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International audience; Background: Oncology is among the most active therapeutic fields in terms of new drug development projects, with increasingly expensive drugs. The expected clinical benefit and cost effectiveness of these treatments in clinical practice have yet to be fully confirmed. Health medico-administrative databases may be useful for assessing the value of anticancer drugs with real-world data.Objective: The objectives of our systematic literature review (SLR) were to analyse economic evaluations of anticancer drugs based on health medico-administrative databases, to assess the quality of these evaluations, and to identify the inputs from such databases that can be used in economic evaluations of anticancer drugs.Methods: We performed an SLR by using PubMed and Web of Science articles published from January 2008 to January 2019. The search strategy focused on anticancer drug cost-effectiveness analyses (CEAs)/cost-utility analyses (CUAs) that were entirely based on medico-administrative databases. The review reported the main choices of economic evaluation methods in the analyses. The quality of the articles was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and risk of bias assessment checklists.Results: Of the 306 records identified in PubMed, 12 articles were selected, and one additional article was identified through Web of Science. Ten of the 13 articles were CEAs and three were CUAs. Most of the analyses were carried out in North America (n = 11). The economic metric used was the cost per life-year gained (n = 10) or cost per quality-adjusted life-year (n = 3). Reporting of the target analysis population and strategies in the articles was in agreement with the CHEERS guidelines. The structural assumptions underpinning the economic models displayed the poorest reporting quality among the items analysed. Representativeness bias (n = 11) and the issue of censored medical costs (n = 8) were the most frequently analysed risks.Conclusion: A comparison of the economic results was not relevant due to the high heterogeneity of the selected studies. Our SLR highlighted the benefits and pitfalls related to the use of medico-administrative databases in the economic evaluations of anticancer drugs.

Healthcare resource allocation decisions made under conditions of uncertainty may turn out to be suboptimal. In a resource constrained system in which there is a fixed budget, these suboptimal decisions will result in health loss. Consequently, there may be value in reducing uncertainty, through the collection of new evidence, to make better resource allocation decisions. This value can be quantified using a value of information (VOI) analysis. This report, from the ISPOR VOI Task Force, introduces VOI analysis, defines key concepts and terminology, and outlines the role of VOI for supporting decision making, including the steps involved in undertaking and interpreting VOI analyses. The report is specifically aimed at those tasked with making decisions about the adoption of healthcare or the funding of healthcare research. The report provides a number of recommendations for good practice when planning, undertaking, or reviewing the results of VOI analyses.

Health care decision makers in many jurisdictions use cost-effectiveness analysis based on health economic decision models for policy decisions regarding coverage and price negotiation for medicines and medical devices. While validation of health economic decision models has always been considered important, many reviews of model-based cost-effectiveness studies report limitations regarding their validation. The current opinion paper discusses four aspects of current health economic decision modeling with relevance for future directions in model validation: increased use of complex models, international cooperation, open-source modeling, and stakeholder involvement. First, new, more complex clinical study designs and treatment strategies may require relatively complex model structures and/or input data analyses. Simultaneously, more widespread technical knowledge along with wider data availability have led to a broader range of model types. This puts extra requirements on model validation and transparency. Second, increased international cooperation of policy makers and, in particular, health technology assessment (HTA) authorities in performing model assessments is discussed in relation to the repeated use of health economic models (multi-use disease models). We argue such coordinated efforts may benefit model validity. Third, open-source modeling is discussed as one possible answer to increased transparency requirements. Finally, involvement of all relevant stakeholders throughout the whole decision process is an ongoing development that necessarily also includes health economic modeling. We argue this implies that model validity should be considered in a broader perspective, with more focus on conceptual modeling, model transparency, accuracy requirements, and choice of relevant model outcomes than previously.

This systematic literature review (SLR) had two objectives: to analyse published economic evaluations of biological disease-modifying anti-rheumatic drugs (bDMARDs) for patients with moderate to severe rheumatoid arthritis (RA) previously treated with DMARDs and to assess the quality of those that included sequences of treatments. We performed an SLR on PubMed, Central, Cochrane, and French databases from January 2000 to December 2018. The search focused on cost-effectiveness/utility/benefit analyses. We extracted data on treatment sequences, outcomes (e.g. quality-adjusted life year) and choices of economic evaluation methods (e.g. model type, type of analysis, and method of utility estimation). We analysed the improvement of methods by comparing two sub-periods (2000–2009 and 2010–2018). The quality of reporting and the quality of the methods were assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) and a set of eight key aspects for a reference case for economic evaluation of bDMARDs based on the Outcome Measures in Rheumatology (OMERACT) and Drummond checklists. Data extraction and study assessment were performed independently by two health economists. From the 824 records identified in the initial search, 51 publications were selected. Of these, 31 included sequences. Individual models such as discrete-event simulations were used in over two-fifths (22/51, 43%) of the selected studies. Few studies (7/51, 14%) used utility scores based on generic instruments (e.g. EQ-5D). Estimation of hospitalization costs was described in only approximately one-third of studies (19/51). Loss of quality of life (QoL) related to adverse events such as tuberculosis and pneumonia was included in one-tenth (5/51, 10%) of the studies. It was difficult to compare the results of the economic evaluations (i.e. incremental cost-effectiveness ratios) due to the high heterogeneity of studies in terms of disease stage, data sources, inputs, and methods of health outcome assessment used. For identified studies including sequences, the CHEERS assessment of reporting quality showed insufficient reporting of uncertainty analyses and utility weights in more than a third of the studies (11/31, 35%; 9/25, 36%). An in-depth assessment of the quality of the studies revealed that only seven, mostly conducted during the sub-period 2010–2018, addressed the majority of methodological quality assessment issues such as the simulation of patient sequence pathways, the use of systematic reviews and meta-analyses of comparative effectiveness, the choice of treatment sequence, and rules for switching. Our SLR identified a lack of high-quality evaluations assessing bDMARD sequences, although some improvements were made in the reporting and modelling of patients’ pathways in studies published after 2010. In order to improve economic evaluations of RA, clear health technology assessment guidance on RA health-related QoL instruments must be provided, and data including long-term disease progression must be made available.

The allocation of health care resources among competing priorities requires an assessment of the expected costs and health effects of investing resources in the activities, and on the opportunity cost of the expenditure. To date, much effort has been devoted to assessing the expected costs and health effects, but there remains an important need to also reflect the consequences of uncertainty in resource allocation decisions and the value of further research to reduce uncertainty. Decision-making with uncertainty may turn out to be suboptimal, resulting in health loss. Consequently, there may be value in reducing uncertainty, through the collection of new evidence, to better inform resource decisions. This value can be quantified using\ud Value of Information (VOI) analysis. This report, from the ISPOR VOI Task Force, describes methods for computing four VOI measures: the Expected Value of Perfect Information (EVPI), Expected Value of Partial Perfect Information (EVPPI), Expected Value of Sample Information (EVSI) and Expected Net Benefit of Sampling (ENBS). Several methods exist for computing EVPPI and EVSI, and this report provides guidance on selecting the most appropriate method based on the features of the decision problem. The report provides a number of recommendations for good practice when planning, undertaking or reviewing VOI analyses. The software needed to compute VOI is discussed, and areas for future research are highlighted.

Models have become a nearly essential component of health technology assessment. This is because the efficacy and safety data available from clinical trials are insufficient to provide the required estimates of impact of new interventions over long periods of time and for other populations and subgroups. Despite more than five decades of use of these decision-analytic models, decision makers are still often presented with poorly validated models and thus trust in their results is impaired. Among the reasons for this vexing situation are the artificial nature of the models, impairing their validation against observable data, the complexity in their formulation and implementation, the lack of data against which to validate the model results, and the challenges of short timelines and insufficient resources. This article addresses this crucial problem of achieving models that produce results that can be trusted and the resulting requirements for validation and transparency, areas where our field is currently deficient. Based on their differing perspectives and experiences, the authors characterize the situation and outline the requirements for improvement and pragmatic solutions to the problem of inadequate validation.

International audience

Objectives Biologic disease-modifying antirheumatic drugs (bDMARDs) are prescribed sequentially in the treatment of rheumatoid arthritis (RA). Healthcare decision makers continue to debate their use, mainly because of their high costs. Our aim was to perform an economic evaluation for France of bDMARD sequences for treatment of moderate-to-severe RA after inadequate response or intolerance to conventional DMARDs (eg, methotrexate). Methods A discretely integrated condition event simulation was developed to track the course of patients from first bDMARD through switches to further lines in a sequence. The model included 11 events, 91 conditions, and 21 controlling equations. Inputs were obtained from a meta-analysis of clinical trials, a French registry, national drug lists, and databases. Survival, time with minimal activity, quality-adjusted life-years (QALYs), and total costs were output. Structural and probabilistic sensitivity analyses were conducted. Results Sequences starting with etanercept biosimilars (ETB) cost less, with ETB–abatacept–infliximab the least expensive: the mean lifetime discounted total cost was €116 912 per patient, with a mean of 11.166 QALYs. Most other strategies were dominated or led to small QALY gains (0.0008-0.0329). Only ETB–tocilizumab–abatacept made it onto the efficiency frontier, but at €955 778 per QALY gained. These results were confirmed in several scenarios and uncertainty analyses. Conclusion Given minor differences in QALYs gained between bDMARD sequences with large cost differences, starting with biosimilars was more efficient than starting with branded products. Our model and findings should provide French and other decision makers with useful tools to address the challenges of comparing sequences of treatments for RA.

ObjectivesThe aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses.MethodsSystematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical.ResultsForty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs.ConclusionsIn MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

International audience; Providing scientific advice and recommendations for public decision making entails identifying, selecting and weighing evidence derived from multiple sources of information through a systematic approach, while taking into account ethical, cultural and societal factors. Integrated in the evaluation process are exchanges between regulatory agencies, private firms, scientific experts and government representatives. In the case of drugs and medical devices, health technology assessment (HTA) agencies are increasingly commissioned to evaluate innovations in order to provide government with recommendations and advice on reimbursement and/or pricing. To undertake this task, HTA agencies [1–6] in Europe and elsewhere have developed methodological guidelines on the economic evaluation of health technologies [7]. One component of these guidelines deals with ways for both manufacturers (pharmaceutical and medical device firms) and HTA agencies evaluators (modelers, economists and public health experts) to address uncertainty. Several types of uncertainty have indeed been identified in HTA: methodological, parameter and structural uncertainty. Most guidelines describe quite well how to deal with the first two categories, although there is still room for improvement. However, recommendations about how to tackle structural uncertainty remain largely elusive. HTA agencies and decision makers may thus be exposed to oversimplifying assessments and recommendations by putting aside complex forms of uncertainty such as struc-tural ‘deep’ uncertainty [8]. The editorial is not intended to promote new approaches to exploring structural uncertainty, rather to emphasizeconcerns related to the topic, such as definition and analysis. Our aim is therefore to highlight the need to renew the analytical framework guidance for HTA.

International audience; Background - Budget impact analysis (BIA) provides short- and medium-term estimates on changes in budgets and health outcomes resulting from the adoption of new health interventions. Objective - The purpose of this study is to present the newly developed French National Authority for Health (HAS) guidelines on budget impact analysis as follows: process, literature review, recommendations and comparisons with other guidelines. Methods - The development process of the HAS guidelines included a literature review (search dates: January 2000 to June 2016), a retrospective investigation of BIA previously submitted to HAS, a public consultation, international expert reviews and approval from the HAS Board and the Economic and Public Health Evaluation Committee of HAS. Results - Documents identified in the literature review included 12 national guidelines, 5 recommendations for good practices developed by national and international society of health economics and 14 methodological publications including recommendations for conducting BIA. Based on its research findings, HAS developed its first BIA guidelines, which include recommendations on the following topics: BIA definition, perspective, populations, time horizon, compared scenarios, budget impact models, costing, discounting, choice of clinical data, reporting of results and uncertainty exploration. Conclusion - It is expected that the HAS BIA guidelines will enhance the usefulness, quality and transparency of BIA submitted by drug manufacturers to HAS. BIA is becoming an essential part of a comprehensive economic assessment of healthcare interventions in France, which also includes cost-effectiveness analysis and equity of access to healthcare.

L’objectif de cet article est de presenter, sans formalisation statistique excessive, la methode des variables instrumentales (VI) pour analyser la securite comparative des interventions en vie reelle. La methode des VI est utilisee dans le cadre des etudes observationnelles. Nous l’illustrerons a l’aide d’un exemple de la litterature portant sur la securite comparative des anti-inflammatoires non steroidiens (AINS) utilisant les preferences de prescription des medecins pour les AINS comme VI. L’approche des VI permet de controler le biais d’indication mais elle est toutefois tres contraignante au niveau de la verification de la validite des VI.

L’effet d’un medicament peut etre different en pratique quotidienne de ce qu’il etait au cours de la recherche clinique ou au moment de la negociation de son prix avant sa mise sur le marche des medicaments remboursables. Les contrats conditionnels, fondes sur les resultats de sante, ont ete crees pour se premunir contre ce risque. Moyennant un accord rapide sur le prix, le laboratoire pharmaceutique prend l’engagement de rembourser en partie ou en totalite la valeur qui a ete negociee si les resultats du traitement ne sont pas a la hauteur des espoirs suscites. Ces contrats d’acces au marche des medicaments remboursables sont etudies ici a la lumiere des schemas d’etudes qui president a leur mise en œuvre. Ils reposent pour l’essentiel sur des etudes descriptives ou normatives sans groupe temoin, etudes qui ne permettent pas de mesurer l’impact du medicament sur la sante. La fixation du prix du medicament sur de telles bases risque d’etre fragilisee par la modeste qualite des preuves avancees pour en justifier l’octroi. Pour remedier a cette situation, nous proposons la mise en place d’etudes observationnelles comparatives, dont les populations devront etre rendues comparables par la mise en œuvre des techniques micro-econometriques appropriees.

Budget impact analysis (BIA) provides short and medium-term estimates on changes in budgets and resources resulting from the adoption of new health interventions.The objective of this article is to present the main messages of the newly developed French National Authority for Health (HAS) guidelines on budget impact analysis : issues, recommendations and perspectives.The HAS guidelines development process was based on data derived from a literature review on BIA (search dates : January 2000 to June 2016), an HAS retrospective investigation, a public consultation, international expert advice, and approval from the HAS Board and the Economic and Public Health Evaluation Committee.Based on its research findings, HAS developed its first BIA guidelines, which include recommendations on the following topics : BIA definition, perspective, populations, time horizon, compared scenarios, budget impact models, costing, discounting, choice of clinical data, reporting of results and uncertainty analysis.The HAS BIA guidelines are expected to enhance the usefulness of BIA as an essential part of a comprehensive economic assessment of healthcare interventions, which itself includes cost-effectiveness analysis and equity of access to healthcare.

International audience; Introduction : L’analyse d’impact budgétaire (AIB) est une approche économique destinée à estimer, sur un horizon temporel à court et à moyen terme, les conséquences budgétaires annuelles de l’adoption d’une intervention de santé.Objectif : L’objectif de cet article est de présenter les principaux enseignements du premier guide de la Haute Autorité de santé (HAS) sur les choix méthodologiques pour la conduite d’une AIB, en synthétisant ses enjeux, recommandations et perspectives.Méthodes : L’identification des choix méthodologiques relatifs à la conduite d’une AIB a été fondée sur une recherche documentaire portant sur la période comprise entre janvier 2000 et juin 2016, une étude-pilote rétrospective portant sur les AIB soumises à la HAS de novembre 2011 à juin 2015, une consultation publique et une relecture d’experts internationaux. Les recommandations formulées ont été approuvées par la Commission d’évaluation économique et de santé publique (CEESP) et le Collège de la HAS.Résultats : Le guide méthodologique propose une définition opérationnelle de l’AIB, les principales différences entre une AIB et une étude coût-efficacité/utilité et des recommandations sur les choix structurants suivants : la perspective, les populations, l’horizon temporel, les scénarios comparés, les modèles d’AIB, les coûts, l’actualisation, le choix des données cliniques, la présentation des résultats d’une AIB et l’exploration de l’incertitude.Conclusion : L’AIB complète l’usage de l’analyse coût-efficacité/utilité et renforce l’importance de l’évaluation économique des interventions de santé en France. Le guide ouvre également des perspectives de recherches complémentaires sur l’articulation entre l’analyse coût-efficacité/utilité, l’AIB et l’équité dans l’accès aux soins.

International audience; Background: Our aim was to review the selection and methods used for deriving health state utility (HSU) estimates included in the cost-utility analyses (CUA) submitted by manufacturers to the National Authority for Health (HAS) during the first 2years after the introduction of the economic evaluation for price setting in France.Methods: We reviewed all manufacturers' submissions that included a CUA and were assessed by HAS by the end of October 2015 (N=34). We reviewed the identification, selection, and methods used to estimate HSU and compared them with those recommended by HAS.Results: A literature review to identify HSU was reported in only 13 (38%) submissions. The instruments for describing HSU were a preference-based generic instrument in 20 (59%) submissions; vignettes in five (15%); a condition-specific instrument in three (9%); and a combination of instruments in six (18%). The valuation perspective was the general population in 26 (76%) submissions; in only nine (26%) submissions, the valuation set was derived from the French general population.Conclusions: We identified numerous concerns in the selection, valuation and use of HSU, as well as a frequent lack of clarity in the methods used. Most submissions (79%) included HSU that did not meet HAS recommendations.

International audience; ObjectivesThe objective of this paper was to evaluate how uncertainty has been accounted for in the cost-effectiveness analyses (CEAs) submitted by manufacturers to the French National Authority for Health (HAS) and to identify recurring concerns in these submissions.MethodsWe used a cross-sectional design to evaluate manufacturers’ submissions from the beginning of the evaluation process in October 2013 to the end of May 2015 (n = 28). The sources of uncertainty attached to these CEAs were categorized and assessed. Relevant data were extracted independently by two assessors.ResultsAdherence to the HAS reference case was generally considered to be acceptable. Methodological uncertainty and parameter uncertainty were the sources of uncertainty that were most frequently explored by manufacturers. The quality of reporting of deterministic sensitivity analysis and probabilistic sensitivity analysis varied substantially across submissions, with a frequent lack of justification of the plausible range of parameter point estimates in 12 submissions (43 %). Structural uncertainty was explored much less frequently. Concerns related to omission of either important clinical events or relevant health states or extrapolation of the effects of the technology beyond the time horizon of the clinical trials were identified in 16 submissions (57 %).ConclusionsThis study presented a characterization of the treatment of uncertainty for the first 28 manufacturers’ submissions to the HAS. This work identified important concerns regarding the exploration of sources of uncertainty. The findings may help manufacturers to improve the quality of their submissions and may provide useful insights for extending guidelines on uncertainty analysis in CEAs submitted to the HAS.

The objectives of this study were to review current methodological guidelines for economic evaluations of all types of technologies in the 33 countries with organizations involved in the European Network for Health Technology Assessment (EUnetHTA), and to provide a general framework for economic evaluation at a European level. Methodological guidelines for health economic evaluations used by EUnetHTA partners were collected through a survey. Information from each guideline was extracted using a pre-tested extraction template. On the basis of the extracted information, a summary describing the methods used by the EUnetHTA countries was written for each methodological item. General recommendations were formulated for methodological issues where the guidelines of the EUnetHTA partners were in agreement or where the usefulness of economic evaluations may be increased by presenting the results in a specific way. At least one contact person from all 33 EUnetHTA countries (100 %) responded to the survey. In total, the review included 51 guidelines, representing 25 countries (eight countries had no methodological guideline for health economic evaluations). On the basis of the results of the extracted information from all 51 guidelines, EUnetHTA issued ten main recommendations for health economic evaluations. The presented review of methodological guidelines for health economic evaluations and the consequent recommendations will hopefully improve the comparability, transferability and overall usefulness of economic evaluations performed within EUnetHTA. Nevertheless, there are still methodological issues that need to be investigated further.

INTRODUCTION:Budget impact analysis (BIA) provides short and medium-term estimated effect of new health interventions on budgets and resources. Since January 2016, BIA is required as part of economic dossiers submitted to the French National Authority for Health (HAS) by manufacturers for innovative drugs with an expected 2-year sales revenue above EUR50 million. To this end and in order to promote good practices for conducting BIA, HAS developed a guide for BIA.Our objectives are: –to present the guide development method and the resulting recommendations;–to compare the HAS BIA guide with existing BIA guides.METHODS:The HAS guide development process rests on findings derived from a systematic literature review on BIA methodology, an HAS retrospective investigation of BIA, public consultation, international expert advice, and approval from the HAS Board and Committee of Health Economic and Public Evaluation (CEESP). Relevant publications were identified through Pubmed and EMBASE and the grey literature (search dates: January 2000 to June 2016).RESULTS:The search strategy captured 144 publications of which 31 were retained (14 methodological papers, 12 national guides and 5 learned society recommendations). On the basis of this result, an extraction template was designed to synthesize the methodological aspects of BIA. Based on its research findings, HAS developed its first BIA guide which includes recommendations on the following main topics: BIA definition, perspective, populations, time horizon, compared scenarios, BIA models, costing, discounting, choice of clinical data, reporting of BIA and uncertainty exploration.Compared to existing BIA guides from other Health Technology Assessment (HTA) agencies, the HAS guide specifically described issues relating to off-label use of drugs, disease-related costs and scenario analysis.CONCLUSIONS:It is expected that the HAS BIA guide will improve the quality, transparency and standardization of BIA in France. It should also enhance the usefulness of BIA as an essential part of a comprehensive economic assessment of health care interventions.

Rationality of household expectations : qualitative tests on french individual data Qualitative answers given in the INSEE conjonctural surveys (1972-1994) by 2500 households in two consecutive years, allow us to test the rationality of price and unemployement expectations. Contrary to the results obtained after a quantification of the data, the rationality properties, in Gourieroux-Pradel test (1986), tend to be verified by part of the population, another part having correct expectations. Finally, the adaptive model seems to be the main expectation process for households., Rationalité des anticipations des ménages. Tests qualitatifs sur données individuelles françaises Les teste de la forme faible de rationalité opérés sur les données quantifiées des Enquêtes de conjoncture auprès des ménages ont abouti au rejet systémati­que de la rationalité (Ghabri et Gardes [1996]) mais l'analyse d'un pseudo-panel montre que les propriétés d'absence de biais et d'efficience sont acceptées pour certaines sous-périodes. Les teste qualitatifs de rationalité de Gouriéroux et Pra-del [1986] fournissent un même résultat pour l'ensemble de la population mais montrent qu'à chaque période, une partie des ménages fait des anticipations rationnelles, une autre partie faisant des anticipations correctes. Par ailleurs, nous vérifions, par un comptage qualitatif, que le modèle adaptatif est le processus majoritaire qui explique la formation des anticipations des ménages., Ghabri Salah, Madre Jean-Loup, Gardes François, Pichery Marie-Claude. Rationalité des anticipations des ménages. Tests qualitatifs sur données individuelles françaises. In: Revue économique, volume 48, n°3, 1997. pp. 639-652.

BACKGROUND: Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2(nd) stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use.METHODOLOGY: In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2(nd) stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation.PRINCIPAL FINDINGS: 629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings.CONCLUSIONS/SIGNIFICANCE: In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up. REGISTRATION: The trial is registered at ClinicalTrials.gov, number NCT00906880.

International audience

These data contributed to a 2007 WHO recommendation for a fractional dosing strategy in the context of severe vaccine shortages during a meningitis epidemic., BACKGROUND: Neisseria meningitidis serogroup A is the main causative pathogen of meningitis epidemics in sub-Saharan Africa. In recent years, serogroup W135 has also been the cause of epidemics. Mass vaccination campaigns with polysaccharide vaccines are key elements in controlling these epidemics. Facing global vaccine shortage, we explored the use of fractional doses of a licensed A/C/Y/W135 polysaccharide meningococcal vaccine. METHODS AND FINDINGS: We conducted a randomized, non-inferiority trial in 750 healthy volunteers 2-19 years old in Mbarara, Uganda, to compare the immune response of the full dose of the vaccine versus fractional doses (1/5 or 1/10). Safety and tolerability data were collected for all subjects during the 4 weeks following the injection. Pre- and post-vaccination sera were analyzed by measuring serum bactericidal activity (SBA) with baby rabbit complement. A responder was defined as a subject with a >/=4-fold increase in SBA against a target strain from each serogroup and SBA titer >/=128. For serogroup W135, 94% and 97% of the vaccinees in the 1/5- and 1/10-dose arms, respectively, were responders, versus 94% in the full-dose arm; for serogroup A, 92% and 88% were responders, respectively, versus 95%. Non-inferiority was demonstrated between the full dose and both fractional doses in SBA seroresponse against serogroups W135 and Y, in total population analysis. Non-inferiority was shown between the full and 1/5 doses for serogroup A in the population non-immune prior to vaccination. Non-inferiority was not shown for any of the fractionate doses for serogroup C. Safety and tolerability data were favourable, as observed in other studies. CONCLUSIONS: While the advent of conjugate A vaccine is anticipated to largely contribute to control serogroup A outbreaks in Africa, the scale-up of its production will not cover the entire "Meningitis Belt" target population for at least the next 3 to 5 years. In view of the current shortage of meningococcal vaccines for Africa, the use of 1/5 fractional doses should be considered as an alternative in mass vaccination campaigns. TRIAL REGISTRATION: ClinicalTrials.gov NCT00271479.

Background. Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are either highly toxic or impracticable in field conditions. We compared the efficacy and safety of the nifurtimox-eflornithine drug combination with the standard eflornithine regimen for the treatment of second- stage disease. Methods. A randomized, open-label, active-control, phase III clinical trial comparing 2 arms was conducted at the Sleeping Sickness Treatment Center, which was run by Medecins Sans Frontieres, in Nkayi, Bouenza Province, Republic of Congo. Patients were screened for inclusion and randomly assigned to receive eflornithine alone (400 mg/kg per day given intravenously every 6 h for 14 days) or eflornithine (400 mg/kg per day given intravenously every 12 h for 7 days) plus nifurtimox (15 mg/kg per day given orally every 8 h for 10 days). Patients were observed for 18 months. The study's outcomes were cure and adverse events attributable to treatment. Results. A total of 103 patients with second-stage disease were enrolled. Cure rates were 94.1% for the eflornithine group and 96.2% for the nifurtimox-eflornithine group. Drug reactions were frequent in both arms, and severe reactions affected 25.5% of patients in the eflornithine group and 9.6% of those in the nifurtimox-eflornithine group, resulting in 2 and 1 treatment suspensions, respectively. There was 1 death in the eflornithine arm and no deaths in the nifurtimox-eflornithine arm. Conclusions. The nifurtimox-eflornithine combination appears to be a promising first-line therapy for second-stage sleeping sickness. If our findings are corroborated by ongoing findings from additional sites (a multicenter extension of this study), the new nifurtimox-eflornithine combination therapy will mark a major and multifaceted advance over current therapies. Human African trypanosomiasis (HAT), or sleeping sickness, remains a public health challenge in sub-Saharan Africa, with an estimated 50,000-70,000 new cases per year, of which ∼20,000 are detected and reported (1). The disease is caused by the protozoan parasite Trypanosoma brucei gambiense, which is transmitted by the tsetse fly (Glossina species), and it pro- gresses from the hemolymphatic first stage to the meningo- encephalitic second stage. It is invariably fatal without appro- priate treatment. Since 1949, melarsoprol is the most commonly used treatment for second-stage HAT. This arsenical derivative is associated with severe toxic effects—in particular, reactive encephalopathy, which is fatal in 10%-70% of cases and affects 5%-10% of treated patients (2, 3). Moreover, in

Objectives: Our objective was to compare the efficacy and safety of three drug combinations for the treatment of late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense. Design: This trial was a randomized, open-label, active control, parallel clinical trial comparing three arms. Setting: The study took place at the Sleeping Sickness Treatment Center run by Médecins Sans Frontières at Omugo, Arua District, Uganda Participants: Stage 2 patients diagnosed in Northern Uganda were screened for inclusion and a total of 54 selected. Interventions: Three drug combinations were given to randomly assigned patients: melarsoprol-nifurtimox (M+N), melarsoprol-eflornithine (M+E), and nifurtimox-eflornithine (N+E). Dosages were uniform: intravenous (IV) melarsoprol 1.8 mg/kg/d, daily for 10 d; IV eflornithine 400 mg/kg/d, every 6 h for 7 d; oral nifurtimox 15 (adults) or 20 (children, Editorial Commentary Background: African trypanosomiasis, or sleeping sickness, is a serious illness that is thought to affect many tens of thousands of people each year in sub-Saharan Africa. The disease is caused by a single-celled parasite that is transmitted to people when they are bitten by an infected Tsetse fly. If the initial phase of the disease is not recognized and treated, the parasite infects the brain, resulting in confusion, sleep problems, and ultimately coma and death. Few treatment options exist, and the most commonly used drug, melarsoprol, is highly toxic; furthermore, parasites are evolving resistance to it in some regions. There is an urgent need to develop new drugs and to evaluate combinations of existing drugs for activity against African trypanosomiasis. Therefore a group of researchers from Epicentre, Médecins Sans Frontières, and the National Sleeping Sickness Control Programme in Uganda performed a trial evaluating the efficacy and safety of three drug combinations. The combinations compared were melarsoprol-nifurtimox, melarsoprol-eflornithine, and nifurtimox-eflornithine, and the researchers planned to recruit 435 people with second-stage African trypanosomiasis in Uganda who would be followed up for 24 months. The primary outcome for the trial was cure rate following treatment. However, once 54 patients had been recruited into the trial, it was obvious that the death rate was much higher among individuals receiving melarsoprol-nifurtimox; the trial was therefore stopped for ethical reasons and this paper reports the results obtained up to that point. What this trial shows: At follow-up, the cure rate observed for the nifurtimox-eflornithine combination was over twice that for melarsoprol-nifurtimox and substantially higher than that for melarsoprol-eflornithine. Although the number of participants recruited into the trial was much lower than originally planned, the differences in cure rates between nifurtimox-eflornithine and the other two treatments were statistically significant. Deaths and serious adverse events were much more common among patients receiving melarsoprol-nifurtimox than the other two combination therapies. Strengths and limitations: Trials evaluating treatments for African trypanosomiasis are very rare, and properly randomized studies such as this one provide important data on the efficacy and safety of different treatments. A high proportion of individuals recruited into the trial were followed up for the full two years, and the primary outcome of the trial—the cure rate—was appropriate. A key limitation of the study is that the trial was terminated early; therefore, the differences in efficacy observed in this trial should not be seen as definitive. Contribution to the evidence: The results from this trial suggest that the nifurtimox-eflornithine combination has potential as a future therapy for stage 2 African trypanosomiasis, and should be evaluated further in clinical trials. Very little other data currently exist on the efficacy and safety of this drug combination.

Joint space width (JSW) and narrowing (JSN) measurements on radiographs are currently the best way to assess disease severity or progression in hip osteoarthritis, yet we lack data regarding the most accurate and sensitive measurement technique. This study was conducted to determine the optimal radiograph and number of readers for measuring JSW and JSN. Fifty pairs of radiographs taken three years apart were obtained from patients included in a structure modification trial in hip osteoarthritis. Three radiographs were taken with the patient standing: pelvis, target hip anteroposterior (AP) and oblique views. Two trained readers, blinded to each other's findings, time sequence and treatment, each read the six radiographs gathered for each patient twice (time intervalor = 15 days), using a 0.1 mm graduated magnifying glass. Radiographs were randomly coded for each reading. The interobserver and intraobserver cross-sectional (M0 and M36) and longitudinal (M0-M36) reproducibilities were assessed using the intraclass coefficient (ICC) and Bland-Altman method for readers 1 and 2 and their mean. Sensitivity to change was estimated using the standardized response mean (SRM = change/standard deviation of change) for M0-M36 changes. For interobserver reliability on M0-M36 changes, the ICCs (95% confidence interval [CI]) were 0.79 (0.65-0.88) for pelvic view, 0.87 (0.78-0.93) for hip AP view and 0.86 (0.76-0.92) for oblique view. Intraobserver reliability ICCs were 0.81 (0.69-0.89) for observer 1 and 0.97 (0.95-0.98) for observer 2 for the pelvic view; 0.87 (0.78-0.92) and 0.97 (0.96-0.99) for the hip AP view; and 0.73 (0.57-0.84) and 0.93 (0.88-0.96) for the oblique view. SRMs were 0.61 (observer 1) and 0.82 (observer 2) for pelvic view; 0.64 and 0.75 for hip AP view; and 0.77 and 0.70 for oblique view. All three views yielded accurate JSW and JSN. According to the best reader, the pelvic view performed slightly better. Both readers exhibited high precision, with SRMs of 0.6 or greater for assessing JSN over three years. Selecting a single reader was the most accurate method, with 0.3 mm precision. Using this cutoff, 50% of patients were classified as 'progressors'.

Joint space width (JSW) and narrowing (JSN) measurements on radiographs are currently the best way to assess disease severity or progression in hip osteoarthritis, yet we lack data regarding the most accurate and sensitive measurement technique. This study was conducted to determine the optimal radiograph and number of readers for measuring JSW and JSN. Fifty pairs of radiographs taken three years apart were obtained from patients included in a structure modification trial in hip osteoarthritis. Three radiographs were taken with the patient standing: pelvis, target hip anteroposterior (AP) and oblique views. Two trained readers, blinded to each other's findings, time sequence and treatment, each read the six radiographs gathered for each patient twice (time interval ≥15 days), using a 0.1 mm graduated magnifying glass. Radiographs were randomly coded for each reading. The interobserver and intraobserver cross-sectional (M0 and M36) and longitudinal (M0–M36) reproducibilities were assessed using the intraclass coefficient (ICC) and Bland–Altman method for readers 1 and 2 and their mean. Sensitivity to change was estimated using the standardized response mean (SRM = change/standard deviation of change) for M0–M36 changes. For interobserver reliability on M0–M36 changes, the ICCs (95% confidence interval [CI]) were 0.79 (0.65–0.88) for pelvic view, 0.87 (0.78–0.93) for hip AP view and 0.86 (0.76–0.92) for oblique view. Intraobserver reliability ICCs were 0.81 (0.69–0.89) for observer 1 and 0.97 (0.95–0.98) for observer 2 for the pelvic view; 0.87 (0.78–0.92) and 0.97 (0.96–0.99) for the hip AP view; and 0.73 (0.57–0.84) and 0.93 (0.88–0.96) for the oblique view. SRMs were 0.61 (observer 1) and 0.82 (observer 2) for pelvic view; 0.64 and 0.75 for hip AP view; and 0.77 and 0.70 for oblique view. All three views yielded accurate JSW and JSN. According to the best reader, the pelvic view performed slightly better. Both readers exhibited high precision, with SRMs of 0.6 or greater for assessing JSN over three years. Selecting a single reader was the most accurate method, with 0.3 mm precision. Using this cutoff, 50% of patients were classified as 'progressors'.

National audience; L’analyse d’impact budgétaire (AIB) évalue les conséquences sur le budget, d’un (ou de) financeur(s) déterminé(s), de l’introduction et de la diffusion sur le marché d’une intervention de santé, visant à en documenter la viabilité ou accessibilité financière.Elle constitue une aide pour la prise de décision de financement des interventions de santé : elle fournit des prévisions sur le différentiel de coûts (surcoûts et/ou économies générés) des interven-tions de santé (avec/sans leur introduction et leur diffusion), sur un horizon de planification budgé-taire déterminé. Elle représente donc une approche complémentaire à l’évaluation de l’efficience (EE). Elle permet d’estimer ce que pourrait être l’impact financier de l’introduction et de la diffusion d’une intervention de santé en se fondant sur la population susceptible de bénéficier de cette inter-vention tandis que l’EE vise à déterminer si l’intervention est coût-efficace dans la prise en charge de la pathologie étudiée au regard de ses comparateurs pertinents.L’AIB constitue une approche économique relativement récente de l’évaluation des interventions de santé. Les premiers travaux identifiés remontent aux publications de Mauskopf (1998) (1) et Trueman et al. (2001) (2). La littérature méthodologique sur le sujet demeure peu abondante au regard de celle portant sur les modèles de décision visant à identifier les interventions de santé les plus efficientes. Au cours de la dernière décennie, le cadre analytique des AIB s’est développé et leur utilisation fait désormais partie, dans certains pays, du processus de soumission réglemen-taire dans le cadre de l’évaluation des interventions de santé. L’AIB est actuellement obligatoire dans certains pays1 et recommandée ou en passe de devenir obligatoire dans d’autres pays ayant adopté l’évaluation de l’efficience (EE).Début 2016, il n’existe pas de recommandations de la HAS portant spécifiquement sur l’AIB. Le guide méthodologique pour l’évaluation économique diffusé en 2012 par la HAS fait uniquement référence au guide du collège des économistes de la santé (CES) produit en 2008 (3) pour la mise en oeuvre d’analyses d’impact budgétaire.