Greg Bacon and Eleanor Denny
In June 2018 the EMA published an update to their Questions and Answers regarding the impact of Brexit on centrally approved medicinal products. This guidance is provided on the basis that the UK will become a third country on 30 March 2019 and so (subject to any agreement) EU rules regarding medicines will no longer apply to it from this date. The EMA has put those in the pharmaceutical industry on notice that they should be prepared for Brexit and below are a list of things the EMA has noted those working in relation to human medicinal products should consider.
Additionally, from 23 January to 9 February 2018 the EMA launched a survey to determine the preparedness for Brexit and a report of its findings was published on 11 July 2018. The EMA contacted 180 marketing authorisation holders (MAHs) that held 694 centrally authorised MAs and asked them about their plans to submit transfers, notifications and/or variations.
Below we have included key considerations taken from the EMA Q&As, alongside key findings from the report regarding MAH preparedness:
- Are you applying for a marketing authorisation (MA) and/or orphan designation (OD)?
- All MA applicants must be established in the EU (EEA);
- Reference medicinal products for generic, hybrid and biosimilar applications must be authorised within the EU (EEA) so post-Brexit all reference medicinal products used must be authorised within the EU-27 (or EEA);
- For applications relying on well-established use or traditional-use registrations, only data sourced from the UK prior to Brexit can be relied on;
- For the purpose of calculating the global marketing authorisation only MAs granted pre-Brexit in the UK can be considered as the “initial MA”; and
- For prevalence calculations for orphan medicinal products UK patients will no longer be taken into account post-Brexit.
- Do you already have an MA or other authorisation/ designation?
- MA and OD holders must be established in the EU (EEA); and
- Sunset clause provisions require products to have been put on the market within the the authorising Member State or on the Union Market and failure to do so for three years means the MA will cease to be valid. Therefore, post-Brexit products that have only placed on the market in the UK will need to also be placed on the market in the Union else their European MA will cease to be valid.
Brexit preparedness: the study found 400 medicines require a transfer of the MA to an MAH within the EU (EEA) and 94% of companies plan to submit the transfer application in due time.
- Where should you locate your key personnel?
- The Qualified Person for Pharmacovigilance (QPPV) must reside and carry out their tasks in the EU (EEA) and any back-up arrangement (including deputy QPPVs) must also be in the EU (EEA); and
- Local representatives should be located in the EU (EEA) plus the necessary amendments to documentation should be made.
Brexit preparedness: of the 335 products from the study that will be required to change the location of their QPPV, 84% are expected to do so on time.
- Do I need to move my manufacturing and batch release sites?
- The pharmacovigilance system master file (PSMF) and batch control sites must be located within the EU (EEA);
- Official Control Authority Batch Release, where required, must be done by Official Medicines Control Laboratories within the EU (EEA) so cannot happen in the UK for products placed on the market after 29 March 2019; and
- Active substances and finished medicinal products manufactured in the UK will be considered as imported into the EU post-Brexit. Therefore, the necessary confirmations and authorisations plus an importer established within the EU (EEA) will be required.
Brexit preparedness: from the study it was found -
- 376 medicines will require their PSMF to have its location changed; however, 60% indicated this might not be made on time;
- 119 medicines need to transfer their batch release site and timely submission is expected from 81% of these;
- 41 variations for quality control changes need to be made and 85% are expected in time; and
- 18 importation sites in the UK need to be relocated to the EU (EEA) but only half the companies responded to the survey and of those only 22% (4 companies) indicated they would be submitting the relevant change before 29 March 2019.
- What will be the implications for inspection findings by UK Competent Authorities (CAs) and for UK Notified Bodies?
- Inspection findings from inspections carried out prior to Brexit by UK CAs should still be implemented; however, post-Brexit UK CAs will not be CAs for the purpose of EU requirements so EU law will not apply to the UK CA inspection findings post-Brexit; and
- After 29 March 2019 Notified Bodies established in the UK cannot act as an applicant for the initial consultation with the EMA for the purpose of medical devices that incorporate medicinal products as an integral part.
Therefore, according to the EU, companies should be proactively preparing for Brexit. The EMA states in the report “Pharmaceutical companies are therefore being strongly advised to submit the necessary changes for the continued maintenance of their marketing authorisations to EMA as early as possible and before the end of Q4 2018 to ensure processing in due time.”
While there is no political certainty, the report from the EMA indicates that MAHs of centrally authorised products are taking the steps the EMA has suggested to prepare for Brexit (although 108 products have been identified as a potential risk for critical supply). Therefore, companies that are not actively preparing are at risk of not being able to place their products on the relevant markets post-Brexit.
 Formally at 11 pm GMT on 29 March 2019.