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Background In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia. Aims The objective of the current paper is to provide a 2020 update of the previous recommendations in accordance with the evidence that has become available since our original recommendations. Methods This paper is based on literature reviews performed by members of the ESCEO working group and followed up with face to face meetings organized for the whole group to make amendments and discuss further recommendations. Results The randomized placebo-controlled double-blind parallel-arm drug clinical trials should be the design of choice for both phase II and III trials. Treatment and follow-up should run at least 6 months for phase II and 12 months for phase III trials. Overall physical activity, nutrition, co-prescriptions and comorbidity should be recorded. Participants in these trials should be at least 70-years-old and present with a combination of low muscle strength and low physical performance. Severely malnourished individuals, as well as bedridden patients, patients with extremely limited mobility or individuals with physical limitations clearly attributable to the direct effect of a specific disease, should be excluded. Multiple outcomes are proposed for phase II trials, including, as example, physical performance, muscle strength and mass, muscle metabolism and muscle-bone interaction. For phase III trials, we recommend a co-primary endpoint of a measure of functional performance and a Patient Reported Outcome Measure. Conclusion The working group has formulated consensus recommendations on specific aspects of trial design, and in doing so hopes to contribute to an improvement of the methodological robustness and comparability of clinical trials. Standardization of designs and outcomes would advance the field by allowing better comparison across studies, including performing individual patient-data meta-analyses, and different pro-myogenic therapies.

Aim: To understand breast cancer patients' trade-offs when choosing treatments and to identify the most important treatment attributes which drive decisions. Materials & methods: A discrete choice experiment was conducted in France, Ireland, Poland and Spain. Progression-free survival, febrile neutropenia, pain, functional well-being and out-of-pocket payment were the treatment attributes. Results: 371 patients were willing to pay €6896 per year for 1 additional year of progression-free survival, €17,288 per year for perfect functional well-being and €15,138 for one pain-free year. Patients are willing to trade off progression-free survival months for better functional abilities and less pain. Conclusion: Patient preferences should be considered by regulatory agencies, reimbursement bodies, payors and clinicians for best treatment choices for the individuals.

Molecular characterization of tumors has shifted cancer treatment strategies away from nonspecific cytotoxic treatment of histology-specific tumors toward targeting of actionable mutations that can be found across multiple cancer types. The development of high-throughput technologies such as next-generation sequencing, combined with decision support applications and availability of patient databases, has provided tools that optimize disease management. Precision oncology has proven success in improving outcomes and quality of life, as well as identifying and overcoming mechanisms of drug resistance and relapse. Addressing challenges that impede its use will improve matching of therapies to patients. Here we review the current status of precision oncology medicine, emphasizing its impact on patients - what they understand about precision oncology medicine and their hopes for the future.Lay abstract Precision oncology offers individualized treatment of cancer on a per-patient basis, based on the unique DNA fingerprint of a patient’s cancer. New, advanced technologies for DNA sequencing have led to rapid advancement in developing novel therapies. Decision-making tools have followed pace, leading to improved matching of therapy to patient, ultimately improving outcomes (including quality of life), building trust between patient and physician, and increasing hope for the future.

Background The accountability for reasonableness (A4R) framework defines 4 conditions for legitimate healthcare coverage decision processes: Relevance, Publicity, Appeals, and Enforcement. The aim of this study was to reflect on how the diverse features of decision-making processes can be aligned with A4R conditions to guide decision-making towards legitimacy. Rare disease and regenerative therapies (RDRTs) pose special decision-making challenges and offer therefore a useful case study. Methods Features operationalizing each A4R condition as well as three different approaches to address these features (cost-per-QALY-focused and multicriteria-based) were defined and organized into a matrix. Seven experts explored these features during a panel run under the Chatham House Rule and provided general and RDRT-specific recommendations. Responses were analyzed to identify converging and diverging recommendations. Results Regarding Relevance, recommendations included supporting deliberation, stakeholder participation and grounding coverage decision criteria in normative and societal objectives. Thirteen of 17 proposed decision criteria were recommended by a majority of panelists. The usefulness of universal cost-effectiveness thresholds to inform allocative efficiency was challenged, particularly in the RDRT context. RDRTs raise specific issues that need to be considered; however, rarity should be viewed in relation to other aspects, such as disease severity and budget impact. Regarding Publicity, panelists recommended transparency about the values underlying a decision and value judgements used in selecting evidence. For Appeals, recommendations included a life-cycle approach with clear provisions for re-evaluations. For Enforcement, external quality reviews of decisions were recommended. Conclusions Moving coverage decision-making processes towards enhanced legitimacy in general and in the RDRT context involves designing and refining approaches to support participation and deliberation, enhancing transparency, and allowing explicit consideration of multiple decision criteria that reflect normative and societal objectives.

Osteoarthritis (OA) is a major cause of pain and physical disability in adults, and an increasingly common disease given its associations with aging and a growing obese/overweight population. Paracetamol is widely recommended for analgesia at an early stage in the management of OA, and, although frequently prescribed, evidence suggests the efficacy of paracetamol for OA pain is low. Furthermore, there have been recent concerns over the safety profile of paracetamol, with reports of gastrointestinal, cardiovascular, hepatic and renal adverse events. This narrative review summarizes recent literature on the benefits and harms of paracetamol for OA pain. Data on long-term paracetamol safety are derived largely from observational evidence, and are difficult to interpret given the potential biases of such data. Nonetheless, a considerable degree of toxicity is associated with paracetamol use among the general population, especially at the upper end of standard analgesic doses. Paracetamol is linked to liver function abnormalities and there is evidence for liver failure associated with non-intentional paracetamol overdose. Safety data for paracetamol use in the older population (aged >65 years) are sparse; however, there is some evidence that frail elderly people may have impaired paracetamol clearance. Given that the analgesic benefit of paracetamol in OA joint pain is uncertain and potential safety issues have been raised, more careful consideration of its use is required.

Background Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are an important drug class in the treatment armamentarium for osteoarthritis (OA). Objective We aimed to re-assess the safety of various SYSADOAs in a comprehensive meta-analysis of randomized placebo-controlled trials, using, as much as possible, data from full safety reports. Methods We performed a systematic review and random-effects meta-analyses of randomized, double-blind, placebo-controlled trials that assessed adverse events (AEs) with various SYSADOAs in patients with OA. The databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus were searched. The primary outcomes were overall severe and serious AEs, as well as AEs involving the following Medical Dictionary for Regulatory Activities (MedDRA) system organ classes (SOCs): gastrointestinal, cardiac, vascular, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue, renal and urinary system. Results Database searches initially identified 3815 records. After exclusions according to the selection criteria, 25 studies on various SYSADOAs were included in the qualitative synthesis, and 13 studies with adequate data were included in the meta-analyses. Next, from the studies previously excluded according to the protocol, 37 with mainly oral nonsteroidal anti-inflammatory drugs (NSAIDs) permitted as concomitant medication were included in a parallel qualitative synthesis, from which 18 studies on various SYSADOAs were included in parallel meta-analyses. This post hoc parallel inclusion was conducted because of the high number of studies allowing concomitant anti-OA medications. Indeed, primarily excluding studies with concomitant anti-OA medications was crucial for a meta-analysis on safety. The decision for parallel inclusion was made for the purpose of comparative analyses. Glucosamine sulfate (GS), chondroitin sulfate (CS) and avocado soybean unsaponifiables (ASU; Piascledine®) were not associated with increased odds for any type of AEs compared with placebo. Overall, with/without concomitant OA medication, diacerein was associated with significantly increased odds of total AEs (odds ratio [OR] 2.22; 95% confidence interval [CI] 1.58–3.13; I2 = 52.8%), gastrointestinal disorders (OR 2.85; 95% CI 2.02–4.04; I2 = 62.8%) and renal and urinary disorders (OR 3.42; 95% CI 2.36–4.96; I2 = 17.0%) compared with placebo. In studies that allowed concomitant OA medications, diacerein was associated with significantly more dermatological disorders (OR 2.47; 95% CI 1.42–4.31; I2 = 0%) and more dropouts due to AEs (OR 3.18; 95% CI 1.85–5.47; I2 = 13.4%) than was placebo. No significant increase in serious or severe AEs was found with diacerein versus placebo. Conclusions GS and CS can be considered safe treatments for patients with OA. All eligible studies on ASU included in our analysis used the proprietary product Piascledine® and allowed other anti-OA medications; thus, the safety of ASU must be confirmed in future studies without concomitant anti-OA medications. Given the safety concerns with diacerein, its usefulness in patients with OA should be assessed, taking into account individual patient characteristics. Electronic supplementary material The online version of this article (10.1007/s40266-019-00662-z) contains supplementary material, which is available to authorized users.

Background: Some controversy exists regarding the safety of intra-articular hyaluronic acid (IAHA) in the management of osteoarthritis (OA). Objective: The objective of this study was to re-assess the safety profile of IAHA in patients with OA, through a comprehensive meta-analysis of randomized, placebo-controlled trials. Methods: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with IAHA in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, cardiac, vascular, respiratory, nervous system, skin and subcutaneous tissue disorders, musculoskeletal, renal and urinary disorders, infections and infestations, and hypersensitivity reaction. Results: Database searches initially identified 1481 records. After exclusions according to the selection criteria, 22 studies were included in the qualitative synthesis, and nine studies having adequate data were ultimately included in the meta-analysis. From the studies excluded according to the pre-specified selection criteria, 21 with other pharmacological OA treatments permitted during the trials were a posteriori included in a parallel qualitative synthesis, from which eight studies with adequate data were finally included in a parallel meta-analysis. Since this meta-analysis was designed to assess safety, the exclusion criterion on concomitant anti-OA medication was crucial. However, due to the high number of studies that allowed mainly concomitant oral non-steroidal anti-inflammatory drugs (NSAIDs), we decided to include them in a post hoc parallel analysis in order to compare the results from the two analyses. No statistically significant difference in odds was found between IAHA and placebo for all types of SOC-related disorders, except for infections and infestations, for which significantly lower odds were found with IAHA compared with placebo, both overall (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.40–0.93; I 2 = 0%) and in studies without concomitant anti-OA medication (OR = 0.49, 95% CI 0.27–0.89). There were significant increased odds of reporting serious AEs with IAHA compared with placebo, both overall (OR = 1.78, 95% CI 1.21–2.63; I 2 = 0%) and in studies with concomitant anti-OA medication (OR = 1.78, 95% CI 1.10–2.89), but not in studies without concomitant anti-OA medication (OR = 1.78, 95% CI 0.92–3.47). Conclusions: Using the available data on studies without any concomitant anti-OA medication permitted during clinical trials, IAHA seems not to be associated with any safety issue in the management of OA. However, this evidence was associated with only a “low” to “moderate” certainty. A possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation.

ObjectiveTo evaluate the efficacy, safety and acceptability of an innovative two-component versus a well-established four-component compression systems in the management of venous leg ulcer.MethodMulticentre randomized controlled trial in patients with active venous leg ulcer. Patients were followed-up monthly for a maximum of 16 weeks. The primary endpoint was the complete healing rate at 16 weeks.ResultsNinety-two patients were randomized to either the two-component BIFLEX® Kit group ( n = 49) or the four-component PROFORE® group ( n = 43). In the full analysis set ( n = 88), a complete healing rate of 48.9% and 24.4% was reported in BIFLEX® Kit versus PROFORE® groups, respectively (i.e. a superiority of 24.5%, p = 0.02). Acceptability of BIFLEX® Kit was higher from both the patients’ and physicians’ perspectives.ConclusionThe BIFLEX® Kit represents a valid alternative therapy in the management of venous leg ulcer according to its clinical efficacy, safety and acceptability with potential positive impacts on healthcare costs.

Resume L’estimation du benefice net permet d’expliciter les fondements des decisions therapeutiques, individuelles et collectives. Cette explicitation est une exigence dans la decision medicale partagee et la pratique de la medecine factuelle ou evidence-based medicine. De nombreuses methodes existent, sans qu’aucune ne puisse s’imposer face a un cahier des charges complexe et devant s’ajuster a l’attente de l’acteur central, le patient ou la societe, et a un eventail infini des contextes possibles. Les enjeux, les limites, les contraintes et les competences a acquerir par tous les acteurs, ont ete discutees par les participants de la table ronde et font l’objet de cet article, permettant de conclure a quelques messages cles et des recommandations. Les efforts de formation de tous les acteurs representent la priorite essentielle.

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.

Estimating net benefit makes possible to clarify the basis for therapeutic decisions on an individual and collective level. This clarification is a must in shared medical decision-making and evidence-based medicine. Numerous methods are available, although none outweigh the others. The complex specifications of net benefit estimation should be tailored to the expectations of the central stakeholder, patient or society, and the unlimited range of potential contexts. The challenges, limitations, constraints and skills to be acquired by all stakeholders were discussed by the participants of the round table. They are described in this article, enabling key messages and guidelines to be presented. The essential priority is to ensure that all stakeholders receive the required training.

Resume Le dispositif medical se caracterise notamment par une grande heterogeneite (de l’abaisse langue a la prothese de hanche, en passant par le dispositif non implantable a invasif), un cycle de vie court des produits avec des innovations incrementales recurrentes (de 18 mois a 5 ans) et un caractere operateur dependant. L’objet de cette table ronde etait de faire des propositions et recommandations sur les prerequis necessaires pour repondre aux attentes des autorites competentes francaises lors de demande d’etudes post-inscriptions des dispositifs medicaux (DM) necessaires en cas d’incertitude sur leurs consequences a court ou long terme. Ces etudes, sous la responsabilite du fabricant ou du distributeur du DM, visent a confirmer en vie reelle la place du DM dans la strategie therapeutique. Ce sont pres de 150 etudes post-inscriptions, concernant principalement des dispositifs de classe III, qui sont en cours et, pour la majorite, confrontees a des difficultes de mise en place ou d’atteinte des objectifs fixes par les autorites competentes. Devant ces constats, la table ronde s’est donc attachee a identifier precisement les conditions de mise en œuvre des etudes post-inscriptions specifiques aux caracteristiques des dispositifs medicaux. Des axes de progres sont envisageables pour ameliorer la realisation des etudes, et par consequent, l’efficience de la prise en charge des dispositifs medicaux par l’Assurance maladie : permettre aux industriels d’anticiper au mieux les demandes d’etudes post-inscriptions, definir un objectif principal unique par etude, integrer une phase de concertation sur le protocole des etudes entre les industriels, les autorites competentes et le comite scientifique, et enfin, sensibiliser et former les professionnels de sante a l’impact des etudes cliniques post-inscriptions dans la prise en charge du dispositif medical par l’assurance maladie.

a b s t r a c t Background: The burden of knee osteoarthritis (OA) in Latin America is unknown. Objective: To determine the demographic, clinical, and therapeutic characteristics of patients with OA in Argentina, Brazil, and Mexico. Material and methods: This is an observational, cross-sectional study of patients with symptomatic knee OA referred from first care medical centers to Rheumatology departments. Results: We included 1210 patients (Argentina 398, Brazil 402, Mexico 410; mean age 61.8 (12) years; 80.8% females). Knee OA pain lasted for 69 months; the duration and severity of the last episode were 190 days and (SD 5.2 (3.3); 74% had functional limitations, but very few patients lost their job because of knee OA. Around 71% had taken medications, but 63% relied on their own pocket to afford knee OA cost. Most demographic and clinical variables differed across countries, particularly the level of pain, disability, treatment, and access to care. The variable country of origin influenced the level of pain, disability, and NSAIDs use in logistic regression models; age, pain, treatment, and health care access influenced at least 2 of the models. Conclusions: The burden of knee OA in Latin American depends on demographic, clinical, and therapeutic variables. The role of such variables differs across countries. The level of certain variables is significantly influenced by country of origin and health care system.

In France, there are large discrepancies regarding flu between the severe disease described by Health Authorities and the disease that people face, considered as usual and benign. Flu prevention is useful, mainly through vaccination. For a well-established influenza-like illness, both individual measures dedicated to the limitation of the disease propagation and symptomatic treatment are to be initiated. Few clinical data are available regarding the most often used treatments for influenza-like illness (paracetamol, homeopathic and symptomatic treatments). The analysis did not show any decrease in the chances of success for patients with more often used drugs, either being under medical prescription, pharmacist advice or self-medication. In front of an influenza-like illness, the recommendations for daily practice can be based on 2 well-defined clinical situations: a specific management for patients at risk, and the influenza-like illness symptoms relief for the others, using a treatment specific for each patient.

International audience; Objectives: The aim of the study was to demonstrate the non-inferiority of a single intra-articular injection of 2.0% non-chemically modified sodium hyaluronate (SH) vs 0.8% hylan G-F 20 (control) in symptomatic knee osteoarthritis.Design: This was a double-blind, randomized, controlled trial conducted in patients with painful tibiofemoral osteoarthritis (American College of Rheumatology criteria) with insufficient response or intolerance to first-line analgesics and regular non-steroidal anti-inflammatory drugs. Subjects received a single intra-articular injection of either SH or hylan G-F 20. The primary outcome was the 6-month change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale (WOMAC A), with a pre-specified lower margin for non-inferiority of 8 mm.Results: Of the 292 patients randomized (SH: 144), 288 received an injection (SH: 142), 266 completed the study (SH: 134). In the Per Protocol dataset (SH: 113, control: 112), the WOMAC A change at 6 months was -34.3 mm (95% confidence interval (CI): -37.8, -30.8) and -36.2 mm (95% CI: -40.3, -32.1) for the SH and hylan G-F 20 patients, respectively (P = 0.5). The intergroup difference was -1.9 mm (95% CI: -7.3, 3.5). Results were similar in the Full Analysis Set (SH: 139, control: 141) with a difference between the groups of -2.9 mm (95% CI: -7.9, 2.2). A total of 31.3% of the injected patients reported a treatment-emergent adverse event, including injection site reactions (pain, inflammation or effusion) which occurred in 8.5% of the SH patients vs 13.0% of the hylan G-F 20 patients. No serious reactions were reported.Conclusions: This clinical trial demonstrated the non-inferiority of a single intra-articular injection of SH vs hylan G-F 20 on the WOMAC A change from baseline at 6 months.

Resume L’objet de cette table ronde etait de faire des propositions et recommandations concernant l’evaluation clinique des dispositifs medicaux (DM). Dans un premier temps, un rappel du parcours reglementaire tant au niveau europeen que francais est indispensable pour aborder ce champ encore jeune et tres evolutif. Puis les principales specificites des DM sont soulignees avec leurs implications sur l’evaluation clinique. Deux domaines, les DM implantables et les DM de compensation du handicap, sont plus particulierement analyses pour les illustrer. Huit propositions et recommandations ont ete retenues par la table ronde. Elles s’adressent a tous les acteurs du DM : industriels, utilisateurs, institutionnels et ont pour but d’ameliorer une evaluation clinique centree sur le patient et a son service.

Objectifs : Malgre l’existence de recommandations pratiques pour le traitement de la gonarthrose, des discordances dans leur application par les cliniciens et par les patients ont ete constatees, entrainant des resultats incomplets. Les donnees de la litterature montrent que la simple diffusion de recommandations therapeutiques n’entraine pas l’adhesion. La recherche suggere que les obstacles a leur mise en application devraient etre identifies et explicitees afin d’ameliorer l’adhesion. Le but de cette etude a ete d’identifier les obstacles a l’utilisation des recommandations concernant le traitement conservateur de la gonarthrose tant de la part des patients, que des medecins generalistes et des kinesitherapeutes. Methode : Apres avoir effectue une revue systematique des resultats et des recommandations de la litterature, douze recommandations therapeutiques principales ont ete elaborees sur quatre themes : medicaments, exercices physiques, autogestion, activites professionnelles. Des groupes de discussion ont ete formes comprenant des patients souffrant de gonarthrose, des medecins generalistes et des kinesitherapeutes, dans le but d’etablir les obstacles a la mise en application de ces recommandations. Resultats : Les patients et les medecins generalistes sont apparus comme generalement fatalistes concernant la gonarthrose, alors que les kinesitherapeutes etaient plus positifs vis-a-vis de l’amelioration a long terme de la gonarthrose. Pour les traitements medicamenteux, des discordances ont ete mises a jour entre les recommandations et l’opinion des cliniciens. Tant les patients que les medecins generalistes ont semble ambivalents vis-a-vis des exercices physiques et de l’activite physique, reconnaissant leur utilite mais les identifiant dans le meme temps comme des causes possibles de gonarthrose. Les patients et les medecins generalistes ont semble considerer l’amaigrissement comme un objectif particulierement difficile a realiser. Conclusion : Des obstacles specifiques a la mise en pratique de chaque recommandation du traitement de la gonarthrose pour chacun des groupes de sujets concernes ont ete identifies. Nous avons elabore des recommandations pour combattre ces obstacles. Les resultats de cette etude peuvent etre utilises pour developper des strategies de mise en application afin de surmonter les obstacles identifies, dans le but de faciliter l’utilisation des recommandations et d’ameliorer l’evolution de la gonarthrose. Niveau de preuve : non adapte

OBJECTIVES: Despite the availability of practice guidelines for the management of knee osteoarthritis, inadequacies in practices of clinicians and patients have been found, leading to suboptimal outcomes. Literature has shown that simply disseminating management recommendations does not lead to adherence. Research suggests that barriers to use should be identified and addressed to improve adherence. The objective of this study was to identify barriers to use of conservative management recommendations for knee osteoarthritis by patients, general practitioners and physiotherapists. METHODS: Following systematic reviews of evidence and guidelines, 12 key management recommendations were elaborated on four themes: medication, exercise, self-management and occupation. Focus groups were separately done with patients with knee osteoarthritis, general practitioners and physiotherapists to assess barriers to the use of recommendations. RESULTS: Patients and general practitioners appeared generally fatalistic with regards to knee osteoarthritis, with physiotherapists being more positive regarding long-term improvement of knee osteoarthritis. For medication, discrepancies were found between recommendations and views of clinicians. Both patients and general practitioners appeared ambivalent towards exercise and activity, recognizing its usefulness but identifying it at the same time as a cause of knee osteoarthritis. Patients and general practitioners appeared to consider weight loss particularly difficult. DISCUSSION/CONCLUSIONS: Barriers specific to each knee osteoarthritis management recommendation and stakeholder group were identified. Recommendations to address these barriers were elaborated. Results of this study can be used to develop implementation strategies to overcome identified barriers, with the goal of facilitating the use of guideline recommendations and improving outcomes.

Introduction:The Accountability for Reasonableness (A4R) framework addresses the legitimacy of coverage decision processes by defining four conditions for accountable and reasonable processes: Relevance, Publicity, Appeals, Implementation. Cost-per-quality-adjusted life year (QALY) and multicriteria-centered processes may have distinct implications for meeting A4R conditions. The aim of this study was to reflect on how the diverse features of decision-making processes can be aligned with A4R conditions to guide legitimized decision-making. Rare disease and regenerative therapies (RDRTs) pose special decision-making challenges and offer a useful case study.Methods:To support reflection on how different approaches address the A4R conditions, thirty-four features operationalizing each condition were defined and organized into a matrix. Seven experts from six countries explored and discussed these features during a panel (Chatham House Rule) and provided general and RDRT-specific recommendations for each feature. Responses were analyzed to identify converging and diverging recommendations.Results:Regarding Relevance, panelists highlighted the importance of supporting deliberation, stakeholder participation and grounding coverage decision criteria in the legal framework, goals of sustainable healthcare and population values. Among seventeen criteria, thirteen were recommended by more than half of panelists. Although the cost-effectiveness ratio was deemed sometimes useful, the validity of universal thresholds to inform allocative efficiency was challenged. Regarding Publicity, panelists recommended communicating the values underlying a decision in reference to broader societal objectives, and being transparent about value judgements in selecting evidence. For Appeals, recommendations included clear definition of new evidence and revision rules. For Implementation, one recommendation was to perform external quality reviews of decisions. While RDRTs raise issues that may warrant special consideration, rarity should be considered in interaction with other aspects (e.g. disease severity, age, budget impact).Conclusions:Improving coverage decision-making towards accountability and reasonableness involves supporting participation and deliberation, enhancing transparency, and more explicit consideration of multiple decision criteria that reflect normative and societal objectives.

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.

Resume Objectifs L’Osteoarthritis Research Society International (OARSI) a publie des recommandations internationales sur la prise en charge de la gonarthrose et de la coxarthrose fondees sur la preuve scientifique et les avis d’experts. Nous proposons une traduction de ces recommandations, ainsi que des commentaires tenant compte des pratiques medicales en vigueur en France, Belgique et Suisse francophone. Ce travail a ete realise par les membres de la section Arthrose de la Societe francaise de rhumatologie. Methodes La traduction a ete effectuee par une societe specialisee dans la traduction d’articles medicaux, avec la collaboration d’un groupe multidisciplinaire d’experts francais, belges et suisses. Le document final est le resultat d’un processus de traduction/contre-traduction et d’une comparaison des documents intermediaires entre eux et avec le document original. La traduction concernait la liste des 25 recommandations et non l’ensemble du document publie par l’OARSI. Il s’agit d’un abrege du document original. Le detail des methodes et l’analyse des resultats publies dans le document original n’ont pas ete traduits dans leur integralite. Resultats Ce document presente la version francaise des 25 recommandations de l’OARSI. Elles concernent les traitements pharmacologiques, non pharmacologiques et chirurgicaux de la coxarthrose et de la gonarthrose. Ces recommandations ont ete commentees par des experts francophones, en tenant compte des pratiques medicales regionales et nationales. Conclusions La traduction en francais, selon une methodologie rigoureuse, des 25 recommandations proposees par l’OARSI, a pour but de servir d’aide aux professionnels de sante, ainsi qu’aux patients et aux decideurs politiques dans la prise en charge des patients souffrant de coxarthrose et de gonarthrose.

Resume Il s’agit d’une etude clinique multicentrique, ouverte, prospective et randomisee, avec groupe temoin, des effets de la ceinture lombaire Lombacross activity produit par la societe Thuasne, sur le mal de dos. Le suivi de test est de trois mois. La population etudiee est composee de deux groupes tires au sort d’une centaine de personnes âgees de 20 a 60 ans souffrant d’un mal de dos subaigu ayant motive la consultation d’un medecin generaliste. L’objectif principal de l’etude est d’evaluer l’efficacite de la ceinture lombaire Lombacross activity utilisee par un groupe comparativement aux traitements medicamenteux usuels utilises par l’autre groupe a l’exclusion de la ceinture. Les resultats sur la douleur, la limitation fonctionnelle et la consommation medicamenteuse sont nettement en faveur de la ceinture qui apparait ainsi comme un traitement plus efficace et tres nettement moins couteux que le medicament. Les inconforts lies au port de la ceinture sont minimes et ne sont rien compares aux risques iatrogenes de certaines medications largement prescrites aux personnes avec un mal de dos.

Resume Le traitement de l’osteoporose par les bisphosphonates peut conduire a une reduction importante des taux de fractures. Toutefois, l’efficacite des bisphosphonates est limitee par la mauvaise persistance des patientes a poursuivre leur traitement. L’introduction de formes a administration hebdomadaire a ete associee a une meilleure observance du traitement. Objectifs Cette etude de modelisation a ete concue pour estimer le gain en matiere de persistance associe a un traitement mensuel et son impact sur les taux de fractures. Methodes Les taux de traitement de l’osteoporose et les taux de persistance a ces traitements ont ete obtenus a partir de donnees sur les prises hebdomadaires et quotidiennes de bisphosphonates extraites d’un panel de medecins generalistes francais et pour la prise mensuelle de bisphosphonates a partir d’une base de donnees des filieres de soins integres aux Etats-Unis (managed care). Les analyses de survie ont ete utilisees pour evaluer la persistance. Les taux de fractures, d’hospitalisations et de surmortalite ont ete appliques en se basant sur des donnees issues d’essais cliniques et de donnees epidemiologiques. Resultats En utilisant un schema therapeutique a prise mensuelle, la reduction du risque de fractures vertebrales et non vertebrales, comparee a des sujets non traites, a ete estimee a 21,2 et 9,5 % respectivement. La reduction du risque d’hospitalisation a ete estimee a 17 % et la reduction de la mortalite a 18,1 %. Ces reductions sont environ 60 % plus importantes que les estimations faites avec une prise quotidienne de bisphosphonates et 25 % plus elevees qu’avec un traitement hebdomadaire. Conclusion Ce modele soutient la notion qu’une meilleure persistance au traitement notamment associee a une prise mensuelle des bisphosphonates pourrait avoir un impact significatif sur le taux des fractures osteoporotiques, ainsi que sur les hospitalisations et la surmortalite qui en decoulent.

Long-term studies of NSAIDs have demonstrated cardiovascular toxicity which poses a general problem of the benefit risk between the relief of the patient's symptoms and the risk of digestive and cardiovascular toxicity. The digestive complications and the risk factors associated with the ingestion of NSAIDs have been defined by numerous studies but the prevention of this digestive toxicity can be attempted. The benefit-risk ratio caused by the digestive and cardiovascular toxicities of the NSAIDs and COX-2 inhibitors must be evaluated for each individual before starting a treatment. For a treatment of short duration in patients with a low risk of digestive and cardiovascular complications, the risk of digestive toxicity must be taken into consideration first and the COX-2 inhibitors are favoured. For a treatment of long duration the risk must be evaluated with the greatest care. In the case of cardiovascular risk factors, the cardiovascular risk must be evaluated and the treatment must be prescribed at the lowest dose for the shortest duration. In patients with very high risk of digestive and cardiovascular complications, since the digestive and cardiovascular extra-mortality associated with the ingestion of NSAIDs or COX-2 inhibitors is high, it is advised to abandon this type of long-term treatment.

The goal of this study was to determine which activities in four domains, daily life, exercises, sports and occupational activities, should be recommended, in favor or against, for the patient suffering from knee or hip OA. Methods Scientific literature was searched in Medline, Embase and Cochrane databases for articles in French or English, reporting original data. The articles were evaluated with standardized epidemiological criteria. Seventy-two articles were retained. Recommendations were graded according to the level of scientific evidence (A high, B moderate, C clinical consensus) and were formulated for primary care. Conclusions and recommendations For activity of daily life (ADL) , the OASIS group states with a moderate level of scientific evidence, that ADL are a risk factor for knee OA and that risk increases with intensity and duration of activity. The group concludes that healthy subjects as well as OA patients in general can pursue a high level of physical activity, provided the activity is not painful and does not predispose to trauma (grade B). Radiographic or clinical OA is not a contraindication to promoting activity in patients who have a sedentary lifestyle (grade C). For exercises and other structured activities pursued with a goal of health improvement, the group states with a high level of scientific evidence that they have a favourable effect on pain and function in the sedentary knee OA patient. The OASIS group recommends the practice of exercises and other structured activities for the sedentary patient with knee OA (grade A). Static exercises are not favored over dynamic exercises, availability, preference and tolerance being the criteria for the choice of an exercise (grade A). As results deteriorate when exercises are stopped, they should be performed at a frequency of between one and three times per week (grade B). Professional assistance can be useful in improving initial compliance and perseverance (grade B). There is no scientific argument to support halting exercise in case of an OA flare-up (grade C). For sports and recreational activity , the group states with a high degree of scientific evidence, that these activities are a risk factor for knee and hip OA and that the risk correlates with intensity and duration of exposure. The group also states, with a high degree of scientific evidence, that the risk of OA associated with sport is lesser than that associated with a history of trauma and overweight. No firm conclusion could be drawn about the possible protective role of sports such as cycling, swimming or golf. The OASIS group recommends that athletes should be informed that joint trauma is a greater risk factor than the practice of sport (Grade A). The high level athlete should be informed that the risk of OA is associated with the duration and intensity of exposure (Grade B). The OA patient can continue to engage regularly in recreational sports as long as the activity does not cause pain (Grade C). The OA patient who practices a sport at risk for joint trauma should be encouraged to change sport (Grade C). For occupational activity , the OASIS group states with a high level of scientific evidence that there is a relationship between occupational activity and OA of the knee and hip. The precise nature of biomechanical stresses leading to OA remains unclear but factors such as high loads on the joint, unnatural body position, heavy lifting, climbing and jumping may contribute to knee and hip OA. The group recommends that taking an occupational history should always be part of managing the OA patient (Grade B). In the knee or hip OA patient, work-related activity that produces or maintains pain should be avoided (Grade B). Physicians should be alerted by the early knee and hip signs and symptoms in workers exposed to stresses that are known or supposed to favour knee or hip OA (Grade C).

Resume Le but de la presente analyse critique de la litterature a ete de determiner, dans quatre domaines d'activite : vie quotidienne, exercices a visee therapeutique, sport et travail, s'il est possible de recommander ou de deconseiller des activites en fonction du caractere normal ou arthrosique du genou ou de la hanche. Methode Une revue de la litterature a partir des bases Medline, Embase et Cochrane ainsi que des revues de litterature pertinente, a permis d'identifier les articles en francais ou en anglais presentant des donnees originales. Les etudes ont ete analysees systematiquement a l'aide d'une grille de criteres epidemiologiques. Soixante-douze etudes de qualite acceptable ont ete retenues. Les recommandations ont ete formulees en tenant compte du niveau de preuve scientifique a l'appui (A : eleve, B : moyen et C : consensus d'experts), avec l'objectif d'etre utile a la prise en charge du patient arthrosique en medecine generale. Conclusions et recommandations Activites de la vie quotidienne (dites non programmees) : on peut admettre avec un niveau d'evidence scientifique moyen que l'activite physique non programmee est un facteur de risque pour l'arthrose du genou, et que le risque augmente avec l'intensite et la duree de ces activites. En consequence, la pratique d'une activite physique a un niveau eleve peut etre poursuivie, autant par les sujets sains que par les patients arthrosiques en general, dans la mesure ou elle n'entretient pas de douleur articulaire et ne predispose pas aux traumatismes (recommandation de grade B). L'arthrose radiologique ou clinique n'est pas une contre-indication a combattre la sedentarite chez les patients dont le niveau d'activite generale est faible (recommandation de grade C). Exercices a visee therapeutique (activites dites programmees) : On peut admettre avec un niveau d'evidence scientifique eleve que les exercices de renforcement ont une action favorable sur la douleur et la fonction chez le sujet sedentaire ayant une arthrose du genou, sans qu'on puisse privilegier une modalite d'exercice particuliere. En consequence, les exercices et autres activites programmees sont recommandes chez le sujet sedentaire atteint d'une arthrose du genou et il n'y a pas lieu de preferer les exercices statiques aux exercices dynamiques, les criteres de choix etant la disponibilite, la preference et la tolerance (recommandation de grade A). Les resultats se degradant a l'arret, il est conseille de poursuivre les autoexercices entre une et trois fois par semaine ; pour ameliorer le taux d'adhesion initiale et l'assiduite par la suite a un regime d'exercices, l'aide d'un professionnel peut s'averer utile (recommandations de grade B). Il n'y a aucun argument scientifique pour interdire les exercices en cas de poussee d'arthrose (recommandations de grade C). Activites de sport et de loisir : on peut admettre avec un niveau d'evidence scientifique eleve que l'activite articulaire liee au sport est un facteur de risque pour l'arthrose du genou et de la hanche, et que le risque est correle avec l'intensite et la duree du niveau d'exposition au sport. On peut aussi admettre avec un niveau d'evidence scientifique eleve que le risque d'arthrose liee au sport apparait relativement moindre que celui des traumatismes et de l'obesite. On ne peut pas conclure sur le role protecteur eventuel de certains sports comme le velo, la nage ou le golf. On ne peut pas conclure non plus sur le risque de la poursuite du sport sur la progression d'une arthrose existante. En consequence, il y a lieu d'informer le sportif que les traumatismes articulaires sont un facteur de risque d'arthrose plus important que la pratique du sport elle-meme (recommandation de grade A). Il y a lieu egalement d'informer les sportifs de haut niveau que le risque articulaire lie aux pratiques sportives est correle a la duree et a l'intensite de l'exposition (recommandation de grade B). Enfin, un patient arthrosique qui pratique une activite sportive reguliere de loisirs peut la poursuivre dans la mesure ou elle n'induit pas de douleur ; si cette activite l'expose a des traumatismes articulaires, il y a lieu alors de recommander un changement d'activite (recommandation de grade C). Travail : on peut affirmer, avec un niveau d'evidence scientifique eleve, qu'il existe une relation entre les activites professionnelles en milieu de travail et l'arthrose du genou et de la hanche. La nature des stress biomecaniques menant a l'arthrose n'est pas connue avec precision. En consequence, il faut tenir compte du role des activites professionnelles dans la prise en charge d'un patient arthrosique (recommandation de grade B). Chez les sujets atteints d'une arthrose du genou ou de la hanche, les activites professionnelles qui induisent ou entretiennent la douleur, doivent etre evitees (recommandation de grade B). Il faut sensibiliser les medecins au depistage des premiers signes et symptomes articulaires du genou ou de la hanche chez des travailleurs exposes a des contraintes connues ou supposees comme favorisant l'arthrose du genou ou de la hanche (recommandation de grade C).

Recent advances in the understanding of the epidemiology of osteoporosis suggest that certain parts of the current European guidelines for the registration of drugs in osteoporosis might be no longer substantiated. The object of this review is to provide the European regulatory authorities with an evidence-based working document providing suggestions for the revision of the "Note for guidance for the approval of drugs to be used in postmenopausal osteoporosis" (CPMP/EWP/552/95). Following an extensive review of the literature (1990-2004), the Group for the Respect of Ethics and Excellence in Science (GREES) organized a workshop including European regulators, academic scientists and representatives of the pharmaceutical industry. The outcomes of this meeting reflect the personal views of those who attended and should not, in any case, be seen as an official position paper of any regulatory agency. The group identified a certain number of points that deserve discussion. They mainly relate to the nature of the indication being granted to new chemical entities (treatment of osteoporosis in women at high risk of fracture instead of prevention and treatment of osteoporosis), the requirements of showing an anti-fracture efficacy on all or on major nonvertebral fractures (instead of the hip), the duration of pivotal trials (2 years instead of 3) and the possibility of considering bridging studies for new routes of administration, new doses or new regimens of previously approved drugs. The group also recommends that an indication could be granted for the treatment of osteoporosis in males on the basis of a placebo-controlled study, with bone mineral density changes after 1 year as the primary endpoint, for medications approved in the treatment of osteoporosis in women at high risk of fractures. © International Osteoporosis Foundation and National Osteoporosis Foundation 2005.

To evaluate the impact of using pain assessment scales on the management of musculoskeletal chronic pain.Cluster-randomized controlled multicentre trial in French general practice settings. Practices were randomized by region before patient recruitment. The inclusion concerned patients suffering from musculoskeletal chronic pain. General practitioners assigned to the scale group used two validated assessment instruments; those assigned to the control group cared for their patients according to their usual practice. The primary end-point was the level of relief obtained and the secondary changes in prescription of painkilling modalities.A total of 155 general practitioners included 772 successive patients suffering from musculoskeletal chronic pain. The control group reported a mean level of relief of 50.7% compared with one of 41.1% in the scale group (p0.0001). In the intervention group, physicians decreased significantly their prescription of level two painkillers.In general practice, the use of pain assessment scales is not associated with greater pain relief. The lesser level of pain relief obtained in the scale group does provide evidence that using pain assessment scales does not enhance the relief of chronic pain in patients in primary care. Guidelines which recommend the systematic use of scales for the assessment and monitoring of chronic pain are not tailored to either the context or the patients encountered in the primary care setting.

Purpose In clinical guidelines for acute and subacute low-back pain, pharmacological treatment is recommended for short-term symptomatic relief. The objective was to study the effect of the guidelines' advise to remain active, alone and with the addition of the drug adenosine tri-phosphate (ATP), in patients with subacute low-back pain. Methods A drug-guidelines effectiveness trial was undertaken simultaneously to an experimental drug efficacy placebo controlled trial in subacute (4–12 weeks) non-specific low-back pain patients. The 132 participating primary care physicians across France were randomised to participate to either trial. In the drug-guidelines trial, all physicians received a quick consultation card containing the key elements of the clinical guidelines and a brochure that gave their patients practical tips to remain active. Patients were then randomised to receive Atepadene®, containing 90 mg of ATP by mouth daily for 30 days (guidelines plus ATP group), or nothing beside the rescue drug that was made available to all patients (guidelines alone group). The principal outcome was functional improvement on the Roland–Morris Disability Questionnaire (RDQ) at 90 days. Results In the drug-guidelines effectiveness trial, 157 patients were randomised. The rate of improvement in the RDQ over the 90 days of follow-up was superior in the group guidelines plus ATP (8.3 points, 95% confidence interval (CI): 7.3–9.3) than in the group guidelines alone (6.5 points, 95%CI: 5.3–7.7) (p = 0.02). In terms of probability of improving between two to five points on the RDQ at 90 days this difference translated in a 2 to 13 times higher probability compared to the group guidelines alone (odds ratios ranging from 2.1, 95%CI: 0.9–5.0 to 12.9, 95%CI: 1.6–103.4). Patients in the group guidelines plus ATP were also three times less likely to report a condition that had worsened or remained unimproved at 90 days (p = 0.02). Conclusion This drug-guidelines effectiveness trial showed a modest advantage of combined specific pharmacologic and non-pharmacological treatments on absolute improvement on the RDQ. A threefold reduction in the risk of chronicity was observed, an important goal in low-back pain guidelines. Copyright © 2005 John Wiley & Sons, Ltd.

Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. Objective: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. Methods: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. Results: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are 'responder' (or 'failure'). The definition of a 'failure' patient would be someone with progression of JSN>0.5 mm over a period of 2-3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. Conclusion: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion. (C) 2004 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Osteoporosis is a general disorder of the skeleton characterised by a decrease in bone mass, with damage to the microarchitecture leading to an increase in bone fragility and fracture risk. The incidence of this illness will increase in the future because of the aging of the population and increasing risk factors. Many guidelines have been proposed by qualified authorities--those of the European Agency for the Evaluation of Medicinal Products (EMEA) being the latest published. The aim of treatment of the osteoporosis is to increase, maintain or improve bone mass as well as its strength, with a view to decreasing the incidence of bone fractures. With regard to preclinical studies, in vitro studies--such as those using osteoblast or osteoclast cultures--allow a better understanding of the mechanism of action of drug treatment. The evaluation of bone quality should be performed in two species, such as the ovariectomised female rat model and larger animals (ewe, sow, primate etc.). Phase I studies are designed to enable determinations of pharmacokinetic profiles and bone diffusion and to offer indications of the putative clinical relevance of the dosages. For phase II studies (double-blind controlled studies versus placebo, ideally with a duration of 24 or sometimes 12 months), tests of three dosages are recommended, and the bone mass is considered as a relevant substitution criterion. The aim of secondary osteoporosis prevention studies (randomised double-blind and comparative controlled design versus placebo) is to avoid the occurrence of new bone fractures, and the main evaluation criterion is the number of patients with new fractures. The study length should not be less than 3 years. For evaluation of primary osteoporosis prevention, efficacy in the prevention of bone fracture is the prerequisite--before the use of bone mass as the main evaluation criterion. This criterion can be evaluated by alterations in bone mineral density at the rachis level. Reference drugs such as estrogens can be an alternative to placebo comparison. The tolerability of drugs for the treatment of osteoporosis requires evaluation in long-term studies and the collection of postmarketing data. The International Conference on Harmonisation (ICH) could lead to uniform guidelines for the US, Europe and Japan.

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

BackgroundPrescribing of antibiotics for upper respiratory tract infections (URTI) varies substantially in primary care.ObjectivesTo describe and compare antibiotic and antipyretic/anti-inflammatory drugs use, URTI symptoms' resolution and occurrence of potentially-associated infections in patients seeking care from general practitioners (GPs) who exclusively prescribe conventional medications (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho).MethodThe EPI3 survey was a nationwide population-based study of a representative sample of 825 GPs and their patients in France (2007-2008). GP recruitment was stratified by self-declared homeopathic prescribing preferences. Adults and children with confirmed URTI were asked to participate in a standardized telephone interview at inclusion, one-, three- and twelve-month follow up. Study outcomes included medication consumption, URTI symptoms' resolution and potentially-associated infections (sinusitis or otitis media/externa) as reported by patients. Analyses included calibration to account for non-respondents and groups were compared using multivate analyses adjusting for baseline differences with a propensity score.Results518 adults and children with URTI (79.3% rhinopharyngitis) were included (36.9% response rate comparable between groups). As opposed to GP-CM patients, patients in the GP-Ho group showed significantly lower consumption of antibiotics (Odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.27-0.68) and antipyretic/anti-inflammatory drugs (OR = 0.54, 95% CI: 0.38-0.76) with similar evolution in related symptoms (OR = 1.16, 95% CI: 0.64-2.10). An excess of potentially-associated infections (OR = 1.70, 95% CI: 0.90-3.20) was observed in the GP-Ho group (not statistically significant). No difference was found between GP-CM and GP-Mx patients.ConclusionPatients who chose to consult GPs certified in homeopathy used less antibiotics and antipyretic/anti-inflammatory drugs for URTI than those seen by GPs prescribing conventional medications. No difference was observed in patients consulting GPs within mixed-practice. A non-statistically significant excess was estimated through modelling for associated infections in the GP-Ho group and needs to be further studied.

Since Albright, [1] some 60 years ago, reported the benefi-cial effects of estrogens for decreasing urinary calcium ex-cretion and suggested that these harmones might be usefulin preventing postmenopausal osteoporosis, estrogen re-placement therapy (ERT) has been consistently regarded asthe first choice for prevention of trabecular and corticalbone loss in postmenopausal women [2–5]. However, seri-ous controversies remain over the cost/effectiveness oftreating every woman at the time of menopause [6], theoptimal timing for starting ERT [5], the minimal effectivedose of ERT acting on bone [7], and the duration of ERTneeded to prevent osteoporotic fractures [8]. The effective-ness of ERT for preventing osteoporosis-related fractures isundisputed and requirements for marketing authorizationfor ERT products have lightened compared with currentrequests for other therapeutic medications developed in thisfield [9, 10]. However, although the skeletal benefits ofERT for preventing trabecular or cortical bone loss canhardly be challenged, one might be wary of published evi-dence that prolonged ERT use unequivocally reduces therisk of hip fracture. Controlled clinical trials and systematicreviews were located using Medline 1970–1999 andEMBASE 1980–1999. Since 1985 we have searched scien-tific journals on bone and bibliographies of review articles.All prospective controlled trials were included for evalua-tion of the effects of hormone replacement therapy (HRT)on bone loss. A total of 57 prospective controlled trials wereidentified, 46 of which were randomized clinical trials(RCTs) and 15 were double blinded. All clinical trials as-sessing the effects of HRT on fracture rates were consid-ered. Two RCTs and one systematic review were identified[11].In the 46 randomized controlled trials comparing estro-gen (with or without progestins) (HRT) with placebo orcalcium on bone loss prevention, the study population var-ied from 14 to 875 women and the duration was from .5 to10 years. In general, they drew similar conclusions, i.e, thatestrogen intervention reduces the rate of postmenopausalbone loss at trabecular and cortical sites. An early double-blind trial [12] reported the preventive effects of HRT oncortical (metacarpal) bone loss for up to 10 years. Morerecent double-blind, placebo-controlled, randomized clini-cal trials confirmed these findings for oral [13], percutane-ous [14, 15], or transdermal [16] estrogens at the spine [13,14, 16], the forearm [16], and/or the hip [13, 16] for up to3 years. Two prospective open studies [17, 18] showedsimilar results for estrogen implants after 1 year. Whenstandardized for technique used for bone mineral density(BMD) assessment, the magnitude of the point estimatedifferences between the HRT and the control group variedgreatly from one study to another, depending upon the doseof HRT used (dose-related effect on bone mass in most

In France, there are large discrepancies regarding flu between the severe disease described by Health Authorities and the disease that people face, considered as usual and benign. Flu prevention is useful, mainly through vaccination. For a well-established influenza-like illness, both individual measures dedicated to the limitation of the disease propagation and symptomatic treatment are to be initiated. Few clinical data are available regarding the most often used treatments for influenza-like illness (paracetamol, homeopathic and symptomatic treatments). The analysis did not show any decrease in the chances of success for patients with more often used drugs, either being under medical prescription, pharmacist advice or self-medication. In front of an influenza-like illness, the recommendations for daily practice can be based on 2 well-defined clinical situations: a specific management for patients at risk, and the influenza-like illness symptoms relief for the others, using a treatment specific for each patient.

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.

Background Selecting an appropriate primary efficacy criterion is of key importance in the design of a randomized controlled trial (RCT) evaluating therapeutic interventions in knee OA. One may choose among various possible primary efficacy criteria which can be classified as 1/ continuous variables such as pain (on a visual analog scale (VAS)) or function by one of the OA-specific available instruments (providing a numeric variation on a scale indicating the amount of therapeutic effect, which clinical relevance has to be established), or 2/ binary global response criteria, such as the OMERACT-OARSI (1), or response criteria based on the Patient Acceptable Symptom State (PASS) or the Minimum Clinical Important Improvement (MCII) applied to pain, function, or patient global assessment (PGA) (2), which results are expressed in % of responders (yes/no). The sensitivity of these global response instruments has not been compared yet. Objectives The aim of this study was to compare responder9s rates using various definitions of response in a knee OA trial of IAHA, and to identify factors associated with a better response. Methods Data obtained from a RCT comparing one single IA injection of 40 mg/2.0ml non-chemically modified HA with 48 mg/6.0ml hylan G-F20 were used for this post hoc analysis (3). As non-inferiority of the non-crosslinked HA was demonstrated over 6 months, data of both treatment groups were pooled (280 patients in the full analysis set, 266 completers). Uni- and multivariate stepwise regression analyses were performed to compare response criteria and identify potential factors associated with the best clinical response. OMERACT-OARSI responder criteria were compared to the PASS (≤40 mm) and MCII (≥15 mm improvement) responder criteria calculated for the following outcomes: pain using WOMAC A1 0–100mmVAS format, physical function using WOMAC C (VAS format) and the 0–100 normalized Lequesne index, and PGA on a 0–100 mmVAS. Results The three most sensitive response instruments were the MCII (relative) for pain, followed by the OMERACT-OARSI responder criteria and the MCII (absolute) for pain with around 80% responders (Fig1). Factors associated with a better response were: a higher pain at baseline (OR [95%CI]: 1.05 [1.02; 1.08]), a shorter delay since diagnosis of knee OA (0.93 [0.88; 0.99]), bilateral knee OA (2.51 [1.11; 5.68], and a better PGA (i.e. a lower score; 0.95 [0.92; 0.98]). Conclusions In this post-hoc analysis, comparing for the first time several definitions of therapeutic response in a clinical trial of IAHA in knee OA, MCII for pain and OMERACT-OARSI criteria seemed to be the most responsive outcome criteria. Response rates were higher in patients presenting with more pain at baseline, a shorter duration since diagnosis, bilateral knee OA and a better PGA. References Pham T et al. Osteoarthritis Cartilage 2004;12:389–99 Tubach F et al. Arthritis Care Res 2012;64:1699–707 Dreiser RL et al. Ann Rheum Dis 2015;74(Suppl 2):376. Abstract no THU0488. Acknowledgement We thank TRB Chemedica, for providing access to their trial Database. Disclosure of Interest E. MAHEU Grant/research support from: TRB Chemedica, L. DREISER Grant/research support from: TRB Chemedica, B. AVOUAC Grant/research support from: TRB Chemedica, T. BARDIN Grant/research support from: TRB Chemedica

The purpose of the Giens round table no. 1 was to make proposals and recommendations regarding the clinical evaluation of medical devices. First, the European and French regulatory rules were examined and compared with the US FDA approach. Thereafter, the main specificities and constraints of the MD sector were underlined and their impact in clinical evaluation described and analyzed. Two areas, cumulating most of these constraints, were consecutively analyzed for concrete case study. Considering a patient-centered approach, the RT issued eight recommendations directed to manufacturers, physicians and policymakers in order to improve clinical evaluation in the medical device field.

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.

Summary: Health claims for food products in Europe are permitted if the nutrient has been shown to have a beneficial nutritional or physiological effect. This paper defines health claims related to bone health and provides guidelines for the design and the methodology of clinical studies to support claims. Introduction: Regulation ( EC ) no. 1924/2006 on nutrition and health claims targeting food products was introduced in Europe stating that health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. The objective of this paper is to define health claims related to bone health and to provide guidelines for the design and the methodology of clinical studies which need to be adopted to assert such health claims. Methods: Literature review followed by a consensus discussion during two 1-day meetings organized by the Group for the Respect of Ethics and Excellence in Science ( GREES ). Results: The GREES identified six acceptable health claims related to bone health based on the potential of food products to show an effect on either the bioavailability of calcium or osteoclast regulatory proteins or bone turnover markers or bone mineral density or bone structure or fracture incidence. The GREES considers that well-designed human randomized controlled trial on a relevant outcome is the best design to assess health claims. The substantiation of health claim could also be supported by animal studies showing either an improvement in bone strength with the food product or showing the relationship between changes induced by the food product on a surrogate marker and changes in bone strength. Conclusion: The consensus reached is that the level of health claim may differ according to the surrogate endpoint used and on additional animal studies provided to support the claim.

Introduction: In 2006, the European Parliament and Council issued a regulation (No. 1924/2006) for the nutrition and health claims made on foods, including food supplements. According to the regulation, the use of nutrition and health claims shall only be permitted if the substance in respect of which the claim is made has been shown to have a beneficial nutritional or physiological effect. In the field of joint and cartilage health, there is no clear scientific-based definition of the nature of such a beneficial nutritional or physiological effect. The objective of this paper is to scientifically define the possible content of health claims related to joint and cartilage health and to provide scientific guidelines for the design of clinical studies which need to be adopted to substantiate such health claims. Methods: Literature review up to September 2011 followed by a consensus expert discussion organized by the Group for the Respect of Ethics and Excellence in Science (GREES). Results: In line with the general principles of the PASSCLAIM and the Codex recommendations, the GREES identified four acceptable health claims related to joint and cartilage health based on the effects on discomfort, joint and cartilage structural integrity or risk factors for joint and cartilage diseases. The GREES considers that randomized controlled trials on a relevant outcome is the best design to assess health claims. Moreover, animal studies could also be of interest to substantiate some health claims, to assess the clinical relevance of endpoints used in human studies or to extrapolate data obtained in patients to the target (apparently) healthy population. Conclusion: According to the methodology and biomarkers used in the study and whether or not additional animal studies are provided to support the claim, various health claims can be acceptable in the field of joint and cartilage health.

Objective.To compare the clinical efficacy of certolizumab pegol (CZP) with that of other anticytokine agents indicated for the treatment of rheumatoid arthritis (RA) with identical therapeutic indication (anti-tumor necrosis factor-α, anti-interleukin 1 or 6), with the objective of determining the noninferiority of CZP.Methods.A systematic review was performed to identify randomized controlled trials that assessed the efficacy of anticytokine agents in combination with conventional disease-modifying antirheumatic drugs (DMARD) after 6 months of treatment, using the American College of Rheumatology (ACR) response criteria, in patients with RA who have shown inadequate response to DMARD including methotrexate. Indirect treatment comparisons were carried out by a multiple-treatment Bayesian random-effects metaanalysis. Data were analyzed using the Markov chain Monte Carlo simulation. Noninferiority of CZP was assessed in comparison with a predefined equivalence margin of 5%.Results.Nineteen placebo-controlled studies were identified: 14 evaluated the efficacy of 5 anti-TNF-α agents (infliximab, etanercept, adalimumab, golimumab, CZP) and 5 evaluated efficacy of 2 anti-interleukin agents (anakinra, tocilizumab). Every treatment showed significant efficacy versus placebo in individual studies. The multiple-treatment metaanalysis showed a highest OR for CZP on ACR20 response. Metaanalysis indicates that the efficacy of CZP according to ACR20 response is superior to that of infliximab, adalimumab, and anakinra, and equivalent or superior to that of etanercept, golimumab, and tocilizumab. According to ACR50 response, the efficacy of CZP is equivalent or superior to that of all other anticytokines.Conclusion.Results of this original multiple-treatment Bayesian metaanalysis indicate that certolizumab pegol is at least as efficacious as the preexisting antirheumatic anticytokine biotherapies.

Background There is a paucity of information describing patients with musculoskeletal disorders (MSDs) using complementary and alternative medicines (CAMs) and almost none distinguishing homeopathy from other CAMs. The objective of this study was to describe and compare patients with MSDs who consulted primary care physicians, either certified homeopaths (Ho) or regular prescribers of CAMs in a mixed practice (Mx), to those consulting physicians who strictly practice conventional medicine (CM), with regard to the severity of their MSD expressed as chronicity, co-morbidity and quality of life (QOL). Methods The EPI3-LASER study was a nationwide observational survey of a representative sample of general practitioners and their patients in France. The sampling strategy ensured a sufficient number of GPs in each of the three groups to allow comparison of their patients. Patients completed a questionnaire on socio-demographics, lifestyle and QOL using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than twelve weeks duration of the current episode. Diagnoses and co-morbidities were recorded by the physician. Results A total of 825 GPs included 1,692 MSD patients (predominantly back pain and osteoarthritis) were included, 21.6% in the CM group, 32.4% Ho and 45.9% Mx. Patients in the Ho group had more often a chronic MSD (62.1%) than the CM (48.6%) or Mx (50.3%) groups, a result that was statistically significant after controlling for patients' characteristics (Odds ratio = 1.43; 95% confidence interval (CI): 1.07 - 1.89). Patients seen by homeopaths or mixed practice physicians who were not the regular treating physician, had more often a chronic MSD than those seen in conventional medicine (Odds ratios were1.75; 95% CI: 1.22 - 2.50 and 1.48; 95% CI: 1.06 - 2.12, respectively). Otherwise patients in the three groups did not differ for co-morbidities and QOL. Conclusion MSD patients consulting primary care physicians who prescribed homeopathy and CAMs differed from those seen in conventional medicine. Chronic MSD patients represented a greater proportion of the clientele in physicians offering alternatives to conventional medicine. In addition, these physicians treated chronic patients as consulting rather than regular treating physicians, with potentially important impacts upon professional health care practices and organisation.