Questions and answers: Orphan-designation application

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This page lists the questions that sponsors may have on applying for orphan designation.

If you have a question that is addressed here, forward your request to orphandrugs@ema.europa.eu.

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1. What is the legal basis for orphan designation?

The legislation on orphan medicinal products, Regulation (EC) 141/2000 of the European Parliament and of the Council, was adopted on 16 December 1999 and published in the Official Journal of the European Communities on 22 January 2000 (Ref. L18/1). This Regulation lays down a Community procedure for the designation of medicinal products as orphan medicinal products and provides incentives for the development and placing on the market of designated orphan medicinal products.

On 27 April 2000, the Commission adopted a Regulation laying down implementing rules and setting out definitions essential for the application of Regulation (EC) 141/2000 (Ref. L103/5). As of 28 April 2000, the date this Regulation entered into force, sponsors have been able to submit applications for orphan medicinal product designation to the European Medicines Agency.

On 29 July 2003, the European Commission adopted a communication (Ref. C178/02) setting out its interpretation on certain matters relating to the implementation of the designation and the market exclusivity provisions.

2. Can an application for orphan medicinal product designation be submitted at any time in the development process?

In accordance with Regulation (EC) 141/2000 of 16 December 1999, the sponsor may submit an application for orphan medicinal product designation to the Agency at any stage of development of the medicinal product. However, the designation application must be submitted before the submission of the application for marketing authorisation.

For the purpose of designation and to support the rationale for the development of the product in the proposed condition some preliminary preclinical and/or clinical data are generally required. A pharmacological concept, not supported by any form of evidence or results, would generally not be considered by the Committee for Orphan Medicinal Products (COMP) as sufficient justification for the designation of the medicinal product in the proposed condition.

A request for designation may be made for an already authorised medicinal product, if the designation request concerns a new orphan indication that is not currently authorised.

3. Can an application for marketing authorisation be submitted before the application for orphan medicinal product designation has obtained an opinion and/or designation? If so, can a fee reduction be granted on condition or refunded once the designation is obtained?

An application for marketing authorisation can be submitted after the application for orphan designation has been submitted, while designation is still pending. It should be noted, however, that a fee reduction for the application for marketing authorisation can only be considered if designation has already been granted at the time of application for marketing authorisation.

If the marketing authorisation application is submitted while the designation is pending, a fee reduction cannot be granted on condition or refunded.

4. Can a product already authorised for a non-orphan indication in the European Union (EU) receive orphan designation for another indication which is orphan?

Yes, under certain circumstances. A request for orphan medicinal product designation may be made for a new orphan indication for an already authorised medicinal product. However, at the stage of applying for the marketing authorisation for the orphan indication, the marketing authorisation holder would be required to apply for a separate marketing authorisation for the orphan indication, using a different proprietary name. It will not be possible to extend the existing marketing authorisation to cover the new orphan indication.

Orphan and ‘non-orphan’ indications may not be covered by the same marketing authorisation.

5. If a medicinal product has already been granted orphan drug designation in the United States or Japan, would this be automatically accepted for the EU?

No, the EU Regulation does not foresee recognition of orphan status granted in other regions. In addition, the criteria for orphan designation are not internationally harmonised. Orphan designation can only be granted in the EU, by the European Commission, once an application for designation has been reviewed by the COMP, in accordance with the procedure laid down in Article 5, Regulation (EC) 141/2000 of 16 December 1999.

6. Once orphan designation is granted, will it be possible to apply for a reduction in fees also for scientific advice, variations and annual fee, or only for a reduction in fees for the marketing authorisation application?

For medicinal products which have been granted orphan designation, reduction of fees or fee waivers will be considered for all types of activities including, fees for pre-authorisation activities such as protocol assistance, the application for marketing authorisation, inspections, and post-authorisation activities such as variations, annual fee etc. The extent of these fee reductions may vary annually, in accordance with the funding approved by the European Commission for these activities.

For more information on fees, please refer to Fees payable to the European Medicines Agency.

7. What are the sponsor’s options in case of negative outcome for orphan designation? What information is published in case of a negative opinion?

When the outcome for a designation application is negative, the COMP will adopt a negative opinion, unless the sponsor chooses to withdraw the application. The sponsor must inform the Agency in writing of the withdrawal before the COMP adopts an opinion, in other words, before the end of the COMP meeting. When the application is withdrawn, no information on the application is made public. The sponsor can re-apply for orphan designation with additional or complementary data at a later stage.

If the sponsor does not withdraw, a negative opinion is adopted by the COMP and is transformed into a Commission Decision, unless an appeal  procedure is triggered. A summary of the negative opinion will be published on the Agency's website and the decision will be entered in the Community register of designated orphan medicinal products.

8. Can the sponsor appeal an opinion issued by the COMP?

Yes, a sponsor can appeal an opinion of the Committee. The detailed grounds for the appeal should be sent to the Agency within 90 days of receipt of the opinion. The grounds for the appeal should be based only on the original information provided in the application for orphan designation, but may include new analyses.

The COMP will discuss the grounds for appeal and will consider whether its opinion should be revised. Once a final opinion is adopted by the Committee, a summary of the opinion will be published on the Agency web-site and the resulting Commission decision will be entered in the Community Register. In case of withdrawal of the appeal by the sponsor, the previous opinion will become final.

9. At the stage of the application for marketing authorisation, does the sponsor of a designated orphan medicinal product have the choice between the centralised procedure and the mutual-recognition procedure?

This was a possibility in the past. According to Art. 3(1) of Regulation No 726/2004 of the European Parliament and the European Council, designated orphan medicinal products are required to apply through the centralised procedure. No medicinal product appearing in the Annex may be placed on the market within the Community unless a marketing authorisation has been granted by the Community in accordance with the provisions of this Regulation.

10. Are orphan medicinal products eligible to receive a marketing authorisation under exceptional circumstances?

As for any medicinal product, a designated orphan medicinal product may be granted a marketing authorisation under exceptional circumstances, subject to annual re-assessment and certain specific obligations, in particular “when the indications for which the product is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence” (Part II.6 of Annex I to Directive 2001/83/EC, as amended).

11. Do medicinal products designated as orphan medicinal products automatically qualify for accelerated review?

The maximum timeframe for the evaluation of a marketing authorisation application under the centralised procedure is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the Committee for Medicinal Products for Human Use (CHMP).

Designated orphan medicinal products will not automatically qualify for accelerated assessment.

However, an accelerated evaluation might be initiated by the CHMP in exceptional cases, when a medicinal product is intended to meet a major public health need.

The justification for a request for accelerated assessment and further details on how to submit a request for accelerated assessment can be found in:

 

12. Does an orphan medicinal product designation in the EU qualify for designation outside Europe?

The Agency encourages parallel applications for orphan designation with regulatory authorities outside the EU, particularly with regulators in the United States and Japan. However, the processes are independent from each other and sponsors should liaise with each of the Authorities for the purpose of applying for orphan drug designation.

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