Applying for marketing authorisation: orphan medicines

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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. 

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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:

  • 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 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 in parallel. 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.

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