Modernising EU legislation: The Alliance for Regenerative Medicine makes the case for ATMPs

Late last month, pharmaphorum met with Stephen Majors, global head of communications for the Alliance for Regenerative Medicine (ARM), to discuss the latest developments in the Advanced Therapy Medicinal Products (ATMP) sector and ARM’s views on regulations within EU general pharmaceutical legislative proposals, joint clinical assessments (JCAs), and health technology assessments (HTAs).

ARM – an international advocacy organisation that champions the benefits of engineered cell therapies and genetic medicines for patients, healthcare systems, and society generally – represents more than 475 members across 25 countries, including emerging and established biotechnology companies, academic and medical research institutions, and patient organisations.

EU legislative proposals and recognising the future potential of ATMPs

Back in April, ARM released a statement on the European Commission's proposal to revise EU pharmaceutical legislation – the most significant revision of that legislation in two decades – commenting that the proposed changes remained focused on conventional medicines of the past, rather than on the ATMPs of the future.

“There’s no doubt this is a significant overhaul in general and a once-in-a-generation overhaul,” Majors said. “We view this, as the voice of the ATMP sector, as an opportunity for the EU not only to bring regulations of policies up to speed with the current state of science and medicine, but also to look into the future and anticipate what's coming and future-proof the EU for the advancement of ATMPs.”

“What we found with the legislative proposal is that it's not ambitious enough in terms of looking at ATMPs as being significantly different and unique,” he explained. “ATMPs were actually called out in the pharma strategy as major milestones of healthcare. That was a signal to us that it was understood that ATMPs were different, that this was the opportunity to modernise the EU's healthcare system to accommodate ATMPs. The proposal itself is really just mainly focused on conventional medicines.”

One example of this is the concept of providing extra market protection – data protection – for providing medicines in all 27 EU member states.

“That's not a huge policy issue for us,” Majors said. “It's much bigger for traditional pharma, but it is a signal to us that there's a misunderstanding of ATMPs because, often, these are gene therapies for rare diseases that are delivered in major centres of excellence. Because of the small patient populations, you're not going to have a centre of excellence in every EU member country. You're going to have patients travelling from one country to another to receive these therapies. What really needs to happen is support for patients being able to do that, rather than this one-size-fits-all model for extra protection for entering all of EU member states.”

“That's at a broad level,” he continued. “Our major policy issues in the legislation are the hospital exemption and the GMO regulation – both of these areas where there are a few positive steps, but still fall short of future-proofing the region for perhaps the next 20 years to make sure that patients have access to ATMPs.”

JCAs, randomised control trials, and impractical metrics for ATMPs

As it stands, the baseline methodologies proposed for the EU JCA starting in 2025 are unsuitable for ATMPs.

“This is another example,” Majors said, “where the EU has a chance to really modernise its healthcare system, and the opportunity to provide a joint clinical assessment that's really forward-looking and modern in its thinking about ATMPs.”

“The baseline methodologies that the HTA coordination group will consider in developing the JCA methodologies come from EUnetHTA 21,” he explained. “In those guidelines, there is a focus on randomised control trials (RCTs) as the key piece of evidence that must be developed. In our view, due to the nature of particularly rare disease gene therapies, it's not possible to conduct a RCT because the patient populations are very small, and they often have diseases that progress very rapidly.”

“It would be impractical, perhaps even unethical, to have a placebo arm,” Majors continued. “There also is the issue of durability. Clearly, in an ideal HTA world, you'd have a medicine, you'd have a clinical trial. You could then take the length of the clinical trials and indication of the durability of the medicine. [But] with ATMPs, it's not possible because you can't have a clinical trial that's 10, 20 years or perhaps even a lifetime long. By those two metrics – questions around durability, lack of RCTs – those 16 therapies out of the 18 currently authorised would either fail both of those metrics or one of those metrics.”

The HTA Stakeholder Network and developing fit for purpose methodology

What, then, does ARM believe should be done to ensure the modernisation of processes so that ATMPs reach the patients on point?

“What we're asking for is different thinking around the RCT issue,” Majors explained. “This can be done through real-world evidence. The durability issue can also be addressed through real-world evidence. We're a member of the HTA Stakeholder Network (HTA-SN), which is a group that's providing input, and we are eager to work with and partner with solutions with the HTA-SN coordination group to ensure ATMPs don't get an inconclusive recommendation because, essentially, the entire JCA is set up to ideally accelerate access and make the system more efficient so that developers aren't going through 27 different HTAs.”

“If all these ATMPs go through the JCA process, and they decide that, based on their methodologies, there's not enough there to make a conclusive recommendation, it'll simply get shifted back to the member states,” he continued. “Essentially, nothing has changed, and we've lost the opportunity to make the system more efficient.”

The HTA-SN is a forum established by the European Commission under the framework set by the EU Regulation on Health Technology Assessment (HTAR/2021). It is composed of 44 organisations and is set up to facilitate dialogue between stakeholder organisations and the HTA Coordination Group (HTA-CG). Dialogue between the HTA-SN and HTA-CG this year aimed to help address gaps in JCA methodology when it comes to ATMPs. The HTA-SN meeting on 14th June focused mainly on presenting the activity plans of the HTA-CG and subgroups until 2025, and discussions included JCA methods for ATMPs and the need for being fit for purpose. The HTA-SN will meet again in Q4 2023.

“Really, it's about this issue of evidence and being a little bit more forward-thinking in the evidence and understanding that the evidence that's developed in ATMP clinical trials is going to be different than traditional pharmaceutical, so you're not going to have that randomised control trial,” Majors explained. “You need to be able to get a general idea of the impact of the therapy during the clinical trial period. Then, to verify the durability, the ongoing impact, you can use real-world evidence, you can use patient data from registries to compare to the patients who are actually receiving the therapy in the real world. There has to be an openness to verifying, after the fact, what appears apparent by the shorter clinical trial period. That's one example.”

“We’re here to work with the HTA Stakeholder Network and with the coordination group on developing models because we don't want to just point out what's wrong and complain,” Majors continued. “We also want to work with them to try to figure something out that will work.”

Divergent interpretation of hospital exemption

In a panel last month – hosted by ARM at the Karolinska Institute in Aula Medica, Stockholm, Sweden – entitled ‘What Impact Will the New EU Joint Clinical Assessment have on the competitiveness of Europe in the ATMP sector’, much of the discussion focused on hospital exemption and what should be done around that as a main focus in addition to GMO and the legislation.

“The hospital exemption is part of the original ATMP regulation from back in 2007,” Majors explained. “This was an intent to provide individual patients who have high unmet medical need, who don't have a treatment ATMP available to them on the market, that's come through the EMA. This was developed as an exemption exception lifeline for those individual cases [and] we fully support that. We think it's really, really important. [However,] since then, there've been divergent interpretations by member states, and so, in some cases, ATMPs or hospital exemption products have been given to much larger sets of patients at varying levels of regulatory oversight in the member state level.”

“That's concerning for a number of reasons,” he continued. “One is, there's no way to verify the clinical safety or efficacy of those products because there's not really transparency or oversight. That could potentially be an issue for patients. The other issue is that it undermines the EMA's regulatory authority. They're a world-leading regulatory body that ATMP developers' companies have to put their products through, with rigorous clinical trial processes and oversight so that you know that, when those products reach the market, they're of very, very high quality and efficacy.”

“If that kind of situation is allowed to continue, it also will potentially discourage ATMP companies from investing in Europe for the long term because they're going through this very rigorous EMA process, and then there are hospital exemption products not having to go through this process,” Majors added. “You have a two-track regulatory pathway. Then, the context for this is that, if you look over the past five years or so, and look at the number of clinical trials, the amount of company formation, and the amount of investment going into Europe compared to North America, US specifically, or in Asia Pacific, China specifically – Europe is clearly stagnating.”

“Basically, with the pharma legislation, this is the right time, we think, for them to go back closer to the original intent of the legislation and to put some guardrails up, so that there're uniform applications in member states,” said Majors. “It's only for individual patients, high unmet medical need, and also a collection of data on cases of hospital exemptions being used, so that everyone is aware of what it's being used for and how effective it is, or how safe it is too.”

Ensuring ATMPs are the future of medicine

The panel also offered a chance for sector and regulator views to be shared and to provide clearer understanding of the potential effects on the ATMP sector. Deliberation of the proposals for EU pharmaceutical legislation in parliament will be a long process, and a crucial one.

“With the pharma legislation revision and the HTA regulation, both these things together are hugely impactful for the future of Europe,” Majors said. “We also think that they're huge opportunities for Europe to re-establish its leadership position in the ATMP sector and ensure patient access to transformative therapies for years to come, and so it's a big opportunity, but it's also one that can't be missed. That's why we're proposing these policies to modernise Europe’s systems to ensure that, in the end, ATMPs – which we believe are the future of medicine – will have a future in Europe and for European patients.”