Clinical trials, Brexit and the question of ‘full alignment’
Gene Matthews, Partner at Leigh Day, reviews the tough decisions the UK has to make regarding its position in the EU regulatory framework post-Brexit.
There is a real and significant risk that the UK is in danger of being out of step with the EU post-Brexit. The term ‘third country’ is used in the EU Treaties to describe a country that is not a member of the EU. In practical terms, this will mean that the UK will not be party to EU legislation. The UK will become a third country on 29 March 2019.
The UK’s relationship forthwith will be secured through bilateral agreements, the terms of which will be determined by both of the relevant parties. Consequently, the nature of the UK’s participation and interaction with the EU will be determined by the nature of any agreement that is reached with the body. Bilateral agreements are likely to be industry specific and this will vary as the UK government has expressed an intention to be closely aligned in some areas. It is likely that in other areas, the UK government will seek to distance itself from our European neighbours.
Within the area of clinical trials, industry experts in both the EU and the UK will want the deep collaboration to continue post Brexit. The reasons for this are numerous; for example, a Royal Society report demonstrates that 80% of UK international research publications include co-authors from the EU. Access to the new portal and database will mean there is a harmonised approach between member states and the UK has a vast amount of expertise and world class facilities for conducting clinical trials.
However, there is a significant risk that the UK will lose its preeminent position in clinical trials and drug development if it officially leaves the EU on terms other than ‘full alignment’. In terms of full alignment, I am defining this in the following terms: Fully implement and participate in the EU CTR system, including access to portal and database. Agreement on health with the EMA as close to the harmonisation the UK would have if it were an EU member state.
This model will result in a close relationship with the EU. Although the UK will maintain third country status, in reality it will completely mirror the EU drug regulatory framework in the same way as a member state. This scenario would be tantamount to the relationship that the EU currently has with other European but non-EU members, such as the EEA and EFTA states. These countries have bespoke and bilateral agreements, some more advantageous than others.
The Norwegian model
Norway, though not part of the EU, has a close relationship with the union. It has a number of acts, some implementing EU-directives, some of them being special national acts. As noted above, it is a member of EFTA, which promotes free trade and economic cooperation between its members within Europe and globally. It is tasked with regulating economic relations between the four states and managing the terms of the EEA agreement, which brings together the member states of the EU (of which there are currently 28) and three of the EFTA (known as the ‘Internal Market’).
It provides for the application of EU legislation covering the four freedoms – the free movement of goods, services, persons and capital – throughout the 31 EEA States. In addition, the Agreement covers cooperation in other important areas such as research and development. It also guarantees equal rights and obligations within the Internal Market for citizens and economic operators in the EEA. Switzerland is not part of the EEA Agreement, but has a set of bilateral agreements with the EU.
EU acts become EEA acts once all parties are in agreement. This process can involve a lot of back and forth between the parties and is itself governed by a regulation (namely Council Regulation (EC) No 2894/94), which aims to secure the objectives of the EEA Agreement, describes the processing of a Joint Committee Decision on the EU side and further acknowledges that the EEA Agreement provides for an EEA Joint Committee with decision-making power and regulates how the EU side decides on its position as regards Joint Committee Decisions.
Clinical Trials are mainly regulated by international and national laws and the European Directive 2001/20/EC, which is fully implemented in the Norwegian equivalent regulation relating to clinical trials on medicinal products for human use.
Norway is intending to implement the CT Regulation. It has finalised the national regulations and is developing the relevant IT framework. The Norwegian Medicines Agency is reviewing and adapting procedures to put this in place.
The UK’s best option
Full alignment is the most attractive option for the UK as it is the only one which gives access to the portal and database that will, in turn, save time and money being wasted. The EMA can grant pharmaceutical companies a single marketing authorisation that provides access across the whole of the EU market.
The UK has a vast number of renowned research institutions and healthcare professionals, which makes the UK a desirable place to conduct clinical trials. It has been noted that the MHRA undertakes 20% to 30% of the vigilance and licensing work that the EMA is responsible for and replacing that will be difficult. The EMA have drafted various documents, including the EMA Brexit Preparedness Business Continuity Plan on the EMA’s website, which outline the difficulties the EU/EMA will face when the UK leaves and, therefore, full implementation is the best option for both the EU and the UK.
Other European countries have taken steps to align their national clinical trial regulatory framework more closely with the proposals in the EU regulation to facilitate a smooth transition once this takes effect, including Belgium, France, Sweden and Germany. The UK has not taken this step because of uncertainty surrounding Brexit. However, if the UK wishes to remain fully aligned, this is a step that should be taken, and soon, to ensure effective application of the regulation. Sweden is proposing two legislative changes to bring its clinical trials regulations in line with the regulation, which are expected to make it faster and easier to get permission for clinical trials.
The UK can put forward a position that it wants to fully align with the CTR and, similar to Sweden, propose legislation to bring the UK’s regulations in line with the CTR and set up computer systems to ensure access to the portal and database. As above, it would be a third country but with a bespoke and bilateral agreement as regards clinical trials and a close relationship between the EMA and MHRA.
It is unclear whether this will be possible; it appears that this is an area in which both the EU and the UK want to maintain their close relationship but fully aligning with the CTR after it has left the EU will attract critics (arguing the UK is still subjecting itself to EU law), and the EU will again accuse the UK of cherry-picking (picking and choosing which regulations to align with). However, bespoke and bilateral agreement(s) in this area could be negotiated and drafted to be beneficial for both parties.
United on clinical trials
On 1 March 2018 a new version of the Model Clinical Trials Agreement came into force, which allows a single model contract for commercial research and development to be used in England, Scotland, Wales and Northern Ireland. Previously companies had to, essentially, go through a separate process and prepare contracts for each of the nations before commencing clinical trials.
This is similar to the position currently under the Clinical Trials Directive (CTD), with every member state having their own application process. The CTR aims to harmonise this by having one application form for all member states. It is encouraging that an agreement between the four UK nations of England, Scotland, Northern Ireland and Wales has been reached as it shows life sciences leaders across the four nations are open to collaboration with each other. Something similar could be agreed between the UK and the EU if life sciences leaders within the UK and EU similarly agree that collaboration between the EU member states and the EU is the best approach.
In addition, the UK would want to maintain UK participation in European Reference Networks (ERN’s) for rare and complex diseases. Other non-EU countries – Norway in particular – have ERN’s and, it would seem there could be little disagreement about the UK’s continued participation in ERNs. It has been reported that, in March 2017, 24 ERNs for rare diseases were commenced by the European Commission and the NHS was involved in 23 (actually leading a quarter of them). However, it must also be pointed out that the legal basis for these networks is the patients’ rights to cross-border healthcare and thus membership of the EU seems integral to them. After 29 March 2019, EU citizens can live, work and study in the UK, but there will be a registration scheme in place (which gov.uk has not yet published any details on). In addition, discussions are still taking place between Norway, Iceland, Lichtenstein and Switzerland about securing the status of their citizens who are resident in the UK.
Theresa May indicates future relationship
The announcement by Theresa May in March that the UK would seek an ‘associate membership’ of the EMA is to be welcomed, but there will need to be full alignment to stand the best chance of maintaining our leading role in clinical trials and drug development.
In terms of “no alignment”, I am defining this in the following terms: Whilst the EU implements the CTR, the UK does not implement the EU CTR and keeps the same UK laws that the CTD put in place. MHRA will likely adapt the CTD to create a bespoke regulatory system, which may not align with the EU CTR.
The UK’s positon would be that of a third country and it would then develop a bespoke system. There are a variety of difficulties with this option, an obvious example being that generated by the proximity of the UK to its European neighbours; it may be difficult for the UK to adopt a completely different approach.
Difficulties in creating a bespoke system
The disadvantages of no alignment are clear (and numerous), but many of these would also apply to partial alignment options. Without consistency in the application and authorisation provisions and processes, and without using the same computer systems, problems will abound.
Information sharing may become a practical problem, with differing computer systems in place. The application of the EU CTR Regulation has already been delayed from the end of 2017 to 2019, as the portal and database system was not up and running in time.
Legal implications may come from the General Data Protection Regulation (GDPR), when it comes into force on 25 May 2018. Participants involved in clinical trials are data subjects under the GDPR and as such have identified rights under it.
Presently, companies are setting up procedures to ensure data is protected after this regulation comes into effect (given that the sanctions for data breaches after May 2018 will be severe). As above, if companies wish to be fully aligned with the CTR then they should start setting up systems now so that clinical trial processes are standardised, making the transition easier and compliant.
As you may be aware, the provisions of the GDPR establish a new class of sensitive personal data, namely biometric and genetic data. There will be new compliance requirements for such data, such as requirements for obtaining consent to process an individual’s data.
If the UK does not align, or has its own application process, consent form or computer systems, pharmaceutical companies may face delays and difficulties in registering the results or marketing the new drug in the EU. There may be delays in processing and, if the consent form does not adhere (or align) with the CTR or GDPR, pharmaceutical companies may face sanctions.
Potential delay to accessing medicines
There will be delays in accessing vital medicines due to regulatory barriers. One article, published by the Brexit Health Alliance, suggests Switzerland experiences delays of 157 days in receiving a drug approved in the EU while for Australia and Canada, the article quotes 6 to 12 months. A Brexit Health Alliance paper published recently also reinforces this point stating that “divergence of standards on issues such as data protection could impact the endeavour to access crucial data from outside the UK”.
The Federal Office of Public Health in Switzerland is assessing what the impact of the regulation will be, and closely monitoring further developments.
Under the old directive, the sponsor had to submit separate applications for a multinational study to the authorities and ethics committees of each of the EU member states involved, in the language of the state in question and, depending on the state, accompanied by additional documentation.
Under the regulation, a single, central application will be sufficient for the whole EU, which can be submitted by the sponsor via an online portal at the EMA. The rules will apply as soon as the planned online portal is up and running, probably at the end of 2018.
The implementation work initiated since the CTR was passed includes the following:
- Online portal set up and developed by the EMA (in collaboration with EU member states and the European Commission).
- Delegated and implementing acts formulated by the European Commission.
- Enactment of national laws governing aspects that the CTR leaves to legislators in EU member states.
In Switzerland, the Federal Office of Public Health is monitoring developments with a view to setting up and developing the online portal and the planned delegated acts, implementing acts and memoranda. Deviating from the regulation could limit the effectiveness of European and global health initiatives, such as pandemic responsiveness and the fight against antimicrobial resistance.
Potential upsides to no alignment
In theory, the UK could be competitive in offering quicker timescales for approval, making the UK more attractive to pharmaceutical companies internationally, but this would be of little assistance when it came to marketing these drugs in the EU if appropriate agreements have not been established.
Similar to the position on trade, and whether the UK will continue in the single market or customs union, this is up in the air. The government states that they will be free to make their own trade deals with non-EU countries, but, in a clinical trial context, companies are attracted to the harmonisation offered by the CTR – one approval system and drugs are given marketing authorisation for the whole of the EU.
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