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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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“Previous discussions in the literature have also posited that patients and families choose to participate in clinical research studies because of desperation and that the expectation of personal benefit can threaten clinical equipoise [3, 4, 6, 7].”
BackgroundKrischer, J. P., Gopal-Srivastava, R., Groft, S. C., & Eckstein, D. J. (2014) · Journal of General Internal Medicine · doi:10.1007/s11606-014-2894-x · Cited by 42
Self-citationRoussel, M., Morin, M., Gagnon, C., & Duchesne, É. (2019) · BMC Musculoskeletal Disorders · doi:10.1186/s12891-019-2458-7 · Cited by 42
Caputo, A. (2014) · Psychology, Health & Medicine · doi:10.1080/13548506.2013.793372 · Cited by 41
“…by low prevalence (less than fi ve in 10,000 citizens in the European Union (EU)), there are, today, between 5000 and 8000 distinct RDs affecting between 27 and 36 million people in the EU countries (European Union Committee of Experts on Rare Diseases [EUCERD], 2012; Griggs et al., 2009).”
BackgroundThe state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap
Jonker, A. H., Tãtaru, E.-A., Graeßner, H., Dimmock, D., Jaffé, A., Baynam, G. S., Davies, J. O. J., Mitkus, S., Iliach, O., Horgan, R., et al. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01059-3 · Cited by 48
Milne, S., Corben, L. A., Roberts, M., Murphy, A., Tai, G., Georgiou‐Karistianis, N., Yiu, E. M., & Delatycki, M. B. (2017) · Clinical Rehabilitation · doi:10.1177/0269215517736903 · Cited by 40
“39 In this study, the main barrier to participation was accessing the rehabilitation facility.”
BackgroundPatient-customized oligonucleotide therapy for a rare genetic disease
Kim, J., Chen, H., Moufawad El Achkar, C., Black, L. E., Douville, J., Larson, A., Pendergast, M. K., Goldkind, S. F., Ea, L., Kuniholm, A., et al. (2020) · Yearbook of pediatric endocrinology · doi:10.1530/ey.17.14.8 · Cited by 39
Class attention to regions of lesion for imbalanced medical image recognition
Zhuang, J., Cai, J., Zhang, J., Zheng, W., & Wang, R. (2023) · Neurocomputing · doi:10.1016/j.neucom.2023.126577 · Cited by 38
“Generally, images of common diseases are easier to collect, while images of rare diseases are not, which may lead to data imbalance issues for model training [9].”
BackgroundPotter, B. K., Chakraborty, P. K., Kronick, J. B., Wilson, K. R., Coyle, D., Feigenbaum, A. J., Geraghty, M. T., Karaceper, M. D., Little, J., Mhanni, A. A., et al. (2012) · Genetics in Medicine · doi:10.1038/gim.2012.153 · Cited by 38
Open Drug Discovery Teams: A Chemistry Mobile App for Collaboration
Ekins, S., Clark, A. M., & Williams, A. J. (2012) · Molecular Informatics · doi:10.1002/minf.201200034 · Cited by 38
Engaging Participants in Rare Disease Research: A Qualitative Study of Duchenne Muscular Dystrophy
Bendixen, R. M., Morgenroth, L. P., & Clinard, K. (2016) · Clinical Therapeutics · doi:10.1016/j.clinthera.2016.04.001 · Cited by 37
eRAM: encyclopedia of rare disease annotations for precision medicine
Jia, J., An, Z., Ming, Y., Guo, Y., Li, W., Liang, Y., Guo, D., Li, X., Tai, J., Chen, G., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx1062 · Cited by 35
Four disruptive strategies for removing drug discovery bottlenecks
Ekins, S., Waller, C. L., Bradley, M. P., Clark, A. M., & Williams, A. J. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.10.007 · Cited by 38
Fiorentino, R. P., Liu, G., Pariser, A., & Mulberg, A. E. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2012.07.011 · Cited by 36
Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease
Rajasekaran, S., Bupp, C. P., Leimanis, M. L., Shukla, A., Russell, C., Junewick, J. J., Gleason, E. G., VanSickle, E., Edgerly, Y. M., Wittmann, B. M., et al. (2021) · eLife · doi:10.7554/elife.67097 · Cited by 34
The Rare Diseases Clinical Research Network Contact Registry update: Features and functionality
Richesson, R., Sutphen, R., Shereff, D., & Krischer, J. P. (2012) · Contemporary Clinical Trials · doi:10.1016/j.cct.2012.02.012 · Cited by 35
“The Principal Investigators of each of the 19 consortia and the DMCC, as well as representatives from multiple NIH sponsors and the network's Coalition of Patient Advocacy Groups, serve on a Steering Committee to guide the strategic growth of the network, and to define research efficiencies and issues that will advanc…”
BackgroundSelf-citationPatient/family views on data sharing in rare diseases: study in the European LeukoTreat project
Darquy, S., Moutel, G., Lapointe, A.-S., d'Audiffret, D., Champagnat, J., Guerroui, S., Vendeville, M.-L., Boespflug‐Tanguy, O., & Duchange, N. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.115 · Cited by 34
Chasing cures: Rewards and risks for rare disease patient organisations involved in research
Pinto, D., Martin, D., & Chenhall, R. D. (2017) · BioSocieties · doi:10.1057/s41292-017-0061-4 · Cited by 33
Ostropolets, A., Zhang, L., & Hripcsak, G. M. (2020) · Journal of the American Medical Informatics Association · doi:10.1093/jamia/ocaa200 · Cited by 39
“12,13 When current evidence fails to provide guidance for the previous scenarios, clinicians have to rely on their limited experience.”
BackgroundPotter, B. K., Little, J., Chakraborty, P. K., Kronick, J. B., Evans, J., Frei, J., Sutherland, S. C., Wilson, K. R., & Wilson, B. J. (2011) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-011-9352-2 · Cited by 33
“…University Avenue, Halifax, Nova Scotia, Canada B3K 6R8 K. Wilson Ottawa Hospital Research Institute and Department of Medicine( University of Ottawa, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4E9 for these patients (Griggs et al. 2009; Leonard 2006; Steiner 2005; Vockley and Vockley 2010).”
BackgroundA hybrid framework with large language models for rare disease phenotyping
Wu, J., Dong, H., Li, Z., Wang, H., Li, R., Patra, A., Dai, C., Ali, W., Scordis, P., & Wu, H. (2024) · BMC Medical Informatics and Decision Making · doi:10.1186/s12911-024-02698-7 · Cited by 35
“Moreover, the absence of timely and accurate diagnoses hinders the development of targeted therapies and limits patients’ access to appropriate care and support services[3, 8].”
BackgroundBell, S., Peng, H., Crapper, L., Kolobova, I., Maussion, G., Vasuta, C., Yerko, V., Wong, T. P., & Ernst, C. (2016) · Stem Cells Translational Medicine · doi:10.1002/sctm.16-0158 · Cited by 30
Characteristics of clinical trials in rare vs. common diseases: A register-based Latvian study
Logviss, K., Krievins, D. K., & Purvina, S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194494 · Cited by 31
Developing interactions with industry in rare diseases: lessons learned and continuing challenges
Berry, S. A., Coughlin, C. R., McCandless, S. E., McCarter, R., Seminara, J., Yudkoff, M., & LeMons, C. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0616-9 · Cited by 31
The Italian National Rare Diseases Registry.
Taruscio, D., Kodra, Y., Ferrari, G., & Vittozzi, L. (2014) · Europe PMC (PubMed Central) · doi:10.2450/2014.0064-14s · Cited by 31
The Haystack Is Made of Needles
Terry, S. F., Shelton, R., Biggers, G., Baker, D. B., & Edwards, K. (2013) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2012.1542 · Cited by 30
“Finding a robust cohort has always been difficult for rare diseases, simply by virtue of their rarity (Griggs et al ., 2009; Gliklich and Leavy, 2011).”
Medford, E., Hare, D. J., & Wittkowski, A. (2017) · JIMD Reports · doi:10.1007/8904_2017_52 · Cited by 30
“It is also important to acknowledge that small sample size is likely to continue to be an issue in future research in this field (Griggs et al. 2009).”
BackgroundIvacaftor in cystic fibrosis with residual function: Lung function results from an N-of-1 study
Nick, J. A., Clair, C. G. S., Jones, M. C., Lan, L., & Higgins, M. (2019) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2019.09.013 · Cited by 31
Grando, S. A. (2018) · International Journal of Dermatology · doi:10.1111/ijd.14143 · Cited by 30
Bascom, R., Schubart, J. R., Mills, S. E., Smith, T., Zukley, L. M., Francomano, C. A., & McDonnell, N. B. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61054 · Cited by 29
Velvin, G., Hartman, T., & Bathen, T. (2022) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-022-02357-y · Cited by 28
Rare disease patient groups as clinical researchers
Polich, G. R. (2011) · Drug Discovery Today · doi:10.1016/j.drudis.2011.09.020 · Cited by 28
Absoud, M., Brex, P., Ciccarelli, O., Diribe, O., Giovannoni, G., Hellier, J. M., Howe, R., Holland, R., Kelly, J., McCrone, P., et al. (2017) · Health Technology Assessment · doi:10.3310/hta21310 · Cited by 28
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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