Download - Rare Diseases Clinical Research Network
Rare Diseases Rare Diseases Clinical Research NetworkClinical Research Network
Progress Report Progress Report National Advisory Research Resources CouncilNational Advisory Research Resources Council
September 21, 2006September 21, 2006
Ronald J. Sokol, M.D.Ronald J. Sokol, M.D.Chair, Steering Committee, RDCRNChair, Steering Committee, RDCRN
BackgroundBackgroundThe Problem:The Problem:• ~ 25 million people in the United States are affected by ~ 25 million people in the United States are affected by
one of approximately 6000 rare diseases:one of approximately 6000 rare diseases:
• <200,000 individuals affected in the U.S. - or -<200,000 individuals affected in the U.S. - or -
• for which no reasonable hope of new industry-for which no reasonable hope of new industry-
sponsored drug development can be expectedsponsored drug development can be expected
Rare Diseases Clinical Research Network Rare Diseases Clinical Research Network
(RDCRN):(RDCRN):• Established in 2003 - 5 year periodEstablished in 2003 - 5 year period
• Four Rare Disease Consortia Four Rare Disease Consortia TenTen by 2004 by 2004
• One Data and Technology Coordinating CenterOne Data and Technology Coordinating Center
• Each Consortia: multiple diseases / investigators / sitesEach Consortia: multiple diseases / investigators / sites
Mission of the RDCRNMission of the RDCRN
• To develop improved diagnostic methods & To develop improved diagnostic methods & treatments for rare diseases by facilitating treatments for rare diseases by facilitating translational research and collaboration between translational research and collaboration between investigators, patient support groups, and the investigators, patient support groups, and the NIH NIH
• To utilize translational research to improve the To utilize translational research to improve the lives of individuals affected by rare diseaseslives of individuals affected by rare diseases
• To develop innovative, scalable techniques for To develop innovative, scalable techniques for conducting clinical research in rare diseasesconducting clinical research in rare diseases
Goals of RDCRNGoals of RDCRN
• Develop innovative tools to collect and manage Develop innovative tools to collect and manage geographically distributed clinical research data geographically distributed clinical research data using standardized data elementsusing standardized data elements
• Conduct clinical-translational research on Conduct clinical-translational research on multiple rare diseases including:multiple rare diseases including:
Longitudinal studies, Diagnostics, and Longitudinal studies, Diagnostics, and Therapeutic trials Therapeutic trials
• Provide training in clinical research on rare Provide training in clinical research on rare diseasesdiseases
• Improve (Web) access to information about rare Improve (Web) access to information about rare diseases; involvement of PAGsdiseases; involvement of PAGs
Configuration of the Configuration of the NetworkNetwork
10 Rare Disease Consortia10 Rare Disease Consortia
• Angelman, Rett, & Prader-Willi SyndromesAngelman, Rett, & Prader-Willi Syndromes
ARPWSC ARPWSC BeaudetBeaudet
• Bone Marrow Failure DiseaseBone Marrow Failure Disease BMFDC BMFDC
MaciejewskiMaciejewski
• Cholestatic Liver DiseaseCholestatic Liver Disease CLiC CLiC SokolSokol
• Clinical Investigations of Neurological Clinical Investigations of Neurological
ChannelopathiesChannelopathies CINCH CINCH GriggsGriggs
• Genetic Disorders of Mucociliary ClearanceGenetic Disorders of Mucociliary Clearance
GDMCC GDMCC KnowlesKnowles
10 Rare Disease Consortia10 Rare Disease Consortia
• Rare Genetic Steroid DiseasesRare Genetic Steroid Diseases RGSDC RGSDC NewNew
• Rare Lung DiseasesRare Lung Diseases RLDC RLDC TrapnellTrapnell
• Rare Thrombotic DiseasesRare Thrombotic Diseases RTDC RTDC OrtelOrtel
• Urea Cycle DisordersUrea Cycle Disorders UCDC UCDC BatshawBatshaw
• Vasculitis Clinical ResearchVasculitis Clinical Research VCRC VCRC MerkelMerkel
• Data and Technology Coordinating CenterData and Technology Coordinating Center
DTCC DTCC
KrischerKrischer• Steering CommitteeSteering Committee PIs, NIH, PAGPIs, NIH, PAG
Geographic Distribution - CentersGeographic Distribution - Centers
CLiCCLiC
RLDCRLDC
ARPWCARPWC
GDMCCGDMCC
UCDCUCDC
VCRCVCRC
BMFDCBMFDC
CINCHCINCH
RGSDCRGSDC
RTDCRTDC
NIHNIH
DTCCDTCC
Geographic Distribution - Clinical SitesGeographic Distribution - Clinical Sites
Toronto,Toronto,CanadaCanada
Paris, Paris, FranceFrance
Edinburgh, Edinburgh, UKUK
Cambridge,Cambridge,UKUKGroningen, Groningen,
NetherlandsNetherlands
TokyoTokyoJapanJapan
Melbourne,Melbourne,AustraliaAustralia
Sao Paulo,Sao Paulo,BrazilBrazil
Lyon,Lyon,FranceFrance
QuebecQuebecCanadaCanada
Bad Bramstedt,Bad Bramstedt,GermanyGermany
LondonLondon
55 Medical institutions32 GCRCs
34 Patient Advocacy Groups34 Patient Advocacy Groups• Alpha-1 FdnAlpha-1 Fdn• Alagille Syndrome AllianceAlagille Syndrome Alliance• American Liver FdnAmerican Liver Fdn• Androgen Insensitivity Support Androgen Insensitivity Support
GroupGroup• Angelman Syndrome FdnAngelman Syndrome Fdn• Aplastic Anemia and MDS Aplastic Anemia and MDS
International Fdn International Fdn • CARES FdnCARES Fdn• Churg-Strauss Syndrome AssnChurg-Strauss Syndrome Assn• Children’s Liver Assn for Support Children’s Liver Assn for Support
ServicesServices• Children’s Liver Disease FdnChildren’s Liver Disease Fdn• CSS Patient GroupCSS Patient Group• Cystic Fibrosis FdnCystic Fibrosis Fdn• Genetic AllianceGenetic Alliance• International Rett Syndrome AssnInternational Rett Syndrome Assn• LAM Fdn LAM Fdn • Magic FoundationMagic Foundation• Muscular Dystrophy Assn Muscular Dystrophy Assn • National Adrenal Diseases FdnNational Adrenal Diseases Fdn
• National Ataxia FdnNational Ataxia Fdn• National Organization for Rare National Organization for Rare
DiseasesDiseases• National Urea Cycle Disorders FdnNational Urea Cycle Disorders Fdn• Pediatric Interstitial Lung DiseasePediatric Interstitial Lung Disease
Family Network FdnFamily Network Fdn• Periodic Paralysis AssnPeriodic Paralysis Assn• Platelet Disorder Support AssnPlatelet Disorder Support Assn• PNH Support GroupPNH Support Group• Polyarteritis Nodosa Support Polyarteritis Nodosa Support
GroupGroup• Prader-Willi Syndrome Assn (USA) Prader-Willi Syndrome Assn (USA) • Primary Ciliary Dyskinesia Fdn Primary Ciliary Dyskinesia Fdn • Pulmonary Alveolar Proteinosis Pulmonary Alveolar Proteinosis
FdnFdn• Pulmonary Fibrosis Fdn Pulmonary Fibrosis Fdn • Takayasu's Arteritis Research Takayasu's Arteritis Research
AssnAssn• The Angelman Syndrome FdnThe Angelman Syndrome Fdn• United Mitochondrial Disease FdnUnited Mitochondrial Disease Fdn• Wegener's Granulomatosis Assn Wegener's Granulomatosis Assn
Patients NIHORD, NCRR, NIAMS,
NICHD, NHLBI, NIDDK, NINDS
Data and TechnologyData and TechnologyCoordinating CenterCoordinating Center
MediaLibrary
Public WebsitePublic Website
ResearchersDoctors Educators
PatientCommunity
PharmaceuticalCompanies
Site
Site
Site
RDCCenter
Site
Site
Site
RDCCenter
Site
Site
Site
RDCCenter
Registries
CPAG
SupportGroups
Integrated NetworkIntegrated Network
ContactRegistry
Clinical ResearchData Bank
DSMB SAB
Clinical DataStandardization
Groups
Progress and Progress and
AccomplishmentsAccomplishments
Rare Diseases Under StudyRare Diseases Under Studyn=45n=45
Alagille SyndromeAlagille SyndromeAlpha-1 Antitrypsin Deficiency Alpha-1 Antitrypsin Deficiency Amegakaryocytic Amegakaryocytic
Thrombocytopenic PurpuraThrombocytopenic PurpuraAndersen-Tawil Syndrome Andersen-Tawil Syndrome Androgen Receptor Defects Androgen Receptor Defects Angelman's Syndrome Angelman's Syndrome Antiphospholipid Antibody Antiphospholipid Antibody
Syndromes Syndromes Aplastic Anemia Aplastic Anemia Apparent Mineralocorticoid Apparent Mineralocorticoid
ExcessExcessArginase DeficiencyArginase DeficiencyArgininosuccinate Lyase Argininosuccinate Lyase
Deficiency Deficiency
Argininosuccinate Synthetase Argininosuccinate Synthetase DeficiencyDeficiency
Autoimmune Neutropenia Autoimmune Neutropenia Bile Acid Synthesis DisordersBile Acid Synthesis DisordersCarbamyl Phosphate Synthetase Carbamyl Phosphate Synthetase
Deficiency Deficiency Catastrophic Antiphospholipid Ab Catastrophic Antiphospholipid Ab
Syndrome Syndrome Churg-Strauss SyndromeChurg-Strauss SyndromeCitrin DeficiencyCitrin DeficiencyCongenital Adrenal Hyperplasia Congenital Adrenal Hyperplasia Cystic Fibrosis Cystic Fibrosis Episodic Ataxias Episodic Ataxias Giant Cell ArteritisGiant Cell ArteritisHeparin-induced Heparin-induced
Thrombocytopenia Thrombocytopenia
Rare Diseases Under StudyRare Diseases Under Study(cont.)(cont.)
Hereditary Interstitial Lung Hereditary Interstitial Lung DiseaseDisease
Large Granular Lymphocyte Large Granular Lymphocyte Leukemia Leukemia
LymphangioleiomyomatosisLymphangioleiomyomatosis
Microscopic PolyangiitisMicroscopic Polyangiitis
Mitochondrial HepatopathiesMitochondrial Hepatopathies
Myelodysplastic Syndromes Myelodysplastic Syndromes
N-Acetylglutamate Synthase N-Acetylglutamate Synthase Deficiency Deficiency
Non-dystrophic Myotonic Non-dystrophic Myotonic Disorders Disorders
Ornithine Transcarbamylase Ornithine Transcarbamylase Deficiency Deficiency
Ornithine Translocase Deficiency Ornithine Translocase Deficiency Syndrome Syndrome
Paroxysmal Nocturnal Paroxysmal Nocturnal HemoglobinuriaHemoglobinuria
Polyarteritis NodosaPolyarteritis Nodosa
Prader-Willi Syndrome Prader-Willi Syndrome
Primary Ciliary DyskinesiaPrimary Ciliary Dyskinesia
Progressive Familial Intrahepatic Progressive Familial Intrahepatic CholestasisCholestasis
PseudohypoaldosteronismPseudohypoaldosteronism
Pulmonary Alveolar ProteinosisPulmonary Alveolar Proteinosis
Pure Red Cell AplasiaPure Red Cell Aplasia
Rett Syndrome Rett Syndrome
Takayasu's ArteritisTakayasu's Arteritis
Thrombotic Thrombocytopenic Thrombotic Thrombocytopenic PurpuraPurpura
Wegener’s Granulomatosis Wegener’s Granulomatosis
National StandardsNational Standards
• Use of standardized terminology/ vocabulary Use of standardized terminology/ vocabulary
(e.g., SNOMED)(e.g., SNOMED)
• Incorporated into protocols, data collection Incorporated into protocols, data collection
forms and CRFs, database, adverse event forms and CRFs, database, adverse event
reporting, etc.reporting, etc.
• Innovative data collection techniques Innovative data collection techniques
• cell phone call-in and reports by participants cell phone call-in and reports by participants
that populate database for CINCHthat populate database for CINCH
Standardization of Protocol Standardization of Protocol Development and ImplementationDevelopment and Implementation
• Standardized Protocol and Consent FormatsStandardized Protocol and Consent Formats
• Standardized Checklist for submission for Standardized Checklist for submission for
approval from DTCC, PRC and DSMBapproval from DTCC, PRC and DSMB
• Manual of Operations templateManual of Operations template
• Protocol Monitoring PlanProtocol Monitoring Plan
• Electronic AE and SAE reporting and reviewElectronic AE and SAE reporting and review
New Review Process for ProtocolsNew Review Process for Protocols
• Protocol Review Committees (PRCs) and Data Protocol Review Committees (PRCs) and Data Safety Monitoring BoardsSafety Monitoring Boards
• Consortium and disease-specific expertiseConsortium and disease-specific expertise
• New Charters and Procedure documentsNew Charters and Procedure documents
• Efficient process that should be conducive to Efficient process that should be conducive to more rapid implementationmore rapid implementation
• Six PRCsSix PRCs
• Three DSMBsThree DSMBs
Data and Data and Technology Technology
Coordinating Coordinating CenterCenter
RARE DISEASES CLINICAL RESEARCH NETWORK DSMBsRARE DISEASES CLINICAL RESEARCH NETWORK DSMBs
Rare Genetic Rare Genetic Steroid Disorders Steroid Disorders
ConsortiumConsortium
Consortium for Clinical Consortium for Clinical Investigation of Investigation of
Neurological Neurological ChannelopathiesChannelopathies
Angelman, Rett, and Angelman, Rett, and Prader-Willi Prader-Willi Syndromes Syndromes ConsortiumConsortium
Urea Cycle Urea Cycle Disorders Disorders
ConsortiumConsortium
Cholestatic Liver Cholestatic Liver Disease Disease
ConsortiumConsortium
Genetic Diseases Genetic Diseases of Mucociliary of Mucociliary
Clearance Clearance ConsortiumConsortium
Rare Lung Disease Rare Lung Disease ConsortiumConsortium
Rare Thrombotic Rare Thrombotic Diseases Diseases
ConsortiumConsortium
Vasculitis Clinical Vasculitis Clinical Research Research
ConsortiumConsortium
Bone Marrow Bone Marrow Failure Disease Failure Disease ConsortiumConsortium
= = NCRR DSMB 1NCRR DSMB 1 = NCRR DSMB 2= NCRR DSMB 2 = NIDDK DSMB= NIDDK DSMB
GreenGreenYellowYellowOrangeOrange
News Coverage of Rare Disease News Coverage of Rare Disease Clinical Research Network LaunchClinical 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.
Studies Open and EnrollingStudies Open and Enrolling
• Enrolling since Jan., 2006Enrolling since Jan., 2006
• 25 approved protocols25 approved protocols
20 enrolling patients – assistance of PAGs20 enrolling patients – assistance of PAGs
• 21 studies under development or current review 21 studies under development or current review by the PRCs or DSMBs, including:by the PRCs or DSMBs, including:
• Novel therapeutic trialsNovel therapeutic trials
• Longitudinal studiesLongitudinal studies
• Diagnostic studiesDiagnostic studies
• Demonstration ProjectsDemonstration Projects
Current Participant AccrualsCurrent Participant Accruals
Tracking of Protocol EnrollmentTracking of Protocol Enrollment
Interactive WebsiteInteractive Website
• Developed by DTCC – Jeff Krischer, PhD Developed by DTCC – Jeff Krischer, PhD
• Accessible and easily navigatedAccessible and easily navigated
• Provides information about each consortium and Provides information about each consortium and each diseaseeach disease
• for publicfor public
• for caregivers and scientistsfor caregivers and scientists
• Media Digital Libraries (e.g., lectures, histology)Media Digital Libraries (e.g., lectures, histology)
• Links to useful websites and PAG organizationsLinks to useful websites and PAG organizations
• Contact RegistryContact Registry
Contact RegistryContact Registry
2588 registrants - 2588 registrants - 68% email, 16% mail, 15% phone68% email, 16% mail, 15% phone
New Diagnostic CapabilitiesNew Diagnostic Capabilities
• CETT Program and CLiCCETT Program and CLiC
• Need for clinical verification of research Need for clinical verification of research genetic testing in CLIA approved laboratorygenetic testing in CLIA approved laboratory
• No clinical testing available for PFIC diseasesNo clinical testing available for PFIC diseases
• Dr. Lee Jun Wong at Baylor, Houston – CETT Dr. Lee Jun Wong at Baylor, Houston – CETT funding (ORD, NIDDK) to set up funding (ORD, NIDDK) to set up MDR3MDR3, , FIC1FIC1 and and BSEPBSEP genotyping genotyping
• Available for CLiC patients (insurance will be Available for CLiC patients (insurance will be charged) and for non-research patientscharged) and for non-research patients
Fellowship TrainingFellowship Training
• 35 current or former trainees35 current or former trainees
• Local trainingLocal training
• Network activitiesNetwork activities
• Evening poster session and keynote speaker Evening poster session and keynote speaker for trainees – April, 2007for trainees – April, 2007
• Invite Trainees to SC meeting next day – Invite Trainees to SC meeting next day – scientific presentations by Consortiascientific presentations by Consortia
• Day-long, academic skills workshop for Day-long, academic skills workshop for research in rare diseases – Sept., 2007research in rare diseases – Sept., 2007
• R13 applicationR13 application
Network Pilot AwardsNetwork Pilot Awards
• New program – 2006-2007New program – 2006-2007
• ORD - $600,000 funds for six pilots – diagnostics ORD - $600,000 funds for six pilots – diagnostics or treatmentor treatment
• Application procedure developedApplication procedure developed
• Each Consortium could submit one applicationEach Consortium could submit one application
• Steering Committee review – awarding decisionSteering Committee review – awarding decision
• Five awardedFive awarded
• e.g., Biomarker study in Urea Cycle e.g., Biomarker study in Urea Cycle Consortium, New molecular techniques for Consortium, New molecular techniques for genetic evaluation in ciliary disorders of lunggenetic evaluation in ciliary disorders of lung
New Grants and Funding SourcesNew Grants and Funding Sources
• Consortia have obtained additional funding to Consortia have obtained additional funding to support activities:support activities:
• Alpha One FoundationAlpha One Foundation
• Supports fellow in Rare Lung Disease C.Supports fellow in Rare Lung Disease C.
• Supports enrollment site in CLiCSupports enrollment site in CLiC
• National Urea Cycles Disorders FoundationNational Urea Cycles Disorders Foundation
• Supporting clinical trial in Urea Cycle C.Supporting clinical trial in Urea Cycle C.
• R01 and R03 supportR01 and R03 support
• Use of GCRCsUse of GCRCs
Thank YouThank You
• Consortia investigators and study Consortia investigators and study coordinatorscoordinators
• DTCC – Jeff Krischer and colleaguesDTCC – Jeff Krischer and colleagues
• NCRR, ORD, NHLDI, NICHD, NIDDK, NCRR, ORD, NHLDI, NICHD, NIDDK, NIAMS, NINDSNIAMS, NINDS
• Patient Advocacy GroupsPatient Advocacy Groups
• Participants and their familiesParticipants and their families
• Foundations and Industry partnersFoundations and Industry partners