Regulatory considerations and directions for the European CAR-T landscape
Regulatory considerations and directions for the European CAR-T landscape are critical themes of the meeting, with an EMA perspective on CAR-T marketing authorization, as well as post marketing safety and efficacy studies. A patient representative provided a personal, non-clinical perspective on CAR T-cell regulation and access. Leading European grants/projects were reviewed in a session that covered progress on the CARAMBA, EURE-CART, CARAT and imSAVAR studies. One of the concluding sessions addressed the key issue of CAR T-cell implementation and practical recommendations coming from Real World evidence in Europe and the USA.
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Marketing authorization of CAR T-cells - the EMA perspective (Martina Schüssler-Lenz, Germany)
Regulators believe that CAR T-cells have the potential to address a significant unmet medical need. As a result, seven products are currently being provided with enhanced regulatory support under the Prime Scheme. Post-authorization evidence generation, and the potential regulatory space for additional CAR T-cell products within the context of EU Orphan legislation, deserve special attention. Manufacturers should take this into consideration before submitting a marketing authorization, and focus on demonstrating non-similarity and significant benefits compared to other authorized CAR T-cell products.
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Creating a country-wide selection algorithm (the Austrian experience) (Ulrich Jäger, Austria)
The Austrian CAR T-cell network country-wide selection algorithm’s major eligibility criteria include ejection fraction >50%, peripheral capillary oxygen saturation (SpO2) >91─92% on room air, European Cooperative Oncology Group performance status (ECOG PS) of 0─1, no central nervous system involvement or major neurological disease as a contraindication, and no active or uncontrolled infection. A total of six CAR T-cell centers are now active in Austria and use this selection algorithm.
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PASS and PAES: The need for registration, short- and long-term follow-up of patients treated with gene therapy medicinal products (Christian Chabannon, France)
Real-World data provide long term evidence for safety and efficacy of CAR-T. This is particularly pertinent to the risk assessment of insertional mutagenesis (leading to secondary malignancies) and germline transmission (potentially contributing to miscarriage, birth defects or neonatal diseases). Through its registry, EMBT has demonstrated its ability to conduct both post-authorization safety studies (PASS) and post-authorization efficacy studies (PAES) in collaboration with HTAs and pharma.
CARAT (H2020, CAR-T manufacturing) (Mario Assenmacher, Germany)
The CARAT (Chimeric Antigen Receptor for Advanced Therapies) project aims to develop a comprehensive toolbox explicitly tailored for automated, easy-to-handle and cost-efficient manufacture of CAR T-cells, including novel tracking tools. More effective and safer cellular products, improved gene delivery, better CAR design and innovative monitoring are the goal, with the future vision of a point-of-care manufacturing of CAR T-cells.
imSAVAR (Ulrike Köhl, Germany)
Toxicities in immunotherapy are not always detectable prior to first-in-human studies. Dr Köhl introduced imSAVAR: A safety avatar for the non-clinical mimicking of the immune system effects of immunomodulatory therapies such as CAR T-cells to develop a platform of processes for non-clinical safety and efficacy assessments of both immune-inflammatory and immune-oncology therapies.
Real-world evidence in the EU (Gilles Salles, France)
A retrospective real-world study of CAR-T treated patients with relapsed/refractory DLBCL across five centers in France showed that long waiting times for treatment (median 40 days) are associated with high refractory rates and that prior therapy were also associated with poorer outcomes. This suggests the sooner viable patients are treated with CAR T-cells the better the chances of survival. Some real-world studies have already been carried out, with data from Germany, Spain and the UK presented at this year’s EHA-EMBT European CAR T-cell meeting. Dr Salles added that a median progression-free survival of 3 months was observed in a French study of 54 patients with DLBCL. He also highlighted that differences between RWE from Europe and the USA may be a result of patient selection, and to capture the efficacy of CAR T-cell therapies in different patient populations, it is important to compare RWE from both Europe and the USA.
Real-world evidence (RWE) in the USA (Marcelo Pasquini, USA)
The Cellular Immunotherapy Data Resource (CIDR), operated by the Center for International Blood and Marrow Transplant Research (CIBMTR) in the USA collects data on long-term safety and efficacy of immunotherapy. In turn, CIDR gives access to this data to a diverse group of clinicians, researchers, manufacturers, payers, regulators and the public. Given the requirements of regulators to follow up patients for at least 15 years post treatment, existing data from the pharmaceutical industry should be incorporated, and collaboration with other organizations such as EHA and EBMT is encouraged, with the goal of facilitating clinically relevant changes in practice and greater implementation of immunotherapy globally.
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