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Rare Diseases Clinical Research Network



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  • 1. Rare Diseases Clinical Research Network Progress Report National Advisory Research Resources Council September 21, 2006 Ronald J. Sokol, M.D. Chair, Steering Committee, RDCRN
  • 2. Background
    • The Problem:
    • ~ 25 million people in the United States are affected by one of approximately 6000 rare diseases:
      • <200,000 individuals affected in the U.S. - or -
      • for which no reasonable hope of new industry-sponsored drug development can be expected
    • Rare Diseases Clinical Research Network (RDCRN):
    • Established in 2003 - 5 year period
    • Four Rare Disease Consortia  Ten by 2004
    • One Data and Technology Coordinating Center
    • Each Consortia: multiple diseases / investigators / sites
  • 3. Mission of the RDCRN
    • To develop improved diagnostic methods & treatments for rare diseases by facilitating translational research and collaboration between investigators, patient support groups, and the NIH
    • To utilize translational research to improve the lives of individuals affected by rare diseases
    • To develop innovative, scalable techniques for conducting clinical research in rare diseases
  • 4. Goals of RDCRN
    • Develop innovative tools to collect and manage geographically distributed clinical research data using standardized data elements
    • Conduct clinical-translational research on multiple rare diseases including:
    • Longitudinal studies, Diagnostics, and Therapeutic trials
    • Provide training in clinical research on rare diseases
    • Improve (Web) access to information about rare diseases; involvement of PAGs
  • 5. Configuration of the Network
  • 6. 10 Rare Disease Consortia
    • Angelman, Rett, & Prader-Willi Syndromes ARPWSC Beaudet
    • Bone Marrow Failure Disease BMFDC Maciejewski
    • Cholestatic Liver Disease CLiC Sokol
    • Clinical Investigations of Neurological Channelopathies CINCH Griggs
    • Genetic Disorders of Mucociliary Clearance GDMCC Knowles
  • 7. 10 Rare Disease Consortia
    • Rare Genetic Steroid Diseases RGSDC New
    • Rare Lung Diseases RLDC Trapnell
    • Rare Thrombotic Diseases RTDC Ortel
    • Urea Cycle Disorders UCDC Batshaw
    • Vasculitis Clinical Research VCRC Merkel
    • Data and Technology Coordinating Center DTCC Krischer
    • Steering Committee PIs, NIH, PAG
  • 9. Geographic Distribution - Clinical Sites Toronto, Canada Paris, France Edinburgh, UK Cambridge, UK Groningen, Netherlands Tokyo Japan Melbourne, Australia Sao Paulo, Brazil Lyon, France Quebec Canada Bad Bramstedt, Germany London 55 Medical institutions 32 GCRCs
  • 10. 34 Patient Advocacy Groups
    • Alpha-1 Fdn
    • Alagille Syndrome Alliance
    • American Liver Fdn
    • Androgen Insensitivity Support Group
    • Angelman Syndrome Fdn
    • Aplastic Anemia and MDS International Fdn
    • CARES Fdn
    • Churg-Strauss Syndrome Assn
    • Children’s Liver Assn for Support Services
    • Children’s Liver Disease Fdn
    • CSS Patient Group
    • Cystic Fibrosis Fdn
    • Genetic Alliance
    • International Rett Syndrome Assn
    • LAM Fdn
    • Magic Foundation
    • Muscular Dystrophy Assn
    • National Adrenal Diseases Fdn
    • National Ataxia Fdn
    • National Organization for Rare Diseases
    • National Urea Cycle Disorders Fdn
    • Pediatric Interstitial Lung Disease Family Network Fdn
    • Periodic Paralysis Assn
    • Platelet Disorder Support Assn
    • PNH Support Group
    • Polyarteritis Nodosa Support Group
    • Prader-Willi Syndrome Assn (USA)
    • Primary Ciliary Dyskinesia Fdn
    • Pulmonary Alveolar Proteinosis Fdn
    • Pulmonary Fibrosis Fdn
    • Takayasu's Arteritis Research Assn
    • The Angelman Syndrome Fdn
    • United Mitochondrial Disease Fdn
    • Wegener's Granulomatosis Assn
  • 11. Integrated Network NIH ORD, NCRR, NIAMS, NICHD, NHLBI, NIDDK, NINDS Data and Technology Coordinating Center Media Library Researchers Doctors Educators Patient Community Pharmaceutical Companies RDC Center Registries Contact Registry Clinical Research Data Bank Clinical Data Standardization Groups Patients Public Website Site Site Site RDC Center Site Site Site Site Site Site RDC Center CPAG Support Groups DSMB SAB
  • 12. Progress and Accomplishments
  • 13. Rare Diseases Under Study n=45
    • Alagille Syndrome
    • Alpha-1 Antitrypsin Deficiency
    • Amegakaryocytic Thrombocytopenic Purpura
    • Andersen-Tawil Syndrome
    • Androgen Receptor Defects
    • Angelman's Syndrome
    • Antiphospholipid Antibody Syndromes
    • Aplastic Anemia
    • Apparent Mineralocorticoid Excess
    • Arginase Deficiency
    • Argininosuccinate Lyase Deficiency
    • Argininosuccinate Synthetase Deficiency
    • Autoimmune Neutropenia
    • Bile Acid Synthesis Disorders
    • Carbamyl Phosphate Synthetase Deficiency
    • Catastrophic Antiphospholipid Ab Syndrome
    • Churg-Strauss Syndrome
    • Citrin Deficiency
    • Congenital Adrenal Hyperplasia
    • Cystic Fibrosis
    • Episodic Ataxias
    • Giant Cell Arteritis
    • Heparin-induced Thrombocytopenia
  • 14. Rare Diseases Under Study (cont.)
    • Hereditary Interstitial Lung Disease
    • Large Granular Lymphocyte Leukemia
    • Lymphangioleiomyomatosis
    • Microscopic Polyangiitis
    • Mitochondrial Hepatopathies
    • Myelodysplastic Syndromes
    • N-Acetylglutamate Synthase Deficiency
    • Non-dystrophic Myotonic Disorders
    • Ornithine Transcarbamylase Deficiency
    • Ornithine Translocase Deficiency Syndrome
    • Paroxysmal Nocturnal Hemoglobinuria
    • Polyarteritis Nodosa
    • Prader-Willi Syndrome
    • Primary Ciliary Dyskinesia
    • Progressive Familial Intrahepatic Cholestasis
    • Pseudohypoaldosteronism
    • Pulmonary Alveolar Proteinosis
    • Pure Red Cell Aplasia
    • Rett Syndrome
    • Takayasu's Arteritis
    • Thrombotic Thrombocytopenic Purpura
    • Wegener’s Granulomatosis
  • 15. National Standards
    • Use of standardized terminology/ vocabulary (e.g., SNOMED)
    • Incorporated into protocols, data collection forms and CRFs, database, adverse event reporting, etc.
    • Innovative data collection techniques
      • cell phone call-in and reports by participants that populate database for CINCH
  • 16. Standardization of Protocol Development and Implementation
    • Standardized Protocol and Consent Formats
    • Standardized Checklist for submission for approval from DTCC, PRC and DSMB
    • Manual of Operations template
    • Protocol Monitoring Plan
    • Electronic AE and SAE reporting and review
  • 17. New Review Process for Protocols
    • Protocol Review Committees (PRCs) and Data Safety Monitoring Boards
    • Consortium and disease-specific expertise
    • New Charters and Procedure documents
    • Efficient process that should be conducive to more rapid implementation
    • Six PRCs
    • Three DSMBs
  • 18. Data and Technology Coordinating Center RARE DISEASES CLINICAL RESEARCH NETWORK DSMBs Rare Genetic Steroid Disorders Consortium Consortium for Clinical Investigation of Neurological Channelopathies Angelman, Rett, and Prader-Willi Syndromes Consortium Urea Cycle Disorders Consortium Cholestatic Liver Disease Consortium Genetic Diseases of Mucociliary Clearance Consortium Rare Lung Disease Consortium Rare Thrombotic Diseases Consortium Vasculitis Clinical Research Consortium Bone Marrow Failure Disease Consortium = NCRR DSMB 1 = NCRR DSMB 2 = NIDDK DSMB Green Yellow Orange
  • 19. News Coverage of Rare Disease Clinical Research Network Launch Expansive Effort Is Begun to Study Rare Diseases The National Institutes of Health has started the first of what will eventually be about 50 clinical studies looking into a variety of rare diseases and disorders. The research involves 10 research consortia studying groups of related rare, and sometimes fatal, diseases that can develop shortly after birth. In most cases, the diseases -- which range from rare blood, liver and lung disorders to a condition that causes temporary paralysis -- lack effective treatments. The NIH is putting $71 million toward the effort over a five-year period.
  • 20. Studies Open and Enrolling
    • Enrolling since Jan., 2006
    • 25 approved protocols
    • 20 enrolling patients – assistance of PAGs
    • 21 studies under development or current review by the PRCs or DSMBs, including:
        • Novel therapeutic trials
        • Longitudinal studies
        • Diagnostic studies
        • Demonstration Projects
  • 21. Current Participant Accruals
  • 22. Tracking of Protocol Enrollment
  • 23. Interactive Website
    • Developed by DTCC – Jeff Krischer, PhD
    • Accessible and easily navigated
    • Provides information about each consortium and each disease
      • for public
      • for caregivers and scientists
    • Media Digital Libraries (e.g., lectures, histology)
    • Links to useful websites and PAG organizations
    • Contact Registry
  • 24.  
  • 25.  
  • 26.  
  • 27. Contact Registry 2588 registrants - 68% email, 16% mail, 15% phone
  • 28. New Diagnostic Capabilities
    • CETT Program and CLiC
      • Need for clinical verification of research genetic testing in CLIA approved laboratory
      • No clinical testing available for PFIC diseases
      • Dr. Lee Jun Wong at Baylor, Houston – CETT funding (ORD, NIDDK) to set up MDR3 , FIC1 and BSEP genotyping
      • Available for CLiC patients (insurance will be charged) and for non-research patients
  • 29. Fellowship Training
    • 35 current or former trainees
    • Local training
    • Network activities
      • Evening poster session and keynote speaker for trainees – April, 2007
      • Invite Trainees to SC meeting next day – scientific presentations by Consortia
      • Day-long, academic skills workshop for research in rare diseases – Sept., 2007
        • R13 application
  • 30. Network Pilot Awards
    • New program – 2006-2007
    • ORD - $600,000 funds for six pilots – diagnostics or treatment
    • Application procedure developed
    • Each Consortium could submit one application
    • Steering Committee review – awarding decision
    • Five awarded
      • e.g., Biomarker study in Urea Cycle Consortium, New molecular techniques for genetic evaluation in ciliary disorders of lung
  • 31. New Grants and Funding Sources
    • Consortia have obtained additional funding to support activities:
      • Alpha One Foundation
        • Supports fellow in Rare Lung Disease C.
        • Supports enrollment site in CLiC
      • National Urea Cycles Disorders Foundation
        • Supporting clinical trial in Urea Cycle C.
      • R01 and R03 support
      • Use of GCRCs
  • 32. Thank You
    • Consortia investigators and study coordinators
    • DTCC – Jeff Krischer and colleagues
    • Patient Advocacy Groups
    • Participants and their families
    • Foundations and Industry partners