Beta-blocker treatments have been introduced in the 1970s as standard treatment of chronic coronary disease and especially for the secondary prevention post myocardial infarction. However, given the recently introduced reperfusion therapies during the acute phase of such myocardial infarctions (thrombolysis and angioplasty) and the administration for secondary prevention of antiplatelet drugs, statins and angiotensin converting enzyme inhibitors, the potential therapeutic benefit of beta-blocker treatment has been challenged in such indication. Many clinical studies have been performed to investigate such issue. Intravenous beta-blocker administration remains recommended during the acute phase of myocardial infarction, mainly in relation to its anti-ischemic and antiarrhythmic actions, despite absence of clear demonstration of benefit on mortality in addition to that induced by reperfusion procedures. In contrast, the survival benefit of beta-blocker treatment in secondary prevention remains demonstrated during the first year post myocardial infarction whatever the level of left ventricular function. The prolongation of beta-blocker treatment beyond one year post myocardial infarction improves survival only in patients with altered left ventricular function (left ventricular ejection fraction < 40%). In patients with preserved left ventricular function, the prolongation of beta-blocker treatment seems only to reduce incidence of hospitalizations for cardiovascular reasons, without improving quality of life.

Le traitement bêta-bloquant a été introduit dans les années 1970 dans l’arsenal thérapeutique de la maladie coronaire et en particulier dans le cadre d’un infarctus du myocarde. Cependant, compte tenu des progrès de sa prise en charge thérapeutique introduits ces dernières décennies, tant lors de sa phase aiguë par les techniques de reperfusion (thombolyse et angioplastie) que par l’introduction en prévention secondaire des anti-agrégants, inhibiteurs de l’enzyme de conversion de l’angiotensine et des statines, l’intérêt thérapeutique des bêta-bloquants dans le cadre d’un infarctus du myocarde a été remis en question et a fait l’objet de nombreuses études cliniques. Le traitement bêta-bloquant à la phase aigüe d’un infarctus du myocarde reste préconisé par voie intra-veineuse principalement pour l’effet anti-ischémique et anti-arythmique qu’il induit. En prévention secondaire, les études récentes ont confirmé le bénéfice du traitement bêta-bloquant sur le pronostic (mortalité et évènements cardiovasculaires majeurs) chez les patients présentant une altération de la fonction ventriculaire gauche (fraction d’éjection <40 %). Des résultats divergents ont été retrouvés par les plus récentes études chez les patients avec fraction d’éjection ventriculaire gauche >40 %, suggérant que le bénéfice du traitement bêta-bloquant ne serait conservé que chez les patients présentant une fraction d’éjection ventriculaire gauche comprise entre 40 et 50 %.

Health technology assessment (HTA) informs public decision-making regarding the use of medical innovations. In France, the national health authority (Haute Autorité de santé, HAS) is the principal body responsible for these assessments. In hospitals, a specific form of HTA-hospital-based HTA (HB-HTA)-has been developed to evaluate technologies in their local context, contributing to better allocation of resources and judicious management of innovation. However, HB-HTA remains underdeveloped in France. In this context, round table no. 4 of the "Ateliers de Giens" (Giens Workshops), a meeting of experts from the fields of academia, medicine, hospital management and industry, looked at the obstacles and solutions that could enable HB-HTA structures in France to do more and do better. The round table identified several major findings that are hampering the development of HB-HTA. First, HB-HTA remains limited regarding its scope of application and number of potential beneficiaries. As a result, the activity suffers from a lack of recognition at an institutional and strategic level. The situation is further hampered by a marked lack of human, organizational and financial resources, as well as extremely limited dissemination of the findings, both internally and externally. Finally, the absence of harmonized assessment methods harms the informative value and impact of these procedures. To address these challenges, the round table formulated five recommendations: (1) expanding the uses of HB-HTA in the health system; (2) increasing recognition for HB-HTA by demonstrating its usefulness; (3) funding of HB-HTA pilot centers and creating the conditions for sustainable funding; (4) structuring the sharing of HB-HTA assessments; and (5) promoting a unified HB-HTA methodology and supporting the training of those involved.

Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20

The repurposing of a medicine already on the market to a new indication could be an opportunity to respond rapidly to a therapeutic need not yet covered, particularly in the context of rare and neglected diseases, or health emergencies. However, at each stage, difficulties may arise that will prevent the repurposed drug from being provided to patients. Beyond fortuity or a systematic strategy to detect a useful pharmacological effect, the implementation of the preclinical and clinical stages is sometimes complicated by the difficulty of accessing the molecule and its pharmaceutical data. Furthermore, relevant clinical results will not always be sufficient to ensure that a marketing authorisation is obtained or that patients receive satisfactory care. In addition to describing these various obstacles, the round table provided an opportunity to put forward recommendations for overcoming them, in particular the creation of a public–private partnership structure with sufficient funding to be able to offer individualised support for projects up to and including the marketing application.

La pandémie de coronavirus disease-19 (COVID-19) a conduit au déploiement d’un effort de recherche académique et industriel sans précédent dont on peut regretter le caractère parfois redondant ainsi que le manque de pilotage tant national qu’international. Pourtant, force est de constater qu’à l’occasion de cette crise, les procédures réglementaires ont été adaptées de même que certains freins dans l’organisation de la recherche clinique ont pu être en partie levés pour contribuer au déploiement d’essais au plus près des patients et faciliter les modalités de suivi et de contrôle. La digitalisation de certains processus et la décentralisation de certaines activités ont pu être mises en œuvre sous couvert d’une mobilisation des autorités et de l’ensemble des acteurs institutionnels, académiques ou industriels. Si outre-manche, l’optimisation des ressources, au travers d’un essai de plateforme unique, a permis de montrer ou d’infirmer l’efficacité de nombreux traitements, en France la crise sanitaire a mis en lumière la fragilité de l’organisation de la recherche clinique, notamment un déficit de coordination et de financement, des difficultés dans la mise en œuvre des études ou encore une certaine frilosité concernant le partage des données. Cependant, la crise a aussi révélé les capacités d’adaptation des différents acteurs et permis l’amélioration de plusieurs processus utiles au déploiement de l’innovation thérapeutique. Gageons que les leçons tirées à l’occasion de cette crise permettront une meilleure efficacité en cas de nouvelle pandémie et surtout que les progrès obtenus continueront de s’appliquer à l’ensemble des activités de recherche clinique futures.

The article presents a list and justification of a number of the most important lessons of the coronavirus pandemic that are directly related to public health issues. The author notes that in the course of the fight against the pandemic, many problematic factors and issues have arisen, the impact of which on the health of the population should be analyzed and evaluated as quickly as possible. The analysis of the lessons of the COVID‑19 pandemic is extremely important for improving the effectiveness of measures to prevent the pandemic, maximizing the consideration and reduction of the risks of possible negative consequences in decision-making, and ensuring appropriate preparedness in the near future.

ContextePour optimiser le bon usage des médicaments, il convient de pouvoir disposer de méthodes de détection des prescriptions hors de leur autorisation de mise sur le marché (AMM), notamment en milieu hospitalier.Objectif de l’étudeÉtudier les performances de la détection des prescriptions hors AMM intrahospitalières chez les patients adultes par le codage classification internationale des maladies–10è édition (CIM-10) des maladies utilisé dans le programme médical du système d’information (PMSI).MéthodesToutes les données de prescriptions hospitalières des médicaments (excluant ceux inscrits sur la liste « en sus de la T2A » (tarification à l’activité), issues des dossiers informatisés de 108 séjours de patients adultes dans trois hôpitaux de l’Assistance publique des Hôpitaux de Paris disposant du module prescription du logiciel Orbis, ont été étudiées. Un comité d’adjudication a établi la référence du caractère AMM ou hors AMM des prescriptions à partir des informations contenues dans le dossier de chaque séjour. Les codages CIM-10 du PMSI des maladies de chaque séjour ont été confrontés aux codes CIM-10 attendus pour les indications AMM de chaque médicament prescrit, afin d’étudier leur performance de détection des prescriptions hors AMM.RésultatsSur 1131 prescriptions analysables, 44 (3,9 %) ont été classées hors AMM par le comité d’adjudication. La sensibilité de la détection des prescriptions hors AMM par l’utilisation des codes CIM-10 a été de 87 (IC 95 % [0,73–0,96]) à 92 % (IC 95 % [0,79–0,98]) et la spécificité de 25 (IC 95 % [0,22–0,27]) à 41 % (IC 95 % [0,38–0,44]) selon le nombre de caractères des codes CIM-10 utilisables.ConclusionsLe pourcentage de prescriptions hors AMM des médicaments intra GHS couramment utilisés en hospitalisation est apparu faible (3,9 %) mais leur détection semi-automatique par l’utilisation des codages CIM-10 s’avère possible avec une bonne sensibilité mais une mauvaise spécificité. Cette méthode pourrait être utilisée pour une première étape de détection des prescriptions hors AMM en la ciblant sur une classe pharmacologique ou une pathologie donnée.

Analysis of off-label prescriptions of medicines in hospital in adult patients and study of feasibility of their detection by use of international disease classification, 10th version (IDC-10 codes). Context. - In order to improve the appropriate use of medicines, a method of detection of off label prescriptions, especially in hospitalised patients, should be available. Study objectives. - Evaluate the performance of the detection of off-label prescriptions in hospitalised patients by use of IDC-10 codes. Methods. - Data prescriptions (excluding those directly taken in charge by the national health care system), clinical history and biological results were extracted from Assistance publique des Hopitaux de Paris (AP-HP) data-warehouse for 108 in-hospital adults patients' journeys. An adjudication committee established the classification reference for the appropriate or off label drug prescriptions status after analysis of medical information for each patient. IDC-10 codification that is performed after every hospitalisation was crossed with those IDC-10 codes that were to be expected corresponding to the marketing authorisation labelling (section 4.1 of specifications of product characteristics [SPC]). Results of IDC-10 coding were compared to the reference for off label use identification. Results. - Out of the 1131 analysed prescriptions, 44 (3.9%) were classified as off label by the adjudication committee. Sensitivity of detection by IDC-10 coding was 87 (95% CI [0.73-0.96]) to 92% (95% CI [0.79-0.98]) and specificity 25 (95% CI [0.22-0.27]) to 41% (95% CI [0.38-0.44]) according to the number of characters of ICD-10 that could be used. Conclusions. - Incidence of in-hospital off label use of drugs (restricted to within drug related groups prescriptions) appeared relatively low (3.9%). Its semi-automatic detection by IDC-10 coding appears feasible with a good sensitivity but a low specificity. Such method could be further assessed as a first step detection focusing on one pharmacological class or on one pathologic condition. (c) 2021 Published by Elsevier Masson SAS on behalf of Societe francaise de pharmacologie et de therapeutique.

Le repositionnement sur une nouvelle indication d’un médicament déjà sur le marché peut être l’occasion de répondre rapidement à un besoin thérapeutique non encore couvert, en particulier dans le cadre des maladies rares ou négligées, ou encore d’une urgence sanitaire. Cependant, à chaque étape, des difficultés peuvent survenir qui empêcheront la mise à disposition du médicament repositionné. Au-delà du hasard ou d’une stratégie systématique de détection d’un effet pharmacologique utile, la mise en œuvre des étapes précliniques et cliniques est parfois rendue délicate par la difficulté d’accès à la molécule et à son dossier pharmaceutique. Par ailleurs, des résultats cliniques pertinents ne seront pas toujours suffisants à garantir l’obtention d’une autorisation de mise sur le marché ou des modalités de prise en charge satisfaisantes pour les patients. Outre la description de ces différents freins, la table ronde a été l’occasion de proposer des recommandations à même de les lever, notamment la création d’une structure en partenariat public-privé, dotée de financements suffisants afin de pouvoir proposer un accompagnement individualisé des projets jusque et y compris la demande de mise sur le marché.

The COVID-19 pandemic led to the deployment of an unprecedented academic and industrial research effort, the sometimes redundant nature of which is regrettable, as is the lack of both national and international management. However, it must be noted that during this crisis, regulatory procedures were adapted and certain obstacles in the organisation of clinical research were partly removed to contribute to the deployment of trials as close as possible to patients and to facilitate monitoring and control procedures. The digitisation of certain processes and the decentralisation of certain activities were implemented under the cover of a mobilisation of the authorities and all institutional, academic and industrial players. While in the UK, the optimisation of resources through a single platform trial has made it possible to demonstrate or invalidate the efficacy of many treatments, in France the health crisis has highlighted the fragility of the organisation of clinical research, in particular a lack of coordination and funding, difficulties in implementing studies and a certain reluctance to share data. However, the crisis has also revealed the adaptability of the various stakeholders and has led to the improvement of several processes useful for the deployment of therapeutic innovation. Let us hope that the lessons learned during this crisis will allow for greater efficiency in the event of a new pandemic and, above all, that the progress made will continue to apply to all future clinical research activities.

The concept of biosimilar medicine was launched by 2001 and 2004 European Directives. First European marketing authorizations were delivered in 2006. They are "copies" of biologically manufactured medicines, mostly proteins. Taking into account the intrinsic variability related to the biological manufacture process, some variation of the chemical structure of the finished compound may be observed. They impact especially the glycosylation residues but not the amino-acid sequence (for proteins). For this reason, the marketing authorization application dossier has to involve, as opposed to the generic medicine procedure, the demonstration of the therapeutic equivalence in at least one clinical indication of the princeps medicine. Introduction of biosimilar medicines of monoclonal antibodies has represented a remarkable event in the domain of rheumatology, gastroenterology and dermatology with infliximab, etanercept and adalimumab biosimilars and in cancerology domains with rituximab, trastuzumab and bevacizumab biosimilars. Biosimilar medicines availability reduces the risk of drug supply rupture of princeps but their main impact is the economic one allowing cost reduction of costly princeps biological medicines. With the acquired clinical experience, the initial fears concerning switch form princeps to a biosimilar for a given patient has progressively disappeared. (C) 2020 Published by Elsevier Masson SAS on behalf of l'Academie nationale de medecine.

R & eacute;sum & eacute; Si la France dispose de nombreux atouts dans le domaine de la sant & eacute; pour devenir un de sant & eacute; et de nombreuses startups), force est de constater qu'elle cumule des freins culturels et r & eacute;glementaires qui limitent une interaction agile et performante entre les industriels et les & eacute;tablissements de sant & eacute;. La table ronde avait pour objectif d'optimiser l'interface entre les startups/industries et les & eacute;tablissements de sant & eacute; universitaires ou non. Plusieurs & eacute;tablissements ont mis en place avec succ & egrave;s des & eacute;quipes et proc & eacute;dures afin de faciliter cette interface, tant vis-& agrave;-vis des & eacute;valuations des technologies, de prestations de service, de transfert de mat & eacute;riel biologique que de collaboration R&D et de contrat de licence. Cependant, il subsiste un manque de culture entrepreneuriale chez les hospitaliers et les universitaires dont la formala valorisation et de la cr & eacute;ation d'entreprises, inexistante. Les industriels, et en particulier les startups, ont souvent une m & eacute;connaissance du milieu hospitalier et de ses contraintes. En cons & eacute;quence, les recommandations des membres de la table ronde sont les suivantes : (1) formation pluridisciplinaire & agrave; l'innovation, la valorisation du personnel porteur de projet et sant & eacute; ; (2) fournir aux acteurs des moyens et ressources d & eacute;di & eacute;es & agrave; l'innovation, en sanctuariaccompagnant la recherche de financements ; (3) d & eacute;velopper et utiliser des m & eacute;thodologies et des outils communs, et (4) co-concevoir et co-construire des solutions de sant & eacute; innovantes, en encourageant l'& eacute;mergence des lieux de cr & eacute;ation participative et interdisciplinaire. L'ensemble

The concept of biosimilar medicine was launched by 2001 and 2004 European Directives. First European marketing authorizations were delivered in 2006. They are "copies" of biologically manufactured medicines, mostly proteins. Taking into account the intrinsic variability related to the biological manufacture process, some variation of the chemical structure of the finished compound may be observed. They impact especially the glycosylation residues but not the amino-acid sequence (for proteins). For this reason, the marketing authorization application dossier has to involve, as opposed to the generic medicine procedure, the demonstration of the therapeutic equivalence in at least one clinical indication of the princeps medicine. Introduction of biosimilar medicines of monoclonal antibodies has represented a remarkable event in the domain of rheumatology, gastroenterology and dermatology with infliximab, etanercept and adalimumab biosimilars and in cancerology domains with rituximab, trastuzumab and bevacizumab biosimilars. Biosimilar medicines availability reduces the risk of drug supply rupture of princeps but their main impact is the economic one allowing cost reduction of costly princeps biological medicines. With the acquired clinical experience, the initial fears concerning switch form princeps to a biosimilar for a given patient has progressively disappeared.

Although France has numerous assets in the realm of health care, such as the excellence of its research teams, the reputation of its healthcare system, and the presence of many startups, all of which are necessary to become a leader in innovation, it also has combined cultural and regulatory barriers that limit the flexibility and efficiency of interactions between companies/startups and public health institutions. Therefore, the aim of the roundtable discussion was to optimize the interface between those businesses and institutions. Several institutions have successfully implemented teams and procedures which aim to facilitate this interface, with regard to assessments of technology, services provided, the transfer of biological material, R&D collaboration, and licensing agreements. However, there is still a notable absence of entrepreneurial culture among hospital and academic research practitioners; their training regarding innovation remains insufficient and business-related value-creation is non-existent in their career evolution. Pharmaceutical companies, and particularly startups, often lack knowledge about hospital environments and their constraints. As a result, the recommendations of the roundtable participants are as follows: (1) promote reciprocal acculturation between public health institutions and startups through multidisciplinary training in innovation, promoting project development and staff recognition within the institution, and improving pharmaceutical companies’ understanding regarding the health care system; (2) provide those involved with means and resources dedicated to innovation by reserving time for innovation at work, securing the status of the staff involved, and aiding in the search for funding; (3) develop and use standard methodologies and tools; and (4) co-design and co-construct innovative health solutions, encouraging the emergence of participatory and interdisciplinary creative spaces. All of these recommendations should help to make the interface between startups/companies and public health institutions more fluid and attractive for those in the health sector.