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Advanced Methods for Dose and Regimen Finding During Drug Development: Summary of the EMA/EFPIA Workshop on Dose Finding (London 4-5 December 2014)
EMA Modelling & Simulat Working Grp, London, England.;Fed Agcy Med & Hlth Prod, Brussels, Belgium.;Univ Limoges, INSERM, UMR850, Limoges, France..
EMA Modelling & Simulat Working Grp, London, England.;European Med Agcy, London, England..
Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland, New Zealand..
AstraZeneca UK Ltd, London, England..
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2017 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, no 7, 418-429 p.Article in journal (Refereed) Published
Abstract [en]

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 postmarketing 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, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder 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 five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (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 III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dosefinding 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.

Place, publisher, year, edition, pages
2017. Vol. 6, no 7, 418-429 p.
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-332437DOI: 10.1002/psp4.12196ISI: 000406417400003OAI: oai:DiVA.org:uu-332437DiVA: diva2:1153065
Funder
EU, FP7, Seventh Framework Programme, 603160
Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2017-10-27Bibliographically approved

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Friberg, Lena EHooker, Andrew

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