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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

A Correction to this article was published on 06 December 2022

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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.

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  1. The word “drug” refers to both small molecules, biologics, and macromolecules. Please see Tables 1–2 for both US and EU definition of molecules.

  2. 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.

  3. A sponsor may request an orphan-drug designation of an already approved drug for an unapproved use.

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  5. Food and Drug Administration, Recommended Tips for Creating an Orphan Drug Designation Application.

  6. Food and Drug Administration, Office of Orphan Products Development: Financial Incentives for CDER Medical Products.

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  8. 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).

  9. Exclusivity can also be “broken” due to drug shortages.

  10. The FDA’s term structural “sameness” and EC’s term structural “similarity” is referred to collectively as structural similarity in this manuscript.

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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.


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Correspondence to Scott W. Roberts.

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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).

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