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- Musuamba, F. T., et al.
(författare)
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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)
- 2017
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 6:7, s. 418-429
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Darwich, Adam S., et al.
(författare)
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Model-Informed Precision Dosing: Background, Requirements, Validation, Implementation, and Forward Trajectory of Individualizing Drug Therapy
- 2021
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Ingår i: Annual Review of Pharmacology and Toxicology. - : Annual Reviews Inc.. - 0362-1642 .- 1545-4304. ; 61:36, s. 1-21
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Tidskriftsartikel (refereegranskat)abstract
- Model-informed precision dosing (MIPD) has become synonymous with modern approaches forindividualizing drug therapy, in which the characteristics of each patient are considered as opposedto applying a one-size-fits-all alternative. This review provides a brief account of the currentknowledge, practices, and opinions on MIPD while defining an achievable vision for MIPDin clinical care based on available evidence.We begin with a historical perspective on variabilityin dose requirements and then discuss technical aspects of MIPD, including the need for clinicaldecision support tools, practical validation, and implementation of MIPD in health care.Wealso discuss novel ways to characterize patient variability beyond the common perceptions of geneticcontrol. Finally, we address current debates on MIPD from the perspectives of the new drugdevelopment, health-care economics, and drug regulations.
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| 3. |
- Mentre, France, et al.
(författare)
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Software for optimal design in population pharmacokinetics and pharmacodynamics : a comparison
- 2007
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Konferensbidrag (refereegranskat)abstract
- Introduction: Following the first theoretical work on optimal design for nonlinear mixed effect models, this research theme has rapidly grown both in methodological and application developments. There are now several different software tools that implement an evaluation of the Fisher information matrix for population PK and PD models and proposed optimization of the experimental designs. In 2006, the Population Optimal Design of Experiments workshop was created with a meeting every year in May (www.maths.qmul.ac.uk/~bb/PODE/PODE2007.html). This year at PODE07 a special session was organized to present different software tools for population PK/PD optimal design and to compare them with respect to their statistical methodology. Objectives: 1) To present the different software tools; 2) To compare the statistical methods implemented in these tools; 3) To report the conclusion of the PODE07 meeting with respect to future software development in population PK/PD design. Methods: The software tools will be compared with respect to: a) their availability, b) required language, c) library of PK or PD models, d) ability to deal with multiresponse models and/or with models defined by differential equations, e) approximations made to compute the Fisher information matrix, f) optimisation criteria, g)optimisation algorithms, h) ability to optimize design structure, i) ability to deal with constraints in sampling times, j) availability of optimisation trough sampling windows, k) assessment of user specified designs, l) ability to deal with unbalanced multiresponse designs, m) ability to deal with correlations between random effects, o) provided outputs ... Results: The five software tools discussed at PODE07 are (in alphabetical order): PFIM (S. Retout & F. Mentré), PkStaMP (S. Leonov), PopDes (K. Ogungbenro & I. Gueorguieva) PopED (A. Hooker), and WinPOPT (S. Duffull). Tables comparing the software with respect to the different aspects described in the method section will be reported. The conclusions of the PODE07 meeting regarding future software development for optimal design in population PK/PD will be presented.
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