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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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BackgroundEvoPreprocess—Data Preprocessing Framework with Nature-Inspired Optimization Algorithms
Karakatič, S. (2020) · Mathematics · doi:10.3390/math8060900 · Cited by 24
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Kinder, B. W., Sherman, A., Young, L. R., Hagaman, J. T., Oprescu, N., Byrnes, S., & McCormack, F. X. (2009) · Respiratory Medicine · doi:10.1016/j.rmed.2009.09.023 · Cited by 24
“Over 7000 rare diseases, each involving fewer than 200,000 US residents, affect nearly 30 million people in the United States.13 Clinical investigators in rare disease research regularly face challenges specific to the study of uncommon disorders, such as the recruitment of sufficient numbers of study subjects for ade…”
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Research challenges in central nervous system manifestations of inborn errors of metabolism
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“Rare diseases such as SCCa of the external auditory canal present challenges to standard clinical trial design and make it difficult to assess the efficacy of various treatment modalities.(19) Our study presents early data from 2 centers working collaboratively to evaluate surgical approaches for managing this disease.”
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Improving the analysis of composite endpoints in rare disease trials
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Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome
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Rare disease patients in India are rarely involved in international orphan drug trials
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“Given the small number of individuals affected by a given condition, it is a challenge to conduct clinical trials [8], but the various incentives for orphan drug (OD) development have nevertheless led to many drugs and other interventions being developed.”
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Galpern, W. R., Coffey, C. S., Albanese, A., Cheung, K., Comella, C., Ecklund, D. J., Fahn, S., Jankovic, J. J., Kieburtz, K. D., Lang, A. E., et al. (2013) · Neurotherapeutics · doi:10.1007/s13311-013-0221-6 · Cited by 17
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Gopal-Srivastava, R., & Kaufmann, P. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-67144-4_6 · Cited by 17
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“Such breakthrough findings were crucial in supporting the development and approval of several new treatments for these diseases.(7,11) Advances in science and technology have created new opportunities and challenges to improve and expand the development of personalized medicine for many neurological rare diseases.”
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“Given the known issues with conducting clinical research into rare conditions, such as, recruitment and funding (Griggs et al 2009), there are very few high-quality studies regarding PDOC and consequently current recommendations are largely based on expert opinion.”
Spelbrink, E. M., Brown, T. L., Brimble, E., Blanco, K., Nye, K., & Porter, B. E. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1109547 · Cited by 16
“…models and research funding further highlight the need for collaboration between clinicians, industry, and patient advocacy groups to advance rare disease research (Griggs et al., 2009; Merkel et al., 2016; Julkowska et al., 2017; Denton et al., 2021; Denton et al., 2022; Yang et al., 2022).”
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“…clinical trials when dealing with very rare diseases and have defended other types of trial designs, such as using external or historical controls or participants serving as their own control, in order to allow development of needed medicines (Buckley, 2008; Griggs et al., 2009; Anonymous, 2010).”
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“Due to specialized challenges facing rare disease researchers, the task of safeguarding patients’ identity is particularly difficult (Griggs et al. 2009).”
BackgroundDoes market exclusivity hinder the development of Follow-on Orphan Medicinal Products in Europe?
Brabers, A. E., Moors, E. H. M., van Weely, S., & de Vrueh, R. L. A. (2011) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-6-59 · Cited by 15
Korchagina, D., Jarosławski, S., Jadot, G., & Toumi, M. (2018) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-030-01207-6_8 · Cited by 15
Caetano, R., Corrêa, M., Villardi, P., Rodrigues, P. H. D. A., & Osorio-de-Castro, C. G. S. (2021) · PLoS ONE · doi:10.1371/journal.pone.0247853 · Cited by 15
“makes them eligible for incentives and benefits to develop and commercialize these products [18].”
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Rare diseases in clinical endocrinology: a taxonomic classification system
Marcucci, G., Cianferotti, L., Beck‐Peccoz, P., Capezzone, M., Cetani, F., Colao, A., Davì, M. V., Uberti, E. C. D., Prato, S. D., Elisei, R., et al. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0202-6 · Cited by 15
The Care Continuum: An Evolving Model for Care and Research in Rare Diseases
Augustine, E. F., Dorsey, E. R., & Saltonstall, P. L. (2017) · PEDIATRICS · doi:10.1542/peds.2017-0108 · Cited by 16
Miller, K. L., Mueller, C. M., Liu, G., Needleman, K. I. M., & Maynard, J. W. (2020) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-020-01514-5 · Cited by 15
Mehr, A. P., Sadeghi-Najafabadi, M., Chau, K., Messmer, J., Pai, R. N., Roy, N., Friedman, D. J., Pollak, M. R., Schlöndorff, J. S., Naljayan, M. V., et al. (2018) · Kidney International Reports · doi:10.1016/j.ekir.2018.09.012 · Cited by 14
“scientists has helped to facilitate the understanding of disease mechanisms and to identify potential therapeutic targets.(14) Furthermore, national and international rare disease patient registries and contact registries have made the enrollment of patients into multicenter clinical trials possible.”
BackgroundUncovering key clinical trial features influencing recruitment
Idnay, B., Fang, Y., Butler, A. M., Moran, J. A., Li, Z., Lee, J., Ta, C., Liu, C., Yuan, C., Chen, H., et al. (2023) · Journal of Clinical and Translational Science · doi:10.1017/cts.2023.623 · Cited by 14
Bai, J. P. F., Stinchcomb, A. L., Wang, J., Earp, J. C., Stern, S., & Schuck, R. N. (2023) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3096 · Cited by 14
Global Opportunities and Challenges for Clinical Neuroscience
Birbeck, G. L., Hanna, M. G., & Griggs, R. C. (2014) · JAMA · doi:10.1001/jama.2014.2744 · Cited by 14
Self-citationThe elephant in the room: ethical issues associated with rare and expensive medical conditions
Mavroudis, C. D., Mavroudis, C. D., & Jacobs, J. P. (2015) · Cardiology in the Young · doi:10.1017/s1047951115002103 · Cited by 15
“The term “orphan” arose from the conflation with this act and the Orphan Drug Act of 1983, whose purpose was to facilitate and incentivise drug development for rare diseases.(2) Thus, the terms “orphan disease” and “rare disease” became interchangeable and share a common legal definition for the ~25 million people in…”
BackgroundVrinten, C., Lipka, A. F., van Zwet, E. W., Schimmel, K. J. M., Cornel, M. C., Kuijpers, M. R., Hekster, Y. A., Weinreich, S. S., & Verschuuren, J. J. G. M. (2015) · BMJ Open · doi:10.1136/bmjopen-2015-007863 · Cited by 14
“N-of-1 trials may be particularly valuable to explore population treatment effects in patients with rare diseases, where parallel-group RCTs may be unfeasible due to small patient numbers.(27,28) A limiting factor to the widespread use of series of n-of-1 trials, however, is the requirement for a stable disease course…”
BackgroundBader, C., Cossin, S., Maillard, A., & Bénard, A. (2018) · BMC Medical Research Methodology · doi:10.1186/s12874-018-0571-1 · Cited by 14
Andrews, S. M., Raspa, M., Edwards, A., Moultrie, R., Turner‐Brown, L., Wagner, L., Rivas, A. A., Frisch, M., & Wheeler, A. (2019) · Journal of the American Medical Informatics Association · doi:10.1093/jamia/ocz208 · Cited by 14
“It is generally more difficult to maintain anonymity of research participants in the case of rare diseases, and individuals with known or suspected genetic conditions are more vulnerable to discrimination or stigmatization if anonymity is not maintained.(29) In the case of genetic forms of IDDs, parents may be concern…”
BackgroundParra-Guillen, Z. P., Fontanellas, A., Jiang, L., Jericó, D., Martini, P. G. V., Vera‐Yunca, D., Hard, M., Guey, L. T., & Trocóniz, I. F. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15040 · Cited by 14
“…for rare diseases such as AIP are challenging due to limited knowledge available, interindividual heterogeneity of symptoms, and the difficulty of conducting epidemiological studies involving large numbers of patients to understand and explore the disease (Dunoyer, 2011; Griggs et al., 2009).”
BackgroundSmilde, B. J., Stockklausner, C., Keen, R. W., Whittaker, A., Bullock, A. N., von Delft, A., van Schoor, N. M., Yu, P. B., & Eekhoff, E. M. W. (2022) · BMC Musculoskeletal Disorders · doi:10.1186/s12891-022-05471-x · Cited by 14
Exploring the role of digital tools in rare disease management: An interview‐based study
Chang, A., Huang, S. D., Benjamin, D. J., Schmidt, J., Palmer, C. G. S., & Garrison, N. A. (2024) · Journal of Genetic Counseling · doi:10.1002/jgc4.1908 · Cited by 13
Potential Reuse of Oncology Drugs in the Treatment of Rare Diseases
Liu, Z., Fang, H., Slikker, W., & Tong, W. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.06.010 · Cited by 13
“Furthermore, many identified patients are children, and this poses unique ethical considerations [11].”
BackgroundSpahr, A., Rosli, Z., Legault, M., Tran, L. T., Fournier, S., Toutounchi, H., Darbelli, L., Madjar, C., Lucia, C., St-Jean, M.-L., et al. (2021) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-021-01953-8 · Cited by 13
Clinical Trials for Rare Lung Diseases: Lessons from Lymphangioleiomyomatosis
Kinder, B. W., & McCormack, F. X. (2010) · Lymphatic Research and Biology · doi:10.1089/lrb.2009.0027 · Cited by 13
“35 Many subjects are hesitant to enroll in trials if they have a likelihood of being assigned a potentially inferior arm (i.e., have a likelihood of not receiving the experimental therapy) or randomized to a placebo.”
InfluentialKienböck Disease: Quality, Accuracy, and Readability of Online Information
Noback, P. C., Trofa, D. P., Dziesinski, L. K., Trupia, E. P., Galle, S. E., & Rosenwasser, M. P. (2018) · Hand · doi:10.1177/1558944718813631 · Cited by 13
“Not surprisingly, conditions of lower prevalence like KD have less federal, state, and private funds dedicated to the creation of patient-centered resources to educate patients about their condition.(30,31) Consequently, it may be even more critical in the cases of conditions like KD that the scarce resources that do…”
BackgroundOARD: Open annotations for rare diseases and their phenotypes based on real-world data
Liu, C., Ta, C., Havrilla, J. M., Nestor, J. G., Spotnitz, H. M., Geneslaw, A. S., Hu, Y., Chung, W. K., Wang, K., & Weng, C. (2022) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2022.08.002 · Cited by 12
Baheti, B., Innani, S., Nasrallah, M., & Bakas, S. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1304191 · Cited by 12
Cutaneous Neurofibromas and Quality of Life in Adults With Neurofibromatosis Type 1
Lin, M. J., Yao, H., Vera, K., Patel, E., Johnson, M., Caroline, P., Ramos, J., Mehta, J., Hu, X., Blakeley, J. O., et al. (2024) · JAMA Dermatology · doi:10.1001/jamadermatol.2024.2912 · Cited by 12
Rare Diseases and Orphan Drugs
Pariser, A., & Yao, L. P. (2013) · Wiley eBooks · doi:10.1002/9781118312087.ch13 · Cited by 12
Rare diseases in healthcare priority setting: should rarity matter?
Albertsen, A. B. (2021) · Journal of Medical Ethics · doi:10.1136/medethics-2020-106978 · Cited by 12
Rudebeck, M., Scott, C., Rhodes, N. P., van Kan, C., Olsson, B., Alsbou, M., Hall, A. K., Sireau, N. T., & Ranganath, L. R. (2021) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-021-02137-0 · Cited by 12
“This has led to patient advocacy groups becoming larger and with greater influence [9].”
BackgroundHirakawa, A., Nishikawa, T., Yonemori, K., Shibata, T., Nakamura, K., Ando, M., Ueda, T., Ozaki, T., Tamura, K., Kawai, A., et al. (2017) · Therapeutic Innovation & Regulatory Science · doi:10.1177/2168479017728989 · Cited by 12
Bonkowsky, J. L., deVeber, G., Kosofsky, B. E., Augustine, E. F., Bassuk, A. G., Brooks‐Kayal, A. R., Felling, R. J., Fullerton, H. J., Glass, H. C., Grinspan, Z. M., et al. (2020) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2020.08.012 · Cited by 13
Daneshvari, S., Youssof, S., & Kroth, P. J. (2013) · Europe PMC (PubMed Central) · Cited by 12
Orphan diseases: state of the drug discovery art
Volmar, C., Wahlestedt, C., & Brothers, S. P. (2016) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-015-0423-0 · Cited by 12
A New START for Sildenafil in Pediatric Pulmonary Hypertension
McElhinney, D. B. (2014) · Circulation · doi:10.1161/circulationaha.114.009584 · Cited by 12
Management of translocation carcinomas of the kidney
Ged, Y. M. A., Feinaj, A., Baraban, E. G., & Singla, N. (2024) · Translational Cancer Research · doi:10.21037/tcr-24-60 · Cited by 11
“Similar to other rare and orphan diseases, the lack of standardized therapies for advanced stages and of biomarkers leads to the lack of a definite treatment protocol, which should be supported by sufficient research proven data (51).”
Groft, S. C., & Gopal-Srivastava, R. (2013) · Clinical Investigation · doi:10.4155/cli.13.101 · Cited by 11
Self-citationClinical Trials In BMT: Ensuring That Rare Diseases and Rarer Therapies are Well Done
Shurin, S. B., Krischer, J., & Groft, S. C. (2012) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2011.10.030 · Cited by 11
Self-citationRaspa, M., Moultrie, R., Wagner, L., Edwards, A., Andrews, S. M., Frisch, M., Turner‐Brown, L., & Wheeler, A. (2020) · Journal of Medical Internet Research · doi:10.2196/16734 · Cited by 11
Online Pediatric Research: Addressing Consent, Assent, and Parental Permission
Brothers, K. B., Clayton, E. W., & Goldenberg, A. J. (2020) · The Journal of Law Medicine & Ethics · doi:10.1177/1073110520917038 · Cited by 11
Medical costs of Alpha-1 antitrypsin deficiency-associated COPD in the United States
Sieluk, J., Slejko, J. F., SILVERMAN, H. J., Perfetto, E. M., & Mullins, C. D. (2020) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-020-01523-4 · Cited by 11
Dahan‐Oliel, N., Cachecho, S., Fąfara, A., Lacombe, F., Samargian, A., & Bussières, A. (2022) · Research Involvement and Engagement · doi:10.1186/s40900-022-00336-y · Cited by 11
“Background Rehabilitation in rare diseases is often under-represented in research due to lack of funding [1, 2], thereby limiting availability of evidence and resources for management.”
BackgroundStatzer, C., Luthria, K. D., Sharma, A., Kann, M. G., & Ewald, C. Y. (2023) · Biomedicines · doi:10.3390/biomedicines11041212 · Cited by 10
“Around 7000 diseases are classified as “Rare and Orphan diseases,” and their number is increasing by almost 300 every year [26] (www.”
BackgroundCoping with small populations of patients in clinical trials
O’Connor, D. J., & Hemmings, R. J. (2014) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2014.931221 · Cited by 11
“There are, however, many different types of clinical study designs and approaches to increase the efficiency of clinical trials where patient numbers are limited [2-5].”
BackgroundLegrand, M. A., Bagouet, F., Merle, B., Gensburger, D., & Chapurlat, R. D. (2023) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2023.104849 · Cited by 10
Changing the Paradigm for the Treatment and Development of New Therapies for FSGS
Spino, C., Jahnke, J., Selewski, D. T., Massengill, S. F., Troost, J. P., & Gipson, D. S. (2016) · Frontiers in Pediatrics · doi:10.3389/fped.2016.00025 · Cited by 10
The unintended effect of the Orphan Drug Act on the adoption of open innovation
Galati, F., & Bigliardi, B. (2016) · Science and Public Policy · doi:10.1093/scipol/scw001 · Cited by 10
Dahan‐Oliel, N., Bedard, T., Darsaklis, V., Hall, J. G., van Bosse, H. J. P., & Hamdy, R. C. (2018) · BMJ Open · doi:10.1136/bmjopen-2017-021377 · Cited by 10
“Comparability and pooling of findings across individual studies in rare diseases often lack standardisation in methodology and will vary in data collection, selection criteria, classification and outcome measures.(12) Currently, there is no comprehensive registry or classification system to support the high-quality st…”
BackgroundStatistical considerations for rare diseases drug development
Chow, S., & Chang, Y. (2019) · Journal of Biopharmaceutical Statistics · doi:10.1080/10543406.2019.1657441 · Cited by 10
“In practice, however, small patient population is a challenge to rare disease clinical trials for obtaining substantial evidence through the conduct of adequate and well-controlled investigations Griggs et al., (2009). For the development of drug products for rare disease development, data collection from adequate and…”
BackgroundNikles, J., Mitchell, G., Clavarino, A., Yelland, M., & Mar, C. D. (2010) · Australian Health Review · doi:10.1071/ah09654 · Cited by 9
Siegel, C. M., Arnon, R., Florman, S. S., Bucuvalas, J. C., & Oishi, K. (2020) · Nutrients · doi:10.3390/nu12102976 · Cited by 10
Raspa, M., Paquin, R. S., Brown, D. S., Andrews, S. M., Edwards, A., Moultrie, R., Wagner, L., Frisch, M., Turner‐Brown, L., & Wheeler, A. (2020) · Value in Health · doi:10.1016/j.jval.2020.06.016 · Cited by 9
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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