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Based on the observation that over the last 30 years the cost of development has risen regularly as the number of new chemical entities reaching the market has fallen, how can "savings" be made in terms of clinical development, the objective being more rapid access to a drug for medical needs that are not covered? Several instruments exist to enable innovative products to be made available more quickly: temporary use authorisations, which are not concerned by this work (ATUs), conditional marketing authorisations (MAs) and MAs under exceptional circumstances. These aspects have been taken up in the European medicines agency (EMA)'s "Road Map", which states "A key issue for Regulators will be if a more "staggered" approval should be envisaged, characterised by a better defined/more restricted population of good responders, followed by a broadening of the population post-authorisation when more "real life" data are available. In addition, maximising the value of information generated in the post-authorisation phase should be developed through the use of cohorts and other prospectively collected use data, especially in the case of conditional marketing authorisations." The rules of procedure of the Transparency Commission for their part provide for the notion of preliminary examination: in order to prepare as best as possible the examination of dossiers of products assumed to be innovative and to limit delays, the office can undertake a preliminary study as soon as the dossier has been filed at the Committee for medicinal products for human use (CHMP). It may, at this time, request the firm to provide further information and may call on external experts. The implementation of this preliminary study does not exonerate the firm of the obligation of filing a complete dossier. The post inscription studies requested by the Transparency Commission (ISPEP - public health benefit and post-marketing studies) are usually requested in the case of hesitations regarding the level of improvement of the medical benefit (ASMR) [level II/III or IV/V]. Such requests mainly concern uncertainties regarding the transposability, the patient profile or correct usage in real life. Among the studies whose results were provided, in 15 cases the results were in line with expectations, in 6 cases they resulted in downward re-evaluations and the final 3 cases were inconclusive. The final recommendations of the round table were: Defining the medical need that is not covered by working in consultation (Industry and Health Authorities); Providing a Complementary Investigations Plan (PIC) after the MA at a very early stage to reinforce the early MA, and/or HTA (health technology assessment) preparation and monitoring (possible constraining actions); Enhanced use of modelling techniques and their transposability; "Intussusception" of phases to optimise the development of a complete dossier; Early "scientific opinions" (EMA, French Health Products Safety Agency [Afssaps], French Health Authority [HAS]); Raising the awareness of the authorities, industry, doctors and patients with regard to controlled observational studies; Developing the use of public data bases.

Resume Partant de la constatation que depuis 30 ans, le cout du developpement augmente regulierement a mesure que le nombre de nouvelles entites chimiques atteignant le marche decroit, comment faire des « economies » en termes de developpement clinique, l’objectif etant un acces plus rapide au medicament, pour les besoins medicaux non couverts ? Plusieurs instruments existent pour permettre une mise a disposition plus rapide de produits innovants : les autorisations temporaires d’utilisation ou ATU (qui ne sont pas concernees par ce travail), les autorisations de mise sur le marche (AMM) conditionnelles, les AMM sous circonstances exceptionnelles. Ces elements sont repris dans la « road map » de l’Agence europeenne du medicament, (European Medicines Agency ou EMA), qui dit : « A key issue for Regulators will be if a more “staggered” approval should be envisaged, characterised by a better defined/more restricted population of good responders, followed by a broadening of the population post-authorisation when more “real life” data are available. In addition, maximising the value of information generated in the post-authorisation phase should be developed through the use of cohorts and other prospectively collected use data, especially in the case of conditional marketing authorisations. » Le reglement interieur de la Commission de transparence pour sa part prevoit la notion d’examen preliminaire : afin de preparer au mieux l’instruction des dossiers des produits presumes innovants et de limiter les delais, le bureau peut engager une etude preliminaire des le depot du dossier au Comite des specialites pharmaceutiques humaines (CHMP). Il peut a cette occasion solliciter de la firme des elements d’information et faire appel a des experts externes. La mise en oeuvre de cette etude preliminaire n’exonere pas la firme de l’obligation de deposer un dossier complet. Les etudes post inscription demandees par la commission de transparence (ISPEP) le sont souvent dans le cas d’hesitations sur le niveau d’amelioration du service medical rendu ou ASMR (niveau II/III ou IV/V). Ces demandes concernent essentiellement des incertitudes sur la transposabilite, le profil patient ou le respect du bon usage. Parmi les etudes dont les resultats ont ete rendus, dans 15 cas les resultats sont en conformite avec les attentes, dans 6 cas elles ont abouti a des reevaluations a la baisse, enfin dans 3 cas elles etaient non conclusives. Les recommandations finales de la Table Ronde etaient : – definition du besoin medical non couvert a travailler en concertation (industriels et autorites de Sante) ; – prevision d’un Plan d’investigations complementaires (PIC) au dela de l’AMM tres tot pour conforter AMM precoce, et/ou preparation HTA et le suivre (actions contraignantes possibles) ; – utilisation accrue des techniques de modelisation et de leur transposabilite ; – « intussusception » des phases pour optimiser le developpement d’un dossier complet ; – « avis scientifiques » precoces (EMA, Agence francaise de securite sanitaire des produits de sante (Afssaps), Haute autorite de sante (HAS)) ; – sensibilisation des autorites, industriels, medecins et patients aux etudes observationnelles controlees ; – developpement de l’exploitation des bases de donnees publiques.

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.

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.

SummaryThe administration of aprotinin during extracorporeal circulation (ECC) reduces blood loss. To explore the mechanism of this effect, a placebo-controlled double-blind study was performed in 20 patients (10 were administered with a high dose of aprotinin, 10 with placebo) undergoing a primary, elective operation of coronary artery bypass grafting (CABG) with ECC. Biological tests were performed at 4 different time points during the operation.A marked reduction in the placebo group of ristocetin-induced platelet agglutination (binding of von Willebrand factor [vWF] to platelet glycoprotein [GP] Ib) was shown during ECC and at the end of surgery, but not in the aprotinin group. This abnormality is not related to the hydrolysis of vWF or GP Ib, since washed platelets were resuspended in pooled normal plasma which provided a constant amount of vWF in this test and since the plasma concentration of the fragment of GP Ib (glycocalicin) did not correlate with this abnormality.Despite a high concentration of heparin (5-7 IU/ml) in patient's plasma during bypass, activation of blood coagulation in both groups was evidenced by an increase in ATm (thrombin-modified antithrombin III) level. The level of ATm in the placebo group reached a maximum at the end of ECC during rewarming, while in the aprotinin group, ATm level at this time point was significantly lower than in the control group. In comparison to the placebo group, the generation of the fibrin degradation products (DDE complexes) was inhibited by aprotinin during ECC, but the level of DDE complexes in the aprotinin group was slightly elevated after ECC, although much less than in the placebo group. Other parameters measured did not show significant differences between the two groups.These results indicate that the hemostatic defect in patients during and after ECC may result, at least in part, from the impairment of GP Ib-dependent platelet adhesion. Therefore, the administration of aprotinin in ECC may improve hemostasis by abrogating this impairment, in addition to the protective effect of aprotinin on hemostatic plug. Activation of blood coagulation occurs during cardiopulmonary bypass despite heparin therapy and this activation seems to be partially inhibited by aprotinin administration.

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.