Impact of RSV test positivity, patient characteristics, and treatment characteristics on the cost of hospitalization for acute bronchiolitis in a French university medical center (2010-2015).

Background: In young children, respiratory syncytial virus (RSV)-related bronchiolitis is typically more severe than other respiratory tract infections, with a greater need for oxygen therapy and respiratory support. Few studies have compared the cost of hospitalization with regard to virological status. The objective of this study was to compare the costs of hospitalization for RSV-positive vs. RSV-negative bronchiolitis in a French university medical center between 2010 and 2015. Methods: The cost models were compared using conventional goodness-of-fit criteria. Covariates included the characteristics of the patients, pre-existing respiratory and non-respiratory comorbidities, superinfections, medical care provided, and the length of stay. Results: RSV was detected in 679 (58.3%) of the 1,164 hospital stays by children under 2 years with virological data. Oxygen therapy and respiratory support were twice as frequent for the RSV-positive cases. The median hospitalization cost was estimated at €3,248.4 (interquartile range: €2,572.1). The cost distribution was positively skewed with a variation coefficient (CV = standard deviation/mean) greater than one (mean = €4,212.9, standard deviation = €5,047, CV = 1.2). In univariate analyses, there was no significant cost difference between the RSV-positive and RSV-negative cases. In the best multivariate model, the significant positive effect of RSV positivity on cost waned after the introduction of medical care variables and the length of stay. The results were sensitive to the specification of the model. Conclusions: It was impossible to firmly conclude that hospitalization costs were higher for the RSV-positive cases.

Economic burden and health-related quality-of-life among infants with respiratory syncytial virus infection: A multi-country prospective cohort study in Europe.

BACKGROUND: Respiratory syncytial virus (RSV) causes a considerable disease burden in young children globally, but reliable estimates of RSV-related costs and health-related quality-of-life (HRQoL) are scarce. This study aimed to evaluate the RSV-associated costs and HRQoL effects in infants and their caregivers in four European countries. METHODS: Healthy term-born infants were recruited at birth and actively followed up in four European countries. Symptomatic infants were systematically tested for RSV. Caregivers recorded the daily HRQoL of their child and themselves, measured by a modified EQ-5D with Visual Analogue Scale, for 14 consecutive days or until symptoms resolved. At the end of each RSV episode, caregivers reported healthcare resource use and work absenteeism. Direct medical costs per RSV episode were estimated from a healthcare payer's perspective and indirect costs were estimated from a societal perspective. Means and 95% confidence intervals (CI) of direct medical costs, total costs (direct costs + productivity loss) and quality-adjusted life-day (QALD) loss per RSV episode were estimated per RSV episode, as well as per subgroup (medical attendance, country). RESULTS: Our cohort of 1041 infants experienced 265 RSV episodes with a mean symptom duration of 12.5 days. The mean (95% CI) cost per RSV episode was €399.5 (242.3, 584.2) and €494.3 (317.7, 696.1) from the healthcare payer's and societal perspective, respectively. The mean QALD loss per RSV episode of 1.9 (1.7, 2.1) was independent of medical attendance (in contrast to costs, which also differed by country). Caregiver and infant HRQoL evolved similarly. CONCLUSION: This study fills essential gaps for future economic evaluations by prospectively estimating direct and indirect costs and HRQoL effects on healthy term infants and caregivers separately, for both medically attended (MA) and non-MA laboratory-confirmed RSV episodes. We generally observed greater HRQoL losses than in previous studies which used non-community and/or non-prospective designs.

Real-world data and evidence in health technology assessment: When are they complementary, substitutes, or the only sources of data compared to clinical trials?

Within the life-cycle assessment of health technologies, real-world data (RWD) have until now been of secondary importance to clinical trial data. The availability of massive, better quality RWD, particularly with the emergence of connected devices, the improvement of methods for characterizing populations, make it possible to have a better insight into the effects of treatment, sometimes on a national scale the importance of RWD is likely to progress in the eyes of health technology assessors, going from being traditionally complementary to possibly replacing clinical trial data. This is the fundamental question that the round table, involving experts from the academic and/or hospital, institutional, and industrial worlds, set out to answer. This work served first to establish the current role of RWD in health technology assessment, by distinguishing the main purposes of RWD, the timing of the evaluation in relation to the life cycle of the technology, and then according to the party commissioning or receiving the outcomes of RWD-based studies. Secondly, the round table proposed six general recommendations for more intensive and decisive use of RWD in the assessment and decision-making process.

The Optimal Sample Size for Usability Testing, From the Manufacturer's Perspective: A Value-of-Information Approach.

OBJECTIVES: For medical devices, a usability assessment is mandatory for market access; the objective is to detect potentially harmful use errors that stem from the device's design. The manufacturer assesses the final version of the device and determines the risk-benefit ratio for remaining errors. Nevertheless, the decision rule currently used to determine the sample size for this testing has statistical limitations and the lack of a clear decision-making perspective. METHODS: As an alternative, we developed a value-of-information analysis from the medical device manufacturer's perspective. The consequences of use errors not detected during usability testing and the errors' probability of occurrence were embedded in a loss function. The value of further testing was assessed as a reduction in the expected loss for the manufacturer. The optimal sample size was determined using the expected net benefit of sampling (ENBS) (the difference between the value provided by new participants and the cost of their inclusion). RESULTS: The value-of-information approach was applied to a real usability test of a needle-free adrenaline autoinjector. The initial estimate (performed on the first n = 20 participants) gave an optimal sample size of 100 participants and an ENBS of €255 453. This estimation was updated iteratively as new participants were included. After the inclusion of 90 participants, the ENBS was null for any sample size; hence, the cost of adding more participants outweighed the expected value of information, and therefore, the study could be stopped. CONCLUSIONS: On the basis of these results, our method seems to be highly suitable for sample size estimation in the usability testing of medical devices before market access.

Optical Coherence Tomography Contribution Assessment in the Revascularization of Long Femoropopliteal Occlusive Lesions (TASC C and D): A Randomized Trial.

BACKGROUND: Endovascular treatment has become the first-line revascularization technique for femoropopliteal lesions. This technique lacks reliable and accurate morphological control of the arterial segment treated. Intraoperative 2-dimensional angiogram consumes iodinated contrast media and increases X-ray exposure; this subsequently provides no 3-dimensional information on the quality of the revascularization completed, what could explain some of the early and late failures of the technique. We evaluated whether intraoperative optical coherence tomography (OCT) control in addition to standard angiogram could improve the primary patency rate at 12 months in comparison to standard angiogram alone in patients with occlusive femoropopliteal lesions. METHODS: The tomography by optical coherence in femoral artery trial is a multicentric, prospective, randomized, controlled, and single-blind study including patients with long de novo occlusive femoropopliteal lesions. The randomization will be achieved in 2 balanced groups of patients after crossing successfully the lesion: group 1 with intraoperative OCT control in addition to standard angiogram and group 2 with standard angiogram alone. The randomization will be stratified by center. The protocol has been submitted and approved by a French ethic's committee under reference number CPP2019-12-098. The study has been registered under the reference number NCT04434586 on the Web site of clinicaltrials.gov. RESULTS: The primary outcome of the study is the primary patency at 12 months. The number of patients who need to be treated is 166 (83 in each group) considering 5% of no workable data. Symptoms' improvement, target lesion revascularization, target vessel revascularization, quality-of-life questionnaires, cost utility, and cost effectiveness will be analyzed as secondary end-point variables at 12 months. CONCLUSIONS: The present study is to evaluate the potential benefit for patients on the result of endovascular revascularization of long occlusive femoropopliteal lesion at 12 months when using intraoperative OCT control.

What is the budget impact of a new treatment or new health technology arriving on the market?

In France, market access for innovative drugs (level I, II & III improvement of medical service rendered having significant impact on health insurance expenditure) involves medico-economic evaluation. In addition to cost-effectiveness analysis (CEA), budget impact analysis (BIA) can be performed, especially since the sustainability of the health insurance system has become a growing concern for all stakeholders. The members of the Giens 2016 round table discussed the contribution of BIA based on a review of the literature on distribution models, the participants' experiences including experience related to the modalities of hospital assessments, and examples from other countries. The round table established recommendations on four elements of interest: 1: the use of BIA from a contractual point of view - between manufacturers and the French Economic Committee for Health Products - during the price negotiations process, and from a prospective point of view within the framework of the annual review of budget expenditures; the definition of the target population and the rhythm of a health product's distribution are also major elements; 2: the interpretation of BIA results in light of CEA results: for what products and at what moment in the life cycle of these products; 3: the integration of the rhythm of a health product's distribution into the BIA; 4: preoccupations about how the level of health product implementation is integrated into the BIA in terms of opportunity cost and organisational quality for the promoter.

Cost-Effectiveness Analysis of Five Competing Strategies for the Management of Multiple Recurrent Community-Onset Clostridium difficile Infection in France.

BACKGROUND: Clostridium difficile infection (CDI) is characterized by high rates of recurrence, resulting in substantial health care costs. The aim of this study was to analyze the cost-effectiveness of treatments for the management of second recurrence of community-onset CDI in France. METHODS: We developed a decision-analytic simulation model to compare 5 treatments for the management of second recurrence of community-onset CDI: pulsed-tapered vancomycin, fidaxomicin, fecal microbiota transplantation (FMT) via colonoscopy, FMT via duodenal infusion, and FMT via enema. The model outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) among the 5 treatments. ICERs were interpreted using a willingness-to-pay threshold of €32,000/QALY. Uncertainty was evaluated through deterministic and probabilistic sensitivity analyses. RESULTS: Three strategies were on the efficiency frontier: pulsed-tapered vancomycin, FMT via enema, and FMT via colonoscopy, in order of increasing effectiveness. FMT via duodenal infusion and fidaxomicin were dominated (i.e. less effective and costlier) by FMT via colonoscopy and FMT via enema. FMT via enema compared with pulsed-tapered vancomycin had an ICER of €18,092/QALY. The ICER for FMT via colonoscopy versus FMT via enema was €73,653/QALY. Probabilistic sensitivity analysis with 10,000 Monte Carlo simulations showed that FMT via enema was the most cost-effective strategy in 58% of simulations and FMT via colonoscopy was favored in 19% at a willingness-to-pay threshold of €32,000/QALY. CONCLUSIONS: FMT via enema is the most cost-effective initial strategy for the management of second recurrence of community-onset CDI at a willingness-to-pay threshold of €32,000/QALY.

Epidemiological impact and cost-effectiveness of introducing vaccination against serogroup B meningococcal disease in France.

INTRODUCTION: Despite its low incidence in France, invasive serogroup B meningococcal disease remains a public health concern. A new vaccine against the disease, Bexsero(®), has been licensed in the EU. We studied the epidemiological impact and cost-effectiveness of routine vaccination using Bexsero(®) in order to inform the decision-making process regarding its potential inclusion in the vaccination schedule. METHODS: A multi-generational Markov model was used. Time horizon was set to 100 years. Five vaccination strategies were evaluated: infants at 3, 5, 6 and 13 months, toddlers at 13, 15 and 27 months and adolescents at 15 years provided 2 doses one month apart. A booster dose at 15 years old and a catch-up for 15 years old subjects during the first 15 years of the programme were added to the infant and toddler strategies. Costs per QALY gained were computed from a restricted societal perspective including direct costs only. Herd immunity was simulated in an alternative base-case scenario and sensitivity analyses. RESULTS: In the base-case analysis without herd immunity and with all cohorts vaccinated, at € 40 per vaccine dose, routine infant vaccination would provide the lowest cost per QALY gained (€ 380,973) despite only preventing 18% of cases. Under the assumption of herd immunity, the adolescent vaccination would provide the lowest cost per QALY gained (€ 135,902) preventing 24% of cases. Infant vaccination with a late booster and catch-up would prevent 51% of cases with a cost of € 188,511 per QALY gained. CONCLUSIONS: Given current meningococcal epidemiology in France and the available data on the protection provided by Bexsero(®), our modelling work showed that routine vaccination against serogroup B meningococcal disease is not cost-effective.

Transfusion strategy in hematological intensive care unit: study protocol for a randomized controlled trial.

BACKGROUND: Packed red blood cell (PRBC) transfusion is required in hematology patients treated with chemotherapy for acute leukemia, autologous (auto) or allogeneic (allo) hematopoietic stem cell transplantation (HSCT). In certain situations like septic shock, hip surgery, coronary disease or gastrointestinal hemorrhage, a restrictive transfusion strategy is associated with a reduction of infection and death. A transfusion strategy using a single PRBC unit has been retrospectively investigated and showed a safe reduction of PRBC consumption and costs. We therefore designed a study to prospectively demonstrate that the transfusion of a single PRBC unit is safe and not inferior to standard care. METHODS: The 1versus2 trial is a randomized trial which will determine if a single-unit transfusion policy is not inferior to a double-unit transfusion policy. The primary endpoint is the incidence of severe complication (grade ≥ 3) defined as stroke, transient ischemic attack, acute coronary syndrome, heart failure, elevated troponin level, intensive care unit transfer, death, new pulmonary infiltrates, and transfusion-related infections during hospital stays. The secondary endpoint is the number of PRBC units transfused per patient per hospital stay. Two hundred and thirty patients will be randomized to receive a single unit or double unit every time the hemoglobin level is less than 8 g/dL. All patients admitted for induction remission chemotherapy, auto-HSCT or allo-HSCT in hematology intensive care units will be eligible for inclusion. Sample size calculation has determined that a patient population of 230 will be required to prove that the 1-unit PRBC strategy is non-inferior to the 2-unit PRBC strategy. Hemoglobin threshold for transfusion is below 8 g/dL. Estimated percentage of complication-free hospital stays is 93 %. In a non-inferiority hypothesis, the number of patients to include is 230 with a power of 90 % and an alpha risk of 5 %. TRIAL REGISTRATION: 14-128; Clinicaltrials.gov NCT02461264 (registered on 3 June 2015).

Extending the Human Papillomavirus Vaccination Programme to Include Males in High-Income Countries: A Systematic Review of the Cost-Effectiveness Studies.

BACKGROUND AND OBJECTIVES: Giving the human papillomavirus (HPV) vaccination to females has been shown to be cost-effective in most countries. The epidemiological evidence and economic burden of HPV-related diseases have gradually been shown to be gender neutral. Randomized clinical trials report high efficacy, immunogenicity and safety of the HPV vaccine in males aged 16-26 years. Some pioneering countries extended their HPV vaccination programme to include males, regardless of the cost-effectiveness analysis results. Nevertheless, decision makers need evidence provided by modelling and economic studies to justify the funding of mass vaccination. This systematic review aims to assess the cost-effectiveness of extending the HPV vaccination programme to include males living in high-income countries. METHODS: A systematic review of the cost-effectiveness analyses of HPV vaccination in males was performed. Data were extracted and analysed using a checklist adapted from the Consolidated Health Economic Evaluation Reporting Standards Statement. RESULTS: Seventeen studies and 12 underlying mathematical models were identified. Model filiation showed evolution in time from aggregate models (static and dynamic) to individual-based models. When considering the health outcomes HPV vaccines are licensed for, regardless of modelling approaches and assumptions, extending vaccinations to males is rarely found to be cost-effective in heterosexual populations. Cost-effectiveness ratios become more attractive when all HPV-related diseases are considered and when vaccine coverage in females is below 40%. CONCLUSION: Targeted vaccination of men who have sex with men (MSM) seems to be the best cost-effectiveness option. The feasibility of this strategy is still an open question, since early identification of this specific population remains difficult.

Assessment and non-clinical impact of medical devices.

Medical devices (MDs) cover a wide variety of products. They accompany changes in medical practice in step with technology innovations. Innovations in the field of MDs can improve the conditions of use of health technology and/or modify the organisation of care beyond the strict diagnostic or therapeutic benefit for the patients. However, these non purely clinical criteria seem to be only rarely documented or taken into account in the assessment of MDs during reimbursement decisions at national level or for formulary listing by hospitals even though multidimensional models for the assessment of health technologies have been developed that take into account the views of all stakeholders in the healthcare system In this article, after summarising the background concerning the assessment of health technologies in France, a definition of non-clinical criteria for the assessment of MDs is proposed and a decision tree for the assessment of MDs is described. Future lines of approach are proposed as a conclusion.

Medico-economic evaluation of healthcare products. Methodology for defining a significant impact on French health insurance costs and selection of benchmarks for interpreting results.

Decree No. 2012-1116 of 2 October 2012 on medico-economic assignments of the French National Authority for Health (Haute autorité de santé, HAS) significantly alters the conditions for accessing the health products market in France. This paper presents a theoretical framework for interpreting the results of the economic evaluation of health technologies and summarises the facts available in France for developing benchmarks that will be used to interpret incremental cost-effectiveness ratios. This literature review shows that it is difficult to determine a threshold value but it is also difficult to interpret then incremental cost effectiveness ratio (ICER) results without a threshold value. In this context, round table participants favour a pragmatic approach based on "benchmarks" as opposed to a threshold value, based on an interpretative and normative perspective, i.e. benchmarks that can change over time based on feedback.

Social participation in patients with multiple sclerosis: correlations between disability and economic burden.

BACKGROUND: Economic costs related to treatment of multiple sclerosis (MS) must be justified by health state, quality of life (QOL) and social participation improvement. This study aims to describe correlations between social participation, economic costs, utility and MS-specific QOL in a sample of patients with MS (pwMS). METHODS: We interviewed 42 pwMS receiving natalizumab and collected clinical data, direct medical costs, productivity loss, utility (EQ5D-VAS), MS-specific QOL (SEP-59), social participation with the Impact on Participation and Autonomy questionnaire (IPA). We performed descriptive and correlation analyses. RESULTS: 41 pwMS, with a mean Expanded Disability Status Scale (EDSS) score of 4.0, completed questionnaires. Mean annual global cost per patient was 68448 +/-33374 Euros and increased with EDSS (r = 0.644), utility (r = -0.456) and IPA (r = 0.519-0.671) worsening. Mean utility was 0.52 +/- 0.28. Correlations between IPA and QOL (EQ5D-VAS or SEP-59) were observed (r = -0.53 to -0.78). Association between QOL and EDSS was smaller (EQ5D-VAS) or absent. Productivity losses were poorly correlated to EDSS (r = 0.375). CONCLUSION: Moderate to strong correlations of social participation with clinical status (EDSS), QOL, utility and economic costs encourage exploring better these links in larger cohorts. The stronger correlation between social participation and QOL than between EDSS and QOL needs to be confirmed.

Medico-economic evaluation of health products in the context of the Social Security Financing Act for 2012.

The participants in round table 6 of the Giens Workshops 2012 drafted recommendations based on the collective interpretation of important elements of the decree concerning the medico-economic evaluation of health products published a few days earlier (02 October 2012). The medico-economic evaluation (MEE), becomes an additional determinant for fixing the prices of health products by the Health products economic committee (Comité économique des produits de santé, CEPS) via the hierarchisation of treatment strategies, and thus modifies the market access conditions. Limiting the analysis to medicinal products and medical devices for which a major, important or moderate improvement in the medical service rendered (ASMR) or of the expected service (ASA) has been requested and presenting a significant budget impact on the Social Security expenses, excludes health products with ASMR or ASA with a lower level requested which often create complex price fixing problems and often have a major budget impact. This latter concept remains to be defined in detail. The MEE envisaged for the first registration must include the need to confirm or refute the initial hypotheses especially concerning the actual position in the therapeutic strategy at the time of renewal of the registration. For the first registration, the conventional reference to European prices guaranteeing a minimum price to innovative medicinal products, the medico-economic models submitted by the industry to the French Drug Authority (Haute autorité de santé, HAS) must be used to guide the compilation of new data to be requested at the time of the registration renewal and to negotiate the level of the discounts in the framework of a price-volume agreement, if applicable. The MEE will allow comparing the result of the analysis to the model hypothesis at the time of the renewal of the registration, which may contribute to the renegotiation (either up or down) of the price of health goods. The costs related to obtaining new data must be controlled. In order for the MEE to allow confirming the relationship between the price requested and the benefit expected, the group privileges the definition of reference values with an indicative and non-normative value, likely to evolve with time rather than a threshold. Concerning the evaluation procedure: the time to market access must not be lengthened; while the possibility of regular meetings between the industry and the HAS is recommended to avoid methodological divergences. A transitory period should allow the implementation of the entire evaluation procedure which must also take into account the specificities of health products registered before the 3 October 2013.

Use of biological mesh versus standard wound care in infected incisional ventral hernias, the SIMBIOSE study: a study protocol for a randomized multicenter controlled trial.

BACKGROUND: In infected incisional ventral hernias (IVHs), the use of a synthetic non-absorbable mesh is not recommended and biological meshes hold promise. However, the level of evidence for their safety and efficacy remains low. METHODS: The SIMBIOSE trial is a multicenter, phase III, randomized, controlled trial comparing the use of a biological mesh versus traditional wound care in patients with an IVH. The primary end point is 6-month infectious and/or wound morbidity. Secondary end points are wound infection and recurrent hernia rates, post-operative pain, quality of life, time to heal, reoperation need, impact of the cross-linked mesh structure, and a medico-economic evaluation. One hundred patients need to be included. RESULTS: The main results expected with biological mesh use are a significant decrease of post-operative morbidity, hernia recurrence, time to heal, and costs with an improved quality of life. CONCLUSIONS: For the first time, the impact of biological meshes in the treatment of IVHs will be evaluated in an academic, randomized, phase III trial to provide scientific evidence (NCT01594450). TRIAL REGISTRATION: ClinicalTrial.gov, NCT01594450.