Plateforme Nationale d'infrastructures de Recherche Clinique. Tranche 1/Phase Recherche Clinique / Clinical Research

Transcription

1 Acronyme du projet/ Acronym of the project Titre du projet en français Plateforme Nationale d'infrastructures de Recherche Clinique Project title in English Coordinateur du projet/coordinatorof the project French Clinical Research Infrastructure Network Nom / Name : Olivier RASCOL Etablissement / Institution : Inserm / CHU de Toulouse / Université de Toulouse Laboratoire / laboratory : CIC de Toulouse Numéro d unité/unit number : CIC9302 Aide demandée/ Requested funding Tranche 1/Phase Tranche 2/Phase Domaines scientifiques/ scientific area Recherche Clinique / Clinical Research Affiliation(s) du partenaire coordinateur de projet/ Organization of the coordinating partner Laboratoire(s)/Etablissement(s) Laboratory/Institution(s) Centre d Investigation Clinique de Toulouse Numéro(s) d unité/ Unit number CIC9302 Tutelle(s) /Research organization reference Inserm, CHU de Toulouse Affiliations des partenaires au projet/organization of the partner(s) Laboratoire(s)/Etablissement(s) Laboratory/Institution(s) Numéro(s) d unité/ Unit number Tutelle(s)/Research organization reference Entreprise(s) / company Secteur(s) d activité/activity field Effectif/ Staff size 1 /309

2 CONTENT 1. SUMMARY 4 2. CONTEXT: SCIENTIFIC ENVIRONMENT AND POSITIONING OF THE INFRASTRUCTURE PROJECT The development of clinical research infrastructures The CIC network and DIRCs on the national and ESFRI roadmaps International benchmarking 9 a) Support to investigation 9 b) Support to study management 10 c) Support to sponsors Current situation in France 11 a) Sponsors 12 b) Clinical trials units and data centres 12 c) Support to investigation PROJECT MANAGEMENT Management 14 a) Relevant experience of the project coordinator 14 b) Coordination modalities Collaboration organization 16 a) Partners description, relevance and complementarity 16 b) Complementarities and add value of the different partners 19 c) Successful joint initiatives already implemented in collaboration between partners to support clinical research in France TECHNICAL AND SCIENTIFIC DESCRIPTION OF THE ACTIVITIES General Overview Presentation of the different Work Packages (WP) 23 WP1 Governance and management 25 WP2 Evaluation 28 WP3 Coordination of services and one-stop shop access at the national level 30 WP4 Development of common tools 33 WP5 Training and communication 37 WP6 Investigation networks 39 WP7 Clinical trial units 42 WP8 Data centers 44 WP9 Europe, connection to ECRIN TRAINING, DISSEMINATION AND EXPLOITATION OF RESULTS Expected impacts of the project 50 a) Impact on academic research 50 b) Impact on industry-sponsored clinical trials 50 c) Impact on healthcare 51 d) Impact on economy Dissemination and/or exploitation of project results, and management of intellectual property 53 a) Dissemination of foreground within 54 b) Dissemination of foreground outside Training of the students and scientific community Management of Intellectual property and exploitation of Foreground 56 2 /309

3 6. FINANCIAL ASSESSMENT APPENDICES References List of acronyms List of publications form Pr Olivier Rascol List of publications from the Clinical Investigation Centers Business plan of the ECRIN-ERIC /309

4 1. SUMMARY Clinical research requires professional, multidisciplinary infrastructures providing support to investigation, to study management, and to sponsors in clinical studies. Strengthening the attractiveness and competitiveness of this infrastructure is a major economic challenge: clinical development is by far the highest industry investment in the biomedical area (2.5 Bn /year); the FP7 now invests 150M /year in clinical trials; and clinical research results in major cost containment in the health systems. France had a pioneering experience in Europe with the creation in most University Hospitals, since 1992, of Clinical Investigation Centers (CIC) providing support to investigation, particularly in experimental medicine and early phase studies. This was achieved in partnership between INSERM and the Ministry of Health. In parallel, the Ministry of Health created in the early 90 s, in University Hospitals too, structures designed to sponsor and coordinate clinical research at the local (DRCI) and later (2006) at the interregional level (DIRC). These infrastructures have now matured and expanded their activity, although not necessarily in a concerted manner. They form a nationwide network that is listed on the national roadmap for research infrastructures (TGIR) and represents the national component of the ESFRI-roadmap infrastructure for clinical research (ECRIN), whose coordination is hosted by France. ECRIN now plays a major role in facilitating multinational clinical trials, and since the FP7 Health priority invests about 150M /year in funding large scale, multinational investigator-driven clinical trials. European countries will now compete for this funding. In the context of a growing European competition, there is an urgent need to improve the effectiveness of the French national system and especially its capacity to support large-scale multi-centric multinational academic clinical trials. Similarly, it is also crucial to increase the attractiveness of France for early development Proof-of-Concept studies sponsored by the pharmaceutical industry. A common analysis made by the 3 academic key players involved into clinical research in France (INSERM, University Hospitals and all Universities attached to these hospitals) is that reaching such goals requires 2 main investments: (1) developing or up-grading a combination of the structures that are currently insufficiently mature or too fragmented in France including: (a) nationwide diseaseoriented investigator networks to support investigation, (b) clinical trial units reaching 4 /309

5 the critical size to efficiently support study design, management and analysis and (c) professional data centres. This should be achieved without necessarily adding new structures, but when possible through incentives to transform, adapt, merge and coordinate existing units to meet these strategic goals; (2) coordinating and simplifying a fragmentized and heterogeneous system preventing rapid and efficient adaptations. The program takes advantage of these common views, which are in line with the recent analysis made by the French pharmaceutical industry (LEEM/ARIIS), to propose a collaborative approach for a more efficacious and competitive implementation and management of multi-centric and international clinical studies, from early translational proof-of-concept aspects (a major opportunity for the French pharmaceutical industry) to large multicentric clinical/epidemiological trials (a field left behind the time in many areas according to many academic investigators and sponsors). To achieve such goals, the infrastructure proposes to invest within 2 consecutive phases: - During the first 24 months of the project (phase I), a first investment will be dedicated to implementing or up-grading the 3 identified clinical research facilities (diseaseorientated clinical Networks, Trial Units (CTUs) and Data Centres) through specifications and competitive calls. In parallel, during the same phase I, investment will be dedicated to setting-up a coordinated and transparent infrastructure: the hub. The definition of governance and management of services will be proposed by the 3 partners of the project and will define common rules for access to the facilities and common procedures of functioning including quality assurance, study management, pharmacovigilance, monitoring, auditing, etc - During phase II (month 24 to 60), once the services infrastructure is established, the last part of the investment will be dedicated to the practical implementation of the infrastructure. This phase is mandatory in order to test, improve and demonstrate efficiency through the first studies using its services, and before allowing the infrastrucutre living its own life. The quantitative objective of this phase is to achieve the technical and scientific management of at least 5 multi-centric research projects funded by the EU (instead of none nowadays) and 15 multicentric early phase clinical trials in partnership with pharmaceutical companies (including SMEs). At the end of this 5-year 5 /309

6 time, costs will be covered by the resources generated through the services provided by its users (national or international academic grants or industrial budgets). Practically, the project is based on 9 strongly interdependent work packages (WP). WP1 will manage the program and define the governance and management for this national clinical research hub infrastructure, whereas WP2 will define its evaluation from the scientific, technical and quality assurance perspective, and WP3 will define common procedures for access to coordinated services. In parallel, WP4 will develop common tools and procedures for QA, study management, pharmacovigilance, monitoring, and interface with the industry and biobank initiatives, and will develop and maintain regulatory, ethical and GCP know-how. WP5 will address training issues, first providing a directory of existing training programs in France and then coordinating collective initiatives between the different partners to propose a comprehensive offer in that field. Based on this governance framework (WP1-3) and on specifications derived from the common tools and procedures (WP4), the project will also allow specifications for developing or upgrading structures supporting investigation to be launched via competitive calls for the creation / upgrade of about 10 to 12 nationwide diseaseoriented investigator networks (WP6), a restricted number (5 to 7) of disease-oriented clinical trial units selected on scientific excellence and reaching the critical size (WP7), and a few (3 to 5) professional data centres providing high quality services based on leading edge technology (WP8). This will enable an efficient connection of the French clinical research infrastructure to the pan-european infrastructure ECRIN (WP9), structuring a clinical research capacity best adapted for large-scale trials and multinational collaboration, and fostering the national participation in, and coordination of multinational clinical trials now funded by the FP7. This major upgrade of this clinical research infrastructure is expected to result in a major economic impact through - a better attractiveness for industry trials (including early proof-of-concept studies and trials initiated by biotechnology and medical device SMEs) - a better attractiveness for EU funded clinical research projects - revenues generated by the development of innovative health products, - cost-containment due to large scale treatment strategy and head-to head comparison trials, leading to evidence-based medical practices, and 6 /309

7 - optimization of treatments, leading to a decreased burden of health expenditures in a healthier population. It is also expected to foster the competitiveness of national clinical research in a rapidly changing environment, as the competition is no longer between Universities or Hospitals within the same country, but rather between Europe and other world regions. Integration and coordination of clinical research infrastructures must therefore be achieved both at the national and the pan-european levels which is the main objective of this program. 7 /309

8 2. CONTEXT: SCIENTIFIC ENVIRONMENT AND POSITIONING OF THE INFRASTRUCTURE PROJECT Clinical research refers to biomedical research performed on human participants, enabling evidence-based medicine and representing a critical step in the generation of medical knowledge, close to its application in humans. The stringent ethical and regulatory framework, the requirement for high quality and credibility of the data and subsequent analyses highlight the need for professional support to clinical research The development of clinical research infrastructure The NIH developed in the 1970s a pioneering model for clinical research infrastructures as hospital based facilities (general clinical research centers, gcrc). In France, the adoption in 1988 of a very stringent legislation on clinical research (the Huriet law), particularly for studies performed on healthy volunteers, resulted in three simultaneous policies: i) The national health insurance system (Assurance Maladie) has been funding clinical research since 1993 through the Programme Hospitalier de Recherche Clinique (PHRC); ii) In 1992, the Ministry of Health started creating clinical research offices (Délégation à la Recherche Clinique, DRC) acting as public sponsors and coordinating clinical research in each University Hospital, later becoming DRCI (for Innovation, 2006), and sharing resources within 7 DIRC at the inter-regional level (Délégation Interrégionale à la Recherche Clinique, 2006) (see chapter 3-2 for a maps of CHU and DIRC in France). iii) This also led INSERM and University Hospital to jointly create, since 1992 and through competitive calls, hospital-based clinical research facilities with specific beds, equipment, and a professional staff, providing professional, high quality support to experimental medicine and early phase clinical trials. This led to the progressive development of 54 Clinical Investigation Centres (CIC), most of them providing generic support to clinical research (CIC-P), but some of them specializing in biotherapy (CIC-BT), in health technology (CIC-IT), or in clinical epidemiology (CIC-EC)(see Chapter 3-2 for a map of CICs in France). iv) This has been complemented since the late 90s by the spontaneous creation of local clinical trial units and/or data centers in several University Hospitals and cancer institutes. Few of these units have presently reached a level of national/international expertise (at the exception for example of cancer or AIDS), and a structured evaluation process has not started yet in most University Hospitals French networks on the national and ESFRI roadmaps In France, translational and early trials are conducted in Clinical Investigation Centres (CIC). The CICs undergo national competitive evaluation every 4 year, as well as audits controlling their quality assurance system and their GCP compliance. The CIC are organized as a nationwide network 1 coordinated by INSERM. In University Hospitals, clinical research has been coordinated by DRCI since They are in charge of promoting and selecting clinical research projects mostly phase 2 and /309

9 type trials. At first, DRCI belonged to informal networks, but later on they were formally organized at the interregional level through DIRC. DIRC have allowed a first attempt to merge means and competences, which can locally insufficient at a given site level. DRCI have also played a part in the training of clinical research professionals. The conception and management of large multicenter trials are often led by the nationwide cooperative groups that have developed in the main fields of research. These cooperative groups are able to promote industrial trials; they work in cooperation with DRCIs for the promotion of academic studies. The CIC network is listed on the national roadmap for large research infrastructures 2 (TGIR) together with the 7 DIRCs, and represents the French component of the pan-european, ESFRI-roadmap 3 clinical research infrastructure (ECRIN 4 ), whose pan-european coordination is also hosted by INSERM. However, the National Strategy for Research and Innovation 5 (SNRI) stresses the need for upgrading this national clinical research infrastructure. Recent developments in the national context offer a unique opportunity for substantial changes affecting clinical research, whose supervision and support was previously split between the research and the health sectors International benchmarking There is a growing competition among countries to foster the competitiveness of national clinical research. For this reason, many countries have massively invested in the development or upgrading of their national clinical research infrastructure. In France, the public sector and the pharmaceutical industry spend huge amounts of money in clinical research, but France, who appeared as a pioneer in Europe in the 1990s, now has to make its infrastructure more competitive in this changing context. In addition, international networking has emerged to facilitate multinational cooperation in clinical research in spite of the fragmentation of health and legislative systems, as access to large patient populations is a critical factor for success. Efficient participation in such multinational initiatives (France hosts the coordination of the pan-european distributed infrastructure ECRIN) requires a better adaptation of the national clinical research infrastructure to international standards and expectations. Benchmarking of support structures in other countries helps define three levels of support to clinical research: a) Support to investigation: these structures support both academic and industrysponsored clinical research, with various models depending on the nature of the clinical studies. Support to experimental medicine and early phase trials: These structures develop high-quality support to clinical studies requiring invasive investigation, whatever the disease area. This is typically achieved through hospital-based clinical research facilities with specific beds, staff and equipment. Derived from the NIH pdf#view=fit&pagemode=none view=fit&pagemode=none /309

10 gcrc model, the UK-CRF 6 and the French CIC mostly correspond to this role, and support both industry-sponsored and investigator-initiated studies. Support to late phase clinical trials: Trials requiring access to large populations of patients and less invasive investigation (typically phase III-IV studies) take advantage of disease-oriented investigators networks recruiting patients throughout the health system, from primary care through university hospitals. Various models exist across the world for instance the clinical research networks (NIHR-CRN 7 ) embedded into the national health services (NHS) in the UK, and associated with a national coordination centre providing generic tools. Interface for industry-sponsored trials: Some countries have developed specific interfaces between industry sponsors and the clinical research capacity. In France, for instance, both the main cooperative groups in their specific fields and the CeNGEPS at a more global level act as an interface through three main mechanisms: local support to patients recruitment, the development of common tools for study management and contracting, and support to disease-oriented investigators networks in areas of major industry investment b) Support to study management: this is typically achieved by clinical trial units (CTU), which are very well developed in the UK and in Scandinavian countries. Most CTUs are located in universities rather than in hospitals, and specialize in a given medical area. They focus on academic trials, providing support to study design and methodology, metaanalyses, randomization, biostatistics, adverse event reporting and study monitoring. Some of them are linked to a professional data centre, using professional databases and software for remote data entry. c) Support to sponsors: academic institutions acting as sponsors may need support for some of the sponsor s tasks at the international level, including interaction with ethics committees, interaction with competent authorities, insurance contracting, adverse event reporting, monitoring. These structures are of particular importance in the Scandinavian countries, where academic investigators also act as sponsors: in Denmark, University Hospitals have developed GCP Units that endorse their sponsor s duties /309

11 Investigator-driven clinical research Industry-sponsored clinical research Support to academic sponsors Industry sponsors Data centres Support to study management Clinical trial units Later phase : Investigator networks Support to investigation Industry study management or CROs Interface with industry sponsors Recruitment, contracting, networks (CeNGEPS)LEEM Early phase / experimental medicine : Clinical research facilities Models for public clinical research infrastructures Of course various combinations exist, and interestingly some models offer multiple levels support. This is illustrated by the German KKS 8, able to provide local support to investigation (including a sub-network for pediatric studies), also acting as a CTU providing support to study management, and supporting Universities in their sponsor s role Current situation in France The current organization in France 9 is quite heterogeneous and only partly covers the expectations and needs of the clinical research community. University Hospitals, INSERM and few disease-oriented structures (cancer, AIDS) plays this role at the regional and/or national level, but overall, national support to large academic trials must be improved, and a pan-european survey 10 has pointed to the fragmentation and poor availability of professional data management tools and data centers in France. As a consequence, various structures have emerged over time (CIC, DRCI, DIRC, URC ) but there are gaps and heterogeneity in competence (and sometimes overlaps), without appropriate and consistent governance, funding, quality audits, or scientific and financial evaluation (see Chapter 3-2: partners description, relevance and complementarities). There are also a number of other structures involved in the support to clinical research activities, with Demotes-Mainard J, Chêne G, Libersa C, Pignon JP : Clinical research infrastructures and networks in France : report on the french ECRIN workshop. Thérapie, 60: , Kuchinke et al. Heterogeneity prevails: the state of clinical trial data management in Europe results of a survey of ECRIN centers. Trials, 11: /309

12 varying levels of maturity depending on the disease area, the most advanced and developed research organization being in the fields of cancer and AIDS. a) Sponsors: Public sponsors are rather well developed in France. University Hospitals sponsor offices, hosted by DRCI, that now undergo scientific and technical evaluation by AERES. The DRCI now share resources within 7 interregional structures (DIRC), that also act as the target for an interface (CeNGEPS) between the industry and the clinical research capacity. Some DRCI, particularly in Paris (APHP) have developed a specific capacity for study management acting as clinical trial units (Unité de Recherche Clinique, URC). Other major institutions have developed their own sponsor capacity at the national level: INSERM (mostly for experimental medicine/ physiopathology), ANRS (for AIDS studies), INCA (for cancer studies) and other academic institutions. b) Clinical trials units and data centres: Although some initiatives bridge the gap in restricted geographic (Paris with the URC system) or disease areas (cancer, AIDS) the competence in support to study management (CTU) is uneven in France. Unlike in other countries where CTUs are created based on competitive calls, undergo peer-review and compete for funding based on scientific excellence, most of the equivalent structures in France are created and funded by public sponsors as an extension of the sponsor office. Such structures have not undergone regular evaluation yet, but should do so in the near future by AERES. The capacity in data management is rather poor in France when compared to neighboring countries (Germany, UK, Switzerland, Scandinavian countries), with few professional softwares, databases, and professional teams reaching the critical mass 11. c) Support to investigation: Local support has largely benefit to experimental medicine and early phase studies because of the implementation of CICs in several University-Hospitals, and a set off cancer or HIV vaccine early phase units, such structures providing dedicated study personnel and investigation beds to help investigators. Interestingly, in France, LEEM and ARIIS recently emphasized the importance for the pharmaceutical industry to re-inforce in our country our capacities in this area, in order to consolidate our position in early drug development phases, as other countries might be intrinsically more competitive for Phase III programs because of costs and patients availabilities. Coordinated actions to improve network activities and shared competence is thus needed, and disease-orientated networks on the model of those developed by ANRS and INCA, and attempts like the CIC disease-oriented networks are needed for experimental medicine and early phase trials. On the other hand, in spite of some exemplary initiatives (ANRS, INCa) and individual efforts to set up University Hospital local facilities (URC, CIC-EC and others) the support to large multicentric academic clinical trials remains under-developed and largely fragmented in many fields in our country. This has limited the development of academicsponsored Phase III-type trials at the national level, and the leadership of our teams in coordinating large international multicentric studies at the European level whereas the expertise of French investigators and the quality of medical research are well recognized. Cooperative groups are efficient tools for fostering the enrolment of patients in clinical studies, and for structuring the clinical research capacity through the development and use of common tools and procedures. University-Hospitals, INSERM, and Universities involved in promoting and supporting such trials have each developed individual strategies. Various initiatives have led for example to the set-up or support of disease-oriented investigators 11 Kuchinke et al. Heterogeneity prevails: the state of clinical trial data management in Europe - results of a survey of ECRIN centres. Trials, 11:79 12 /309

13 networks (including the recent CeNGEPS funding to investigators networks for industrysponsored trials, or the identification of disease-specific CIC networks). However, in most instances neither systematic approach nor coordinated efforts or funding have been obtained (except cancer through INCa, or ANRS for AIDS) and overall, most partners confess that key technical facilities still remain insufficient to up-grade the French system to the level of its European competitors in terms of networks, CTUs and data centers. Based on this context, the project aims at bridging this gaps by: 1- gathering together all players in clinical research at the national level 2- offering a national hub able to accept through competitive calls clinical research projects from early translational research up to large multicentre intervention, prevention and epidemiological studies. 13 /309

14 3. PROJECT MANAGEMENT 3-1. Management a) Relevant experience of the project coordinator Olivier Rascol, MD, PhD, born in 1958, is the project coordinator. He is Professor of Clinical Pharmacology in the Toulouse University Hospital since He obtained his MD in Neurology (Toulouse, 1985) and his PhD in Neurosciences (Paris, 1992). Dr Rascol is running the Toulouse Clinical Investigation Centre (CIC9302) since 1994 (last evaluation : A+) and chairs the national network of French CICs since He is running the thematic CIC Network in Neurosciences since and is also part of the Research Group on Motricity of INSERM UMR U825 (last evaluation : A+). Since 2007, he coordinates the French Reference Center for Multiple System Atrophy (a rare atypical parkinsonian syndrome). As a clinical neuropharmacologist, Pr Rascol is acknowledged as one of the top world leaders for the development and assessment of antiparkinsonian therapies. During the last 2 decades, he has been instrumental in designing and implementing early proof-of-concept and Phase III clinical trials that brought from R&D to the market most recent antiparkinsonian medications (ropinirole IR and ER, rasagiline, entacapone, pramipexole ER). This was achieved via long-standing collaborations with international academic research groups and large pharmaceutical companies in Europe and in the US. Pr Rascol has published > 300 articles in international peer-reviewed scientific journals (NEJM, Lancet, Lancet Neurol, Ann Neurol, Neurology, Arch Neurol, Brain, Mov Disorders ) and his Factor H is 49. He has been or is currently at the editorial board of international scientific journals (Lancet Neurol, Neurology, Eur J Neurol, Mov Disorders, J Neural Transm, Evidence Medicine...) (The list of publications is enclosed in Appendix 3).. He has also exerted international responsibilities within several scientific societies: he was Secretary of the Movement Disorders Society from 2006 to 2009, he is a member of the WFN Research Group for PD and Related Disorders and will be the next chairman of the European Movement Disorders EFNS/MDS-ES group. Pr Rascol organized the MDS- PD Paris meeting in 2009 (>5000 participants). Apart from this international scientific expertise, Pr Rascol has also largely participated over the past 20 years in the implementation and functioning of most French structures developed to support Clinical Research in France. He is therefore familiar with all mechanisms and partners governing Clinical Research in this country, from their background and achievements to their fragmentations and limitations. Indeed, Pr Rascol is exerting or has exerted many responsibilities in Clinical Research for the different partners of the project: for INSERM, he co-chaired the COSSEC from 2000 to 2004, he coordinates the CIC 9302 since 1994, he chaired the evaluation group of CIC from 2006 to 2009, he is a member of the evaluation experts for the joint call for Clinical Transaltional Research by Ministry of Health-INSERM, he chairs the CIC Neurosciences network since and the French national network of CIC since 2008; for University Hospitals, he runs de Toulouse CIC from 1994, he is at the board of the Toulouse Délégation à la Recherche Clinique et à l Innovation (DRCI) since 2004 and at the board of the Délégation Inter-Regionale à la Recherche Clinique (DIRC Sud-Ouest) since its creation in 2007; for the Ministry of Health, he is expert at the Programme de Recherche 14 /309

15 Hospitalière (PHRC) and is the PI of several national multi-centric PHRC programs; for Universities, he is member of the Council of the Medical Faculty of Toulouse since 2004 and participates in several training programs (Master, University Diploma on Clinical research); for AVIESAN, he is one of the experts of the Public Health ITMO; for the Cengeps, he is a member of the Scientific Committee from its creation. At the European level, Pr Rascol has served as an expert for EMEA and for the UK PD Society. He has acted as an external international expert to assess the German KKS PD network. He has run several WP of European PCRDs. As the current chair of the French Neurosciences CIC network, he acts as the contact person of the ECRIN network for clinical Neurosciences projects. With such an experience in clinical research in France and abroad, combining both an investigator-based as well as a sponsor-based perspective and having participated in the functioning of many of the French infrastructures set-up in the field, Pr Rascol has an in depth global view on the achievements, strengths and challenges faced in by our Clinical Research system, including its diversity, heterogeneity and insufficiencies. He also has a long experience of partnership with the pharmaceutical companies who are and will remain major actors of the field. He is aware of their own challenges and priorities, but he also knows the existence of converging interests between public and private initiatives, and has demonstrated in the past within the Toulouse CIC how feasible and beneficial such a partnership can be for simultaneous high scientific valorizations and positive economical developments. b) Coordination modalities Coordination and organizational modalities, a proposed organization chart, modalities and rules for use and access to the hub, training and communication aspects are all developed in the 9 different work package (WP) of the following paragraph (See Chapter 4: Technical and scientific description of the activities). These key aspects represent the core of the first 24 months of the investments of the F- CRIN project (phase I), bridging and bringing together in a unique collaborative joint initiative the 3 key partners of Clinical Research in France, namely INSERM, the University Hospitals and the Universities. Considering the diversity of participants, their past implication and the importance of the stakes, the present program cannot propose at this stage a finalized organization for this novel infrastructure. Common principles have been agreed through high decision level meetings between the partners, and it is proposed that the first 24 months of the project will be dedicated to finalizing these crucial issues, with clear objectives and timely deliverables corresponding to specific work packages (WP) run by the best possible experts in the field in France (see Chapter 4: technical and scientific description of the activites). 15 /309

16 3-2. Collaboration organization a) Partners description, relevance and complementarity The partners of the project represent the key organizations involved in the management, promotion and support of academic clinical research in France: INSERM, University Hospitals and Universities. They are namely designated as INSERM, Conférence des Directeurs des Hopitaux, Conférence des Présidents de CME, Conférence des Doyens des Facultés de Médecine (the last 3 conférences being coordinated within the «CNCR»), and the Conférence des Présidents d Université. Participant 1: INSERM (National Institute for Health and Medical Research): The French National Institute of Health and Medical Research (Inserm) is a public scientific and technological institute focusing entirely on human health. In 2008 Inserm took on the responsibility for the strategic, scientific and operational coordination of biomedical research. Ten thematic institutes (ITMO) were created in the light of this new coordination role. From the outset, Institute has forged close partnerships with the other public and private research establishments as well as hospitals to fulfill its missions. 80% of Inserm s 318 research units are currently set up in university hospitals or cancer research centers. Inserm plays a leading role in creating the European Research Area and boosts its standing abroad through close partnerships (teams and partner laboratories abroad). Inserm s 315 Units (01/01/2008) Lille Rouen Amiens Brest Rennes Caen Angers IdF Orléans Reims Nancy Strasbourg Nantes Tours Dijon Besançon Poitiers Limoges Clermont Ferrand Lyon Bordeaux Toulouse St Etienne Grenoble Marseille Nice Montpellier Participant 2: The conference of the Presidents of the Medical Hospital committees (CME) (Conférence des Présidents de Commission Médicale d Etablissement ) The presidents of the CME of the 29 French University hospitals (CHU) are members of the assembly representative of all practitioners working in University hospitals. This assembly is in charge of practical training of health professionals. The assembly is a 16 /309

17 APPEL A PROJETS driving force for the promotion of Clinical Research in University hospitals and public cancer centers. Map of the French University Hospitals (CHU for Centres Hospitaliers Universitaires) Participant 3: The conference of Hospitals Chief executive (Conférence des Directeurs Généraux de CHU) : This assembly gathers Chief Executives of University and Regional hospitals with the mission to improve patients care and hospitals efficiency and to promote the assets of University hospitals. The assembly is a major interplay for the Ministry of Health with respect of the implementation of Health policy in the University hospitals, with special interest for the development of Clinical Research. This conference interacts strongly and frequently with the other bodies described below. Participant 4: The conference of the deans of Schools of Medicine (Conférence des Doyens des Facultés de Médecine ): The assembly of the deans of the Faculties of Medicine warrants the quality and progression of medical training in the French universities. By promoting academic formation and medical research within these universities, this body is also a driving force in quality of care. CNCR (Comité National de Coordination de la Recherche) : CNCR is an entity coordinating the efforts of the precedent conferences (CHU directors (Chief executives), Faculty Deans and Presidents of CME) to make clinical research in University Hospitals visible and coherent. It relies on 6 working parties organized in thematic networks (quality promotion, trial security, harmonization of practices, evaluation, innovation, development). Participant 5: Conférence des Présidents d Université (CPU) : The CPU brings together all types of French Universities (Universités Technologiques, Instituts Nationaux Polytechniques, Ecoles Normales Supérieures et Grands Etablissements). The CPU represents here all the Universities attached to the University hospitals. It represents and 17 /309

18 defends the interest of 109 higher education member institutions. With the law on the independence of universities placing them at the heart of the research policy, they will also be a key partner. In a context of profound change of the higher education and research sector, the CPU has the role promoting the French university system and its values. Other parties (non contracting): Apart from the 5 official partners of the project, several other entities corresponding to academic and industrial major actors in the field are directly concerned by the project. They all have officially been informed of the project and have provided official support to the project. ARIIS (Alliance for Research and Innovation in Health Industries) is composed of representatives of the French health industries (LEEM) dealing with research and innovation. It has launch the 1st directory of R&D centers of pharmaceutical companies, A platform for studies, deliberation and proposals (A PLEA FOR LIFE SCIENCES) was drawn up under the auspices of the Scientific Board with the participation of many parties. Its aim is to draw attention to the scale of the challenges which concern the future of France and to the urgent need to respond ambitiously. ARIIS recently emphasized the importance for the pharmaceutical industry in France to up-grade and facilitate early phase studies (Phase I-II) in the international competition of drug development. CeNGEPS (National Centre for management of trials on health products) is an innovative model for support, through a tax collected from the industry, to the interface between industry sponsors and the clinical research capacity. Its main objective is to foster patients recruitment through specific staff, but it also supports investigators networks and the development of common tools (study management tool, costing template, support to contracting) to facilitate public-private partnerships. ANRS (National Agency for Research on AIDS and Viral Hepatitis) is the leading organization for research on the HIV/AIDS ad Hepatitis epidemics in France. It is a funding body mobilizing teams in areas it deems priorities. ANRS sponsors clinical trials and cohort studies, many of which have been milestones in improving the treatment of people infected by HIV or viral hepatitis. INCa (National Cancer Institute) is a health and science agency dedicated to cancerology. It operates on an interdisciplinary basis, with the aim of federating, uniting and mobilising players and resources around joint projects. It provides relevant information to the population, patients and healthcare professionals, and ensures that there is a continuum between care and research. The Institute launches calls for projects to support structures and fund innovative initiatives in the fields of research, care, prevention, screening and patient support Aviesan (Alliance for health and life science research) includes 8 main public institutions with which universities and university hospitals are partnered. The main objectives of Aviesan are to coordinate the strategic analysis, scientific programming and operational implementation of life and health science research and to give a fresh boost to translational research by speeding up the transfer of fundamental knowledge to clinical application and to increase cross-disciplinarity. AVIESAN is organized in thematic multi-organization institutes (ITMOs), the role of which is to chair the strategic debates within their own scientific community. 18 /309

19 b) Complementarities and added value of the different partners The association of the different partners and other parties within the project covers most of the landscape of clinical research in France, from early translational steps to later phases and larger studies (clinical trials or epidemiological approaches), from a private or an academic perspective. Each one brings its history, its experience, its interests and have accepted to work together for common goals that are crucial to improve the position of France in the international competition. The following section briefly summarizes the most illustrative examples of add-values brought by the partners (or other parties) to the project: INSERM Inserm has more than 300 research Units, including the CICs (see below), providing a unique potential for translational activities. Inserm has developed during the past a respected experience in evaluation of research units and in running large national and international collaborative research programs. Inserm also has experience in sponsoring clinical research projects at the national level (Department of Clinical Research and COSSEC) and at the European level (ECRIN) University Hospitals The 29 University hospitals have developed local and national experience in sponsoring clinical trials via their Delegations à la Recherche Clinique et à l Innovation (DRCI). DRCI were recently formally organized at the interregional level through 7 DIRC. DIRC have allowed a first attempt to mutualization means and competences, which can be locally insufficient at a given site level. The 7 DIRC are listed on the national roadmap on research infrastructures. The University Hospitals provide also most the largest access to patients. Moreover, some of them have developed local clinical research facilities for clinical research methodology and data centers (such as URCs at APHP). A specific national grant from the Ministry of Health (PHRC) has been implemented to fund clinical research trials in the University hospitals and a part of a special budget allocated to the University Hospitals by the Ministry of Health (MERRI) is also dedicated to fund some clinical research structures such as the CICs and DRCIs. Universities The recent law on the Independence des Universités reinforces the role of Universities in Research in France. The French Universities also provide most of the training expertise in fields relevant to clinical research, including methodology, GCP, Biostatisitcs, Pharmacology ARIIS ARIIS has a national and international view on worldwide R&D in the pharmaceutical industry and supports nitiatives aiming at facilitating and developing Clinical Research in France. ANRS and INCa Both disease-oriented agencies have been pioneer and successful in setting-up disease oriented clinical research infrastructures that can serve in many instances as models for F- CRIN goals. 19 /309

20 c) Successful joint initiatives already implemented in collaboration between 2 partners to support clinical research in France: > Clinical Investigation Centers (INSERM & University hospitals) Since 1992, in partnership with different University Hospitals, INSERM created Clinical Investigation Centers, to facilitate the transfer of knowledge and investigations from experimental labs to patients. CIC offer high quality clinical investigations facilities. There are currently 54 CICs located in 20/29 University Hospitals in France: (a) 27 poly-thematic CICs (P), which act as hospital-based clinical research facilities providing generic support to experimental medicine and early phase investigation at the local level, with specific beds, equipment and staff; (b) 10 biotherapy CICs (BT), which focus on trials for gene and cellular therapies, coupled to facilities for cell and vector processing (c) 8 technology innovation CICs (IT), which are translational research centers developing both the preclinical and clinical proof of concept in selected areas of health technology (from lasers through tissue engineering) and (d) 9 clinical epidemiology CICs (EC), which are designed for support to epidemiological studies, performed outside the hospital. (The list of publications is enclosed in Appendix 4) Since 2003, INSERM in coordination with University Hospitals, has organized the French CICs into both a national CIC network and disease-oriented networks (cardiovascular, neurosciences, paediatrics, thrombosis, diabetes and metabolic diseases, gastrology/enterology/hepatology, technologicals innovations, etc.). This organization strengthens the collaboration of CICs working on the same themes, fosters the set-up of joint research projects and ensures the harmonization of good clinical and laboratory practices. The following map illustrates the distribution of the French CIC network. As mentioned above, the CIC network is as the French component of the ESFRI-roadmap ECRIN infrastructure, and is listed on research infrastructures. Each CIC is created after competitive evaluation as a joint venture between INSERM and a University Hospital, undergoes competitive scientific and financial peer-review, as well as system quality and GCP audits. 20 /309