Cancer Research UK and UCL Cancer Trials Centre, University College London, 90 Tottenham Court Road, London, W1T 4TJ, UK.
MRC Biostatistics Unit Hub for Trials Methodology Research, University of Cambridge, Cambridge Institute of Public Health, Forvie Site, Robinson Way, Cambridge Biomedical Campus, Cambridge, CB2 0SR, UK.
BMC Med Res Methodol. 2019 Jan 18;19(1):18. doi: 10.1186/s12874-018-0638-z.
The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce.
To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM.
An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design.
The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.
持续评估法（CRM）是一种基于模型的 I 期临床试验设计方法，旨在找到新疗法的最大耐受剂量（MTD）。与传统的 3+3 设计等基于规则的方法相比，CRM 更能准确地确定 MTD，后者被用于大多数 I 期临床试验。此外，CRM 还比 3+3 设计在更接近 MTD 的剂量下分配了更多的试验参与者。然而，CRM 在临床研究中的采用速度却非常缓慢，使试验参与者、药物开发和患者面临风险。已经确定了增加 CRM 使用的障碍，最明显的是临床医生和统计学家缺乏如何在实践中应用新设计的知识。目前没有关于使用 CRM 进行剂量发现研究的临床医生的教程、指南或建议。此外，支持考虑将 CRM 用于其试验的临床医生的实用资源也很稀缺。
为了克服这些障碍，我们提出了一种使用 CRM 设计剂量发现研究的结构化框架。我们为关键设计参数提供建议，并建议进行试验前模拟工作，以使设计适应特定的试验。我们提供了支持临床医生和统计学家的实用工具，包括软件推荐，以及可编辑并插入试验方案的模板文本和表格。我们还提供了使用 CRM 进行和报告剂量发现研究的指南。
提供了一组初始设计建议来启动设计过程。为了补充这些建议和其他资源，我们描述了两个使用 CRM 的已发表的剂量发现试验。我们讨论了它们的设计、如何进行和分析，以及将它们与 3+3 设计下的情况进行比较。
我们提供的框架和资源面向新接触 CRM 设计的临床医生和统计学家。在这篇当代指导论文中提供关键资源有望提高 CRM 在 I 期剂量发现试验中的采用率。
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