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Sökning: WFRF:(Hemmings S)

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  • Musuamba, F. T., et al. (författare)
  • 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
  • Ingår i: CPT. - 2163-8306. ; 6:7, s. 418-429
  • 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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  • Lochner, Christine, et al. (författare)
  • Genetics and personality traits in patients with social anxiety disorder: a case-control study in South Africa.
  • 2007
  • Ingår i: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - 0924-977X. ; 17:5, s. 321-7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Social anxiety disorder (SAD) is among the most common of all psychiatric disorders with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD has a strong familial basis, there are few studies of potential candidate genes. In addition to a genetic association, there is also the possibility that temperamental risk factors for the disorder may be genetically transmitted. Against this background, our aims were threefold: i.) to compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of these participants to investigate the role of genes encoding components of serotonergic (5-HT) and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in temperament dimensions between carriers of different (dominant vs. recessive) alleles for selected polymorphisms in SAD patients. METHODS: Sixty-three patients (n=63; 35 male, 28 female) with a DSM-IV diagnosis of generalized SAD and SPIN-scores >18, and age-matched control participants (n=150; 31 male, 119 female) were included in the study. The Temperament and Character Inventory (TCI) was used to measure behaviours associated with specific personality dimensions (i.e. temperament/character). DNA was extracted and genotyped to investigate the role of select candidate genes encoding components in serotonergic and dopaminergic pathways in mediating the development of SAD. To achieve this, the frequency of variants in 5-HT and DA genes was compared between a Caucasian subset of SAD patients (n=41) and a convenience sample of Caucasian controls (n=88), using case-control association analyses. We also investigated the frequency of variants in 5-HT and DA-related genes across temperament characteristics in SAD patients, using analyses of variance (ANOVA). RESULTS: Patients scored significantly higher on harm avoidance (p<0.001) but lower on novelty seeking (p=0.04) and self-directedness (p=0.004) compared to controls. In the Caucasian subset, there was a difference between patients and controls in distribution of the 5-HT(2A)T102C polymorphism, with significantly more patients harboring T-containing genotypes (T-containing genotypes: [T/T+T/C] vs. [C/C]) (chi2=7.55; p=0.012). Temperament dimensions did not, however, differ significantly between carriers of different (dominant vs. recessive) alleles for the 5-HT(2A)T102C polymorphism in SAD patients. CONCLUSIONS: The results suggest a possible role for the 5-HT(2A)T102C polymorphism in the development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless, serotonergic variants, and their associations with temperaments (e.g. reward dependence) deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be delineated.
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  • Marshall, S F, et al. (författare)
  • Modeling and simulation to optimize the design and analysis of confirmatory trials, characterize risk-benefit, and support label claims
  • 2013
  • Ingår i: CPT. - 2163-8306. ; 2, s. e27-
  • 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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