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Clinical research for rare disease: Opportunities, challenges, and solutions
Open accessAbstract
Over 7000 rare diseases, each <200,000 US residents, affect nearly 30 million people in the United States. Furthermore, for the 10% of people with a rare disease and for their families, these disorders no longer seem rare. Molecular genetics have characterized the cause of many rare diseases and provide unprecedented opportunities for identifying patients, determining phenotypes, and devising treatments to prevent, stabilize, or improve each disease. Rare disease research poses challenges to investigators requiring specific approaches to: (1) the design of clinical studies; (2) the funding of research programs; (3) the discovery, testing, and approval of new treatments, and (4) the training of clinical scientists. Rigorous, statistically-valid, natural history-controlled, cross-over, and n-of-1 trials can establish efficacy and support regulatory approval of new treatments for rare diseases. The U.S. Orphan Drug Act of the U.S. FDA has stimulated industry investment in clinical trials to develop treatments for rare diseases. For trainees interested in finding a treatment for a rare disease, a commitment to longitudinal care of patients provides a base for the characterization of phenotype and natural history, a stimulus for innovation, a target population for research and helps fund training and research. The scientific methodology, financial resources, and logistics of clinical research for rare diseases have changed dramatically in the past two decades resulting in increased understanding of the pathophysiology of these disorders and direct benefit to patients.
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“While glioblastoma is the most common malignant primary brain tumor26–28, it is still classified as a “rare” disease, as its incidence rate (i.e., 3/100,000 people) is substantially lower than the rare disease definition rate (i.e., <10/100,000 people)24.”
From Federated learning enables big data for rare cancer boundary detection (2022) · cites this paper as [24]
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“FL has tremendous potential in healthcare22,23, particularly towards addressing health disparities, under-served populations, and “rare” diseases24, by enabling ML models to gain knowledge from ample and diverse data that would otherwise not be available.”
From Federated learning enables big data for rare cancer boundary detection (2022) · cites this paper as [24]
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Drug repurposing for rare diseases
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“Crossover trials are considered appropriate only if the illness remains stable throughout the evaluation period (e.g., chronic conditions), and if treatments exhibit rapid and dramatic “on/off” effects and have short wash out periods (9, 13, 14).”
InfluentialBupp, C. P., VanSickle, E., Michael, J., Schultz, C. R., Nguyen, K., Hoefer, M., Rajasekaran, S., & Bachmann, A. S. (2025) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.32138 · Cited by 2
“…more patients could have known or novel therapies applied early in their disease course. a third of all deaths of children in the first year of life, largely because less than 5% of rare diseases have approved treatment options available (Griggs 2009; Rare Diseases at FDA 2022; Rare Diseases 2023).”
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Introduction to Human Glycosylation Disorders
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“Rare diseases collectively affect approximately 30 million Americans(2) [1].”
BackgroundNag, H. E., Nærland, T., & Øverland, K. (2021) · International Journal of Disability Development and Education · doi:10.1080/1034912x.2021.1888893 · Cited by 2
“This is a known challenge in research regarding rare disorders (Griggs et al., 2009).”
BackgroundAs associações de doenças raras em Portugal: Uma fonte importante de apoio psicossocial
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Enfermedades raras y trayectorias terapéuticas de pacientes: ¿qué sabemos hoy?
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Study based on electronic Health recOrds to identify Patients at high-risk of fabry diseasE—HOPE
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“It is also crucial to promote local research and medical groups and their collaboration with international networks, enabling training, knowledge transfer, and participation in multicenter projects on RD [24, 43].”
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Orphan Drug Development: Opportunities and Challenges from a Midsized to Large Company Perspective
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Rare Diseases Challenges and Opportunities
Gopal-Srivastava, R., & Groft, S. C. (2013) · Communications in medical and care compunetics · doi:10.1007/978-3-642-38643-5_29 · Cited by 1
“The RDCRN supported by the ORDR in collaboration with eight other NIH research Institutes and Centers, requires active collaboration with patient advocacy groups (PAGs) (Griggs et al. 2009).”
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Definition and Classification of Diffuse Cystic Lung Diseases
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“The rarity of these particular diseases manifest into problems in terms of (a) designing clinical studies3; (b) funding of research programs; (c) the discovery, testing, and approval of new treatments; and (d) the training of clinical scientists (Griggs et al., 2009).”
BackgroundThirty-Four Years of Online Pharmaceutical Marketing Research: A Bibliometric Analysis
Boateng, S. L., & Donkor, P. O. (2022) · Advances in theory and practice of emerging markets · doi:10.1007/978-3-030-77987-0_8 · Cited by 1
ORPHAN DISEASES: DIAGNOSIS, PROBLEMS, PROSPECTS
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The Effect of Biomarkers on Clinical Trial Risk in Gastric Cancer
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HealthBridge: A Decentralized and Interoperable Healthcare App for Rare Disease Communities
Guo, Z., Wang, Y., Liang, A., Devanter, W. V., & Zhang, P. (2023) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm58861.2023.10385268 · Cited by 1
“…work is similar in modular design, we implement a mobile application utilizing a permissioned network, returning the ownership of data to the patients and providing additional security for the rare disease community, as they are more vulnerable to inference or re-identification attacks [31], [32].”
Method
Metadata
- Authors
- Griggs, R. C., Batshaw, M., Dunkle, M., Gopal-Srivastava, R., Kaye, E., Krischer, J., Nguyen, T., Paulus, K., & Merkel, P. A.
- Affiliations
- University of Rochester Medicine (US)
- Children's National (US)
- National Organization for Rare Disorders (US)
- National Institutes of Health (US)
- University of South Florida (US)
- United States Food and Drug Administration (US)
- Boston University (US)
- Corresponding author
- Griggs, Robert C.
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 96
- Issue
- 1
- Pages
- 20-26
- ISSN
- 1096-7192 (ISSN-L)
- PMC
- PMC3134795
- OpenAlex
- W2132265655
- Cited by
- 401
- References
- 21
- Citations by year
- 2026: 21 · 2025: 22 · 2024: 22 · 2023: 20 · 2022: 38 · 2021: 43 · 2020: 25 · 2019: 26 · 2018: 27 · 2017: 23 · 2016: 18 · 2015: 25 · 2014: 25 · 2013: 22 · 2012: 17
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u54ns059065-07)
- National Heart, Lung, and Blood Institute (U54HL077878)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK078377)
- National Institute of Neurological Disorders and Stroke (U54-NS059065)
- National Center for Research Resources (U54RR019478, U54RR019453, U54RR019259, R13RR024337, U54RR019497, U54RR019498, U54RR019480, U54RR019397, U54RR019484)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ethics in Clinical Research
- Keywords
- rare diseases, orphan drugs, Orphan Drug Act, clinical trial design, natural history research, N-of-1 trials, crossover trial, regulatory approval, drug development, clinical research funding, molecular genetics
- MeSH terms
- Workforce, Clinical Trials as Topic, Financing, Government, Humans, Orphan Drug Production, United States, Drug Design, Rare Diseases, Biomedical Research, Public-Private Sector Partnerships
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