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

1. IRDiRC: State of the Art
Paul Lasko, PhD
Canadian Institutes of Health Research
Chair, IRDiRC Executive Committee
1

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. Improved international collaboration
and coordination could better facilitate
research and could reduce inequities
for patients.

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. 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. Goals of IRDiRC by 2020
200 new therapies
for rare diseases
Means to diagnose
most rare diseases
6

7. Current status of research
in the field of rare diseases
based on Orphanet data
7

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. 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. Number of genes tested in each
country in Europe by year
2010 2011
2012
2013

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. 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. IRDiRC—ambitious goals (diagnostic tools for
all rare diseases, 200 new therapies by 2020)

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. Instruments to reach the goals
 Increase research volume
 Boost cooperation between researchers
 Speed up R&D
15

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. Boycott et al. (2013)
Nature Reviews of Genetics
(EMA approvals)
The rate of approvals for new orphan therapeutics is not yet increasing

18. Boycott et al. (2013)
Nature Reviews of Genetics
Many different technologies show promise for orphan disease treatment

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. 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. 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. 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. • 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. 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 www.irdirc.org).
 Every member has one seat on the Executive Committee
and can nominate one member to one Scientific
Committee or Working Group.

25. Governance structure
25
25

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. 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. 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. 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. 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. 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. 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. 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: http://www.irdirc.org/
33

34. 34

35. The Canadian FORGE project
An example of a successful national
rare disease research consortium,
proving that collaboration produces
results

36. 36

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. 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. 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. Map of International Collaborators

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. 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

43. 2014 ACTION PLAN: ADOPT AND PROMOTE
STANDARDS FOR INTEROPERABILITY / DATA
SHARING
43

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. 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.  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. Fruit trees and genes…
Levels of complexity

49. Matchmaker Workshop
API – Application Programming Interface
Boston
October 2013

50. 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

51. Thank you!
51