Orphan drug designation in the EU and the US

Pharmaceutical companies play the major role in the provision of medicines in the health systems of the EU and the US. Pharmaceutical firms are commercial enterprises which are in most cases public companies. When developing new medicines the companies invest a considerable amount of money and therefore, the market for a medicine needs to have a corresponding size to ensure the return of investment.


However, there are also diseases which only occur in a small group of patients, so call rare or orphan diseases, thus the market for medicines treating a rare disease is likewise small and the financial interest of companies in these diseases is as a consequence limited. To encourage the development of medicines for rare disease the EU member states and the USA have established programmes which provide incentives for companies developing orphan drugs.


Definition of orphan or rare disease


In the EU the definition of medicines for rare diseases is laid down in Regulation (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 1999 (EC/141/2000); Article 3 summarises the criteria which a medicine has to fulfill to receive for an orphan drug designation in the EU.


“A medicinal product shall be designated as an orphan medicinal product if its sponsor can establish:

  • a) that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10 thousand persons in the Community when the application is made, or that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community would generate sufficient return to justify the necessary investment;


  • b) that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.”

In both cases, there must also be either no satisfactory method of diagnosis, prevention or treatment of the condition concerned is authorised, or, if such a method does exists, the medicine must be of significant benefit to those affected by the condition.


The orphan drug definition in the US is similar to that of the EU; however, the disease does not have to be a life-threatening, or chronically debilitating condition. As specified in 21 CFR Part 316 and in accordance to the Orphan Drug Act, the disease prevalence for therapies qualifying under the Orphan Drug Act is as follows:

“The disease or condition for which the drug is intended affects fewer than 200,000 people in the United States or, if the drug is a vaccine, diagnostic drug, or preventive drug, the persons to whom the drug will be administered in the United States are fewer than 200,000 per year”.




In the EU, the major incentive offered is market exclusivity for 10 years. According to Regulation 141/2000, Article 8 (EC/141/2000) … ”the Community and the Member States shall not, for a period of 10 years, accept another application for a marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product”.

In addition, the EU provides further incentives during the development of an orphan drug as well as after the approval of the product; these incentives include (see Incentives and Explanatory note on fees payable to the European Medicines Agency, EMA/348317/2010

  • Protocol assistance (a form of Scientific Advice) which is free of charge (regular fees for advice on CMC, nonclinical and clinical questions add up to 76 300 EUR)
  • Fee reduction and exemptions
  • Pre-authorisation inspection are free of charge (regular fees for each inspection inside or outside the Community are 19 100 EUR)
  • 50% fee reduction for Marketing Authorisation Application (regular fees for a single strength associated with one pharmaceutical form and one presentation: 254 100 EUR)
  • Post-authorisation activities, including annual fees, during the first year after marketing authorization are free of charge (e.g. regular annual fee for each Marketing Authorisation of a medicinal product: 91 100 EUR)

Further measures have been introduced to support research into orphan medicinal products by the European Commission and Member States of the EU.


In the US, in accordance with Orphan Drug Act the orphan designation qualifies the sponsor of the product for tax credit and marketing incentives, i.e. market exclusivity and fee exemption. The law provides 7-year-marketing exclusivity to sponsors of approved orphan products. A marketing application for a prescription drug product that has been designated as a drug for a rare disease or condition is not subject to a prescription drug user fee unless the application includes an indication for other than a rare disease or condition.

In addition, the Orphan Products Grants Program provides funding for clinical research that tests the safety and efficacy of drugs, biologics, medical devices and medical foods in rare diseases or conditions.


How to apply for orphan drug designation


In the EU, the Committee for Orphan Medicinal Products (COMP) is in charge of reviewing orphan drug application. Upon a positive decision of the COMP the European Commission may grant the orphan status.


The sponsor submits an application for orphan drug designation in accordance to the “Guideline on the format and content of applications for designation as orphan medicinal products and on the transfer of designations from one sponsor to another” (ENTR/6283/00 Rev 3) to the Scientific Advice and Orphan Drug Sector of the EMA and to the appointed COMP coordinator. Submission deadlines for orphan drug applications are provided on the EMA website (Submission_deadlines). The application will include details on the target condition, the proposed indication and the medical plausibility, a justification of the life-threatening or debilitating nature of the condition, information on the prevalence of the condition and on the existence of other methods of diagnosis, prevention or treatment. In addition, translations of the active substance and proposed indication in all EU language are part of the application.


In the US, the sponsor has to submit an application to the Office for Orphan Products Development (OOPD) to obtain orphan drug status. Similar to the EU the request will include a description of the rare disease or condition, a description of the drug and a discussion of the scientific rationale for the use of the drug for the rare disease or condition, a summary of the regulatory status and marketing history of the drug in the United States and in foreign countries (see FDA website How to Apply for Designation as an Orphan Product).


Current developments


In the recent years there have been several joint initiatives of the EMA and the FDA. One of these also concerns the orphan drugs. The FDA and the EMA have established collaboration on orphan designations and administrative simplification. As a result there is a Common EMEA/FDA Application Form For Orphan Medicinal Product Designation (see EMA/FDA_Common_Application_form) which can be used by sponsors seeking orphan drug status on both sides of the Atlantic. Last year the FDA and the EMA announced that they have agreed to accept the submission of a single annual report from sponsors of orphan products (drugs and biologics) designated for both the US and the EU.


By Dr. Manuela Kohler, Principal Consultant Pharmatching GmbH

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