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Regulatory Strategy for Registering Rare Disease Products in the EU: What You Need to Know

According to the European Medicines Agency (EMA), approximately 30 million people living in the EU suffer from a rare disease and rely on the Orphan Drug Regulation (Regulation (EC) Nº 141/2000) to bring treatment to market.

Published on:
January 11, 2023
Given that the regulation is likely to change considerably, drug developers may need to revisit their development strategy. In the meantime, building a strategy around these evergreen elements continues to be key to successful commercialization."

An orphan drug is defined as a drug or biological product used for the prevention, diagnosis, or treatment of a rare disease. In the EU, a rare disease is a condition affecting fewer than 5 in 10,000 European citizens. Today there are over 6,000 identified rare diseases and 95% do not have an authorized treatment.1  

In 2022, proposed amendments to the current Orphan Drug Regulation were brought to the European Commission (EC) and are still under discussion. While the regulation changes evolve, understanding the current Orphan Drug Program, its limitations, and the proposed amendments are essential for building a robust drug development and regulatory plan that secures a successful rare disease product registration in the EU market. 

Today’s Orphan Drug Framework in the EU 

Adopted in December 1999, the Orphan Drug Regulation outlines the procedures and criteria for orphan drugs as well as related incentives. The regulation also established the Committee for Orphan Medicinal Products (COMP), responsible for recommending orphan designation of medicinal products for rare diseases (orphan medicinal products, OMP). 

Orphan Drugs need to meet the following eligibility criteria: 

  • Disease/Condition prevalence: Less than 5 in 10,000 EU citizens. This data must be focused on Europe for the EU market  
  • Medical plausibility: Data (non-clinical and clinical if available) should support the rationale for using the drug in the disease. Sponsor should be concise, descriptive, and clear in how the data findings relate to the disease 
  • Significant benefit: Evidence (bibliographic or experimental, as applicable) supporting that no satisfactory methods of treatment exist, or if any such methods exist, the drug candidate must be of significant benefit to those affected by the condition 
  • Clinical superiority: Only applicable at the time of license application if the same drug is approved for the same use

As soon as the Orphan Drug criteria are met, companies may apply for Orphan Drug Designation (ODD). The EU Regulatory procedure provides the possibility to perform a pre-submission meeting where the sponsor receives a preliminary response from the EMA on the robustness of the draft ODD application.  

For the official submission, sponsors must use the EMA’s IRIS system. The IRIS system has several requirements that must be met for both the sponsor and the drug. Additionally, the sponsor should have a permanent physical address in the EEA (EU, Iceland, Liechtenstein, and Norway). After ODD is granted, sponsors must submit annual reports through IRIS portal as well as the orphan maintenance report and similarity report at the time of license application. 

Orphan Drug Development Incentives 

The main incentive for the development of Orphan Drugs is 10 years of market exclusivity. Other incentives include:  

  1. Financial incentives including fee waivers and EU funding programs  
  2. Protocol assistance from EMA 
  3. Programs to expedite development and approval including accelerated assessment as well as priority medicines (PRIME)

Since the orphan drug regulation took effect in 2000, there has been steady growth for new marketing authorizations in the EU, and the European Orphan Drug market is forecasted to grow 7.66% from 2022 to 2027, reaching 55.65B by 2027.2 

Limitations of the Current Orphan Drug Regulation 

In 2020, the EC published an evaluation of the regulation’s performance from 2000 to 2017, and the findings/limitations of the current regulation are leading the review of key elements for amendment. The main goal of the EC, through the proposed amendment, is to foster research and development of OMP as well as improve availability and access for patients. 

The top four limitations of the current regulation are: 

  1. Most OMP development focuses on disease areas where treatments already exist3
    From 2000–2017, 72% of all authorized OMPs targeted a disease that already had at least one authorized treatment available. 
  2. OMP development is not equally focused on adults and children4
    Only 12% of ODD treat conditions only affecting children, while 70% of rare diseases are exclusively pediatric onset. And 90% of all rare diseases manifest in childhood.
  3. OMP development benefits only a limited number of diseases4
    From 2000–2019, 67% of ODD targeted the same three disease areas: blood/blood forming organs, antineoplastic and immunomodulating agents, and dermatology.
  4. OMP development concentrates on the “least rare” diseases4,5
    While 96% of rare diseases have a prevalence of less than 1 in 10,000, from 2000–2019 60% of ODD and 56% of authorized OMPs targeted rare diseases with a prevalence of greater than 1 in 10,000.

Proposed changes to the ODD Regulations 

Revising Orphan Drug Regulation would have a direct impact on the drug development for rare diseases. The goal is to provide more access to patients—and deliver that access on a faster timeline.  

Initially, the proposed changes to the regulation included reduced duration and added conditionality for the market exclusivity, as well as changing the ODD designation eligibility criteria. Changes to the designation itself would include implementing a limited validity, lowering the disease prevalence to focus on the rarest diseases, and adding an accumulative prevalence threshold for drugs that address more than one rare disease. 

However, drug developers consider that the proposed changes will not help OMP developers raise funds and continue drug development. Overall, the orphan regulatory framework still needs to be defined and aligned with other upcoming changes, like the pharmaceutical legislation update. In any case, significant impact on the development of OMP is anticipated.   

Building an effective regulatory strategy 

Given that the regulation is likely to change considerably, drug developers may need to revisit their development strategy. In the meantime, building a regulatory strategy around these evergreen elements continues to be key to successful commercialization: 

  • Full understanding of the disease or condition and patient need 
  • Early engagement with patient associations and Key Opinion Leaders  
  • Partnership approach with regulators at the earliest appropriate time 
  • Leverage of orphan and SME status 
  • Establish relationships and develop ongoing conversations with regulators, patients, and KOLs throughout the product development lifecycle
Want more information on regulatory strategy for registering rare disease products in the EU?  

Our in-house team of experts understands the evolving ODD regulatory landscape and can guide you in real-time on the changing regulations will help you build an effective strategy that can adapt to changes and maintain your development timelines.  


1 2021 European Expert Group on Orphan Drug Incentives Report. 

2 Evaluate pharma 2019, Orphan Drug Report. 

3 European Commission, Commission Staff Working Document Evaluation, page 40 

4 European Expert Group on OD Incentives, page 16. 

5 Wakap, S. N., Lambert, D. M., Olry, A., Rodwell, C., Gueydan, C., Lanneau, V., … & Rath, A. (2020). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. European Journal of Human Genetics, 28(2), 165-173.  

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