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Brexit Update: Authorities Speak Up 2017-12-08

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November 2017 provided a crescendo of Brexit related news. European Medicines Agency (EMA) provided further guidance on Brexit with updated Q&As [1,2], the European Union (EU) voted to relocate the EMA to Amsterdam, EMA provided Brexit statements at an SME meeting [3], Medicines and Healthcare products Agency (MHRA) provided their position at a recent workshop [4], and Heads of Medicines Agencies (HMA) contributed to a Brexit discussion [5]. Then as December started, Mrs May and Mr Juncker met and failed to agree to move to a second phase in the Brexit negotiations, before making a breakthrough in the early hours of 8th December to pave the way for trade discussions. So where are we now? Let us first sum up the situation and then present an account of some of these recent meetings.

  • The government of the United Kingdom (UK) would like a close relationship with the EU, and MHRA have started to give some indication of what they would like that to be [4]. But as the leaving party, the UK government appears unable to give clear guidance to industry during the negotiating phase. The issue of regulatory alignment and/or equivalence will be a growing debate in the year to come in all trade sectors.
  • The position of EMA, European Commission (EC) and HMA has been delivered and repeated consistently. The only way for companies to ensure continuity of supply of medicines in the EU is to prepare for the UK to become a third country after 29th March 2019 [1,2,6]. The consequences of this position are becoming clear, and the assessment of regulatory impact has been reviewed and published by many, including Diamond Pharma Services [7]. Now that Brexit negotiations appear to be entering the second phase, trade discussions can begin. Whilst this is a great breakthrough, the task ahead in all trade sectors is immense. All authorities will honour the deal struck at the political level, but until a deal is done, the third country message is likely to remain unchanged.
  • Industry, particularly large pharmaceutical companies, are acting on Brexit already. Regulatory strategy dictates that companies need to plan back from 29th March 2019. That leaves little time available to execute Brexit plans. Large companies set their annual budgets based on business need, risk and opportunity, therefore, decisions are already being taken that will affect workload and resourcing in pharmaceutical companies based in Europe for many years to come. By the time the UK and the EU come to an agreement, industry will already have made irreversible decisions. Those not acting are increasing the risk to their portfolio and could face resource, capacity and timeline challenges as any putative transitional or implementation period is pure speculation.

TOPRA: A conversation with HMA, 1st December 2017, Estonia

Ian Hudson (Chief Executive, MHRA) provided an overview of the HMA workplan. He described the 11 priorities set by HMA for the year ahead and explained that the workplan had been reviewed to take into consideration issues related to Brexit. HMA had reached no consensus to remove any priorities because of Brexit, but the issues related to Brexit were bigger and had more widespread impact than initially thought, consequently a delay to activities was inevitable.

Brexit continued to be a recurring comment in all sessions through the day, and one session was dedicated entirely to Brexit.

Hugo Hurts (Executive Director, MEB) presented the case for managing Brexit from the point of view of decentralised procedures. He announced that HMA had formed a Brexit Task Force (BTF) in November 2017, comprising 18 heads of agency with both the CMDh and CMDv represented and co-chaired by Hugo and Thomas Heberer (BVL). Hugo pitched a refreshingly nuanced argument for all involved to take responsibility. He warned that it was not realistic to expect that the BTF could provide recommendations. Instead he argued that the BTF could evaluate, inform and share information to allow industry to plan ahead. Hugo reiterated the message that the only way to ensure continuity of supply of medicines in Europe is to prepare for a worst case Hard-Brexit scenario where the UK becomes a third country on 29th March 2019. Hugo acknowledged that this was not desirable, but it was the only credible scenario to consider under the circumstances and that industry could not wait. Any transitional phase or extension period for the implementation of Brexit is purely speculative. This message is consistent with all announcements made by EMA and EC in recent months.

The reasons given for industry to plan ahead are:

  1. Products registered by the decentralised procedure number in the 1000s (unlike centralised products which are in the 100s). The sheer volume means that the capacity for all parties to respond in a timely fashion will be a challenge.
  2. For decentralised products, all ongoing procedures need to be complete before license transfers from UK to EU RMS can be made. MHRA had 3000 open renewals earlier in 2017, but a dedicated task force has brought that number down to 700 and MHRA intends to close out all active renewals by the end of the year.
  3. Taking into account all the activities needed to transfer a product portfolio requires companies to work back from 29th March 2019. That leaves only 16 months left to act.

In the spirit of accountability Hugo explained that cooperation between industry and HMA was needed. Industry can help agencies by providing the following information:

  • Where do companies plan to move MRP/DCP products?
  • How many products will be transferred and how many would be allowed to fall off EU markets?
  • When will licenses be transferred?

HMA believe they can help industry by:

  • Increasing oversight of transfer activities to ensure regulatory continuity in the network.
  • Avoiding duplication of activities by collaborating between CMDh, CMDv and other HMA working groups and building on existing activities.
  • Coordinating Brexit queries and responses.
  • Closely aligning with EMA on preparedness activities.
  • Making recommendations to industry (although Hugo was concerned that industry be realistic about how far those recommendations could go).
  • Identifying capacity problems and helping to fix gaps within the HMA network, or communicating the challenges with industry.
  • Continuing and refining capability/capacity mapping exercises across national competent authorities.

Zaide Frias (Head of EMA Human Medicines Evaluation Division, EMA) provided a brief statement about the requirements from a centralised EMA perspective. These views have been widely communicated by EMA in recent months and did not deviate from the account provided in a recent EMA meeting [3]. In brief:

  • EMA has conducted a survey of national agencies to identify capabilities and capacity to account for the departure of MHRA contribution to EMA workload.
  • UK workload is being redistributed.
  • Intense discussion with The Netherlands government has begun to plan for the relocation.
  • The staff survey carried out by EMA suggests that 81% of EMA staff will relocate.
  • To ensure that supply of medicines in the EU will not be affected, the EMA considers that industry should plan for the UK to become a third country after 29th March 2019. That means that all licenses must be held by legal entities in the EU. This also has consequences for batch release and PV as reported previously [1,2,6,7].
  • In a recent EMA SME Info meeting, the impact of the UK being a third country was also considered from the perspective of the clinical development stage [3]. All EU procedures, such as SME and Orphan Designations, will need to be held in a legal entity in the EU. Furthermore, investigational medicinal products manufactured in the UK would need to be imported into the EU for clinical trials, and UK based sponsors would need an EU Legal Representative. Any other position related to political agreements regarding regulatory alignment were speculation. If an alternative position was agreed between the UK and the EU then EMA would adjust their position, but not before such an agreement was made.

Susanne Keitel (Director, EDQM) presented a case where Brexit had a smaller impact on post market testing compared to EMA considerations. After Brexit, the UK will remain a member of the Council of Europe and will be a signatory on the Ph. Eur. The UK’s National Institute for Biological Standards and Controls (NIBSC) will also remain a member of the General European Official Medicines Control Laboratory Network (GEON). However, the UK could not contribute to mutual recognition, decentralised and centrally approved product test programmes. Despite these restrictions, the network for testing organisations is considered to be robust and other nations could contribute further to assigned workload. However, significant sampling is carried out in the UK, particularly for biologics and this could be a cause for concern. One recommendation made is that applicants provide two (and not one) options for Official Control Authority Batch Release test sites to help for capacity planning.

Virginia Acha (Global Regulatory Policy, EU, EMEA, APAC, MSD Europe) provided an industry perspective making use of data from The European Federation of Pharmaceutical Industries Associations (EFPIA) [8]. Virginia made the compelling case that industry needs a clear and transparent framework. In the absence of clarity, pharmaceutical companies will make financial, facilities and resourcing decisions that will have long-lasting effects for all parties. Companies will need to alter resource and strategy plans based on the need to ensure continued supply of medicines. That means that some supply chains, batch release and pharmacovigilance strategies will be duplicated or moved, as there is not sufficient time before 29th March 2019 to delay. The requirements for the UK becoming a third country are clear, but the scale and timeline for the change is unprecedented. Large pharmaceutical companies are already acting as they identify that there are capacity challenges for both industry and the regulators.

The following statistics were presented to highlight the scale of the task ahead:

  • 45% of the pharmaceutical industry surveyed considered that WTO rules will cause supply delay.
  • 45 million patient packs per month are supplied from the UK to EU.
  • 37 million patient packs per month are supplied from the EU to UK.
  • UK exports 2,900 medicinal products to the EU, 90% are final product.
  • EU exports 3,200 medicinal products to the UK, 70% are final product.
  • 1500 ongoing clinical trials in the EU are conducted by UK sponsors.
  • 400 centrally approved licences are based with MAHs in the UK.
  • 1300 EU authorised products are tested and released in the UK.

Virginia suggested that the MHRA are unable to provide further guidance, as they are restricted by the UK Government’s negotiating strategy. However, she stressed that industry is not helped by suggestions of transitional deals, extensions or implementation periods. Both the UK and the EU will need to provide clear guidance about what a transition period means. Until that clarity is provided industry has no option but to prepare for the worst case Hard-Brexit.

Ian Hudson (MHRA) had been unable to stay for the whole conference, so the audience were left to speculate about any future UK regulatory environment. Fortunately, two days earlier some thoughts were provided at the MHRA meeting reported below.

Applying for a Marketing Authorisation in the UK? Advice from the Regulator on getting it right first time for abridged applications, 29th to 30th November 2017, UK

During the meeting there were two panel discussions and a Q&A session, all related to Brexit. Here are the main takeaway points:

  • The MHRA is still very much geared towards a harmonious working relationship post-Brexit as close as possible to how we currently work in Europe on a regulatory level. This is the current MHRA stance.
  • It is expected that CEPs, European monographs and Ph.Eur methodology will be acceptable in the UK after Brexit but this has to be confirmed.
  • Discussions are ongoing at EMA level right now about acceptability of European reference products and UK products as European reference products for ongoing and historically approved procedures. A Q&A is expected in the coming months.
  • MHRA position in the interests of public health is not for human beings to undergo further unnecessary clinical trials (such as new BE studies) as a direct result of the consequences of Brexit due to changes in acceptability of EU/UK reference products.
  • MHRA will continue to act as RMS until the date of Brexit and expect all EU national competent authorities to accept their assessments post-Brexit if they were started prior to 29th March 2019.
  • MHRA and HPRA (IE) are working together to ensure where possible that joint packs can still be accepted post-Brexit to ensure continuity of supply to patients. Feasibility in law making will play a part in these discussions. It is a major desire from both sides to find a compromise. Ireland will have significant medicinal product supply issues unless a workable solution is found.
  • All of these points are caveated with the fact that discussions on medicines regulation at the political level are yet to start. They expect major progress on this in the coming weeks (i.e. December 2017).
  • UK has begun transposing EU law into UK law in draft format behind the scenes so that industry can continue to operate immediately after Brexit. Assuming the UK will seek to work (as it currently hopes to) as closely as possible with EU member states post-Brexit it makes sense that UK law is aligned as closely as possible to EU law post-Brexit.

References

  1. Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure. 
  2. Questions and answers related to the United Kingdom’s withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the Centralised Procedure.
  3. SME Info Day: Supporting innovative medicines’ development and early access, 17th November 2017, EMA, UK.
  4. Applying for a Marketing Authorisation in the UK? Advice from the Regulator on getting it right first time for abridged applications, 29th-30th November 2017, UK.
  5. TOPRA: A conversation with HMA, 1st December 2017, Estonia.
  6. Questions and Answers related to the United Kingdom's withdrawal from the European Union with regard to national authorised medicinal products for human use.
  7. Brexit Considerations for March 2019, Diamond Pharma Services.
  8. EFPIA Brexit Survey Results.
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