Trial separation: Brexit effect on pharma26 July 2018
In 2019, the UK will end its membership of the EU, and with it a series of mechanisms that bind it to a continent-wide set of regulations for clinical trials. Emma Cave, a professor of healthcare law at Durham University, tells Greg Noone about the uncertainty felt among pharmaceutical companies regarding the future of the sector post-Brexit.
On 8 June, the managing board of the European Medicines Agency (EMA) sat down for their monthly meeting in the organisation’s London offices. As the murmuring in the room ebbed away and the shuffling of papers began, the group turned to the main item on the agenda: the consequences of Brexit on their humble institution. A centralised database and IT portal designed to register new clinical trials across Europe was, according to the minutes, “nearing completion” and currently in an “intensive phase of testing”.
Further delays to the project, however, should be expected. Unforeseen snags might arise, after all, from the imminent move to Amsterdam.
The UK’s withdrawal from the EU in 2019 will profoundly affect its healthcare system in a number of ways, especially as 5.6% of National Health Service (NHS) staff are EU nationals, and access to the vast, trained labour pool of doctors and nurses that the continent provides has now been thrown into doubt. Funding will also be impacted, for better or worse, depending on which side of the Brexit debate you fall. ‘Leavers’ contend that withdrawal will mean more money is available for the NHS in the absence of membership fees. ‘Remainers’, meanwhile, argue that funding will drop simply by virtue of the UK’s diminished economic performance as a result of exiting the single market. Even the steady supply of medicines is in doubt. In early July, the NHS’s chief executive officer, Simon Stevens, said that plans were under way to secure supplies of drugs and medical equipment in the event of no deal being concluded between the UK and EU.
The EU lost that London feeling
The aforementioned issues have dominated public discussion of Brexit in relation to healthcare. Indeed, there has been relatively little said in mainstream circles about how withdrawal will impact the UK’s clinical trials sector.
As home of the EMA, the country has benefitted from the knowledge and expertise of its 900 staff, as well as the presence of healthcare companies that flocked to London to be based close to the agency. An EMA membership allowed the UK to participate in an EU-wide market authorisation system, streamlining the approvals process for new medical products across Europe. More broadly, UK pharmaceutical companies and healthcare bodies have benefitted from a much larger pool of participants in clinical trials. According to Cancer Research UK, more than 5,000 trials involved patients from the country and the EU. Over a quarter of the trials funded by the charity involved subjects from other member states.
Being a part of a pan-EU clinical trials sector has had its drawbacks for the UK. Conduct in this area is determined by the EU’s Clinical Trials Directive 2001/20/EC (CTD), which was originally written to standardise clinical trials across member states once and for all.
However, the law was strongly criticised by many in the pharmaceutical industry for dramatically increasing the bureaucracy, costs and delays associated with new trials. As a result, the number of new applications sank by a quarter during 2007–11.
“The CTD led to increased bureaucracy that damaged the attractiveness of the UK and EU as cross-border trial locations,” explains Emma Cave, a professor in healthcare law at Durham University. “Problems in the UK were exacerbated by goldplating some of the requirements of the directive to enhance the protection of research subjects.”
Cave was equally critical about the directive in an editorial she wrote for the BMJ in April 2017. Despite its failings, she argued, it was not a valid argument for Brexit. Indeed, Cave says that the directive’s imminent replacement by Regulation (EU) No 536/2014 will remedy most of its deficiencies.
The new law “sets out streamlined processes for authorising clinical trials and measures to enhance transparency and efficiency,” states Cave. “The UK pharmaceutical industry played an important role in shaping the regulation, and the Association of the British Pharmaceutical Industry stressed the importance of long -term access to EU funding and regulatory alignment.”
It seemed that the road was clear for the new law to be implemented in the UK. The vote to exit the EU in June 2016 raised new questions about whether that was even possible.
“The regulation was agreed in 2014, but it won’t come into force until 2019,” says Cave, meaning that implementation will occur after the negotiations between the EU and UK on their future relationship have concluded. “Brexit is likely to occur before the regulation comes into force. This means it’s unlikely to be captured by the promised European Union (Withdrawal) Act 2018, which is designed to repeal the European Communities Act 1972 and bring implemented EU legislation into UK law.”
In April 2018, the UK Government confirmed its intention to implement the regulation after the Brexit process has been completed. Even so, while “the government’s announcement is a strong indicator of the importance of the clinical trials industry, there are potential capacity issues, given the many competing areas of negotiation, and the limited timescales”, adds Cave.
One area of concern is the UK’s imminent withdrawal from the EMA. Despite the government stating that it desired some form of associate membership, thereby avoiding the ‘third-country’ status befalling Norway or the US, this has not stopped experts speaking out about the dangers withdrawal will spell for due diligence on drug approval and the impact it will have on the attractiveness of the UK’s clinical trials sector.
“Instead of sharing this work with European colleagues, we will either just have to accept what they say or duplicate all that work,” said neurology professor Dr Malcom Macleod, in a recent interview with The Scotsman newspaper. “We know that drug companies seek regulation in the largest markets first, and so they are likely to apply for approval for the European market with 435 million people before applying to the UK market with 65 million people.”
In a debate in the UK's House of Lords, the government’s spokesperson on the issue, Baroness Goldie, reiterated that it was “keen to explore the terms on which the UK could remain part of EU agencies that are critical for medicines.” However, she admitted that key elements in the new EU clinical trials regulation remain outside of the UK’s control, including using a single assessment model and shared IT portal.
Cave believes maintaining access to these features of the new regulation would help preserve the status quo of the UK's clinical trials sector. “The portal is a key component of the new regulation,” she explains. “It will be set up and maintained by the EMA, in collaboration with member states and the European Commission. The portal is designed as a single entry point for authorisation, and the database will enhance transparency.”
Another area in which the UK Government could reduce uncertainty would be if it applied for the membership of the International Council of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). It is, Cave says, “a global regulatory body with a strong harmonisation agenda, focusing on the development and registration of pharmaceutical products. Post-Brexit, the UK can apply for observer status at the ICH and, two years later, for regulatory membership.”
Such a move, which would align the UK more closely with international ethical and clinical practices, could serve to enhance its influence within the global clinical trials sector. The fractious debate currently roiling the government is about what negotiation strategy should be adopted with the EU that could potentially lead to a Brexit where no deal is reached.
Indeed, the Medicines and Healthcare products Regulatory Agency (MHRA) recently said it is preparing for all scenarios, including a hard Brexit. The impact the separation will ultimately have on foreign investment in the UK’s clinical trials sector is hard to predict.
“Brexit is creating regulatory uncertainty,” Cave states. “Misalignment with the EU could increase the burden on the MHRA and potentially lead to disinvestment if the EMA offers a more streamlined process. But the UK is committed to alignment, and to assuring global supply chains by enhancing links with international regulators. Brexit will influence foreign investment, but so too will the potential to integrate the NHS into research and the UK’s strong reputation for innovation.”