Dr Paula Salmikangas is the chair of the committee for advanced therapies (CAT) at the European Medicines Agency
Phacilitate: Following on from Glybera, the recent approval of Holoclar has provided another important ‘first’ for Europe’s cell & gene therapy community and another step forward for the field in general. Reflecting today upon the review processes for both of these products, what would you pick out as the key learnings for developers of other, novel, previously unapproved modalities e.g. of CAR T-cell immunotherapies?
Dr Salmikangas: First of all, both cases, Glybera and Holoclar, involved very rare conditions. In fact, what we have seen through our Scientific Advice system is that half of the ATMPs under development are for orphan indications. This is clearly setting some challenges when it comes to the patient populations and efficacy data especially - how to get solid proof of efficacy for these kinds of novel therapies?
When it comes to cancer therapies, there will generally be more patients, but even so, in those cases, I think it must be very clear from the beginning that the study designs are well planned and comparators considered carefully, and also that the product is standardised from the beginning. That’s critical, especially when we talk about cell-based products because we see a clear link between the quality and efficacy of the product. I hope that the stakeholders really use the opportunity to approach regulatory bodies, both nationally and at EMA level, to address all possible problems before they begin clinical trials because once the trial has commenced, it’s too late to start making significant changes.
Clearly, there are multiple points in the development of these products where problems can arise and I hope that we could solve them together.
Phacilitate: Staying with CAR T-cell therapeutics, it seems as though every pharma and ATMP biotech company is looking to bring this technology area into their clinical pipelines at the moment, which will further increase the number of cell & gene therapy clinical trials taking place in Europe each year. How are the EMA and the CAT planning for the likely future scenario of a rapid increase in the number of pivotal trials for CAR T-cell therapies?
Dr Salmikangas: We are preparing ourselves quite well for these forthcoming novel products. We are trying to follow what is happening; we have informal meetings with the companies developing these CAR T-cells, as well as other novel technologies. We are taking part annually in several key scientific meetings and also arranging our own training sessions on the margins of those meetings, which allows CAT members to liaise with the scientific community. This ensures both parties are well aware of where the scientific field is going and what kind of developments we are going to face over the next few years as these products advance towards the market.
Of course, we are trying to train ourselves as much as possible, our assessors as well. The EMA, together with the medicines agencies network, has created a new common base for training and we are sharing these activities more and more, and informing all assessors throughout Europe of forthcoming training programmes to increase their potential to become very skilled and properly prepared for future activities.
Phacilitate: The regulatory classification of a consequent pathway to approval for CAR T-cell technologies in Europe is clearly of great interest to the global industry. Can you outline for us the scope of - and process/timeline for - the review of ATMP classifications, which is expected to take place this year and perhaps discuss how this might be expected to impact this particular technology area?
Dr Salmikangas: The reflection paper on the classification of ATMPs is under finalisation, I presume that we are going to make the final decision next week. For products like CAR T-cells, I don’t see any differences in future because when it comes to cell-based products, the two nominators for a product to fall under ATMP classification are substantial manipulation and non-homologous use. CAR T-cells are genetically modified, cultured cells and are heavily manipulated, so they definitely comply with the definitions of ATMPs. Depending on the technology, it may though be that some of them become somatic cell therapies and some gene therapies.
In that regard, there will, of course, be some consequences when it comes to the requirements but not that much because we basically have the same requirements for all ATMPs, scientifically speaking. When there is persistent genetic material added to the cells, it means that there will be longer follow-up periods than what we expect for normal cell-based products.
So I don’t think there will be tremendous changes relating to CAR T-cells, based on our revision, but we may well see some other novel products falling under ATMP classification. We have already notified that products based on the enzymatic digestion of tissues to release cell-cell contacts and the administration of these separate cells with a view to treating patients or to regenerate a function, will be considered as ATMPs. We are going to leave some room open for justification from the applicants, otherwise, I think this is one of the major changes that is going to impact the borderline cases.