Orphan medicinal products
Source: gov.uk (2025-03-11)

The MHRA will review applications for orphan designation at the time of a marketing authorisation (MA) or variation application.

1. Overview

This guidance gives an overview of orphan medicinal products to support development in rare disease, marketing exclusivity for the products, and how to apply.

See the UK Rare diseases strategy (https://www.gov.uk/government/publications/uk-rare-diseases-framework) for other supportive activities.

2. Application process

The MHRA is responsible for reviewing applications from companies for orphan designation at the time of a marketing authorisation application (MAA). There is no orphan designation step prior to application for a marketing authorisation in the UK.

The authorisation of orphan medicinal products will change following implementation of the Windsor Framework. Reference should be made to the Human Medicines Regulations 2012 (HMRs), as amended. The HMRs have been amended by Human Medicines (Amendments relating to the Windsor Framework) Regulations 2024 (S.I. 2024/832) which come into force on 1 January 2025.

2.1 Prior to 1 January 2025

If a medicinal product fulfils the criteria to be designated and authorised as an orphan in the EU under Regulation (EC) 141/2000, a Great Britain (GB) orphan MAA can be made under regulation 50G of the Human Medicines Regulation 2012 (as amended). A UK-wide orphan MAA can only be considered in the absence of an active EU orphan designation.

If, prior to EU authorisation, a UK-wide orphan marketing authorisation is granted and the medicinal product subsequently receives EU orphan designation, the market authorisation holder (MAH) would need to submit a variation to amend their UK MA to a Great Britain orphan MA.

2.2 From 1 January 2025

Following implementation of the Windsor Framework on 1 January 2025 marketing authorisations granted for products that fulfil UK orphan criteria will be valid UK-wide regardless of whether there is an EU orphan designation or EU authorisation as an orphan medicinal product.

2.3 Criteria for UK orphan designation

To qualify for orphan designation in an orphan condition, a medicine must meet the following criteria. These will be considered in relation to Great Britain only until 1 January 2025:
- it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating
- the prevalence of the condition in UK must not be more than 5 in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development
- no satisfactory method of diagnosis, prevention or treatment of the condition concerned exists in UK or, if such a method exists, the medicine must be of significant benefit to those affected by the condition
- satisfactory methods may include authorised medicinal products, medical devices or other methods of diagnosis, prevention or treatment which are used in UK
3. How to apply

Marketing authorisation applicants should submit the UK Orphan Drug Application Form (https://assets.publishing.service.gov.uk/media/671277c5b22a14f7ee18ee57/12._1_UK_Orphan_Drug_Application_Form_-_0.2.pdf) with their MAA in module 1.2 of the eCTD, specifically indicating in the cover letter their intention to seek an orphan designation.

The MHRA application forms can be used to determine what information is needed in the application. If the correct information is not provided in the application it will not be validated.

Applications for orphan designation will be examined by the MHRA, taking the advice of the Commission on Human Medicines (CHM) (https://www.gov.uk/government/organisations/commission-on-human-medicines), as appropriate. A decision on fulfilment of the orphan criteria runs in parallel with the assessment of the marketing authorisation procedure.

Following the validation of the MAA, a decision on orphan status will be made at the time of the decision on approval of the marketing authorisation (see guidance on). Any questions concerning the fulfilment of the orphan designation criteria will be raised with the company during the evaluation of the MAA.

If the MHRA concludes that the criteria for orphan designation are not met, there will be an opportunity to appeal the decision to the CHM before the MA is granted. The applicant should inform the MHRA of the intention to appeal as soon as possible.

4.Market exclusivity period

On grant of a marketing authorisation with orphan status, the medicinal product will benefit from UK orphan rewards of up to 10 years of market exclusivity from similar products in the approved orphan indication. During that period a marketing authorisation will not be granted for a similar product in the approved orphan indication.

However, Regulation 58D of the Human Medicines Regulation 2012 (as amended) establishes the possibility for the UK Licensing Authority to request that the market exclusivity be reduced from 10 to 6 years, under certain circumstances, if the orphan criteria are no longer met in relation to the medicinal product.

The start of this market exclusivity period will be set from the date of first approval of the product in Great Britain or, from 1 January 2025, in UK.

The market exclusivity periods remaining for centrally authorised orphan medicine marketing authorisations granted prior to 1 January 2021 that have been converted to Great Britain or UK marketing authorisations will continue to apply. It is not necessary to submit orphan maintenance reports to the MHRA, but they can be provided as additional information.

The MHRA does not issue orphan designations separately from the MA. Therefore, if a change of ownership application is submitted, the orphan designation will automatically transfer.

5. Paediatric indications

Orphan medicines authorised in Great Britain or UK with the results of studies from a completed paediatric investigation plan (PIP) included in the product information are eligible for an additional 2 years of market exclusivity.

6. Variation applications (section 4.1 of the summary of products characteristics)

Marketing authorisation holders with orphan status are required to submit the UK Orphan Drug Application Form (https://assets.publishing.service.gov.uk/media/5fedefc58fa8f53b80abedc3/GB_Orphan_Drug_Application_Form.docx) with their variation MA application for new or extensions to orphan therapeutic indications. The orphan criteria will be assessed in parallel to the approval of the new indication.

A new period of market exclusivity is only given if the applied for therapeutic indication falls within a new orphan condition.

For non-orphan indications, a new marketing authorisation application is required.

7. Fees

The MHRA offers incentives in the form of market exclusivity and full or partial refunds of marketing authorisation fees to encourage the development of medicines in rare diseases. Waiver from scientific advice fees will also be available for UK based small and medium sized companies (SMEs).

There are no additional fees to apply for orphan designation. Information on fee waivers and refunds for orphan medicines is provided in the amended MHRA application fees (https://www.gov.uk/government/publications/mhra-fees/current-mhra-fees).

8. Small and medium sized company (SME) status

Companies who have, or intend to seek, SME status should ensure that they have the relevant documentation in place if an SME fee refund is to be applied for.

The MHRA has published information on payment easements for SMEs (https://www.gov.uk/government/publications/mhra-fees/payment-easements-and-waivers-for-small-and-medium-companies). The cover letter should also specify that SME status has been approved.

9. Orphan register

All medicines that gain an orphan marketing authorisation from the UK Licensing Authority will be listed on its Orphan Register (https://www.gov.uk/government/publications/orphan-registered-medicinal-products).

When the period of market exclusivity for an indication ends, the orphan designation for that indication expires and is removed from the Orphan Register. The product will remain on the Orphan Register if other authorised orphan indications remain within their period of exclusivity.

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. The product will be removed from the Orphan Register.

10. Further information

For further information, email our Customer Services Centre at xxx@xxx.xx (mailto:xxx@xxx.xx) or call xx-xxxx-xxxx.