One of the most time-sensitive topics at this week’s Medicines for Europe 18th Regulatory and Scientific Affairs Conference, held January 31 to February 1 in London, United Kingdom, was preparing for the United Kingdom’s upcoming withdrawal from the European Union.
One of the most time-sensitive topics at this week’s Medicines for Europe (MFE) 18th Regulatory and Scientific Affairs Conference, held January 31 to February 1 in London, United Kingdom, was preparing for the United Kingdom’s upcoming withdrawal from the European Union.
Moderator Beata Stepniewska, MPharm, deputy director general and head of regulatory affairs at MFE, opened the panel by saying that “we would have preferred to delete this session and forget the word ‘Brexit,’” referring to recent UK political developments that could have—but failed to—bring clarity to the Brexit landscape. She added that with just 59 days to go before Brexit, the organization has a responsibility to guide its members through what is shaping up to be a “quite painful process.”
The European Commission’s Perspective
Beginning the discussion and providing a view from the European Commission (EC)’s perspective was Florian Schmidt, legal advisor in the directorate general for health and food safety in the EC.
According to Schmidt, one thing about Brexit is clear: regardless of whether a deal is ratified or the United Kingdom leaves the European Union without an agreement, Brexit will cause “significant disruption,” and the fallout is “one that both sides have to deal with” through action from regulatory authorities.
In the case of a ratified UK—EU agreement, a transition period, extending to the end of 2020, will be instituted to ease the process of moving to separate regulation. However, in the event of a no-deal outcome, there will be no transition period, and all administrative actions needed to prepare for Brexit—such as moving marketing authorizations to remaining member states, making changes to clinical trials, and adapting labeling for medicines—will have to be completed prior to March 30, 2019.
The bottom line, said Schmidt, is that no drug maker can rely on the transition period.
Where the United Kingdom Stands
Giving the UK regulator’s perspective was Keith McDonald, deputy director of the licensing division of the Medicines and Healthcare products Regulatory Agency (MHRA).
“Everybody who reads a newspaper or watches the news is as well informed as I am” about where the political process related to Brexit stands, said McDonald. While MHRA’s preferred outcome would be a deal to minimize disruption, in a no-deal scenario, MHRA’s priority will be to ensure timely patient access to medicine and while maintaining standards of safety, quality, and efficacy.
To that end, the UK Human Medicines Regulation was amended to harmonize with current EU legislation. Additionally, EU marketing authorizations will be automatically granted UK status, the MHRA will roll out new review procedures for biosimilars and new active substances, incentives for orphan drug development will be put forth, and data and marketing exclusivity will be provided. Furthermore, batch testing will take a “whitelist” approach to EU and European Economic Area sites, parallel imports will be allowed, and importation of investigational medicinal products will be permitted for clinical trials.
MHRA’s no-deal plans also include transitional marketing authorization provisions under which legal establishment of a marketing authorization holder in the UK will be allowed to take place until the end of 2020, and package leaflets can be updated prior to the end of 2021.
Handling Centrally Authorized Products
Marie-Helene Pinheiro, PharmD, industry stakeholder liaison for the European Medicines Agency (EMA), reported that the reallocation of duties for evaluating centrally authorized products (CAPs) “seems, as far as we know, to have been implemented quite smoothly.”
Pinheiro explained that UK rapporteurs have been reallocating duties to EU rapporteurs through a “shadowing” program and collaborating on reports. The shadow rapporteurs will become the new leads starting on March 30, and marketing authorization holders have been informed of the reassignments.
While the reallocation of duties has progressed smoothly, CAPs themselves are another matter. According to Pinheiro, only 27% of all affected CAPs have completed all of the necessary pre-Brexit changes. Among companies that have not completed all steps for their CAPs, 76% need to submit manufacturing site changes and 87% need to submit qualified person for pharmacovigilance changes. As of November 2018, there were 19 products for human use that appeared to be at risk of not making changes in time.
With just 8 weeks to go before Brexit, she said, it is crucial that companies engage with the EMA swiftly and make all changes as soon as possible.
Reference Member State Changes and Marketing Authorizations
Kora Doorduyn-van der Stoep, PharmD, member of The Coordination Group for Mutual Recognition and Decentralised Procedures: Human (CMDh) and the Medicines Evaluation Board of the Netherlands, explained that drug makers need to submit changes on time to member states whom they would like to serve as new Reference Member States (RMS) for regulatory procedures.
While a marketing authorization will not be invalidated if an RMS is not transferred in time, it will be impossible to submit a new regulatory procedure until the transfer is complete.
If a company uses the UK as an RMS and the transfer is not complete at the time of Brexit, the drug maker must find a new member state and resubmit an application. For critical products, CMDh will publish further advice on how these procedures will be handled.
Currently, 3 companies have 13 ongoing marketing authorization applications with UK as an RMS that are at high risk of not being finalized by March 30, and what will become of those applications is an “ongoing discussion.”
The Potential for Supply Disruption
Britt Vermeij, PharmD, deputy chair of the regulatory and scientific committee at Teva, said that supply disruption could result from delays to the site transfer for batch testing. Currently, based on a survey of industry, it has become clear that products used in immunology, oncology, and metabolic disorders, among others, could be impacted, and these may be “the tip of the iceberg.”
Paul Fleming, technical director of the British Generic Manufacturers Association, added that the industry is working hard to minimize the impact of Brexit on the supply of medicine. Generic and biosimilars makers, as well as other areas of industry, have begun to stockpile at least 6 extra weeks’ worth of medicines.
“This is not a last-minute activity” that will start in March, he explained, but an ongoing effort that includes weekly meetings with MHRA, the department of transport, and other parts of the government, as well as logistics firms.
While the current supply “looks good” from a UK perspective, however, it is becoming clear that disruptions could last as long as 6 months, not just 6 weeks. Furthermore, given that the supply chain is increasingly global, the effects of a disruption may be felt worldwide, not just in the UK and EU context.
The Need for Action
Rita Purcell, deputy chief executive of Ireland’s Health Products Regulatory Authority, urged drug makers to take swift action to prepare for Brexit and not wait any further for political developments to provide clarity.
“We’ve been told all along to prepare for the worst,” she said, but emphasized that a no-deal outcome is even worse for industry than a “hard Brexit,” and she fears that industry’s hopes for a transition period could mean that few are fully prepared for the realities of a no-deal scenario.
Companies urgently need to review their supply chains for capacity as well as compliance and transit documentation in addition to reviewing their regulatory compliance. Above all, she said, if in doubt about their readiness, drug makers must get in touch with regulators immediately to seek solutions.
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