Brexit: EMA’s regulatory guidance on centrally approved medicinal products – the present state of play

The champagne bottles have been drained in Amsterdam and tears dried in Milan and Bratislava but the serious work of mapping out the practical implications of Brexit continues at the European Medicines Agency (EMA).

The EMA and the European Commission issued a Notice in May 2017 confirming that "unless the withdrawal agreement establishes another date" the United Kingdom will become a "third country" at midnight on 30 March 2019 as all Union primary and secondary legislation will cease to apply to it. Questions and Answers drafted jointly by the European Commission and the EMA have helped to orientate companies within the future landscape. Those Q&As were updated on 1 December and now also include useful guidance related to marketing authorisation procedures. Further, jointly authored Practical Guidance has also been published by EMA to provide procedural and practical guidance regarding the submission of changes and related fees.

1. The Practical Guidance provides helpful guidance related to variation applications, transfers of marketing authorisations, as well as some other changes:

Variation applications:

• Brexit related variations can be grouped where this does not delay the implementation of changes that need to be in place by 30 March 2019.
• Complex related changes can be submitted as a single Type II variation rather than a series of individual Type IB and 1A variations.
• The Qualified Person certifying each batch of finished product and the site of batch control must be in the EEA, or, in the case of a site, a country covered by a mutual recognition agreement. The authorised importation site for products manufactured outside the EEA must also be in the EEA. The Practical Guidance sets out which variation pathway should be followed for the addition or replacement of this information in a marketing authorisation.

Marketing authorisation transfers:

• Proof of establishment of a new marketing authorisation holder within the EEA must be submitted by a marketing authorisation holder transferring a marketing authorisation out of the United Kingdom. The transfer must be completed before 30 March 2019. It will not be possible to group several marketing authorisations under one single transfer application.
• Where the name of the product needs to be changed to reflect the transferee a Type IA variation should be submitted in advance of the transfer application.
• Regulatory procedures can run in parallel with Brexit related transfer applications.
• An application for transfer or change in name and address of the sponsor of an orphan designated product should preferably be submitted in advance of an application for transfer of a marketing authorisation. At the latest, the two should be submitted in parallel. A separate application should be submitted for each orphan designation.
• Companies submitting a large volume of transfer applications from one UK based marketing authorisation holder to a single transferee in the EEA can submit a combined version of each required supporting document (except product information and mock ups) with each application, stating in their cover letter that the documents are identical. The transferee may also sign a unique statement to cover its own obligations on the transfer. This should simply the transfer procedure and reduce the processing time at the EMA.
• Where the only change in the artworks is the name of the marketing authorisation holder a written confirmation to this effect will be acceptable and the requirement for mock ups waived.

Other changes:

• The Qualified Person for Pharmacovigilance and the Pharmacovigilance Master File must reside in the EEA. Changes can be notified for medicinal products for human use through the Article 57 database. A variation is not required. Separate procedures apply for veterinary medicines.
• New templates are provided to notify changes to the person responsible for scientific service and the person responsible for batch recall and quality defects.

2. Previously focused on issues related to establishment requirements within the EEA, the revised Questions and Answers also address some new issues, in particular related to marketing authorisation applications, and confirm that:

• Generic/hybrid applications for which marketing authorisations will be granted after 29 March 2019 should refer to a reference medicinal product that is or has been authorised in an EU-27 Member State or one of the three contracting EEA states.
• Bioequivalence studies that have been conducted with a medicinal product sourced in the UK can be used in generic/hybrid marketing authorisation applications only if the marketing authorisation for that application will be granted before 30 March 2019. The EMA will look at exceptional cases if this could lead to the unnecessary duplication repetition of studies in humans or animals.
• Marketing authorisations granted before 30 March 2019 by the United Kingdom can still be considered as the initial marketing authorisation in the EU for the purposes of delineating a global marketing authorisation
• Data sourced from the United Kingdom before 30 March 2019 can be taken into account to demonstrate that the active substance of a medicinal product in the claimed therapeutic indication has been in well-established use within the EEA for at least 10 years with recognised efficacy and an acceptable level of safety for the purposes of an application for a marketing authorisation on the basis of well-established use pursuant to Article 10a of Directive 2001/83/EC.
• Data sourced from the United Kingdom before 30 March 2019 can be taken into account to demonstrate that a traditional herbal medicinal product has been in medicinal use throughout a period of at least 15 years within the EEA.
• Patients in the United Kingdom should no longer be taken into account in the calculation of the prevalence of disease for applications for orphan designation or prevalence.
• Any local representative mentioned in the product information located in the United Kingdom and nominated for Member States other than the United Kingdom will have to be changed by a variation application fully implemented before 30 March 2019 to a local representative located in the EEA. The deletion of any mention of a local representative in the United Kingdom will need to be changed as part of a future regulatory procedure affecting the annexes at the earliest opportunity after 29 March 2019.
• In the case of a centrally authorised medicinal product that has only been marketed in the United Kingdom, the placing on the market in the United Kingdom before 30 March 2019 will be taken into account to determine the applicability of the sunset clause for that product.

The Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) has also updated its Q&A for marketing authorisation holders of nationally authorised products for human use on 1 December 2017.

3. In October, the EMA published its Brexit Preparedness Business Continuity Plan (BCP) following an earlier information note in August, which has not been updated following the decision on its relocation to Amsterdam. The BCP, however, specifically indicates that "the physical move to the new EMA seat will require a second BCP to be invoked addressing business continuity before, during and after the physical move. Such second BCP, the EMA Relocation BCP, will be developed once the decision on the location of the new EMA premises has been taken and more information is available on the timetable for relocation to the new host MS". As Amsterdam was amongst the EMA employees' preferred host cities, staff retention is expected to be pretty high, which will hopefully limit disruption of the EMA's activities.

We can expect more to come from the EMA on Brexit related procedures and we should soon start to hear from the MHRA how its post Brexit procedures will work.

The Life Sciences industry will be fervently hoping that its recent united call for a transition period after 30 March 2019, giving a longer period of time in which to implement these changes, will be heeded. There is much work to be done.