The scientific drive of Spanish hospitals has made a scenario unimaginable very recently and unprecedented in the world begin to become a reality: that public health can largely address types of cancer such as multiple myeloma. This is the milestone achieved by a network of health centers, led by the Clínic of Barcelona and of which the hospitals 12 de Octubre in Madrid, Virgen del Rocío in Seville, Salamanca, Virgen de la Arrixaca in Murcia, and Clínico de Santiago are part de Compostela and the Navarra University Clinic, the latter the only one in the privately owned group. , from the Carlos III Health Institute (ISCIII) is the one that has managed to promote the project.
“We are in a special and beautiful moment in which the fruits of many years of work are being reaped. There is still a way to go, but it has been proven that. And this has great advantages. One is that these therapies are four times cheaper, which contributes to the sustainability of the system. Another is that production is done close to the patient and represents a scientific boost to the public network,” says hematologist José María Moraleda, coordinator of the TERAV NETWORK and member of the Spanish Society of Hematology and Hemotherapy (SEHH).
The price of the latest CAR-T therapies approved by the European Medicines Agency (EMA) is close to 400,000 euros per patient, while the cost of those produced at the Clínic does not exceed 90,000. CAR-Ts have been obtained in patients until now considered incurable. The treatments consist of extracting immune system cells from the patient to genetically reprogram them, so that when they return to the body they destroy those causing the disease.
The progress of the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) of the Hospital Clínic is what has catalyzed these advances. So far, the entity has managed to develop two therapies: for those over 25 years of age and ARI-0002h, against multiple myeloma. The first became the one authorized by a regulatory agency in February 2021, while the second – whose use is now extended in the public system – received last July
Manel Juan, head of the Immunology Service at the Hospital Clínic and promoter of these advances, describes the current scenario as an “opportunity.” “ARI-0002h offers an option to patients who would not otherwise have access to the treatments they need. There are two approved commercial therapies for multiple myeloma. [Abecma y Carvycti]but these do not reach many patients for several reasons: lack of production capacity of pharmaceutical companies, commercial strategies, high prices… Our role, more than competition for the industry, is one of complementarity to ensure that patients have a “greater accessibility to the therapies they need.”
ARI-0001, for its part, is the only CAR-T approved and available in Spain to treat patients over 25 years of age with acute lymphoblastic leukemia (ALL). In total, according to Juan, both therapies have been administered to almost 450 patients in clinical trials, as compassionate use or through hospital exemption, which allows public hospitals to develop non-industrial treatments in some circumstances.
Currently, the production of the vast majority of ARI-0002h is carried out at the Clínic with the cells sent to them by the hospitals in the network, which take care of the entire care part—diagnosis, treatment, evolution of the patients… —. Although the objective is that little by little more hospitals develop the knowledge to also deal with production, until now only the Navarra University Clinic has begun to do so, mainly for patients at the Salamanca University Hospital.
The advance of CAR-T developed in public, so-called “academic” hospitals has aroused the misgivings of pharmaceutical companies that have these therapies approved by the EMA, which in some cases may see it as a kind of unfair competition. This opposition acquires special relevance at a time when the European Union is processing and some actors fear that the powerful lobbys of the sector stop the academic CAR-T. “The industry maneuvers in Brussels to assert its interests. Pharmaceutical companies intend, from what we have seen, to prevent academic CAR-T in the indications in which a commercial one exists. This would mean the end of ARI-0002h”, warns
These fears have a precedent: regulation 1394/2007. This standard, which regulated advances in advanced therapies 17 years ago, accepted the positions of the sector when considering CAR-T as a medicine and, therefore, left them subject to its legal and commercial conditions (patents, financing mechanisms public…).
Lola Hernández, head of the National Bone Marrow Plan, calls that decision an “error.” “CAR-Ts are something closer to an allogeneic transplant [de células madre] than to a medication as such. That is, basically it is a procedure that obtains cells from the patient and administers them again once modified. And patenting that has significant drawbacks. First, in the ethical field, because basically it means selling the patient their own cells at a very high price. And, secondly, because it limits the development of knowledge and the access of patients to therapies,” he censures.
Regulation 1394/2007 granted CAR-T the status of medicines, but also provided for some avenues that allow public hospitals to continue with the research and development of advanced therapies. One of them is the one that the Hospital Clínic has resorted to and that is now at the center of the negotiations in Brussels: the hospital exemption.
“We can consider the hospital exemption as an intermediate step to reach the ultimate goal of any therapy, which is centralized approval by the EMA. But this is an enormously expensive procedure that is usually only within the reach of the pharmaceutical industry. The exemption, on the other hand, allows hospitals that have been successful with some therapy, on a smaller scale but with the same effectiveness and safety, to achieve a first approval by national agencies,” explains Moraleda.
The Farmaindustria employer association, for its part, considers that “the hospital exemption makes a lot of sense in the search for certain treatments without an approved therapeutic alternative, but this exceptional situation should not be perpetuated.” In this sense, the sector defends that “in the case of academic CAR-T that have this hospital exemption in Spain and a subsequent European marketing authorization is granted to an industrially manufactured medicine for the same disease, two medicines should not be maintained with different authorization standards.”
The underlying idea is that academic therapies should meet “the same standards of quality, efficacy and safety” that the EMA imposes on commercial ones, an argument that is rejected by supporters of academic CAR-T. “The standards they meet are also sufficient. We are not talking about artificial molecules, we are talking about cells and clinical procedures. The tests carried out have shown that academics obtain equal or better results than commercial ones,” says Lola Hernández.
César Hernández, general director of the Common Portfolio of Services and Pharmacy of the Ministry of Health, values “the coexistence [en el sistema sanitario] of commercial CAR-T and academics” which shows “the support for public research and the commitment that these developments follow the appropriate regulatory channel that allows them to obtain a marketing authorization and increase competition in the market.”
Industry movements in Brussels have sought to block this avenue, which worries the majority of actors involved. Nicolás González Casares, responsible for the pharmaceutical directive for the Socialist Group in the European Parliament, considers, however, that the Spanish model is not at risk. “The development of academic CAR-Ts has proven not only to have a first-rate scientific basis, but also allows the creation of tremendously important innovation ecosystems with a huge future,” he says.
The strategic interest of the countries will be what, ultimately, will allow finding the formula for academic and commercial CAR-T to coexist in health systems. “In the previous mandate there was time for Parliament to establish its position, but the procedure was paralyzed with the elections. Now the countries in the Council must do the same and issues of national interest will have great weight there,” concludes González Casares.
