After many years of momentum towards greater harmonisation, the European Union finds itself at a crossroads in 2018, with member states conflicted about whether or not they should press ahead towards greater political and fiscal integration or call a halt to the process (or indeed even break away).

However there is one specialist area in which there is unquestionably a growing appetite for European greater collaboration: health technology assessment of innovative medicines.

This manifested itself in early 2018, when the European Commission launched long-awaited plans to make the first step towards a single HTA process for the EU. This would most likely take the form of mandatory uptake of a single clinical assessment across all member states – something which the Commission wants to make law in 2019.

Such an idea was once anathema to the pharmaceutical industry – as companies feared it would lead to a so-called ‘Euro NICE’ (after England’s HTA organisation), which would restrict and limit market access to innovative new treatments.

Make no mistake, this fear still exists, but limited and clearly defined harmonisation is being embraced. Europe’s industry organisation EFPIA has thrown its weight behind the plans – believing that eliminating unnecessary duplication and creating a single clinical assessment methodology will in fact speed up access, rather than limit it.

Conversely, there is still great suspicion of pharma among some government agencies and non-governmental organisations in Europe, who distrust its profit motive and are wary of any changes which they think might give the industry an upper hand.

Beneluxa takes the lead

However, there are some signs that a two-way openness to new ways of working can address patient access and healthcare sustainability. In fact across Europe, countries aren’t waiting for an EU-wide framework, and are banding together to pool HTA resources and give themselves greater negotiating power with pharma companies. The most advanced of these groups is Beneluxa. The initiative which was launched in 2015 with the Netherlands, Belgium and Luxembourg, with Austria joining in 2016 and Ireland earlier this year, and has so far focused on appraising high cost orphan medicines.

These five members represent a total of 43m people, giving them a much greater collective bargaining power, and puts the alliance on a par with Spain (considered one of the ‘big five’ European markets) in terms of population covered.

In the summer Beneluxa was able to announce its first successful deal with a pharma company, with the Netherlands and Belgium granting market access to Biogen’s Spinraza after conducting a joint HTA appraisal. Spinraza (nusinersen) is the first drug approved to treat spinal muscular atrophy (SMA), an often-fatal genetic disease, which affects muscle strength and movement, and can strike in infancy or in childhood, categorised into subtypes 1-4.

This was second time lucky for Beneluxa – its first joint appraisal on Vertex’s Orkambi broke down without a market access agreement. But Biogen and Beneluxa have both pronounced themselves pleased with the process – which for now is entered into on a voluntary basis. The Netherlands’ health minister Bruno Bruins said at the time of the agreement in July: ‘First and foremost, the positive outcome is wonderful news for the young SMA patients and their families, both in the Netherlands and Belgium. “It is also a very clear and promising example of the benefits of working together on price negotiations and pharmaceutical policy. Biogen’s willingness to engage in a joint process and discover the benefits of gaining swift access in several markets at the same time is a positive development. Therefore I hope more companies will follow this example.”

The deal went live in August in the Netherlands and in September in Belgium and involves a confidential price agreement on Spinraza’s list price of €499,800 for a year’s treatment being substantially reduced – although just how much of course remains unknown.

Erik Smets, Head of Market Access Europe at Biogen comments: “We’re very happy that we came to this satisfactory conclusion for our patients and their families. These types of initiatives always come with opportunities and challenges. I think this is a pioneering endeavour both on our part and on the part of the HTA agencies.” He says the key was that Netherlands and Belgium showed flexibility in their cost- effectiveness assessment. “It was a very collaborative and open approach. All parties involved recognised that there were limitations and uncertainty in the data set, while at the same time recognising the value inside, and trying to find a way forward.”

The group expanded to five members when Ireland joined in June: Health ministers L-R: Luxembourg’s Lydia Mutsch, Belgium’s Maggie De Block; The Netherlands’ Bruno Bruins, Ireland’s Simon Harris; Austria’s Dr. Clemens Auer

Ending the ‘information asymmetry’

Marcel van Raaij is Director, Pharmaceutical Affairs & Medical Technology at the Netherland’s ministry for health, and is one of the leaders of Beneluxa.

He makes it quite clear that one of the main rationales for starting the alliance was the sense that pharmaceutical companies had an unfair advantage over national health systems and HTA organisations – what economists call ‘information asymmetry’.

“The pharmaceutical companies know every detail about their product and the reimbursement system in each country, while at the same time two countries in Europe often wouldn’t know anything about the situation in their neighbouring countries.

“Addressing that was the first principle. The second principle was that we want to provide sustainable access to innovative medicines for our patients, and that means we have to move towards this kind of collaboration.”

So is the pharmaceutical industry right to fear that this is simply an effort to drive down prices and not increase access? Marcel says that’s not the case. “The central issue is not procurement per se, it’s about sustainable access” he says, but does concede that having this greater buying power is a part of it.

“But you know, the layers below that, such as joint HTA and information sharing, are equally as important in helping to prepare for new products coming to the market.”

Spinraza is the first drug to go through the BeNeLuxA process

Expansion on the horizon?

The initiative’s leaders have made it clear they are open for other European nations to join. There were rumours that France had shown an interest in coming on board. If that were to happen, this could well be a game changer for HTA in Europe, as France is one of the continent’s most important markets, with IQVIA data showing its pharma budget worth around €29bn ($33bn) annually.

However don’t be surprised if France doesn’t join Beneluxa, as having such a dominant partner could be disadvantageous for the smaller countries.

“[The alliance] being as big as possible is not the principle goal. We want to have a collaboration between countries that are in a similar position,” says Marcel.

“That means two things: we must share a similar vision on the pharmaceutical agenda, and they must have more or less the same economic position. If the differences between the countries are too large then it will become more difficult for industry to engage with a very diverse group of countries.”

He says the founding members had a ‘very detailed look’ at the systems in Austria and Ireland to ensure they could be aligned and have a ‘fruitful collaboration’.

It’s still early days in the five-way partnership, and Austria and Ireland haven’t yet taken the lead role in any assessments, but that time will come. The group is currently trying out different models of joint working, depending on the type of product. So in one instance the Belgian (RIZIV) and the Dutch HTA institute (ZorgInstituut Nederland, ZiN) jointly produce a report.

In this case one institute undertakes the clinical assessment and the other oversees the cost- effectiveness assessment for both countries.

The agencies are also reusing each other’s drug assessment reports in order to cut out unnecessary duplication.

Marcel says the initiative will seek more harmonisation on the methodological side – something which has been driven in Europe in particular by another Netherlands-based collaborative, Eunethta, the European network for health technology assessment. It has helped drive harmonisation in clinical and cost-effectiveness methodology – although deciding on cost- effectiveness thresholds remains a national and political decision, closely guarded by member states.

The opportunity for pharma

The offer from Beneluxa for pharma is clear, then: while this nascent system is a gamble, if a company can present a compelling cost- effectiveness picture, it could land a ‘yes’ from five separate markets in one fell swoop, providing faster market access to those patients than they would otherwise have had.

Marcel says the companies that have engaged with Beneluxa so far have been open-minded, and wants to encourage more to volunteer for the process.

“We’re keen to get more companies involved. Industry sometimes complains about the burden of all these procedures for reimbursement for all European countries, and that they would see it to be much more aligned. So Beneluxa is their opportunity to make the first move.”

He says some industry reticence is notable. “Some companies don’t want to be involved in a process they don’t know very well, and would rather see how the early pilots work out. Of course I understand that, but we’re open to engaging with any company, and open to any suggestions or dialogue. We invite companies to be proactive, transparent and flexible.”

Outcomes-based agreements as standard in the future?

As the collection of real-world evidence (RWE) is part of the Spinraza agreement, I ask whether or not this will become standard in the future – and hand in hand with outcomes-based reimbursement agreements.

“It could very well be that we end up with a model based on an outcome agreement in the future. That’s not a goal in itself, but we should certainly not exclude it from the possibilities, we’re open to every kind of proposal,” he adds.

One prerequisite for a shift towards an outcomes-based reimbursement model is of course healthcare systems having reliable data generating and sharing capabilities to provide the necessary evidence. This remains something done at a national or regional level in each European country, making progress inevitably slower.

Erik Smets says this is a challenge for the industry and healthcare systems. “We need to collaborate with payers and HTA bodies to address this. We have found very collaborative partners in the Dutch healthcare system, among others, but it certainly is a challenge operationally. But it’s something we’re committed to as a company and we believe partnerships with healthcare systems will pay off in the long term.”

One of Beneluxa’s most important projects currently is the plan to commission a joint horizon- scanning system, with a decision due in 2019. This will help create a single, accurate picture of the industry pipeline and allow earlier market entry conversations to take place.

An EU HTA framework

The European Commission legislative proposals could, of course, have the greatest impact on the future of HTA harmonisation in Europe. Not surprisingly, the current proposals have sharply divided opinion of the EU’s 27 member states (with the UK of course planning to exit in March 2019). This would see a so-called ‘mandatory-mandatory’ system, ie mandatory participation in a joint clinical assessment and most significantly, mandatory uptake of the recommendations.

Many member states object to the plan, concerned that a mandatory European HTA system will restrict their decision-making power and control over their medicines budgets.

Meanwhile, there are some major concerns for pharma, too: some stakeholder groups want to use the legislation to enforce complete transparency on drug pricing negotiations, something which the industry will resist fiercely.

Marcel says Beneluxa is in favour of the EU co-operation, but sees its alliance as much less problematic, arising as it does from a common need in each country. “The difference is that the Benelux collaboration is a member state- driven process....as you know in Europe there are differing views on how far a commission-driven approach with a central regulation should do. “I hope we can come to some agreement but in the end it’s not only a methodological issue it’s also a political issue.”

Erik says Biogen is watching the debate about how to move the proposals forward with interest. “We want to ensure rapid and sustainable access to innovation in the interest of patients. We wouldn’t want to see it [a new HTA framework] used as a way to delay access by, for example, going to unfeasible standards across the health ecosystems we operate in. That’s an element the industry would have some concern about.”

The idea of contemplating whether or not this process might one day lead to a single EU pricing structure, however, is too far for most stakeholders to contemplate. This goes for member states, who have always said their health spending policy is a national question alone.

Erik agrees this is too distant a prospect. “That’s a totally different discussion. The European Commission proposal does leave the decision on price to the individual member states. The European clinical assessment is more driven towards HTA and focused on the clinical components of a clinical comparative effectiveness appraisal.”

The scale and the complexity of the challenge makes it difficult to predict how things will pan out. “There are a lot of moving parts in this, which make it difficult to see how this will evolve,” says Erik. “We’re starting with lots of local regulations which have to be aligned. So there’s lot of opportunities, but still also hurdles to clear before it can become reality on a large scale.”

The logic of European countries pooling resources in HTA, then, is widely shared, but there is no clear consensus about how greater integration should proceed, and how far it should go – yet. The ‘holy grail’ would of course be to grant rapid access to patients to effective new treatments, while supporting an innovative industry and also operating a sustainable healthcare system – however these goals are often perceived to be in tension with each other, or even outright conflict.

All change in Europe in 2019

2019 will be a momentous year in Europe, and not just because of Brexit. A new European Parliament will be elected, along with the appointment of a new president of the European Commission and a new Commission. A new president of the European Council and of the European Central Bank will also be chosen, with the 27 states also having to sign off on a crucial five-year budget for 2021-27.

Add in the political crises being caused by the rise of anti-immigration sentiment and populism, and Europe’s priorities and political balance could be very different by next summer. Nevertheless, a familiar EU political compromise is likely to prevail if and when the current HTA proposals are amended, agreed and become law, which could be by 2020.