Marketing authorisation and market exclusivity

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If the sponsor of a medicine with an orphan designation submits an application for marketing authorisation to the European Medicines Agency, it should also submit a request for maintenance of the orphan designation in parallel. Sponsors may also need to submit an evaluation of orphan similarity. This enables the Agency to determine whether the medicine can maintain its status as an orphan medicine and benefit from market exclusivity.

Orphan designation and marketing-authorisation application

When an application for orphan designationis still pending at time of submission of the application for marketing authorisation, it is nevertheless possible for the medicinal product to be authorised as an orphan medicine provided that the orphan designation is adopted by the Committee for Orphan Medicinal Products (COMP) and confirmed by the European Commission (EC) before the granting of marketing authorisation. 

However, in such cases, the eligibility to the centralised procedure (which precedes the submission of the application for marketing authorisation) cannot be based on Article 3(1) and point 4 of the Annex to Regulation (EC) No 726/2004. Similarly, a fee reduction will not be applicable, as this can only be considered if orphan designation has already been granted at the time of submission of the application for marketing authorisation.

In advance of submission of an application for marketing authorisation, irrespective of whether the medicinal product in question has been designated as orphan or not, a sponsor is advised to check the Community register of orphan medicinal products for information on medicinal products designated as orphan which are under market exclusivity protection.

If any of the designated orphan medicinal products has been granted a marketing authorisation in the European Union (EU), and a period of market exclusivity is in force, a sponsor should attach to the marketing-authorisation application a similarity report addressing the possible similarity between new medicinal products and the orphan medicinal product(s) which have received a marketing authorisation. Detailed information on submission of a similarity report is available on the EMA’s marketing-authorisation application pre-submission guidance webpage.

This legal requirement arises from Article 8(1) of the Orphan Regulation (EC) No 141/1200 which provides that where a marketing authorisation in respect of an orphan medicinal product is granted, the Agency 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. Point 3 of the Article 8 specifies that a marketing authorisation may be granted, for the same therapeutic indication, to a similar medicinal product if:

  • the holder of the marketing authorisation for the original orphan medicinal product has given his consent to the second applicant, or;
  • the holder of the marketing authorisation for the original orphan medicinal product is unable to supply sufficient quantities of the medicinal product, or;
  • the second applicant can establish in the application that the second medicinal product, although, similar to the orphan medicinal product already authorised, is safer, more effective or otherwise clinically superior.

Commission Regulation (EC) No 847/2000  defines the concept of similar medicinal product and clinical superiority. Article 3, defines similar medicinal product as a medicinal product containing a similar active substance or substances as contained in a currently authorised orphan medicinal product, and which is intended for the same therapeutic indication.

It also defines similar active substance as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular features) and which acts via the same mechanism.

Based on the above mentioned definitions, the assessment of similarity between two medicinal products takes into consideration the following criteria:

  • principal molecular structural features;
  • mechanism of action;
  • therapeutic indication.

If significant differences exist within one or more of these criteria, the two products will not be considered as similar. These criteria are explained in:

Where the Committee for Medicinal Products for Human Use (CHMP) concludes that the application for marketing authorisation is not similar to an authorised orphan medicinal product or, if similar, that one of the derogations provided for in Article 8(3) of the Orphan Regulation (EC) No 141/1200 claimed by the applicant applies, this will not prevent the granting of the marketing authorisation/extension to the marketing authorisation, provided that the quality, safety and efficacy of the medicinal product are demonstrated.

Should the CHMP conclude that the product which is the subject of the application for marketing authorisation is considered similar to an authorised orphan medicinal product and none of the derogations applies, the CHMP will adopt an opinion recommending the refusal of the granting of the marketing authorisation/extension to the marketing authorisation, irrespective of the demonstration of the quality, safety or efficacy of the medicinal product.

Review of orphan designation at time of marketing authorisation or extension to marketing authorisation

If the sponsor of a medicine with an orphan designation submits an application for marketing authorisation or an extension to an existing marketing authorisation, it should also submit a report on maintenance of the orphan designation in parallel. This enables the Agency to determine whether the medicine can maintain its status as an orphan medicine and benefit from market exclusivity.

Market exclusivity is linked to the maintenance of the orphan designation when the medicine receives a marketing authorisation for the indication concerned.

The COMP reviews the maintenance of orphan designation based on the data available at the time and a report on the maintenance of the designation criteria, which the sponsor supplies at the same time as the application for marketing authorisation. This report includes data on:

  • the current prevalence of the condition to be diagnosed, prevented or treated, or the potential return on investment;
  • the current life-threatening or debilitating nature of the condition;
  • the current existence of other methods for the diagnosis, prevention or treatment of the condition;
  • if applicable, a justification of the medicine's significant benefit.

The COMP's review is carried out independently of, but in parallel to the evaluation of the marketing-authorisation application by the CHMP. The COMP opinion on review of the orphan designation follows the CHMP positive opinion on marketing authorisation. The COMP opinion is sent to the EC, which has 30 days to endorse it. A report on whether the medicine still meets the criteria of orphan designation is published together with an EPAR on the medicine's orphan designations page.

A template is available for the report on the maintenance of the designation criteria:

Market exclusivity

Medicines that still meet the criteria for orphan designation benefit from the incentive of ten years of market exclusivity once they are approved for marketing in the European Union. This protects them from market competition with similar medicines with similar indications once they are approved and is intended to encourage the development of medicines for rare diseases.

Market exclusivity is awarded by the European Commission and is specifically linked to one specific orphan designation for which a marketing authorisation has been granted.

Each orphan designation carries the potential for one market exclusivity for a particular indication. A medicine that has several separate orphan designations for different indications can have several separate market exclusivities if these refer to separate designated conditions.

The period of market exclusivity is extended by two years for medicines that also have complied with an agreed paediatric investigation plan (PIP). Each orphan designation for a product linked to a separate orphan condition is eligible for a two-year extension if this is accounted for in the PIP. The extension is granted by the European Commission based on the positive compliance check from the Paediatric Committee and opinion from the CHMP. 

For more information, see 

A designated orphan medicinal product shall be removed from the Community register of orphan medicinal products at the end of the period of market exclusivity.

Expiry of orphan designations

When the period of market exclusivity for an indication ends, the orphan designation for that indication expires and is removed from the Community register of orphan medicinal products. 

Once all of the orphan designations associated with an approved medicine have expired or been withdrawn by the sponsor, the medicine ceases to be classified as an orphan medicine and no longer benefits from the orphan incentives.

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