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Background There is a paucity of data on the epidemiology, survival estimates and healthcare resource utilisation and associated costs of patients with progressive fibrosing interstitial lung disease (PF-ILD) in France. An algorithm for extracting claims data was developed to indirectly identify and describe patients with PF-ILD in the French national administrative healthcare database. Methods The French healthcare database, the Système National des Données de Santé (SNDS), includes data related to ambulatory care, hospitalisations and death for 98.8% of the population. In this study, algorithms based on age, diagnosis and healthcare consumption were created to identify adult patients with PF-ILD other than idiopathic pulmonary fibrosis between 2010 and 2017. Incidence, prevalence, survival estimates, clinical features and healthcare resource usage and costs were described among patients with PF-ILD. Results We identified a total of 14,413 patients with PF-ILD. Almost half of them (48.1%) were female and the mean (± standard deviation) age was 68.4 (± 15.0) years. Between 2010 and 2017, the estimated incidence of PF-ILD ranged from 4.0 to 4.7/100,000 person-years and the estimated prevalence from 6.6 to 19.4/100,000 persons. The main diagnostic categories represented were exposure-related ILD other than hypersensitivity pneumonitis (n = 3486; 24.2%), idiopathic interstitial pneumonia (n = 3113; 21.6%) and rheumatoid arthritis-associated ILD (n = 2521; 17.5%). Median overall survival using Kaplan–Meier estimation was 3.7 years from the start of progression. During the study, 95.2% of patients had ≥ 1 hospitalisation for respiratory care and 34.3% were hospitalised in an intensive care unit. The median (interquartile range) total specific cost per patient during the follow-up period was €25,613 (10,622–54,287) and the median annual cost per patient was €18,362 (6856–52,026), of which €11,784 (3003–42,097) was related to hospitalisations. Limitations included the retrospective design and identification of cases through an algorithm in the absence of chest high-resolution computed tomography scans and pulmonary function tests. Conclusions This large, real-world, longitudinal study provides important insights into the characteristics, epidemiology and healthcare resource utilisation and costs associated with PF-ILD in France using a comprehensive and exhaustive database, and provides vital evidence that PF-ILD represents a high burden on both patients and healthcare services. Trial registration ClinicalTrials.gov, NCT03858842. ISRCTN, ISRCTN12345678. Registered 3 January 2019—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03858842

International audience; Objectives: To describe the long-term effectiveness and safety of certolizumab pegol in patients with moderate-to-severe rheumatoid arthritis (RA) in a real-world setting in France.Methods: ECLAIR was a 3-year longitudinal, prospective, observational, multicentre study. The primary objective was to describe the EULAR response after 1 year of certolizumab pegol treatment. Other endpoints included DAS28, clinical disease activity index, health assessment questionnaire disability index, fatigue assessment scale, patient's assessment of arthritis pain, patient and physician global assessments of disease activity, patient quality of life, and long-term safety.Results: A total of 792 patients were enrolled, of whom 776 comprised the safety set, and 733 the full analysis set. In the full analysis set, 559, 469 and 430 patients had a 12-, 24- and 36-month visit, respectively. This included 378, 296 and 246 patients still receiving certolizumab pegol at these visits. The percentage of EULAR responders was 75.3% (305/405 patients with an available EULAR response) at 12, 76.5% (261/341) at 24, and 79.6% (226/284) at 36 months. Among those still receiving certolizumab pegol, the percentage of EULAR responders was 81.7% (237/290) at 12, 81.1% (185/228) at 24, and 87.3% (158/181) at 36 months. Sustained improvements were observed in other effectiveness outcomes. Overall, 45.1% (350/776) of patients experienced 776 adverse drug reactions. No new safety signals were identified.Conclusions: This is the first prospective, observational study of an anti-TNF treatment in France. The results confirm the effectiveness and safety profile of certolizumab pegol treatment in patients with RA in a real-world setting.

Aims: ILDs are a heterogeneous group of disorders with distinct clinical, radiological and prognostic characteristics, which encompass a wide range of conditions. In some patients with fibrosing ILDs, a progressive phenotype similar to that observed in IPF may develop during the course of the disease. The collective estimated prevalence of PF-ILDs is 0.22, 0.59, and 2.0 per 10.000 persons in Belgium, Greece, and France respectively. The PROGRESS study aimed at assessing the epidemiology of non-IPF PF-ILD patients and associated health consumptions and outcomes in a real life nationwide setting in France. Methods: A longitudinal retrospective cohort study was conducted using the French administrative healthcare database (SNDS) between January 2010 and December 2017. Non-IPF PF-ILD patients were identified using an US algorithm based on ICD-10 codes and adapted to French specificities. Results: 17,560 non-IPF PF-ILD patients were identified. In 2017, the prevalence and incidence of non-IPF PF-ILD were respectively 17.9 per 100.000 and 3.0 per 100.000 per year. Sex ratio was close to 1 (51.2% of men) and mean age was 68.5 years (±15.2). Major underlying ILD diagnoses were non-autoimmune-related (50.0%), autoimmune-related (40.0%) and sarcoidosis (10.0%). The median overall survival of non-IPF PF-ILD patients was estimated at 4.1 years. The survival rate was 76.0%, 57.7%, 44.5%, and 33.7% at 1, 3, 5, and 8 years respectively. Conclusion: Based on an algorithm, non-IPF PF-ILD is rare and is associated with a poor prognosis comparable to that of IPF.

Aims: Interstitial lung disease (ILD) is frequent in patients with systemic sclerosis (SSc). It is characterized by progressive decline in lung function and is the leading cause of death in patients with SSc. In Europe, the prevalence and annual incidence of SSc-ILD have been estimated at 1.7-4.2 per 100,000 and 0.1-0.4 per 100,000 per year, respectively. This study aimed at assessing the epidemiology and mortality of patients with SSc-ILD in a real life nationwide setting in France. Methods: A longitudinal retrospective cohort study was conducted in the French administrative health care database. SSc-ILD patients were identified using an algorithm based on ICD-10 codes of SSc and of lung fibrosis between January 2010 and December 2017. Results: Among 9817 SSc patients identified, 3460 had associated ILD (35.0%). In 2017, the prevalence and incidence of SSc-ILD were respectively 4.5 per 100,000 (4.3-4.7) and 0.4 per 100,000 per year (0.3-0.5). Patients were predominantly females (75.6%) with a mean age of 60.7 years (±14.5). 73.6% and 20.8% of patients respectively had at least one claim of systemic corticosteroids and mycophenolate mofetil treatments during the study period. The overall survival rate was estimated to be 92.9%, 81.8%, 70.5%, and 65.1% 1, 3, 5, and 8 years, respectively. Median survival was better in women. Conclusion: This study demonstrated that SSc-ILD is a rare disease with significant mortality.

ObjectiveTo evaluate the performance of clinical criteria for predicting late treatment failure in patients with early non-response to certolizumab pegol (CZP).MethodsA protocol-specified analysis of interim data from ECLAIR, a 3-year longitudinal, prospective, observational, multicentre study of patients with active rheumatoid arthritis (RA) initiating CZP treatment in France, was conducted. Clinical measures assessed were Clinical Disease Activity Index (CDAI), Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28(ESR)) and Health Assessment Questionnaire Disability Index (HAQ-DI). Early non-response was measured at 3 months (M3) and failure to achieve low disease activity (LDA) at 12 months (M12).Results574/792 enrolled patients were treated at M3. The numbers available for predictability analyses were 532 (CDAI), 434 (DAS28(ESR)) and 496 (HAQ-DI). Of the three indices evaluated, the highest predictor of non-response value was observed for the CDAI (88.8% (95% CI 81.0 to 94.1)), indicating that up to 88% of patients identified as non-responders at M3 failed to achieve LDA at M12, regardless of baseline disease severity or treatment history. The specificity for this measure was also very high (96.0%), indicating that less than 5% of patients who achieved CDAI response at M12 had not responded at M3. Similar predictability was observed for DAS28(ESR), but only in patients with high disease activity at baseline and/or those previously treated by a biological disease-modifying antirheumatic drug.ConclusionCDAI non-response at M3 is a predictor of failure to achieve the therapeutic target of LDA at M12 in patients with RA initiating treatment with CZP.

The incidence of intussusception in infants varies around the world. The epidemiology of intussusception in France has never been prospectively studied. We performed a prospective observational study with systematic inclusion of all infants aged1 year with suspected intussusception admitted to the emergency departments of the hospitals in the eastern region of France (98,000 live births per year), from 4/1/2008 to 3/31/2012. Cases were classified using the Brighton Collaboration classification. In total, 185 infants with suspected intussusception were included of which 169 were idiopathic intussusception. Among these 169 cases, 115 (68%) were classed as Brighton level 1 (confirmed cases). Overall incidence of intussusception over the 4 years of the study was 29.8 (95% CI 24.6-35.7) cases per 100,000 live births for level 1 and 37.5 (95% CI 31.7-44.2) cases per 100,000 live births for all cases (levels 1-4). Annual incidence rates of level 1 intussusception were as follows: 44 (95% CI 31.9-59.3), 30.9 (20.9-44.2), 21.7 (13.4-33.2) and 22.1 (13.7-33.8) per 100,000 live births in the 1st, 2nd, 3rd and 4th study years, respectively.The incidence rate of intussusception in the eastern part of France is comparable to that of other European countries. There was a significant trend towards a decrease in the incidence of intussusception. What is known • Intussusception is the most frequent causes of intestinal obstruction in infants and young children. Overall incidence of intussusception in infants aged1 year varies widely around the world. No specific epidemiological studies have not been conducted in France on intussusception. What is new: • This prospective and multicenter study provides important information about the epidemiology of intussusception in infants in France over a period of 4 years.

Background Utilization of sedative hypnotic drugs for sleeping disorders (SD) raises concerns, particularly among older people. This study compared utilization of conventional psychotropic drugs for SD among patients seeking care from general practitioners (GPs) who strictly prescribe conventional medications (GP-CM), regularly prescribe homeopathy in a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). Methods This was a French population-based cohort study of GPs and their patients consulting for SD, informed through the Pittsburgh sleep quality index (PSQI) questionnaire. Information on psychotropic drugs utilization was obtained from a standardized telephone interview at inclusion, one, three and 12 months. Results 346 patients consulting for SD were included. Patients in the GP-Ho group experienced more often severe SD (41.3%) than patients in the GP-CM group (24.3%). Adjusted multivariate analyses showed that patients who chose to be managed by GP-Ho were less likely to use psychotropic drugs over 12 months as opposed to the GP-CM group, with Odds ratio (OR) = 0.25; 95% confidence interval (CI): 0.14 to 0.42. Patients in the GP-Mx group also used less psychotropic drugs but the result was not statistically significant (OR = 0.67; 95% CI: 0.39–1.16). Rates of clinical improvement of the SD did not differ between groups. Conclusions Patients with SD who chose to consult GPs certified in homeopathy consumed less psychotropic drugs and had a similar evolution of their condition to patients treated with conventional medical management. This result may translate in a net advantage with reduction of adverse events related to psychotropic drugs.

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.

Resume Les dispositifs medicaux (DM) couvrent une large variete de produits. Ils accompagnent, au gre des innovations technologiques, l’evolution des pratiques medicales. Les innovations dans le champ du DM peuvent ameliorer les conditions d’utilisation de la technologie de sante et/ou modifier l’organisation des soins au-dela du strict benefice therapeutique ou diagnostique pour le patient. Cependant, ces criteres non purement cliniques semblent n’etre que rarement documentes ou pris en compte dans l’evaluation des DM lors des decisions de remboursement au niveau national ou de referencement au niveau des etablissements de sante alors meme que des modeles d’evaluation multidimensionnelle des technologies de sante, prenant en compte le point de vue de l’ensemble des acteurs du systeme de sante, ont ete elabores. Dans cet article, apres avoir rappele le contexte de l’evaluation des technologies de sante en France, une definition des criteres d’evaluation non clinique des DM est proposee et un arbre de decision pour l’evaluation des DM est decrit. Des pistes de reflexion sont proposees en conclusion.

Background Treat-to-target strategies for rheumatoid arthritis (RA) require reliable clinical markers of treatment response in order to adapt therapy. Markers of early treatment failure can be used to ensure that patients (pts) are not unnecessarily exposed to ineffective therapy. Data from interventional clinical trials suggest that early clinical measures of disease activity (such as CDAI, DAS28 or HAQ-DI) after 12 weeks (wks) of treatment can reliably predict treatment failure at 1 year (yr).1–3 However, it is unknown how such indicators perform in real-world settings. Objectives To evaluate the performance of clinical markers of early treatment failure (Wk12) as predictors of treatment failure at 1yr in everyday clinical practice. Methods Data from a 1yr interim analysis of the ECLAIR study were used: a longitudinal, prospective, observational, multicentre study of pts with RA starting treatment with certolizumab pegol (CZP) in France. Pts were evaluated at study entry and thereafter at 3-monthly routine consultations. Disease activity was assessed at each visit using CDAI, DAS28 and HAQ-DI. At Wk12, pts with missing data or no longer taking CZP were excluded from the analyses. Linear interpolation, LOCF or NRI were used to impute missing data at 1yr, including data from pts who left the study early. Different definitions for treatment non-response were applied based on CDAI or ΔDAS28 and ΔHAQ-DI relative to pre-treatment values. Non-response at Wk12 was defined as CDAI>10, ΔDAS28 22, DAS28>3.2 and HAQ-DI>0.5. Positive predictive values (PPV; proportion of treatment failures at 1yr in Wk12 non-responders) were used to evaluate the predictive performance of each tool. Results Overall, 792 pts were enrolled and data from 730 pts analysed. Performance of CDAI at predicting treatment failure at 1yr was assessed in 532 pts (198 data values missing at Wk12). Response and failure rates at Wk12 and 1yr are presented (see Table). The PPV for CDAI was 88.8%, indicating that almost 9/10 pts identified as non-responders at Wk12 fail to respond at 1yr. Specificity was also high (96.0%), indicating that Conclusions The PPV describing the performance of early CDAI measure as a predictor of treatment failure at 1yr among CZP-treated RA pts was high; 88.8% of pts identified as non-responders at Wk12 will represent a treatment failure at 1yr. Simple tools such as CDAI, assessed during routine consultations, may be reliable markers to predict treatment failure without need for complementary biological tests. References Keystone EC. J Rheumatol 2011;38:990–6. Curtis JR. Arth Care Res 2012;64:658–67. van der Heijde D. J Rheumatol 2012;39:1326–33. Acknowledgements This study was funded by UCB Pharma. We thank the patients and their caregivers in addition to the investigators and their teams who contributed to this study. We also thank Isabelle Bru (UCB Pharma) who helped conduct the ECLAIR study. Editorial services were provided by Costello Medical Consulting. Disclosure of Interest A. Saraux Consultant for: UCB Pharma, R. M. Flipo Consultant for: UCB Pharma, F. Fagnani Consultant for: UCB Pharma, J. Massol: None declared, B. Combe Grant/research support from: Merck Pfizer Inc, Roche-Chugai, Consultant for: Merck, Pfizer, Roche-Chugai, UCB Pharma, Bristol-Myers Squibb, Celgene, Eli Lilly, Speakers bureau: Merck, Pfizer, Roche-Chugai, UCB Pharma, Bristol-Myers Squibb, Celgene, Eli Lilly, Novartis, P. Huot-Marchand: None declared, J. M. Joubert Employee of: UCB Pharma, J. Dunkel Employee of: UCB Pharma, G. Cukierman Employee of: UCB Pharma

Health technology assessment seeks to inform health policy- and decision-makers by promoting use of current best evidence and by addressing country specific factors, such as local context and values. In France, public health benefit (PHB) is one of the criteria used to inform decisions on the reimbursement of medicines. This article describes the methodological framework and the results after five years of assessment of PHB, by the French National Authority for Health. The semi-quantitative method used includes three dimensions that are: (1) the ability of a drug to improve the population's health status, (2) the drug's adequacy to cover public health needs, and; (3) the impact of the drug on the healthcare system. From 2005 to 2010, the PHB of 530 drugs was estimated, and 72% were assessed as having no PHB. The PHB was “low” for 88% of drugs expected to have a PHB, “medium” for 10%, and was considered to be “high” in only one case. The results of this experience show that it is feasible to assess the public health impact of drugs. But the high level of uncertainties at the time of a drug's first appraisal limits the assessment, which obviously has to be completed by reappraisal with post-marketing studies.

Background Before establishing a prospective cohort, an initial pilot study is recommended. However, there are no precise guidelines on this subject. This paper reports the findings of a French regional pilot study carried out in three nephrology departments, before realizing a major prospective Non Dialysis Chronic Renal Insufficiency study (ND-CRIS). Methods We carried out an internal pilot study. The objectives of this pilot study were to validate the feasibility (regulatory approval, providing patients with information, availability of variables, refusal rate of eligible patients) and quality criteria (missing data, rate of patients lost to follow-up, characteristics of the patients included and non-included eligible patients, quality control of the data gathered) and estimate the human resources necessary (number of clinical research associates required). Results The authorizations obtained (CCTIRS – CNIL) and the contracts signed with hospitals have fulfilled the regulatory requirements. After validating the information on the study provided to patients, 1849 of them were included in three centres (university hospital, intercommunal hospital, town hospital) between April 2012 and September 2015. The low refusal rate (51 patients) and the characteristics of non-included patients have confirmed the benefit for patients of participating in the study and provide evidence of the feasibility and representativeness of the population studied. The lack of missing data on the variables studied, the quality of the data analyzed and the low number of patients lost to follow-up are evidence of the quality of the study. By taking into account the time spent by CRAs to enter data and to travel, as well as the annual patient numbers in each hospital, we estimate that five CRAs will be required in total. Conclusion With no specific guidelines on how to realize a pilot study before implementing a major prospective cohort, we considered it pertinent to report our experience of P-ND-CRIS. This experience confirms that i) feasibility, ii) quality of data and iii) evaluating the resources required must be validated before carrying out a large prospective cohort study such as ND-CRIS. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0463-3) contains supplementary material, which is available to authorized users.

Purpose The reimbursement of phytotherapy drugs for the treatment of mild anxiety and insomnia ended in March 2006 in France. The aim of this study is to investigate the short-term impact of stopping phytotherapy reimbursement. Methods We monitored the prescriptions of 27 422 patients who received hypnotic and sedative phytotherapy drug treatment at least once in the 12 months preceding the end of reimbursement and made contact with their prescribing physician at least once in the following 12 months. A control cohort was recruited from patients fulfilling the same inclusion criteria in the 24 months before de-reimbursement and their prescriptions in the following 12 months were monitored. The impact of the end of reimbursement is estimated comparing prescription switches in these cohorts. Results Before the end of reimbursement, 7684 (28%) patients being prescribed delisted phytotherapy drugs had the relevant drug marketing authorization approval (DMAA) indications. Co-prescriptions of hypnotic and sedative drugs concerned 40% of patients. Of the 4646 DMAA patients exclusively prescribed phytotherapy, 640 (14%) switched to hypnotic or sedative drugs only after the end of reimbursement, 3266 (70%) stopped all treatments and 740 (16%) carried on with a non-reimbursed phytotherapy prescription. When compared to the control cohort, patients exposed to de-reimbursement were more likely to switch to psychotropic drugs (OR = 1.46). Conclusions Ending the reimbursement of common drugs on the basis of insufficient evidence regarding their effectiveness or the low level of severity of their target pathologies should be accompanied by information or advice to prescribing health care actors. Copyright © 2012 John Wiley & Sons, Ltd.

The assessment of a health technology is frequently accompanied by uncertainty about its impact, at short or long terms, on the health of the population. The Health Authorities may request additional « post-registration » data that will allow a relevant reassessment of these technologies. The responsibility to collect this information lies with the industry and the HAS evaluates the methodology. This guideline provides practical benchmarks on methodological aspects of these studies. It describes the different types of studies to consider depending on the objectives, including the use of databases and cohorts and European studies. It emphasizes the importance of establishing a scientific committee, clearly defining the objectives of the study, justifying the methodological choices, documenting the representativeness or completeness of centers, investigators and patients, limiting the number of lost of follow-up patients and missing data, describing the statistical analysis methods, the bias and their possible impact on results. The publication of the results of these studies is strongly encouraged.

The aim of this Round Table was to perform an initial assessment of the state of play of the impact of drugs on the environment. Demographic growth throughout the world and drug consumption which is constantly on the increase result in an ever increasing presence of medicinal substances in the various compartments (air, water, soil) with potential repercussions on the environment and on health. For the first time, the Giens pharmacology workshop have scheduled this topic outside the conventional sphere of action of Giens. A very high level of interest in this topic came forward both from the members of the round table and the listeners and it is certain that the round table opens the door to new initiatives for a subject about which there is still little knowledge. The following issues were therefore successively addressed: the fragmentation of the knowledge about the subject and its deficiencies concerning the impact on health, both of the wastes as a whole and that of specific drugs, the performances of the water treatment methods, the sources of pollution, the environmental impact, the lines of regulatory development, the impact on the environment and health and the training programmes to be set up among all protagonists, both professional and in the general public.

Resume L’objet de cette Table Ronde etait de faire un premier etat des lieux sur l’impact des medicaments sur l’environnement. La croissance demographique dans le monde, la demande de sante de plus en plus forte, la consommation de medicaments qui ne cesse de se developper, conduisent a une presence de plus en plus importante des substances medicamenteuses dans les differents compartiments (air, eau, sol) avec des repercussions potentielles sur l’environnement et la sante. Pour la premiere fois les Ateliers de Pharmacologie de Giens ont programme ce theme en dehors du champ d’action classique de Giens. Un interet tres important pour ce theme s’est degage tant des membres de la Table Ronde que des auditeurs, et il est certain que celle-ci ouvre la porte a de nouvelles initiatives pour un sujet encore mal connu. Ont donc ete abordes successivement : l’eclatement des connaissances sur le sujet, et leurs insuffisances concernant l’impact sanitaire aussi bien des rejets dans leur globalite que de certains medicaments particuliers, les performances des methodes de traitement des eaux, les sources de pollution, l’impact environnemental et l’impact sanitaire, les pistes d’evolution reglementaires et les formations a mettre en place aupres de tous les acteurs professionnel et grand public.

Introduction Prescription of medicines by telephone (PMT) in the call Center 15 is a reality, but has never been studied. Objective The objective was a Qualitative and quantitative study of the PMT. Method A monocentric and observational study of calls for a week of the center 15 of Besancon (France) was performed. Material Computer records and dial center 15 recordings of telephone conversations were analyzed. Variables analyzed were characteristics of callers, context of the requirement, analysis of compliance with the summary of product characteristics and mode of access to medicines. Results Among 1183 appeals studied, a PMT was performed in 379 cases (32%). New and isolated prescriptions are the most frequent. 68% of PMT correspond to optional prescriptions. The 539 drugs prescribed belong to 4 main groups: analgesics, non steroidal anti-inflammatory, anti spasmodic, anti-diarrheal. In 9 out of 10 cases these drugs are from the family pharmacy. Conclusion The PMT at the center 15 is realized in one third of cases. This work helps highlight the shortcomings of the practice in terms of safety and security requirement of the proceedings against the recommendations of the French High Authority for Health.

Resume La population cible d’un medicament en vue du remboursement peut inclure differentes populations qui peuvent se recouvrir partiellement : la population qui a ete etudiee dans les essais cliniques, celle de l’autorisation de mise sur le marche (AMM), celle du service medical rendu (SMR), celle de l’amelioration du service medical rendu (ASMR), etc. Sa definition qualitative et quantitative implique des enjeux importants en termes de sante publique et economique. Des recommandations ont ete faites afin de clarifier les definitions, d’eclaircir les souhaits des decideurs publics et d’ameliorer les methodes et les sources permettant une quantification des populations cibles.

Les etudes post-inscription documentent, en situation reelle, les conditions de mise sous traitement, les populations reellement traitees, les durees de traitement, l'observance, les benefices des traitements, l'impact du traitement sur les strategies therapeutiques, l'organisation des soins et l'impact de sante publique, ... Leurs donnees sont utilisees notamment lors d'une reevaluation anticipee ou lors du renouvellement d'inscription au remboursement. Cent trente quatre demandes de la Commission de la Transparence (CT) et/ou du Comite Economique des Produits de Sante (CEPS) ont ete faites depuis 1997 et leurs resultats sont pris en compte et participent a la reevaluation du Service Medical Rendu (SMR) et de l'Amelioration du Service Medical Rendu (ASMR) anticipes. Au cours de cette table ronde des Rencontres Nationales de Pharmacologie Clinique de Giens, les difficultes de realisation des etudes post-inscription medicaments ont ete identifiees et des propositions ont ete formulees dans les domaines du dialogue autour de la demande, de la previsibilite et de l'anticipation des demandes et de la formation des medecins.

Non-interventional research is an essential approach to gathering data in different situations and it often complements other research methodologies, such as biomedical research and research aimed at evaluating usual care. Yet the legislative framework for this type of research is nonexistent, and this void poses a number of problems for non-interventional researchers, including an absence of any guarantee of quality and therefore of reliability, a limited recognition of the research beyond our borders, cumbersome administrative procedures, and a lack of visibility. In light of the growing demand for data, particularly in post marketing authorisation for drugs, which largely relies on non-interventional methods, the Round Table participants have issued a set of proposals for a future legislative framework for this type of research.

Resume L’interet de sante publique des medicaments (ISP) est un critere d’evaluation recent (decret d’octobre 1999) et specifiquement francais qui, faute d’elements disponibles au moment de son appreciation, reste a ce jour souvent incompletement documente dans les dossiers de transparence. En effet, lors de la demande de premiere inscription d’un medicament sur la liste des specialites remboursables, les donnees cliniques dont on dispose sont en general les seules contenues dans le dossier d’enregistrement. Ces donnees sont issues d’un programme de developpement desormais global, construit bien longtemps avant le depot du dossier d’inscription au remboursement, qui ne prevoit pas de facon systematique de renseigner les donnees necessaires a l’evaluation de l’ISP. On comprend donc la difficulte d’anticipation et de documentation de ce critere recent et hexagonal. En France, l’ISP est a la fois l’un des criteres d’admission au remboursement des medicaments et un element de pilotage d’une politique de sante nationale. Son evaluation permet par ailleurs d’identifier les besoins et les objectifs des etudes post-inscription qui font l’objet d’une clause conventionnelle lors du passage au Comite Economique des Produits de Sante (CEPS). Situee en aval de l’evaluation de l’autorisation de mise sur le marche (AMM), l’evaluation du critere ISP lui fait suite et la complete. Pour comprendre comment anticiper l’evaluation de l’ISP des medicaments, il faut prendre en compte ce qui le distingue de l’etape prealable de l’AMM. Tandis que l’evaluation en vue de l’AMM cherche a determiner si le medicament est potentiellement utile dans une indication donnee, l’evaluation de l’ISP cherche a quantifier l’importance du service que ce medicament peut rendre a une population donnee, compte tenu des meilleurs traitements disponibles dans cette population. Alors que l’AMMest octroyee au vu des donnees de l’enregistrement qui renseignent sur le benefice clinique du medicament dans une population limitee qui est celle des essais et dans des conditions d’un essai therapeutique, l’ISP s’interroge sur l’effet de ce medicament a l’echelle d’une population generale, dans la vie reelle. Les composantes de l’ISP d’un medicament pour lequel une premiere inscription est sollicitee sont la reponse attendue de ce medicament pour couvrir un besoin de sante publique, son impact attendu sur l’etat de sante de la population et eventuellement sur le systeme de sante. L’impact d’un medicament sur la sante d’une population doit etre mesure sur des criteres de sante publique qui peuvent etre selon les cas des criteres de morbi-mortalite et/ou de qualite de vie. Or, peu de medicaments comprennent d’emblee dans leur dossier d’enregistrement des donnees portant sur ces criteres et l’on ne connait pas toujours suffisamment la valeur predictive des criteres intermediaires utilises dans les essais pour permettre de quantifier le benefice attendu sur ces dits criteres. De plus, il est rare de disposer de donnees permettant de quantifier l’effet du medicament selon les differentes caracteristiques de la population cible. Enfin, il est frequent de ne pas disposer au moment de l’evaluation de donnees epidemiologiques precises de la population francaise correspondant a l’indication du medicament. Dans ces conditions, il est ainsi difficile d’estimer le nombre attendu d’evenements evites grâce a la mise a disposition d’un medicament. Pour mieux documenter l’ISP, les membres de la table ronde ont suggere : (i) d’adapter le plan de developpement clinique en particulier en integrant, parmi les criteres de jugement des essais, des criteres pertinents en termes de sante publique et en veillant a une heterogeneite suffisante des populations incluses dans les essais ; et (ii) de chercher a recueillir suffisamment tot des donnees epidemiologiques nationales fiables ainsi que les elements necessaires a l’estimation de la transposabilite des donnees des essais a la population cible francaise (capacite a reperer les patients a traiter, adaptation du systeme de sante. . . ). Concernant les donnees epidemiologiques, les membres de la table ronde ont considere que les besoins etaient diversement couverts selon les pathologies. Pour repondre aux besoins d’estimation des populations cibles des medicaments dans des indications precises, ils ont suggere de recourir autant que de besoin a des etudes ad hoc . Par ailleurs, les etudes epidemiologiques a visee de marche, sous reserve d’une methodologie acceptable ne devraient pas etre rejetees systematiquement et meriteraient d’etre presentees. Pour pouvoir estimer la taille de l’impact theorique attendu d’un medicament en population, les membres de la table ronde ont souligne la necessite de disposer de resultats d’etudes ayant des criteres adaptes a ces objectifs. Dans un premier temps, ils ont suggere de realiser un travail consensuel de definition des criteres par pathologie. D’une discussion sur la representativite des populations, il est ressorti qu’il serait souhaitable mais illusoire d’inclure dans les essais une population parfaitement representative de la population a traiter. L’effet du medicament doit donc etre modelise (modele d’effet) pour pouvoir etre estime pour l’ensemble de la population. Or, pour pouvoir disposer d’un modele d’effet fiable, il faut que la population incluse soit suffisamment heterogene, d’ou la demande d’influer sur l’heterogeneite des populations lors de la decision methodologique des essais. Lorsque le critere evalue au cours du developpement ne correspond pas au critere d’ISP, la seule facon d’estimer le nombre d’evenements correspondant au critere d’ISP est de recourir la encore a la modelisation, celle-ci n’etant toutefois possible que lorsque la litterature scientifique a etabli un lien fiable entre les deux criteres. Dans ce cas, c’est ce nouveau modele qui devrait etre applique a une population francaise cible pour estimer l’effet attendu. En conclusion, les possibilites d’estimer l’impact attendu des medicaments sur la sante d’une population donnee sont actuellement limitees. Ces limites paraissent d’autant plus regrettables qu’une telle estimation est possible et realiste sans necessiter le bouleversement des plans de developpement. Les suggestions generales de modifications des plans de developpement proposees par les membres de la table ronde ont paru d’autant plus recevables que les ajouts demandes ne devraient pas beneficier seulement a la France mais a toutes les autorites de sante des pays qui souhaiteraient estimer l’impact attendu d’un medicament sur leur territoire. Anticiper les besoins en termes de complements de donnees cliniques, epidemiologiques et de donnees permettant de juger de la transposabilite des resultats des essais a la pratique clinique est une condition sine qua non a l’amelioration des possibilites d’estimation de l’ISP. L’anticipation de ces besoins devrait etre effectuee suffisamment tot par les entreprises pharmaceutiques qui devraient beneficier d’une concertation avec les autorites de sante et avec les responsables de la politique de sante publique francais. Par ailleurs, en raison de sa vocation universelle il a ete propose que les demarches et publications necessaires soient entreprises afin que le critere ISP soit reconnu au niveau europeen.

Key points The therapeutic value of drugs is currently assessed by the “commission de la transparence” (transparency committee), which since January 2005 has reported to the Haute autorite de sante (high health authority). After a drug is authorized for sale, this committee evaluates its therapeutic value, or more precisely, interest, taking into account other drugs already on the market to treat the same disease and the position of the drug expected in the overall therapeutic strategy of the concerned disease. The committee uses scientific methodology to determine the level of “expected medical service” and also evaluates the advantages that the new drug instead of this drug is expected to provide compared with other drugs for the same indication. The public health contribution of the drug is one of the criteria considered. A new methodology and clarification of its definition make it possible to assess this with precision. Quantification of these criteria results in a score for the drug that determines whether or not it will be reimbursed by the national health insurance fund. This score also helps the drug economics committee determine a price for the drug (improvement of the expected medical service).

International audience

More and more frequently, the health authorities and the French assessment agencies are led to issue Marketing Authorizations (MAs), give opinions on the eligibility for reimbursement of drugs or to draft recommendations for clinical practice based on the results of foreign studies. The results of these studies are more or less difficult to transpose to French practice. These difficulties generate varying degrees of uncertainty concerning the effect to be expected of a drug. A more or less extensive loss of effect is sometimes even predictable. Some of the difficulties in transposition are discussed in this article and proposals for action are made in order to allow one, in the long term, to predict in the most precise manner possible the effects to be expected from a drug in the French population and be able to verify this prediction at an interval from its eligibility for reimbursement.

De plus en plus souvent, les autorites de sante et les agences d'evaluation francaises sont conduites a delivrer des AMM (Autorisation de Mise sur le Marche), a rendre des avis sur l'admission au remboursement de medicaments ou a elaborer des recommandations pour la pratique clinique a partir de resultats d'etudes etrangeres. Les resultats de ces etudes sont plus ou moins difficiles a transposer a la pratique francaise. Ces difficultes generent une incertitude de degre variable sur l'effet a attendre d'un medicament. Une perte d'effet plus ou moins importante est quelquefois meme previsible. Quelques unes des difficultes de transposition sont discutees dans cet article et des propositions d'actions sont formulees pour permettre, a terme, de predire de la facon la plus precise possible les effets a attendre d'un medicament en population francaise et de pouvoir verifier cette prediction a distance de son admission au remboursement.

Resume L’infliximab represente un progres therapeutique majeur dans la PR. Nous avons evalue le maintien therapeutique de l’infliximab au cours de la PR et analyse les causes d’arret. Patients et methodes. – Ont ete incluses les PR ayant beneficie de ce traitement a partir d’avril 2000, hors protocoles, selon le libelle d’AMM (3 mg/kg, perfusion a S0, S2, S6, puis toutes les 8 semaines) avec evaluation du nombre de perfusions, des effets secondaires, de la non efficacite. La courbe de maintien therapeutique est etablie selon la methode de Kaplan Meier. Les causes d’arret du traitement ont ete analysees. Resultats. – Quarante et un patients, correspondant a des indications de « la vraie vie » ont pu etre inclus. L’âge moyen est de 54 ans, l’anciennete de la PR de neuf ans, avec trois traitements de fond anterieurs. Le nombre moyen de perfusion est de 10,8 par patient, avec un nombre total de perfusions de 461, la duree moyenne de suivi sous traitement est de 15,3 mois. Le taux de maintien therapeutique exprime en probabilite d’etre encore sous traitement a 6, 12, 24 mois est respectivement de 82, 74, 67 %. Les causes d’arret sont : echappement therapeutique, pour six patients (42,8 % des arrets), reaction allergique, trois patients, inefficacite primaire, infection severe, desir de grossesse, mauvaise observance, perdu de vue, un cas chaque fois. Cinquante-neuf episodes d’effets secondaires ont ete recenses, leur profil etait superposable aux donnees de la litterature et de pharmacovigilance. Conclusion. – Le maintien therapeutique de l’infliximab dans la PR en pratique courante (67 % a 2 ans) est superposable aux donnees de la litterature et confirme les resultats des etudes controlees.

Round table no. 2 was devoted to the postmarketing evaluation of drugs. The debates involved both the questions posed by postmarketing evaluation and the methods for responding to them. The major categories of questions likely to be posed are as follows: efficacy in actual situations; safety in actual situations; prognostic factors and patients responding; place in the therapeutic strategy; impact on the healthcare care system; the ‘joined’ population (those who actually obtain benefit); and drug utilisation review. In addition, the methodological approaches have been divided into three categories: the experimental approach, the observational approach and the modelling approach. Each of these methodological approaches has been qualified with respect to each of the questions. The objective was neither to establish a classification of the methods according to the level of proof, nor to propose methodological formulae. Instead, the participants applied themselves to describe the strengths and the limits of the different methods for each of the questions in turn. The debates then focused on the process of identification of pertinent questions and appropriate methods. In this context, the round-table participants applied an analysis of the current system of postmarketing study projects and formulated some propositions for their improvement. Finally, the place of existing databases in the postmarketing evaluation was discussed and the participants emphasised the importance of initiating a very detailed assessment of the information that could be provided by such databases before instituting ad hoc studies.

OBJECTIVES a) To investigate responsiveness to exogenous catecholamines in rat endotoxin shock by studying both myocardial and vascular functional parameters, and to determine the relationship of these parameters with other relevant biological parameters of the adrenergic pathway, such as myocardial beta-adrenergic receptors and cyclic adenosine monophosphate (cAMP); b) to investigate the role of tumor necrosis factor (TNF)-alpha via prophylactic anti-TNF-alpha monoclonal antibody administration. DESIGN Experimental, comparative hospital. SETTING Laboratory in a university hospital. SUBJECTS Male Sprague-Dawley rats, weighing 280 to 340 g. INTERVENTIONS Intravenous injection of Escherichia coli endotoxin (5 mg/100 g) in the first group; injection of the same dose of endotoxin preceded by 2 mg/100 g of anti-TNF-alpha monoclonal antibody in the second group; injection of saline in the third (control) group. MEASUREMENTS AND MAIN RESULTS TNF-alpha concentration was measured before and during the first 3 hrs in all three groups. Myocardial and vascular functional parameters were obtained, respectively, from Langendorff perfused hearts and isolated aortic rings. Adrenergic biochemical parameters (catecholamines, density and affinity of beta-receptors, and isoproterenol-stimulated myocardial cAMP) were determined 3 hrs after injections in the three groups. After endotoxin injection, serum TNF-alpha concentrations peaked at 60 mins (2496 +/- 412 pg/mL) and returned slowly to control values at 3 hrs; serum TNF-alpha concentrations remained under the limit of detection in the other two groups. When compared with the control group, plasma concentrations of epinephrine and norepinephrine were significantly (p < .05) increased. Baseline values for differential left ventricular pressure and coronary flow were significantly (p < .001, p < .01, respectively) reduced in the endotoxin group; heart rate remained unchanged. In the endotoxin and control groups, isoproterenol induced a similar increase in differential left ventricular pressure and in heart rate. Anti-TNF-alpha antibody increased cardiac response by partially preventing the decrease by endotoxin in differential left intraventricular pressure. Maximal specific binding of 125iodocyanopindolol and myocardial cAMP accumulation were significantly (p < .01) reduced in the endotoxin group in comparison with the control group. Anti-TNF-alpha antibody prevented the endotoxin-induced decrease in cAMP synthesis (p < .05) but did not modify the density of receptors. Affinity of receptors was similar in the three groups. In aortic rings, endotoxin administration significantly (p < .01) shifted the dose-response curve to norepinephrine to the right, both in the presence and absence of endothelium. NG-monomethyl-L-arginine significantly increased the contractions to attain the control level: p < .001 in the presence of endothelium; p < .05 in the absence of endothelium. Anti-TNF-alpha antibody did not prevent endotoxin-induced vascular hyporeactivity to norepinephrine in either endothelium-intact or -denuded rings, but partially attenuated the decrease in maximal response. CONCLUSIONS In ex vivo experiments, 3 hrs after endotoxin injection, vascular responsiveness was sharply decreased. This impaired response was improved in vitro by the inhibition of nitric oxide. The heart response to isoproterenol, nevertheless, was maintained, even though there was an obvious decrease in receptor density and an impaired myocardial accumulation of cAMP. Anti-TNF-alpha antibody partially prevented the alteration of both myocardial pressure response to isoproterenol and biochemical parameters, and was not efficacious in preventing vascular hyporeactivity to vasoconstrictor agents.

Reimbursement of drugs by public or private insurance systems is increasingly problematic, including in supposedly “rich” countries. There is an international consensus to consider the benefit of a Health technology assessment to clarify decisions on reimbursement by the collectivity, and this includes taking account of the target population of the new drug. The authors debate about the urgent need of a better quantification of the target population, which must include a qualitative description of this target population and a scientific extrapolation of the target population, which is certainly the most challenging problem.

Background Homeopathic care has not been well documented in terms of its impact on patients' utilization of drugs or other complementary and alternative medicines (CAM). The objective of this study was to describe and compare patients who visit physicians in general practice (GPs) who prescribe only conventional medicines (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho). Material and methods The EPI3-LASER study was a nationwide observational survey of a representative sample of GPs and their patients from across France. Physicians recorded their diagnoses and prescriptions on participating patients who completed a self-questionnaire on socio-demographics, lifestyle, quality of life Short Form 12 (SF-12) and the complementary and alternative medicine beliefs inventory (CAMBI). Results A total of 6379 patients (participation rate 73.1%) recruited from 804 GP practices participated in this survey. Patients attending a GP-Ho were slightly more often female with higher education than in the GP-CM group and had markedly healthier lifestyle. They did not differ greatly in their comorbidities or quality of life but exhibited large differences in their beliefs in holistic medicine and natural treatments, and in their attitude toward participating to their own care. Similar but less striking observations were made in patients of the GP-Mx group. Conclusion Patients seeking care with a homeopathic GP did not differ greatly in their socio-demographic characteristics but more so by their healthier lifestyle and positive attitude toward CAM. Further research is needed to explore the directionality of those associations and to assess the potential economic benefits of homeopathic management in primary care.

The reimbursement of phytotherapy drugs for the treatment of mild anxiety and insomnia ended in March 2006 in France. The aim of this study is to investigate the short-term impact of stopping phytotherapy reimbursement.We monitored the prescriptions of 27,422 patients who received hypnotic and sedative phytotherapy drug treatment at least once in the 12 months preceding the end of reimbursement and made contact with their prescribing physician at least once in the following 12 months. A control cohort was recruited from patients fulfilling the same inclusion criteria in the 24 months before de-reimbursement and their prescriptions in the following 12 months were monitored. The impact of the end of reimbursement is estimated comparing prescription switches in these cohorts.Before the end of reimbursement, 7684 (28%) patients being prescribed delisted phytotherapy drugs had the relevant drug marketing authorization approval (DMAA) indications. Co-prescriptions of hypnotic and sedative drugs concerned 40% of patients. Of the 4646 DMAA patients exclusively prescribed phytotherapy, 640 (14%) switched to hypnotic or sedative drugs only after the end of reimbursement, 3266 (70%) stopped all treatments and 740 (16%) carried on with a non-reimbursed phytotherapy prescription. When compared to the control cohort, patients exposed to de-reimbursement were more likely to switch to psychotropic drugs (OR = 1.46).Ending the reimbursement of common drugs on the basis of insufficient evidence regarding their effectiveness or the low level of severity of their target pathologies should be accompanied by information or advice to prescribing health care actors.

Objective The objective of this study was to assess the effect of physician practicing preferences (PPP) in primary care for homeopathy (Ho), CAM (Complementary and alternative medicines) with conventional medicine (Mx) or exclusively conventional medicine (CM) on patients with musculoskeletal disorders (MSDs), with reference to clinical progression, drug consumption, side effects and loss of therapeutic opportunity. Methods The EPI3-MSD study was a nationwide observational cohort of a representative sample of general practitioners (GP) and their patients in France. Recruitment of GP was stratified by PPP, which was self-declared. Diagnoses and comorbidities were recorded by GP at inclusion. Patients completed a standardized telephone interview at inclusion, one, three and twelve months, including MSD-functional scales and medication consumption. Results 1153 MSD patients were included in the three PPP groups. Patients did not differ between groups except for chronicity of MSDs (>12 weeks), which was higher in the Ho group (62.1%) than in the CM (48.6%) and Mx groups (50.3%). The twelve-month development of specific functional scores was identical across the three groups after controlling for baseline score (p > 0.05). After adjusting for propensity scores, NSAID use over 12 months was almost half in the Ho group (OR, 0.54; 95%CI, 0.38–0.78) as compared to the CM group; no difference was found in the Mx group (OR, 0.81; 95% CI: 0.59–1.15). Conclusion MSD patients seen by homeopathic physicians showed a similar clinical progression when less exposed to NSAID in comparison to patients seen in CM practice, with fewer NSAID-related adverse events and no loss of therapeutic opportunity. Copyright © 2012 John Wiley & Sons, Ltd.

Modeling consists in aggregating separate pieces of knowledge, according to a given structure and rules. It allows studying the behavior of more or less complex systems by simulation techniques. Modeling is used in different state-of-the-art technological domains (meteorology, aeronautics). Its use has grown for the evaluation of medicines and medical devices, from conception to prescription (marketing authorization, reimbursement, price setting and re-registrations). It follows a scientific approach and is the object of good practice recommendations. Coupling models to virtual populations allows obtaining realistic results at the population level, testing diagnostic or therapeutic strategies, as well as estimating the consequences of transposing the results of clinical trials to the population. Through examples, the participants of the Round Table analyzed the contributions of the coupling of models and realistic virtual populations, and proposed guidelines for their judicious and systematic use.

Resume La modelisation permet d’agreger un ensemble de connaissances, selon une structure et des regles determinees. Elle permet l’etude du comportement de systemes plus ou moins complexes par des simulations. La modelisation est utilisee dans differents domaines technologiques de pointe (meteorologie, aeronautique). Elle devient reconnue pour l’evaluation therapeutique des medicaments et dispositifs medicaux, de leur conception a la prescription (autorisation de mise sur le marche [AMM], remboursement, fixation des prix et reinscriptions). Elle suit une demarche scientifique et fait l’objet de recommandations de bonnes pratiques. Le couplage de modeles a des populations virtuelles permet de rendre des resultats realistes a l’echelle de populations, et de tester des strategies diagnostiques ou therapeutiques, ainsi que les consequences liees a la transposition des resultats d’essais cliniques. A l’aide d’exemples, les participants de la table ronde ont analyse les apports du couplage de la modelisation aux populations virtuelles et proposent des recommandations pour leur utilisation judicieuse systematique.