# Presentation: 161254

## Rare Diseases Clinical Research Network

**Progress Report ****National Advisory Research Resources Council**
**September 21, 2006**
**Ronald J. Sokol, M.D.**
**Chair, Steering Committee, RDCRN**

## 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**

## 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**

## 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**

## Configuration of the Network

## 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**** **

## 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**

## Geographic Distribution - Centers

**CLiC**

**RLDC**

**ARPWC**

**GDMCC**

**UCDC**

**VCRC**

**BMFDC**

**CINCH**

**RGSDC**

**RTDC**

**NIH**

**DTCC**

## Geographic Distribution -  Clinical Sites

**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**

## 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 **

## Integrated Network

**NIH****ORD, NCRR, NIAMS,****NICHD, NHLBI, NIDDK, NINDS**** **

- Data and TechnologyCoordinating Center

- MediaLibrary

- Researchers

- Doctors

- Educators

- PatientCommunity

- PharmaceuticalCompanies

- RDCCenter

- Registries

**Integrated Network**

- Contact
- Registry

- Clinical ResearchData Bank

- Clinical DataStandardizationGroups

## Progress and Accomplishments

## 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 **

## 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 **

## 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**

## 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**

## 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**

## RARE DISEASES CLINICAL RESEARCH NETWORK DSMBs

**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**

## 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.

## 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**

## Current Participant Accruals

## Tracking of Protocol Enrollment

## 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**

## Slide 25

## Slide 26

## Contact Registry

**2588 registrants - ****68% email, 16% mail, 15% phone**

## 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**

## 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**

## 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**

## 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**

## 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**