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