Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov.
Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov.
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DOI：
10.1136/bmjopen-2017-018320
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发表时间：
2018-02-10
期刊：
影响因子：
2.9
通讯作者：
Kesselheim AS
中科院分区：
文献类型：
--
作者：
Bothwell LE;Avorn J;Khan NF;Kesselheim AS
本文综述了实施适应性设计临床试验的特点，并提供了此类试验的监管经验的例子。对EMBASE、PubMed、科克伦对照临床试验注册中心、Web of Science和ClinicalTrials. gov中的适应性设计临床试验进行审查。排除I期和无缝I/II期试验。从试验中提取的变量包括基本研究特征、适应性设计特征、独立数据监查委员会（DMC）的规模和使用以及盲法中期分析。我们还检查了适应性试验在向美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）提交的新药申请中的使用情况，并记录了监管机构在适应性设计方面的经验。142项研究符合纳入标准。最近，世界各地的研究人员公开报道使用自适应设计的情况有所增加。最常见的适应类型是无缝II/III期（57%）、组序贯（21%）、生物标志物适应性（20%）和适应性剂量探索设计（16%）。大约三分之一（32%）的试验报告了独立的DMC，而6%的试验报告了盲态中期分析。我们发现，9%的适应性试验用于FDA产品批准考虑，12%用于EMA产品批准考虑。国际监管机构在适应性试验方面的经验好坏参半。许多具有适应性试验的产品申请在药物申办者和监管机构之间就适应性设计进行了广泛的通信，在某些情况下，监管机构要求对研究设计进行修订或变更。适应性设计的广泛使用将需要新药申请申办者在试验的规划和实施过程中与监管科学家进行合作。研究者需要更一致地报告旨在保护机密性并最大限度地减少中期分析期间潜在操作偏倚的保护措施。
This review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials. Review of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs. 142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs. Wider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis.
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影响因子：
120.7
作者：
Dorsey, E. Ray;de Roulet, Jason;Moses, Hamilton, III
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