Post-approval studies in France, challenges facing medical devices.

Medical devices are characterized notably by a wide heterogeneity (from tongue depressors to hip prostheses, and from non-implantable to invasive devices), a short life cycle with recurrent incremental innovations (from 18 months to 5 years), and an operator-dependent nature. The objective of the current round table was to develop proposals and recommendations concerning the prerequisites needed in order to meet the French health authorities expectations concerning requests for post-approval studies for medical devices, required in cases where short and long-term consequences are unknown. These studies, which are the responsibility of the manufacturer or the distributor of the medical device, are designed to confirm the role of the medical device in the therapeutic management strategy in a real-life setting. There are currently approximately 150 post-approval studies underway, mainly concerning class III devices, and the majority face difficulties implementing the study or meeting the study objectives. In light of this, the round table endeavored to clearly identify the conditions for implementation of post-approval studies specific to the characteristics of medical devices. Various areas of progress have been envisaged to improve the performance of these studies, and by consequence, the efficiency of reimbursement of medical devices by the national health insurance. These include providing manufacturers with the opportunity to better anticipate post-approval requirements, defining a study-specific primary objective, integrating a phase allowing dialogue between the manufacturer, the health authorities and the scientific committee, and increasing awareness and training of health professionals on the impact of post-approval clinical studies in terms of the reimbursement of medical devices by the national insurance.

Scientific evaluation and pricing of medical devices and associated procedures in France.

Medical devices are many and various, ranging from tongue spatulas to implantable or invasive devices and imaging machines; their lifetimes are short, between 18 months and 5 years, due to incessant incremental innovation; and they are operator-dependent: in general, the clinical user performs a fitting procedure (hip implant or pacemaker), a therapeutic procedure using a non-implantable invasive device (arrhythmic site ablation probe, angioplasty balloon, extension spondyloplasty system, etc.) or follow-up of an active implanted device (long-term follow-up of an implanted cardiac defibrillator or of a deep brain stimulator in Parkinson's patients). A round-table held during the XXVIII(th) Giens Workshops meeting focused on the methodology of scientific evaluation of medical devices and the associated procedures with a view to their pricing and financing by the French National Health Insurance system. The working hypothesis was that the available data-set was sufficient for and compatible with scientific evaluation with clinical benefit. Post-registration studies, although contributing to the continuity of assessment, were not dealt with. Moreover, the focus was restricted to devices used in health establishments, where the association between devices and technical medical procedures is optimally representative. An update of the multiple regulatory protocols governing medical devices and procedures is provided. Issues more specifically related to procedures as such, to non-implantable devices and to innovative devices are then dealt with, and the proposals and discussion points raised at the round-table for each of these three areas are presented.

Budget impact of intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency in France.

AIMS: This analysis aims to evaluate the budget impact of intravenous iron therapy with ferric carboxymaltose for patients with systolic chronic heart failure and iron deficiency, from the perspective of the French public health insurance. METHODS AND RESULTS: A budget impact model was adapted to forecast the budget impact over 5 years, according to two scenarios: one where patients receive ferric carboxymaltose according to market share forecast and another where patients are not treated for iron deficiency. Clinical data were extrapolated from pooled data from four randomized controlled trials. The time horizon was extended to 5 years by applying transition probabilities estimated from the CONFIRM-HF trial. Epidemiological parameters for France were derived from the literature. Cost parameters were derived from national available databases. In the base case analysis, the modelled 5 year cost difference between the scenarios with ferric carboxymaltose vs. no iron deficiency treatment in a population of 189 334 prevalent and incident patients led to €0.8m savings. The cumulative savings resulted from a reduction in the hospitalization costs associated with worsening heart failure (€-35.8m) as well as a reduction in the follow-up costs (€-2.9m). These cost savings outweighed the costs of ferric carboxymaltose treatment (€37.7m). Sensitivity analyses showed that the budget impact varied from €-34m to €+146m. Parameters with the most impact on the budget were the hospitalization rate for patients not treated for iron deficiency, the number of ambulatory sessions needed, the absence of hospitalization cost differentiation between New York Heart Association classes, and administration settings costs. CONCLUSIONS: Iron deficiency treatment with ferric carboxymaltose in systolic chronic heart failure patients results in an improvement of New York Heart Association class and thereby increases the well-being of the patients, while providing an overall cost saving for the French national health insurance.

Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine.

This experiment was aimed at exploring the role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine. During the induction phase (Days 1, 3, 5 and 7), male Long-Evans adult rats were treated with the neurotensin antagonist SR-48692 (160, 320 or 640 microg/kg, i.p.) or its vehicle, followed by morphine (5.0 mg/kg, i.p.) or its vehicle, and their locomotor activity (ambulatory, non-ambulatory and vertical activity) was measured for 2 h. One week after the last injection, each group received a single injection of morphine (2.5 mg/kg, i.p.) and their locomotor activity was again measured for 2 h (sensitization test, day 14). Results show that SR-48692 alone did not change locomotion. Morphine stimulated locomotor activity, an effect that was stronger on day 7 than on day 1. The two higher doses of SR-48692 attenuated the acute stimulant effect of morphine and prevented the observed increase from day 1 to day 7. The sensitization test on day 14 showed that rats pre-treated with morphine alone displayed significantly stronger ambulatory and vertical activity than vehicle pre-treated rats, a sensitization effect that was attenuated by SR-48692. The present results suggest that endogenous neurotensin contributes to the acute locomotor stimulant effect of morphine and to the induction of its sensitization.

Cost-effectiveness of drug-eluting stents versus bare-metal stents in patients undergoing percutaneous coronary intervention.

OBJECTIVE: To determine the cost-effectiveness of drug-eluting stents (DES) compared with bare-metal stents (BMS) in patients requiring a percutaneous coronary intervention in France, using a recent meta-analysis including second-generation DES. METHODS: A cost-effectiveness analysis was performed in the French National Health Insurance setting. Effectiveness settings were taken from a meta-analysis of 117 762 patient-years with 76 randomised trials. The main effectiveness criterion was major cardiac event-free survival. Effectiveness and costs were modelled over a 5-year horizon using a three-state Markov model. Incremental cost-effectiveness ratios and a cost-effectiveness acceptability curve were calculated for a range of thresholds for willingness to pay per year without major cardiac event gain. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Base case results demonstrated that DES are dominant over BMS, with an increase in event-free survival and a cost-reduction of €184, primarily due to a diminution of second revascularisations, and an absence of myocardial infarction and stent thrombosis. These results are robust for uncertainty on one-way deterministic and probabilistic sensitivity analyses. Using a cost-effectiveness threshold of €7000 per major cardiac event-free year gained, DES has a >95% probability of being cost-effective versus BMS. CONCLUSIONS: Following DES price decrease, new-generation DES development and taking into account recent meta-analyses results, the DES can now be considered cost-effective regardless of selective indication in France, according to European recommendations.

Role of CD4 receptor down-regulation during HIV-1 infection.

Human immunodeficiency virus has evolved several redundant mechanisms to remove its receptor, the CD4 molecule, from the cell surface. Indeed, HIV-1 encodes three proteins, Nef, Vpu and Env, that have a profound effect on CD4 trafficking and catabolism. Given this functional convergence, it is believed that cell surface CD4 regulation constitutes an important determinant of viral replication and pathogenesis in vivo. This review highlights recent progress made in our understanding of the molecular mechanisms underlying the down-regulation of the CD4 receptor by HIV-1 and describes our current comprehension of the role of CD4 down-regulation during HIV-1 infection.

Physiological stress responses in defensive individuals: age and sex matter.

The association between defensiveness and physiological responses to stress were evaluated in 81 healthy working men and 118 women, aged 20 to 64 years (M=41; SD=11.45). Participants underwent laboratory testing during which they were exposed to interpersonal stressors. Heart rate (HR), heart rate variability (HRV), blood pressure (BP), and salivary cortisol were measured. Defensiveness was evaluated using the Marlowe-Crowne Social Desirability Scale. In women, higher defensiveness was associated with greater BP and HR reactivity to stress (p<.05). In older men, lower defensiveness was associated with increased systolic BP reactivity to stress (p<.02), delayed HRV recovery (p<.02), and greater salivary cortisol levels (p<.02). In conclusion, greater defensiveness was associated with increased reactivity to stress in women whereas in older men, lower defensiveness was associated with elevated cardiovascular, autonomic, and endocrine responses to stress.

Defensiveness and metabolic syndrome: impact of sex and age.

The association between defensiveness and metabolic burden, as well as the moderating effects of sex and age were evaluated in 199 healthy working men (N=81) and women (N=118), aged 20-64 years (M=41; S.D.=11.45). Defensiveness (Marlowe-Crowne Social Desirability Scale) and parameters of metabolic syndrome (MS; waist circumference, HDL, triglycerides, glucose, 24h ambulatory blood pressure) were obtained. In men, defensiveness was inversely related to MS burden (Beta=-.288; p=.001), as well as to individual measures of SBP, DBP, glucose and waist circumference (p<.05). In older women, high defensiveness was associated with a greater MS burden (p=.050) and glucose level (p=.005) while the reverse was true in younger women (p=.012). In conclusion, defensiveness was associated with a worse metabolic profile in older women but may be protective for men and younger women. Understanding the pathophysiological processes underlying these associations could elucidate sex and age differences and inform prevention efforts.

Prospective evaluation of psychological distress and psychiatric morbidity in recurrent vasovagal and unexplained syncope.

UNLABELLED: Syncope is experienced by a third of the population, and in the absence of cardiac pathology is most commonly of vasovagal (VVS) or unexplained origin (US). Psychiatric morbidity has been observed in up to 81% of patients with US but findings with VVS are contradictory. Little is known regarding the chronicity of their psychiatric morbidity. OBJECTIVE: To determine the psychological profile of patients with recurrent syncope prior to and following diagnostic head-up tilt testing (HUT), and whether it predicts syncope recurrence. METHOD: Seventy-three women and 43 men (mean age=48+/-16.6) were recruited from all consenting patients referred for HUT. Psychological status (Psychiatric Symptom Index, Anxiety Sensitivity Index (ASI), Fear of Blood Injury Subscale) and presence of mood/anxiety disorders (Primary Care Evaluation of Mental Disorders) were evaluated 1 month prior to and 6 months following HUT. Follow-up data were collected for 83 patients (mean age=48+/-17.34). RESULTS: At baseline, clinically significant levels of distress were observed in 60% of patients. Those with US (negative HUT) had a fivefold greater risk of suffering from a depressive or anxiety disorder compared to VVS (positive HUT) after controlling for significant covariates. There was no significant change in distress level over follow-up, although psychiatric morbidity dropped from 33% to 22% (P=.049). Syncope recurrence was predicted by elevations in baseline psychological distress (OR=1.544, P=.013) independently of lifetime number of syncopes. CONCLUSIONS: Patients exhibited high levels of psychological distress and psychiatric morbidity despite reassurance and education received after HUT. Improved screening for and treatment of psychological distress in these patients is critical.

Vpu exerts a positive effect on HIV-1 infectivity by down-modulating CD4 receptor molecules at the surface of HIV-1-producing cells.

Human immunodeficiencey virus, type 1 (HIV-1) encodes three proteins, Nef, Vpu, and gp160, that down-modulate surface expression of the CD4 receptor during viral infection. In the present study, we have investigated the role of CD4 down-modulation in the HIV-1 infection cycle, primarily from the perspective of Vpu function. We report here that, like Nef, Vpu-mediated CD4 degradation modulates positively HIV-1 infectivity. Our data reveal that accumulation of CD4 at the cell surface of Vpu-deficient HIV-1-producing cells leads to an efficient recruitment of CD4 into virions and to an impairment of viral infectivity. This CD4-mediated inhibition of viral infectivity was not observed when a CD4 mutant unable to bind Env gp120 was used or when VSV-G glycoprotein was utilized to pseudotype viruses, suggesting that an interaction between CD4 and gp120 is required for interference. Indeed, protein analysis of Vpu-defective viral particles reveals that CD4 recruitment is associated with an increased formation of gp120-CD4 complexes at the virion surface. Interestingly, we did not detect any difference at the level of total virion-associated Env glycoproteins between wild-type and Vpu-defective virus, indicating that accumulation of CD4 at the cell surface and recruitment of CD4 into Vpu-defective HIV-1 particles exert a negative effect on viral infectivity, most likely by promoting the formation of nonfunctional gp120-CD4 complexes at the virion surface. Finally, we show that both Vpu- and Nef-induced CD4 down-modulation activities are required for production of fully infectious particles in CD4+ T cell lines and primary cells, an observation that has clear implications for viral spread in vivo.

CD4 dimers constitute the functional component required for T cell activation.

The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.