A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the Orphan Drug Act

Fermaglich, Lewis J.; Miller, Kathleen L.

doi:10.1186/s13023-023-02790-7

Cited by 135Pharmaceutical Economics and PolicyPharmaceutical studies and practicesBiomedical Ethics and Regulation

A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the Orphan Drug Act

Open access

Fermaglich, Lewis J., Miller, Kathleen L.·2023·Orphanet Journal of Rare Diseases

DOI 10.1186/s13023-023-02790-7PMC PMC10290406

Open this paper in CoChat — free account Open PDF

Abstract

Background: Rare diseases affect more than 30 million Americans. The passage of the Orphan Drug Act (ODA) in the United States in 1983 represented a launching point for a rare disease drug development revolution for these patients. Financial incentives provided by the ODA through its Orphan Drug Designation Program, in addition to remarkable scientific advances over the past 40 years, have led to hundreds of drug approvals for rare diseases. Our research examines the rare diseases that have been targeted by orphan drug designations and subsequent approvals since the law was enacted. Methods: Using an internal FDA database, we classified and analyzed all orphan drug designations and approvals from 1983 to 2022 by disease and therapeutic area. Results: Over the 40 years of the ODA, 6,340 orphan drug designations were granted, representing drug development for 1,079 rare diseases. Additionally, 882 of those designations resulted in at least one FDA approval for use in 392 rare diseases. Much of this development has been concentrated in oncology as seven of the top ten most designated and approved diseases were rare cancers. Conclusions: Researchers have estimated that there may be 7000–10,000 rare diseases that have been identified and described. Based on our study, we can conclude that around 5% of rare diseases have an FDA-approved drug and up to 15% of rare diseases have at least one drug that has been developed and shown promise in their treatment, diagnosis or prevention. Funding of basic and translational science for rare disease drug development should continue in order to bring therapies to the millions of affected patients who remain without treatment options.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1186/s13023-023-02790-7

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Around 95% of rare diseases have no FDA-approved drugs and up to 85% of rare diseases do not have even one drug developed that would show promise in rare disease treatment, diagnosis or prevention.
“Moreover, around 95% of rare diseases have no FDA-approved drugs and up to 85% of rare diseases do not have even one drug developed that would show promise in rare disease treatment, diagnosis or prevention21.”
From A foundation model for clinician-centered drug repurposing (2024) · cites this paper as [21]
The molecular basis of many rare diseases remains poorly understood.
“For instance, the molecular basis of many rare diseases remains poorly understood21.”
From A foundation model for clinician-centered drug repurposing (2024) · cites this paper as [21]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Rare-disease genetics in the era of next-generation sequencing: discovery to translation
Boycott, K. M., Vanstone, M. R., Bulman, D. E., & MacKenzie, A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3555 · Cited by 760 · see citing works
How many rare diseases are there?
Haendel, M., Vasilevsky, N., Unni, D., Bologa, C., Harris, N., Rehm, H., Hamosh, A., Baynam, G., Groza, T., McMurry, J., et al. (2020) · Nature Reviews Drug Discovery · doi:10.1038/d41573-019-00180-y · Cited by 554 · cited 1× · see citing works
“Now, four decades later, hundreds of “orphan” drugs have been approved for use in the 7000–10,000 diseases and conditions that are considered rare.[3].”
Background
Mondo: Unifying diseases for the world, by the world
Vasilevsky, N. A., Matentzoglu, N. A., Toro, S., Flack, J. E., Hegde, H., Unni, D. R., Alyea, G. F., Amberger, J. S., Babb, L., Balhoff, J. P., et al. (2022) · doi:10.1101/2022.04.13.22273750 · Cited by 107 · see citing works
Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases
Miller, K. L., Fermaglich, L. J., & Maynard, J. W. (2021) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-021-01901-6 · Cited by 96 · see citing works
Self-citation
CFTR modulator therapies – Effect on life expectancy in people with cystic fibrosis
Balfour-Lynn, I. M., & King, J. A. (2022) · Paediatric Respiratory Reviews · doi:10.1016/j.prrv.2020.05.002 · Cited by 85 · see citing works
The Orphan Drug Act. The first 7 years.
Asbury, C. H. (1991) · PubMed · Cited by 70 · see citing works
Investigating the landscape of US orphan product approvals
Miller, K. L., & Lanthier, M. L. (2018) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-018-0930-3 · Cited by 52 · see citing works
Self-citation
Should rare diseases get special treatment?
Magalhães, M. D. A. F. M. (2021) · Journal of Medical Ethics · doi:10.1136/medethics-2021-107691 · Cited by 48 · see citing works
Important Role of Translational Science in Rare Disease Innovation, Discovery, and Drug Development
Pariser, A., & Gahl, W. A. (2014) · Journal of General Internal Medicine · doi:10.1007/s11606-014-2881-2 · Cited by 42 · see citing works
The Orphan Drug Act
Asbury, C. H. (1991) · JAMA · doi:10.1001/jama.1991.03460070075046 · Cited by 37 · see citing works
The economics of moonshots: Value in rare disease drug development
Yates, N. A., & Hinkel, J. M. (2022) · Clinical and Translational Science · doi:10.1111/cts.13270 · Cited by 25 · see citing works
Drugs and biologics receiving FDA orphan drug designation: an analysis of the most frequently designated products and their repositioning strategies
Miller, K. L., Kraft, S., Ipe, A., & Fermaglich, L. J. (2021) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2021.2047021 · Cited by 21 · see citing works
Self-citation
FDA’s Office of Orphan Products Development: providing incentives to promote the development of products for rare diseases
Patel, S., & Needleman, K. I. M. (2019) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-019-09645-4 · Cited by 13 · see citing works
R&D and market size: Who benefits from orphan drug legislation?
Gamba, S., Magazzini, L., & Pertile, P. (2021) · Journal of Health Economics · doi:10.1016/j.jhealeco.2021.102522 · Cited by 11 · see citing works

Flagged first, then by citations

Sorted by citations

A foundation model for clinician-centered drug repurposing
Huang, K., Chandak, P., Wang, Q., Havaldar, S., Vaid, A., Leskovec, J., Nadkarni, G. N., Glicksberg, B. S., Gehlenborg, N., & Zitnik, M. (2024) · Nature Medicine · doi:10.1038/s41591-024-03233-x · Cited by 249 · see citing works
“For instance, the molecular basis of many rare diseases remains poorly understood 21 .”
Background
Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy
Michaeli, D. T., Michaeli, T., Albers, S., Boch, T., & Michaeli, J. C. (2023) · The European Journal of Health Economics · doi:10.1007/s10198-023-01639-x · Cited by 133 · see citing works
A roadmap for affordable genetic medicines
Kliegman, M., Zaghlula, M., Abrahamson, S. L., Esensten, J. H., Wilson, R. C., Urnov, F. D., & Doudna, J. A. (2024) · Nature · doi:10.1038/s41586-024-07800-7 · Cited by 69 · see citing works
Drug repurposing for Alzheimer’s disease and other neurodegenerative disorders
Cummings, J. L., Zhou, Y., Stone, A. V., Cammann, D., Tonegawa‐Kuji, R., Cacho, J. R. F., & Cheng, F. (2025) · Nature Communications · doi:10.1038/s41467-025-56690-4 · Cited by 61 · see citing works
Invisible patients in rare diseases: parental experiences with the healthcare and social services for children with rare diseases. A mixed method study
Domaradzki, J., & Walkowiak, D. (2024) · Scientific Reports · doi:10.1038/s41598-024-63962-4 · Cited by 31 · see citing works
Considerations for mRNA Product Development, Regulation and Deployment Across the Lifecycle
Skerritt, J. H. (2025) · Vaccines · doi:10.3390/vaccines13050473 · Cited by 30 · see citing works
Rare diseases: still on the fringes of universal health coverage in Europe
Tumiene, B., Juozapavičiūtė, A., & Andriukaitis, V. (2023) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2023.100783 · Cited by 22 · see citing works
Genomics of drug target prioritization for complex diseases
Chen, R. K., Duffy, Á., & Do, R. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-025-00904-4 · Cited by 22 · see citing works
The role of public health in rare diseases: hemophilia as an example
El-Sayed, A., Reiss, U. M., Hanna, D. A., & Bolous, N. S. (2025) · Frontiers in Public Health · doi:10.3389/fpubh.2025.1450625 · Cited by 16 · see citing works
Artificial intelligence in rare diseases: toward clinical impact
Amorim, A. M. B., Orzeł, U., Caniceiro, A. B., Rosário‐Ferreira, N., & Moreira, I. S. (2025) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2025.10.010 · Cited by 14 · see citing works
Orphan Drug Label Expansions: Analysis Of Subsequent Rare And Common Indication Approvals
Miller, K. L., & Lanthier, M. L. (2024) · Health Affairs · doi:10.1377/hlthaff.2023.00219 · Cited by 13 · see citing works
Self-citation
Challenges and Possible Strategies to Address Them in Rare Disease Drug Development: A Statistical Perspective
Chen, J., Nie, L., Lee, S., Chu, H., Tian, H., Wang, Y., He, W., Jemielita, T., Gruber, S., Song, Y., et al. (2025) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3631 · Cited by 13 · see citing works
Analysis of the first ten years of FDA’s rare pediatric disease priority review voucher program: designations, diseases, and drug development
Mease, C., Miller, K. L., Fermaglich, L. J., Best, J., Liu, G., & Torjusen, E. (2024) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-024-03097-x · Cited by 12 · see citing works
Self-citation
Rare Disease Drug Repurposing
Nijim, S., Korsunska, A., Zinski, J. M., Bolden, S. E., Zuccato, M., Repasky, M., & Fajgenbaum, D. C. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.8330 · Cited by 12 · see citing works
Rare disease challenges and potential actions in the Middle East
Fasseeh, A. N., Korra, N., Al-Jedai, A. H., Seyam, A. M., Almudaiheem, H., Alabdulkarim, H. A., Janahi, M., Gamal, M., Fahmy, S., Dallal, S. A. M. A., et al. (2025) · International Journal for Equity in Health · doi:10.1186/s12939-025-02388-4 · Cited by 11 · see citing works
Comparative analysis of FDA approvals by top 20 pharma companies (2014–2023)
Schuhmacher, A., Gassmann, O., Hinder, M., & Hartl, D. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104128 · Cited by 11 · see citing works
mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node
Ritter, L. M., Annear, N. M. P., Baple, E., Ben-Chaabane, L. Y., Bodi, I., Brosson, L., Cadwgan, J., Coslett, B., Crosby, A. H., Davies, D., et al. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-03740-1 · Cited by 10 · see citing works
The Lived Experience of Pediatric Gene Therapy: A Scoping Review
Kimberly, L. L., Hunt, C., Beaverson, K. L., James, E. S., Bateman-House, A., McGowan, R., & deSante-Bertkau, J. E. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.157 · Cited by 9 · see citing works
Integrating Machine Learning-Based Approaches into the Design of ASO Therapies
Leckie, J., & Yokota, T. (2025) · Genes · doi:10.3390/genes16020185 · Cited by 9 · see citing works
Realizing the Potential of Gene Therapies for Rare and Ultra-Rare Inherited Diseases
Booth, C., & Aiuti, A. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.127 · Cited by 9 · see citing works
Availability and Access to Orphan Drugs for Rare Cancers in Bulgaria: Analysis of Delays and Public Expenditures
Kostadinov, K. R., Popova-Sotirova, I., Marinova, Y., Мусурлиева, Н., Iskrov, G. G., & Stefanov, R. S. (2024) · Cancers · doi:10.3390/cancers16081489 · Cited by 10 · see citing works
Increasing Diversity, Equity, Inclusion, and Accessibility in Rare Disease Clinical Trials
Baynam, G. S., Baker, S., Steward, C. A., Summar, M. L., Halley, M. C., & Pariser, A. (2024) · Pharmaceutical Medicine · doi:10.1007/s40290-024-00529-8 · Cited by 8 · see citing works
Rare Disease Innovation at the FDA—Opportunities for Implementation
Shore, C., Worku, T., & Kahn, J. (2024) · JAMA · doi:10.1001/jama.2024.20358 · Cited by 8 · see citing works
Reforming the innovation system to deliver affordable medicines: a conceptual framework of pharmaceutical innovation as a complex adaptive system (forest) and theory of change
Moon, S., Ruiz, A. A., Vieira, M., Large, K. E., & Slovenski, I. (2025) · Journal of Pharmaceutical Policy and Practice · doi:10.1080/20523211.2024.2436899 · Cited by 8 · see citing works
Somewhere to go: a position paper on addressing gaps in transition care for adults with childhood-onset rare diseases
Tosi, L. L., Hart, T. S., Beug, G., Carter, E., & Perfetto, E. M. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-03973-0 · Cited by 8 · see citing works
Patient Enrollment per Month (Accrual) in Clinical Trials Leading to the FDA Approval of New Cancer Drugs
Michaeli, D. T., Michaeli, T., Albers, S., & Michaeli, J. C. (2024) · Targeted Oncology · doi:10.1007/s11523-024-01081-w · Cited by 8 · see citing works
Evolving Concept of Value in Health Economics and Outcomes Research: Emerging Tools for Innovation and Access to Cell and Gene Therapies for Rare Diseases
Toro, W., Yang, M., Patel, A., Su, Z., Dabbous, O. H., & Garrison, L. P. (2024) · Value in Health · doi:10.1016/j.jval.2024.12.006 · Cited by 7 · see citing works
Human-based complex in vitro models: their promise and potential for rare disease therapeutics
Parvatam, S., Pistollato, F., Marshall, L. J., Furtmann, F., Jahagirdar, D., Choudhury, M. C., Mohanty, S., Mittal, H., Meganathan, S., & Mishra, R. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1526306 · Cited by 7 · see citing works
Expanded Spectrum and Increased Incidence of Adverse Events Linked to COVID-19 Genetic Vaccines: New Concepts on Prophylactic Immuno-Gene Therapy, Iatrogenic Orphan Disease, and Platform-Inherent Challenges
Szebeni, J. (2025) · Pharmaceutics · doi:10.3390/pharmaceutics17040450 · Cited by 6 · see citing works
“You get left behind and lost in a complex world of rare care”: equity in access to rare disease care—learnings from the Australian Rare Disease Awareness, Education, Support, and Training (RArEST) project
Palmer, E. E., Recsei, K., McKnight, L., Roberts, N., Baynam, G. S., Zurynski, Y., Farrar, M. A., Healy, L., Millis, N., Zurynski, Y., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105710 · Cited by 5 · see citing works
Prioritizing disease-associated missense variants with chemoproteomic-detected amino acids
Palafox, M. F., Boatner, L. M., Wilde, B. R., Christofk, H. R., Backus, K. M., & Arboleda, V. A. (2025) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2025.04.017 · Cited by 5 · see citing works
Leveraging generative AI to assist biocuration of medical actions for rare disease
Niyonkuru, E., Caufield, J. H., Carmody, L., Gargano, M. A., Toro, S., Whetzel, P. L., Blau, H., Gomez, M. S., Casiraghi, E., Chimirri, L., et al. (2024) · Bioinformatics Advances · doi:10.1093/bioadv/vbaf141 · Cited by 5 · see citing works
Digital health technology use in clinical trials of rare diseases: a systematic review
Mao, X., Zeng, D., Wang, X., Pearce, D. A., Baynam, G. S., Chavannes, N. H., Chung, W. K., Wu, H., Tham, Y. C., Zhang, S., et al. (2025) · Communications Medicine · doi:10.1038/s43856-025-01137-6 · Cited by 5 · see citing works
Advances in Bone-Targeting Drug Delivery: Emerging Strategies Using Adeno-Associated Virus
Sato, T., Chaugule, S. R., Greenblatt, M. B., Gao, G., & Shim, J. (2024) · Human Gene Therapy · doi:10.1089/hum.2024.034 · Cited by 5 · see citing works
Therapeutic Orphan No More: Role for Clinical Pharmacology and Translational Science in Developing Therapeutics for Rare and Neglected Diseases
Ramamoorthy, A., Younis, I. R., Wen, Y., Mehanna, M., Giacomini, K. M., & van der Graaf, P. H. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3474 · Cited by 5 · see citing works
Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research
Iyer, K. A., Tenchov, R., Sasso, J. M., Ralhan, K., Jotshi, J., Polshakov, D. A., Maind, A., & Zhou, Q. A. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00722 · Cited by 6 · see citing works
Bioinformatics and AI/ML approaches using multi-omics data to accelerate diagnosis and delivery of precision care for patients with rare diseases
Singh, K., Usman, S., Zeeshan, S., Yanamala, N. V. K., Nichols, M., Bhise, V. V., Bokhari, S., Sengupta, P. P., & Ahmed, Z. (2025) · Methods in cell biology · doi:10.1016/bs.mcb.2025.03.018 · Cited by 5 · see citing works
Trends in FDA drug approvals: 2021–2024 insights & innovations
Raut, G., & Sharma, S. (2025) · Annales Pharmaceutiques Françaises · doi:10.1016/j.pharma.2025.06.004 · Cited by 5 · see citing works
Rare disease 101: an online resource teaching on over 7000 rare diseases in one short course
Dunne, T. F., Jeffries, D., & McKay, L. (2024) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-024-03286-8 · Cited by 5 · see citing works
Strategies to Advance Drug Repurposing for Rare Diseases
Hong, D., & Kesselheim, A. S. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.8339 · Cited by 4 · see citing works
Information content as a health system screening tool for rare diseases
Groza, T., Robinson, P. N., Lim, W. K., Narasimhalu, K., Hsieh, J. Y. C., Yeo, K. K., Goh, B. K., Thomas, T. G. S., Wong, T. Y., Karnani, N., et al. (2025) · npj Digital Medicine · doi:10.1038/s41746-025-02096-x · Cited by 4 · see citing works
Non-oncology orphan drug development: Productivity and probability of success
Parker, S., Hajjar, J. E., Jonker, A. H., Kahn, S. R., Kritikou, P., Kyriakopoulou, C., & Haight, A. R. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104568 · Cited by 4 · see citing works
Unifying the odyssey: artificial intelligence for rare disease diagnosis and therapy
Ho, M., Žitnik, M., Azachi, R., Basu, S., Rajpurkar, P., & Sidlow, R. (2026) · Health and Technology · doi:10.1007/s12553-026-01057-y · Cited by 4 · see citing works
Management of rare and undiagnosed diseases: insights from researchers and healthcare professionals in Türkiye
Durmuş, S., Yücesan, E., Aktug, S., Utz, B., Çağlayan, A. O., Gençpınar, P., Günay, Ç., Oktay, Y., Yildirim, R. N., Yigit, A., et al. (2025) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1501942 · Cited by 4 · see citing works
The Six Ds of Exponentials and drug discovery: A path toward reversing Eroom’s law
Tropsha, A., Martin, H., & Cherkasov, A. R. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104341 · Cited by 4 · see citing works
A map of molecular drug targets and therapeutics for the US FDA-approved drugs: The impact of expedited regulatory pathways and first-in-class drug approvals on drug innovation
Balakumar, P., Mulukuri, N. V. L. S., & Jagadeesh, G. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108945 · Cited by 4 · see citing works
The Orphan Drug Act at 40: Legislative Triumph and the Challenges of Success
Saltonstall, P. L., ROSS, H., & KIM, P. T. (2023) · Milbank Quarterly · doi:10.1111/1468-0009.12680 · Cited by 4 · see citing works
The advantages of rare disease biobanking: A localised source of genetic knowledge to benefit the South African rare disease community and related stakeholders worldwide
Dercksen, M., Conradie, E. H., Hendriksz, C. J., Malherbe, H. L., & Vorster, B. C. (2023) · South African Medical Journal · doi:10.7196/samj.2023.v113i12.1507 · Cited by 4 · see citing works
Pivotal trial characteristics and types of endpoints used to support Food and Drug Administration rare disease drug approvals between 2013 and 2022
Hong, K., Nugent, B. M., Bandukwala, A., Schuck, R. N., Tomita, Y. A., Pepe, S., Doi, M., Winiecki, S. K., & Lee, K. J. (2025) · Clinical Trials · doi:10.1177/17407745241309318 · Cited by 3 · see citing works
Long-Term Follow-Up of Patients Receiving Cell and Gene Therapy Products
Irinyi, L., Mintzes, B. J., Warning, J., Collie, L., Rush, A., Turtle, C. J., & Byrne, J. A. (2025) · Human Gene Therapy · doi:10.1177/10430342251403439 · Cited by 3 · see citing works
Advances in glycosaminoglycan based diagnostic strategies for mucopolysaccharidoses
Pathak, A., & Poluri, K. M. (2026) · Glycoscience & Therapy · doi:10.1016/j.glycos.2026.100036 · Cited by 3 · see citing works
“We are ambassadors, we are advocates”: rare disease patient advocacy groups as knowledge brokers across health and social systems—a qualitative study from Poland
Domaradzki, J. (2026) · Frontiers in Public Health · doi:10.3389/fpubh.2026.1743598 · Cited by 3 · see citing works
Impact of changes in regulatory framework on approval of medicines for rare diseases and applicability to market access policies
Brown, F., Vargas, M., Stanisic, S., Fatzinger, G., & Iliach, O. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1474087 · Cited by 3 · see citing works
Perspective on Clinical Trials: What Researchers Need to Know
Barde, P. J., & Barde, M. (2025) · Springer eBooks · doi:10.1007/978-3-031-81787-8_11 · Cited by 3 · see citing works
Iron(III) Complexes with Substituted Salicylaldehydes: Synthesis, Interaction with DNA and Serum Albumins, and Antioxidant Activity
Papadopoulos, Z., Hatzidimitriou, A. G., & Psomas, G. (2025) · Molecules · doi:10.3390/molecules30112383 · Cited by 3 · see citing works
A surrogate endpoint-based provisional approval causal roadmap, illustrated by vaccine development
Gilbert, P. B., Peng, J., Han, L., Lange, T., Lu, Y., Nie, L., Shih, M., Waddy, S. P., Wiley, K., Yann, M. L.-J., et al. (2024) · Biostatistics · doi:10.1093/biostatistics/kxaf018 · Cited by 3 · see citing works
Legal Regime for Circulation of High-Tech Medicinal Products: Experience of Interstate Integration Associations
Ponomareva, D. V. (2025) · Lex genetica. · doi:10.17803/lexgen-2025-4-2-28-46 · Cited by 3 · see citing works
Trends, lag and characteristics of rare disease drug approval in the USA and China, 1983–2022
Wang, S., Liu, X., Zou, Y., Tang, Y., Zuo, W., Jiang, R., Shang, J., Tian, X., Liu, Q. P., Xu, T., et al. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-04175-4 · Cited by 3 · see citing works
CURE ID : A Platform to Collect Real‐World Treatment Data for Drug Repurposing in Rare Genetic Disorders
Farid, T., Ruzhnikov, M. R. Z., Duggal, M., Tumas, K. C., Strongin, S. R., Sid, E., Fuchs, S. R., Sacks, L. V., Pichard, D. C., Pilgrim-Grayson, C., et al. (2025) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.32153 · Cited by 3 · see citing works
The Orphan Drug Act and rare cancers: a retrospective analysis of oncologic orphan drug designations and associated approvals from 1983-2022
Ipe, A., Fermaglich, L. J., Kraft, S., Mease, C., Le, T., & Miller, K. L. (2024) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2024.2333245 · Cited by 3 · see citing works
Self-citation
Integrated Applied Clinical Pharmacology in the Advancement of Rare and Ultra‐Rare Disease Therapeutics
Ryder, S. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3382 · Cited by 3 · see citing works
Leveraging Generative AI to Accelerate Biocuration of Medical Actions for Rare DiseasePreprint
Niyonkuru, E., Caufield, J. H., Carmody, L., Gargano, M. A., Toro, S., Whetzel, T., Blau, H., Soto, M., Casiraghi, E., Chimirri, L., et al. (2024) · medRxiv · doi:10.1101/2024.08.22.24310814 · Cited by 3 · see citing works
The Promise and Challenges of Genomics for Patients and Families Affected by Rare Conditions
Andersen, C. A., Pelling, A. L., & Wynn, S. L. (2025) · Annals of Human Genetics · doi:10.1111/ahg.70008 · Cited by 2 · see citing works
Application of observational research methods to real-world studies for rare disease drugs: A scoping review protocol
Patel, Y. P., Ghaddar, L., Lin, Y., Karim, N., Chan, K., Dupuis, L. L., & Tadrous, M. (2025) · PLoS ONE · doi:10.1371/journal.pone.0304540 · Cited by 2 · see citing works
Advances in Cell and Gene Therapy for Rare Disease Treatment
Baek, H. J., Nam, Y., Rim, Y. A., & Ju, J. H. (2025) · International Journal of Stem Cells · doi:10.15283/ijsc25028 · Cited by 2 · see citing works
A case-based explainable graph neural network framework for mechanistic drug repositioning
Gonzalez-Cavazos, A. C., Tu, R., Sinha, M., & Su, A. I. (2026) · Bioinformatics · doi:10.1093/bioinformatics/btag008 · Cited by 2 · see citing works
Analysis of Real‐World Data Utilization in the Orphan Drug Approval Process: Focusing on New Drug Marketing Applications Submitted to the FDA
Kim, M., & Hong, E. (2026) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.70228 · Cited by 2 · see citing works
Strategic consensus on the clinical translation of advanced therapies in paediatric rare neurological disorders
Lim, N., Meagher, C. E., Bye, A., Lorentzos, M., Dale, R. C., Mohammad, S. S., Howell, K. B., Palmer, E. E., Woodcock, I. R., Macdonald‐Laurs, E., et al. (2026) · Neurotherapeutics · doi:10.1016/j.neurot.2026.e00921 · Cited by 2 · see citing works
The Role of Pharmacogenomics in Rare Diseases
Man, A., Groeneweg, G. S. S., Ross, C. J., & Carleton, B. (2024) · Drug Safety · doi:10.1007/s40264-024-01416-6 · Cited by 2 · see citing works
Repurposing With Purpose: Treatment of Bachmann–Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies
Bupp, 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 · see citing works
Analysis of the Structural Transformations Underlying the Design of Innovative Next-in-Class Drugs
Balakin, K. V. (2023) · Russian Journal of General Chemistry · doi:10.1134/s107036322315001x · Cited by 2 · see citing works
Antisense oligonucleotides in rare neurogenetic disorders
Shin, H. J., Ko, A., Oh, J., & Kang, H. (2024) · Journal of genetic medicine · doi:10.5734/jgm.2024.21.2.41 · Cited by 1 · see citing works
Precision Omics Initiative Sweden (PROMISE): A New Model for Biomedical ResearchPreprint
mpe, A. K. A., Gudmundsson, S., Walsh, C. P., Lindblad‐Toh, K., Johansson, &., Clareborn, A., Ameur, A., Edsjö, A., Fioretos, T., Ehrencrona, H., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4992987 · Cited by 2 · see citing works
Trends from two decades of orphan designations in paediatric rare neuromuscular diseases
Duarte, D. M., Lima, M. B. D. S., & Sepodes, B. M. N. (2024) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2024.122989 · Cited by 1 · see citing works
Re-envisioning clinical trial design in systemic sclerosis
Volkmann, E. R., Tashkin, D. P., & Smith, V. M. (2025) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2025.2500612 · Cited by 1 · see citing works
Nadir Hastalıklarda Tedaviye Erişim: Mevcut Durum, Engeller ve Çözüm Önerileri
Yıldırım, M., & Keskin, H. (2025) · Sağlık Bilimlerinde Değer · doi:10.33631/sabd.1507046 · Cited by 1 · see citing works
The EMA as a potential driver of competitiveness of orphan medicines in Europe: a focus on regulatory incentives and funding opportunities
Gomez-Ferreria, M. A., Garcia-Muñoz, V., & Zwiers, A. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-04095-3 · Cited by 1 · see citing works
Advancing ATMPs for orphan diseases: redefining the roles of pharmaceutical companies and academia
Hidalgo‐Simon, A., & Booth, C. (2025) · Blood Immunology & Cellular Therapy · doi:10.1016/j.bict.2025.100023 · Cited by 1 · see citing works
Adverse events experienced by people living with chronic rare diseases: A scoping review
Kwaan, L., Aldous, C. M., & Malherbe, H. L. (2025) · Rare · doi:10.1016/j.rare.2025.100116 · Cited by 1 · see citing works
How social pharmaceutical innovations are addressing problems of availability, accessibility and affordability of drugs for rare diseases
Douglas, C. M. W., Kleinhout‐Vliek, T., Hagendijk, R., Rabeharisoa, V., Boon, W., Aith, F., Cláudio Cordovil Oliveira, U. F. R. J., Grunebaum, S., & Moors, E. H. M. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-04132-1 · Cited by 1 · see citing works
Genetic Targets, Financial Creativity: BridgeBio’s Model for Sustainable Drug Development
Shukla, C. G., Tendler, I., Kumar, N., & Lo, A. W. (2025) · Drug Discovery Today · doi:10.1016/j.drudis.2025.104583 · Cited by 1 · see citing works
Why is the pharmaceutical industry investing in targeted therapies? The emergence of “premium pharma”
Martin, P. A., Ding, J., & Hanchard, M. (2025) · Social Science & Medicine · doi:10.1016/j.socscimed.2025.118888 · Cited by 1 · see citing works
A multi-task learning approach for prediction of missing bioactivity values of compounds for the SLC transporter superfamily
Cerimagic, T., Sosnin, S. D., & Ecker, G. F. (2026) · Digital Discovery · doi:10.1039/d5dd00536a · Cited by 2 · see citing works
Australia’s top 10 rare disease research priorities: a priority setting partnership
Sivaramakrishnan, H., Reilly, M., Jaffe, A. B., Baynam, G., Helwani, F., McKenzie, A., & Finlay-Jones, A. (2026) · Journal of Rare Diseases · doi:10.1007/s44162-026-00146-w
Trends in oncology marketing applications in the European Union: a five‐year systematic review
Basto, R., Karaya, S., & Zwiers, A. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1738701 · Cited by 1 · see citing works
Menkes Disease: Another Example of Progress in the Development of Pharmaceuticals for Rare Childhood Diseases, But Much Still Remains to Be Done
Beninger, P. R. (2026) · Clinical Therapeutics · doi:10.1016/j.clinthera.2026.02.014 · Cited by 1 · see citing works
Knowledge-Graph Framework for Rare Disease Drug Repurposing Using Genes, Pathways, and Orphan Drug Labels
Martinez, J., & Lopez, C. (2026) · Pharmacophore · doi:10.51847/4hpglzx1ca · Cited by 1 · see citing works
Mutation-centric kinase drug repurposing for rare cancers
Chan, M., Ma, H., Subbiah, V., & Gujral, T. S. (2026) · Nature reviews. Cancer · doi:10.1038/s41568-026-00944-w · Cited by 1 · see citing works
Molecular Diagnosis to Individualized Therapies in Rare Genetic Diseases: New Approach Methodologies, RNA Therapeutics, and the Case for a Human-First Filter
Anwar, S., & Yokota, T. (2026) · Genes · doi:10.3390/genes17070780 · Cited by 1 · see citing works
From Challenge to Opportunity: How Shwachman–Diamond Syndrome Became a Promising Target for Therapy Development
Hars, E. S., & McReynolds, L. J. (2024) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.3393 · Cited by 1 · see citing works
Reframing risks in rare diseases: economics of networks, spillovers, and scale
Runge, C. F., Campbell, J. D., & Runge, C. P. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1516725 · Cited by 1 · see citing works
Current State and Demographic Trends of Medically Underserved Populations in Rare Disease Research in the United StatesPreprint
Manjunatha, L., Saundarya, M. S., Dokuru, D. R., Venugopal, N., Waldrop, J. N., Blount, L. G., Kartha, R. V., & Rajasimha, H. K. (2025) · medRxiv · doi:10.1101/2025.04.30.25326209 · Cited by 1 · see citing works
Should We Call Every Cancer a Rare Cancer?
Nabhan, C., & Subbiah, V. (2026) · Journal of Clinical Oncology · doi:10.1200/jco-26-00596 · Cited by 1 · see citing works
Designing therapies relevant in human genetic disorders
Smith, M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23648-8.00011-5
Use of Basket Trials to Solve Sleep Problems in Patients with Rare Diseases
Pullen, L. C., Bott, N., McCanless, C., Revana, A., Sevinc, G., Gorman, C., Duncan, A., Poliquin, S., Pfalzer, A. C., Schmidt, K. Q., et al. (2024) · Clocks & Sleep · doi:10.3390/clockssleep6040044
Characterizing circulating biomarkers for childhood dementia disorders: A scoping review of clinical trials
D’Silva, A., Barnes, J., Djafar, J. V., Bhattacharya, K., Yan, J., Mohammad, S. S., Bandodkar, S., Johnson, A., Tchan, M. C., Miteff, C., et al. (2025) · Neurotherapeutics · doi:10.1016/j.neurot.2025.e00546
Model-informed drug development in rare diseases
Brine, N., Dyer, C., & Smith, K. (2025) · Medical Writing · doi:10.56012/sbrq7799
How many zebras are there now? An updated report on publications on rare diseases in medical literature
Moroz, T., Taylor, M., Schmitt, P., Donovan, D. J., & Nori, M. (2025) · Future Rare Diseases · doi:10.1080/23995270.2025.2499402
Insights into Support Systems for Orphan Drug Development: A Comparative Study
Leng, Y., Tang, Y., Yu, W., Hou, Y., He, H., Han, Y., Huang, H., Zhang, W., & Li, N. (2025) · Therapeutic Innovation & Regulatory Science · doi:10.1007/s43441-025-00833-8
Epidemiology of Rare Diseases
Eslick, G. D. (2025) · Springer eBooks · doi:10.1007/978-1-4614-6625-3_91-1

Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years
Braun, M. M., Farag-El-Massah, S., Xu, K., & Coté, T. R. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3160 · Cited by 148 · see citing works
Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases
Miller, K. L., Fermaglich, L. J., & Maynard, J. W. (2021) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-021-01901-6 · Cited by 96 · see citing works
Self-citation
The Orphan Drug Act and rare cancers: a retrospective analysis of oncologic orphan drug designations and associated approvals from 1983-2022
Ipe, A., Fermaglich, L. J., Kraft, S., Mease, C., Le, T., & Miller, K. L. (2024) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2024.2333245 · Cited by 3 · see citing works
Self-citation
FDA Orphan Designations, Approvals, and Regulatory Review Time since the Enactment of the Orphan Drug Act (1983)Preprint
Althobaiti, H., Seoane-Vazquez, E. C., Brown, L. M., Fleming, M. L., & Rodríguez-Monguió, R. (2022) · Research Square · doi:10.21203/rs.3.rs-1919358/v1
Analysis of orphan designation status for FDA approved drugs, and case studies in oncology, neuroscience and metabolic diseases
Brown, D. G., & Wobst, H. J. (2023) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2023.117170 · Cited by 8 · see citing works

Authors: Fermaglich, L. J., & Miller, K. L.
Affiliations: United States Food and Drug Administration (US)
Corresponding author: Fermaglich, Lewis J.
ORCID: Fermaglich, Lewis J.
Miller, Kathleen L.
Venue: Orphanet Journal of Rare Diseases
Publisher: Springer Science and Business Media LLC
Published: 2023-06-23
Volume: 18
Issue: 1
Pages: 163-163
ISSN: 1750-1172 (ISSN-L)
DOI: 10.1186/s13023-023-02790-7
PMC: PMC10290406
OpenAlex: W4381839562
Cited by: 134
References: 14
Citations by year: 2026: 41 · 2025: 58 · 2024: 28 · 2023: 7
FWCI: 27.29
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Social Sciences › Economics, Econometrics and Finance › Economics and Econometrics › Pharmaceutical Economics and Policy
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Health Sciences › Medicine › Physiology › Biomedical Ethics and Regulation
Keywords: rare diseases, orphan drugs, Orphan Drug Act, orphan drug designation, drug approval, rare tumor, anticancer drug development, therapeutic areas, FDA drug approval, rare disease drug development
MeSH terms: Humans, Neoplasms, Orphan Drug Production, United States, United States Food and Drug Administration, Drug Approval, Rare Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the Orphan Drug Act

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks