The Committee for Advanced Therapies (CAT) of the European drug agency EMA not only reviews new ATMPs, but is also a valuable inquiry resource for researchers developing an ATMP. So says Dr. Patrick Celis of the CAT, who will be one of the speakers at a FAST webinar on ATMPs on March 11.

The various Advanced Therapy Medicinal Products (ATMPs) such as gene therapies, cell therapies and tissue engineering offer unique opportunities for treating conditions for which no effective therapy currently exists. Therefore, FAST is pleased to contribute to the realization of the opportunities and possibilities in this field, with timely availability and cost control obviously being points of attention. To guide ATMP developers through a complex field, FAST is organizing three webinars on March 11, 18 and 25, covering various challenges of ATMP development and regulation. A number of webinar speakers will be featured in the coming period. This time it is Dr. Patrick Celis, who has been responsible for the organization and scientific support of the CAT since its inception in 2009. Originally a pharmacist, Celis trained and received his doctorate from the University of Leuven.

Early contact

ATMP development is a complex process, where each step can have implications for final market approval and application. ATMPs are often developed by small companies or academic groups that do not have much experience with all the procedures involved. Celis therefore emphasizes that it often makes a lot of difference in terms of time, money and chances of success if the company or academic group contacts the CAT early on. “When I speak for people developing ATMPs, I often start by saying: we are not your enemy,” he says.

The development of an ATMP begins in the basic laboratory, with the discovery of a possible mechanism of action. Once evidence is provided that this principle is indeed effective, the hope grows that researchers have a potential therapy on their hands. With some sleight of hand, they manage to produce a batch of the ATMP suitable for initial administration to humans. To the researchers’ delight, the ATMP appears to be safe and effective. Yet it may turn out that this enthusiasm was premature. If the manufacturing process is insufficiently standardized, the ATMP has not been thoroughly characterized, or significant modifications are still needed to produce the product on a larger scale, it is often necessary to redo (part of) the preclinical and clinical development. This is necessary because there is insufficient certainty that it is the same product or because extrapolation of the earlier results to the commercial product is not possible. Celis: “You would be surprised how often these things still go wrong. We will advise to rather go a little slower and build the file carefully, so that there are no surprises later on, with all the delays and costs that that entails.’

Classification

An initial reason to contact the CAT may be to explore which category a new treatment falls into and what the associated regulatory regime is. ‘By doing the classification in time, unnecessary costs or wasted time can be avoided,’ Celis said. He cites as an example the potential new uses of bone marrow stem cells that were investigated in the early years of the CAT: ‘There was already decades of experience in hematology with the regular bone marrow or hematological stem cell transplant. This falls under the Substances of Human Origin (SoHO) regime in the European Union. But if someone wants to inject bone marrow cells into the heart or brain to promote tissue repair there, we ask the question: is that part of the normal functions of bone marrow cells? It probably is not, and then the product is still an ATMP, even if the preparation is relatively simple. That means the manufacturer has to demonstrate safety and efficacy for this new application.’ A similar classification problem can arise when a cell therapy is intended for tissue repair and thus must be evaluated in the context of a tissue engineered product (TEP). Cell therapies and TEPs are both ATMPs, but different rules apply, for example in terms of endpoints in clinical trials.

In the vast majority of cases there is not much discussion about classification, but sometimes it is really a challenge for the CAT to strike the right balance between the need for a strict regulatory framework of a product on the one hand and the public health aspects on the other. Celis cites as a current example the steps currently being taken toward in vitro fertilization (IVF) with eggs created from induced pluripotent stem cells. ‘IVF is not covered by drug legislation. But with such a complex process as the production of oocytes from skin cells, you would want a very strict regime to apply, with high requirements in terms of quality, safety and effectiveness. We have flagged this and are now asking the European Commission as the legislative body to think about this, so that hopefully we will have an appropriate answer when it becomes possible to use this procedure in the clinic.’

Another example of shifting classifications are gene editing techniques such as CRISPR/CAS9. The CAT has proposed to legislators that the definition of gene therapies be modified so that all such techniques will be included. ‘In vivo gene editing in particular requires extra attention and care, because the genome may also be altered at sites other than just the target site. Over time, these off-target effects can have major consequences, for example, the development of tumors or changes in germline cells.

Asked whether classification can also help speed up the development process, Celis says, “Classification takes place quite early in the process. And in most cases the producer will already make a correct assessment of the classification. So you could say that that contribution is usually not that big. But I think that classification step does contribute to producers contacting the CAT at an early stage. And as I said, there’s definitely a gain from that .’

Meet Patrick Celis during the first webinar scheduled for March 11 from 4:00 pm – 5:00 pm. In addition to Patrick addressing classification of ATMPs during a meet the expert session. Pim Pijnappel & Dirk van Asseldonk will explain the case: LentiCure. And there are two more meet the experts sessions with Mariette Driessens of VSOP on patient participation and Marcel Hoefnagel of CBG on product development. Sign up now!