Advanced methods for dose and regimen finding during drug development: Summary of the EMA /EFPIA workshop on dose finding (London 4-5 December 2014)

Flora T Musuamba, Efthymios Manolis, Nick Holford, S. Y. Amy Cheung, Lena Friberg, Kayode Ogungbenro, Martin Posch, James Yates, Scott Berry, Neal Thomas, Solange Corriol-Rohou, Björn Bornkamp, Frank Bretz, Andrew C Hooker, Piet H. Van Der Graaf, Joseph Standing, Justin Pittaway-Hay, Susan Cole, Valeria Gigante, Kristin KarlssonThomas Dumortier, Norbert Benda, Francesca Serone, Shampa Das, Anne Brochot, Ehmann Falk, Rob Hemmings, Ine Skottheim Rusten

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Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late stage attritions in clinical development and post marketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, EMA in collaboration with EFPIA hosted a multi-stakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include 5 advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod and model averaging) and 3 methods for study design optimization (FIM based methods, clinical trial simulations and adaptive studies). Pairwise comparisons were also discussed during the workshop, however mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for Phase 3 is an estimation problem and should not be addressed via hypothesis testing. Dose selection for Phase 3 trials should be informed by well designed dose finding studies, however the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.
Original languageEnglish
JournalClinical Pharmacology & Therapeutics
Issue number7
Publication statusPublished - 19 Jul 2017


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