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Chimeric Antigen Receptor-T cells (CAR-T) are considered novel biological agents, designed to selectively attack cancer cells expressing specific antigens, with demonstrated clinical activity in patients affected with relapsed/refractory B-cell malignancies. In consideration of their complexity, the use of CAR-T requires dedicated clinical setting and health care practitioners with expertise in the selection, treatment, and management of toxicities and side effects. Such issue appears particularly important when contextualized in the rapid progress of CAR-T cell treatment, translating into a constant need of updating and evolution. Moreover, the clinical grade manufacturing of CAR-T cells is complex and implies articulated regulatory and organizational aspects. The main goal of this review is to summarize and provide an accurate analysis of the clinical, logistic, and regulatory requirements of CAR-T cell centers. Finally, we describe a new occupational figure called "CAR-T specialist" devoted to the establishment and coordination of the required facilities and regulatory landscape in the context of cancer centers., (Copyright © 2020 Gotti, Defrancesco, D’Angelo, Basso, Crotto, Marinelli, Maccalli and Iaconianni.)

Background: Potency is a quantitative measure of the desired biological function of an advanced therapy medicinal product (ATMP) and is a prerequisite for market approval application (MAA). To assess the potency of human skeletal muscle-derived cells (SMDCs), which are currently investigated in clinical trials for the regeneration of skeletal muscle defects, we evaluated acetylcholinesterase (AChE), which is expressed in skeletal muscle and nervous tissue of all mammals., Methods: CD56+ SMDCs were separated from CD56- SMDCs by magnetic activated cell sorting (MACS) and both differentiated in skeletal muscle differentiation medium. AChE activity of in vitro differentiated SMDCs was correlated with CD56 expression, fusion index, cell number, cell doubling numbers, differentiation markers and compared to the clinical efficacy in patients treated with SMDCs against fecal incontinence., Results: CD56- SMDCs did not form multinucleated myotubes and remained low in AChE activity during differentiation. CD56+ SMDCs generated myotubes and increased in AChE activity during differentiation. AChE activity was found to accurately reflect the number of CD56+ SMDCs in culture, their fusion competence, and cell doubling number. In patients with fecal incontinence responding to SMDCs treatment, the improvement of clinical symptoms was positively linked with the AChE activity of the SMDCs injected., Discussion: AChE activity was found to truly reflect the in vitro differentiation status of SMDCs and to be superior to the mere use of surface markers as it reflects not only the number of myogenic SMDCs in culture but also their fusion competence and population doubling number, thus combining cell quality and quantification of the expected mode of action (MoA) of SMDCs. Moreover, the successful in vitro validation of the assay proves its suitability for routine use. Most convincingly, our results demonstrate a link between clinical efficacy and the AChE activity of the SMDCs preparations used for the treatment of fecal incontinence. Thus, we recommend using AChE activity of in vitro differentiated SMDCs as a potency measure in end stage (phase III) clinical trials using SMDCs for skeletal muscle regeneration and subsequent market approval application (MAA).

The objective of the research is to analyze the legal regulation in the transplantology field at the present stage in Ukraine. To address identified challenges, the author investigates the foreign countries experience and suggests ways of improving certain mechanism for legal regulation in the field of organ transplantation and anatomical materials. The empiric material of the study included a wide range of legal instruments regulating this sphere of legal relationships, information regarding the problems of their application, statistics, expert analysis of Ukrainian and foreign researchers. Methodological mechanism of current research includes such methods: systematic, logical and formal, structural-functional, comparative. The research found that the most world's successful model for the organization of transplantation is in Spain. Additionally, the criteria for the reception of such a model are singled out as well as certain aspects of their application in Ukraine are analyzed. Particularly, the most important criteria are: universal and general territorial proliferation of national health systems; relevant economic resources (special attention is paid to the fact that transplantation is not a medicine of luxury, and an adequate compensation to hospitals for transplantation operations should serve as a main economic aspect); an adequate and necessary number of doctors and nurses; the availability of advanced technical options for medical mechanical ventilation (air conditioning of dead bodies). The research led to the following overall findings. Due to the rapid development of medical and biological sciences, there is an urgent need on further investigation of legal, moral and ethical, general medical aspects of transplantation with subsequent proposals for improving legislation in the field of human organs transplantation and other anatomical materials. At the same time, development of appropriate legislation by complex groups of cross-disciplinary specialists and experts (in medicine, biology, law and bioethics) is the key to legal regulation effectiveness.

Xenotransplantation attracted interest from regulatory authorities, particularly after the demonstration of pig-to-human transmission of porcine endogenous retrovirus (1996). This added to the risk of a product, resulting in a Guidance of the US Food and Drug Administration (2003). This addresses the full flow chart in product manufacturing, starting with the designated pathogen-free status of the source animal; and special aspects regarding the recipient like informed consent and monitoring for infectious pathogens. Also archiving of records from the donor and recipient, as well as storage of samples is described. The European Medicines Agency issued a Guideline on xenogeneic cell therapy products (2009). Cell-based medicinal products are subject to specific regulations and directives, which apply also to xenogeneic products: the xenotransplant guidances/guidelines are an addition to these regulations. Noteworthy, acellular products like heart valves and decellularized cornea are not considered a cell therapy product, but rather a medical device with its own regulation. WHO issued relevant documents, especially about safety, and the International Xenotransplantation Association published consensus documents, a.o., addressing preclinical efficacy requirements before entering clinical trials. This manuscript presents an overview of the regulatory framework, with special focus on cell therapy products necause these are expected to reach the market first (i.e., pancreatic islets, hepatocytes and cellularized cornea); major illustrations are from the European situation. Albeit being complex, the regulation of xenotransplant products does not form a block in product development, but rather supports the introduction of efficacious and safe products to meet the medical need., (Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.)

Gene-therapy medicinal products are currently applied to patients enrolled in authorized clinical trials to demonstrate safety and efficacy. Given a positive outcome, marketing authorization can subsequently be achieved via the centralized procedure coordinated by the European Medicines Agency. With Regulation (EC) No. 1394/2007 in force, advanced therapy medicinal products, including gene- and cell-therapy products, can be excepted from the obligation of obtaining a marketing authorization via the centralized procedure under specific conditions (so-called "hospital exemption"). This hospital exemption allows the application of gene-therapy medicinal products prepared on a non-routine basis for an individual patient and used under the exclusive professional responsibility of a medical practitioner. Here, we explain the requirements to be fulfilled in order to fall under this exemption, the implementation of this regulation into the German national legislation, and its impact on gene-therapy product development in the future.

The transplantation of human cells and tissues has become a global enterprise for both life-saving and life-enhancing purposes. Yet current practices raise numerous ethical and policy issues relating to informed consent for donation, profit-making, and quality and safety in the procurement, processing, distribution, and international circulation of human cells and tissues. This paper reports on recent developments in the international debate surrounding these issues, and in particular on the attention cell and tissue transplantation has received in WHO's ongoing process of updating its 1991 Guiding principles on human organ transplantation. Several of the organizers of an international working group of stakeholders from a wide range of backgrounds that convened in Zurich in July 2006 summarize the areas of normative agreement and disagreement, and identify open questions regarding facts and fundamental concepts of potential normative significance. These issues must be addressed through development of common medical, scientific, legal and ethical requirements for human cell and tissue transplantation on a global basis. While guidance must accommodate the distinct ethical issues raised by activities involving human cells and tissues, consistency with normative frameworks for organ transplantation remains a prime objective.

The concept of stem cell therapy has engaged the attention of the public and scientists alike. Intensive research effort is focused upon understanding the biology and therapeutic potential of embryonic and adult stem cells, with the eventual goal of treating such pathologies as Parkinson's disease, diabetes, neurological injury and degenerations and cancer. Ex vivo expansion and transplantation of limbal epithelial stem cells to the corneas to treat blinding ocular surface disease was one of the first stem cell therapies to successfully reach the clinic. However, limbal epithelial stem cell research and therapy delivery has remained largely within the noncommercial academic clinician-scientist environment from which it was originally pioneered. In our experience, gaining regulatory approval has been as great a hurdle as surmounting the scientific challenges of stem cell therapy. Based upon our model of delivering 'accredited' limbal epithelial stem cell therapy to patients in compliance with Good Manufacturing Practice and the new European Union Tissues and Cells Directive, we address the key regulatory questions. This may help colleagues who are developing innovative academic research-driven stem cell therapies regarding donor consent, raw materials, quality assurance, laboratory specification, indemnity and funding.

Advances in biomedical technology has enabled the research and use of novel therapies in cellular transplantation. A number of trials using chondrocyte and autologous skin products are underway and will soon become commercially available for clinical utilization. However, the Korea Food and Drug Administration currently lack systematic regulations for efficacy and safety evaluation of the emerging therapies. Specifically, dose related studies are uncontrolled and availability of clinical research centers is inadequate. Thus, patients are receiving therapy without guidelines for indication, dose, and adequate safety profiles. We propose criteria for cases in which these therapies can be used and advocate IRB determined quality assurance for future research.

With the advancement of medical science, most cancers in children are now treatable, the cure rate being almost 85%. In boys, one side effect of treatment (chemotherapy and radiotherapy) is destruction of the sperm precursor cells in the testis, resulting in the failure of sperm formation after puberty, and consequent infertility. At the time of anti-cancer treatment, future fertility of the boy patient is at the very bottom of the relative quality of life (RQL) parameters list; however, in adults infertility is an important issue following cure from cancer. In this article we have first reviewed the existing situation with regard to the state of the art of fertility preservation in young boys with cancer, and have then raised clinical and ethical issues and suggested a way forward. The review concludes with the emphasis that certain important issues still need to be resolved and, until these are, then the different techniques available should be confined to approved, ethical clinical trials where efficacy and safety can be fully evaluated.