Following a tumultuous week in the Brexit negotiations, a ‘no-deal’ outcome remains a possibility. The life sciences sector remains one of the most exposed to such a scenario, and the UK Government has released three notices on different aspects: i) how medicines, medical devices and clinical trials would be regulated; ii) submitting regulatory information on medical products; and iii) batch testing medicines, in the event of “no deal”. In addition, the Medicines and Healthcare products Regulatory Agency (MHRA) has launched a consultation on how the legislation should be modified in the event of a ‘no deal’. On the other side of the Channel the European Medicines Agency (EMA) has been forced into the third phase of its Brexit preparedness business continuity plan.
Regulation of medicines, medical devices and clinical trials
The existing regulatory framework for these areas is a comprehensive EU legislative regime. The regime includes legislation and regulatory bodies such as the European Medicines Agency (EMA) and the EU medicines regulatory network (EMRN). The UK also has some domestic capabilities and the national agency, the MHRA, is recognised as a responsive, helpful, and forward-looking agency.
In the event of a ‘no deal’ Brexit, it appears that the UK will adopt a pragmatic approach and aim to keep changes to minimum. Indeed the UK is planning to align itself with future EU Regulations not yet implemented. What this means for each area is explored below.
Unsurprisingly, the UK’s role in the EMA and the EMRN would cease, with the MHRA picking up any functions previously performed by EU bodies. This will require changes in the Human Medicines Regulations 2012, which the MHRA is now reviewing (see below). The implications of these changes touch on a number of areas, summarised below.
The holding of, and applications for, marketing authorisations (MAs) will change. Many medicines are centrally approved by the EMA, and all of these will be automatically converted into UK MAs for the UK. However the MA holder will have to subsequently provide the MHRA with baseline data regarding the medicine. The exact requirements for these data will be a subject of the consultation. Applications for a new MA after Brexit will have to be the subject of a UK application and be assessed by the MHRA in all cases, as the centralised and decentralised procedures will no longer extend to the UK. The same applies to medicines in the middle of the application process with the EMA when Brexit occurs; a new application will have to be made to the MHRA. However, the MHRA will take into consideration any opinions made by the Committee for Medicinal Products for Human Use. Applications for Advanced Therapy Medicinal Products (gene therapy, somatic cell therapy or tissue engineering) will be dealt with in the same way. Generic manufacturers should note that as the MHRA will not have access to the data provided in support of EU approved reference products, any applications looking to rely on a reference product need to ensure that that product has been authorised in the UK.
MA holders will have to carefully consider the new legal presence requirements. For each MA the MHRA requires there to be a named individual, the Qualified Person for Pharmacovigilance, who is contactable for safety issues. That person can currently be located anywhere in the EU. After Brexit the Qualified Person must be established in the UK. However for existing MA holders not yet fulfilling this requirement there will be a grace period until the end of the 2020 to make the move.
This ties into the changes for the pharmacovigilance regime. At present this is coordinated at an EU level, but in the event of a ‘no deal’, all responsibility will shift to the MHRA. The MHRA’s approach to pharmacovigilance is part of the consultation they are currently conducting, but at the very least, MA holders will have to submit relevant data directly to the MHRA. The data will include pharmacovigilance reporting from across the globe, not just for medicines administered in the UK.
The online sale of medicines is a growing area and one that the EU regulates by requiring EU-based online retailers to display a common logo. This logo can be issued by any competent national authority, including the MHRA. After Brexit, UK-based retailers will no longer be in the EU and therefore will not be subject to this requirement; however, the UK plans to investigate introducing a similar scheme, to be implemented from 2021.
Some things are, however, due to stay the same. There are no planned changes to the data and market exclusivity periods for UK MAs. Good practice guidelines for areas including manufacture and distribution of medicines will stay in place, and the UK will adopt the current rules for the EU exhaustion regime to cover parallel distribution and imports.
A number of areas will be the subject of further consultation to establish a new UK approach in the event of a ’no deal‘ scenario, including orphan medicines, paediatric medicines, and packaging and leaflets.
This notice also directs readers to the separate notice on batch testing and certification which can be found here.
The UK will continue to recognise CE marked devices approved for the EU market. If this arrangement were to cease, businesses will be given sufficient time to prepare although what constitutes “sufficient” is not elaborated on. From exit day the MHRA will take full responsibility for post-market surveillance and make its own decisions on whether a device can be marketed. These decisions can be made regardless of the positions adopted by other European regulators or the European Courts.
The Medical Devices Regulation and In-Vitro Medical Devices Regulation, which have already been adopted, are set to apply in the EU from May 2020 and May 2022 respectively. The UK Government has committed itself to complying with all the key elements of these Regulations. Presumably this will be achieved by domestic legislation but this is not made explicit in the notice.
Clinical trials are currently governed by UK legislation, the Medicines for Human Use (Clinical Trials) Regulations 2004, and managed nationally. Under the European Union (Withdrawal) Act 2018 these will remain in force and much of the trial administration will continue as before, including the ability to participate in multinational trials.
As the new EU Clinical Trials Regulation will not apply on 29 March 2019 it will not form part of domestic legislation after Brexit. (The Regulation will apply six months after the EU publishes a notice stating that the clinical trials portal and database is fully functional. With no notice yet published and Brexit less than six months away the Regulation will not therefore apply by 29 March 2019, although the EU anticipates the Regulation will start to apply later during 2019.) However the UK Government’s stated aim is to align domestic legislation with the Clinical Trials Regulation as soon as it comes into force.
Submitting regulatory information on medical products
This notice highlights the full extent of the regulatory networks currently in place at a European level. The networks include portals for applications (CESP and the EMA Gateway), recording clinical trials (EudraCT), and pharmacovigilance reports (EudraVigilance). There is also EUDAMED for medical devices and EU-CEG for other products such as e-cigarettes. Each of these networks allow a stakeholder to input the information once and have it shared around all EU and EEA countries.
If there is a ‘no-deal’ Brexit the UK would no longer be a part of these networks and the sharing of information between the UK and the rest of the EU would finish. This means that any regulatory information would have to be submitted to a new national portal run by the MHRA rather than the equivalent European portal. This portal will handle the full suite of activities including marketing authorisation applications, periodic safety update reports, paediatric investigation plans and clinical trial applications.
Information required by both UK and EU regulators would therefore have to be submitted twice. However the UK is aiming to minimise complications by following existing processes, and accepting applications and data in the form currently used by the EU. For example the MHRA will accept the electronic common technical document (eCTD) currently used by the EMA for a marketing authorisation application. Further guidance on these new systems is set to be released by the end of 2018.
Batch testing medicines
This notice is concerned with batch testing of human medicines by manufacturers and the associated qualified person (QP) certification and release. Batch testing is the process by which a manufacturer tests the composition of the medicine, which the QP then confirms meets the requirements of the marketing authorisation and can be supplied or exported.
Currently medicines can be batch tested anywhere in the EU, EEA, or a third country with whom the EU has a mutual recognition agreement. These third countries include Australia, Canada, Japan, and Switzerland. If a batch is approved by a QP in any of these countries it can be supplied throughout the EU and EEA without any further certification. Medicines manufactured outside of these countries must be batch tested upon being imported into the EU, but this need only be done once before circulating freely.
Once again the UK is taking a pragmatic approach. Medicines batch tested in countries on an MHRA-approved list can continue to be supplied into the UK. On exit day those countries will be those in the EU and EEA, and third countries under a mutual recognition agreement (listed above); and so the status quo will be maintained. This same approach will apply to Investigational Medicinal Products (IMPs) which are used in clinical trials (save that there are no mutual recognition agreements for IMPs with third countries).
However there is no guidance on whether the EU will adopt the same approach; namely whether medicines batch tested in the UK can freely circulate in the EU.
The consultation press release details the ambitions of a post ‘no deal’ Brexit MHRA as establishing “a regulatory system that continues to protect the interests of patients and strengthens the UK life sciences industry”; developing “new innovative licensing routes, the possibility of new global partnerships, and a competitive fee structure”; and ensuring “that UK patients are able to access the best and most innovative medicines and medical devices and that their safety is protected”.
The consultation builds on the regulation of medicines, medical devices and clinical trials ‘no deal’ notice, and is designed to give stakeholders the opportunity to comment on proposed changes in domestic legislation should a ‘no deal’ Brexit occur. It is comprised of the draft text for the statutory instruments required to update domestic legislation, an impact assessment, a questionnaire for stakeholders and an annex describing the proposed changes.
In the ‘no deal’ notice dealing with the regulation of medicines, medical devices and clinical trials readers are informed that the areas of packaging and leaflets, orphan medicines, and paediatric medicines will be addressed in the consultation. Therefore this section will focus on providing additional information on those three areas.
With regards to packaging the Government is proposing that the transition period before MA holders have to amend packing and leaflets would extend to the end of 2021. As companies would have to move their MAs to the UK by the end of 2020, this would give MA holders a full further year to implement the required changes on packaging/labelling.
For paediatric medicines the proposal appears to closely mirror the current EU framework, save that decisions will switch from the EMA to the MHRA. For example the rewards (such as the six month SPC extension) will remain the same, and the MHRA can rely on opinions from European bodies if an application has already been submitted and an opinion given. The exception to this is if UK unmet clinical needs differ from those in the EU, necessitating a different or more focused assessment.
This approach is similar for orphan designations. The criteria to achieve an orphan designation would be amended to match the prevalence of rare diseases in the UK population. Further, rather than seeking a pre-approval orphan designation, as is currently the case in the EU, companies will now apply for orphan status as part of the MA application. However the rest of the regulatory framework and incentives would remain on similar terms.
The consultation finishes on 1 November 2018.
EMA Brexit preparedness Business Continuity Plan (BCP)
Meanwhile the EMA is also ramping up preparations to deal with Brexit, and as of 1 October 2018, has entered the third phase of the Brexit preparedness BCP. The EMA recognised that Brexit was likely to jeopardise the ability of the EMA to operate in a ‘business as usual’ mode, in large part because of the move from London to Amsterdam. Therefore the BCP was set up in May 2017 as a plan to be implemented in order to maintain key operations in the result of ‘business as usual’ not being achievable.
The EMA originally planned for two phases. Each of these represented a new level of contingency planning, and the initial hope was that neither would be required. Each phase envisages the identification and suspension of low priority activities such that work in high priority areas can continue. However both of these phases have had to be used, and have proved insufficient due to the EMA already losing staff in anticipation of the move. Therefore the third phase was instigated on 1 October 2018, with a fourth phase planned for January 2019.
The third phase has seen the EMA redirecting resources from international cooperation, development of guidelines (with the exception of those relating to Brexit), interaction with stakeholders and the publication of clinical data. The impact on international cooperation has seen the EMA adopting a reactive rather than proactive role in the harmonisation of global medicines, and a possible scaling back of engagement in the global public health issues such as antimicrobial resistance and vaccines. The EMA is hoping that these activities can be ramped back up in July 2019, but given that the agency expects to lose almost a third of its staff, it may be a while before full operation is resumed.
The UK Government appears to have recognised that, given the current large role of the EU in regulating medicines, the life sciences sector would be heavily exposed by a ‘no deal’ Brexit. As a result the Government has adopted a pragmatic approach, seeking to keep immediate change to a minimum and give businesses time to make any changes that are required. However some of those changes are substantial and businesses should be planning for a ‘no deal’ Brexit well in advance of 29 March 2019, particularly if negotiations break down in the following weeks.