From Individual to Population Preferences:Comparison of Discrete Choice and Dirichlet Models for Treatment Benefit-Risk Tradeoffs

Introduction. The Dirichlet distribution has been proposed for representing preference heterogeneity, but there is limited evidence on its suitability for modeling population preferences on treatment benefits and risks. Methods. We conducted a simulation study to compare how the Dirichlet and standard discrete choice models (multinomial logit [MNL] and mixed logit [MXL]) differ in their convergence to stable estimates of population benefit-risk preferences. The source data consisted of individual-level tradeoffs from an existing 3-attribute patient preference study (N = 560). The Dirichlet population model was fit directly to the attribute weights in the source data. The MNL and MXL population models were fit to the outcomes of a simulated discrete choice experiment in the same sample of 560 patients. Convergence to the parameter values of the Dirichlet and MNL population models was assessed with sample sizes ranging from 20 to 500 (100 simulations per sample size). Model variability was also assessed with coefficient P values. Results. Population preference estimates of all models were very close to the sample mean, and the MNL and MXL models had good fit (McFadden's adjusted R2 = 0.12 and 0.13). The Dirichlet model converged reliably to within 0.05 distance of the population preference estimates with a sample size of 100, where the MNL model required a sample size of 240 for this. The MNL model produced consistently significant coefficient estimates with sample sizes of 100 and higher. Conclusion. The Dirichlet model is likely to have smaller sample size requirements than standard discrete choice models in modeling population preferences for treatment benefit-risk tradeoffs and is a useful addition to health preference analyst's toolbox

Freestyle pedicled perforator flaps: safety, prevention of complications, and management based on 85 consecutive cases.

Background: Despite the widespread use of free perforator flaps, pedicled perforator flaps seem not to be as widely accepted, probably because of the fear of vascular complications caused by transfer of a flap attached only by its vascular pedicle, prone to shearing, kinking, and trauma. In this article, the authors report on their experience with 85 consecutive cases, focusing on incidence, prevention, and management of complications. Methods: Eighty-five consecutive cases were treated over 6 years at the Plastic and Reconstructive Surgery Department of the University of Palermo for defects of different causes that were reconstructed with a freestyle pedicled perforator flap, in every region of the body, including the head and neck (41.2 percent), trunk (20 percent), upper limb (7.1 percent), and lower limb (31.8 percent). The majority of flaps (67.1 percent) were 180-degree propeller perforator flaps. Results: Complete flap survival was observed in 93 percent of cases. Six flaps (7 percent) had vascular complications that were managed with venous supercharging (two cases), derotation (one case), conservative management (two cases), or secondary skin grafting (one case). The authors provide their approach to each situation to prevent or manage complications. Conclusions: The 93 percent success rate in this series seems to be acceptable and demonstrates that these flaps might be safely included in the authors’ routine. If the flaps are appropriately planned and executed, with the suggestions provided in this article, some mistakes can be avoided to make these flaps even safer

European medicines agency approval summary: zaltrap for the treatment of patients with oxaliplatin-resistant metastatic colorectal cancer

On 1 February 2013, a marketing authorisation valid throughout the European Union was issued for aflibercept (Zaltrap) in combination with irinotecan/5-fluorouracil/ folinic acid chemotherapy for the treatment of adults with metastatic colorectal cancer resistant to or progressive after an oxaliplatin-containing regimen. Aflibercept is a recombinant fusion protein which blocks the activation of vascular endothelial growth factor (VEGF) receptors and the proliferation of endothelial cells, acting as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as placental growth factor and VEGF-B. The use of aflibercept was studied in a randomised, double-blind, placebo-controlled phase III study, in patients with metastatic colorectal cancer (mCRC) who had previously been treated with an oxaliplatinbased treatment with or without prior bevacizumab. Aflibercept (n=612) was compared with placebo (n=614), both in combination with FOLFIRI (infusional fluorouracil, leucovorin and irinotecan). The primary endpoint of the study was overall survival (OS). The median OS in the intent-to-treat population was 13.5 months in subjects treated with aflibercept compared with 12.1 months for subjects in the control arm (stratified HR=0.817, 95% CI 0.714 to 0.935, stratified pvalue=0.0032). The frequency of adverse events was higher in the aflibercept arm compared with the placebo arm, reflecting the toxicity profile of anti-VEGF agents in combination with chemotherapy. This paper is based on the scientific review of the application leading to approval of aflibercept in the EU. The detailed scientific assessment report and product information for this product are available on the European Medicines Agency website

Quantifying preference in drug benefit-risk decisions

Benefit-risk assessment is used in various phases along the drug lifecycle, such as marketing authorization and surveillance, health technology assessment (HTA), and clinical decisions, to understand whether, and for which patients, a drug has a favorable or more valuable profile with reference to one or more comparators. Such assessments are inherently preference-based as several clinical and nonclinical outcomes of varying importance might act as evaluation criteria, and decision makers must establish acceptable trade-offs between these outcomes. Different healthcare stakeholder perspectives, such as those from patients and healthcare professionals, are key for informing benefit-risk trade-offs. However, the degree to which such preferences inform the decision is often unclear as formal preference-based evaluation frameworks are generally not used for regulatory decisions, and, if used, rarely communicated in HTA decisions. We argue that for better decisions, as well as for reasons of transparency, preferences in benefit-risk decisions should more often be quantified and communicated explicitly

Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting

Purpose: To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity. Methods: Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the “Stichting Hemato-Oncologie voor Volwassenen Nederland” (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents’ willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR). Results: Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS. Conclusion: Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients.</p

EMEA and Gene Therapy Medicinal Products Development in the European Union

The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines Evaluation Agency (EMEA) via the centralized procedure is the only available regulatory procedure for obtaining marketing authorization for gene therapy (GT) medicinal products in the European Union. The responsibility for the authorization of clinical trials remains with the national competent authorities (NCA) acting in a harmonized framework from the scientific viewpoint. With the entry into force of a new directive on good clinical practice implementation in clinical trials as of 1 May 2004, procedural aspects will also be harmonized at EU level. Scientifically sound development of medicinal products is the key for the successful registration of dossiers and for contributing to the promotion and protection of public health. The objective of this paper is to introduce the EMEA regulatory processes and scientific activities relevant to GT medicinal products

Effectiveness of integrated care model for type 2 diabetes: A population-based study in Reggio Emilia (Italy)

Aims To compare the effectiveness of integrated care with that of the diabetes clinic care model in terms of mortality and hospitalisation of type 2 diabetes patients with low risk of complications. Methods Out of 27234 people with type 2 diabetes residing in the province of Reggio Emilia on 31/12/2011, 3071 were included in this cohort study as eligible for integrated care (i.e., low risk of complications) and cared for with the same care model for at least two years. These patients were followed up from 2012 to 2016, for all-cause and diabetes-related mortality and hospital admissions. We performed a Poisson regression model, using the proportion of eligible patients included in the integrated care model for each general practitioner as an instrumental variable. Results 1700 patients were cared for by integrated care and 1371 by diabetes clinics. Mortality rate ratios were 0.83 (95%CI 0.60-1.13) and 0.95 (95%CI 0.54-1.70) for all-cause and cardiovascular mortality, respectively, and incidence rate ratios were 0.90 (95%CI 0.76-1.06) and 0.91 (95%CI 0.69-1.20) for all-cause and cardiovascular disease hospitalisation, respectively. Conclusion For low risk patients with type 2 diabetes, the integrated care model involving both general practitioner and diabetes clinic professionals showed similar mortality and hospitalisation as a model with higher use of specialized care in an exclusively diabetes clinic setting

Florintesa, a program agreement for the italian botanical gardens and the national floristic heritage.

OUR CLAIM: "The Botanical Gardens are, par excellence, responsible for carrying out the important mission of the conservation of our flora, through specific actions on live plants and their seeds, along with education and outreach aimed at spreading a new environmental culture, more careful and respectful of the essential needs of life, more sensible to the aesthetic and scientific value of the national flora" To overcome the isolation and strengthen their role in our society, the University Botanical Gardens have become promoters of national and European consortiums: examples are the working group "Botanical and Historic Gardens" of the Italian Botanical Society (1) and, on the global level, the Botanic Garden Conservation International (2). Aims and tasks of the Botanical Gardens in the second millennium have been the topic of a thorough debate, with specific references to the provisions of the United Nations Programme for a sustainable development. In particular, the Action Plan for Botanic Gardens in the European Union (3) identifies the following major assets: scientific research, conservation of plant diversity, public advisory services on it, environmental education related to it. To pursue these objectives, initiatives are constantly needed to enhance the visibility of the institutions involved and help them to perform their functions. in this contest was born FLORINTESA FLORINTESA is a program agreement, funded by the Italian Ministry of Education (MIUR) with identification code ACPR12_00201, involving as partners ENEA, Plinianum Forum and the Italian Botanical Society, which contributes to bridge the still existing gap between the scientific research, the technical action of conservation and preservation of plant diversity and the public awareness on such themes. The main objectives of the FLORINTESA can be summarized as follows: - Establishing an institutional network service for information and dissemination on the flora of Italy, with reference to the role of Botanical Gardens as centers of research and knowledge on the national flora, as well as on the assessment and conservation of its rarest species,; - Disseminating and publicizing the activities of the University Botanical Gardens for the flora of Italy; - Increasing the visibility of the Italian Botanical Society and of its working group on "Botanical and Historic Gardens"; - Disseminating the achievements and helpful assistance offered by the Botanical Gardens in the implementation of the National Strategy for Biodiversity (4) and the Natura 2000 Network (5), through initiatives such as the Italian Germplasm Banks Network (6), the International Foundation pro Herbario Mediterraneo (7), the pan-Mediterranean Genmeda network (8), the Horti Mediterranei Educational Network (9). The flora of Italy will be the leitmotif of the actions envisaged in FLORINTESA, highlighting the unique role of the University Botanical Gardens and their respective institutions as "engines of knowledge" on the national flora heritage, as "engines of awareness" on the important issue of conservation of flora and habitats, as "engines of passion" for the grateful acknowledgement of the role of plants as primary producers not only of resources in the natural ecosystems, but also of inspiring beauty in the human cultures. The kick-off meeting, open to all members of the Italian Botanical Society, will take place in Rome, at the Auditorium of the Accademia Nazionale dei Lincei, on January 23, 2014

Distribution of human beta-defensin polymorphisms in various control and cystic fibrosis populations.

Abstract Human beta defensins contribute to the first line of defense against infection of the lung. Polymorphisms in these genes are therefore potential modifiers of the severity of lung disease in cystic fibrosis. Polymorphisms were sought in the human beta-defensin genes DEFB1, DEFB4, DEFB103A, and DEFB104 in healthy individuals and cystic fibrosis (CF) patients living in various European countries. DEFB1, DEFB4, and DEFB104 were very polymorphic, but DEFB103A was not. Within Europe, differences between control populations were found for some of the frequent polymorphisms in DEFB1, with significant differences between South-Italian and Czech populations. Moreover, frequent polymorphisms located in DEFB4 and DEFB104 were not in Hardy Weinberg equilibrium in all populations studied, while those in DEFB1 were in Hardy Weinberg equilibrium. Sequencing of a monochromosomal chromosome 8 mouse-human hybrid cell line revealed signals for multiple alleles for some loci in DEFB4 and DEFB104, but not for DEFB1. This indicated that more than one DEFB4 and DEFB104 gene was present on this chromosome 8, in agreement with recent findings that DEFB4 and DEFB104 are part of a repeat region. Individual DEFB4 and DEFB104 PCR amplification products of various samples were cloned and sequenced. The results showed that one DNA sample could contain more than two haplotypes, indicating that the various repeats on one chromosome were not identical. Given the higher complexity found in the genomic organization of the DEFB4 and DEFB104 genes, association studies with CF lung disease severity were performed only for frequent polymorphisms located in DEFB1. No association with the age of first infection by Pseudomonas aeruginosa or with the FEV1 percentage at the age of 11-13 years could be found