Rare Diseases Clinical Research Network

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

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

8. Geographic Distribution - Centers

9. Geographic Distribution - Clinical Sites

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 DiseaseFamily 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

12. Progress and Accomplishments

13. Rare Diseases Under Studyn=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

19. News Coverage of Rare Disease Clinical Research Network Launch

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

27. Contact Registry

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 NCRR, ORD, NHLDI, NICHD, NIDDK, NIAMS, NINDS Patient Advocacy Groups Participants and their families Foundations and Industry partners