In an extensive recent PharmaBoardroom conversation, EMA Head of Advanced Therapies Ana-Hidalgo-Simon highlighted some of the most important trends around advanced therapy regulation in Europe. Hidalgo-Simon touched on why moderate growth in regulatory applications is a positive development for the EMA, how patient insights are being better incorporated into the regulatory process, the important role of ‘hospital exemptions’ in providing one-off access to treatments, and why the Agency is taking a cautious approach to the collection of real-world evidence.
Increasing Application Numbers
“We have seen rising numbers of regulatory applications for advanced therapies over the past two years and this growth can clearly be seen in the amount of scientific advice being given and the number of Innovation Task Forces (ITFs) meetings supported. However, while application and approval numbers are both rising, the pace at which they are doing so is slower than we had anticipated. Directors at EMA and other key regulatory bodies such as the US Food and Drug Administration (FDA) were predicting between ten and 12 advanced therapy approvals per year in the early 2020s. We are not yet seeing these numbers, which reflects how difficult these products are to develop, how many hurdles there are to overcome, and – of course – the slowing effect that the COVID-19 pandemic has had.
“This steady growth is welcome as the system was perhaps not yet ready to deal with a sudden explosion of submissions and associated surge in workload. These therapies are complex, difficult, and have a huge public health impact, which means that the development and approval process is long and challenging.”
Patient Insight Incorporation
“The fact that patients are getting both more sophisticated and more involved is a very welcome development for EMA. They have been part of the CAT from the beginning and are not just passengers but full members. Patient group representatives have full voting rights within the Committee and actively contribute to our discussions on everything from scientific advice to classifications and certifications.
“Representatives of patients groups also act as our loudspeakers outside of the Agency, communicating both within their own associations but also with other associations outside their disease areas. They go to conferences, are involved in our teaching exercises, and contribute to the regulatory documentation that the Committee produces.”
Hospital Exemption Progress
“Hospital exemptions are a very local way to authorise medicines and have a very important role to play in one-off treatments. An example might be a baby born with an essential part of its throat missing. This missing part can be grown locally in a lab using the baby’s own cells and then transplanted. For these one-off treatments, permission is sought on a national level.
“These therapies by definition don’t travel outside of a particular hospital. But if enough experience and data are accumulated, they could be reproduced elsewhere and end up becoming a commercialised medicine. EMA recognises the importance of this pathway and has worked on taking several products developed in this manner and bringing them to Europe-wide use.
“Of course, we would always like to see these treatments produced a lot closer to the patient – ideally in the same hospital – rather than flying them across the world. Many hospitals in Europe now have GMP-accredited facilities to do so, but it will take time to get to the final destination.”
RWE: A Cautious Approach
“Because of the uncertainty surrounding the long-term effects of these therapies, we require significant post-authorisation commitments. In contrast to chemical medicines – which EMA approves with a lot of confidence and for which there are thousands of patients in clinical trials – there is a huge amount of uncertainty around ATMPs. There are relatively few participants in clinical trials for these therapies – many of which treat rare diseases – and blind randomised trials are not possible. While not all ATMP approvals are conditional, given the reduced level of evidence available, it makes sense to take a more cautious path.
“This cautious approach involves very clearly defining the patient subsets that will benefit from a particular ATMP. In complex fields, such as gene editing and modified bone marrow stem cell transplantation, we must define indications where there is good evidence that a therapy will be effective. For this reason, many of these therapies are indicated for very well determined groups of patients with a genetic variation that can be measured. Additionally, given that many of these therapies are being administered as a one off ‘cure for life’, long-term data requirements are crucial. Expanding a therapy out to wider patient populations requires even more data.
“The 15-year requirement was chosen as it represents a decent period for tracking the effects of a treatment. If no detrimental side effects have been detected over a 15-year period, we can be reasonably sure that a therapy is safe. For this, registries and RWE capture needs to be developed along the way.
“For EMA as a regulator, this requires flexibility in choosing between what is ‘must have’ and what is ‘nice to have’ information; a difficult balance to strike and one which we can improve. However, at the end of the day, our mandate is public health, which we must continue to pursue.”
Who Guards the Data?
“There is no single right way of collecting and storing such data. There are two major concerns: where the data is coming from in terms of both input and maintenance and who decides who uses it and for what. Both are extremely difficult to resolve.
“EMA defines what it would like in a perfect world and then sees how close it can get to that. Ideally, such data would be stored in well-established public bodies, such as universities or hospitals, because companies – by their nature – go bankrupt, sell products, or merge with other firms. Given that we require 15 years of data, we want to be sure that the institution holding that data is still around in 15 years’ time.
“Other challenges include compatibility; registries and databases are put in place by different people at different moments of history, meaning that it’s difficult to communicate with each other. Moreover, keeping the data clean is very expensive, as is the task of following up with patients annually, the issue of consent, questions around intellectual property, and ensuring that the actors conducting RWE studies are doing them properly. If unfair top-line results are returned – as happened during COVID-19 – these can be very frightening and easily misinterpreted.
“Therefore, we must always remember the importance of these data and be open to coming together in inter-stakeholder partnerships.”