Faciliating More Efficient Negotiations for Innovative Therapies: A Value-Based Negotiation Framework

OBJECTIVES: An increasing number of innovative therapies (e.g., gene- and cell-based treatments) have been developed in the past 20 years. Despite the significant clinical potential of these therapies, access delays may arise because of differing perspectives of manufacturers and payers regarding issues such as the value of the product, clinical and financial uncertainties, and sustainability.Managed entry agreements (MEAs) can enable access to treatments that would not be reimbursed by conventional methods because of such concerns. However, although MEA typologies exist, there is currently no structured process to come to agreements on MEAs, which can be difficult to decide upon and implement.To facilitate more structured MEA negotiations, we propose a conceptual "value-based negotiation framework" with corresponding application tools. METHODS: The framework was developed based on an iterative process of scientific literature review and expert input. RESULTS: The framework aims to (i) systematically identify and prioritize manufacturer and payer concerns about a new treatment, and (ii) select a mutually acceptable combination of MEA terms that can best address priority concerns, with the lowest possible implementation burden. CONCLUSIONS: The proposed framework will be tested in practice, and is a step toward supporting payers and manufacturers to engage in more structured, transparent negotiations to balance the needs of both sides, and enabling quicker, more transparent MEA negotiations and patient access to innovative products

Comparison between the STENTYS self-apposing bare metal and paclitaxel-eluting coronary stents for the treatment of saphenous vein grafts (ADEPT trial)

Aims To describe the safety and performance of STENTYS self-expandable bare metal stents (BMS) versus paclitaxel-eluting stents (PES) in saphenous vein grafts (SVGs). Methods and Results A randomised controlled trial was performed in four hospitals in three European countries between December 2011 and December 2013. Patients with de novo lesions (>50% stenosis) in an SVG with a diameter between 2.5–6 mm were included. Primary endpoint was late lumen loss at 6 months. Secondary endpoints included procedural success and the occurrence of major adverse cardiac events (MACE) at 12 months. A total of 57 patients were randomised to STENTYS self-apposing BMS (n = 27) or PES (n = 30). Procedural success was obtained in 89.5%. No significant differences in late lumen loss were found between BMS and PES at 6 months (0.53 mm vs 0.47; p = 0.86). MACE rates at 12 months were comparable in both groups (BMS 22.2% vs. PES 26.7%; p = 0.70). Conclusions Treatment of SVGs with STENTYS self-expandable stents is safe and effective. No significant differences were found in late lumen loss and MACE between BMS and PES

Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD.

BACKGROUND: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD. METHODS: 219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time. FINDINGS: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group. INTERPRETATION: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results

Gender-Specific Modulation of the Response to Arterial Injury by Soluble Guanylate Cyclase α1

Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of α and β subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1-/-), resulting in a non-functional heterodimer. Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1-/- mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively. Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1-/-. In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. 3H-thymidine incorporation in cultured sGCa1-/- smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1-/- M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1-/- M than in WT M mice (p<0,05 for both) but were not different in F mice. Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1-/- mice and a gender-specific effect on the adaptive response to vascular injury

Performance-based financing as a health system reform : mapping the key dimensions for monitoring and evaluation

Peer reviewedPublisher PD

Safer Sex as the Bolder Choice: Testosterone Is Positively Correlated with Safer Sex Behaviorally Relevant Attitudes in Young Men

Introduction.  Higher testosterone (T) is tied to risk‐taking, especially in financial domains but also in health domains relevant to acquiring sexually transmitted infections (STIs). However, safer sex constructs could themselves carry the possibility of “social risk” due to sexual stigma or embarrassment, or could involve boldness or confidence because they could represent status displays of frequent sexual activity. Aim.  To determine how T and behaviorally relevant attitudes about sexual risk‐taking are linked, to better understand biopsychosocial aspects of sexual health related to STIs. Methods.  In 78 first‐year male college students, we examined correlations between salivary T and behaviorally relevant safer sex attitudes assessed via questionnaires. Main Outcome Measures.  T, via saliva; safer sex attitudes, via a composite and the University of California, Los Angeles Multidimensional Condom Attitudes Scale (MCAS). Results.  Higher T was significantly correlated with higher scores on the following: safer sex likelihood composite, r (73) = 0.33, P  = 0.003; the MCAS safer sex resilience, r (32) = 0.36, P  = 0.037; and the MCAS condom purchase comfort, r (32) = 0.37, P  = 0.031. Associations between T and safer sex likelihood and resilience were still robust after controlling for potential confounds, though the association between T and purchase comfort diminished to a trend. Conclusions.  Higher T was positively linked with safer sex attitudes, especially those most closely tied to STI risk avoidance. Thus, future research and interventions for STI prevention should address the possibility that safer sex may be paradoxically perceived as a “bold” or “risky” choice even as it decreases STI risk. van Anders SM, Goldey KL, Conley TD, Snipes DJ, and Patel DA. Safer sex as the bolder choice: Testosterone is positively correlated with safer sex behaviorally relevant attitudes in young men. J Sex Med 2012;9:727–734.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90413/1/j.1743-6109.2011.02544.x.pd

The GUINEVERE Project for Accelerator Driven System Physics

paper 9414International audienceThe GUINEVERE project is part of the EUROTRANS Integrated Project of the 6th EURATOM Framework Programme. It is mainly devoted to ADS on-line reactivity monitoring validation, sub-criticality determination and operational procedures (loading, start-up, shut-down, ...) as a follow-up of the MUSE experiments. The project consists in coupling a fast lead core, set-up in the VENUS reactor at SCK*CEN Mol (B), with a GENEPI neutron source under construction by CNRS. To accommodate the accelerator in a vertical coupling configuration, the VENUS building is being heightened. The fast core will be loaded with enriched Uranium and will be moderated and reflected with solid lead (zero power experiment). For the purpose of the experimental programme, the neutron source has to be operated not only in pulsed mode but also in continuous mode to investigate the current-to-flux reactivity indicator in representative conditions of a powerful ADS. In this latter mode it is also required to make short beam interruptions to have access to the neutron population decrease as a function of time: from this spectrum it will be possible to apply different analysis techniques such as "prompt decay" fitting techniques and "source jerk" techniques. Beam interruptions will be repeated at a programmable frequency to improve time spectra statistics. Different sub-criticality levels (keff=0.99, 0.97, 0.95, ...) will be investigated in order to obtain a full set of data points for the final overall validation of the methodology. This paper describes the status of the experimental facility assembling, and the foreseen experimental programme to be started

The GUINEVERE project at the VENUS facility

Proc. on CD Rom log315International audienceThe GUINEVERE project is an international project in the framework of IP-EUROTRANS, the FP6 program which aims at addressing the main issues for ADS development in the framework of partitioning and transmutation for nuclear waste volume and radiotoxicity reduction. The GUINEVERE project is carried out in the context of domain 2 of IP-EUROTRANS, ECATS, devoted to specific experiments for the coupling of an accelerator, a target and a subcritical core. These experiments should provide an answer to the questions of online reactivity monitoring, sub-criticality determination and operational procedures (loading, start-up, shutdown, …) in an ADS by 2009-2010. The project has the objective to couple a fast lead core, within the VENUS building operated by the SCK•CEN, with a neutron generator able to work in three different modes: pulsed, continuous and continuous with beam interruptions at the millisecond scale. In order to achieve this goal, the VENUS facility has to be adapted and a modified GENEPI-3C accelerator has to be designed and constructed. The paper describes the main modifications to the reactor core and facility and to the accelerator, which will be executed during the years 2008 and 2009, and the experimental programme which will start in 2009

The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization