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.

The aim of this study is to define chemical categories that can be applied to regulatory read-across assessments for repeated-dose toxicity, by classifying toxic substances based on their structures and mechanism of actions (MoAs). Hemolytic anemia, which often appears primarily, was examined as an example. An integrated database was constructed by collecting publicly available datasets on repeated-dose toxicity, in which 423 out of a total of 1518 chemicals were identified as capable of inducing hemolytic anemia. Subsequently, by grouping these chemicals based on their chemical structures and plausible MoAs on hemolytic substances, we identified the following categories: (i) anilines, (ii) nitrobenzenes, (iii) nitroanilines, (iv) dinitroanilines, (v) ethylene glycol alkyl ethers, (vi) hydroquinones, (vii) oximes, and (viii) hydrazines. In these categories, the toxicant and the measurable key events leading to hematotoxicity were identified, thereby allowing us to justify the categories and to discriminate the category substances. Moreover, toxicokinetics seems to critically affect the hemolytic levels of the category substances. Overall, the categories were validated through a comprehensive analysis of the collected information, while the utility was demonstrated by conducting a case study on the selected category. Further endeavors with this approach would attain categories for other organ toxicity endpoints.