Embracing model-based designs for dose-finding trials

作者：Love Sharon B^*; Brown Sarah; Weir Christopher J; Harbron Chris; Yap Christina; Gaschler Markefski Birgit; Matcham James; Caffrey Louise; McKevitt Christopher; Clive Sally; Craddock Charlie; Spicer James; Cornelius Victoria

来源：British Journal of Cancer, 2017, 117(3): 332-339.

DOI：10.1038/bjc.2017.186

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

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.

• 出版日期2017-7-25