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Resume Le concept de telemedecine a ete officialise en France avec la loi hopital patients sante territoires (HPST) de 2009 et le decret d’application de 2010. De nombreuses experimentations ont ete mises en œuvre et les institutions de regulation (Ministere, Agence regionale de sante [ARS], Haute autorite de sante [HAS]…) ont emis diverses orientations et recommandations tant sur le volet organisationnel que sur les attentes d’evaluation. C’est dans ce contexte que la table ronde a souhaite emettre des recommandations sur differents axes de la telesurveillance medicale (la place de la telesurveillance medicale, le parcours reglementaire, les principes d’evaluation, les modalites de prises en charge et les conditions pour un deploiement perenne et fluide). Si les nouvelles approches utilisant la telesurveillance medicale, font l’objet de nombreuses etudes conduisant au postulat qu’il existe un benefice a la fois sur un plan clinique et pour la qualite de vie du patient, la demonstration de l’impact sur l’organisation des soins et du benefice medico-economique restent a mieux preciser (criteres, methodes, moyens). De meme, les cadres contractuels du deploiement de la telesurveillance existent mais sont complexes ; ils font appels a de nombreux interlocuteurs (Direction generale de l’offre de soins [DGOS], ARS, HAS, Agence des systemes d’information partages de sante [ASIP], Commission nationale informatique et libertes [CNIL], Conseil national de l’ordre des medecins [CNOM]…) qui beneficieraient du partage d’une meme approche et de fluidifier les partenariats. A ce stade, l’enjeu est aussi de definir les conditions permettant la validation d’un modele economique stable pour engager des changements organisationnels. La problematique est ici de mener de front son evaluation et sa mise en œuvre. L’acces aux donnees patients, en particulier a celles des caisses d’Assurance maladie et leur exploitation, pourrait permettre une plus grande efficacite de la demarche. De plus, la non-fongibilite budgetaire des differentes enveloppes budgetaires des differents secteurs d’activites limite la consolidation des impacts economiques. Les modalites de financement devront donc etre adaptees a cette nouvelle repartition des roles, a la fois au cœur du systeme de sante et de l’ecosysteme industriel. Toutes ces evolutions contribueront a ce que les responsables de notre systeme de sante puissent porter cette nouvelle ambition en etroite relation avec tous les acteurs de cette economie.

Resume Le dispositif medical se caracterise par une grande heterogeneite (de l’abaisse langue a l’equipement d’imagerie, en passant par le dispositif implantable ou invasif), un cycle de vie court des produits avec des innovations incrementales recurrentes (de 18 mois a 5 ans) et un caractere operateur dependant : le plus souvent l’utilisateur clinicien doit realiser un acte de pose (prothese de hanche, stimulateur cardiaque), un acte therapeutique qui utilise un dispositif invasif non implantable (sonde d’ablation d’un foyer arythmique, ballonnet d’angioplastie, systeme de spondyloplastie par extension) voire un acte de suivi des dispositifs actifs implantes (suivi au long court des patients beneficiant d’un defibrillateur cardiaque, ou des malades parkinsoniens implantes d’un systeme de stimulation cerebrale profonde). La table ronde a souhaite se concentrer sur les procedures d’evaluation scientifique des dispositifs medicaux et des actes associes en vue de leur tarification et financement par l’Assurance maladie. Elle a ainsi pose pour postulat que le corpus de donnees disponibles etait suffisant et compatible avec une evaluation scientifique du benefice clinique. Les etudes post-inscription, qui participent a la continuite de l’evaluation des dispositifs medicaux, n’ont pas ete abordees. En outre, elle a choisi de centrer ses reflexions sur les dispositifs utilises dans les etablissements de sante (ES), les plus representatifs de l’association entre dispositifs et actes medicaux techniques. Le contexte des multiples procedures reglementaires, permettant la prise en charge des dispositifs medicaux et des actes, est rappele. Les problematiques liees plus specifiquement aux actes eux-memes, aux dispositifs medicaux non implantes et aux dispositifs medicaux innovants sont ensuite developpees. Dans chacune des trois situations, les propositions et les points de discussion de la table ronde sont presentes.

Resume L’objectif de la table ronde etait d’aborder la place de la neuroimagerie clinique et preclinique dans le developpement de nouveaux medicaments dans les pathologies neurodegeneratives pour la premiere fois lors des rencontres de Giens. Les participants venaient de de l’academie, du monde de la recherche clinique et fondamentale, de l’industrie du medicament et de l’imagerie, de l’Agence nationale de securite du medicament et des produits de sante (ex-Afssaps [Agence francaise de securite sanitaire des produits de sante]). Ils ont fait le constat de l’impact important de la neuroimagerie dans la connaissance des maladies neurodegeneratives, en particulier la maladie d’Alzheimer et dans le developpement des medicaments. Ils ont identifie les differentes approches techniques utilisees, les innovations a venir, des exemples a succes de travail en consortium mais egalement un risque trop important de ne pas pouvoir exploiter la neuroimagerie a tous les niveaux de la recherche. Dans ce contexte, la table ronde a conclu et a propose differentes mesures pour renforcer la place meritee de l’imagerie.

Resume Le developpement clinique de medicaments disease-modifiers dans la maladie d’Alzheimer se heurte a des difficultes methodologiques dont temoignent plusieurs echecs recents de medicaments en phase III. Compte-tenu des enjeux financiers inherents au passage en phase III et du risque d’investir en pure perte de l’energie pour l’evaluation d’un mauvais candidat-medicament, la question cruciale reste la decision de go/no go entre la phase II et la phase III dont l’objectif est certes de selectionner une molecule susceptible d’etre efficace en phase III mais plus encore d’ecarter d’un developpement ulterieur les candidats aux effets insuffisants. Aucun consensus n’existe aujourd’hui sur la meilleure conception possible des etudes de phase II pour tenter d’eclairer au mieux la decision de go/nogo. Les difficultes de choix de la meilleure conception d’etude concernent tout aussi bien la population-cible, les criteres de jugement en particulier le recours a des biomarqueurs, le plan experimental ou la duree des etudes. L’objet de la Table Ronde (TR) a ete de rassembler les points de vue d’experts francais issus du monde academique, industriel ou reglementaire afin d’arriver a une proposition consensuelle sur la meilleure conception possible que devraient utiliser les etudes de phase II dans la maladie d’Alzheimer.

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

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

Resume La place relative des essais cliniques comparatifs et des etudes observationnelles (cohortes ou etudes castemoins) a ete etudiee dans l’objectif d’evaluer l’efficacite, la tolerance et l’interet de sante publique d’un medicament. L’essai randomise, comparatif, realise en double insu est la meilleure methode pour estimer l’efficacite d’un traitement. Il permet l’estimation la moins biaisee et la plus robuste de la relation causale. Dans certaines situations et sous certains criteres, des etudes observationnelles peuvent avoir valeur de preuve d’efficacite. Les etudes cliniques randomisees comparatives en pre- et post-AMM (autorisation de mise sur le marche) permettent d’identifier les effets indesirables plus rares et de les comparer au traitement de reference. Avant l’AMM, les donnees de securite regroupees des differents essais comparatifs peuvent permettre d’estimer des evenements indesirables relativement frequents et les sujets a risque. Cependant, l’etude observationnelle est plus adaptee pour evaluer la securite d’emploi dans les conditions reelles d’utilisation. Par definition, un medicament a un impact sur la sante des populations s’il permet d’ameliorer directement ou indirectement son etat de sante. Un medicament aura un interet majeur en termes de sante publique s’il reduit la mortalite ou la morbidite liee a cette maladie ou s’il ameliore la qualite de vie des patients qui en sont atteints. Avant la commercialisation d’un produit, la modelisation est l’approche de choix pour quantifier l’impact attendu. En post-AMM, les essais pragmatiques et les etudes observationnelles sont les methodes de reference pour definir la population rejointe, l’efficacite et la tolerance en situation reelle et l’interet en sante publique d’un medicament. En conclusion, l’essai clinique randomise reste la reference pour l’evaluation de l’efficacite, l’etude observationnelle ayant une valeur confirmatoire. L’etude observationnelle est plus adaptee pour evaluer la securite d’emploi dans les conditions reelles d’utilisation, l’essai clinique ayant des indications limitees. Pour l’interet de sante publique, la modelisation est l’approche de choix en pre-AMM. En post-AMM, les essais pragmatiques et les etudes observationnelles sont les references.

The European Directive on clinical trials of medicinal products will fall within the scope of the legislation of Member States on 1 May 2004. In France, this adaptation will be carried out by a public health bill concerning, among other things, the reform of the current Huriet-Serusclat law, and by means of regulations. For trials concerning the initial administration of a product to human subjects, the group suggested the following recommendations: In French texts, to include a deadline of 30 days for the initial authorisation by the competent authority (Afssaps [Agence francaise de securite sanitaire des produits de sante]). To maintain an observed deadline of 20 days (35 official days) for the decision of the Ethics Committee (EC) [Committee for the Protection of Persons (CPP)]. To obtain a more specific evaluation of the pharmaceutical dossier of the investigational medicinal product (IMP) from the competent authority. To provide both bodies with nonclinical and possibly clinical data concerning the IMP information of the participants and their consent. To follow the recommendations posted on the Afssaps website for the entire IMP dossier. To submit a protocol under the International Committee on Harmonisation (ICH) E6 format adapted for phase I and, possibly as a separate document, justification of a certain number of points (a total of ten) that are more specific to this trial phase to facilitate and improve the document review while also providing the expected guarantees. To limit the 'substantial' amendments to those provided for in the European guidelines. To break the blind for every serious event reported to the sponsor by the investigator, and report to the competent authority any serious adverse event related to the IMP or to the trial or without documented cause, while keeping ECs and investigators informed. Furthermore, certain points concerning the authorisations for packaging, labelling and dispensing of the batches of medicinal products for clinical trials will need to be specified for these early studies. All these recommendations are intended to help promote the development of studies involving the initial administration of medicinal products in France.

Resume La Directive Europeenne Essais Cliniques des medicaments devra entrer dans le droit des etats membres le 1 er mai 2004. En France, c’est par un projet de loi de Sante Publique portant entre autres sur la reforme de l’actuelle loi Huriet-Serusclat et par des textes reglementaires que cette transposition s’effectuera. Le groupe a propose, pour les essais des premieres administrations d’un produit a l’homme, un certain nombre de recommandations : • Inscrire dans les textes francais un delai de 30 jours pour l’autorisation initiale de l’autorite competente (Afssaps [Agence francaise de securite sanitaire des produits de sante]). • Maintenir un delai observe de 20 jours (35 jours officiels) pour l’avis du « Comite d’Ethique » experimental (CPP [Comite de Protection des Personnes]). • Obtenir de l’autorite competente l’evaluation plus specifique du dossier pharmaceutique du medicament. • Fournir aux deux instances des donnees non cliniques et eventuellement cliniques concernant le medicament a l’essai, les elements pour l’information du sujet et son consentement. • Pour l’ensemble du dossier du medicament experimental, suivre les recommandations postees sur le site de l’Afssaps. • Soumettre un protocole au format ICH (International Conference on Harmonisation) E6 adapte pour la phase I et eventuellement, de facon separee, les elements de justification d’un certain nombre de points (dix en tout) plus specifiques a cette phase d’essai pour faciliter et ameliorer la revue documentaire tout en fournissant les garanties attendues. • Restreindre les seuls amendements « substantiels » a ceux prevus par la ligne directrice europeenne. • Lever l’insu pour tout evenement indesirable grave (EIG) declare par l’investigateur au promoteur et declarer a l’autorite tout EIG lie au produit ou a l’essai ou encore sans cause etayee tout en tenant informes les CPP et les investigateurs. Par ailleurs, il restera a preciser certains points concernant les autorisations de conditionnement, d’etiquetage et de dispensation des lots d’essais cliniques pour ces etudes precoces. L’ensemble de ces recommandations s’inscrit dans une volonte de favoriser le developpement des etudes de premiere administration sur le territoire francais.

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

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

To assess the impact of cystic fibrosis (CF) and treatment on quality of life (QOL) from childhood throughout adult age, two versions of the Cystic Fibrosis Questionnaire (CFQ), were developed and validated in France: the CFQ 14+ for teenagers and adults, the CFQ Child P, a parent-proxy evaluation for children aged 8–13. They include three modules for assessing QOL, symptoms and health perception. Nine QOL dimensions were identified: physical functioning, energy/well-being, emotions, social limitations, role, embarrassment, body image, eating disturbances and treatment burden. Items were derived from 33 interviews with patients and parents. Item reduction and assessment of internal consistency, convergent and discriminant validity were based on a large cross-sectional survey among 393 patients and parents. A second study was conducted among 124 patients and 85 parents to test reproducibility and responsiveness, confirm the subscale structure and assess scalar properties using Rasch analysis. All psychometric properties were successfully demonstrated and both the CFQ 14+ and the CFQ Child P French questionnaires are now well validated. German and Spanish validated adaptations are available, an English validation is in progress. Conclusion: The CFQ 14+ and CFQ Child P are well validated, multilingual measures which allow QoL assessment in children, teenagers and adults with CF.

International audience; The concept of telemedicine was formalised in France in the 2009 "Hospital, patients, health territories" (loi hôpital, patients, santé, territoire) law and the 2010 decree through which it was applied. Many experiments have been carried out and the regulatory institutions (Ministry, Regional Health Agency [Agence régionale de santé, ARS], French National Health Authority [Haute autorité de santé, HAS], etc.) have issued various guidance statements and recommendations on its organisation and on the expectations of its evaluation. With this background, the round table wanted to produce recommendations on different areas of medical telemonitoring (the role of telemonitoring, the regulatory system, the principles for assessment, methods of use and conditions for sustained and seamless deployment). Whilst many studies carried out on new medical telemonitoring approaches have led to the postulate that it offers benefit, both clinically and in terms of patient quality of life, more information is needed to demonstrate its impact on the organisation of healthcare and the associated medico-economic benefit (criteria, methods, resources). Similarly, contractual frameworks for deployment of telemonitoring do exist, although they are complicated and involve many different stakeholders (Director General fo the Care Offering [Direction générale de l'offre de soins, DGOS], ARS, HAS, Agency for Shared Health Information Systems [Agence des systèmes d'information partagés de santé, ASIP], French National Data Protection Commission [Commission nationale informatique et libertés, CNIL], French National Medical Council [Conseil national de l'Ordre des médecins, CNOM], etc.) that would benefit from a shared approach and seamless exchange between the partners involved. The current challenge is also to define the conditions required to validate a stable economic model in order to promote organisational change. One topical issue is placing the emphasis on its evaluation and operation. Access to patient data, particularly data from the health insurance funds and the use of these data, may enable the process to be more effective. In addition, the budgetary non-fungibility of the various financial envelopes for the different areas of work, restricts the consolidation of financial impact. Funding methods will need to be adapted to this new distribution of roles, both at the centre of the healthcare system and in the industrial ecosystem. All of these changes will help the leaders of our healthcare system to bring this new ambition closer to all of the people working in the health economy.

Medical devices are many and various, ranging from tongue spatulas to implantable or invasive devices and imaging machines; their lifetimes are short, between 18 months and 5 years, due to incessant incremental innovation; and they are operator-dependent: in general, the clinical user performs a fitting procedure (hip implant or pacemaker), a therapeutic procedure using a non-implantable invasive device (arrhythmic site ablation probe, angioplasty balloon, extension spondyloplasty system, etc.) or follow-up of an active implanted device (long-term follow-up of an implanted cardiac defibrillator or of a deep brain stimulator in Parkinson's patients). A round-table held during the XXVIII(th) Giens Workshops meeting focused on the methodology of scientific evaluation of medical devices and the associated procedures with a view to their pricing and financing by the French National Health Insurance system. The working hypothesis was that the available data-set was sufficient for and compatible with scientific evaluation with clinical benefit. Post-registration studies, although contributing to the continuity of assessment, were not dealt with. Moreover, the focus was restricted to devices used in health establishments, where the association between devices and technical medical procedures is optimally representative. An update of the multiple regulatory protocols governing medical devices and procedures is provided. Issues more specifically related to procedures as such, to non-implantable devices and to innovative devices are then dealt with, and the proposals and discussion points raised at the round-table for each of these three areas are presented.

A cohort is a group of individuals sharing some characteristics, followed longitudinally. Essential tools of epidemiology, these studies provide pieces of evidence of the relationship between an exposition and outcomes in order to guide public health policies. In France, many cohorts have been conducted over the past few years. Sometimes, initiated by independent research teams (e.g. E3N) but more often, either requested by health authorities in a global public health plan (e.g. MEMENTO in the Alzheimer plan) or conducted to investigate a safety issue (e.g. France Coag). Besides, post authorization studies often consist in prospective cohorts. Because of objectives, designs and governance arrangements diversity; participants questioned whether it was interesting for researchers, regulators and industrials to use this epidemiological tool. Some findings about difficulties met in cohorts' establishment have been shared by each other. In order to make cohorts more efficient, participants have made some recommendations.

A cohort is a group of individuals sharing some characteristics, followed longitudinally. Essential tools of epidemiology, these studies provide pieces of evidence of the relationship between an exposition and outcomes in order to guide public health policies. In France, many cohorts have been conducted over the past few years. Sometimes, initiated by independent research teams (e.g. E3N) but more often, either requested by health authorities in a global public health plan (e.g. MEMENTO in the Alzheimer plan) or conducted to investigate a safety issue (e.g. France Coag). Besides, post authorization studies often consist in prospective cohorts. Because of objectives, designs and governance arrangements diversity; participants questioned whether it was interesting for researchers, regulators and industrials to use this epidemiological tool. Some findings about difficulties met in cohorts' establishment have been shared by each other. In order to make cohorts more efficient, participants have made some recommendations.

As the failure of several recent Phase III drug development programmes bears witness, the clinical development of “disease-modifying” drugs in Alzheimer’s disease has been confronted with challenging methodological difficulties. Taking into account the financial stakes involved taking drug candidates to the Phase III stage of development, and the risk of investing time and resources fruitlessly in the evaluation of poor candidate drugs, the crucial decision remains whether to proceed from Phase II to Phase III (Go/Nogo). The aim of Phase II studies is to select a molecule likely to be effective in Phase III, but also to eliminate candidate-drugs with an inadequate effect. No consensus currently exists on the best possible design of Phase II studies to inform the Go/Nogo decision optimally. The challenges in choosing the best study design relate to the target population, the end-point criteria used, in particular the use of biomarkers, the experimental protocol, and the study duration. The objective of the Round Table (RT) was to gather the opinions of French experts from the academic, industrial, and regulatory world in order to arrive at a consensus recommendation for the best possible design to be used in Phase II studies in Alzheimer’s disease.

The roundtable 1 “Relevance of the evaluation criteria used in clinical trials for Alzheimer’s disease” made reference to the guideline published by the EMEA (European Medicines Agency) in July 2008 on the development of new treatments for Alzheimer’s disease (AD) and other dementias, and addressed principally two of the three indications listed in the guideline: symptomatic improvement and disease-modification (primary prevention was hardly discussed). The discussions focussed on two main aspects: improvement of the selection of patients in clinical trials and clinical evaluation and biomarkers. The following suggestions were made: – Reinforce the interest for clinical trials at the early stages of AD (including prodromal stage), particularly for disease-modifiers. – Strengthen the research centers’ expertise with biomarkers, in a perspective of subsequent use in clinical trials, either for the description of the patients included, or as part of selection criteria. Furthermore, ongoing intercenter validation studies, in France, of neuro-imaging and biomarker assays in CSF, are essential for preparing multicenter clinical trials. – Facilitate the conduct of ancillary studies with biomarkers, grafted on clinical studies. – Further develop the training and experience of raters with functional scales, which are now required as one of the two primary endpoints in pivotal clinical trials, and with the additional items of ADAS-cog (Alzheimer’s Disease Assessment scale, Cognitive sub scale), which are useful for the early stages of AD. – Improve knowledge of functional clinical scales by in depth analysis of available databases, through public/private collaborations. – Improve knowledge of relationship between rating scales used in clinical trials and tools used in clinical practice (which are usually different), in order to provide supporting evidence for the interpretation of the clinical relevance of clinical trials results. – Consider the potential needs of adaptation of rating scales to the societal changes, in particular for the evaluation of cognitive performance. – Discuss the possibility of measures for extending data protection for candidate disease-modifiers, considering the negative impact for all players of the constraints of duration and the difficulties of clinical trials. – Further discuss the ethics and acceptability of placebo-controlled monotherapy studies on durations of 6-9 months.

International audience; L’intégrité des données recueillies dans les essais cliniques et leur utilisation sont un élément fondamental de la démarche scientifique, et de la confiance que l’on peut avoir dans cette démarche. Les exemples de fraudes sont légion, et régulièrement répétés. L’objectif de cette table ronde était de faire le point sur la définition de la fraude, sur sa reconnaissance et sa prévention, en particulier dans le système institutionnel. La fraude implique une intention de tromper et va du camouflage, de l’incompétence à l’invention de toutes pièces d’études, de patients ou de données. Sa fréquence est difficile à évaluer, mais semblerait atteindre au moins 1 % des études ou publications. Cette fraude peut impliquer l’éthique (avis du CPP [comité de protection des personnes]a posteriori, non-respect des demandes du CPP, défaut de consentement) ou toutes les étapes de la réalisation à l’interprétation des essais ou études. L’identification des fraudes est rendue difficile par le risque pris par l’« avertisseur » (whistle blower), qu’il faut protéger. La recherche de la fraude est implicite dans les bonnes pratiques cliniques que devraient appliquer tous les promoteurs industriels mais qui est moins souvent mise en application par les promoteurs institutionnels. Il conviendrait donc de prévoir des recommandations pour la mise en place de procédures de détection des fraudes en particulier dans les études institutionnelles. Diverses méthodes statistiques peuvent être utilisées pour détecter les invraisemblances suggestives de fraude. Une fois la fraude identifiée, sa gestion n’est en général pas prévue ou anticipée. Ici encore des procédures ou recommandations devraient être proposées.

International audience; The integrity of the data from clinical trials and of its use is an essential element of the scientific method, and of the trust one can have in this method. There are many examples of fraud, and they recur regularly. The objective of this round table was to work on the definition of fraud, on its recognition and prevention especially in the institutional system. Fraud involves an active decision to cheat, and ranges from trying to hide incompetence to wholesale invention of data, patients or studies. Its frequency is difficult to evaluate but might be as high as 1% of all studies or publications. Fraud can involve ethics (post-hoc IRB [institutional review board] approval, IRB requests not applied, lack of consent), or any of the steps from realisation to interpretation of studies or trials. Identification of fraud is made harder by the usual risk for the whistle-blowers, who must be protected. Seeking fraud is implicit in Good Clinical Practices (GCP) that all industry sponsors must apply, but that are less often applied by institutional sponsors. It might be useful to install procedures to detect fraud in studies, especially institutional. Various statistical methods can be used to identify unusual data patterns that could suggest fraud. Once fraud is identified, its management is often not foreseen. Here again, clear procedures or recommendations would be of help.

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

The European Directive on clinical trials of medicinal products will fall within the scope of the legislation of Member States on 1 May 2004. In France, this adaptation will be carried out by a public health bill concerning, among other things, the reform of the current Huriet-Sérusclat law, and by means of regulations. For trials concerning the initial administration of a product to human subjects, the group suggested the following recommendations: In French texts, to include a deadline of 30 days for the initial authorisation by the competent authority (Afssaps [Agence française de sécurité sanitaire des produits de santé]). To maintain an observed deadline of 20 days (35 official days) for the decision of the Ethics Committee (EC) [Committee for the Protection of Persons (CPP)]. To obtain a more specific evaluation of the pharmaceutical dossier of the investigational medicinal product (IMP) from the competent authority. To provide both bodies with nonclinical and possibly clinical data concerning the IMP information of the participants and their consent. To follow the recommendations posted on the Afssaps website for the entire IMP dossier. To submit a protocol under the International Committee on Harmonisation (ICH) E6 format adapted for phase I and, possibly as a separate document, justification of a certain number of points (a total of ten) that are more specific to this trial phase to facilitate and improve the document review while also providing the expected guarantees. To limit the 'substantial' amendments to those provided for in the European guidelines. To break the blind for every serious event reported to the sponsor by the investigator, and report to the competent authority any serious adverse event related to the IMP or to the trial or without documented cause, while keeping ECs and investigators informed. Furthermore, certain points concerning the authorisations for packaging, labelling and dispensing of the batches of medicinal products for clinical trials will need to be specified for these early studies. All these recommendations are intended to help promote the development of studies involving the initial administration of medicinal products in France.

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

To assess the impact of cystic fibrosis (CF) and treatment on quality of life (QOL) from childhood throughout adult age, two versions of the Cystic Fibrosis Questionnaire (CFQ), were developed and validated in France: the CFQ 14+ for teenagers and adults, the CFQ Child P, a parent-proxy evaluation for children aged 8-13. They include three modules for assessing QOL, symptoms and health perception. Nine QOL dimensions were identified: physical functioning, energy/well-being, emotions, social limitations, role, embarrassment, body image, eating disturbances and treatment burden. Items were derived from 33 interviews with patients and parents. Item reduction and assessment of internal consistency, convergent and discriminant validity were based on a large cross-sectional survey among 393 patients and parents. A second study was conducted among 124 patients and 85 parents to test reproducibility and responsiveness, confirm the subscale structure and assess scalar properties using Rasch analysis. All psychometric properties were successfully demonstrated and both the CFQ 14+ and the CFQ Child P French questionnaires are now well validated. German and Spanish validated adaptations are available, an English validation is in progress.The CFQ 14+ and CFQ Child P are well validated, multilingual measures which allow QoL assessment in children, teenagers and adults with CF.

A drug's lifetime, whether it is short or long, may go through fantastic new developments. Such is the case with beta-blockers, some of which have long been prescribed in heart failure before having made the definite proof of their efficacy, provided they are used carefully regarding the Good Product Use. On the other hand, the development of mibefradil, a calcic antagonist prescribed in the treatment of hypertension and angina pectoris, was stopped abruptly a few weeks before its launching because of the occurrence of serious side effects in patients suffering from heart failure. These examples, which are taken amongst others, clearly show the difficulties encountered by pharmaceutical companies that are concerned in putting forward innovative, efficacious, and ... secure drugs.

To compare the efficacy and the safety of a single intramuscular dose of ceftriaxone, 50 mg/kg, vs. a 10-day course of amoxicillin/clavulanate (amox/clav) therapy, 80 mg/kg/day of amoxicillin: 10 mg/kg/day of clavulanate in three divided doses, in children with acute otitis media (AOM) and to evaluate the changes in nasopharyngeal flora after treatment.In a prospective, comparative, open randomized, multicenter trial, children were scheduled to return for visits on Days 12 to 14 (main end point) and Days 28 to 42 after the beginning of treatment for AOM. A nasopharyngeal swab for bacterial culture was obtained before the treatment and at Days 12 to 14.Between February, 1995, and May, 1996, 513 children with a mean age of 14.2 +/- 6.7 months were enrolled. All the patients were evaluable for the safety and intent-to-treat analyses and 463 for the per protocol efficacy. At Days 12 to 14 clinical success was obtained in 186 of the 235 children (79%) given ceftriaxone and in 188 of the 228 children (82.5%) treated with amox/clav. Among the patients with clinical success on Days 12 to 14, the success was maintained at Days 28 to 42 for 108 of 183 (59%) patients in the ceftriaxone group and 103 of 187 (55%) patients in the amox/clav group. Before the antibiotic treatment the percentages of children carrying Streptococcus pneumoniae (59.1%), Haemophilus influenzae (39.4%), Moraxella catarrhalis (55.7%) and the rate of penicillin-resistant S. pneumoniae (52.2%) were comparable between the 2 groups. At Days 12 to 14 the carriage of S. pneumoniae and M. catarrhalis was significantly different between the patients treated with ceftriaxone, 43.9 and 42.2, respectively, and the patients treated with amox/clav, 17.4 and 11.1%, respectively. Among the children carrying S. pneumoniae at Days 12 to 14, the percentage of penicillin-resistant strains reached 63.4% in the ceftriaxone treatment group and 83.0% in the amox/clav treatment group, (P = 0.02). Adverse events (mainly diarrhea) related to the study medication were reported more frequently (P0.0001) in the amox/clav treatment group.In an area with a high rate of penicillin-resistant S. pneumoniae, a single dose of ceftriaxone is as efficient as a 10-day course of amox/clav in the treatment of AOM in young children. There was for the two regimens an increased rate of penicillin-resistant strains among the pneumococci carried, whereas the chance for a child to carry a penicillin resistant S. pneumoniae did not increase after treatment.

OBJECTIVES A prospective study in the Paris region to evaluate the clinical and bacteriologic epidemiology of acute otitis media in infants in whom oral antibiotic therapy resulted in clinical failure. METHODS The study included 186 children with a mean age of 17.5 +/- 13.1 months. Two-thirds of them attended a day-care center and 40.8% had a history of recurrent otitis media. The most frequently prescribed prior antibiotics were amoxicillin-clavulanic acid (43% of cases), an oral third generation cephalosporin (22.6%), erythromycin-sulfisoxazole (11.8%) and a first generation cephalosporin (10.2%). The average duration of antibiotic therapy was 6.9 +/- 2.65 days. Specimens for bacterial cultures included 188 samples of middle ear fluid obtained by tympanocentesis and 37 collected from otorrhea fluid. RESULTS One hundred forty-one samples (62.7%) from 126 children yielded 170 bacterial isolates. In 60 children (32.3%) the culture of the ear pus was sterile. Among the 170 bacterial isolates: 67 (39.4%) were Streptococcus pneumoniae (59 patients), of which 77.6% had reduced susceptibility to penicillin (PRSP with penicillin MIC > or = 0.125 mg/l); 61 (35.9%) were Haemophilus influenzae (56 patients) of which 49.2% were beta-lactamase producers; and 8 were Moraxella catarrhalis (8 patients), of which 87.5% were beta-lactamase producers. Thirty-six patients were infected by S. pneumoniae with penicillin MIC > or =1 mg/l. In our study attending day-care center (P = 0.04), temperature >38 degrees C with signs of otalgia (P = 0.02), age