Abstract
BackgroundModern designs for dose-finding studies (e.g., model-based designs such as continual reassessment method) have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design. However, implementing such designs requires time and specialist knowledge.MethodsWe present a practical approach to developing a model-based design to help support uptake of these methods; in particular, we lay out how to derive the necessary parameters and who should input, and when, to these decisions. Designing a model-based, dose-finding trial is demonstrated using a treatment within the AGILE platform trial, a phase I/II adaptive design for novel COVID-19 treatments.ResultsWe present discussion of the practical delivery of AGILE, covering what information was found to support principled decision making by the Safety Review Committee, and what could be contained within a statistical analysis plan. We also discuss additional challenges we encountered in the study and discuss more generally what (unplanned) adaptations may be acceptable (or not) in studies using model-based designs.ConclusionsThis example demonstrates both how to design and deliver an adaptive dose-finding trial in order to support uptake of these methods.
Highlights
IntroductionModern designs for dose-finding studies (e.g., model-based designs such as continual reassessment method) have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design
Modern designs for dose-finding studies have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design
The setting for this paper is the AGILE platform trial [20], which seeks to find a safe dose range and preliminary efficacy testing for a number of potential treatments for COVID-19; in particular, we focus on one of the treatments (Molnupiravir) undergoing testing in AGILE
Summary
Modern designs for dose-finding studies (e.g., model-based designs such as continual reassessment method) have been shown to substantially improve the ability to determine a suitable dose for efficacy testing when compared to traditional designs such as the 3 + 3 design. Implementing such designs requires time and specialist knowledge. A rich literature [1,2,3] exists highlighting the benefits of model-based [4,5,6], model-assistant [7, 8] and curve-free approaches [9, 10] over traditional, simple rule-based methods (such as the 3 + 3 design) for recommending a dose for efficacy testing. The uptake of these new methods has been slow [11] and several obstacles to their use have been
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