RECHERCHE TRANSLATIONNELLE RECHERCHE CLINIQUE. COUTS et FINANCEMENTS

Transcription

1 RECHERCHE TRANSLATIONNELLE RECHERCHE CLINIQUE COUTS et FINANCEMENTS Pr. Jean François DELFRAISSY ANRS / IMMI / CHU Bicêtre Journée Recherche & Santé AVIESAN 20 Janvier 2012 C N R

2 23 DECEMBER 2011 VOL 334 SCIENCE

3 HPTN 052 : Study Design Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 Randomization Immediate ART CD Delayed ART CD4 250 Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death Cohen et al., Abstract MOAXO102, IAS Rome

4 HPTN 052: HIV-1 Transmission 1763 couples Total HIV-1 Transmission Events: 39 Immediate Arm 4 Delayed Arm M. USD P< Cohen et al., Abstract MOAXO102, IAS Rome

5 5 M. USD

6 RECHERCHE TRANSLATIONNELLE Composante majeure de la recherche biomédicale Elle assure le continu entre recherche cognitive et recherche clinique Elle fait poser des questions à la recherche fondamentale, dérivées de l observation de patients (ou de groupes et cohortes) Elle se développe à proximité du patient avec un objectif possible (mais non obligatoire) d application rapide au bénéfice du malade.

7 HIV controllers HIV CONTROLLER : Lambotte et al. Clin Infect Dis 2005 HIV-1 infection > 10 years > 90% of plasma HIV-RNA measurements < 400 copies/ml No anti-retroviral treatment <1% of currently followed HIV-1- infected patients

8 HIV controllers Patients with a spontaneous control of HIV replication Attenuated virus Reduced genetic susceptibility to HIV Viral entry Cellular HIV restriction factor Effective immune response +++ A consortium of several research teams supported by grants from ANRS starts in 09/2005 : the ANRS HIV Controllers study

9 INSTITUT PASTEUR Infectability of autologous CD4 T cells, DCs Control of HIV by CD8 T cells Gianfranco Pancino Role of NK cells Daniel Scott-Algara Modulation of HLA Olivier Schwartz State of CD4 activation HIV specific CD4T cell response Lisa Chakrabarti Humoral immune response Chritiane Moog INSERM U778, Strasbourg HIV specific CD8 T cell response Alain Venet INSERM U802, Bicêtre ANRS EP36 I II III IV V COHORTE CO 18 PI: Olivier Lambotte Epidemiology : national registry > cohort 33 infectious diseases departments Laurence Meyer JF DELFRAISSY INSERM U822, Bicêtre USA Duke Human Vaccine Institute Humoral immune response Barton Haynes, David Montefiori, Guido Ferari, Georgia Tomaras pdc Jean-Philippe Herbeuval CNRS UMR8147, Paris Genetic protection Genome Wide Analysis Ioannis Theodorou Inserm U543, Paris Presence of defective virus O Lambotte INSERM U802, Bicêtre Quantification of HIV RNA+ DNA Christine Rouzioux Virology department, Necker Hospital, Paris EUROPE : Collaboration with CASCADE COHERE Laurence Meyer, Olivier Lambotte

10 GENOMIC IN HIV INFECTION : PHENOTYPE / GENOTYPE Three major GWAS studies in cohorts of HIV infected patients for the discovery of new genes influencing the disease. Among common genetic variants the MHC locus has the major effect on HIV disease progression. One study from the CHAVI group Fellay et al. Science 2007 and two ANRS studies Dalmasso et al. PLOS One and Leclerc et al. J. Inf. diseases 2009). Several variants besides classical class I antigen presenting genes are novel pathways are under exploration. ANRS Cohorts SEROCO, PRIMO, HIC European Cohorts Patients > 4000 Follow up since 1988 I. Théodorou La Pitié INSERM

11 Formes graves H1N1: FluBAL (10/2009) Objectif: caractérisation immuno-virologique in situ des formes pulmonaires graves chez des patients ventilés Sous type viral particulier : mutations? Comparaison des réponses immunitaires in situ pulmonaires, aux réponses dans le sang Exploration de la relation entre la réplication virale et la réponse immunitaire pulmonaire Etude du rôle des surinfections pulmonaires bactériennes ou virales éventuelles Recherche d un déficit immunitaire cellulaire et/ou d un processus d activation Collaboration avec Flu-CO: cohorte prospective multicentrique (n=1500) identifier les facteurs de risque, cliniques, virologiques épidémiologiques, immunologiques et génétiques) Cortiflu: Essai thérapeutique randomisé (n=438) évaluation des corticostéroides faibles doses dans le traitement des formes sévères

12 Recherches Clinique et Translationnelle : Des contraintes particulières (1) 1. Contraintes réglementaires 2. Une évolution de la Recherche Clinique Phénotype de qualité génotype Cohortes Long Terme Nouveaux métiers de Recherche Clinique et translationnelle 3. Budgets importants Coût élevé pour la partie clinique Coût élevé des nouvelles technologies: génomique 4. Les financements Une petite partie du PHRC (80 M euros/an) ANR? Autres : ANRS, INCA, FRM?, contrat spécifique INSERM

13 Recherches Clinique et Translationnelle : Des contraintes particulières (2) Elaboration des projets Multi disciplinarité Importances des consortiums Culture différente des équipes Aspects internationaux Rôle des Associations de patients Groupes de travail avant l Appel d Offres Evaluation des projets Plus complexe que «Basic Science» Expertises différentes: importance des Biostatisticiens Compétition budgétaire avec le fondamental Valorisations/Publications Moyen, Long terme Place des jeunes scientifiques dans les publications par rapport aux cliniciens Visibilité plus faible pour les décideurs Science > New England Journal of Medicine?

14 BUDGET = BUDGET DE RECHERCHE + SURCOUT HOSPITALIER ANRS 147 Optiprim ANRS 157 RocNRal Budget de recherche Surcoût hospitalier Total Coût/participant Effectif N=90 (45 centres) N=90 (17 centres) Phase III II Durée 48 mois 24 mois Traitement Pentathérapie vs trithérapie Primo Infections bithérapie 14

15 Budget de recherche ANRS 147 Optiprim ANRS 157 RocNRal Soutien clinique Virologie / pharmacologie Immunologie Radiologie / Activation/inflammation / Questionnaire participant en ligne / Coursier prélèvements Prestataire pharmaceutique Documents de l essai Assemblée générale investigateurs Monitorage Total budget recherche (n=90)

16 Surcoût hospitalier ANRS 147 Optiprim ANRS 157 RocNRal Consultations, prélèvements Examens biologiques Biothèques Pharmacie Frais fixes Total surcoût (n=90)

17 Coût moyen d un Essai Thérapeutique Phase IB- IIA Tolérance Pharmaco N= k Phase IIB Pharmaco Premières données d efficacité N= k à 500 k Phase III Efficacité N=100 à m à 2 m 17

18 ANRS % Distribution of funds according to research area 2010 Basic Science 24 % Vaccine 8 % Clinical trials and cohorts (HIV) 25 % Epidemiology socio-behavioral science 5 % Research in the developing world 21 % Hepatitis B and C 17 % 18

19 PUBLICATIONS ANRS Fondamental VIH Vaccin SHS PED Clinique VIH Hépatites virales TOTAL

20 Pharmaceutical Industry / ANRS Partnership Pharmaceutical companies are essential partners for most clinical trials Contractual framework needs to be established for each trial/company Free access to drugs (expiration dates) Data ownership and access to the database Company observers seat in trial scientific committees Confidentiality Publication rules Funding of sub-studies of particular interest Obligations and Rights AC5 SSC members also participate to drug companies advisory boards 20

21 Pharmaceutical Industry / ANRS Partnership Mutual interest but not always easy! for the Company Non-pivotal study but, filed as part of EMEA/FDA Substantial cost savings Scientific credibility for ANRS Early access to new drugs Scientific & international acknowledgement Publication materials Examples : FTC, raltegravir, darunavir, etravirine 21

22 FINANCEMENTS PHRC National (80 M ) PHRC Inter-régional PHRC K (Cancer-Inca) Soutien aux techniques innovantes INSERM-DGOS (Recherche Translationnelle) Contrat de Recherche Clinique AP-HP ANRS (VIH Hépatites) ARC, AFM, Ligue Fondation Alzheimer, autre EUROPE : Financement Réseaux Recherche au SUD? Recherche en situation d urgence? 22

23 Appels d Offres 2012 INSERM-DGOS en partenariat avec l AFM (Association Française contre les Myopathies) 107 lettres d intention déposées. Après la pré-sélection, 45 projets ont été déposés. Le Comité d Arbitrage a retenu 19 projets dont 2 financés par l AFM (à hauteur de chaque). La DGOS et l Inserm abondent leur financement. 16 projets sont financés à hauteur de (chaque) par l Inserm et de (chaque) par la DGOS. 1 projet est financé à hauteur de par l Inserm et de par la DGOS.

24 PHRC Total PHRC hors cancer (n) PHRC «infectieux» hors cancer (n) % hors cancer Financement PHRC «infectieux» sur 3 ans Financement PHRC Global % 6.7 M 61 M (12 H1N1) 12% 6.86 M 59 M % 4.01 M 48 M % 3.78 M 45 M % 3.71 M 35 M % M 34 M % M 33 M

25 PHRC NATIONAL 2012 Nutrition et obésité Maladie d Alzheimer et vieillissement Santé mentale, autisme, suicide Pédiatrie Maladies chroniques Maladies rares Douleur, fin de vie Accidents vasculaires cérébraux Médecine de ville Handicap Résistance aux antibiotiques Programme blanc

26 French International Research Network CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

27 FIN

28 Organization of Clinical Research The task of ANRS is to fund and lead research in all areas related to HIV/AIDS and Hepatitis B and C Multi-disciplinary organization with clinicians, virologists, pharmacists, methodologists, experts in social and behavioral sciences and patients representatives Clinical trials HIV: AC5 Cohorts: AC7 Hepatitis B and C: AC24 Co-infections: AC5/24 Developing countries: AC12, CSS6 Clinical research and pathogenesis: CSS3, CSS7 and CCS4 Medical virology: AC11, AC33 HIV and aging, reservoir, genomic 28

29 Evaluation and implementation of a new trial Projects can be submitted anytime to AC5 for evaluation, there is no call for proposals to improve reactivity Projects are first discussed and developed within the appropriate AC5 sub-group Full protocol is then presented and discussed at the AC5 SSC with a secret vote to accept of reject the proposal The protocol is finalized with the ANRS clinical research department The protocol with its budget is approved by the director of ANRS The trial is presented to the TRT-5 for discussion in particular the informed consent sheet. Implementation of the study - ANRS is the sponsor of HIV clinical trials - One ANRS clinical trial unit is involved - Scientific committee is appointed - DSMB for all trials - Sites, labs and pharmacies selection 29

30 Locations ANRS Clinical Sites Metropolitan France and overseas departments and territories Hospital sites in University and non-university hospitals Medical Resources Medical doctors for patients management and follow-up Personnel dedicated to research : clinical monitors (MEC), technicians (TEC) Laboratory Resources Virology : AC11 network (viral load, genotypes) Immunology : standardization, quality controls Pharmacology : standardization, quality controls Personnel dedicated to research : biological monitors (MEB), technicians (TEB) Pharmacies : Drug delivery and accountability 30

31 Network of French ANRS sites 190 ANRS clinical sites 31

32 ANRS Clinical Sites Network 37 main sites in university hospitals, 50% of which are located in the Paris area Cohort of > 50,000 HIV-infected patients Major role in trial recruitment : 87% of patients are enrolled in these sites 10-20% of patients followed in these sites are enrolled in ANRS clinical studies (trials and cohorts) Also involved in clinical research sponsored by major pharmaceutical companies 32

33 HIV Controllers : Major role of CD8 T Cell response The HIV controller phenotype is not the consequence of replicationincompetent virus, at least in most patients (Lamine et al. AIDS 2007) Transmission of replication competent virus Evolution of the viral sequences; co or surinfection No genetic protection of CD4+ T cells against HIV infection Results of GWA point to a role both of genes of adaptative immunity (HLA B C) and of genes of innate immunity (MICA MICB C4) Dalmasso et al. PLoS One 2008 No evidence for a major role of humoral immunity (Lambotte et al. AIDS 2009) Heterogeneity in Neutralizing antibodies responses Role of ADCC Presence of functionnal central memory and effector memory CD4+ T cells with HIV-specific CD4+ T cells (Potter et al. J Virol 2007) Strong and efficient HIV specific CD8 T cell response which are able to suppress HIV replication (PNAS 2007, Immunity 2008) O. Lambotte Hôpital Bicêtre INSERM

34 Microbiology and Infectious Diseases Key points: France 2011 Major Institutions : Institut Pasteur, Inserm, CNRS, IRD Others : ANRS, CEA, CIRAD, INRA, INVS, Universities 12% of French research forces: 300 teams, 2000 Scientists & Technical staff 18% of French biomedical publications: 5000 publications per year Translationnal and clinical research: 35 clinical units involved, including HIV and hepatits Network of vaccine research centers Large research network in ressources limited countries CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

35 Responsiveness to H1N1 pandemic in France 30 research projects - Cohorts: households, infected - Case-control studies - Serosurveys - Severe disease: ARDS - Social and Human Sciences - Diagnostics - Basic research - Vaccine trials and observational studies Main funders: 13m Total funding Public: Inserm, Ministries Research and Health, ANRS Private: Roche, GSK, Fondation Mérieux CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

36 Assessment: The strong points IMMI/AVIESAN, reactive, flexible and well recognized as chair and coordinator of scientific acitivities Interactions with Ministries (Research & Health) and Public Health Surveillance bodies Rapid implementation of multidisciplinary projects, including with ressources limited countries teams Effective and quick responses of the regulatory agencies Data quickly reported to the French health authorities More than forty international scientific publications CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

37 Assessment: The weak points Difficulties to implement and maintain the projects in the absence of proper funding Complexity of the financial process: several funders Few social and human scientific teams involved No access to biological collections, nor to dedicated plateforms Few European and International collaboration CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

38 Research: a key factor to be prepared to respond to an epidemic threat CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

39 How to implement research to respond to an epidemic threat? Set up an Organisation: Decision-making body: rapid mobilisation and effective response Linked to public health surveillance Dedicated and long-term funding Define a Strategy: Mock-up cohorts «Academic» Contract Research Organization Tools for detection and identification of new infectious agents CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD

40 How to implement research to respond to an epidemic threat? Implement Research Programme: Transdisciplinary and International research programmes based on platforms and networks Partnership with southern countries Partnership with the private sector Improve Communication: Decision-making process: expertise and KABP studies In a European and International CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD perspective

41 30 years of HIV/AIDS translational science 6,6 Million of people on ARV therapy in LMIC 4 HIV IAS UNGASS Global Fund AIDS First RDT HIV Testing AZT therapy ARV Resistance Protease inhibitor Fusion inhibitor Integrase & CCR5 inhibitor HIV Quantification PMTCT HAART Circumcision HPTN 052 Therapy and prevention research ARV as prevention (Caprisa, Iprex) Prophylactic and therapeutic vaccine research

42 HIV-1 Transimssions Linked HIV transmission All HIV transmission Cumulative probability Delayed Immediate Cumulative probability Delayed Immediate Years since randomization Years since randomization No. at risk Immediate Delayed No. at risk Immediate Delayed Cohen et al., Abstract MOAXO102, IAS Rome

43 30 years of HIV/AIDS translational science 6,6 million Number of people under HAART in LMIC Number of people annually infected with HIV Number of AIDS related death in LMIC HIV IAS UNGASS Global Fund 2,5 million 1,7 million AIDS AZT therapy PMTCT First RDT HAART Circumcision (60%) HPTN 052 HIV Testing ARV Resistance HIV Quantification Therapy and prevention research Protease inhibitor Fusion inhibitor Integrase & CCR5 inhibitor ARV as prevention (Caprisa, Iprex) Prophylactic and therapeutic vaccine research

44 Despite unprecedented international efforts, HIV/AIDS remains a key challenge in global health equity and development. North America 1.3 million Caribbean Latin America 1.5 million Central and Western Europe North Africa and Middle-East Sub-Saharan Africa 22.9 million Eastern Europe and Central Asia 1.5 million Eastern Asia South and South- East Asia 4 million Oceania UNAIDS, WHO million of PLWH HIV/AIDS remains at the 2nd position on the list of death caused by infectious diseases with 5500 deaths and 7400 new infections every day More than 95% in resource-limited countries About 60% of HIV+ persons ignore their serological status (15 to 50% in Europe ) Still a sensitive topic (sex & addiction, stigma, politics, religion,media..)

45 Coordinated action 5 (AC5) Expertise in clinical trials in the field of HIV/AIDS Define scientific priorities for clinical trials in France and developed countries (North) Assess submitted clinical trial proposals Follow-up of implemented clinical trials 5 different AC5 sub-groups: Antiretroviral treatment strategies (Pr. C Katlama) Immunotherapy and cancer (Pr. Y Levy) Pharmacology (Dr. AM Taburet) Treatment-related toxicities (Dr. JP. Viard and J. Capeau) Mother and child (Pr. S Blanche) 45

46 Recherches interventionnelles Recherches non-interventionnelles Recherche interventionnelle est définie par l article L1121-1, alinéa 1 du CSP comme une recherche organisée et pratiquée sur l être humain en vue du développement des connaissances biologiques et médicales. La simple prise de sang n est pas considérée comme une intervention. En revanche, un prélèvement naso-pharyngé est considéré comme une intervention. Recherche non interventionnelle est définie par l article L du CSP comme une recherche dans laquelle tous les actes sont pratiqués et les produits utilisés de manière habituelle sans aucune procédure supplémentaire ou inhabituelle de diagnostic ou surveillance. Toute randomisation est explicitement interdite dans le cadre de la recherche non interventionnelle.