As of March 30, 2019, the United Kingdom will become a “third country.” Applicants and marketing authorization holders (MAHs) of centrally authorized medicinal products for human and veterinary use should consider how Brexit will impact their medicines and make the necessary changes in a timely manner before that date. The European Medicines Agency (EMA) recently published Additional Guidance for procedures related to Brexit for medicinal products for these centrally authorized products. The Additional Guidance provides clarifications on practical and procedural requirements regarding the submission of changes to marketing authorizations and related fees that MAHs should follow. The Additional Guidance also addresses the transfer of orphan designations.
Practical and Simplified Requirements
Prepare for Transfer of Marketing Authorization
In order to continue to market centrally authorized medicinal products in the European Economic Area (EEA) after the “cut-off” date of March 30, 2019, any MAH currently established in the United Kingdom (the Transferor) will need to transfer its marketing authorization to a MAH established in one of the remaining countries of the EEA (the Transferee) in accordance with the current procedure provided for in Regulation (EC) No 2141/96.
In this respect, supporting documents for the transfer application will need to be provided, such as a proof of establishment for the new MAH within the EEA, issued in compliance with national provisions. Transferors should note that marketing authorizations cannot be grouped under one single transfer application. Each marketing authorization will have to be submitted through one transfer application, even where several marketing authorizations are transferred from one Transferor to the same Transferee. However, in such a case, the Additional Guidance provides for some simplifications in order to facilitate handling of Brexit-related transfer applications. For example, a combined version of each required supportive document (except product information and, when applicable, mock-ups) can be created covering all products affected.
Note that an application for transfer of orphan designation must be submitted, preferably, in advance of, or at the latest in parallel with, the application for transfer of the marketing authorization.
Regulatory procedures can run in parallel with the Brexit-related marketing authorization transfer application. In case the transfer application must be submitted while procedures requiring an immediate Commission Decision are ongoing, MAHs should consider the timelines of the respective procedures and plan in order to avoid a situation where the decision-making processes of the procedures would overlap. In that regard, MAHs should contact the EMA before submitting the transfer application in order to discuss the handling of any planned/ongoing procedures.
On the day the Additional Guidance was issued, associations representing the European and British life science industry urged the United Kingdom and the 27 remaining European Union (EU) Member States for a clear transition period, to ensure that there will be no disruption in the supply of medicines to patients after March 30, 2019. The European Federation of Pharmaceutical Industries and Associations (EFPIA) issued a slide show on the results of a survey it conducted on the impact of Brexit on the supply of medicines. The results of the survey underline the scale and importance of addressing medicines issues as part of the Brexit discussions. In this respect, EFPIA warns that there is already too little time to transfer marketing authorizations before Brexit.
For the marketing of a medicinal product in the EEA it is required that some activities, such as those relating to batch release, are performed in the EEA. Products that only have batch release and quality control testing sites for finished products in the United Kingdom will need to change the batch release and testing sites. For products that have other batch release and testing sites within the EEA, MAHs may choose to delete the United Kingdom site(s) or to replace them. For finished products manufactured in the United Kingdom, an importation site in the EEA will need to be introduced. In many cases, a single site can perform manufacturing, testing, importation and/or batch release activities. In case MAHs choose to move part or all of these activities, the Additional Guidance describes different non-exhaustive scenarios that may apply. The scenarios provide a useful step in helping pharmaceutical companies classify Brexit-related changes and their impact on the manufacturing activities for medicinal products.
In addition, the new guidance provides clarifications on issues such as the grouping of Brexit-related variations, the procedure to submit a transfer or change in the name/address of an orphan drug designation sponsor and the steps pharmaceutical companies should take to submit changes regarding the Qualified Person responsible for Pharmacovigilance (QPPV) and/or changes in the Pharmacovigilance Master File (PSMF) location.
Updated Brexit Q&As
The Additional Guidance should be read in conjunction with an updated Questions and Answers (Q&As) document, which was published by the European Commission and the EMA on December 1, 2017. The document addresses the legal consequences for MAHs of centrally authorized medicinal products when the United Kingdom becomes a “third country” after Brexit.
The updated Q&As document sets out further guidance related to the impact of Brexit on marketing applications and authorizations for several types of medicines, specifically hybrid, generic and biosimilar medicinal products. A generic or hybrid application refers to information that is contained in the dossier of a reference medicinal product (RefMP) that is or has been authorized in the EEA. Generic/hybrid marketing authorizations granted before March 30, 2019 referring to a RefMP authorized by the United Kingdom remain valid. Generic/hybrid applications for which marketing authorizations will be granted as of March 30, 2019 should refer to a RefMP that is or has been authorized in one of the 27 remaining EU Member States or an EEA State. Those considerations concerning the choice of RefMP are also applicable to biosimilars. However, MAHs should consult the Guideline on similar biological medicinal products for the available scientific guidance when considering using a non-EEA authorized comparator (i.e., a non-EEA authorized version of the reference medicinal product) in the development of a biosimilar. Batches of the RefMP released by the United Kingdom as of March 30, 2019 will not be considered as an EEA authorized comparator.
Preparing for the consequences of Brexit is not only a significant matter for the EMA itself but also for pharmaceutical companies. Before March 30, 2019, MAHs currently established in the United Kingdom will need to transfer their marketing authorizations of centrally authorized medicinal products to MAHs established in one of the remaining EEA countries. Moreover, MAHs will have to ensure that activities relating to batch release are performed in the EEA after the “cut-off” date. Setting up such new activities may be a significant exercise for some MAHs. The newly published Additional Guidanceand updated Q&As document will contribute to ensuring the continued marketing of medicinal products in the EEA following the United Kingdom’s withdrawal from the EU.
Pharmaceutical companies should review the Additional Guidance and the updated Q&As document and consider making the necessary changes to their marketing authorizations and batch release activities in light of Brexit. The EMA is preparing a series of further Brexit-related guidances which will be published on its website. Pharmaceutical companies should therefore monitor EMA’s dedicated webpage on the consequences of Brexit.