Facing the Brexit Trial

Theresa May’s Brexit deal was rejected in the UK House of Commons by 230 votes – the biggest defeat by a UK government in British parliamentary history. Following the record loss, the UK government backed an amendment tabled by senior Conservative backbencher Graham Brady, which seeks to replace the Irish backstop with “alternative arrangements.” But within minutes of the Commons backing the plan, a spokesman for European council president, Donald Tusk, said the EU would not permit any changes to the deal already agreed.

The British position (no backstop, no single market, no customs union, no dependence on the ECJ), the Irish position (backstop, no hard border), and that of the EU (backstop, indivisibility of the four freedoms, no cherry-picking) are mutually exclusive (1). Unless a compromise can be found, the UK will leave the EU without a deal on March 29, 11pm London time.

Hard Brexit looks more likely than ever. And it’s up to pharma companies and the government to put in place plans to minimize the impact on patients. We’ve written previously about the fragility of pharma’s supply chains, with ingredients and products often crossing UK/EU borders multiple times in the development, manufacturing and distribution process – sometimes being “dropshipped” directly to customers within 24 hours of an order being placed (2). There’s a real concern that regulatory uncertainty and delays at borders after a “no deal” Brexit will result in shortages of approved medicines.

The drug development industry also faces real problems if hard Brexit comes to pass. If companies can’t deliver materials used in ongoing clinical trials, then there’s a risk patients could miss doses. Of course, this could delay regulatory approvals, but for the individual patients enrolled in trials, it could have serious immediate consequences.

“There are patients in late stage oncology trials that are really relying on these investigational products,” says Paul Hegwood, President of Clinical Supply Services at Catalent. “Missing a shipment and a patient dosing can be catastrophic. The clinical supplies industry, from sponsors to clinical supplies organizations, are dedicated to finding ways to make sure this does not happen as a result of a ‘no-deal’ Brexit.”

Putting on a supply clinic

A major problem for companies is taking action in anticipation of an event, which at the time of writing is still only a possibility – one which all sides are determined to avoid. Hegwood says there have been a range of responses from drug development companies. “Some sponsors have taken a low risk course of action and they’ve decided to ask us to move supplies from the UK to our site in Germany, which allows us to continue distribution without issues,” he says. “Other companies have asked us to do impact studies, and there are some who are still in the ‘wait and see what happens’ mode. Once we get a definite decision I think there may be a surge in activity as companies start moving to protect supplies or, if it’s not hard Brexit, everyone will stand down.”

Problems may arise if too many companies wait until the last minute to take action. Catalent has been working with companies to bulk up supplies. “This should help provide some additional runway. If we have released supplies in the UK before March 29, we can continue to ship those from a quality and regulatory perspective into the EU. So, with additional supplies we can buy more time to react in the event of a sudden no deal.”

Having to ship urgently isn’t unusual in the clinical trials business, as companies marry up investigational products with a regionally recruited patient. Catalent has put additional resources into this area in case a company isn’t fully prepared. “Importer of record services, VAT services, import licenses and approvals… these areas are going to need a lot of attention,” says Hegwood. “So we have put in place a ‘special service team’ of logistics people to help us navigate across trade barriers.”

Companies might also be faced with the physical challenge of moving products across borders, if ports and roads become slow or unmanageable after a sudden Brexit. But the administrative burden associated with no deal is arguably the bigger problem. As with approved products, clinical trial materials exported from the UK to the EU after Brexit will have to be certified once the supplies have entered the EU by an EU-based Qualified Person (QP). “It’s a very specific capability and QPs are personally accountable when they approve and release a batch. It’s always a challenge to find experienced QPs,” says Hegwood.

In our previous feature (1), a major concern for Sascha Sonnenberg, VP Commercial Operations Americas and EMEA at Marken – a company that specializes in supply chain solutions for clinical trials – was that a shortage in QPs could “delay or endanger ongoing trials.” Hegwood agrees that companies may be scrambling to find more QP capacity in the event of no deal, but that there are contract agencies that offer QP services and QPs that work on a consultancy basis. “I think there’s enough capacity to go around.”

Hegwood believes the biggest challenge will be faced by those UK-based companies that don’t have any facilities or legal entities in the EU. He suggests such companies look at working with a partner that has locations on both sides of the border to get them though the Brexit transition.

Advanced therapies; advanced problems?

The advanced therapies sector is another area of particular concern. Materials in this sector are often living cells with very short shelf lives, and the patients being treated – either with approved products or treatments in clinical trials – are very ill. Many of these therapies are autologous, which means cells are taken from a patient, shipped to a manufacturing facility to be manipulated, then shipped back to the patient for treatment. “You can’t stockpile because products are manufactured on a patient-by-patient basis,” says Matthew Lakelin, Chief Scientific Officer at TrakCel – which provides technologies for companies moving cell therapies across borders. “It presents some unique challenges.”

Lakelin believes courier companies are key to getting it right. “We would strongly recommend using a premium courier company,” he says. “They have operatives that understand import and export legislation associated with these products. They also have boots on the ground at customs so that they can get the products through.”

Having a cultural understanding of these products is perhaps more important than in other sectors. “The best courier companies understand that they hold a person’s chance of a life in their hands when they carry the products into their van,” says Lakelin. “This can prevent many simple logistical errors. They also have the ability to store products at the correct temperature in validated units while waiting for customs clearance.”

Can a white glove courier guarantee that there won’t be any problems at this stage? Lakelin thinks it’s difficult to guarantee anything. “Normally, if you’re trying a new shipping route for example, you’d run some test shipments. But you don’t have the luxury of this approach if you already have a clinical trial ongoing or a marketed therapy where patients need supply,” he says. But there are some extreme steps companies are able to take due to the small volumes involved; for example, Lakelin says that companies can have products hand carried onto airplanes and delivered in person. This is commonly done for stem cell transplants – the Anthony Nolan group (a UK-based charity) have volunteers who will deliver a bag of stem cells at the drop of a hat to a patient. “Courier companies can provide this service, but they don’t have any volunteers so it is incredibly expensive,” says Lakelin. “It wouldn’t really be feasible in the long run. And if there isn’t an agreement in place to keep planes flying, there could be major problems for the industry and for patients.”

Uncertain times

In our most recent Brexit article (1), David Jefferys, Senior Vice President for Global Regulatory, Healthcare Policy and Corporate Affairs for Eisai Europe, and Chairman of Eisai’s Global Regulatory Council said, “When companies are thinking about investing in the UK, the uncertainty is definitely having a negative impact.” And the clinical trials industry is no exception – especially in the face of a no-deal Brexit.

“For about a year now, our European customers have avoided the uncertainty around Brexit by not planning to open or actually opening clinical trial sites in the UK,” says Lakelin. “The major challenge for UK-based companies is that they have to get their products into Europe and back again, and we know of at least one that has opened a secondary manufacturing facility in mainland Europe.”

Miguel Forte, Chief Executive Officer of Zelluna Immunotherapy, says they have considered doing a clinical trial in the UK, but then uncertainty around Brexit flared up. “The UK has a lot of centers of excellence for cell and gene therapies, which we would appreciate being able to access. Plus, the MHRA is a very knowledgeable authority to go to for advice,” he says. “But the uncertainty around the regulatory environment in the short to medium term is a negative impact factor in our decision.”

Ezequiel Zylberberg, Strategic Alliances Manager at Akron Biotech – a US-based company that provides raw materials and manufacturing services/technologies for the production of advanced therapeutics medicinal products, says that sudden potential changes in the regulatory environment as a result of Brexit is creating uncertainty for his company and his clients. “It may shape our clients decisions in terms of where they choose to conduct their trials. However, decisions around clinical trials management take a long time to materialize, so the full impact on business likely won’t be felt for a year or two,” he says. “I’m not sure companies are ready to completely change strategic direction before we have an answer on the legal framework.”

For Akron, Zylberberg is mostly concerned about the effect on global regulatory harmonization of GMP regulations. “What do we mean when we say an ‘ancillary material was produced under current GMPs’? The industry has not coalesced around a single definition and I think geographic fragmentation will lead to a greater fragmentation in our language. And that’s one of the things we’re worried about,” he says. “An event like Brexit really reasserts the importance of working with international organizations such as ISO to make sure we have common nomenclature. Because if the cell and gene therapy industry is to reach its potential, we need to be speaking the same language.”

Mitigation limitations

A major problem for companies is understanding how a no-deal Brexit may play out in practice. Many have anticipated long queues of trucks leading up to UK ports as a result of new checks on the EU side. But it is unclear whether controls on the EU side will be implemented in full on Brexit day. Plus, some haulage companies may refrain from exporting until they know exactly what will be involved – some companies may also conclude that the new costs associated with trading with the EU aren’t worth it. These factors could combine to reduce port traffic and delays in the short term. Then there’s the possibility of Article 50 being extended – or even revoked altogether. Is the most likely outcome of all that both sides can come to an agreement akin to the Withdrawal Agreement? Perhaps, but nobody at this stage dares rule out the worst predictions of no deal, which demands serious preparation. But just how prepared is the drug development industry?

“There’s an abundance of information out there about the consequences of no deal and I do believe that most companies in the clinical development space are prepared and have contingency plans in place,” says Hegwood. “But there are no guarantees. Recently our couriers have had to put some destinations on hold because they couldn’t land their planes as a result of extreme weather in the US, for example. I do think the potential impact of sudden regulatory and trading changes could be huge, but I think I can speak for the entire clinical supply industry when I say that we will do everything humanly possible to make sure that we can get clinical shipments through the minefield created by a hard Brexit.”