Orphan Designation 

An “orphan designation” is granted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for a drug/biologic to create financial incentives for developing therapies for rare diseases.  

This article focuses on incentives offered, the prevalence that defines an orphan disease, as well as the procedural process of obtaining the designations. 

Introduction 

A rare disease is, as implied, a disease that affects a relatively low number of patients in the population. Many (over 6,000) rare diseases have been identified to date, and it is estimated that 3.5% – 5.9% of the worldwide population is affected by these diseases. 72% of rare diseases are genetic, while others result from infections, allergies, and environmental causes. Due to the low prevalence of each disease, medical expertise is rare, and knowledge and effective care are extensively lacking. In the past, drug manufacturers would not invest in therapies for rare diseases as they could not cover the vast costs of drug development and profit from marketing drugs to such small groups of patients. Despite the urgent need for rare disease¹ medicines, they came to be known as orphans of health systems, as companies would not develop these medicines, and the patient was often denied proper diagnosis and treatment² of therapies for orphan diseases.   

In order to encourage the development, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) launched programs to create financial incentives for developing these therapies. An “orphan designation” is granted for a drug/biologic developed to treat an orphan disease. However, the agencies have some differences in the incentives offered, the prevalence that defines an orphan disease, as well as the procedural process of obtaining the designations.  

Since their inception, orphan designation programs have successfully created incentives for developing orphan drugs. For example, in 1983, the US Congress passed the Orphan Drug Act (ODA) laid down in 21 Code of Federal Regulations (CFR) §316³ to create financial incentives for orphan drug developers. Since 1983, the Act has resulted in the development of more than 250 orphan drugs, which are available to treat a potential patient population of more than 13 million Americans². 

The current article provides information on the EMA orphan designation program.  

Orphan Medicinal Product Designation in EMA (EU) 

Orphan Medicinal Product Designation (OMPD) is based on the criteria laid down in Regulation (EC) No 141/2000⁶. To be eligible for orphan designation in Europe, a medicine must meet the following criteria: 

• It must be intended for treating, preventing, or diagnosing a life-threatening or chronically debilitating disease 

• No satisfactory method of diagnosis, prevention, or treatment of the condition concerned can be authorized, or if such a method exists, the medicine must be of significant benefit to those affected by the condition 

• The condition’s prevalence in the EU must be at most 5 in 10,000, or it must be unlikely that marketing the medicine would generate sufficient returns to justify the investment needed for its development 

How to Submit a Request for an OMPD 

Sponsors need to use EMA’s secure online IRIS platform⁷ to submit applications for orphan designation and to manage pre- and post-designation activities. To submit via IRIS, the company should be incorporated in the EU or be submitted under a representative incorporated in the EU. The application can be submitted directly to EMA or have a pre-submission meeting (teleconference) with the EMA, should the sponsor feel they could benefit from a preliminary discussion before the submission. For example, suppose this is the first time the sponsor approaches the COMP (Committee for Orphan Medicinal Products). In that case, the pre-submission call explains in detail the process, what is expected to be included in the application, and in which order.  

The scientific document of the application (~30 pages) includes the following: 

• Description of the condition: details of the condition, proposed orphan indication, medical plausibility, justification of the life-threatening or debilitating nature of the condition  

• Prevalence of the condition: prevalence of the orphan disease or condition in the European Union (based on established literature references and current EU population estimates) 

• Potential for return on investment: (only if prevalence is more than 5 in 10,000) 

• Other methods for diagnosis, prevention, or treatment of the condition: details of any existing diagnosis, prevention or treatment methods, justification as to why methods are not satisfactory / justification of the significant benefit 

• Description of the stage of development: summary of the development of the product (proof of concept studies, in vitro and in vivo data [including toxicology if available], clinical studies [if available]), details of current regulatory affairs status and marketing history in the EU and non -EU countries  

In addition, sponsor and regulatory details are provided, as well as translations of the active substance and the indication (26 EU languages) should be submitted. Companies that have a “micro, small and medium-sized enterprises” (SME) status⁸ are not required to submit translations. 

The application can be submitted only on specific dates according to predetermined timelines⁹. An initial draft application is submitted for validation, after which the final documents are submitted.  

Applications for orphan designation are examined by the EMA’s Committee for Orphan Medicinal Products (COMP). The evaluation process takes a maximum of 90 days from validation confirmation. The agency sends the COMP opinion to the European Commission (EC), which is responsible for granting the orphan designation. 

The benefits of an EMA orphan designation  

• Ten years of market exclusivity 

• Access to the centralized authorization procedure. This allows companies to make a single application to the EMA, resulting in a single opinion and a single decision from the EC, valid in all EU Member States. Sponsors may also have access via orphan designation to conditional approval (which is conducted under the centralized procedure) 

• Additional incentives for SMEs – administrative and procedural assistance from the Agency’s SME office and fee reductions. For example, the translation mentioned above is not required 

• Fee reductions- companies applying for designated orphan medicines pay reduced fees for regulatory affairs activities. This includes reduced fees for protocol assistance (and free for academia sponsors), marketing authorization applications, inspections before authorization, applications for changes to marketing authorizations made after approval (variations), and reduced annual fees 

Annual report  

An annual summary of information on the status of orphan drug development should be submitted. These are short documents (~10 pages) submitted between 12 and 14 months from the date of initial designation acceptance annually. The summaries include a review of preclinical and clinical studies performed and planned, a short description of the investigation plan for the coming year, and any anticipated or current problems/difficulties in testing/potential changes that may impact orphan designation.  

Acronyms and abbreviations 

COMP, Committee for Orphan Medicinal Products; EMA, European Medicines Agency; OMPD, Orphan Medicinal Product Designation; SME, Small and Medium-Sized Enterprises. 

References