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Commentary: Ahead of the Curve |

Rare Diseases ResearchCollaborative Rare Diseases Research: Expanding Collaborative Translational Research Opportunities FREE TO VIEW

Stephen C. Groft, PharmD
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From the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD.

Correspondence to: Stephen C. Groft, PharmD, Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-4874; e-mail: Stephen.Groft@nih.gov


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(1):16-23. doi:10.1378/chest.13-0606
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Extensive public-private partnerships, including the National Institutes of Health (NIH) and the rare diseases community, which is seeing a renewed industry interest in smaller niche markets, have resulted in an increase of interventions for rare diseases. Significant collaborative efforts are required among the pharmaceutical industry, foundations, patient-advocacy groups, academic and government investigators and funding programs, regulatory scientists, and reimbursement agencies to meet the unmet diagnostic and treatment needs for approximately 25 million people in the United States with 7,000 rare diseases. The expanding role and outreach activities of patient-advocacy groups have increased public awareness. In the United States, a rare disease is defined as a disorder or condition with a prevalence of < 200,000 people. In 2011, the NIH provided > $3.5 billion for rare diseases research, including $750 million for orphan product development activities, nearly 11.4% of the NIH research budget. Several research institutes and centers of the NIH, including the National Center for Advancing Translational Sciences, have initiated varied translational research efforts to address the absence of preclinical and clinical data required for regulatory review purposes. Clinicians can expect to see significant increases in requests from patients and their families to participate in patient registries and natural history or observational studies to gather specific information from a larger pool of patients on the progression of the disease or response to treatments. An expanding emphasis on rare diseases provides hope for the millions of patients with rare diseases.

Numerous efforts and major emphases by the rare diseases community, including the National Institutes of Health (NIH), have resulted in increased possible interventions and diagnostics for rare diseases. Despite these intensive efforts, lack of appropriate diagnostics and interventions still exist for most rare diseases. The current model of product development is very costly, requires too long to complete studies, and is extremely susceptible to failure. Estimates have been made of nearly 10 to 15 years of research and development efforts costing > $1 billion. Five of 5,000 experimental compounds that enter preclinical testing progress to evaluation in humans and only one of these five compounds receives approval from the US Food and Drug Administration (FDA) for use in humans.1,2 These results provide little hope for obtaining a product approval for most patients with one of the nearly 7,000 rare diseases.

To meet the therapeutic needs of approximately 25 million people in the United States with a rare disease, extensive partnerships are required with the pharmaceutical industry, contract research organizations, philanthropic foundations, patient-advocacy groups and their medical and scientific advisory boards, academic and government research investigators, regulatory agency scientists, government funding and reimbursement agencies, and the public. Unmet public health needs remain for most patients with rare diseases.

Rare diseases span the medical specialty practices and can manifest symptoms in multiple organs. Providing appropriate care for patients with rare diseases is challenging and requires considerable efforts from medical specialists to develop the knowledge base for clinicians who have patients in their care. In the United States, a rare disease is defined as a disorder or condition with a prevalence of < 200,000 people.3 The global goals remain the same: to develop products for the prevention, diagnosis, or treatment of rare diseases. This article presents significant issues and highlights collaborative approaches to product development.

Growing interest in rare diseases resulted from a confluence of events and activities. There is acceptance and public recognition that rare diseases represent a global public health problem due to the lack of appropriate treatments, multiple hospitalizations over a lifespan, and a lengthy diagnostic odyssey. The expanding role and outreach activities of patient advocacy groups (PAGs) have increased public awareness, as well as public, media, and legislative interest in rare diseases. Disease-specific PAGs are reliable research partners and assist in patient recruitment for clinical trials and review of clinical protocols and informed consent documents.

Revitalization of interest in rare diseases occurred with an increased understanding of individual rare diseases and potential application of this knowledge to common diseases. Doubling of the NIH research budget between 1998 ($13.7 billion) and 2003 ($27.1 billion) expanded scientific opportunities and led to many discoveries at academic institutions with rare diseases emphasis. The fiscal year 2011 budget for the NIH was $30.62 billion. The NIH provided > $3.5 billion for rare diseases research, including $750 million for orphan product development activities. This represents nearly 11.4% of the NIH research budget and reflects a continued emphasis on rare diseases by the NIH.4 Expanded national and international interest has resulted in an increase in the number of research investigators experienced in research design with small patient populations at multicenter, international clinical sites.

Increased industry interest in smaller niche markets has resulted in more interventions and diagnostics products becoming available. Long and Works5 reported the current pipeline of new products and treatments in development reflects diverse clinical research programs across many different therapeutic areas. Approximately 8,000 biopharmaceutical projects are in clinical development for > 5,400 potential new treatments. The pipeline includes 1,800 projects for rare diseases and at least 400 for diseases for which no new therapies have been approved in at least a decade.5 At least 577 products use new technologies, such as cell and gene therapies, antisense RNA interference therapy, and monoclonal antibodies, to precisely target the disease site. An additional 155 projects relate to personalized medicine.5

Opportunities for repurposing of approved and investigational products and licensing of products and technologies from discoveries at academic research centers are leading to more directed translational research activities. An increased emphasis on public-private-partnerships (PPPs) uses the strengths and resources of research partners.

Since the implementation of the Orphan Drug Act (Public Law 97-414) in 1983, > 400 products have been approved by the FDA.6 Several products for pulmonary-related conditions (Table 1) received the orphan product designation and are eligible for research and development incentives, such as 7 years of exclusive marketing privileges, tax credits for clinical trials with orphan products, and possible waiver of fees to file an investigational new drug (IND) or a new drug application.7 Key collaborations in the research and development activities involve the leaders of PAGs and their scientific and medical advisory boards. Patient organizations provide resources for research studies and assistance in recruiting patients to participate in clinical trials. Selected successful support organizations include the Cystic Fibrosis Foundation, the LAM (lymphangioleiomyomatosis) Foundation, the Pulmonary Hypertension Association, the Alpha-1 Foundation, and the Primary Ciliary Dyskinesia Foundation.

Table Graphic Jump Location
Table 1 —Orphan Product Approvals for Pulmonary-Related Disorders

ALK = anaplastic lymphoma kinase; AT-III = antithrombin III; CABG = coronary artery bypass graft; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; FDA = US Food and Drug Administration; MDR-TB = multidrug resistant TB; NSCLC = non-small cell lung cancer; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PCP = Pneumocystis carinii pneumonia; RDS = respiratory distress syndrome; WHO = World Health Organization.

Several research institutes and centers of the NIH have implemented varied translational research initiatives to respond to scientific opportunities and the need for interventions for the prevention, diagnosis, or treatment of rare diseases. They have increased their resources to bridge existing data gaps. In addition to the traditional research grants and contracts to investigators to complete the necessary studies, unique collaborative programs and resources from the NIH’s research programs address the absence of preclinical and clinical data required for regulatory review purposes. Several of these programs are presented in Table 2 as selected models of collaborative efforts. Each program requires discussion and communication with responsible program staff prior to submitting a grant application.

Table Graphic Jump Location
Table 2 —Selected Translational Research Programs at NIH Institutes

NCATS = National Center for Advancing Translational Sciences; NCI = National Cancer Institute; NHGRI = National Human Genome Research Institute; NHLBI = National Heart, Lung, and Blood Institute; NIAID = National Institute of Allergy and Infectious Diseases; NICHD = National Institute of Child Health and Human Development; NIH = National Institutes of Health; NINDS = National Institute of Neurological Disorders and Stroke.

The mission of the National Center for Advancing Translational Sciences (NCATS), established in December 2012, is to catalyze the generation of innovative methods and technologies to enhance the development and testing of diagnostics and therapeutics across a wide range of human diseases and conditions.8 Recent research advances and an improved understanding of the molecular basis of diseases have identified numerous possible compounds for therapeutic development. The NIH, in response to the decrease in products for high-need diseases, including rare and neglected diseases, initiated new, strategic PPPs to enable successful approaches to treatment and to facilitate diagnostics development. NCATS will attempt to reduce the risk of product failure, enable product development to become more economically feasible, and facilitate long-term commitments by the private sector in collaboration with public sector organizations, the pharmaceutical industry, the NIH, the FDA, academic research centers, and PAGs. Selected programs integrated into NCATS include the Clinical and Translational Science Awards Program of 60 national medical research institutions working together to improve clinical and translational research nationwide, including the patient recruitment tool, ResearchMatch.9

The Therapeutics for Rare and Neglected Diseases (TRND) program is an intramural research and therapeutic development program for rare and neglected diseases. The TRND program provides resources to develop collaborative therapeutic development projects with intramural and extramural scientists, not-for-profit organizations, the for-profit industry, and international partners who have promising drug or financial resources to translate the promising lead compounds into therapeutic candidates. The goal is to develop potential compounds that eliminate barriers to studies in humans. Examples of selected programs include the following disorders: Niemann-Pick disease type C, sickle cell disease, Duchenne muscular dystrophy, creatine transporter defect, and pulmonary alveolar proteinosis.10

Another program, Bridging Interventional Development Gaps (BrIDGs), makes available critical resources needed for the development of new therapeutic agents. Successful applicants receive access to NIH contractors who conduct preclinical synthesis, formulation, pharmacokinetic, and toxicology services at no cost to the investigator. BrIDGs has generated data to support 12 INDs that have been cleared by the FDA and one clinical trial application that has been cleared by Health Canada. Twelve projects have been evaluated in clinical trials. Three BrIDGs-supported agents have gone as far as phase 2 human clinical trials. Third-party investors have licensed six agents during or after their development by BrIDGs. Examples of diseases accepted into the program include fibrodysplasia ossificans progressiva, anemia of inflammation, spinal cord injury, and hypoparathyroidism.11

Coordinating Rare Diseases Research

The Office of Rare Diseases Research (ORDR), established in 1993, received a legislative mandate in 2002.12 The ORDR continues to provide an emphasis on unmet research needs of the rare diseases community. The mission of the ORDR is to provide integrated activities that advance research and therapies for rare diseases and to coordinate NIH-wide rare disease research activities.

The ORDR coordinates the Rare Diseases Clinical Research Network (RDCRN) with eight NIH institutes and centers (National Institute of Neurological Disorders and Stroke; National Institute of Child Health and Human Development; National Institute of Allergy and Infectious Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; and National Cancer Institute). Table 3 includes 17 distinct, clinical research consortia and a data management coordinating center (DMCC). The purpose of the RDCRN is to facilitate clinical research of rare diseases by supporting (1) collaborative clinical research studies of rare diseases, including longitudinal and natural history studies of individuals with rare diseases; (2) training programs with > 100 new clinical investigators of rare diseases having completed the training program; and (3) the establishment of a partnership role of PAGs through the Coalition of Patient Advocacy Groups.13 The DMCC serves as a facilitating center to (1) assist collaborators in the design of clinical protocols, and with data management, and analyses; (2) develop a coordinated clinical data management system for the collection, storage, and analysis of data from multiple diseases and multiple clinical research sites; (3) develop tools for an Internet-based recruitment and referral system with a patient contact registry; and (4) construct a portal for access and integration of public data resources.

Table Graphic Jump Location
Table 3 —Rare Diseases Clinical Research Network

The RDCRN has initiated natural history studies and clinical trials at participating institutions worldwide. Clinical studies are open and are actively recruiting study participants. The consortia cooperative agreement awards are expected to be recompeted and awards made in 2014.

The NIH and the ORDR recognize the value of the coordination, exchange, and dissemination of information on the investigation of basic and clinical research aspects of rare diseases with academic investigators, PAGs, foundations, industry, and the FDA. The ORDR cosponsors a broad array of scientific meetings with NIH institutes and centers and other federal agencies, including the FDA, the Centers for Disease Control and Prevention, and the Health Resources and Services Administration. More than 1,200 ORDR-cosponsored conferences have successfully identified research opportunities and established research priorities with program announcements to solicit research applications. Agreements have been reached on diagnostic and monitoring criteria for clinical research protocols, animal models, biospecimen repositories, and patient registries. Support has been provided for selected recent conferences on lympangioleiomyomatosis, pheochromocytoma, ataxia telangiectasia, nonceroidal lipofuscinosis, myasthenia gravis, primary immune deficiencies, and muscular dystrophies.14

Increasing emphasis is being placed on the development and use of patient registries by patients and the research communities. Clinicians can expect to see significant increases in the number of registries and increased requests by patients to participate in patient registries.15 Patients’ clinical information, and demographic, medical, and family histories are collected, stored, and available in registries for retrieval in a standardized and secure way. The aggregated, de-identified data may be used to develop biomedical research hypotheses for epidemiology or public health surveillance studies, to recruit subjects for clinical trials, to add to the knowledge base of a rare disease, to learn about population-behavior patterns, and may be required to meet postapproval surveillance regulatory requirements.16 A wide range of patient registries exists to meet needs at a global level and may be developed for individual rare diseases and a group of related disorders, and includes a metaregistry from the Agency for Health Research and Quality Registry of Patient Registries.17

The pilot project, Global Rare Diseases Patient Registry Data Repository (GRDR), was initiated by the ORDR to collect de-identified patient clinical data for research, to test data mapping and the data import/export processes of new and existing registries, and to promote data sharing.18 Common data elements and questions assist in the collection of related data from numerous sources to enable communication and transfer of information among the registries.1921 A Web-based template will become available to assist PAGs or researchers wishing to establish patient registries. The success or failure of a registry depends upon the accuracy and quality of information entered from patients, family members, and health-care providers. Populating data fields in patient registries directly from existing electronic health-care records and information technology systems should help reduce the costs of gathering data in a standardized fashion, particularly at the point of contact between health-care providers and patients or their families.

There has been an increasing emphasis on the need and value of natural history studies. A major goal of natural history studies is to gather specific and potentially more useful information on the progression of a disease or response to extended treatments across the lifespan. They may be useful for initiating epidemiologic studies, developing research hypotheses to be tested in clinical trials, identifying genetic variability in patients with rare diseases, establishing clinical end points for trials, and providing an active list of possible study participants for ongoing and planned clinical trials. Constant access to patients willing to participate in clinical trials will provide smooth transitions from phase 1 through phase 3 studies, with limited delays between phases due to difficulties encountered in patient recruitment.22

With the ready access and the acceptance of the numerous collaborative approaches and resources available from many sources, more rapid development of products will occur. Successful models are emerging for facilitating rare disease research and development of orphan products. This model requires a change of emphasis by the research community and the development of new or use of existing databases and biospecimen repositories. For most rare diseases, PPPs are required for successful development of diagnostics and treatments for rare diseases. Even with primary interest of the pharmaceutical industry, PPPs are required to address the many needs of conducting research and for moving therapeutics through the various stages of development required to gain regulatory approval for products.

Increased emphasis by government research and regulatory initiatives, and expanded emphasis on rare diseases by many members of the pharmaceutical, biotechnology, and medical devices industries provide hope for the millions of patients with rare diseases. This growing interest is occurring as several of the larger pharmaceutical companies are supporting dedicated rare disease development programs.

More recent discoveries of the molecular basis of rare diseases have enabled the identification of many possible therapeutic interventions. The NIH has initiated new programs and expanded existing programs to provide the collaborative efforts required to stimulate product development or provide necessary data to overcome the barriers that prevent a product from moving to the next stage of development for rare and neglected diseases.

Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

BrIDGs

Bridging Interventional Development Gaps

DMCC

Data Management Coordinating Center

FDA

US Food and Drug Administration

IND

investigational new drug

NCATS

National Center for Advancing Translational Sciences

NIH

National Institutes of Health

ORDR

Office of Rare Diseases Research

PAG

patient advocacy group

PPP

public-private partnership

RDCRN

Rare Diseases Clinical Research Network

TRND

Therapeutics for Rare and Neglected Diseases Program

Collins F. An audience with..Francis Collins. Interviewed by Asher Mullard. Nat Rev Drug Discov. 2011;10(1):14. [CrossRef] [PubMed]
 
Pharmaceutical and Research Manufacturers Association.Drug discovery and development. Pharmaceutical Research and Manufacturers of America website.http://www.phrma.org/research/drug-discovery-development. Accessed February 18, 2013.
 
Health Promotion and Disease Prevention Amendments of 1984, Public Law 98-551, October 30, 1984.
 
Long G, Works J. Innovation in the biopharmaceutical pipeline: a multidimensional view. Pharmaceutical Research and Manufacturers of America website.http://phrma.org/sites/default/files/2435/2013innovationinthebiopharmaceuticalpipeline-analysisgroupfinal.pdf. Accessed February 18, 2013.
 
Orphan Product Approvals and Designations Orphan Drug Product designation database. Food and Drug Administration website.http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. Accessed February 18, 2013.
 
Orphan Drug Act, Public Law 97-414, January 4, 1983.
 
Collins FS. Reengineering translational science: the time is right. Sci Transl Med. 2011;3(90):90cm17. [CrossRef] [PubMed]
 
Harris PA, Scott KW, Lebo L, Hassan N, Lightner C, Pulley J. ResearchMatch: a national registry to recruit volunteers for clinical research. Acad Med. 2012;87(1):66-73. [CrossRef] [PubMed]
 
McKew JC, Pilon AM. NIH TRND program: successes in preclinical therapeutic development. Trends Pharmacol Sci. 2013;34(2):87-89. [CrossRef] [PubMed]
 
Bridging Interventional Development Gaps (BrIDGs) program. National Center for Advancing Translational Sciences website.http://www.ncats.nih.gov/about/faq/bridgs/bridgs-faq.html. Accessed February 18, 2013.
 
Rare Diseases Act of 2002, Public Law 107-280, November 6, 2002.
 
Griggs RC, Batshaw M, Dunkle M, et al; Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009;96(1):20-26. [CrossRef] [PubMed]
 
ORDR co-sponsored scientific conferences. National Institutes of Health Office of Rare Diseases Research website.http://rarediseases.info.nih.gov/Scientific_Conferences.aspx. Accessed February 18, 2013.
 
Forrest CB, Bartek RJ, Rubinstein Y, Groft SC. The case for a global rare-diseases registry. Lancet. 2011;377(9771):1057-1059. [CrossRef] [PubMed]
 
Rubinstein YR, Groft SC, Bartek R, et al. Creating a global rare disease patient registry linked to a rare diseases biorepository database: Rare Disease-HUB (RD-HUB). Contemp Clin Trials. 2010;31(5):394-404. [CrossRef] [PubMed]
 
Rubinstein YR, Groft SC. Driving interest in consolidating resources for the creation of a global rare disease patient registry. Contemp Clin Trials. 2010;31(5):393. [CrossRef] [PubMed]
 
About the Registry of Patient Registries (ROPR). Agency for Health Research and Quality website.https://patientregistry.ahrq.gov/about/. Accessed February 18, 2013.
 
Common Data Elements Overview. National Institutes of Health Office of Rare Diseases Research website.http://www.grdr.info/index.php?option=com_content&view=article&id=3&Itemid=5. Accessed February 18, 2013.
 
Maximizing what we learn from clinical trials: National Institute of Neurological Disorders and Stroke Common Data Elements. National Institutes of Health National Institute of Neurological Disorders and Stroke website.http://www.ninds.nih.gov/about_ninds/message/message-CDE.htm. Accessed February 18, 2013.
 
Common Data Element Resource Portal. National Library of Medicine website.http://cde.nih.gov. Accessed February 18, 2013.
 
Workshop on Natural History Studies of Rare Diseases. Food and Drug Administration website.http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/OOPDNewsArchive/ucm292294.htm. Accessed February 18, 2013.
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Orphan Product Approvals for Pulmonary-Related Disorders

ALK = anaplastic lymphoma kinase; AT-III = antithrombin III; CABG = coronary artery bypass graft; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; FDA = US Food and Drug Administration; MDR-TB = multidrug resistant TB; NSCLC = non-small cell lung cancer; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PCP = Pneumocystis carinii pneumonia; RDS = respiratory distress syndrome; WHO = World Health Organization.

Table Graphic Jump Location
Table 2 —Selected Translational Research Programs at NIH Institutes

NCATS = National Center for Advancing Translational Sciences; NCI = National Cancer Institute; NHGRI = National Human Genome Research Institute; NHLBI = National Heart, Lung, and Blood Institute; NIAID = National Institute of Allergy and Infectious Diseases; NICHD = National Institute of Child Health and Human Development; NIH = National Institutes of Health; NINDS = National Institute of Neurological Disorders and Stroke.

Table Graphic Jump Location
Table 3 —Rare Diseases Clinical Research Network

References

Collins F. An audience with..Francis Collins. Interviewed by Asher Mullard. Nat Rev Drug Discov. 2011;10(1):14. [CrossRef] [PubMed]
 
Pharmaceutical and Research Manufacturers Association.Drug discovery and development. Pharmaceutical Research and Manufacturers of America website.http://www.phrma.org/research/drug-discovery-development. Accessed February 18, 2013.
 
Health Promotion and Disease Prevention Amendments of 1984, Public Law 98-551, October 30, 1984.
 
Long G, Works J. Innovation in the biopharmaceutical pipeline: a multidimensional view. Pharmaceutical Research and Manufacturers of America website.http://phrma.org/sites/default/files/2435/2013innovationinthebiopharmaceuticalpipeline-analysisgroupfinal.pdf. Accessed February 18, 2013.
 
Orphan Product Approvals and Designations Orphan Drug Product designation database. Food and Drug Administration website.http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. Accessed February 18, 2013.
 
Orphan Drug Act, Public Law 97-414, January 4, 1983.
 
Collins FS. Reengineering translational science: the time is right. Sci Transl Med. 2011;3(90):90cm17. [CrossRef] [PubMed]
 
Harris PA, Scott KW, Lebo L, Hassan N, Lightner C, Pulley J. ResearchMatch: a national registry to recruit volunteers for clinical research. Acad Med. 2012;87(1):66-73. [CrossRef] [PubMed]
 
McKew JC, Pilon AM. NIH TRND program: successes in preclinical therapeutic development. Trends Pharmacol Sci. 2013;34(2):87-89. [CrossRef] [PubMed]
 
Bridging Interventional Development Gaps (BrIDGs) program. National Center for Advancing Translational Sciences website.http://www.ncats.nih.gov/about/faq/bridgs/bridgs-faq.html. Accessed February 18, 2013.
 
Rare Diseases Act of 2002, Public Law 107-280, November 6, 2002.
 
Griggs RC, Batshaw M, Dunkle M, et al; Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol Genet Metab. 2009;96(1):20-26. [CrossRef] [PubMed]
 
ORDR co-sponsored scientific conferences. National Institutes of Health Office of Rare Diseases Research website.http://rarediseases.info.nih.gov/Scientific_Conferences.aspx. Accessed February 18, 2013.
 
Forrest CB, Bartek RJ, Rubinstein Y, Groft SC. The case for a global rare-diseases registry. Lancet. 2011;377(9771):1057-1059. [CrossRef] [PubMed]
 
Rubinstein YR, Groft SC, Bartek R, et al. Creating a global rare disease patient registry linked to a rare diseases biorepository database: Rare Disease-HUB (RD-HUB). Contemp Clin Trials. 2010;31(5):394-404. [CrossRef] [PubMed]
 
Rubinstein YR, Groft SC. Driving interest in consolidating resources for the creation of a global rare disease patient registry. Contemp Clin Trials. 2010;31(5):393. [CrossRef] [PubMed]
 
About the Registry of Patient Registries (ROPR). Agency for Health Research and Quality website.https://patientregistry.ahrq.gov/about/. Accessed February 18, 2013.
 
Common Data Elements Overview. National Institutes of Health Office of Rare Diseases Research website.http://www.grdr.info/index.php?option=com_content&view=article&id=3&Itemid=5. Accessed February 18, 2013.
 
Maximizing what we learn from clinical trials: National Institute of Neurological Disorders and Stroke Common Data Elements. National Institutes of Health National Institute of Neurological Disorders and Stroke website.http://www.ninds.nih.gov/about_ninds/message/message-CDE.htm. Accessed February 18, 2013.
 
Common Data Element Resource Portal. National Library of Medicine website.http://cde.nih.gov. Accessed February 18, 2013.
 
Workshop on Natural History Studies of Rare Diseases. Food and Drug Administration website.http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/OOPDNewsArchive/ucm292294.htm. Accessed February 18, 2013.
 
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