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Brexit was complicated enough for life science companies in terms of the future regulatory relationship between the UK and the EU. They now have to consider the added complexities of the Northern Ireland Protocol.

As things stand, when the transition period relating to the UK's departure from the EU, ends on 31 December, the UK regulator, the MHRA, will issue its own marketing authorizations (MAs) for products currently approved through the EU centralized procedure. However, these MAs will only be valid in the island of Great Britain, which comprises three of the four nations that make up the UK: England, Scotland and Wales. 

The fourth nation, Northern Ireland, will for regulatory purposes continue to be regarded as an EU member state, which means that marketing authorizations issued by the European Commission will remain valid in Northern Ireland. However, responsibility for those products once they are on the market will fall to the MHRA, which will also have to ensure EU rules are applied, even though it has no say in the setting of those rules.

Moreover, despite Northern Ireland being considered equivalent to an EU member state, a Qualified Person based there will not be able to release products for marketing in the EU. In addition, goods manufactured in Northern Ireland will be classified as manufactured in the UK.

These outcomes are a result of the Northern Ireland Protocol that was agreed as part of the new Withdrawal Agreement signed by the UK and the EU in 2019, under which Northern Ireland will remain part of the UK’s customs territory but will also be partly in the EU single market. Customs checks and controls will apply to products moving from Great Britain to Northern Ireland, but will not be required between Northern Ireland and the Republic of Ireland, thereby helping to avoid a “hard border” on the island of Ireland.

"Any product placed on the market in Northern Ireland will have to be covered by an EU regulatory procedure." – Emma Du Four, AbbVie

The regulatory consequences of these complex arrangements were discussed during the UK BioIndustry Association’s latest Brexit webinar, held on 16 July. BIA CEO Steve Bates described the situation as “one location but two regulatory systems: you have the MHRA responsible for running the situation [in Northern Ireland] but [European Medicines Agency] rules will apply.” Bates said Northern Ireland was “in some sense both in the EU market” but also “part of the common UK market. How will that work for regulated goods?” he asked.

No UK Guidance – Yet

Part of the problem is that while the EU has issued guidance on how the Northern Ireland Protocol (NIP) will be applied in this area, the UK government has not, despite repeated calls from industry for it to do so. The future arrangements will also depend on whether the UK and the EU manage to negotiate a comprehensive mutual recognition agreement (MRA) on regulation, which could resolve these issues at a stroke.

“We don’t have the UK’s interpretation of how medicines will be handled when moving in and out of Northern Ireland,” said Emma Du Four, head of international regulatory policy and intelligence at AbbVie.

“All you have is the European Commission guidance on how they interpret the Northern Ireland Protocol, which was updated in March," Du Four said. The commission guidance, she explained, says that "the movement of medicines from GB into NI is classified as importation into the EU, so NI is classified essentially as a member state for that purpose.”

"If we can have recognition between Europe and the UK in its entirety, many of these challenges will go away" – Emma Du Four, AbbVie

As soon as products are imported, “a set of regulatory requirements kicks in that is fairly significant to handle," Du Four said. "It really does underline the importance of an MRA: if we can have recognition between Europe and the UK in its entirety, many of these challenges will go away.”

In the meantime, “we have to move forward with the EU view, which is that any medicine or device placed on the market in Northern Ireland will need to be authorized under EU regulatory procedures,” said Du Four, who also heads up the BIA’s regulatory affairs advisory committee.

At the same time, the MHRA remains responsible for placing products on market and monitoring them. This means the MHRA will be a “passive recipient” of those decisions but it “will be responsible for those products once they are on the market,” Du Four observed.

The absence of any specific guidance from the UK government “means you defer to the commission guidance,” she said. “Obviously that is not ideal. We would like joint guidance with agreed positions by both parties, but when only one party issues guidance, then by default you have to look to that. We are promised that guidance from the UK will come, hopefully in the coming weeks, if not months, but I would encourage everyone to look at scenarios in the EU guidance, which is basically that any product placed on the market in Northern Ireland will have to be covered by an EU regulatory procedure.”

Industry had been hoping for as much regulatory cooperation as possible between the UK and the EU to avoid these kinds of problems, but things are not looking good, particularly given the parlous state of the negotiations on the future trade relationship.

“At the beginning of the year we were very much waiting to see what the UK/EU relationship would look like, and hoping for a cooperative environment, but I think we have got to a point where we have to take forward a scenario where it is quite likely that we will have separation” between the UK and EU systems, Du Four said.

"NI will continue to be covered under an EU license and the grandfathered license issued by the MHRA will specifically cover Great Britain only." – Emma Du Four, AbbVie

On the marketing authorization front, the MHRA said last month that it would have a new licensing route available for innovative products. (Also see "UK Unveils Go-It-Alone Drug Approval System" - Pink Sheet, 10 Jun, 2020.) Du Four said there would be a “grandfathering of existing centralized authorizations to allow a GB national license” for those products.

“I intentionally use the term GB,” she said. “Originally we were thinking of it as a UK national license that would cover NI and GB, but in fact what has changed is that NI will continue to be covered under an EU license and the grandfathered license issued by the MHRA will specifically cover Great Britain only.”

Under the new process, if the CHMP issues a positive opinion, the MHRA will take that opinion and “issue a GB license in the same time frame as the European Commission,” Du Four said. “So for upcoming submissions that process will be in place, and you won’t need to submit separately to the MHRA.” But she also noted that the national licensing route would remain open to companies, “and that might work strategically better for you.”

The Pink Sheet asked what would happen if the CHMP issued a positive opinion before the end of 2020 but the marketing authorization decision was not expected until 2021. In response, Du Four said that “you will hear the term ‘in-flight’ used.” The MHRA, she said, had agreed to take those opinions and use the new assessment route “and have the MHRA issue a GB license".

It is not clear exactly what processes the MHRA will follow once the CHMP opinion has been delivered, or what documentation will be required of the applicant for a GB license. The MHRA said it could not comment at the moment but added that "guidance will be published soon on our future regulatory requirements." 

Shared Packs?

Having one MA for NI and another for GB raises questions of course for companies wanting to market products in both territories. This, Du Four said, was where “supply chain decisions and regulatory considerations start to merge and drive company decisions.”

While the EU license will cover NI and there will be a separate GB authorization, “there is still the potential for a shared pack as long as your SmPC and package insert text remain identical,” she said.

“There are challenges around how you will achieve that, but certainly the commission guidance acknowledges the possibility of putting that UK product license number in the blue box area of the pack that goes to Ireland. There is a regulatory route to achieve that but [it] is not the only consideration as there are many other supply chain elements that will decide whether if a joint pack is viable.”

Batch Release

Du Four was also asked what would happen with regard to the testing and release of product batches by Qualified Persons (QPs) in Northern Ireland. “It depends on what role they are playing,” she said.

If the QP is based in Northern Ireland, “they cannot release product for the EU. Northern Ireland will be considered equivalent to a member state as a recipient of the outcome of regulatory procedures and cannot be the location for any EU activities like batch release,” and any QP release activity in NI “will only be applicable to the UK market.”

This situation highlighted the interplay between the supply chain and regulatory considerations, “because as product moves in and out of NI it is not an equivalent move in both directions. If you go from GB to NI, that is importation, and as things stand there is the potential for that to be the first point of entry into the EU. So all the normal testing and release would need to happen, but at that point NI can’t do that for the whole of Europe.”

This also highlighted the importance of mutual recognition arrangements (MRAs). Du Four said. “Otherwise you create a very complex situation. In reality most medicinal products will need to move through other EU member states and flow into NI to avoid that duplication of testing and release.”

As for goods manufactured in Northern Ireland, Du Four said these would be classified as manufactured in the UK: “Northern Ireland’s status as equivalent to an EU member state is only for the purpose of regulatory decisions” and “actual manufacturing, testing and release activities in Northern Ireland would not be recognized by the EU.”

Du Four made it clear that all her assessments of the situation were based on the commission’s interpretation of the NIP in its updated guidance. She said: “[At present]. we have no basis to guide you in any different way. It is a bit like preparing for no deal Brexit – if you prepare for this interpretation, you should be good. At this point in time we don’t see any indication that there will be any different interpretation before the end of the year.”

The AbbVie regulatory affairs expert noted that while these were not new issues and they had all been raised with the UK authorities over the past 18 to 24 months, she held out some hope that the government would take steps to clarify the situation. “These issues are being tackled now and we hope to see some movement and guidance soon.”

Bates noted that the government had expressed a willingness for a “bare bones” MRA to keep “certain elements of the recognition of processes in place”. The BIA chief executive added: “I don’t think we have clarity yet as to whether this has been accepted. I imagine this will continue to be part of the negotiations through summer and potentially through August.”

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