The Impact of Early-Phase Trial Design in the Drug Development Process.
The Impact of Early-Phase Trial Design in the Drug Development Process.
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DOI：
10.1158/1078-0432.ccr-18-0203
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发表时间：
2019-01-15
期刊：
影响因子：
--
通讯作者：
Petroni GR
中科院分区：
文献类型：
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作者：
Conaway MR;Petroni GR
目前正在使用的许多治疗药物都是使用3+3决策规则进行剂量确定的。在过去的30年里，已经提出并评估了几种剂量探索设计，包括“连续再评估方法”（CRM）和“贝叶斯最优区间设计”（BOIN）。本研究调查了早期设计的选择对进入药物开发管道的药物将有两个成功的III期试验的可能性的作用。使用模拟，在药物开发过程中，从最初的剂量发现到两个验证性III期试验，对假设药物人群中的每种药物进行了跟踪。通过改变I、II和III期试验的设计，可以评估设计选择对III期试验成功的药物比例的影响。结果表明，使用CRM或BOIN而不是3+3大大提高了成功进行III期试验的有效药物的比例，其中CRM的效果大于BOIN。更大规模的II期试验放大了I期设计的效果。结果强调了早期设计选择的重要性。与CRM或BOIN相比，使用3+3导致成功进行III期试验的药物较少。这种差异在高效药剂中更为明显。此外，结果显示了充分把握度的II期试验的重要性。
Many of the therapeutic agents that are being used currently were developed using the 3+3 decision rule for dose-finding. Over the past 30 years, several dose-finding designs have been proposed and evaluated, including the ‘continual reassessment method’ (CRM) and the ‘Bayesian optimal interval design’ (BOIN). This research investigates the role of the choice of an early phase design on the likelihood that drugs entering the drug development pipeline will have two successful phase III trials. Using simulation, each agent in a population of hypothetical agents was tracked through the drug development process, from initial dose-finding to two confirmatory phase III trials. Varying the designs of the phase I, II, and III trials allows for an assessment of the effect of the choice of designs on the proportion of agents with successful phase III trials. The results indicate that using the CRM or BOIN, rather than the 3+3 substantially enhances the proportion of effective agents that have successful phase III trials, with the CRM having a greater effect than BOIN. A larger phase II trial magnifies the effect of the phase I design. The results underscore the importance of the choice of the early phase designs. Use of the 3+3 results in fewer agents with successful phase III trials compared to the CRM or BOIN. The difference is more pronounced among highly effective agents. In addition, the results show the importance of a sufficiently powered phase II trial.