How to design a dose-finding study using the continual reassessment method

Research output: Contribution to journalArticle

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How to design a dose-finding study using the continual reassessment method. / Wheeler, Graham M; Mander, Adrian P; Bedding, Alun W; Brock, Kristian; Cornelius, Victoria; Grieve, Andrew; Jaki, Thomas; Love, Sharon B; Odondi, Lang'o; Weir, Christopher J; Yap, Christina; Bond, Simon J.

In: BMC Medical Research Methodology, Vol. 19, No. 1, 18, 18.01.2019.

Research output: Contribution to journalArticle

Harvard

Wheeler, GM, Mander, AP, Bedding, AW, Brock, K, Cornelius, V, Grieve, A, Jaki, T, Love, SB, Odondi, L, Weir, CJ, Yap, C & Bond, SJ 2019, 'How to design a dose-finding study using the continual reassessment method', BMC Medical Research Methodology, vol. 19, no. 1, 18. https://doi.org/10.1186/s12874-018-0638-z

APA

Wheeler, G. M., Mander, A. P., Bedding, A. W., Brock, K., Cornelius, V., Grieve, A., Jaki, T., Love, S. B., Odondi, L., Weir, C. J., Yap, C., & Bond, S. J. (2019). How to design a dose-finding study using the continual reassessment method. BMC Medical Research Methodology, 19(1), [18]. https://doi.org/10.1186/s12874-018-0638-z

Vancouver

Author

Wheeler, Graham M ; Mander, Adrian P ; Bedding, Alun W ; Brock, Kristian ; Cornelius, Victoria ; Grieve, Andrew ; Jaki, Thomas ; Love, Sharon B ; Odondi, Lang'o ; Weir, Christopher J ; Yap, Christina ; Bond, Simon J. / How to design a dose-finding study using the continual reassessment method. In: BMC Medical Research Methodology. 2019 ; Vol. 19, No. 1.

Bibtex

@article{9dd99fb2400846d997c81fcc0d019440,
title = "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 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.",
keywords = "Adaptive designs, Continual reassessment method, Dose escalation, Dose-finding, Maximum tolerated dose, Phase I trials",
author = "Wheeler, {Graham M} and Mander, {Adrian P} and Bedding, {Alun W} and Kristian Brock and Victoria Cornelius and Andrew Grieve and Thomas Jaki and Love, {Sharon B} and Lang'o Odondi and Weir, {Christopher J} and Christina Yap and Bond, {Simon J}",
year = "2019",
month = jan,
day = "18",
doi = "10.1186/s12874-018-0638-z",
language = "English",
volume = "19",
journal = "BMC Medical Research Methodology",
issn = "1471-2288",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

T1 - How to design a dose-finding study using the continual reassessment method

AU - Wheeler, Graham M

AU - Mander, Adrian P

AU - Bedding, Alun W

AU - Brock, Kristian

AU - Cornelius, Victoria

AU - Grieve, Andrew

AU - Jaki, Thomas

AU - Love, Sharon B

AU - Odondi, Lang'o

AU - Weir, Christopher J

AU - Yap, Christina

AU - Bond, Simon J

PY - 2019/1/18

Y1 - 2019/1/18

N2 - 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.

AB - 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.

KW - Adaptive designs

KW - Continual reassessment method

KW - Dose escalation

KW - Dose-finding

KW - Maximum tolerated dose

KW - Phase I trials

UR - http://www.scopus.com/inward/record.url?scp=85060127979&partnerID=8YFLogxK

U2 - 10.1186/s12874-018-0638-z

DO - 10.1186/s12874-018-0638-z

M3 - Article

C2 - 30658575

AN - SCOPUS:85060127979

VL - 19

JO - BMC Medical Research Methodology

JF - BMC Medical Research Methodology

SN - 1471-2288

IS - 1

M1 - 18

ER -