| 151. |
- 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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| 152. |
- Quintana, H. K., et al.
(författare)
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Diabetes, hypertension, overweight and hyperlipidemia and 7-day case-fatality in first myocardial infarction
- 2016
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Ingår i: International Journal of Cardiology Metabolic & Endocrine. - : ELSEVIER SCI LTD. - 2214-7624. ; 12, s. 30-35
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Tidskriftsartikel (refereegranskat)abstract
- Background: Out-of-hospital deaths due to a first myocardial infarction (MI) are frequent and a big challenge for prevention. Increased knowledge about factors influencing MI fatality is needed. Metabolic risk factors have been studied in relation to MI fatality in-hospital but studies considering also out-of-hospital deaths are few. Aim: To assess howdiabetes and other metabolic risk factors associate with death within 7 days after first time MI among subjects aged between 45 and 70 identified in Stockholm County 1992-1994. Methods: Data were collected using questionnaires (close relatives of fatal cases were asked to fill the questionnaire), physical examinations, national registers and autopsy reports. Risk ratios (RR) of 7-day MI fatality with 95% confidence intervals (CI) associated with the risk factors under study were calculated using binomial regression with log link. Results: Out of 1905 first time MI cases included, 524 died within 7 days. After adjustments for age, sex, current smoking, education and general comorbidity, diabetes, but not hypertension and hyperlipidemia, was associated with MI fatality (RR 1.68, 95% CI 1.20-2.28). Overweight, as compared to normal BMI, was inversely associated with MI fatality (multiple adjusted RR 0.68, 95% CI 0.49-0.94); obesity results pointed in the samedirection (multiple adjusted RR 0.79, 0.52-1.16). Conclusions: In this population-based inception cohort study, diabetes but not hypertension and hyperlipidemia were associated with MI fatality. This further emphasizes the importance of diabetes as a cardiovascular risk factor and the need for close surveillance of diabetic patients. Overweight was however associated with decreased MI fatality.
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| 153. |
- Radnahad, N, et al.
(författare)
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Is the association of QTc with atrial fibrillation and stroke in cohort studies a matter of time?
- 2022
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Ingår i: Open heart. - : BMJ. - 2053-3624. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the association of the heart rate-corrected QT interval (QTc) with the risk of atrial fibrillation (AF) and ischaemic stroke.MethodsWe estimated the risk of AF and ischaemic stroke associated with QTc duration (ms) by Cox regression in study participants from the cohort of 60-year-old men and women from Stockholm (60YO) (n=4232). Univariate and multivariate adjusted risk estimates were expressed as HR and 95% CI. Main results were validated in elderly patients with AF, included in the Carebbean-e study, where an ECG in sinus rhythm (SR) (ECG-SR) recorded before the ECG diagnostic for (ECG-AF) was available (n=803). We estimated the correlation between the time interval (years) between the ECG-SR and ECG-AF with the QTc duration, by the Spearman correlation coefficient (rho).ResultsIn the 60YO, the highest QTc duration quartile (>427 ms) associated with the AF risk (n=435) with a multivariable adjusted HR of 1.68 and 95% CI (1.26 to 2.24). No association was observed with ischaemic stroke. In the Carebbean-e study, no significant association was observed between the QTc duration measured on the ECG-SR and risk of ischaemic stroke during follow-up. QTc duration showed an inverse correlation (rho: −0.26, p<0.0001) with the time interval intercurred between ECG-SR and ECG-AF.ConclusionsThe association of QTc duration with AF risk might depend on the time interval between the QTc measurement and the clinical diagnosis of AF. No association was observed between QTc duration and ischaemic stroke.
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