Over the decades, the EU has spearheaded the adoption of advanced therapy medicinal products (ATMPs) such as cell and gene therapies. However, changes are needed to ATMP regulations to keep Europe competitive with the rest of the world.
The EU has a rich resource base in terms of biotech innovation. Over the last decades, this helped the region see one of the world’s first approvals of ATMPs: the gene-modified cell therapy Glybera, which was greenlit in 2012 for the treatment of the ultra-rare disease lipoprotein lipase deficiency.
ATMPs differ from traditional pills as they can be based on living cells or viral vectors that carry a DNA payload. They have the potential to stop a disease in its tracks with just one or two doses, such as CAR-T cell therapies for the treatment of rare forms of blood cancer.
However, this novel type of therapy also provides challenges for healthcare systems and for drug developers, summarized in the “four As:” authorization, availability, assessment and affordability.
For example, the development and manufacture of ATMPs is currently difficult, slow and costly. And developers often place a huge price tag on these therapies — CSL’s newly approved gene therapy Hemgenix recently earned the title of the most expensive drug ever earlier this year when it was priced at $3.5 million for a single dose.
This pricing approach has raised issues in the EU. One stark example is the failed attempt by the U.S. firm bluebird bio to roll out its gene therapy Zynteglo after being approved by the European Commission. A pricing dispute with the German healthcare authorities in 2021 led bluebird bio to withdraw its gene therapy offerings from the continent.
With friction over reimbursement strategies, the EU faces challenges in allowing its patients access to ATMPs. In an event hosted at the European Parliament, the industry group the Alliance for Regenerative Medicine (ARM) discussed with lawmakers and regulators how to smooth the path of ATMPs into patients.
The EU is losing competitiveness in ATMP development
According to a call to action published by the ARM, the EU overall is falling behind the U.S. and Asia when it comes to the number of therapeutic developers, clinical trials, and investments nurturing the development of ATMPs.
“I’m stressed to see the stagnation in Europe,” said Miguel Forte, CEO of the Belgian cell therapy firm Bone Therapeutics and member of the ARM’s board. He added that it’s important to avoid creating situations where companies remove ATMPs from the market when they can’t get them to patients.
“Science is not different across the Atlantic. Patients are not different across the Atlantic. Access should not be different across the Atlantic,” said Forte.
Part of the issue is the EU’s regulatory and access mechanisms for ATMPs to patients. For example, the EU has strict controls on the development and marketing of products based on genetically modified organisms (GMOs). These controls were primarily aimed at protecting the agricultural sector, but also complicate the process of using GMOs in clinical trials. Providing an exemption for ATMPs could therefore smooth the process for drug developers.
“The GMO legislation is a low-hanging fruit and we shouldn’t even be talking about it,” said Forte. “We just have to be doing it.”
The EU’s medicines regulation: strong but fragmented
While Europe’s market is more difficult to navigate than in other regions, its regulatory system has shown some agility with newer types of therapy, said representatives from the European Commission and European Medicines Agency (EMA) at the event.
In any case, a strong regulatory system can also help companies to market their ATMPs fast, noted Patrick Celis, scientific administrator, Committee for Advanced Therapies at the EMA. “There’s a clear path forward so [companies] know what the expectations are and they know what to do next and what we expect to get the product approved.”
Since legislation opened the way in 2007, 23 ATMPs have been approved in the EU, which is about the same amount as the U.S. Food and Drug Administration has greenlit.
However, a general weakness of the EU is the fragmented market, meaning that drug developers must arrange reimbursement in each member state separately.
Regulatory progress is underway
In an attempt to modernize and harmonize the access of patients to medicines, the EU launched a new pharma strategy in 2020. This is a roadmap that is intended to boost biotech innovation, digital infrastructure and collaboration between stakeholders in the bloc.
In addition, the EU launched new legislation relating to health technology assessments (HTA) in January 2022. The so-called EU HTA Regulation is designed to help EU member states to measure how effective health technologies are, and decide how to reimburse the technology. It also promotes collaboration between member states to reduce the fragmentation of reimbursement.
The EMA and European Commission have also paid close attention to ATMPs specifically: in 2017, the organizations released a joint action plan with the mission to better tailor their systems to the unique requirements for ATMP developers. For example, doctors and researchers were connected into so-called European reference networks (ERNs) to make it easier to diagnose and fight rare diseases, including those that could be treated with ATMPs.
EU HTA regulations aren’t flexible enough
The industry generally welcomed the EU’s HTA overhaul. According to Chris Vann, chief operating officer at Autolus, it’s a promising move to address the four As, and to harmonize the EU’s reimbursement negotiations with ATMP developers.
“It’s also going to be really important to pool expertise because these are difficult challenges we face to actually make the products accessible,” said Vann.
Additionally, increasing the communication between member states can boost the pool of patients available to help develop new therapies. This is especially useful when dealing with rare diseases that might only affect 500 patients per year.
However, Vann cautioned that the HTA regulation shouldn’t end up being just another administrative hurdle without speeding up access to patients. And the ARM voiced concerns that current HTA guidelines are designed to process conventional medicines, for instance, requiring randomized controlled clinical trials.
“ATMPs often can’t have [randomized controlled trials] in the rare disease space because there just aren’t enough patients for a particular indication, or it may even be unethical to give a patient a placebo when they’re facing a very serious disease that may in fact be fatal,” said Stephen Majors, director of public affairs at ARM.
Instead, he suggested that flexibility is needed, such as giving all patients the therapy and using real-world data to validate the outcomes after.
Taking hospital exemptions back to their roots
In existing EU legislation, a hospital exemption protocol allows an organization to sell its ATMP without a marketing authorization. This is reserved for exceptional cases where no other treatment options are available. This provision allows patients to access potentially life saving therapies that would normally be off limits.
“I definitely think it is still necessary as the commercially driven development might not be able to cater for the over 6,000 rare diseases that are currently present, and particularly the 85 to 90 per cent of these diseases that have a prevalence of less than 100,000,” said Simone Boselli, director of public affairs at the European Organisation for Rare Diseases.
The success of the scheme is leading to suggestions for expanding its use. However, implementation of hospital exemptions isn’t uniform across EU member states, allowing some companies an unfair advantage. Too much deregulation can also make it harder to collect data on the treatments for use in HTA and approval decisions.
“Hospital exemption has a value but should not be a replacement of the structured framework,” said Celis. “Deregulation could end up with Europe becoming even less attractive because you would then have more ‘me too’ products being developed and used on the hospital exemption.”
Therefore, the industry cautions against loosening the hospital regulations. Instead, use them as they were originally intended: treating rare disease patients with few other options.
Careful regulation could let Europe lead the ATMP space
In spite of the EU’s fragmented regulatory and reimbursement system, it has a lot of potential for improvement when it comes to fostering the ATMP scene.
“People will go to where they believe there is an opportunity to bring real change for patients,” said Vann. “I believe that Europe and the EU could be well placed to be leaders in the field, but it will require careful legislation and a very thoughtful approach to solving the problems that are inherent to ATMPs.”
Failure to make these changes could mean millions of patients fail to access a potentially life-saving therapy. And according to a member of the European parliament at the event, Susana Solís Perez, the legislation could also have an impact on the health of Europe’s small to medium-sized enterprises.
“We need to hear from all the stakeholders, and we think we need an open dialog to find this balance between innovation and ensure patient access to ATMPs,” she concluded.