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BMC Medical Research Methodology
Published in: BMC Medical Research Methodology 1/2019

Open Access 01-12-2019 | Technical advance

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

Authors: 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

Published in: BMC Medical Research Methodology | Issue 1/2019

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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.
Appendix
Available only for authorised users
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Metadata
Title
How to design a dose-finding study using the continual reassessment method
Authors
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
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Medical Research Methodology / Issue 1/2019
Electronic ISSN: 1471-2288
DOI
https://doi.org/10.1186/s12874-018-0638-z

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