Division of Translational Research & Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
Division of Translational Research & Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
Contemp Clin Trials. 2021 Sep;108:106517. doi: 10.1016/j.cct.2021.106517. Epub 2021 Jul 25.
Operating characteristics for proposed clinical trial designs provide insight into performance regarding safety and accuracy, allowing the study team and review entities to determine the design's suitability to achieve the study's proposed objectives. Advances in cancer therapeutics have augmented the needs of early phase clinical trial design. Additionally, advances in research on early-phase trial design have led to the availability of a wide range of methods that show vast improvement over outdated approaches.
Three trials utilizing variations of the 3 + 3 decision rule are discussed. The protocols lacked detail, including operating characteristics and guidance for decision-making that deviated from the 3 + 3 decision rule and MTD determination. We provide a discussion of the statistical issues associated with each design and operating characteristics for the proposed design compared to alternatives better suited to achieve the aims of each trial.
Our results illustrate how operating characteristics inform a design's safety and accuracy. Operating characteristics can unmask poor behavior, such as a high percentage of particiapnts exposed to overly toxic doses, a low probability of correctly identifying the MTD, and inappropriate early study termination.
Selection of early-phase trial design has significant implications on a trial's ability to meet its objectives. Operating characteristics are a necessary component in the design and review of a protocol, determining if the study's objectives can be achieved and documenting the study's scientific validity. Continued use of outdated approaches due to historical acceptance hinders scientific rigor and the effort to move effective agents through the drug development process.
拟议临床试验设计的操作特性可深入了解安全性和准确性方面的性能，使研究团队和审查实体能够确定设计是否适合实现研究的既定目标。癌症治疗的进步增加了早期临床试验设计的需求。此外，早期试验设计研究的进展导致了广泛的方法的出现，这些方法与过时的方法相比有了很大的改进。
讨论了三种利用 3+3 决策规则变化的试验。这些方案缺乏细节，包括操作特性和决策偏离 3+3 决策规则和 MTD 确定的指导。我们提供了与每个设计相关的统计问题的讨论，并与更适合实现每个试验目标的替代方案相比，提出了拟议设计的操作特性。
我们的结果说明了操作特性如何为设计的安全性和准确性提供信息。操作特性可以揭示不良行为，例如暴露于过度毒性剂量的参与者比例高、正确识别 MTD 的概率低以及不适当的早期研究终止。
早期试验设计的选择对试验实现其目标的能力有重大影响。操作特性是方案设计和审查的必要组成部分，决定了研究目标是否可以实现，并记录研究的科学有效性。由于历史上的接受，继续使用过时的方法会阻碍科学严谨性，并阻碍有效药物通过药物开发过程。
