Genomic Medicine in France

1. Genomic Medicine in France

2. Agenda20 juillet 2016 1-Présentation du plan validé 2-Gouvernance du plan: comité de pilotage interministériel de décembre, mise en place du comité opérationnel et du comité de suivi 3- Calendrier: déroulé des actions, réunions des comités 4- Discussion

3. All startedwith : Terms of Engagmentletterfrom the Prime Minister The Prime Ministerentrusted Aviesan with the task of examiningthe current landscape for incorporating genome sequencing in the context of the healthcare pathway by touching on the following four points in his mission statement: • Defining the presence and importance of genomic sequencing in current medical practices as well as expected future developments in the coming 10 years. • Evaluating France’s positioning in the field of genomic research and its role in current health plans and priorities to be implemented in line with national strategies for health and research • Evaluating the issues related to innovation and technology transfer and economic growth, taking into account technological aspects, management of large data sets and ethical implications. • Proposing a long-term medico-economic model integrating coverage by medical insurance and the establishment of an industrial sector to support such an initiative.

4. A Co-Constructed National Plan • More than 160 people mobilized under an Aviesan presidency • Institutional representatives • transversal competences across fields of research, health and industry • Research and health agencies • Central administrations of ministries • Representatives from the industry (Ariis, IT,…) • CNAM and HAS • CGI, • Toulouse School of Economics…

5. JUNE – OCTOBER 2015, ANALYSIS • International state of the art and prospects in 10 years • Innovation and industrial stakes • Current situation in France: research and technical applications • Infrastructure and organisation WorkMethodology An Interim Report… OCTOBER 2015 TO MARCH 2016 • Proposal for national organization … a national structuringproject… 22 JUNE 2016 Annoucment of a National Plan

6. French genomic medicine Plan 2025 What ambition? What issues?

7. Ambition of the French Genomic Medicine Plan 2025 • Integrate sequencing in the routine and clinical practice Implement a general healthcare pathway for all French patients with cancer, rare diseases or common diseases that includes access to genomic medicine for all those concerned (patients and eventually family members depending on diagnosis) by 2025 • Develop a national genomic medicine sector • Place France amongst the leading countries in the field of genomic medicine in the next ten years in order to export its expertise developed in this area and establish a medical and industrial sector of genomic medicine.

8. Integrate sequencing into a generic healthcare pathway Request for exam, pre-analytic, analytic, biological interpretation, returned Request for exam Agreement Pre-analytic sampling National database of Clinico-biological Meta-data Patient/doctor dialogue Shared decisions Genomic data Clnical data Support for the therapeutic decision Support for the diagnostic decision Sequences analyzed Support tools for analysis Research Technical validation Biological validation and interpretation “Diagnostic Laboratory”

9. Challenges on the 2020 horizon • Patient: personalized treatments • a diagnosis based on the integration of genomic data with all classical clinical data • adequate care by the health care system (information, consent , secondary findings , return of results , and sharing and security of data, ethics). • Adequate care through the healthcare system (information, consent, secondary findings, return of results, data sharing and security, ethics). • Healthcare system: Equal access to sequencing (110 000 patients 310 000 analyses) rare diseases, cancers (~60 000 patients per year) • Economics: an integrated industry sector dedicated to precision medicine A hybrid system of care/research To over come scientific and technical hurdles, molecular exploration of pathologies, matching of heterogeneous databases, interpretation of large scale data, etc. • Practitioner: Diagnostics and therapeutics adjusted for validated indications • A set of validated indications • A digital file associated with each patient (genomic data + clinical data) • Identification of variants for a particular pathology , good practices related to secondary findings • Tools for exploring data and elaborating therapeutic strategies

10. French genomicmedicine plan 2025 How to organize?

11. Develop capacities of sequencing within a network • Action 1 Transfer of sample Transfer of Variant call File (VCF) CAD Sequencing Sampling Standardized procedures and processes Reference platform (CRefIX)

12. Develop capacities of sequencing within a network (action 1) • Establishment of first three platforms with the choice of: • Sites • Sequencing technologies • Storage architecture • Calculation architecture • Software specifications CAD • Deployment of material and software solutions • Installation of matching and automatic annotation of varients software • Installation of collaboration software with CAD • Sending of preliminary data to CAD • Certification of health data custodian • Launch in collaboration with CAD • Rolling out of 9 other platforms

13. CAD: Manage and exploit the volume of data generated • Action 2 Linking with clinical databses Transfer of Variant call File (VCF) Expert annotation and validation of variants CAD Sequencing Standardized procedures and processes Methods, service tools (clinical, research, industrial) CRefIX

14. CAD (action 2) : services • Services for industry • Feasibility of spedific genotype clinical trials • Assistance in recruiting patients • Pharmacogenetics: longitudinal studies • Services for patients • Consent • Access to data • Other services • Access to or interconnection with other databases • Methodological support • Analysis tools allowing the integration of toher omics data CAD National database of Clinico-biological Meta-data • Services for research • Validation of therapeutic hypotheses • Biological research: cross analysis of different pathologies, access to raw data extraction • Clinical research: virtual studies, validation of companion tests, biomarkers,… • Epidemiological research Services for the clinic • Tools to support therapeutic decisions • Tools to support analysis, tools of comparison • Data manipulation training « Laboratoire d’analyse »

15. CRefIX : ensure technogical and informatic development • Sequencing from paraffin embedded biopsies • Sequencing from liquid biopsies • Sequencing from plasma DNA • Long reads • New sequencing technologies • Action 4 Center of Reference Standardized procedures and processes Industrialization of procedures and deployment R&D Network of platforms CAD Ethics and regulation • Deployment and lauch • Informatic and bio-informatic developments (cloud algorithm) • New means of computing • Regulation and ethics (informed consent). • Coding of data • Dedicated intensive computing • Innovative ways of computing Training • Process development and harmonization of protocols and methods

16. Needs from hardware to software Storage Computing Software tools • Level 1 : Acquisition of varients • Managment/follow-up • Quality control • Matching of varients • Varient calling • Management of workflow (2048 cores + 8 To)* x10 > ~70Pb/year • Level 2 : Annotation and validation • Storage • Automatic annotation • Validation / Reporting • Exchange of information • Level 3 : Methodology • Digital models, data mining CAD > ~70Pb/year 2x + growth • Level 3 : Rresearch and development • Software support (anonymi\zation, coding, compression, parallelization, visualization, certification) • Digital models Innovative computing means  Teratec

17. Pilot projects: Overcoming barriers in the genomic healthcare pathway Clinical data Types of sequencing, analysis and data linking • Action 5 Modes and types of sampling Collection of consents Transport and transfer to sequencing centers • Interpretation Laboratoire d’analyse CAD Types of data transfer to CAD Quality control Elaboration, validation et transmission of summaries Putting in place staff for sequencing, varient extraction, analysis and intepretation

18. ENSURE IMPLEMENTATION AND GROWTH Clinical Data CRefIX Sampling • Interpretation “Analysis laboratory” CAD Support tools for analysis Sending and collecting • Guarantee a secure, ethic, and quality healthcare pathway • Deployment of new competences • Establish a way of validating of clinical indications • Establish a reference center for innovation, expertise and transfer (CRefIX) • Overcome technological, clinical and regulatory barriers encountered along the pathway

19. Industrialsector(Actions 9&10) Build up a industrial sector able to export tools, services, standards or validated biomarkers developed in France. • Standardization (at European level), anonymization, encryption • Big data, soft data • Data analysis • Clinical and research services • Methodological support • Software development • Interconnection to other databases • Instrumentation, medical devices, new genomic sequencing,… • Business models

20. PUT IN PLACE THE TOOLS FOR A GENOMIC HEALTHCARE PATHWAY Action 1 Creation of a network of sequencing Action 2  Creation of a Collector Analyser of Data (CAD) to process and use the volume of data generated Action 3  Allow the integration and use of patient data in the healthcare pathway Ensure operational implementation and growth Action 4  Put in place a center of reference, innovation, expertise and transfer (CREFIX) Action 5  Overcome technological, clinical and regulatory barriers encountered along the pathway Action 6 Set up an evaluation and validation system of new indications for access to genomic diagnosis Action 7 Have new skills and personnel capable of meeting the challenge of analyzing and interpreting Action 8 Guarantee a secure and quality healthcare pathway IMPLEMENT MONITORING AND MANAGEMENT TOOLS Action 9 Mobilize industry stakeholders around the project Action 10 Guide sector activities to address industry problems in the genomic healthcare pathway Action 11 Monitor the field of genomic medicine on the international level Action 12 Implement a program dedicated to health economic aspects Action 13Organize information, consultation, and involvement of concerned stakeholders in society Action 14 Governance of Plan A plan organized around 3 Major Objectives – 14 actions

21. Funding: 670 M€ PUT IN PLACE THE TOOLS FOR A GENOMIC HEALTHCARE PATHWAY : 526M€ Action 1 Creation of a network of sequencing: 341M€ Action 2 Creation of a Collector Analyser of Data (CAD): 185M€ Ensure operational implementation and growth: 138M€ Action 4 Center of reference, innovation, expertise and transfer (CREFIX): 66 M€ Action 5 Overcome technological, clinical and regulatory barriers encountered along the pathway: 32M€ Action 6 Set up an evaluation and validation system of new indications: 40M€ IMPLEMENT MONITORING AND MANAGEMENT TOOLS: 6M€ Action 9- Action 14 Mobilize industry stakeholders around the project and address industry problems Monitor the field of genomic medicine on the international level Implement a program dedicated to health economic aspects Organize information, consultation, and involvement of concerned stakeholders in society Governance of Plan

22. Gouvernance Comité de pilotage élargi interministériel Composition: cabinets des ministres chargés de la recherche, de la santé, et de l’industrie et des directeurs des administrations centrales de ces ministères et des autres ministères impliqués, du directeur général de la Cnamts, du (de la) Président(e) de l’HAS, d’un représentant des directeurs généraux des agences régionales de santé, du président d’Aviesan et des associations représentant les malades et les usagers de la santé Fréquence: une fois par an -> décembre 2016 en présence du PM Mission: le comité veille à la réalisation du plan par la mobilisation des partenaires et des moyens et oriente sa mise en œuvre. Il peut proposer des adaptations du Plan en fonction de l’évolution du contexte.

23. Gouvernance (2) Comité de suivi Composition: les pilotes d’actions et les institutions et Tutelles impliquées. Fréquence: une fois par trimestre -> fin octobre 2016 Mission: Le comité planifie la mise en oeuvredes actions et s’assure de leur déroulement selon le calendrier prévisionnel, il apprécie les résultats du Plan à l’aide d’indicateurs et suit l’évolution de la dépense par rapport au budget prévu.

24. Gouvernance (3) Comité opérationnel (comop) Composition: les pilotes d’actions Fréquence: une fois par mois -> septembre 2016 Mission: pilotage opérationnel des actions du Plan

25. Organisation du comop Présidence Aviesan Responsable du COMOP : F Lethimonnier (dir ITS Aviesan) Secrétaire générale : N Manaud (dir adjointe ITS Aviesan) Chargé de mission pour le suivi: tbd 1-     Groupe Projet : Mise en œuvre de la mesure 1 (12 plateformes) Pilotes : DGOS et Frédérique Nowak (INCA) Financement : PFSS Objectifs Q42016 : rédaction et lancement de l’AO plateforme & Démonstrateur Crefix Membres : DGOS, Inca, DG CHU, Privé, Juridique (MASS), experts Cofraq,

26. Organisation du comop (2) • 2-     Groupe Projet : CAD : • Pilotes : F Lethimonnier,  F Montarras (VP immobilier, P7) • (Inès Amado/Pauline Solignac, DVS Aviesan Biomarqueur) • Financement : PIA2 et PIA3 • Objectifs Q42016: • - Début étude de faisabilité, identification consultant, financement (FL), • - Logistique, préparation de l’implantation P7 (FM) • Membres: Aviesan, Inria, CEA, Juridique (F. Lesaulnier), industriels, MASS, MESR • 3-     Groupe Projet de mise en œuvre du CRefIX (mesure 4) • Pilote: JF Deleuze (CEA, CNG), Alain Viari (INRIA) • (Peggy Baudouin, DVS Aviesan DM) • Fimancement: PIAVE, PIA2, PIA3 • Objectifs QA 2016: • Préparation du projet public-privé (PIAVE) (JFD), démonstrateur de plateforme • Préparation du projet public-privé sur la partie data en lien avec le CAD (A Viari) • Membres: Aviesan, CNG, Inria, CEA, Juridique (F. Lesaulnier), Privé, CGI, MASS, MESR

27. Organisation du comop (3) 4-     Groupe Projets Cliniques Pilotes (mesure 5) Pilote : Aviesan A) déficience intellectuelle,TFrebourg/H. Dollfus Financement : MASS Objectif : Q4 2016: Protocole, financement, sélection des sites, mise en œuvre du projet B) Projet pilote cancer du côlon et sarcomes, C. Chomiène (ITMO Cancer) Financement : plan cancer Objectif  Q4 2016: suivre la mise en œuvre des projets, indicateur Q4 à préciser C) diabète, C Boitard (ITMO PMN) Financement : MESR, MASS Objectifs : étude de faisabilité du projet en 2016 Génétique population générale », E. Genin  Financement : MESR Objectif : Objectif : mise en œuvre du projet

28. Organisation du comop (4) 5-     Groupe Projet filière industrielle (mesures 9 et 10) : Pilote : P Tambourin Financement : MESR, PIAVE Objectif : en lien avec le CRefIX, construire un modèle économique au niveau des maillons industriels 6-     Groupe : Intégration système de soins, Réglementation, Ethique Pilote : A. Cambon- DGS, Membres CNAMTS Objectifs 2016 à préciser

29. Calendrier COMOP: chaque mois à partir de septembre Comité de suivi: une fois par trimestre, prochain en novembre 2016 Comité de pilotage interministériel: décembre 2016 Une zone de partage de données sera prochainement mise en place