Moving Beyond 3+3: The Future of Clinical Trial Design.
Moving Beyond 3+3: The Future of Clinical Trial Design.
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DOI：
10.1200/edbk_319783
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发表时间：
2021-06-01
期刊：
影响因子：
--
通讯作者：
Hong, David S
中科院分区：
文献类型：
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作者：
Kurzrock, Razelle;Lin, Chia-Chi;Hong, David S
对规范的3+3剂量递增I期临床试验设计的操作特征提出了疑虑。然而，传统的3+3设计仍然是最常用的。尽管已经暗示坚持这种设计是由于顽固地不愿意采用变化，尽管其他设计在假设的计算机生成的模拟模型中表现更好，但继续坚持3+3剂量递增I期策略更有可能，因为这些设计在真实的世界中表现最好，以可接受的精度精确定位正确的剂量和重要的副作用。除了统计模拟之外，几乎没有数据可以反驳3+3方法的假定缺点。即便如此，为了解决基因和免疫靶向化合物的独特细微差别，已经提出了各种发明性的1期试验设计。开发这些疗法的策略已经启动了首次人体研究，旨在获得远远超过典型I期设计规模的广泛患者数据，并模糊剂量选择和疗效评估之间的区别。最近有希望的癌症治疗的I期试验评估了各种剂量和时间表的客观肿瘤反应和持久性，并纳入了跨越各种组织学或生物标志物定义的肿瘤亚型的多个扩展队列，有时导致美国食品和药物管理局在I期后批准。本文从多个利益相关者的角度回顾了I期设计的最新创新，并为未来的试验提供了建议。
Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.