Brexit Regulatory Issues: What You Need To Know
Brexit has been an ever-present issue for professionals in the life sciences sector since 2016. We have worked with many companies in preparing them for the changes that will come from the UK leaving the EU. Here, we have created a ‘long read’ blog looking at Brexit regulatory issues and what you need to know to ensure that you are prepared for the changes that it will bring about.
Table of Contents:
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Brexit & Pharmaceuticals
RMS In the UK? Here Is What You Need To Do
Reference Member States (RMS) have rarely been changed, as there has been no need to do so. Brexit has changed all of that and now many companies are having to change their RMS because the UK decided to leave the EU. Typically, the Marketing Authorisation Holder (MAH) can request a change of RMS only under exceptional circumstances, one of these being, of course, Brexit; All companies that have a marketed product for which the RMS for a Mutual Recognition Procedure (MRP) or Decentralised Procedure (DCP) is currently the UK will have to change their RMS to inside the EU.
What Does An RMS Do?
They act as:
- scientific assessor of a dossier
- regulatory advisor to the applicant
- moderator between applicant and CMS
The RMS provides regulatory and scientific advice as well as assessment reports, they decide on timetables, evaluate responses, organize and chair break-out sessions, refer to the CMDh, inform the EMA if there is no consensus after referral, inform the applicant and Concerned Member State (CMS) after the positive conclusion and prepare the final assessment report as well as the public assessment report.
There is ample motivation to do some research on the different Health Authorities (HA).
Here are a few things to consider when choosing a new RMS:
Know Your RMS
Previous experiences with an HA can be of major advantage. These connections often make sure procedures move along according to the set timetables without any unforeseen trouble because you understand their point of view, they speak the same language so to speak. These professionals look out for, and mitigate, unforeseen delays due to their experience with that Reference Member State; they are familiar with their workload, approach, and the way they communicate.
Differences Among Health Authorities
Although we’re all in the EU, every member state is responsible for their own day-to-day business. Some might be better communicators, others more prone to act in a timely matter, and others more inclined to be open to more pragmatic approaches. Companies are especially recommended to check the pass-through times and a backlog of a possible new RMS and are required to contact the Health Authority in advance to check their availability to take over as Reference Member State for existing procedures. Besides there is also a difference in not every HA has extensive experience acting as a Reference Member State at all.
If The RMS Has Experience In A Therapeutic Area
Some RMS have more experience than others in certain therapeutic areas. If you are a generic manufacturer you might want to check the originator’s Reference Member State; which is often also the RMS for other generics. This is noticeable when an originator product goes off-patent because almost all generics manufacturers will tend to apply with this same RMS with which the original was registered.
Other questions to consider, include:
- Does a Health Authority have a special focus regarding specific therapeutic areas?
- Have they been involved in the development of certain guidelines?
- If the new RMS is going to be one of the current CMS, recall what the attitude towards the product was during a previous application.
These are all questions worthwhile to investigate before making a final decision.
Location Of The Company
Though it might seem like an open door, avoiding language barriers and having the proper infrastructure in place is always a benefit to the daily business. It’s also strategic to choose your Reference Member State according to your company’s EU affiliates; opening up the possibility of direct communication with the HA. Increased contact and the ease of face-to-face counsel can contribute positively. This is especially useful considering we’re working in a regulatory universe that seems to thrive mainly on communication through elaborate documents. Besides these advantages, it also allows affiliates to join the strategic conversation with HQ and to increase their visibility and experience.
There are several commercial reasons to interact with a certain RMS; straight-forward aspects like fees charged by Health Authorities, the market size of the Reference Member State, and are there key opinion leaders available?
Some practicalities to keep in mind:
- there can be no change of RMS during an ongoing procedure (of importance for timing/planning);
- it is the obligation of the MAH to ensure that both the current RMS and the future RMS accept the change of RMS;
- it is the responsibility of the MAH to supply to the new RMS if any dossier/ assessment reports or other relevant materials are missing or for any reason not already in possession of the new RMS.
Centralised Procedure Medicinal Products
How will the UK’s departure from the EU impact on medicinal products for human and veterinary health? The Q & A document “Questions and Answers to United Kingdom’s withdrawal from European Union about Medicinal Products for Human and Veterinary use within the framework of the Centralised Procedure” was updated to Rev 03 which was published on the 19.06.2018. The following points were added to Rev. 03:
- For human medicinal products placed on the market after the 30.03.2019, the Official Control Authority Batch Release will have to be carried out by an Official Medicines Control Laboratory located in the EEA for official batch release or by an officially recognised partner for official batch release. The EDQM can provide a list of Official Medicines Control Laboratories on request at email@example.com that may be in a position to provide official batch release certificates for different products.
- For veterinary medicinal products, the MAH will need to identify a Competent Authority located in the EEA region to carry out the Official Batch Protocol Review and Evaluation or to appoint an officially recognised partner to carry out the Review and Evaluation.
- It is expected that findings of inspections to determine GMP compliance, Good Clinical Practice compliance, and Pharmacovigilance compliance conducted by the UK Competent Authority before the 30.03.2019 will be implemented by the companies inspected.
- From the 30.09.2019, UK Notified Bodies will lose their status as an EU Notified Body. As a consequence of this, the Notified Bodies in the UK will no longer be able to be an applicant in an initial consultation procedure with the EMA and the EMA will no longer be able to issue a scientific opinion to them as notified bodies of a third country.
- MAH’s currently using multi-country packs that include the UK may find they need to adapt their packaging. The important consideration, in this case, is to ensure the product labelling and Patient Information leaflet are fully in line with the Summary of Product Characteristics authorised in the EU.
- Where a MAH relies on the service of a deputy QPPV as part of its back-up arrangements in the absence of the QPPV, the arrangements should ensure that the deputy QPPV is established and performs his/her tasks in the EEA.
- Information on how the UK’s withdrawal from the Union affects CE Certification of medical devices by UK’s Notified Bodies can be found in the “Commission notice on the withdrawal of the UK and EU rules in the field of industrial products”.
(Reference: Questions and Answers to the United Kingdom’s withdrawal from the European Union concerning Medicinal Products for Human and Veterinary use within the framework of the Centralised Procedure Rev 03 published 19.06.2018.)
What impact will this have for the Marketing Authorisation Holders? We look at some of the key areas that will affect Marketing Authorisation Holders when Brexit becomes a reality.
Qualified persons for pharmacovigilance and their deputies currently residing in the UK
The qualified person responsible for pharmacovigilance (QPPV) must reside and carry out his/her tasks in a Member State of the Union (EEA). This is the case for both humans (Article 8 of Directive 2001/83/EC) and veterinary (Article 74 of Directive 2001/82/EC) medicinal products. Post-Brexit therefore, MAHs must either appoint a new QPPV residing and carrying out his/her tasks in the Union (EEA) or request their QPPV to relocate and carry out his/her tasks in the Union (EEA). All updates to the QPPV details must of course be updated in the Article 57 database for human medicines, and through a variation for veterinary medicines.
Article 2 of Commission Implementing Regulation (EU) No 520/2012 mandates the availability of back-up arrangements in the absence of the QPPV (i.e. Deputy QPPV). As the tasks of QPPV need to be carried in a Member State of the Union (EEA), the back-up arrangements for cases of absence of the QPPV, which replace such tasks, also need to be performed in the Union (EEA).
With most QPPVs thought to currently reside in the UK1, this change will result in major restructuring for MAHs. MAHs are also reminded that PSMF locations must also be within the Union (EEA).
Marketing authorisation holders established in the UK
EU law requires that marketing authorisation holders are established in the EU (or EEA) [Article 2 of Regulation (EC) No 726/2004]. Through the EEA Agreement, this is extended to include also Norway, Iceland, and Liechtenstein. For centrally authorised medicinal products the marketing authorisation holder will need to ensure that MAH’s have been transferred to a holder established in the Union (EEA). The transfer of the marketing authorisation should have been completed and implemented by the marketing authorisation holder before 30 March 2019.
Batch release from a UK site
Similarly, for batch release, Article 51(1) of Directive 2001/83/EC and Article 55(1) of Directive 2001/82/EC requires that the qualified person (QP) of the manufacturing and importation authorisation holder is responsible to certify that each batch of a medicinal product intended to be placed on the EEA market was manufactured under EU GMP requirements and the marketing authorisation. The batch release site has to be located in the Union (EEA). For centrally authorised medicinal products the marketing authorisation holder will, therefore, need to transfer its current UK based site of batch release to a location established in the Union (EEA) and submit the corresponding variation.
Certification can only be performed by a Qualified Person of the manufacturer and/or importer who is identified in the marketing authorisation and they also need to be located in the Union (EEA).
Manufacturing site of an active substance or finished product in the UK
Active substances or finished products produced in UK sites have been considered as ‘imported active substances’ or ‘imported medicinal products’ since March 2019.
Active substances originating from a third country must, therefore, be accompanied by a written confirmation from the competent authority of the exporting country that the standards of GMP of the plant manufacturing the active substance are at least equivalent to those laid down by the union (EEA).
For finished products, the competent authorities of the Union (EEA) ensures that the import of medicinal products into their territory is subject to an authorisation under Article 40(3) of Directive 2001/83/EC and Article 44(3) Of Directive 2001/82/EC. The authorisation is granted when a number of conditions, as defined in Articles 41 and 42 of Directive 2001/83/EC and Articles 45 and 46 of Directive 2001/82/EC, are fulfilled (e.g. availability of a qualified person within the Union (EEA), GMP inspection).
Introduction of a new manufacturing site for the active substance or the finished product and their respective consequential changes can be submitted as a Type II variation separately for the active substance and the finished product, thereby replacing a large grouping of Quality IB (and IA) variations for the consequential change.
Legal basis of MAA’s
With the UK becoming a ‘Third Country’ after Brexit, it also has implications when considering the choice of the legal basis for marketing authorisation applications.
Hybrid/generic applications refer to the information contained in the dossier of another EU ‘reference product’. Generic/hybrid marketing authorisations granted before the end of October 2019 referring to a Reference product authorised by the UK remain valid. Generic/hybrid applications for which marketing authorisations granted after the end of October 2019 should refer to a reference product that is or has been authorised in an EU-27 Member State or a contracting state of the EEA.
Similarly, with well-established use applications and demonstrating use in the community for more than 10 years, UK data to support such claims only cover the period when the UK was a member state of the EU.
The reader is referred to both the Brexit practical guidance document and the Q and A documents on the EMA website for more information.
Brexit & Medical Devices
Brexit & the EU Authorised Representative
From January 1st, 2021 the UK will be completely outside of the European Union. Negotiations regarding a future trade deal are ongoing, while Covid-19 restrictions continue. The UK is expected to leave the end of the year and has the option, until June 30th, to seek an extension to the December 31st, 2020 departure date. We look at the latest on the EU Authorised Representative and Brexit.
Since 2016 we have engaged with many companies that wish to move their EU Authorised Representative from the UK to Ireland. We have assisted them in moving their EU Authorised Representative from the UK to Ireland. However, there are still many companies that have not yet appointed a new representative. Our advice to them is to ‘act now’.
Companies that use UK based Authorised Representatives will be required to have an EU based Authorised Representative. Medical device manufacturers based outside of Europe who currently use the services of a UK based Authorised Representative are advised to consider switching Authorised Representatives as soon as possible. It should be noted that transitioning to a new Authorised Representative involves appointing a new service provider for this purpose but also has implications for labelling, quality systems, registrations in the Member States, and Certificates of Free Sale among other documentation areas. A streamlined and efficient changeover plan should be discussed with the Authorised Representative service provider to ensure an orderly transition.
For a limited time, the UK will accept CE marked EU approved devices. The MHRA has advised that it will be carrying out a public consultation on the issue to look at how the UK might introduce its equivalent of CE Marking as the UK moves away from reliance on EU structures.
UK-based Notified Bodies are longer be able to assess the conformity of medical devices for devices to receive the CE mark and enter the EU market.
Therefore, the MHRA will no longer be able to oversee Notified Bodies in the way that it does now.
The UK’s MHRA will continue to provide UK post-market surveillance of medical devices and it would be in a position to decide on the marketing of any device within the UK.
Brexit & Pharmacovigilance
The UK as a Third Country
When the UK finally leaves the EU, it will be classed as a third country by the EMA. It is inevitable that if the EU QPPV resides in the UK you will be affected by Brexit and the UK’s decision to leave the EU. The demand for QPPVs is putting severe pressure on all UK MAHs with products in the EU. The demand has lessened the availability of EU QPPV resources throughout the EU, a fact that each MAH needs to be aware of.
Therefore, companies that have not yet arranged for an EU based QPPV must do so urgently. And our team of EU based QPPV’s can help.
Brexit will impact on many aspects of the life sciences sector. One of the areas that will be most impacted will be the role of the Qualified Person for Pharmacovigilance (the QPPV). In this article, we consider the impact that the UK’s exit from the EU will have on the role and the measures that companies will need to take once Brexit happens.
As per DIR Art 104 (3), the Qualified Person for Pharmacovigilance (QPPV) shall reside and operate in the EU. Following EEA agreements, they may also reside and operate in Norway, Iceland or Liechtenstein.
But what will happen to the QPPV post-Brexit? Well, the short answer is in the question “exit”.
The European Medicines Agency (EMA) Questions and Answers related to the UK`s withdrawal from the EU regarding the medicinal products for human use, provides guidance on the role of the QPPV post-Brexit. As it stands:
Any QPPV currently residing in the UK will need to change his/her place of residence and carry out his/her tasks in the Union (EEA) or a new QPPV residing in the Union (EEA) will need to be appointed.
As the tasks of QPPV need to be carried in a Member State of the Union (EEA), the back-up arrangements for cases of absence of the QPPV, which replace such tasks, also need to be performed in the Union (EEA).
UK Pharmacovigilance System Master File (PSMF)
According to Commission Implementing Regulation (EU) No 520/2012, the PSMF must be located within the Union (EEA), subsequently, the marketing authorisation holder will need to change the location of the PSMF to a Member State within the Union (EEA).
Brexit brings an uncertain future for UK based QPPVs and considering the above they potentially have one of three options:
- change position, or
- accept redundancy
In 2018 the EMA launched a survey to gather information from MAHs about their preparedness for Brexit. Of the 1165 human medicinal products registered centrally with the EMA, 427 of these have been registered by a UK-based MAH and 323 utilise UK QPPV services. The survey showed that the UK has a large talent pool of PV professionals and various questions remain for UK based QPPVs that can’t relocate. Additionally, given that the area is so niche, the increased demand for QPPV services will put severe pressure on the recruitment industry.
Our Recommendation for EU Based QPPV
We are recommending that all MAHs affected by Brexit ensure that they have a post Brexit EU QPPV in place straight away. Also, whatever your plans and changes in QPPV, make sure details are updated in Article 57 database!
The UK PSMF – What Will It Look Like?
How will the Pharmacovigilance System Master File (PSMF) be impacted by the UK’s departure from the EU? What actions will companies with a UK Marketing Authorisation Holder (MAH) need to take in the event of a no-deal Brexit? We consider the questions and advise on what you need to consider and what you need to do if you are impacted.
The MHRA will follow a similar approach to the EMA for the management of PV activities, meaning that the following legal obligations will apply to a UK based MAH in a no-deal scenario:
- Operation of a pharmacovigilance system
- Appoint a QPPV that resides and operates in the UK
- Maintain a PSMF (located in the UK)
What will the “UK PSMF” Look Like?
Firstly, the format and content of the UK PSMF are equivalent to that of the EU PSMF, so that’s helpful! Most MAHs are already familiar with the requirements of the EU PSMF and they follow the guidance outlined in GVP Module II. However, one should also be aware of the minimum requirements for the content and maintenance of the “UK PSMF” as laid out in HMR Schedule 12A.
Question: Do you have more than one PV system?
If so, the UK PSMF must describe the global PV operations and reflect the global availability of safety information for the UK authorized products however, the annexed content should be specific to UK authorized products.
Furthermore, all UK PSMFs must be registered with the MHRA and a unique PSMF number requested for each pharmacovigilance system for UK authorized products. Where the pharmacovigilance system is shared by several MAHs, a single request for a UK PSMF number should be submitted to the MHRA.
Brexit & Clinical Trials
How will clinical trials be impacted by the UK’s decision to leave the European Union?
The United Kingdom’s decision to leave the European Union (EU) will present significant implications for the pharmaceutical industry. Clinical trial sponsors and associated partners should be prepared for a variety of scenarios arising from Brexit which could impact the manufacturing, licensing, and distribution of health products between Ireland and the UK.
Clinical trial sponsors will have to navigate different sets of guidelines, which could potentially increase study times and inflate costs.
Firstly, how clinical trials are conducted in the EU will undergo a major change when the Clinical Trial Regulation comes into application. The Regulation (EU No 536/2014) harmonises the assessment and supervision processes for clinical trials throughout the EU, via a centralised portal, and will come into force in 2020. Since this will happen after the UK leaves the EU, the UK will not be in line with EU regulations and the UK’s future alignment will be subject to negotiations with the EU. In the case of No-Deal Brexit scenario regarding medicinal products between the EU and the UK, the following issues concerning clinical trials with medicinal products must be observed:
Establishment requirements for a sponsor or legal representative
The sponsor of a clinical trial or his legal representative must be located in a Member State of the EU or another State party to the Agreement on the European Economic Area (EEA). In the case of clinical trials where the sponsor or the legal representative is still established in the UK, their registered office must be transferred to the EU/EEA or a legal representative in the EU/EEA must be designated by the time Brexit becomes effective.
Manufacture and batch release of investigational medicinal products
The batch release of investigational medicinal products must take place in the EU/EEA. After Brexit, manufacturers responsible for final batch release who are established in the UK will no longer be able to certify clinical trial batches for the EU.
Shipping of investigational medicinal products/medicinal products from the UK will now constitute an import
After Brexit, the shipping of investigational medicinal products and other medicinal products from the UK to the EU/EEA will constitute an import. This also applies if only parts of the manufacture take place in the UK, e.g. study-specific packaging or labelling of investigational medicinal products.
Implications of Brexit and the issue of clinical trials need to be highlighted as some of the most important aspects of the negotiations. Besides, the Irish clinical trial infrastructure is showing growth at a steady pace with an increasing number of trial sites now open across the Irish network. With the UK planning on leaving the EU, Ireland is perfectly positioned to take on the country sponsor role for more clinical trials. Acorn Regulatory is assisting clients in preparing for Brexit, assessing the impact of different Brexit scenarios, and how to mitigate risks identified.
What We Are Doing To Prepare Our Clients for Brexit
We have established an internal task force to generate action plans for the pharma, PV, devices, and clinical clients. Prepare for Brexit and ensure the ongoing success of your company by talking to the Brexit experts. Contact us by email: firstname.lastname@example.org, by phone: 00353 52 61 76 706 or complete the form below and we will get back to you.
Further Reading from Acorn Regulatory
Our pharmaceutical regulatory affairs team is staffed by experts who have considerable expertise in the sector. Every team member has at least 15 years of experience in the pharmaceutical sector assisting pharmaceutical companies with their regulatory issues. Since 2002, our pharmaceutical regulatory affairs specialists have been working with clients all over the world. Read more about our pharmaceutical services here.
Our medical device regulatory affairs consultants have a well deserved reputation for excellence with our global client base. The team is staffed by individuals with significant experience in industry and with national authorities.
The medical devices team, headed by John Seekings, is working with companies to assist them on numerous issues, some of which are detailed below. Perhaps the biggest issue right now for medical device companies is the advent of the new medical device regulations (MDR) which will come into force on May 26th 2021. Acorn Regulatory can assist your company in preparing for the new regulations and ensuring ongoing compliance. Read more about our medical device services here.
We offer a complete and comprehensive pharmacovigilance service to assist you in meeting your legal obligations as Marketing Authorisation Holder (MAH). Our pharmacovigilance consultants have significant experience in working with companies all over the world.
As a company that works with a global client base, we handle a wide range of pharmacovigilance related issues for client companies. Some of the most frequently requested services that we offer are detailed below. If we can assist you, then please get in touch with us. Read more about our pharmacovigilance services here.
The Acorn Regulatory team is staffed by specialists with a wide variety of expertise. Our Medical and Clinical services team, led by Dr. Danica Cvetkovic, assists companies in the management of clinical trials, medical writing, and the provision of medical information services. Read more about our medical and clinical services here.