Biennial Report of the Director

Centers of Excellence
Rare Diseases Clinical Research Network

Establishment of the Rare Diseases Clinical Research Network

The Rare Diseases Clinical Research Network (RDCRN) was established in 2003 by the Office of Rare Diseases Research (ORDR) in collaboration with six NIH ICs. The RDCRN has developed a novel collaborative model of rare disease research in a number of ways including integration of patient advocacy groups as research partners. Its purpose is to facilitate clinical research in rare diseases through support for 1) collaborative clinical research in rare diseases, including longitudinal studies of individuals with rare diseases, clinical studies and trials; 2) training of clinical investigators in rare diseases research; 3) pilot and demonstration projects; 4) a test bed for distributed clinical data management that incorporates novel approaches and technologies for data management, data mining, and data sharing across rare diseases, data types, and platforms; and 5) access to information related to rare diseases for basic and clinical researchers, academic and practicing physicians, patients, and the lay public.

In February 2008, ORDR, in collaboration with several NIH ICs, opened a re-competition for funding support for the network and the Data Management and Coordinating Center (DMCC). The resulting network consists of 19 consortia and a Data Management Coordinating Center, each with cooperative agreement awards for five years. ORDR is collaborating with NINDS, NIAID, NIAMS, NICHD, NIDCR, NHLBI, NIDDK, and NCI.

The DMCC houses all data for the network centrally via in-house scalable and customizable electronic data capture systems. Some of the data systems built by the DMCC for the RDCRN include a specimen collection, shipment, and tracking system; randomization system; participant management system with electronic case report forms; standardized and automated report sets (accrual, demographics, adverse events, compliance, study status); automated XML/CSV data sets with associated data dictionaries; and an Adverse Event Data Management System for real time reporting, submission, and review of adverse events.

An additional feature, the RDCRN Contact Registry, together with consortia information, is designed for access by the general public [https://www.rarediseasesnetwork.org Exit Disclaimer]. Users access an enrollment form for the Contact Registry via one of 19 consortium-specific web pages. The RDCRN consortia web pages and associated links to the Contact Registry are accessible from disease-specific searches on a variety of internet browsers. 171 diseases are represented by 9,806 registrants. The Contact Registry has been utilized as a pathway for informing registrants about studies. The first instance of this success was a partnership between the DMCC and the Vasculitis Clinical Research Consortium (VCRC) whereby over 500 subjects were recruited and the study was completed within three months.

The DMCC also maintains the public web pages and portals for all consortia within the network. Since August 2009, the public web pages have experienced over 600,000 visits with 515,000 visits occurring in the last 12 months.

Clinical trials and research studies and network collaborations have resulted in 279 publications including one book, nine book chapters, three conference posters, 45 conference papers, two special publications, and 219 journal articles.

How the RDCRN Functions within the NIH Framework

Each consortium develops and, after approval, carries out clinical protocols for a set of related rare diseases with guidance from one or several of the participating institutions. A steering committee guides the network. The steering committee consists of the principal investigator of each consortium and the DMCC, the RDCRN program coordinator from ORDR, NIH program scientists from the participating ICs, and the Chair of the Coalition of Patient Advocacy Groups (CPAG) in the network.

The network’s improved infrastructure and functions build on lessons learned in previous years and uses those approaches that have proven to be most effective while searching for additional efficiencies and innovation.

Description of Disease or Condition

A disease is defined as rare if fewer than 200,000 persons in the United States have it. There are more than 6,500 rare diseases for which fewer than 250 treatments have been approved as orphan products, drugs that are specifically developed to treat a rare disease. Approximately 80 percent of rare diseases are thought to be of genetic origin. It is estimated that at least 50 percent of the patients are children. The National Organization for Rare Disorders (NORD) estimates that about 1 in 10 people in the U.S. have a rare disease, which translates to as many as 25 to 30 million people. The 19 consortia below study the listed rare diseases and many others which are listed at the network web site https://rarediseasesnetwork.epi.usf.edu/ Exit Disclaimer:

The Angelman, Rett, and Prader-Willi Syndrome Consortium (ARPWSC):

The Autonomic Disorders Consortium (ADC):

The Brain Vascular Malformation Consortium:

The Chronic Graft vs. Host Disease (GVHD) Consortium:

The Clinical Research Consortium for Spinocerebellar Ataxias:

The Consortium for the Clinical Investigation of Neurologic Channelopathies (CINCH):

The Dystonia Coalition:

The Genetic Disorders of Mucociliary Clearance Consortium:

The Inherited Neuropathies Consortium (INC)

The Nephrotic Syndrome Study Network (NEPTUNE):

The North American Mitochondrial Disease Consortium (NAMDC)

The Porphyrias Consortium:

The Primary Immune Deficiency (PID) Treatment Consortium (PIDTC)

The Salivary Gland Carcinomas Consortium (SGCC):

The Vasculitis Clinical Research Consortium (VCRC)

The Lysosomal Disease Network

The Sterol and Isoprenoid Diseases Consortium (STAIR)

Burden of Illness

The burden of illness for all rare diseases is difficult to assess because of the large number of disorders, the complexity of each disease, and the very limited availability of prevalence and incidence data. Overall, all the rare diseases listed above and the others studied are devastating and costly, not only for the patients but also for the family. This is due partly because of the disease severity and partly because diagnosis can take a long time, often occurring well after symptoms have appeared. In addition, often treatment is not available once a disease is diagnosed. Moreover, it is impossible to assess the pain, suffering, and lost opportunities experienced by patients and their families. Because of these variables, these rare diseases specifically and others generally represent a disproportionate share of health care spending. In addition, few drug companies conduct research into rare diseases since it is difficult for them to recover the costs of developing treatments for small, geographically dispersed populations.

Scope of NIH Activities: Research and Programmatic

The RDCRN brings together experts who are skilled in studying, diagnosing, and treating particular groups of rare diseases and who train junior faculty and postgraduate fellows. In addition, the network enables each consortium to gather groups of patients with similar or related disorders, fosters basic scientific investigation and longitudinal natural history and epidemiological studies which in the past have often not been funded, encourages synergy in translational research, and enhances opportunities for collaborative clinical investigation.

NIH Funding for FY 2010 and FY 2011

NIH funding for the RDCRN was $20.80 million for 19 consortia and the DMCC in FY 2010 and $16.60 million in FY 2011. The total cost over five years for the RDCRN’s Phase II is estimated to be $117 million.

FY 2010 and FY 2011 Progress Report

Programmatic and Research Activities and Outcomes

The RDCRN is unique in its approach to addressing rare diseases. Previously, the NIH ICs funded research on individual rare diseases in their respective disease-type or organ domain. In the first two years since the second grant cycle of the RDCRN (August 2009 to September 2011), the network has activated 41 multi-site clinical research studies. The Network has 78 active studies which are accruing at over 162 clinical centers; 26 of the enrolling clinical centers are located internationally (with representation from the United Kingdom, Netherlands, Germany, France, Italy, Spain, Switzerland, Canada, Iceland, and Australia). In addition, 100 trainees were prepared to lead future rare diseases research. Since August 2009, 10 studies have completed accrual and are in the final analysis phase. In addition, a total of 8,329 participants have been enrolled since the beginning of the second grant cycle. The network established a comprehensive training program for clinical investigators and developed a network-wide web site to inform the public, physicians, patients, and investigators about the rare diseases under study. The network’s aims continue to include training a cadre of young investigators in the clinical and physiological processes associated with each disease and pharmacologic aspects of specific rare diseases. The network’s training includes instruction on and experience with methodologies for patient-oriented clinical research in rare diseases, including biostatistics and epidemiology, and the conceptualization, ethics, design, implementation, analysis, and reporting of controlled clinical trials. An integrated training program provides supervision by clinicians and biostatisticians with extensive experience in investigating rare diseases and developing novel therapies. The training program also provides an integrated statistics, epidemiology, and computer science curriculum; seminars on clinical trial design; courses in the basic sciences underlying experimental therapeutics and in ethics; and career development support.

Findings in recent publications are examples of just a few of the scientific-research accomplishments of the RDCRN:

Table 4-5. Rare Diseases Clinical Research Network
Institution and Location Year Established
University of Pennsylvania, Philadelphia, PA (previously Boston University School of Medicine, Boston, MA) 2003
Children’s National Medical Center, Children’s Research Institute, Washington DC 2003
University of Alabama at Birmingham, AL (previously Baylor College of Medicine, Houston, TX) 2003
University of Rochester, NY 2003
University of South Florida, Tampa, FL 2003
University of North Carolina, Chapel Hill, NC 2004
Columbia University Medical Center, New York, NY 2009
Emory University, Atlanta, GA 2009
Fred Hutchinson Cancer Research Center, Seattle, WA 2009
Mayo Clinic College of Medicine, Rochester, MN 2009
Mount Sinai School of Medicine of NYU, New York, NY 2009
Oregon Health and Sciences University, Portland, OR 2009
University of California, San Francisco, CA (two locations) 2009
University of Florida, Gainesville, FL 2009
University of Michigan at Ann Arbor, MI 2009
University of Minnesota Twin Cities, Minneapolis-St. Paul, MN 2009
University of Texas MD Anderson Cancer Center, Houston, TX 2009
Vanderbilt University Medical Center, Nashville, TN 2009
University of Iowa, IA (previously Wayne State University, Detroit, MI) 2009