The U.S. Food and Drug Administration and European Commission have developed successful orphan drug legislation to promote the research, development, and marketing approval of drugs to treat rare diseases. Central to these regulations are the concepts of structural similarity and clinical superiority/significant benefit to achieve orphan drug exclusivity. However, differences in health authority expectations remain regarding the qualification for an orphan drug designation, defining structural similarity, and demonstrating clinical superiority/significant benefit. These differences can create sponsor company uncertainty regarding the approvability of products (e.g., blocking risk by an existing orphan product) and divergent orphan drug decisions among health authorities. A comprehensive assessment of current regulations, case studies in exclusivities, and recommendations for improvement are presented.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Data sharing not applicable to this article as no datasets were generated or analysed for this publication.
The word “drug” refers to both small molecules, biologics, and macromolecules. Please see Tables 1–2 for both US and EU definition of molecules.
A non-rare disease or condition occurring in >200,000 persons may also be designated as an orphan drug if an orphan subset of the patient population can be justified based upon drug toxicity, mechanism of action, or previous clinical experience with the drug.
A sponsor may request an orphan-drug designation of an already approved drug for an unapproved use.
Food and Drug Administration, Orphan Drug Designation Request Form, OMB Control Number 0910–0167.
Food and Drug Administration, Recommended Tips for Creating an Orphan Drug Designation Application. https://www.fda.gov/media/111762/download
Food and Drug Administration, Office of Orphan Products Development: Financial Incentives for CDER Medical Products. https://www.fda.gov/media/135236/download
Food and Drug Administration, Designating an Orphan Product: Drugs and Biological Products. https://www.fda.gov/industry/developing-products-rare-diseases-conditions/designating-orphan-product-drugs-and-biological-products
Orphan products are exempt the US Pediatric Research Study Requirements (PREA). While pediatric exclusivity usually attaches to the end of all existing marketing exclusivity and patent periods, pediatric exclusivity runs concurrently with orphan exclusivity. See Food and Drug Administration, Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and Cosmetic Act: Frequently Asked Questions on Pediatric Exclusivity (505A). https://www.fda.gov/drugs/development-resources/qualifying-pediatric-exclusivity-under-section-505a-federal-food-drug-and-cosmetic-act-frequently
Exclusivity can also be “broken” due to drug shortages.
The FDA’s term structural “sameness” and EC’s term structural “similarity” is referred to collectively as structural similarity in this manuscript.
European Medical Agency, Orphan designation: overview. https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation-overview
European Medical Agency, Legal framework: orphan designation. https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designation/legal-framework-orphan-designation
European Medical Agency, Decision of the Executive Director: On fee reductions for designated orphan medicinal products, EMA/135645/2020.
European Medical Agency, Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan drug, EMA/COMP/15893/2009 Final.
European Medical Agency, Points to consider on the Calculation and Reporting of the Prevalence of a Condition for Orphan Drug Designation, EMA/COMP/436/01 Rev.1.
European Medical Agency, Recommendations on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation, EMA/COMP/15893/2009.
European Medical Agency, Application for orphan medicinal product designation.
European Medical Agency, Sponsor’s guide to an orphan drug designation.
Miller KL, Fermaglich LJ, Maynard J. 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 disease. Orphanet J Rare Dis. 2021;16:265.
Food and Drug Administration, Developing Products for Rare Diseases & Conditions. https://www.fda.gov/industry/developing-products-rare-diseases-conditions
European Medical Agency, Annual report on the use of the special contribution for orphan medicinal products, EMA/307192021, 15 February 2021.
See 21 CFR 316.3 and the FDA OOPD webinar described in reference 5.
For the FDA’s guidance for determining sameness of monoclonal antibodies, see U.S. Food and Drug Administration Guidance for Industry “Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations”, April 2014.
Determining sameness for ATMP’s does not rely on a structural similarity argument and thus was excluded from this discussion. For additional information, see U.S. Food and Drug Administration Guidance for Industry “Interpreting Sameness of Gene Therapy Products Under Orphan Drug Regulations”, September 2021.
Commission regulation (EU) 2018/781.
European Medical Agency ATMP similarity considerations have been omitted from this discussion.
European Medical Agency, Guideline on aspects of the application of Article 8(1) and (3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus authorized orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity, 2008/C 242/08.
European Medical Agency Updated (Co)Rapporteurs’ Joint CHMP Assessment Report, Rev. 06.20.
Manley PW, Stiefl N, Cowan-Jacob SW, et al. Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg Med Chem. 2010;18:6977–86.
For additional discussion regarding the use of 2D chemical fingerprints to determine structural similarity, see: Franco, P.; Porta, N.; Holliday, et al. Molecular similarity considerations in the licensing of orphan drugs. Drug Discovery Today. 2017;22:377–81 and references cited therein.
Lanar S, Acquadro C, Seaton J, et al. To what degree are orphan drugs patient-centered? A review of the current state of clinical research in rare diseases. Orphanet J Rare Dis. 2020;15:134.
Østergaard H, Bjelke JR, Hansen L, et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-Glycans in the activation peptide. Blood. 2011;118:2333–41.
Refixia: EPAR—product information, Annex I, updated version 02/08/2017. https://www.ema.europa.eu/en/documents/product-information/refixia-epar-product-information_en.pdf
Zaman R, Islam RA, Idnat N, et al. Current strategies in extending half-lives of therapeutic proteins. J Control Release. 2019;301:176–89.
Ettingshausen CE, Hegemann I, Simpson ML, et al. Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-FC fusion protein: a randomized trial. Res Pract Thromb Haemost. 2019;3:268–76.
A similar opinion was provided about the recombinant fusion protein linking coagulation factor IX with human albumin (albutrepenonacog alfa).
Fregonese L, Greene L, Hofer M, et al. Demonstrating significant benefit of orphan medicines: analysis of 15 years of experience in Europe. Drug Discovery Today. 2018;23:90–100 (and references cited therein).
Food and Drug Administration, Clinical Superiority Findings. https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/clinical-superiority-findings
The authors additionally wish to thank Sebastian Roehrich, Amr Abdallah, Anja Markert, Jane Møll Pedersen, Karen Schumann, and Michael Søberg Christensen for the careful review of this manuscript.
No funding was granted for the preparation or authorship of this article.
Conflict of interest
The views expressed in this article are those of the authors and do not necessarily reflect the opinions of their companies/institutions. All authors are currently employed by Novo Nordisk.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Roberts, S.W., Elvang, T.L.B., Syed, L. et al. Regulatory Considerations Toward Orphan Drug Designation and Orphan Drug Exclusivity in the United States and European Union: Structural Similarity, Clinical Superiority/Significant Benefit, and Case Studies. Ther Innov Regul Sci 57, 386–395 (2023). https://doi.org/10.1007/s43441-022-00477-y