Embracing model-based designs for dose-finding trials

Journal article

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.

Conclusion
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 does-finding trials in academia.

Authors: Love, S; Brown, S; Weir, C; Harbron, C; Yap, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: British Journal of Cancer
• Volume: 117
• Issue: 3
• Pages: 332–339
• Publication date: 2017-06-29
• Acceptance date: 2017-05-04
• DOI: 10.1038/bjc.2017.186
• EISSN: 1532-1827
• ISSN: 0007-0920
• Keywords: CRM; model-based design; 3+3; phase I; dose-finding trials