Embracing model-based designs for dose-finding trials

Research output: Contribution to journalArticle

Authors

  • Sharon B Love
  • Sarah Brown
  • Christopher J Weir
  • Chris Harbron
  • Birgit Gaschler-Markefski
  • James Matcham
  • Louise Caffrey
  • Christopher McKevitt
  • Sally Clive
  • James Spicer
  • Victoria Cornelius

Colleges, School and Institutes

External organisations

  • Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, NDORMS, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7LD, UK.
  • University of Leeds
  • Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, UK.
  • Roche Pharmaceuticals, 6 Falcon Way, Shire Park, Welwyn Garden City AL7 1TW, UK.
  • Cancer Research UK Clinical Trials Unit, Institute of Cancer & Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
  • Boehringer Ingelheim Pharma GmbH &Co. KG, Biostatistics and Data Sciences, Birkendorfer Strasse 65, Biberach an der Riss 88400, Germany.
  • AstraZeneca, DaVinci Building, Melbourn Science Park, Royston SG8 6HB, UK.
  • School of Social Work and Social Policy, Trinity College Dublin, College Green, Dublin 2, Ireland.
  • King's College London
  • Edinburgh Cancer Centre, Western General Hospital, Edinburgh EX4 2XU, UK.
  • Division of Cancer Studies, Bermondsey Wing, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
  • Imperial College London

Abstract

BACKGROUND: Dose-finding trials are essential to drug development as they establish recommended doses for later-phase testing. We aim to motivate wider use of model-based designs for dose finding, such as the continual reassessment method (CRM).

METHODS: We carried out a literature review of dose-finding designs and conducted a survey to identify perceived barriers to their implementation.

RESULTS: We describe the benefits of model-based designs (flexibility, superior operating characteristics, extended scope), their current uptake, and existing resources. The most prominent barriers to implementation of a model-based design were lack of suitable training, chief investigators' preference for algorithm-based designs (e.g., 3+3), and limited resources for study design before funding. We use a real-world example to illustrate how these barriers can be overcome.

CONCLUSIONS: There is overwhelming evidence for the benefits of CRM. Many leading pharmaceutical companies routinely implement model-based designs. Our analysis identified barriers for academic statisticians and clinical academics in mirroring the progress industry has made in trial design. Unified support from funders, regulators, and journal editors could result in more accurate doses for later-phase testing, and increase the efficiency and success of clinical drug development. We give recommendations for increasing the uptake of model-based designs for dose-finding trials in academia.

Details

Original languageEnglish
Pages (from-to)332-339
Number of pages8
JournalBritish Journal of Cancer
Volume117
Issue number3
Early online date29 Jun 2017
Publication statusPublished - 25 Jul 2017

Keywords

  • model-based design, dose-finding trials, phase I, CRM, 3+3