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Drug safety: UK and EU post-Brexit

Published on 10/09/18 at 01:05pm

What does Brexit mean for drug safety in Europe and the United Kingdom? Louis Goss looks into Britain’s exit from the European Union and asks what the future might hold for pharmacovigilance on both sides of the channel.

It could be said that current notions of drug safety and pharmacovigilance were first developed in Britain. The ‘Apothecary Wares, Drugs and Stuffs Act’, passed by Henry VIII in 1540, was the first official act aimed at ensuring the safety of drugs and medicines. The ruling, which granted appointed officials the power to destroy ‘defective, corrupted’ and ineffective medicines, allowed elected representatives from the Royal College of Physicians the capacity to fine offenders ‘one hundred shillings’ for every drug safety offense that had been committed. In the 400 years that followed, these procedures developed relatively slowly, as drug safety regulation and pharmacovigilance systems were slowly put into place. However, although it was with the emergence of the modern world and the development of the nation state that systems ensuring the safety of medicines became widespread; to some extent the current crisis can be seen as one in which the nation state threatens to disrupt the systems and methods that are used to ensure the safety of drugs in modern Europe.

Nonetheless, despite centuries of development, by the middle of the 20th century, the regulations in place were still rudimentary in comparison to the systems we use today. Notably those systems failed to prevent the thalidomide disaster of the late 1950s and early 1960s. Although the sedative thalidomide, sold under the brand name Immunoprin, was marketed as an ‘astoundingly safe’ remedy for morning sickness, it was revealed in 1962 that the drug had caused an estimated 10,000 babies to be born with malformed limbs.

It is somewhat telling that regulators in the United States did not approve thalidomide due to concerns about the safety of the drug. It is also worth noting that the decision was made by the Canadian-American pharmacologist Frances Oldham Kelsey during her first month of working at the United States Food and Drug Administration (FDA). Despite pressure from both Grünenthal who manufactured thalidomide and the wider public, Kelsey, who was one of just seven full-time staff at the FDA in 1960, withheld approval for thalidomide and requested further studies. The episode in many ways demonstrates the importance of individuals in the regulatory process. However despite widespread criticism of what was seen at the time as a controversial stance, Oldham-Kelsey’s decision did result in her becoming the second woman in American history to receive the President’s Medal for Distinguished Federal Civilian Service after the extent of the thalidomide disaster came to light.

Nevertheless, while the thalidomide tragedy may well have been one of the worst drug safety disasters to have ever occurred, the thalidomide disaster accentuated the importance of pharmacovigilance in maintaining public health. The response to the infamous crisis led directly to the development of modern pharmacovigilance practices, as the public reaction and the backlash from the press prompted the foundation of a broad set of institutions focused towards ensuring the safety of drugs in both Europe and across the globe.

Each of these organisations was developed in conjunction with the implementation of a series of directives aimed at ensuring high standards of drug safety in Europe and the United States. These directives subsequently led to the foundation of the European Medicines Agency (EMA), which since being founded in the mid-1990s has overseen the move towards regulatory harmonisation across the EU. The EMA has also played a fundamental role in monitoring drug safety in recent years.

However, as the UK prepares for its exit from the European Union, what the future holds for drug safety and pharmacovigilance, in both the UK and the EU, has become increasingly unclear.

What’s the problem?

Although the terms on which Brexit will be delivered still remain unclear, various issues have been identified as potential stumbling blocks for drug safety on both sides of the channel. For the most part, these problems relate to the future of the relationship between the UK and the EMA.

Currently, the UK’s pharmacovigilance processes are deeply intertwined with those of the European Union. The United Kingdom, for example, uses the EU data processing network EudraVigilance to report and record suspected adverse drug reactions (ADRs). Equally, the UK is a fully integrated member of the EMA and its network of public institutions and contract research organisations, the ‘European Network of Centres for Pharmacoepidemiology and Pharmacovigilance’ (ENCePP). As such, much of the country’s regulation and infrastructure is tied into that of the European Union. This includes much of the regulation surrounding Qualified Persons for Pharmacovigilance and Risk Management Plans, for example.  However, while the UK does rely on EU infrastructure in order to ensure that the drugs consumed within the country are safe, Britain is also a major contributor towards the EU-wide endeavour of monitoring the safety of medicines.

It is also important to note that the UK’s pharmacovigilance practices have both evolved in conjunction with and have shaped those of the EMA. Essentially, since the European agency was founded in 1995, UK regulation has corresponded with that of the European Union. Significantly, this has allowed the UK access to the European market, as drugs approved by the EMA are granted approval in all EU and EEA member states including Iceland, Liechtenstein and Norway. However Brexit, if it was to reverse the efforts towards harmonisation that have been put into place thus far, could acts as a significant hindrance to the pharmaceutical industry as a whole.

Brexit and EudraVigilance

The EU data processing network EudraVigilance was launched in 2001. The system monitors adverse drug reactions and provides effective analysis of data in order to enable the early detection of potential drug safety issues.  Sir Alasdair Breckenridge, a member of the Advisory Board for The Pistoia Alliance and a former chair of the Medicines and Healthcare Products Regulatory Agency (MHRA), explained to Pharmafocus: “The current European PV system, EudraVigilance, comprises of both passive and active safety surveillance. This model relies upon spontaneous reports generated by patients, healthcare professionals and industry, with the UK said to contribute the most.”

However, in a report published in June 2018 the EMA claimed that they “are working on the assumption that the UK will leave the European Union as of 30 March 2019 and will become a ‘third country’ thereafter. Therefore as of 30 March 2019 the UK will no longer participate in the work of the Agency. This means that access to a number of systems and applications supporting the approval and safety monitoring of medicines across the EU would have to be closed to the UK as of that date.” In essence, this would mean that the UK would be required to develop its own pharmacovigilance system.  Additionally, the EU system would lose the UK’s contributions.

As stated by Sir Breckenridge: “If the UK cannot contribute to EudraVigilance after Brexit, the UK will have to establish its own passive surveillance system, which will be smaller than the current one. This will be a lose-lose situation for both the UK and the EMA. Whether this eventuality will occur, depends on the nature of the deal that is reached over the UK medicines regulation. It will, however, still need to be seriously considered by the industry ahead of the end result.”

In large part, the extent to which a data processing network such as EudraVigilance is effective directly corresponds to the quantity of data available to that particular system. As such, the size and scale of the EU increases the effectiveness of the EudraVigilance data processing system. Thus the UK’s exit from the European Union would not only reduce the UK’s pharmacovigilance capabilities but it could also negatively impact the effectiveness of EudraVigilance as a whole. “It is worth noting that conversations have mainly focussed on how Brexit will impair the UK, but Europe will suffer just as much,” Sir Breckenridge added. “The expertise and commitment from the UK has been and still is, central to EudraVigilance and drug safety surveillance. Its absence will be missed following Brexit and the EU will have to work out how best to proceed to protect the safety of its patients.”

Significantly, it would be unlikely that the UK would be able to develop a more effective system of monitoring adverse drug safety issues. This is mainly due to the UK’s relatively small population in comparison to that of the European Union, as reiterated by Tom Cowap, a Director at the global investment banking and asset management firm Alantra: “[EudraVigilance] benefits from scale and it’s difficult to see a smaller region being better at detecting potential drug safety issues than a larger region.”

Sir Breckeridge expanded upon the issue: “When it comes to pharmacovigilance, size matters and the bigger the database the greater the safety accorded to patients. If the UK is unable to share data and records with the EMA, patient safety will suffer. From an industry perspective, companies will have to duplicate efforts and file reports including Periodic Safety Update Reports (PSURs) to both the EMA and the UK’s respective body. As an industry which is already struggling with productivity, this is something companies could really do without.”

Professor Saad Shakir, the Director of the Drug Safety Research Unit (DSRU) in Southampton, agreed, suggesting that “It would be unreasonable and impractical for the UK to set up its own system”. However, Professor Shakir emphasised the fact that in July of this year, MPs voted 305-301 in favour of continued participation in the regulatory network operated by the EMA.  The vote made clear that “It shall be the objective of an appropriate authority to take all necessary steps to implement an international trade agreement, which enables the UK to fully participate after exit day in the European medicines regulatory network partnership between the European Union, European Economic Area and the European Medicines Agency.” The vote also confirmed that an “appropriate financial contribution” would be made.

As such, Professor Shakir suggested that “continued participation in EudraVigilance” would be the most likely outcome of Brexit negotiations. In addition he noted that this could take the form of a “standalone sub agreement.”  Thus in regards to EudraVigilance, while Britain’s withdrawal would almost certainly have a negative impact on drug safety in both the UK and the European Union, as of now the UK’s potential withdrawal from the data processing network seems unlikely.

Drug safety and the movement of people

Freedom of movement within the European Union became a major issue during the Brexit campaign. As Lord Ashcroft’s Election Day poll pointed out, one third (33%) of Leave voters said the main reason for voting Leave was that leaving “offered the best chance for the UK to regain control over immigration and its own borders.” Similarly, The Economist called attention to the fact that in areas in which the “foreign-born populations increased by more than 200% between 2001 and 2014, a Leave vote followed in 94% of cases.”

However, the issue has also become particularly important to the pharmaceutical industry. As explained by Professor Shakir: “There are two issues here; one is the question of Qualified Persons for Pharmacovigilance (QPPV’s)… The other relates to the movement of scientific talent.”

Currently a sizeable portion, if not the majority of QPPV’s in the European Union, reside in the United Kingdom. However, the European Parliament Directive 2001/83/EC states that QPPV’s must reside inside the EU. The directive rules that all EMA marketing authorisation holders must have a permanent and continuous QPPV at their disposal and that the particular Qualified Person must reside and operate inside the European Union. As such, the sizeable number of QPPV’s living in Britain will be put in a particularly difficult situation following the UK’s exit from the EU. It has been suggested that Qualified Persons will be presented with two choices. They could either continue in their roles as QPPV’s by relocating to a country inside the European Union, or alternatively they could get another job!

Either way, Brexit poses a significant issue in regards to the question of QPPV’s. Significantly, companies in Britain may struggle to find new QPPVs located inside the EU. Equally, the European Union will lose access to a large portion of European QPPVs who are currently living in the UK. However, Professor Shakir notes that the QPPV issue may be “negotiable if the UK retains membership of the EU regulatory system”. Cowap expanded on the point by saying: “I don’t think a lot of businesses have arrangements in place at the moment and I don’t think they’ll have those QPPV arrangements in place by March next year. However, I also don’t think that if those product arrangements are not in place, product supplies of key drugs would be prevented.”

In essence, if handled badly the QPPV issue could become mutually destructive. However because of this, there is some expectation that a deal will be negotiated in which the QPPV’s living in the UK will continue to be recognised by the EU. Professor Shakir suggested that there might be a general push towards the regulatory aspect becoming ‘a self-contained issue’.  He continued in stating that “because of the importance of continued availability of medicines, both for people in the UK and Europe… one hopes that this will be taken aside, whether we reach an agreement or not”.   

Secondly, there is the broader issue of the movement of scientific talent within the EU. As Professor Shakir notes: “Medicines regulation and pharmacovigilance are like all scientific disciplines. If you go to any good department of any scientific organisation in the UK, you will see that a significant proportion of the PhD students and the researchers are from outside of the UK.” Thus Brexit threatens to cut off the supply of labour coming from the EU. This in turn could negatively impact Britain’s pharmacovigilance capabilities.

However, Cowap was hopeful in suggesting that the issue may not be as pressing as it may seem. “People are definitely worried about immigration issues in terms of importing talent but it’s important to note that there’s a lot of home-grown talent here.  We have some of Europe’s leading universities, and we have the best linkage in Europe between those universities and the private sector.

He continued, noting: “It’s interesting when people talk about immigration, as they always talk about the negatives to us, rather than the negatives to countries in the European Union. It’s important to remember that you don’t need to move human capital to access it. You have great minds here that are home-grown and it’s likely that other countries in Europe will still want to access that talent, whether that’s paying other companies to access those services or building sites here.”

As such, issues surrounding freedom of movement are yet to be resolved. However Professor Shakir seemed optimistic in saying that he thought “we have handle on these issues”. He went on to suggest that the scientific community were “getting assurance from the government that employment, especially in high value jobs, and movement of people in that direction… will not be affected”.

The current situation

The future of pharmacovigilance and drug safety in both the UK and the European Union is largely dependent on a deal that is yet to be negotiated. Thus the future remains uncertain. As put succinctly by Professor Saad Shakir: “The devil will be in the details. However we as outsiders don’t have much material to work on other than the big intentions”. We do however know that during the implementation period, which will run between March 2019 and December 2020, not much will change; in essence British businesses will have the same rights as EU-based companies. In regards to pharmacovigilance specifically, QPPV’s living in the United Kingdom will be allowed to remain in the UK. Equally, there will be continued mutual recognition of manufacturing and distribution licenses.

As expanded upon by a spokesperson for the MHRA: “During the Implementation Period, our access to one another’s markets will remain unchanged and on the current terms, and the UK will have access to EMA pharmacovigilance databases. This means citizens and businesses in the UK and across the EU can plan with confidence for life after our withdrawal, on the basis that businesses can operate as now, throughout the implementation period.” The UK will however lose its right to vote in both EMA and EU committees.

This does not however mean that it is currently possible to accurately predict the terms on which an eventual deal (or lack of one) will be made. Nevertheless much can be said about the various factors that will shape the final result of negotiations. As Cowap stated: “It’s important to talk about the context. While, forty-five million packs of medicine leave the UK each month for Europe, thirty-seven million packs of medicine leaving Europe come to the UK. You can’t just stop that. Medicines have to keep moving. Just from an altruistic viewpoint no one wants that flow of medicines to be obstructed. However, no government party wants to get involved in the fallout from that either.”

It is also important to consider the significance of the United Kingdom within the context of drug safety and pharmacovigilance in the European Union. The MHRA noted that: “As a leader in the area of pharmacovigilance, the UK already makes a substantial contribution to the work of the European network across this area; we are active participants in pharmacovigilance organisations, projects such as Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action and WEB-RADR (a mobile app for patients and healthcare professionals to report ADR’s to EU regulators) and databases such as EudraVigilance. As such, we believe a continued close relationship will be of significant benefit to not just UK patients, but also EU patients for whom the UK makes a significant public health contribution.” Cowap reiterated the MHRA’s sentiment in calling attention to the fact that the UK has the “highest number of sites certified to receive pharmaceutical products from third party non-EU countries” as he suggested that the UK’s contributions are “fundamental to the flow of drugs into Europe”.  As such, negotiations will undoubtedly take the UK’s contributions into account.

Additionally, it is important to note that MPs voted in favour of continued participation with the EMA regulatory network. This stance was repeated in the policy paper published under the title The future relationship between the United Kingdom and the European Union, released in July of this year. As stated by a spokesperson from the MHRA: “The White Paper reiterates that the UK will seek to participate in the European Medicines Agency (EMA).” The agency continued in saying: “In the unlikely event that the UK and EU do not reach an agreement as a result of these negotiations, the UK will of course maintain high standards of public health and patient safety.  The MHRA is working on contingency plans for a range of possible scenarios and will ensure that public health is protected.”

Thus, as of now, it seems likely that for the benefit of both the UK and the EU, there will be an effort to retain the current status quo, at least in regards to medicines.  As stated by Professor Shakir: “One would like to think that politicians on both sides would like to sequestrate the whole issue and separate it from any results of the negotiations in general. I think because of the importance of continued availability of medicines for both people in the UK and in Europe, there’s an attempt to make this a self-contained issue.”

Hope for the future

In many ways, the question posed by the Brexit referendum was an existential one. The referendum asked voters to determine the way in which Britain should conduct its interactions with the rest of the world. In this way voters were asked to determine the UK’s future. Thus the result of the referendum determined that Britain would have to significantly alter its approach. However, while for many the result of the referendum incited feelings of existential angst, for others it posed an opportunity.

Cowap expanded on the point, saying: “I think long-term there are real potential benefits.”  Although he was clear in stating that he had not been in favour of Brexit during the run-up to the referendum, Cowap argued that it was important to take a pragmatic approach in looking towards the future: “It’s happened now and we should look for positives rather than negatives.” He was forthright in saying that “the benefits that are to be had are long-term and not short-term… in the short-term, the best case would be that things carries on as usual; however, I do think there’ll be some short-term pain, and I think there’ll be some logistical challenges to businesses.”

However, he continued in saying that “one of the areas that could benefit is clinical trials. If you make it easier to run clinical trials, that’s making regulations not lighter but easier to use and more user friendly.  You can then become more of a centre for clinical trials and that ties in nicely with the NHS having one of the biggest sources of centralised data in the world. There’s huge potential for that.” He also pointed out that while the largest pharma market in the world is the United States, the fastest growing markets are in the far East and the middle East as he suggested that Brexit offers “the potential to harmonise much more quickly with other regions”.

Sir Breckenridge expanded on the idea in stating that: “To limit adverse effects following Brexit, the UK should establish its own safety system or collaborate with regulatory authorities outside Europe. Discussions around this idea have already been held with the US Food and Drug Administration (FDA) and Australia’s respective body, the TGA. By collaborating with other agencies, the UK will be able to improve patient safety by sharing data and its expertise across other countries.” As such, Brexit may actually allow for a more global Britain. Steve Arlington, President of The Pistoia Alliance, a not-for-profit alliance of life science companies, vendors, publishers, and academics, agreed: “Regardless of the Brexit outcome, the UK is likely to work closely with all other markets.”

However the Brexit referendum above all asked the UK to reconsider its relationship with the European Union. In the same way, the vote to Leave has forced the EU to reconsider its relationship with the UK. Various models have been proposed since Brexit came to the forefront, as commentators asked whether we would model ourselves after a Norway or Switzerland-style relationship or whether instead we would pursue a no-deal arrangement or so-called ‘hard Brexit’. However, Professor Shakir was unambiguous in stating: “The UK has made it very clear, both at the big picture and the medicines regulation level, that they don’t want Norway. They don’t want to pursue a Norway model because Norway complies with all the regulations but does not have a vote. The UK is a bigger country than that. We are the country of Darwin and Fleming and we cannot sit in a meeting where we allow small European countries to decide without having a say. So I can see why the parliament wants continued involvement.”

The MHRA expanded on the issue in stating that “The UK is proposing a UK-EU free trade area underpinned by a common rulebook on industrial goods where the UK makes an upfront choice to continue ongoing harmonisation with EU rules on goods. This would cover only those rules necessary to provide for frictionless trade at the border. The Government is proposing participation by the UK in those EU agencies that provide authorisations for goods in highly regulated sectors such as the European Medicines Agency.”

Arlington also emphasised the importance of maintaining a close relationship with the EMA: “To avoid any further disruption following Brexit, the UK must aim to keep its guidelines and standards as close to the EMA model as possible.” He added that “[The UK] must also ensure it is aligned with the FDA to guarantee compliance in the US market and prevent causing any new obstacles for pharmaceutical companies.”

Thus a future deal would likely see Britain seek to retain ties with the EMA as closely as possible. However in the longer term, Brexit may offer room for improvement. This improvement would essentially be linked to the fact that in the longer term, Brexit may allow for greater harmonisation with other regions outside of the European Union.

Going forwards

Overall, the future of drug safety is yet to be determined. It could be said that the nation’s health is in the hands of a group of unpredictable and highly changeable politicians, thus Brexit might be significant cause for concern. However, those who commented remained hopeful. Professor Shakir concluded in saying that he remained “agnostic”; he continued in noting that as “a medical research scientist… I work with data. I want to see more data in order to form conclusions”. He was however clear in stating that “public health should be above politics.”  

Steve Arlington was in agreement as he suggested: “The industry must not see Brexit as an obstacle to collaboration and should continue to come together to ensure patient safety remains a key focus across the globe.” Cowap too advised that “it’s just about being sensible and keeping that harmonisation in place. It’s important to not put in artificial or unnecessary barriers to trade when considering the movement of a product that is fundamental to human life”.

Fortuitously the MHRA agreed, saying in a statement that “both the UK and the EU want to ensure that European manufacturing continues to thrive in an increasingly competitive global market”.

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