🟠 Moderate Evidence
Regulatory approval pathways for rare disease treatments are diverging sharply between the United States and European Union. According to a retrospective observational analysis published in PLOS Medicine by researchers Jin Ding, Michael M. Hopkins, and Paul A. Martin, only 29% of FDA orphan drug approvals between 2011 and 2023 received corresponding European Medicines Agency (EMA) marketing authorisation with orphan designation. This growing discordance means patients in different regions face unequal access to treatments developed for conditions affecting fewer than 200,000 people in the US or Europe.
Key takeaways
- Of 814 FDA orphan drug approvals (2011–2023), only 29% received matching EMA approval with orphan status; 38% were authorised by EMA without orphan designation; 33% were not authorised by EMA
- Approvals in the 2017–2023 period showed significantly lower odds of EMA authorisation than those approved in 2011–2016 (odds ratio 0.66)
- Non-cancer orphan drugs faced substantially worse approval prospects at EMA than cancer-focused treatments
- This regulatory gap threatens equitable access to rare disease treatments and may reflect divergent scientific or policy standards between US and EU regulators
Study at a Glance
| Source | PLOS Medicine |
| Study type | Retrospective observational analysis with descriptive and univariable logistic regression |
| Sample size | 814 FDA orphan drug approvals |
| Population | Orphan-designated drugs approved by FDA between 2011 and 2023 |
| Country | United States and European Union |
Regulatory Fate of FDA Orphan Drug Approvals at EMA
Of 814 FDA approvals 2011–2023, distribution by EMA outcome
Source: Ding, Hopkins, Martin, PLOS Medicine 2024 | Georgian Medical Journal News
Widening approval gap between regulators
The research team, drawing on data from the FDA Orphan Drug Designations and Approvals Database and the EMA medicines database, documented a systematic pattern of regulatory divergence. Over the 13-year study period, 814 drugs received FDA orphan designation and approval; however, their trajectories at EMA varied dramatically. The most striking finding was the temporal trend: drugs approved in the 2017–2023 period were significantly less likely to receive EMA authorisation compared with those approved between 2011 and 2016, with adjusted odds ratio of 0.66 (95% confidence interval [0.48, 0.92]; p = 0.013).
This suggests the gap is not merely a reflection of slower EMA processes, but rather a genuine divergence in approval standards or priorities. Clinical approval patterns now differ markedly between the two largest pharmaceutical markets globally, potentially reflecting distinct approaches to evidence evaluation or different assessments of benefit-risk ratios in rare disease populations.
Therapeutic area and company size shape approval prospects
The analysis identified non-cancer orphan drugs as facing substantially worse odds of EMA approval than cancer-focused treatments. According to the PLOS Medicine study, the therapeutic area was a significant predictor of regulatory discordance—a finding that may reflect either different scientific evidence standards for oncology versus other rare diseases, or regulatory prioritisation of cancer drugs at EMA. Company characteristics also mattered: smaller companies and those headquartered outside the US or EU faced additional barriers to securing matching EMA approvals.
These factors collectively point to structural differences in how the FDA and EMA approach orphan drug evaluation. The FDA has long emphasised accelerated pathways for rare diseases; EMA regulations exist alongside this framework but may apply different evidentiary thresholds or risk-assessment methodologies. The widening gap raises questions about regulatory harmonisation and whether divergence serves patients well or creates fragmented access to critical treatments.
Implications for patients and drug developers
The 33% of FDA orphan approvals not authorised by EMA at all represents a direct access gap: patients with rare diseases in the EU may be denied treatments approved for the same conditions in the US. The additional 38% authorised without orphan status presents a different challenge—these drugs lose benefits such as extended market exclusivity and reduced regulatory fees, potentially affecting future development investment. For pharmaceutical companies, particularly smaller ones, the regulatory complexity now demands dual-track development strategies, increasing costs and timelines for rare disease therapeutics.
The findings published in PLOS Medicine also suggest that patients and advocacy groups should be aware that FDA orphan designation does not guarantee global access. Rare disease communities in Europe may need to engage directly with EMA on drug dossiers if FDA approval has already occurred, rather than assuming parallel pathways will follow.
Of 814 FDA orphan drug approvals between 2011 and 2023, only 29% received corresponding EMA marketing authorisation with orphan designation, while 33% were not authorised by EMA at all. Approvals in the 2017–2023 period showed significantly lower odds (OR 0.66) of EMA authorisation than those from 2011–2016.
— Jin Ding, Michael M. Hopkins, and Paul A. Martin, PLOS Medicine (2024)
What this means
Frequently asked questions
Why do FDA and EMA approve different orphan drugs?
The FDA and EMA use distinct regulatory frameworks and may apply different evidence thresholds, post-market safety monitoring standards, and benefit-risk assessments. According to the PLOS Medicine analysis, non-cancer drugs face particularly divergent outcomes, suggesting therapeutic area-specific differences in how each agency weighs evidence. Company size and headquarters location also influence approval probability, indicating structural barriers beyond purely scientific factors.
What is orphan drug designation and why does it matter?
Orphan designation is granted to drugs targeting rare diseases (affecting fewer than 200,000 people in the US or Europe) and confers benefits such as extended market exclusivity, fee waivers, and priority review. According to the FDA’s Orphan Drug Program, these incentives encourage development of treatments for conditions that would otherwise be unprofitable to pursue. Losing orphan status—as happens to 38% of drugs in this analysis—reduces these commercial protections.
What can be done to reduce this regulatory gap?
Strengthened dialogue between FDA and EMA on evidence standards, harmonisation of guidance documents, and alignment of benefit-risk frameworks could reduce discordance. The study authors note that unmeasured factors contribute to discordance, highlighting the need for deeper investigation into the specific reasons behind regulatory divergence. Joint working groups on rare disease pathways may be particularly valuable.
As rare disease research accelerates globally, the FDA–EMA approval gap may widen further without intervention. Pharmaceutical companies, patient advocacy organisations, and policymakers should use this analysis as evidence for regulatory dialogue. The stakes are high: rare disease patients often have no alternative treatments, making equitable access across regions a matter of public health equity and precision medicine implementation.
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