www.nature.com/bmt CORRESPONDENCE OPEN Role of Hospital Exemption in Europe: position paper from the Spanish Advanced Therapy Network (TERAV) © The Author(s) 2023 Bone Marrow Transplantation (2023) 58:727–728; https://doi.org/ Exemption. In addition, patients treated with ATMP through 10.1038/s41409-023-01962-0 Hospital Exemption should be followed up in registries collect- ing health outcomes, such as those recommended by the EMA and lead by EU based scientific societies. This would be essential TO THE EDITOR: for ensuring not only transparency on the safety and availability The Hospital Exemption rule is considered a valuable European of these products, but also to generate scientific knowledge and legislative initiative that guarantees patient access to novel increase the efficiency of the Health Systems and the awareness therapies based on the use of advanced therapy medicinal of all the stakeholders interested, including academia, pharma- products (ATMPs) in the Member States. On the occasion of the ceutical industry, regulators, and especially patients’ update of the European General Pharmaceutical Legislation, the associations. Spanish Network of Advanced Therapies (TERAV, formerly TerCel), As expected, the number of ATMPs approved by Hospital Exemption is very limited in the EU, and these products have 1234567890();,: which has played a recognized leadership in Europe in the development of both academic and pharmaceutically commer- been mainly developed to provide treatments for patients not cialized ATMPs [1], would like to make the following position included or ineligible for participating in clinical trials or where statement: ATMPs were not considered suitable for commercial develop- The Hospital Exemption Clause was established in the European ment. Hospital Exemption is therefore an essential tool to ensure ATMP regulation EC1394/2007 (Article 28) [2], to enable manu- timely access to safe, effective, and legally regulated treatments facturing of ATMPs outside the standard centralized marketing for patients with rare diseases or those lacking effective authorization common pathway, with the following conditions: treatments or better therapeutic alternatives [4]. Therefore, “ATMP is prepared on a non-routine basis according to specific Hospital Exemption is a stimulus to promote innovation in quality standards, and used within the same Member State in a advanced therapies in European academic institutions. As hospital under the exclusive professional responsibility of a medical commented before, the most positive consequence is the practitioner, in order to comply with an individual medical increased access of advanced therapies to our patients. The prescription for a custom-made product for an individual patient” main reasons for this are, amongst others, the fact that they may and “Manufacturing of these products shall be authorized by the cover indications not yet approved for commercial CARTs and competent authority of the Member State. Member States shall other ATMPs, the expedited manufacturing time (and at a lower ensure that national traceability and pharmacovigilance require- cost) of an academic product, and that they may provide ments as well as the specific quality standards at Community level in treatment for diseases where pharmaceutical companies are not respect of advanced therapy medicinal products for which focused on. Besides, Hospital Exemption clause alleviates the authorization is required pursuant to Regulation”. worrying difficulties of supplies to European countries of ATMPs It is relevant to stress that products administered throughout manufactured outside the EU. Hospital Exemption are under the oversight of the correspond- Moreover, it is very important to highlight our support of the ing national competent authority of each Member State after use of the exemption clause with academic ATMPs also for careful risk-benefit analysis of the medicinal product. This indications in which there is a commercial product approved, as in includes for instance, in the “Spanish Model”, a thorough the case for instance of CAR-T in hematological malignancies, evaluation by the Spanish Agency of Medicines and Medical since many patients do not have access, for a number of reasons, Devices (AEMPS) of preclinical and clinical data, as well as the to the approved commercial products. Moreover, these develop- inspection and accreditation of the GMP Cell Production Facility ments may provide important technical and manufacturing and a Pharmacovigilance Plan, among other aspects, which improvements that can lead to greater efficacy, lower toxicity or are similar to those required for a centralized marketing better access. In this regard, we are looking forward to the authorization, in order to ensure the quality, safety and efficacy successes of the EMA pilot program recently launched to help of the pharmaceutical product. An unsolved potential problem academic and non-profit developers navigate the regulatory that the updated regulation should define is the lack of processes and optimize development of ATMPs within the EU harmonization in the requirements established for Hospital [5, 6]. Exemption in the different Member States [3]. On the basis of In our opinion, the centralized approval and the Hospital our very positive experience, we strongly suggest to extend this Exemption are more complementary than competitive Spanish Model to those systems where preclinical and clinical approaches, and Hospital Exemption represents a unique oppor- data or other more stringent criteria are not evaluated for tunity of partnership between academia and pharmaceutical product approval. industry in the benefit of patients, and is one of the most In this setting, is important to note that we strongly support important assets in the European Union to get these highly the establishment of a public EU registry of the uses innovative and disruptive therapies accessible to our national and characteristics of ATMPs available through Hospital health systems. Received: 6 March 2023 Revised: 13 March 2023 Accepted: 17 March 2023 Published online: 25 March 2023 Correspondence 728 ✉ Fermín Sánchez-Guijo 1 , Cristina Avendaño-Solá2, 2. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 Lina Badimón3, Juan A. Bueren4, Josep M. Canals5,6, November 2007 on advanced therapy medicinal products and amending Directive Joaquim Delgadillo 7, Julio Delgado8, Cristina Eguizábal9, 2001/83/EC and Regulation (EC) No 726/2004. María-Eugenia Fernández-Santos 10, Damián García-Olmo11, 3. Cuende N, Ciccocioppo R, Forte M, Galipeau J, Ikonomou L, Levine BL, et al. Patient access to and ethical considerations of the application of the European Union Gloria González-Aseguinolaza12, Manel Juan8, hospital exemption rule for advanced therapy medicinal products. Cytotherapy. Francisco Martín13,14, Rosario Mata15, Nuria Montserrat16,17, 2022;24:686–90. Antonio Pérez-Martínez 18, José A. Pérez-Simón 19, 4. Fox T, Bueren J, Candotti F, Fischer A, Aiuti A, Lankester A, et al. Access to gene Felipe Prósper 20, Álvaro Urbano-Ispizua8, Agustín G. Zapata21, therapy for rare diseases when commercialization is not fit for purpose. Nat Med. Anna Sureda22 and José M. Moraleda 23 2023. https://doi.org/10.1038/s41591-023-02208-8. 1 University of Salamanca, IBSAL-University Hospital of Salamanca, 5. Juan M, Delgado J, Calvo G, Trias E, Urbano-Ispizua A. Is Hospital Exemption an Salamanca, Spain. 2Clinical Pharmacology Department, Hospital alternative or a bridge to european medicines agency for developing academic Universitario Puerta de Hierro-Majadahonda, IDIPHISA, Madrid, chimeric antigen receptor T-cell in Europe? Our experience with ARI-0001. Hum Spain. 3Department of Molecular Pathology and Therapeutics, IR Gene Ther. 2021;32:1004–7. 6. EMA pilot offers enhanced support to academic and non-profit developers of -Hospital de la Santa Creu i Sant Pau, IIBSantPau, CiberCV, advanced therapy medicinal products (29/09/2022). https://www.ema.europa.eu/ Barcelona, Spain. 4Biomedical Innovation Unit, CIEMAT, CIBER Rare en/news/ema-pilot-offers-enhanced-support-academic-non-profit-developers- Diseases and IIS Fundación Jiménez Díaz, Madrid, Spain. 5Creatio - advanced-therapy-medicinal-products. Production and Validation Center of Advanced Therapies; and Laboratory of Stem Cells and Regenerative Medicine, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, ACKNOWLEDGEMENTS Institute of Neurosciences, University of Barcelona, Barcelona, Spain. We are grateful to the 32 academic research groups and 14 GMP production facilities 6 August Pi i Sunyer Biomedical Research Institute (FRCB-IDIBAPS), from the Spanish Network of Advanced Therapies (TeraV, https://www.redterav.es). Barcelona, Spain. 7Banc de Sang i Teixits, Barcelona, Spain. 8Hospital TERAV Network is supported by Instituto de Salud Carlos III (ISCIII) and Funded by the Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, European Union – NextGenerationEU, Recovery, Transformation and Resilience Plan Spain. 9Cell Therapy, Stem Cells and Tissues Group, Basque Center for (Reference RD21/0017/0001). Blood Transfusion and Human Tissues, Biocruces Bizkaia Health Research Institute, Galdakao, Spain. 10ATMPs Production Unit. IiS- Gregorio Marañón Health (IiSGM), Gregorio Marañón General AUTHOR CONTRIBUTIONS University Hospital, Madrid, Spain. 11“Fundación Jiménez Díaz” FSG, CA and JMM conceived and drafted the manuscript. All other co-authors contributed by critically reviewing the paper and actively participating in the University Hospital. Universidad Autónoma de Madrid, Madrid, Spain. 12 discussions leading to obtain the final version, that was approved for all authors. Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Programa de Terapia Génica y Regulación de la expresión Génica, Pamplona, Spain. 13Gene & Cell Therapy Group. GENYO, COMPETING INTERESTS Centre for Genomics and Oncological Research: Pfizer/University of The authors declare no competing interests. Granada/Andalusian Regional Government, Granada, Spain. 14Dpt. de Bioquimica y Biologia Molecular III e Inmunologia. Facultad de Medicina, Universidad de Granada, Granada, Spain. 15Coordination ADDITIONAL INFORMATION Unit of the Andalusian Network for the Design and Translation of Correspondence and requests for materials should be addressed to Fermín. Advanced Therapies, Seville, Spain. 16Pluripotency for Organ Sánchez-Guijo. Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, Reprints and permission information is available at http://www.nature.com/ Spain. 17Catalan Institution for Research and Advanced Studies reprints (ICREA), Barcelona, Spain. 18Universidad Autónoma de Madrid, Institute for Health Research (IdiPAZ), University Hospital La Paz, Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Madrid, Spain. 19Department of Hematology, University Hospital Virgen del Rocio, Instituto de Biomedicina de Sevilla (IBIS)/CISC, Universidad de Sevilla, Sevilla, Spain. 20Servicio de Hematologia y Terapia Celular, Clinica Universidad de Navarra, IdISNA, CIBERONC Open Access This article is licensed under a Creative Commons and CCUN, Pamplona, Spain. 21Faculty of Biology. Dept of Cell Attribution 4.0 International License, which permits use, sharing, Biology, Complutense University, Madrid, Spain. 22Departament adaptation, distribution and reproduction in any medium or format, as long as you give d’hematologia, Institut Català d’Oncologia-Hospitalet, Institut appropriate credit to the original author(s) and the source, provide a link to the Creative d’Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Commons licence, and indicate if changes were made. The images or other third party Barcelona, Barcelona, Spain. 23University of Murcia, IMIB—University material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the Hospital Virgen de la Arrixaca, Murcia, Spain. ✉email: ferminsg@usal.es article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by/4.0/. REFERENCES 1. Sánchez-Guijo F, García-Olmo D, Prósper F, Martínez S, Zapata A, Fernández-Avilés F, et al. Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative © The Author(s) 2023 translational research. Cytotherapy. 2020;22:1–5. Bone Marrow Transplantation (2023) 58:727 – 728