How to plan for successful maintenance of orphan designation in the EU

Around 36 million people in the European Union live with a rare disease. (EMA, 2025). More than 95% of rare diseases still lack authorised therapies.

The EU Orphan Regulation (EC) No 141/2000 has been central to stimulating innovation in rare diseases. Incentives for orphan drug designation (ODD) include protocol assistance, substantial fee reductions, access to the centralised authorisation procedure, and a ten-year period of market exclusivity following marketing authorisation (MA) (EMA, 2010).

The pathway to ODD is relatively well understood, but the subsequent requirement to maintain ODD status at the time of the marketing authorisation application (MAA) is often not accounted for during development (EMA, 2010). However, maintenance of orphan status is not merely a final administrative hurdle; it is a critical assessment in which the Committee for Orphan Medicinal Products (COMP) evaluates whether the key orphan designation criteria are still met (see below). The COMP decision can influence both regulatory and commercial strategies, particularly as the landscape of rare disease research becomes more competitive and as the EU pharmaceutical framework continues to evolve.

This blog explores:

1. How sponsors can plan effectively for orphan maintenance review
2. The importance of early regulatory engagement
3. The complexities of demonstrating significant benefit over any existing therapies

It highlights the increasing role of indirect comparisons to demonstrate significant benefit, when this is required. Practical issues and emerging expectations for orphan drug developers are considered.

Why Maintenance of Orphan Designation Matters

Under the Orphan Regulation (EC, 2000), a product can receive ODD at any stage prior to an MAA. Designation provides structured support, but it does not guarantee that the product will retain its orphan status at the time of MAA (EMA, 2016).

During review of the MAA, the COMP conducts a parallel assessment to determine if the product still meets the three pillars of orphan criteria:

• Prevalence remains below 5 in 10,000 (or insufficient returns justify incentives)
• The condition remains life-threatening or chronically debilitating
• The medicine provides a significant benefit over satisfactory methods of diagnosis, prevention or treatment. (EC, 2000)

Only if these criteria are still met and the product is not considered similar to an already authorised orphan therapy (unless derogation applies) (EMA, 2016), will the European Commission (EC) confirm the orphan status of the applicant’s product and grant market exclusivity (EMA, 2010).

As the number of approved orphan therapies grows and standards of care evolve, the bar for demonstrating significant benefit is rising. So, sponsors need to engage with regulators early and plan their evidence strategies well before commencing confirmatory trials to ensure that data will be generated which will demonstrate that orphan criteria remain fulfilled at the time of the MAA.

1.   Planning effectively for an Orphan Maintenance Review

Design Early for a Successful Maintenance Outcome

A strong orphan maintenance dossier results from decisions made years before the MAA. But, in the development of orphan therapies the first hurdle is how to demonstrate safety and efficacy in small, heterogeneous populations with limited natural history. Such constraints require increasingly creative clinical trials to be designed. Only then can it be determined whether the evidence from these trials will also demonstrate the significant benefit of the therapy during the orphan maintenance review – a second, but critical, hurdle.

Plan evidence generation with significant benefit in mind

Sponsors should evaluate at the outset:

• What are the existing satisfactory methods?
• Are direct comparative trials possible? If not, what indirect comparisons would be considered acceptable?
• What clinically relevant endpoints will support orphan maintenance?

Because the COMP expects robust justification of clinical benefit at MAA, planning of evidence strategies needs to align with this expectation.

Address the reality of rare disease study design

Randomised controlled trials may be impractical or ethically challenging for rare diseases. Small, heterogeneous populations limit statistical power. In such cases, sponsors should plan:

• Early alignment with regulators on pragmatic and innovative trial designs
• Use of real-world data to contextualise outcomes
• Clearly defined external control strategies where appropriate

These early considerations can prevent the sponsor being forced to later rely on naive side-by-side comparisons, which the COMP frequently challenges.

Consider similarity with an authorised orphan product early

Another consideration during MAA preparation is the possible similarity with an orphan product(s) that is already authorised. If an authorised orphan product already exists for a condition that is related to the indication of the sponsor’s orphan product, the sponsor must submit:

• A similarity assessment (Module 1.7.1) and, if the two products are deemed similar,
• A derogation justification (Module 1.7.2), demonstrating consent from the MAH of the authorised product or supply shortage or clinical superiority (EMA, 2016)

Assessment of similarity takes into account:

• Principal molecular structural features
• Mechanism of action
• Therapeutic indication

A sponsor, therefore, needs to be continually mapping the evolving competitive landscape throughout the development of its orphan therapy.

2.   Seeking Early COMP Dialogue Before MAA Submission

In the EU, sponsors of orphan therapies are encouraged to engage with the regulators early and often, maximising the regulatory toolbox – including protocol assistance and expedited pathways such as PRIME when appropriate.

Key advantages of early dialogue include:

• Clarity on what evidence framework COMP considers appropriate for demonstrating significant benefit
• Opportunity to discuss and / or refine the proposed comparison methodology
• Early visibility of any gaps in clinical evidence

About six months before an MAA is filed, applicants have an opportunity to discuss their proposed strategy for orphan maintenance during the standard pre-submission meeting.

3.   The Complexities of Demonstrating Significant Benefit

One of the most complex elements of the maintenance report is the demonstration of significant benefit over authorised therapies; this can be considerably harder to demonstrate at the time of the MAA than at the initial ODD.  

Significant benefit must be demonstrated either by showing a clinically relevant advantage over existing satisfactory methods, or by demonstrating a major contribution to patient care.

Indirect Comparisons: A Necessary Tool and a Regulatory Challenge

Direct, head-to-head trials are the most robust method for demonstrating significant benefit but are often unfeasible in rare diseases. COMP may therefore accept alternative comparative approaches such as indirect comparisons or qualitative comparisons.

A Changing Regulatory Landscape: Implications for Orphan Maintenance

The ongoing reform of the EU pharmaceutical legislation proposes several changes for developers of orphan medicines:

• Variable market exclusivity (10, 9 or 5 years may be granted depending on unmet need and product type)
• 1 additional year may be granted for EU-wide launch within defined timelines
• Removal of the “return on investment” criterion
• Limiting orphan designation to 7 years of validity (renewable upon presentation of current evidence)

These reforms aim to rebalance incentives while addressing disparities in treatment across EU Member States.

Overall, the reforms raise expectations around the evidence supporting orphan designation and maintenance. This makes the timely generation of high quality of evidence even more critical.

The Maintenance of An Orphan Designation is Not an Administrative Step

Maintaining orphan designation at the time of an MA is far more than an administrative milestone. It is a rigorous evaluation that demands foresight, methodological rigor and an honest appraisal of the product’s value relative to existing therapies.

Three lessons stand out:

1. Maintenance planning starts early

Sponsors must design their clinical and evidence strategies with significant benefit in mind, long before pivotal trials begin.

2. Indirect comparisons must be credible and clinically meaningful

The increasing scrutiny of the COMP means that naïve comparisons are rarely sufficient. Whether using sophisticated modelling or qualitative reasoning, the approach must reflect clinical reality and clearly justify why the product offers a substantively better treatment option.

3. The regulatory environment is evolving

The proposed EU reforms will continue to shape expectations around unmet need, data quality and access. Significant benefit arguments will need to be stronger, more methodologically robust and more patient centred.

As rare disease pipelines grow and therapeutic landscapes become more complex, the ability to integrate regulatory foresight with innovative evidence generation will be essential. Sponsors who build orphan maintenance into their development plans, rather than treating it as end-stage task, will be best positioned to successfully navigate the COMP assessment and ultimately bring transformative therapies to those patients who need them most.

References:

Applying for marketing authorisation: Orphan medicines | European Medicines Agency (EMA). (2010, March 30). https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/orphan-designation-marketing-authorisation/applying-marketing-authorisation-orphan-medicines

Commission Notice on the Application of Articles 3, 5 and 7 of Regulation (EC) No 141/2000 on Orphan Medicinal Products (2016). https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=oj:JOC_2016_424_R_0003

Orphan designation: Overview | European Medicines Agency (EMA). (n.d.). Retrieved 3 December 2025, from https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview

Orphan incentives | European Medicines Agency (EMA). (2010, March 30). https://www.ema.europa.eu/en/human-regulatory-overview/research-development/orphan-designation-research-development/orphan-incentives

Pre-authorisation guidance | European Medicines Agency (EMA). (2016, May 3). https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/pre-authorisation-guidance

Regulation—141/2000—EN - EUR-Lex. (n.d.). Retrieved 3 December 2025, from https://eur-lex.europa.eu/eli/reg/2000/141/oj/eng

Regulation—847/2000—EN - EUR-Lex. (n.d.). Retrieved 3 December 2025, from https://eur-lex.europa.eu/eli/reg/2000/847/oj/eng