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- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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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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- Marshall, S F, et al.
(författare)
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Modeling and simulation to optimize the design and analysis of confirmatory trials, characterize risk-benefit, and support label claims
- 2013
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Ingår i: CPT. - : Wiley. - 2163-8306. ; 2, s. e27-
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Tidskriftsartikel (refereegranskat)abstract
- The role of modeling and simulation (M&S) in the design and interpretation of phase III studies, from break out session 4 of the European Medicines Agency (EMA)/European Federation of Pharmaceutical Industries and Associations (EFPIA) M&S workshop, was divided into themes illustrated with case studies (Table 1): (1) M&S being conducted to support the design of confirmatory trials; (2) longitudinal model-based test as primary inferential analysis (biosimilarity and disease progression trials); (3) assessment of benefit–risk ratio, approval and labeling of an unstudied dose or dosing regimen, and development of future regulatory guidance.
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