IRDiRC: State of the Art. By Paul Lasko, PhD


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I will discuss the formation and subsequent growth of IRDiRC into an organization with nearly 40 public and private funder members who have collectively pledged over 1 billion euros for rare disease research. I will also present the goals of IRDiRC, the plan that has been developed to achieve them, and the progress that has been made thus far. Finally, I will explore how additional organizations can take part in this international collaborative effort

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IRDiRC: State of the Art. By Paul Lasko, PhD

  1. 1. IRDiRC: State of the Art Paul Lasko, PhD Canadian Institutes of Health Research Chair, IRDiRC Executive Committee 1
  2. 2. Rare disease research in 2010  Large-scale global effort but there is substantial fragmentation.  Huge variations among different countries as to availability of diagnostics and therapeutics.  Breakthrough in genomic sequencing technology that greatly lowers cost and makes feasible diagnostic exome sequencing.
  3. 3. Improved international collaboration and coordination could better facilitate research and could reduce inequities for patients.
  4. 4. International Rare Disease Research Consortium (IRDiRC) Cooperation at international level to stimulate, better coordinate and maximize output of rare disease research efforts around the world 4
  5. 5. IRDiRC – basic principles  Co-operation at international level to stimulate, better coordinate & maximise output of rare disease research efforts around the world  Teams up public and private organisations investing in rare diseases research  Research funders with relevant programmes >$10 million US over a 5-year period can join & work together  Each organisation funds research its own way  Funded projects adhere to a common framework 5
  6. 6. Goals of IRDiRC by 2020 200 new therapies for rare diseases Means to diagnose most rare diseases 6
  7. 7. Current status of research in the field of rare diseases based on Orphanet data 7
  8. 8. 5707 ongoing research projects, covering 2129 diseases, excluding clinical trials European rare diseases research landscape (36 countries) (February 2014) 513 Gene search 595 Mutations search 281 Gene expression profile 393 Genotype-phenotype correlation 1048 In vitro functional study 509 Animal model creation / study 748 Human physiopathology study 179 Pre-clinical gene therapy 90 Pre-clinical cell therapy 31 Pre-clinical vaccine development 452 Observational clinical study 224 Epidemiological study 295 Diagnostic tool / protocol development 158 Biomarker development 25 Medical device / instrumentation development 79 Health sociology study 15 Health economics study 72 Public health / health services study 8
  9. 9. Possibility to diagnose Rare Diseases: over 2 362 genes tested to date Number of genes tested by country Number of rare diseases tested by country (April 2014) 9
  10. 10. Number of genes tested in each country in Europe by year 2010 2011 2012 2013
  11. 11. Medicinal products on the European market in 2013 67 orphan medicinal products 92 medicinal products without orphan designation with at least an indication for a rare disease or a group of rare disease (January 2014)
  12. 12. Percentage of clinical trials by category International rare diseases clinical trial landscape  2476 ongoing national or international clinical trials for 629 diseases in 29 countries (April 2014) 12 1% 78% 1% 2% 16% 1% 1% cell therapy clinical trial drug clinical trial gene therapy clinical trial medical device clinical trial protocol clinical trial vaccine clinical trial other trial
  13. 13. IRDiRC—ambitious goals (diagnostic tools for all rare diseases, 200 new therapies by 2020)
  14. 14. Growth of IRDiRC  Third coordination meeting was held in Montreal (9-10 Oct 2011), sponsored by IG and Genome Canada.  Initially involved EU, NIH, Canada, Italy, Spain.  Funder members commit a minimum of USD 10M to rare disease research over a 5-yr period.  Present commitment exceeds $1B worldwide.  Formally launched in 2012, first public symposium held in Dublin in April 2013.  Second public symposium planned for Shenzhen, China, November 7-9, 2014.
  15. 15. Instruments to reach the goals  Increase research volume  Boost cooperation between researchers  Speed up R&D 15
  16. 16. While the pace of gene discovery based on whole exome sequencing is increasing… …it will need to triple for IRDiRC’s 2020 goal to be met! Boycott et al. (2013) Nature Reviews of Genetics
  17. 17. Boycott et al. (2013) Nature Reviews of Genetics (EMA approvals) The rate of approvals for new orphan therapeutics is not yet increasing
  18. 18. Boycott et al. (2013) Nature Reviews of Genetics Many different technologies show promise for orphan disease treatment
  19. 19. Principles applying to research activities 19 Sharing and collaborative work in RD research  Sharing of data and resources  Rapid release of data  Interoperability and harmonization of data  Data in open access databases Scientific standards, requirements and regulations in RD research  Projects should adhere to IRDiRC standards  Develop ontologies and biomarkers  Cite use of databases and biobanks in publications
  20. 20. Principles applying to research activities 20 Participation by patients and / or their representatives in research  Act in the best interest of patients  Involve patients in all aspects of research  Involve patients in governance of registries  Involve patients in the design, conduct and analysis of clinical trials  Acknowledge patients’ contribution in articles
  21. 21. Principles applying to Funding Bodies 21  Promote the discovery of genes  Promote the development of therapies  Fund pre-clinical studies for proof of concept  Promote harmonization, interoperability, sharing, open access to data  Promote coordination between human and animal models  Promote active exchanges between stakeholders through dissemination of ongoing projects and events
  22. 22. Indicators of output 22  Research activity No. of IRDiRC members / allocated budget  For diagnostics No. of new causative genes discovered / No. of clinical tests of diagnostics/ No. of diseases with available test / by country and by region  For therapeutics No. of designations / No. of clinical trials / Attrition rate / No. of diseases covered/ Type of products No. of disease registries / sources of clinical data
  23. 23. • Australia – Western Australian Department of Health • Canada – Canadian Institutes for Health Research – Genome Canada • China – Beijing Genomics Institute – Chinese Rare Disease Research Consortium • EU – European Commission • Finland – Academy of Finland • France – French Association against Myopathies – Agence National de la Recherche – Lysogene • Georgia – Children’s New Hospital Management Group • Germany – Federal Ministry of Education and Research • Italy – Italian Higher Institute of Health – Telethon Foundation • International Consortium – E-RARE 2 Consortium • Netherlands – The Netherlands Organization for Health Research and Development – Prosensa • Republic of Korea – Korean National Institute of Health • Spain – National Institute of Health Carlos III • UK – National Institute for Health Research • USA – Food and Drug Administration Orphan Products Grants Program – Isis Therapeutics – National Human Genome Research Institute (NIH) – National Center for Advancing Translational Sciences (NIH) – National Cancer Institute (NIH) – National Eye Institute (NIH) – National Institute of Neurological Disorders and Stroke (NIH) – National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH) – National Institute of Child Health and Human Development (NIH) – NKT Therapeutics – Office of Rare Diseases (NIH) – PTC Therapeutics – Sanford Research Institute • International Pharma Companies – Genzyme (Sanofi) – Shire Present list of IRDiRC funder members
  24. 24. New members wanted  Members can be public or private sector entities, profit or non-profit organizations.  Members must pledge a minimum of USD 10 million for rare disease research over the next five years. This money is not given to IRDiRC but is spent on internal programs.  Members must agree to follow IRDiRC policies and guidelines (available on  Every member has one seat on the Executive Committee and can nominate one member to one Scientific Committee or Working Group.
  25. 25. Governance structure 25 25
  26. 26. Executive Committee: FUNDING AGENCIES 26 Paul Lasko (chair of IRDiRC) •Canadian Institutes for Health Research •Canada Christopher Austin •National Center for Advancing Translational Sciences (NIH) •USA Pedro Cortegoso Fernández •National Institute of Health Carlos III •Spain Hugh Dawkins •Western Australian Department of Health •Australia Ruxandra Draghia-Akli •European Commission •Europe Stephen Katz •National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH) •USA Enrico Garaci •Istituto Superiore de Sanita •Italy Nicolas Lévy •French Foundation for Rare Diseases •France Pamela McInnes •Office of Rare Diseases (NIH) •USA Pierre Meulien •Genome Canada •Canada Lucia Monaco •Telethon Foundation •Italy Katherine Needleman •Office of Orphan Products Development (FDA) •USA
  27. 27. Executive Committee: FUNDING AGENCIES 27 Marie-Christine Ouillade •French Muscular Dystrophy Association •France Willem Ouwehand •National Institute for Health Research •UK Melissa Parisi •National Institute of Child Health and Human Development (NIH) •USA Hyun-Young Park •Korea National Institute of Health •Korea Jeffery Schloss •National Human Genome Research Institute (NIH) •USA Ralph Schuster •Federal Ministry of Education and Research •Germany Bertrand Schwartz •Agence Nationale de la Recherche •France Danilo Tagle •National Institute of Neurological Disorders and Stroke (NIH) •USA Edward Trimble •National Cancer Institute (NIH) •USA Santa Tumminia •National Eye Institute (NIH) •USA Sonja van Weely •The Netherlands Organisation for Health Research and Development •Netherlands Heikki Vilen •Academy of Finland •Finland
  28. 28. Executive Committee 28 INDUSTRY Karen Aiach •Lysogene •France Luc Dochez •Prosensa •Netherlands Diane Goetz •PTC Therapeutics •USA Carlo Incerti •Genzyme •USA Robert Mashal •NKT Therapeutics •USA Brett Monia •Isis Pharmaceuticals •USA Philip Vickers •Shire •USA Béatrice de Montleau •European Organisation for Rare Diseases (EURORDIS) •Europe Peter Saltonstall •National Organization for Rare Disorders (NORD) •USA Sharon Terry •Genetic Alliance •USA PATIENT ORGANISATIONS
  29. 29. Executive Committee 29 Ning Li •Beijing Genomics Institute (BGI) •China David Pearce •Sanford Research •USA Qing K Wang • Chinese Rare Disease Consortium • China Oleg Kvlividze •Children’s New Hospitals Management Group •Georgia Daria Julkowska •E-RARE 2 Consortium •Europe RESEARCH INSTITUTES CONSORTIUM OF RESEARCH INSTITUTES HOSPITALS CONSORTIUM OF FUNDING BODIES
  30. 30. Diagnostics Scientific Committee (DSC) 30 Kym Boycott (chair) •Children's Hospital Eastern Ontario •Canada Han Brunner •Nijmegen University Hospital •Netherlands Michael Bamshad •Seattle Children's Hospital •USA Johan Den Dunnen •Center for Human and Clinical Genetics •Netherlands Xavier Estivill •Genomic Regulation Centre •Spain Milan Macek •Charles University Prague •Czech Republic Gert Matthijs •University Hospital Leuven •Belgium Woong-Yang Park •Samsung Genome Institute •Korea Peter Propping •University of Bonn •Germany Pak-Chung Sham •Chinese Rare Disease Research Consortium •China Jun Wang •BGI •China
  31. 31. Interdisciplinary Scientific Committee (ISC) 31 Hanns Lochmüller (chair) •University Newcastle upon Tyne •UK Jamel Chelly •National Institute of Health and Medical Research •France Angel Carracedo •University of Santiago de Compostela •Spain Jack Goldblatt •Genetic Services and the Familial Cancer Program of Western Australia Petra Kaufmann •National Institute of Neurological Disorders and Stroke •USA Alastair Kent •Genetic Alliance •UK Jeffrey Krischer •University of South Florida •USA Bartha Maria Knoppers •McGill University •Canada Samantha Parker •Orphan Europe Recordati Group •France Rumen Stefanov •Medical University of Plovdiv •Bulgaria Domenica Taruscio •Italian National Centre for Rare Diseases •Italy
  32. 32. Therapies Scientific Committee (TSC) Yann Le Cam (chair) •EURORDIS (France) Gert-Jan Van Ommen •Leiden University Medical Centre (Netherlands) Giles Campion •Prosensa Therapeutics (Netherlands) Seng Cheng •Rare Diseases Science Genzyme Corporation (USA) Adam Heathfield •Pfizer (UK) Maria Mavris •EURORDIS (France) Fulvio Mavilio •Genethon (France) John McKew •NIH (USA) Elizabeth McNeil •NIH (USA) Luigi Naldini •Telethon Institute (Italy) Glen Nuckolls •NIH (USA) Asla Pitkänen •University of Eastern Finland (Finland) Karin Rademaker •University Medical Centre (Netherlands) Robert Schaub •NKT Therapeutics (USA) Josep Torrent i Farnell •Spanish Medicines Agency (Spain) Marc Walton • FDA (USA) Ellen Welsh •PTC Therapeutics (USA) Anne Zajicek •NICHD (USA)
  33. 33. IRDiRC Scientific Secretariat  In place at Inserm US14, at the Rare Disease Platform, Paris, France  FP7 contract for 6 years since October 2012: « Support IRDiRC »  Management of the network / assistance to Executive Committee, Scientific Committees and Working Groups  Management of the website: 33
  34. 34. 34
  35. 35. The Canadian FORGE project An example of a successful national rare disease research consortium, proving that collaboration produces results
  36. 36. 36
  37. 37. Kym Boycott, PhD, MD, FRCPC, FCCMG Clinical Geneticist, Department of Genetics Investigator, Children’s Hospital of Eastern Ontario Research Institute Associate Professor, Department of Pediatrics, University of Ottawa 1 Gene per Week Translating Discoveries to the Care of Patients with Rare Diseases
  38. 38. FORGE Canada Consortium  Objectives  Rapidly identify genes for rare pediatric single- gene disorders  2 years  April 2011 to March 2013  Total funding level ~$5M  Establish a sustainable national consortium focused on rare disorders
  39. 39. FORGE Clinical Network Dr. Gudrun Aubertin Dr. Jan Friedman Dr. Francois Bernier Dr. Ordan Lehman Dr. Bridget Fernandez Dr. Sarah Dyack Dr. Edmond Lemire Dr. Albert Chudley Dr. Victoria Siu Dr. Malgorzata Novaczyk Dr. Linda Kim Dr. Peter Kannu Dr. David Chitayat Dr. Rosanna Weksberg Dr. Marjan Nezarati Dr. Kym Boycott Dr. Sandra Farrell Dr. Jacques Michaud Dr. Sebastian Levesque Dr. Régen Drouin Dr. Bruno Maranda Toronto Montreal 21 Sites 80 Physicians 50 Scientists FORGE Clinical Network
  40. 40. Map of International Collaborators
  41. 41. One Gene per Week 110 disorders solved April 2011 – March 2013 184 Disorders 60% solved 45% novel 5% mechanism 50% diagnosis 40% unsolved 1/3 no plausible variants 2/3 too many variants
  42. 42. The rule of 1/3  1/3 novel genes  1/3 diagnosis in known disease gene Atypical phenotypes Conflation of 2 diseases New mechanisms  1/3 need more work
  44. 44. Workshop on Terminologies for RD – Paris, 12 September 2012  Many terminologies in use to describe phenomes - No interoperability  Joint EuroGenTest and EUCERD workshop  Organized by Ségolène Aymé  Agreement to define a core set of terms common to all terminologies and a methodology  Core set identified by cross referencing  HPO  PhenoDB  Orphanet  UMLS: MeSH, MedDRA, SnoMed CT  LDDB  Elements of morphology 44 Adoption of a core set of >2,300 terms common to all terminologies Workshop of validation, Boston 21-22 October 2013  Workshop supported by HVP and EuroGenTest  Organized by Ada Hamosh  Expert review of the initial proposal  Selection of 2,370 terms  Decision to propose them for adoption by all terminologies  Establishment of the International Consortium for Human Phenotype Terminologies – ICHPT  Publication on the IRDiRC website with definitions from  HPO  Elements of morphology
  45. 45. Standardization of Phenotype Ontologies Workshop SYMPATHI, 19 Apr 2013, Dublin Organized by IRDiRC, supported by the University of Dublin, FORGE and EuroGenTest Conclusion: Adopt HPO & ORDO & cross-reference with OMIM
  46. 46.  PhenoTips and PhenomeCentral  Repository of data  Hub for data sharing  CareforRare, RDConnect  NIH undiagnosed patients 46 Adoption of a core set of >2,300 terms common to all terminologies  ClinVar and ICCG  Public archive of variants and assertions about significance  NCBI resource  Decipher Database of Chromosome imbalances and phenotypes  Using Ensembl resources  Sanger Institute  Wellcome Trust
  47. 47. Fruit trees and genes… Levels of complexity
  48. 48. Matchmaker Workshop API – Application Programming Interface Boston October 2013
  49. 49. Genome-Phenome Matchmaker Two WGs to look at: 1)levels of data sharing 2)API to connect discoverable data – operational fall 2014 – Matchmaker 1.0 Matchmaker Pro – 2015-2016 A list of databases to use for data deposition and that can be connected by Matchmaker needs to be developed and made available on the IRDiRC website – mid 2014
  50. 50. Thank you! 51