Dealing With Brexit: EMA Offers Firms Advice On More Thorny Questions
Executive Summary
The European Medicines Agency has updated its guidance on Brexit to offer companies more advice on the regulatory changes they will need to make in areas like transfers of MAs, rapporteurships and orphan designations, multi-country packs, and Article 58 opinions.
Companies with medicines that have been reassigned from a UK rapporteur to one in another EU country should be aware that they may be asked to provide the new rapporteur with information on their plans for forthcoming regulatory applications so that the authorities in that country can better predict the increase in their workload and plan the allocation of resources.
The advice comes in the European Medicines Agency’s updated guidance documents, which outline the steps companies need to take before Brexit to ensure their medicines can continue to be marketed in the EU.
“Companies are reminded to plan for the UK’s withdrawal from the EU on 29 March 2019 in order to avoid any impact on the continuous supply of medicines for human and veterinary use within the EU and are advised to regularly check EMA’s dedicated web page on the consequences of the UK’s withdrawal from the EU,” the agency comments.
The EMA is acting on the assumption that the UK will become a “third country” after March next year. The European Commission pointed out recently that “unless a ratified withdrawal agreement establishes another date or the European Council unanimously decides that the Treaties cease to apply at a later date,” the UK will become a “third country” as of the Brexit date. Agreement on a transition period to December 2020 was reached on March 19 this year, but this still has to be ratified as part of the withdrawal agreement, and there is no guarantee that the withdrawal agreement will be concluded in time.
"MAHs may be invited to support the knowledge transfer by providing information on upcoming planned regulatory applications" – EMA guidance
Rapporteurships
One important consequence of the UK’s decision to leave the EU is that all UK rapporteurships and co-rapporteurships for centrally authorized medicines have to be transferred to (co-)rapporteurs in one of the other 27 EU countries plus Iceland and Norway. More than 370 products are involved, and the EMA informed the relevant marketing authorization holders (MAHs) of the reallocations at the end of April. (Also see "EMA To Re-Prioritize Tasks To Cope With ‘Higher Than Expected’ Staff Losses" - Pink Sheet, 8 Jun, 2018.)
The EMA has already told companies that a “knowledge transfer package” for each product will be provided to the new (co-)rapporteurs in September. This will contain background data on the product’s regulatory and evaluation history, including the most recent benefit-risk assessment. The updated guidance says that MAHs “may be invited to support the knowledge transfer, e.g. by providing information on upcoming planned regulatory applications in order to help each national competent authority to forecast upcoming workload to better support the planning of resources, particularly for complex products in the portfolio.”
It also makes clear that where a regulatory procedure involving a reallocated product is expected to conclude after the Brexit date, the new (co-)rapporteur will take the lead in that particular procedure, but will only take full responsibility for the product as of March 30, 2019. Until then, the current (co-)rapporteur will retain overall responsibility and conduct the assessment of any procedures that will be completed before Brexit.
MAAs Completing After Brexit
The guidance also advises companies as to what they should do about marketing authorization applications (MAA) that are expected to receive a decision from the commission after March 29, 2019. In the case of these products, the qualified person for pharmacovigilance (QPPV), the pharmacovigilance system master file (PSMF), the batch release and control sites, the intended Official Medicines Control Laboratory, and the nominated local representative will all have to be located in the EU.
“Where it has not been possible to amend the application in this regard prior to the submission of the MAA, such change will need to be made during the procedure,” the updated guidance says. “In order to request the above listed changes, a cover letter highlighting the proposed changes and updated affected dossier documents will need to be submitted as part of responses to the [EMA's] Day 120 List of Questions or Day 180 List of Outstanding Issues.”
Applicants are encouraged to request such changes as early as possible, “in particular with regards to manufacturing sites, as the acceptability of the proposed changes will need to be assessed, which may impact the timelines of the procedure.”
Where an MAA was initially planned for a UK-based company, and it was not possible to change the applicant to a non-UK EU entity before the MAA was submitted, a change of applicant will need to be made during the approval procedure. The guidance describes the documents that will need to be submitted, again as part of responses to the Day 120 LoQs or Day 180 LoOIs.
Multi-Country Packs
The EMA's guidance also looks at the ability of companies to market multi-country packs in the UK after Brexit. Such medicines are labeled in a way that allows them to be marketed in several EU member states with the same packaging, with the summary of product characteristics being the same in all the markets concerned.
Marketing a multi-country pack in a third country (i.e., the post-Brexit UK) "will normally not be possible," the EMA says. "Marketing authorisation holders currently using multi-country packs that include the UK may therefore have to adapt their packaging.”
Under EU legislation, member states can require the inclusion of certain additional labeling information in a restricted area (the so-called "blue box"), “provided that all the strict conditions for application of Article 57 or Article 62 of Directive 2001/83/EC and Article 63 of Directive 2001/82/EC are fulfilled.” In applying these provisions, while it may be possible to include additional information on the label or package leaflet, the product labeling and package leaflet “must be fully in line with the summary of product characteristics as authorised in the EU,” it stresses.
The guidance also offers advice in the following areas:
Article 58 opinions. These are scientific opinions from the EMA’s drug evaluation committee, the CHMP, on medicines intended to be used outside the EU. The holder of such an opinion must be established in the EU/EEA, so by the Brexit date either the opinion must be transferred to a holder in the EU/EEA (in the same way as transfer of an MA) or the nominated contact point (the person authorized to communicate on behalf of the MAH) must be changed.
Good Practice Inspections. “It is expected,” the EMA says, “that findings of inspections, in particular to determine compliance with good manufacturing practice, good clinical practice and pharmacovigilance obligations, conducted by the UK competent authority before 30 March 2019, are implemented by the inspected entities in accordance with the applicable legislation.”
The pharmacovigilance system master file. The PSMF must be located in an EU/EEA country, either at the site where the MAH’s main pharmacovigilance activities are performed, or where the QPPV operates. This requirement should be taken into account if the PSMF is located in the UK and the MAH needs to change the PSMF location to an EU/EEA member state.
Multiple orphan transfers. In order to make it easier to handle a large volume of orphan designation transfers from a UK-based sponsor to one in the EU/EEA, a combined version of each supporting document required (apart from product-specific information) can be created covering all orphan designations affected. Among other things this will require proof of establishment of the new sponsor, a letter of authorization from that sponsor where applicable, and a separate product transfer form for each designation.
QPPV back-up arrangements. If the QPPV is absent, back-up arrangements apply, and these must be carried out in an EU/EEA member state. Where an MAH relies on the services of a deputy QPPV as part of its back-up arrangements, the deputy must operate in the EU/EEA.
From the editors of Scrip Regulatory Affairs.