Remaining (Pharmaco)Vigilant Post-Brexit

On June 23, 2016, the UK narrowly voted to leave the European Union. Since then, the country’s two major political parties – Labour and the Conservatives – have accepted the result as a binding commitment and have pledged to deliver Brexit. On March 29 this year, the government triggered Article 50, starting a clock that will stop ticking at midnight on March 28, 2019. And yet no detailed Brexit plans have materialized and, over the next two years, negotiations over both the terms of departure and a future relationship will need to take place. The vital practice of monitoring the effects of drugs after they have been licensed for use – pharmacovigilance – will also need to feature in both sets of negotiations.

Pharmacovigilance activities across the EU are highly integrated between marketing authorization holders and competent authorities. Moreover, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) has been highly influential in developing pharmacovigilance science and practice in the EU. Brexit has the potential to significantly disrupt these activities, which could have adverse consequences for patient safety. One immediate consequence of the UK’s intention to leave the EU will be the EMA’s departure from its current location in Canary Wharf, London. Several cities across Europe are pitching for the right to host this prestigious agency and a decision should be made in October. But damage is already being done; morale is reportedly low amongst the agency’s 850 staff, not all of whom will be willing or able to relocate – particularly the UK citizens who may lose their right to work elsewhere in the EU. This distraction may reduce the EMA’s capacity to conduct its routine work and is highly likely to affect its ability to deliver on major IT projects, such as the upgrade of the Article 57 medicinal product database to the IDMP (Identification of Medicinal Products) standard. There will also be knock-on effects on Marketing Authorization Holders (MAHs).

The break up

Not only are the EMA headquarters set to leave London, but it also seems likely that the UK will not be part of the EMA post-Brexit, according to the UK Secretary of State for Health (1). Outside of the EMA, I can see two potential scenarios for how the regulatory framework in the UK may look from April 2019.

The first and, by industry consensus, the best option is for the UK pharmaceutical industry to continue to operate in alignment with the EU regulatory framework and to participate in EU regulatory procedures. In this scenario, the UK would aim to maintain alignment with current and future EU pharmacovigilance regulations, while also continuing to contribute to the advancement of pharmacovigilance science and practice. The use of the word “alignment” is key, as it implies that the UK will not be bound fully to follow these regulations and could adapt or ignore them depending on what the country considers appropriate. Alignment of the UK and EU regulatory frameworks would help to reduce the impact of additional costs and regulatory burdens relating to pharmacovigilance activities in the UK and EU post-Brexit. With respect to the Article 57 and EudraVigilance databases, the UK could benefit from continued access to both.

The second scenario involves the MHRA working independently outside the EU regulatory system. It may include a mix of alignment with some EU regulations, regulations from other agencies (for example, the FDA) and perhaps UK specific pharmacovigilance regulations post-Brexit. This model would be complex and would take time to set up, as the UK regulatory system is currently fully aligned to that of the EU. Under this model, access to the Article 57 and EudraVigilance databases would probably not be available to the UK.

With either model, retaining as many of the current arrangements with the EU as possible is desirable to minimize additional costs and administrative burdens. In particular, this should include continued use of the EMA’s Good Pharmacovigilance Practice (GVP) guidance. The UK, via the MHRA, has played a key role in the development and application of the EU’s pharmacovigilance systems. Hopefully, this will continue, although any influence is likely to diminish post-Brexit.

What of the QPPVs?

Another problem for the pharmacovigilance community is the uncertainty surrounding the status of UK-based QPPVs (Qualified Person for Pharmacovigilance). To sell into the European Economic Area (EEA), each MAH requires the services of an EEA-QPPV, who is responsible for ensuring the safety of the company’s products and compliance with its pharmacovigilance obligations. The EEA-QPPV must live and work within an EEA country and some member states also require a national QPPV (although not the UK). At present, it is estimated that there are a total of 1,358 QPPVs in the EEA – 153 of which are based in the UK. For these UK-based EEA-QPPVs, their futures are in question – not to mention their support teams in their QPPV offices. As a single entity, the community of UK-based QPPVs has a huge wealth of knowledge and experience of pharmacovigilance and has been instrumental in driving the development of the current European pharmacovigilance legislation.

It is highly unlikely, however, that there will be a role for UK-based EEA QPPVs post-Brexit – if it is a hard Brexit. At the end of April, the EMA and the Heads of Medicines Agencies (CMDh) issued notices that stated very clearly that some pharmacovigilance activities must be conducted from within the EEA (2)(3).

This includes EEA-QPPVs, and indicates that MAHs should start making arrangements to ensure compliance with this post-Brexit. MAHs may not be able to recruit new QPPVs and associated personnel to replace all those currently working in the UK. Free movement of UK-based QPPVs to remaining EU/EEA member required,   or a transitional agreement.

Preparing for the worst

Since 2012, MAHs are required to maintain a Pharmacovigilance System Master File (PSMF), which describes the company’s pharmacovigilance system. The PSMF should be located at the site where the EEA-QPPV is based, or where the bulk of the company’s EU pharmacovigilance activities are conducted. It is generally an electronic document, so relocation from the UK is unlikely to be a concern for most MAHs. The PSMF concept is starting to be adopted by other agencies outside of the EEA, but unfortunately, this has resulted in some companies having multiple PSMFs. Hopefully, the UK will continue to accept the EU PSMF template and not require companies to develop a UK-specific document.

Over the last few years, there has been a concerted effort – through safety referrals (for example Article 31 referrals) and work-sharing assessment of Periodic Safety Update Reports (PSURs) – to reduce duplication of activities relating to assessment of emerging safety concerns and changes to benefit/risk profiles of established medicines. Previously, each national competent authority assessed PSURs submitted to them by MAHs. For generic products, they could receive multiple PSURs for a single active substance from multiple MAHs, but at different times. Work-sharing assessment changed this; a single authority now assesses the PSURs received from all MAHs across the EU, and all covered the same review period. The result is harmonized assessment and harmonized recommendations for labeling changes or other safety actions. In 2016, this was further streamlined and simplified following the introduction of the single assessment portal.

There is a big question over how these PSUR single assessment procedures will be conducted post-Brexit. It is not the EMA that conducts the assessment, but the national competent authorities. Of the approximately 1300 actives for which a lead member state for assessment has been assigned, approximately 16 percent have been assigned to the UK’s MHRA – significantly more than any other competent authority. If the MHRA is unable to provide such assessment activities post-Brexit, the work will have to be reassigned to the other member states, which will pose two problems: first, it is not clear that the other member states will have the resources to perform this function in the initial post-Brexit period; second, member state competent authorities are paid to perform this assessment, so it could represent a significant loss of revenue for the MHRA. How will the budget hole be filled? Will it introduce new or higher fees for pharmacovigilance services?

At the time of writing, there are very few knowns and many unknowns regarding the impact of Brexit on pharmacovigilance but, as an industry, we must prepare for the worst. With luck and a fair wind, the negotiations – particularly those relating to pharmaceutical regulation – will progress smoothly and quickly so that the uncertainty regarding the future of pharmacovigilance in both the UK and the EU is limited.

Just before this article was published, the UK’s general election was decided. The clear and unequivocal mandate that Theresa May sought has not been granted to her by the UK electorate.What is certain is that there is much work ahead for both MAHs and the competent authorities across Europe.

John Barber is EEA-QPPV and Head of Pharmacovigilance, European Operations at Dr. Reddy’s Laboratories. The views expressed are personal and do not necessarily reflect those of John’s employer or any other organization with which he is affiliated.