Discordance in orphan drug approvals between the U.S. Food and Drug Administration and the European Medicines Agency: A retrospective observational analysis

Background The United States (US) and European Union (EU) have long-established orphan drug regulations to incentivise the development of medicines for rare diseases. While the numbers of orphan approvals have risen rapidly, there is increasing discordance in regulatory outcomes between the US and EU. This discordance primarily stems from two sets of cases: US Food and Drug Administration (FDA) orphan approvals not authorised by the European Medicines Agency (EMA), and FDA orphan approvals with EMA authorisation but without orphan designation. We examined factors associated with these two sets of cases to understand the growing gap in orphan approvals between the US and EU.

Methods and findings We collected data on FDA orphan drug approvals between 2011 and 2023 from the FDA Orphan Drug Designations and Approvals Database and their corresponding EMA regulatory status from EMA medicines database. We used descriptive statistical analysis to examine trends and identify discordance in outcomes between agencies. Univariable logistic regression assessed pre-specified factors associated with discordance, including therapeutic area (cancer/non-cancer), company size (large/medium/small), company headquarters location (US/EU/others) and approval period (2011–2016/2017–2023). The main methodological limitations are that the study identified associations but does not establish causality, with unmeasured factors potentially contributing to the observed discordance.

Of 814 FDA orphan approvals, only 29% received corresponding EMA marketing authorisation with orphan designation. A further 38% were authorised by the EMA but without orphan status, while the remaining 33% were not authorised by the EMA. Compared with the 2011–2016 period, cases in the 2017–2023 period were associated with lower odds (OR 0.66 (95% CI [0.48,0.92]; p = 0.013)) of EMA marketing authorisation. Compared with cancer approvals, non-cancer approvals were associated with lower odds (OR 0.53 (95% CI [0.38, 0.75]; p < 0.001)) of having EMA marketing authorisation, but when authorised, were associated with higher odds (OR 2.36 (95% CI [1.50, 3.70]; p < 0.001)) of receiving orphan designation. Compared with large companies, orphan approvals from small and medium-sized companies were associated with lower odds (OR 0.45 (95% CI [0.28, 0.74]; p = 0.001) and (OR 0.29 (95% CI [0.20, 0.43]; p < 0.001)) of EMA marketing authorisation, but among authorised products they were associated with higher odds (OR 2.95 (95% CI [1.75, 4.99]; p < 0.001) and (OR 2.14 (95% CI [1.17, 3.90]; p = 0.014)) of orphan-designated marketing authorisation, respectively. EU companies were associated with higher odds (OR 1.69 (95% CI [1.17–2.43]; p = 0.005)) of receiving EMA orphan approvals compared with US companies.

Conclusions Between 2011 and 2023, regulatory outcomes for orphan drug approvals increasingly diverged between the FDA and the EMA, particularly for cancer indications and approvals sponsored by small US sponsors. Among FDA orphan drugs authorised by the EMA, many were not designated as orphan products because of regulatory differences, particularly regarding requirements around significant benefit and biomarker-defined sub-populations in oncology. FDA-approved orphan drugs that lack EU marketing authorisation may be withheld by companies not because of regulatory barriers but due to insufficient commercial incentives to launch in Europe, resulting in fewer treatment options for European rare disease patients. Our findings suggest that orphan incentives are not the primary driver of commercial EU-launch decisions and therefore incremental changes to regulatory incentives seem unlikely to improve the access to orphan drugs for EU patients.