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Mesenchymal stromal cells (MSCs) have been used in multiple clinical trials for steroid-refractory moderate-severe (grade II-IV) acute graft-versus-host disease (aGVHD) across the world over the last two decades. Despite very promising results in a variety of trials, it failed to get widespread approval by regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. What lessons can we learn from this for future studies on MSCs and other cell therapy products? Broad heterogeneity among published trials using MSCs in aGVHD was likely the core problem. We propose a standardized approach in regards to donor-related factors, MSCs-related characteristics, as well as clinical trial design, to limit heterogeneity in trials for aGVHD and to fulfill the requirements of regulatory agencies. This approach may be expanded beyond MSCs to other Cell and Gene therapy products and trials in other diseases., Competing Interests: Declaration of Competing Interest JJB consulting Bluerock, Bluebird bio, Sanofi, SmartImmune, Immusoft, Sobi, Advanced Clinical, Merck. SK, Sven Kili Consulting Ltd., Saisei Ventures, CCRM. MF is CEO of Kiji Therapeutics., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The field of regenerative medicine, including cellular immunotherapies, is on a remarkable growth trajectory. Dozens of cell-, tissue- and gene-based products have received marketing authorization worldwide while hundreds-to-thousands are either in preclinical development or under clinical investigation in phased clinical trials. However, the promise of regenerative therapies has also given rise to a global industry of direct-to-consumer offerings of prematurely commercialized cell and cell-based products with unknown safety and efficacy profiles. Since its inception, the International Society for Cell & Gene Therapy Committee on the Ethics of Cell and Gene Therapy has opposed the premature commercialization of unproven cell- and gene-based interventions and supported the development of evidence-based advanced therapy products. In the present Guide, targeted at International Society for Cell & Gene Therapy members, we analyze this industry, focusing in particular on distinctive features of unproven cell and cell-based products and the use of tokens of scientific legitimacy as persuasive marketing devices. We also provide an overview of reporting mechanisms for patients who believe they have been harmed by administration of unapproved and unproven products and suggest practical strategies to address the direct-to-consumer marketing of such products. Development of this Guide epitomizes our continued support for the ethical and rigorous development of cell and cell-based products with patient safety and therapeutic benefit as guiding principles., Competing Interests: Declaration of Competing Interest Hamid R. Bidkhori is the chancellor of the Biomedical Research Ethics Committee of Academic Center for Education, Culture and Research (ACECR) - Mashhad. He is a member of the International Society for Cell & Gene Therapy (ISCT), the International Society for Extracellular Vesicles (ISEV) and the ISCT Committee on the Ethics of Cell and Gene Therapy. Rachele Ciccocioppo is a member of the Advisory Board of Takeda (Italy) for the use of mesenchymal stromal cells in fistulizing Crohn's disease. Natividad Cuende is a member of the Governing Council of the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Medicine and Medical Device Agency). She is member of the ISCT Committee on the Ethics of Cell and Gene Therapy and the ISCT Legal and Regulatory Affairs Committee–Europe. She is also member of the Spanish Guarantee Committee for Donation and Use of Human Cells and Tissues of the Spanish Ministry of Science and Innovation. She is not paid for these roles. Bambi Grilley is affiliated with QBRegulatory Consulting LLC that has provided regulatory affairs and project management support to AlloVir, Marker Therapeutics, LOKON Pharma, Tessa Therapeutics and March Biosciences. She is a member of ISCT and its Ethics of Cell and Gene Therapy (ECGT) Committee and is the incoming Chief Regulatory Officer of ISCT. She is not paid for her roles in ISCT. Conflict of interest is managed in accordance with Baylor College of Medicine policy and oversight. Laertis Ikonomou has written an expert report in a class action lawsuit filed against a business selling unproven “stem cell”-based interventions, and wrote the report on a pro bono basis. He is a member of the ISCT and the International Society for Stem Cell Research (ISSCR) and the chair of the ISCT Committee on the Ethics of Cell and Gene Therapy. He is not paid for these roles. Conflict of interest is managed in accordance with University at Buffalo policy and oversight. Aaron D. Levine is a member of ISCT and its ECGT committee. He is not paid for these roles. Levine's research program is supported by the National Science Foundation (NSF) (Grant No. EEC-1648035). Bruce Levine has received compensation for serving on the scientific advisory boards of Akron Bio, Avectas, Immuneel, Immusoft, In8bio, Ori Biotech, Oxford Biomedica, UTC Therapeutics and Vycellix. He has received compensation for consulting for GSK. He has received compensation and equity from Capstan Therapeutics as a co-founder and member of the Scientific Advisory Board. As co-founder of Tmunity Therapeutics, he received equity. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. Megan Munsie is a member of the International Society for Stem Cell Research and its Ethics Committee and Public Policy Committee. She is also the President of the Australasian Society for Stem Cell Research. Munsie's research program is supported by the Novo Nordisk Foundation Center for Stem Cell Medicine (NNF21CC0073729). John E. J. Rasko: employment: Royal Prince Alfred Hospital; consultancy and honoraria: Rarecyte, Gilead, Roche, Novartis, Bluebird Bio, Spark therapeutics, Cynata, Pfizer; equity: Genea; shareholder: Rarecyte, Woke; DSMB: Diamond Fanconi anemia trial; research funding: National Health and Medical Research Council (NHMRC), New South Wales Cancer Council, Cancer Institute NSW (CINSW), Therapeutic Innovation Australia, Philanthropic foundations; Chair, Gene Technology Technical Advisory Committee, Office of The Gene Technology Regulator, Australian Government. Leigh Turner served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee. He is also a member of the International Society for Stem Cell Research and its Ethics Committee and Membership Committee. Turner's research program is supported by the Pew Charitable Trusts. Daniel J. Weiss served as a compensated expert witness for the US government in a criminal case and as a pro bono expert witness in a class action lawsuit. He is a member of ISCT and its ECGT committee and is former Chief Scientific Officer of the ISCT. He is not paid for his roles in the ISCT. Dr. Weiss has received compensation for consulting with Mesoblast Inc., NextCell Inc., United Therapeutics. Inc. and Vertex Inc. Conflict of interest is managed in accordance with University of Vermont policy and oversight. Patricia J. Zettler reports serving as a consultant to the US Food & Drug Administration. All the other authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Hospital exemption (HE) is a regulated pathway that allows the use of advanced therapy medicinal products (ATMPs) within the European Union (EU) under restrictive conditions overseen by national medicine agencies. In some EU countries, HE is granted for ATMPs with no demonstrated safety and efficacy; therefore, they are equivalent to investigational drugs. In other countries, HE is granted for ATMPs with demonstrated quality, safety and efficacy and for which centralized marketing authorization has not been requested. The Committee on the Ethics of Cell and Gene Therapy of the International Society for Cell & Gene Therapy reflects here on the ethical issues concerning HE application from the perspective of the patient, including risk-benefit balance, accessibility and transparency, while providing evidence that HE must not be regarded as a conduit for unproven and unethical ATMP-based interventions. Indeed, HE represents a legal instrument under which a patient's need for access to novel ATMPs is reconciled with ethics. Moreover, for some unmet medical needs, HE is the only pathway for accessing innovative ATMPs. Nonetheless, HE harmonization across EU Member States and limitations of ATMP use under the HE rule when similar products have already been granted centralized marketing authorization to avoid a parallel regulatory pathway are controversial issues whose political and economic consequences are beyond the scope of this review. Finally, the institution of an EU registry of HE applications and outcomes represents a priority to improve transparency, reduce patient risks, increase efficiency of health systems, facilitate company awareness of business opportunities and boost progressive entry of ATMPs into the therapeutic repertoire of health systems., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Often, novel gene and cell therapies provide hope for many people living with incurable diseases. To facilitate and accelerate a successful regulatory approval and commercialization path for effective, safe and affordable cell and gene therapies, the involvement of patient advocacy groups (PAGs) should be considered early in the development process. This report provides a thorough overview of the various roles PAGs play in the clinical translation of cell and gene therapies and how they can bring about positive changes in the regulatory process, infrastructure improvements and market stability., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)