计”（SED）的新的改进设计，旨在不仅从研究中剔除高安慰剂反应的患者，还剔除对任何治疗均无反应的患者。SED开始于一个双盲安慰剂导入期，随后在第一阶段采用传统的平行设计。只有在第一阶段对药物有反应的患者才会在第二阶段被重新随机分组接受药物或安慰剂治疗。我们针对一个由四个患者亚组组成的混合人群模拟数据，这些亚组在对药物和安慰剂的反应方面是预先确定的。通过关注那些反应能反映药物疗效的目标患者，我们评估了不同设计的偏差、均方误差和检验效能。我们证明，与其他设计相比，SED对目标治疗效果的估计偏差较小，并且总体上产生相当高的检验效能。
