EMA, MHRA, and FDA: A Comparative Guide to Orphan Drug Regulations and how they affect medicine developers.
Orphan Definition Thresholds
The EU and UK eligibility criteria require that a medicinal product must address a life-threatening or chronically debilitating condition affecting ≤5 in 10,000 or one with insufficient return on investment, and it must offer a significant benefit over existing methods, if any exist.1 The fundamental U.S. orphan criteria involve a rare disease or condition that affects <200,000 persons total in the U.S. or shows an inability to recover costs.2
Designation Timing and Process
- European Medicines Agency (EMA) & The Food and Drug Administration (FDA): Orphan designation can be granted early in development (even pre-clinical or Phase 1). 1,2-3
- Medicines and Healthcare Products Regulatory Agency (MHRA): Orphan designation assessed only at time of Marketing Authorisation Application (MAA).4
The EMA has a dedicated committee, the Committee for Orphan Medicinal Products (COMP), the FDA has the Office of Orphan Products Development (OOPD), while MHRA handles orphan applications internally.
Regulatory Coordination
In the US, the FDA created Project Orbis, a collaborative initiative which includes the MHRA and other regulatory authorities to review oncology medicines, which may also include orphan oncology medicinal products.
The EMA and FDA share information on orphan medicines under their confidentiality arrangement and have developed common procedures. The MHRA is actively working to align appropriate regulatory pathways with global regulatory agencies under the new framework for rare diseases. Additionally, the EMA, MHRA and FDA all participate in the International Council for Harmonisation (ICH), aligning technical requirements.
Market Exclusivity Periods
- EU/UK: 10 years, extendable to 12 with completion of the paediatric investigation plan and inclusion of the results in the product information.1 4
- EU/UK includes a clause to reduce to 6 years if the criteria for orphan designation are no longer met (though the EU may abolish this in future).1 4
- U.S: 7 years exclusivity with no exclusivity reduction once granted, except in cases of clinical superiority.2
Financial & Development Incentives
Orphan maintenance, orphan similarity & clinical superiority
At the time of a medicine’s approval, the EMA requires applicants to demonstrate that the medicine maintains its status as an orphan medicine by submitting an orphan maintenance report. The EMA then determines if all criteria to maintain the medicine’s orphan designation at the time of authorisation have been met, thus enabling the orphan medicine to benefit from the 10-year market exclusivity.
Additionally, the applicant must also justify, in advance of submitting an MAA, that the medicinal product in question is not infringing the market exclusivity of another orphan product in the same indication. The applicant should attach asimilarity report to the MAAaddressing the possible similarity between the new medicinal product and the orphan medicinal product(s) which have received a marketing authorisation.
In the US, a similar concept appears as the “clinical superiority” requirement: a second drug with the same active substance and indication will not get orphan exclusivity unless it is clinically superior to the first demonstrated by means of greater efficacy, greater safety in a substantial portion of the target populations, or in unusual cases a major contribution to patient care (preventing duplicate drugs from using the system).2 Thus, while the legal mechanisms differ, EMA and FDA both ensure that me-too products don’t simply piggyback on orphan incentives without offering additional benefit.
The EU can still approve the drug but just not grant orphan exclusivity if the orphan designation criteria are not met at the time of the MAA when the orphan maintenance report is submitted . Similarly, in the US, if an orphan drug designation is granted, and if the drug receives marketing approval for the designated use, for the drug to be eligible for orphan drug exclusivity, the sponsor must demonstrate that the drug is clinically superior to any previously approved same drug for the same use. Any claim for clinical superiority could require a head-to-head trial.2 However, in relation to orphan similarity in the EU, if the product is similar to an already authorised orphan product, then unless one of the derogations applies (consent from original MAH, supply issues, clinical superiority), the entire MAA is refused.
Pediatric Oncology Requirements: The RACE Act (US)
A significant change affecting orphan drugs in oncology was the implementation of the RACE for Children Act in August 2020.5 This law closed a loophole by requiring that even orphan-designated cancer drugs must conduct pediatric studies if the drug’s molecular target is relevant to pediatric cancers. Previously, any orphan designation exempted a drug from pediatric study obligations under the Pediatric Research Equity Act (PREA). Now, orphan oncology drugs no longer get a blanket exemption. This represents a shift in regulatory processes aimed at pediatric cancer drug development (this aligns with the focus on oncology orphans; many new cancer drugs have orphan status).5
Post-Approval Access & HTA
Outside the scope of regulatory approval but important in practice, orphan drugs face differing reimbursement processes. The EU member states each handle pricing/HTA, and the UK has a specialised Highly Specialised Technologies (HST) appraisal route in NICE for ultra-orphan drugs (ultra-rare conditions, typically with a prevalence of ≤1 in 50,000) with higher cost-effectiveness thresholds.6 The US, lacking a single health technology authority (HTA) body, relies on insurance and market dynamics, but the high cost of many orphan drugs has been a policy discussion point. All regulators have shown flexibility in adaptive approvals or use of surrogate endpoints for serious rare diseases, given the small trial populations.
- UK: NICE’s HST route for ultra-orphan drugs (≤1 in 50,000).6
- EU: Each member state handles pricing/HTA.
- US: No centralised HTA; market-driven, cost is a concern.
Summary
While the EMA, MHRA, and FDA share a common goal of incentivising rare disease treatment development, their frameworks differ in timing, exclusivity, and incentives. EU regulation reforms may introduce a tiered system and the UK is developing its own identity post-Brexit.
How Somerville Development Partners can help
We have supported the development and approval of numerous orphan drugs across different therapeutic areas and rare diseases. We have an expert understanding of orphan drug development and regulatory science.
We can help you:
- Compile your orphan drug designation application.
- Address challenges and respond to questions often faced by orphan drug developers.
- Demonstrate that your medicine maintains its status as an orphan medicine by submitting an orphan maintenance report.
- Compile your similarity report in preparation for submitting your marketing authorisation application.
