How to design a dose-finding study using the continual reassessment method
Abstract Introduction 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 des...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | BMC Medical Research Methodology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12874-018-0638-z |
| _version_ | 1818287196439838720 |
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| author | Graham M. Wheeler Adrian P. Mander Alun Bedding Kristian Brock Victoria Cornelius Andrew P. Grieve Thomas Jaki Sharon B. Love Lang’o Odondi Christopher J. Weir Christina Yap Simon J. Bond |
| author_facet | Graham M. Wheeler Adrian P. Mander Alun Bedding Kristian Brock Victoria Cornelius Andrew P. Grieve Thomas Jaki Sharon B. Love Lang’o Odondi Christopher J. Weir Christina Yap Simon J. Bond |
| author_sort | Graham M. Wheeler |
| collection | DOAJ |
| description | Abstract Introduction 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-13T01:36:39Z |
| format | Article |
| id | doaj.art-51facf067584416fafcc8f930ffd8346 |
| institution | Directory Open Access Journal |
| issn | 1471-2288 |
| language | English |
| last_indexed | 2024-12-13T01:36:39Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Research Methodology |
| spelling | doaj.art-51facf067584416fafcc8f930ffd83462022-12-22T00:03:53ZengBMCBMC Medical Research Methodology1471-22882019-01-0119111510.1186/s12874-018-0638-zHow to design a dose-finding study using the continual reassessment methodGraham M. Wheeler0Adrian P. Mander1Alun Bedding2Kristian Brock3Victoria Cornelius4Andrew P. Grieve5Thomas Jaki6Sharon B. Love7Lang’o Odondi8Christopher J. Weir9Christina Yap10Simon J. Bond11Cancer Research UK and UCL Cancer Trials Centre, University College LondonMRC Biostatistics Unit Hub for Trials Methodology Research, University of Cambridge, Cambridge Institute of Public HealthRoche PharmaceuticalsCancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of BirminghamSchool of Public Health, Imperial College LondonUCB Pharmaceuticals LtdDepartment of Mathematics and Statistics, Fylde College, Lancaster UniversityOxford Clinical Trials Research Unit, Centre for Statistics in Medicine, NDORMS, University of Oxford, Botnar Research CentreOxford Clinical Trials Research Unit, Centre for Statistics in Medicine, NDORMS, University of Oxford, Botnar Research CentreEdinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences, University of EdinburghCancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, University of BirminghamMRC Biostatistics Unit Hub for Trials Methodology Research, University of Cambridge, Cambridge Institute of Public HealthAbstract Introduction 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s12874-018-0638-zAdaptive designsContinual reassessment methodDose escalationDose-findingMaximum tolerated dosePhase I trials |
| spellingShingle | Graham M. Wheeler Adrian P. Mander Alun Bedding Kristian Brock Victoria Cornelius Andrew P. Grieve Thomas Jaki Sharon B. Love Lang’o Odondi Christopher J. Weir Christina Yap Simon J. Bond How to design a dose-finding study using the continual reassessment method BMC Medical Research Methodology Adaptive designs Continual reassessment method Dose escalation Dose-finding Maximum tolerated dose Phase I trials |
| title | How to design a dose-finding study using the continual reassessment method |
| title_full | How to design a dose-finding study using the continual reassessment method |
| title_fullStr | How to design a dose-finding study using the continual reassessment method |
| title_full_unstemmed | How to design a dose-finding study using the continual reassessment method |
| title_short | How to design a dose-finding study using the continual reassessment method |
| title_sort | how to design a dose finding study using the continual reassessment method |
| topic | Adaptive designs Continual reassessment method Dose escalation Dose-finding Maximum tolerated dose Phase I trials |
| url | http://link.springer.com/article/10.1186/s12874-018-0638-z |
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