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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Glioblastoma is the most common malignant primary brain tumor, but it is classified as a rare disease because its incidence rate of 3 per 100,000 people is below the rare disease definition rate of less than 10 per 100,000 people.
“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]
Federated learning has tremendous potential in healthcare, particularly towards addressing health disparities, under-served populations, and rare diseases, by enabling machine learning models to gain knowledge from ample and diverse data that would otherwise not be available.
“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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Murphy, S. M., Puwanant, A., & Griggs, R. C. (2012) · Annals of Neurology · doi:10.1002/ana.23672 · Cited by 49 · see citing works
“When drugs are marketed with a higher cost per QALY, in some instances NICE has entered a cost-sharing or risk-sharing agreement with the company marketing the drug.71 For rare diseases, the National Murphy et al: Orphan Product Designation October 2012 487 Specialist Commissioning Advisory Group (NSCAG) advises the D…”
BackgroundInfluentialSelf-citationMucci, V., Canceri, J. M., Brown, R., Dai, M., Yakushin, S. B., Watson, S. R. D., Ombergen, A. V., Topsakal, V., de Heyning, P. V., Wuyts, F. L., et al. (2018) · Journal of Neurology · doi:10.1007/s00415-017-8725-3 · Cited by 47 · see citing works
“Despite the potential risk of inclusion of non-MdDS sufferers, this category was maintained, based on previous research indicating that patients living with undiagnosed or highly debilitating conditions often resort to self-education through internet literature searches [9] and support group discussions [18].”
BackgroundNatural History of Leigh Syndrome: A Study of Disease Burden and Progression
Lim, A. Z., Ng, Y. S., Blain, A. P., Jimenez‐Moreno, C., Alston, C. L., Nesbitt, V., Simmons, L., Santra, S., Wassmer, E., Blakely, E. L., et al. (2021) · Annals of Neurology · doi:10.1002/ana.26260 · Cited by 46 · see citing works
Targeted therapy in rare cancers—adopting the orphans
Munoz, J. L., & Kurzrock, R. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.160 · Cited by 46 · see citing works
Potter, B. K., Khangura, S. D., Tingley, K., Chakraborty, P. K., & Little, J. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.42 · Cited by 46 · see citing works
Drug development challenges and strategies to address emerging and resistant fungal pathogens
McCarthy, M. W., & Walsh, T. J. (2017) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2017.1328279 · Cited by 46 · see citing works
“Fungal disease research poses a number of challenges to clinical investigators (henceforth referred to as ‘trialists’), including the design of clinical studies, funding for clinical research programs, and the discovery, testing, and approval of new treatments [13,14].”
BackgroundIn silico clinical trials for pediatric orphan diseases
Carlier, A., Vasilevich, A. S., Maréchal, M., de Boer, J., & Geris, L. (2018) · Scientific Reports · doi:10.1038/s41598-018-20737-y · Cited by 45 · see citing works
“As an example, the inner circle shows how a conceptual model (1) of cartilage generation can be translated in a schematic (2) and mathematical representation (3).”
BackgroundA small n sequential multiple assignment randomized trial design for use in rare disease research
Tamura, R., Krischer, J. P., Pagnoux, C., Micheletti, R. G., Grayson, P. C., Chen, Y., & Merkel, P. A. (2015) · Contemporary Clinical Trials · doi:10.1016/j.cct.2015.11.010 · Cited by 43 · see citing works
“[1] make a number of recommendations for clinical trials in rare diseases, including testing more than one therapy within each patient.”
BackgroundSelf-citationTingley, K., Coyle, D., Graham, I. D., Chakraborty, P. K., Wilson, K. R., & Potter, B. K. (2021) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-020-01624-0 · Cited by 42 · see citing works
“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 · see citing works
Self-citationRoussel, M., Morin, M., Gagnon, C., & Duchesne, É. (2019) · BMC Musculoskeletal Disorders · doi:10.1186/s12891-019-2458-7 · Cited by 42 · see citing works
Caputo, A. (2014) · Psychology, Health & Medicine · doi:10.1080/13548506.2013.793372 · Cited by 41 · see citing works
“…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 41 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 36 · see citing works
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 · see citing works
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 35 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
Ostropolets, A., Zhang, L., & Hripcsak, G. M. (2020) · Journal of the American Medical Informatics Association · doi:10.1093/jamia/ocaa200 · Cited by 33 · see citing works
“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 · see citing works
“…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 34 · see citing works
“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 · see citing works
Characteristics of clinical trials in rare vs. common diseases: A register-based Latvian study
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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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 30 · see citing works
Grando, S. A. (2018) · International Journal of Dermatology · doi:10.1111/ijd.14143 · Cited by 30 · see citing works
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 · see citing works
Velvin, G., Hartman, T., & Bathen, T. (2022) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-022-02357-y · Cited by 28 · see citing works
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 · see citing works
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 · see citing works
- 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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