Applying for marketing authorisation: orphan medicines

The European Medicines Agency (EMA) assesses whether a medicine continues to meet the criteria for maintaining its orphan status in parallel with assessing an application for marketing authorisation.

Sponsors may also need to submit an evaluation of orphan similarity. This enables EMA to determine whether the medicine can maintain its status as an orphan medicine and benefit from market exclusivity.

From 19 September 2018, sponsors need to use EMA's IRIS system to submit all post-designation activities. EMA will not be able to process any submissions outside of IRIS. For information and guidance on using IRIS, please see Applying for orphan designation.

Orphan similarity

In advance of marketing authorisation application, irrespective of whether the medicinal product in question has been designated as orphan or not, the applicant 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 in Pre-authorisation guidance.

This legal requirement arises from Article 8(1) of the Orphan Regulation (EC) No 141/1200. This 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 ten years, accept another marketing authorisation application, 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 Article 8 specifies that a marketing authorisation may be granted, for the same therapeutic indication, to a similar medicinal product if:

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 marketing authorisation application 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 applicant demonstrates the quality, safety and efficacy of the medicinal product.

Should the CHMP conclude that the product which is the subject of the marketing authorisation application is similar to an authorised orphan medicinal product and none of the derogations apply, 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

If the sponsor of a medicine with an orphan designation submits a marketing authorisation application or an extension to an existing marketing authorisation, it should also submit a report on maintenance of the orphan designation with the application for marketing authorisation in a case of approved accelerated review (150 days) or around day 121 of the normal MA procedure (210 days). The maintenance report should be submitted via the IRIS system, only after the sponsor receives the confirmation that the validation of the application for marketing authorisation has been completed. The sponsor's 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.

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

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 on the sponsor's report, and issues an orphan maintenance assessment report.

The COMP carries out its review independently of, but in parallel to the evaluation of the marketing authorisation application by the CHMP.

The COMP adopts an opinion on the review of the orphan designation following the CHMP positive opinion on the marketing authorisation application. EMA sends the COMP opinion to the European Commission.

As of 17 January 2018, the European Public Assessment Report (EPAR) for every newly-authorised medicine contains the orphan maintenance assessment report for all positive and negative COMP opinions, as well as withdrawals.

Pending orphan designation applications at time of marketing authorisation

When an application for orphan designation is still pending at the time of marketing authorisation application, 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 marketing authorisation application) 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 marketing authorisation application.

Voluntary sharing of market launch intentions: pilot project

From 25 March 2021, marketing authorisation applicants for orphan medicines and medicines to treat cancer will be invited to take part in a pilot project by declaring their market launch intentions on a voluntary and confidential basis.

The pilot aims to help regulators understand why delays may occur in the marketing of certain medicines in EU Member States after they receive a marketing authorisation.

EMA will invite marketing authorisation applicants to share this information via an online survey at the time of validation or when they receive the CHMP opinion. 

They will be also asked to provide feedback on challenges and limiting factors they face in ensuring the availability of their medicines in the EU.

The pilot project will run for 18 months, until August 2022.

The European Commission, EMA and the national competent authorities are running this pilot in the context of the Pharmaceutical strategy for Europe.

More information and guidance for applicants is available on the European Commission's website and in the question-and-answer (Q&A) document below. 


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