Medical and Regulatory Affairs

Brexit is Pressuring Sponsors. Here’s How We’re Responding.

Months before Britons voted narrowly to leave the European Union (EU) in June 2016, then-U.K. Prime Minister David Cameron called a vote to withdraw from “the gamble of the century” and warned of dire political and economic repercussions. More than two-and-a-half years later, Cameron’s warning sounds more prescient than ever.

Countless unanswered questions confront British lawmakers and businesses as they face down the March 29 deadline for leaving the 28-nation political and economic bloc. It’s no trivial concern: Life science companies represent a significant share of the U.K. economy, employing more than 480,000 people and contributing £30 billion (approximately $39.2 billion) to the country’s economy, according to a report from Pricewaterhouse Coopers. As part of the EU, Britain is part of a single market that enables goods, services, people — and money — to freely cross the borders of member countries.

Disrupting that arrangement could have disastrous consequences, both commercially and for the development of life-changing medicines. So with the Brexit deadline drawing near, British pharma companies have a lot of preparations to make. But with much uncertainty still surrounding the transition, just what do they need to prepare for?

Premier Research is working hard to anticipate what our customers need and to help them navigate this fraught landscape.

The Elusive Pursuit of a Deal

Planning for a complex transition is difficult enough when you know what you’re preparing for, and much tougher when you’re aiming at a moving target like Brexit. In January, British Prime Minister Theresa May’s Brexit plan suffered a spectacular defeat in Parliament, raising anew the prospect of a no-deal departure that could upend trading and cripple the British economy. Many in the business community are advocating to delay the divorce’s effective date to allow more time for negotiations.

However Britain leaves the EU, the European Medicines Agency (EMA) will move to Amsterdam, a transition that will be disruptive all by itself, as relocating a large agency is a complicated endeavor. And what about potential EMA changes to how products developed and tested in the U.K. are evaluated for use on the European continent?

Some of the impacts are certain. For example, EU law specifies that to sell medical products in the EU, market authorization holders must be located in the European Economic Area. Likewise, any regulatory procedures such as quality control and pharmacovigilance must be performed in the EEA.

Barring exceptions under a Brexit deal, product licenses and sites for testing and certification would need to move from the U.K. to an EU country. Sponsors will also need to meet new regulations in the U.K., meaning that whenever there are sites in a clinical trial within both the U.K. and an E.U. country, some duplicate roles will be needed to cover each region.

The EU’s Clinical Trials Directive and CT Regulation requires a legal representative for sponsors who are not established within the European Economic Area (EEA). Since the U.K. would become a third-party country with Brexit, existing and new trials run in EU countries by UK sponsors would require the appointment of a valid legal representative located within the EEA.

This legal representative is responsible for ensuring compliance with the sponsor’s obligations pursuant to the Regulation. This implies that the legal representative should be empowered to act on behalf of the sponsor and that the Member States may address the legal representative with any request related to the conduct of a clinical trial. With more than a dozen offices across continental Europe, Premier Research can cover this role for customers. Contact us to learn more.

Another sticking point affects companies developing orphan drugs. A small British immunotherapy company working on a drug to treat neonatal lung disease had to shift the registration of its orphan designation to an EU country to eventually market its product across Europe. The company turned to Premier Research to establish orphan drug legal representation in the EU, freeing the company to pursue development of its breakthrough drug unencumbered by arcane legal concerns.

British industry and government alike are hoping to maintain connections with the EMA post-Brexit. Parliament declared in July 2018 its desire

to secure an international agreement through which the U.K. may continue to participate in the European medicines regulatory network partnership between the EU, EEA, and the European Medicines Agency, ensuring that patients continue to have access to high-quality, effective, and safe pharmaceutical and medical products, fully aligned with the member states of the EU and EEA.

How We’re Responding

With pharma companies stuck awkwardly in the crosshairs of all this uncertainty, we have assembled an expert working group staffed by our regulatory, study start-up, legal, pharmacovigilance, finance, data protection, and risk management leadership to anticipate these needs and to consult with an industry taking aim at this fast-moving target. This group is constantly monitoring Brexit’s fast-paced evolutions and educating and supporting our internal teams and Brexit-vexed customers.

Here are some of the specific areas we’re prepared to address:

Marketing authorizations (MAs). Our regulatory department can relocate U.K. companies’ marketing authorizations, including orphan drug designations and pediatric investigation plans (PIPs) to EEA countries, as required under Brexit.

Qualified person for pharmacovigilance (QPPV). The QPPV and a deputy must be resident in an EU or EEA country. In the event there is no deal between the EU and the U.K., it will no longer be acceptable for the EU QPPV to reside in the U.K., as the kingdom will cease to be part of the EU or EAA. Reciprocally, the Medicines and Healthcare products Regulatory Agency has confirmed that a U.K. QPPV will also have to be established and resident in the U.K. from day one. The recent MHRA guidance for a potential no-deal Brexit, however, allows for a temporary exemption until the end of 2020, and the exemption would allow an EU/EEA QPPV to temporarily assume responsibility for the U.K. MAs until a QPPV who resides and operates in the U.K. can be established.

At present, there is no indication from the EU that a reciprocal exemption will exist for EU QPPVs currently residing in the U.K. Therefore, companies must prepare for both eventualities, and this can be problematic, particularly when considering relocation of key personnel. For companies that have a QPPV residing in the U.K. and a deputy QPPV residing in the EU, the most obvious and quickest solution would be to flip the responsibilities so that the QPPV becomes the U.K. QPPV and the deputy QPPV becomes either temporarily or permanently the EU QPPV while a deputy QPPV is identified.

In some cases, additional QPPV or deputy QPPV representation will be needed from day one. With personnel all over Europe, Premier Research can easily assign interim QPPV representation or work with companies on a longer-term strategy.

EudraVigilance. It’s currently unclear what, if any, access the U.K. and the MHRA will have to EudraVigilance. In the event of a no-deal Brexit, the MHRA will have no access, and the MHRA’s current advice is that, following Brexit, all SUSARs (suspected unexpected serious adverse reactions) may require submission through alternative IT systems. The MHRA has said further guidance will be provided on what these systems are in the coming weeks, but it is reasonable to consider that the current MHRA eSUSAR platform is a strong contender. Registering for this platform is relatively quick and easy, and Premier Research can help customers accomplish this.

Clinical supply chain. Impacts on clinical supply chain management will depend on the type of Brexit (soft, hard, or no deal). But in any instance, the whole supply chain will suffer process variations sooner or later that we can start to mitigate by planning ahead of time. We have assessed our vendors to ensure that they have Brexit plans in place. Recent MHRA guidelines around a no-deal Brexit suggest some flexibility recognizing QP certification done in an approved country (which would initially include all EU/EEA countries).

This means that stakeholders will not need to QP certify the Investigational Medicinal Product (IMP) in the U.K. if it has already been certified in one of the countries on the approved country list. However, other EU countries have not yet decided how to proceed in case the QP certification was done in the U.K. For example, BfArM, the German authority overseeing drugs and medical devices, advises that after Brexit, an extension of the shelf life of an already released batch will require release by a QP established in the EU/EEA. It should be noted that changing the manufacturer responsible for final batch release constitutes a substantial amendment.

Premier Research is assessing the position of the competent authorities and advising customers on the best way to proceed.

Cross-border data transfers. The EC’s declaration on the future relationship between the European Union and the United Kingdom envisions that, when the U.K. leaves the EU, the European Commission will start the assessment to formally recognize U.K. data protection laws and allow data to move from the EU to the U.K. We have identified U.K.-based sponsors for whom this will be an issue and have a plan to update contracts accordingly.

Third-party vendors. Our depot and distribution partners and our clinical supply partners have verified that they have physical locations in multiple EU countries, as well as in the U.K. Thus, any needed restructuring regarding depot locations or sourcing can offset potential import/export issues into and out of the EU or U.K.

Our working group* is constantly monitoring Brexit’s twists and turns and is on the move to educate and support our internal teams and customers throughout this challenging period.

* The Premier Research Brexit working group consists of:
• Andrea Ochoa — VP, Global Study Start Up
• Ellen Teplitzky — VP, Legal Affairs, Contracts
• Katharine Chorlton — Director, Regulatory Affairs
• Ken Clark — Sr. Director, Procurement and Vendor Management
• Lee McGuinness — Ex. Director, Safety, Pharmacovigilance
• Charl Marais — Sr. Director, Operational Risk Management
• Victoria Watts — Data Protection Officer
• Zoe Teychenne — Sr. Director, HR
• Carlo Simoncelli — Global Taxation Manager, Finance