期刊
BMC MEDICAL RESEARCH METHODOLOGY
卷 19, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12874-018-0638-z
关键词
Adaptive designs; Continual reassessment method; Dose escalation; Dose-finding; Maximum tolerated dose; Phase I trials
资金
- MRC Network of Hubs for Trials Methodology Research [MR/L004933/1-R/N/P/B1]
- Cancer Research UK
- Medical Research Council [MC_UP_1302/2]
- Senior Research Fellowship - National Institute for Health Research [NIHR-SRF-2015-08-001]
- Cancer Research UK [C5529/A16895, C22436/A15958]
- NHS Lothian via the Edinburgh Clinical Trials Unit
- NIHR Office for Clinical Research Infrastructure (NOCRI)
- MRC [MC_UP_1302/2, MR/L004933/2, MR/L004933/1] Funding Source: UKRI
IntroductionThe 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.MethodsTo 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.ResultsAn 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.ConclusionsThe 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.
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