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Objective: To position the Brazilian Transplant System within the context of the 4 Strategic Lines of Action proposed by the Pan-American Health Organization., Method: A specialist analysis was conducted through comparative analyses of the 4 Strategic Lines of Action, objectives, and indicators outlined in the Action Plan, along with the donation and transplantation system in accordance with Brazilian transplantation law. Subsequent to an in-depth review of the document issued by the health authority, a series of meetings involving 8 specialists in organ donation and transplantation were conducted. During these meetings, discussions were carried out with the objective of numerically interpreting each strategy presented in the document, and recommendations constructed., Results: Four strategies were evaluated and only 2 of them the third (81,3%) and the fourth (90%) do not achieve the indicators to complete the objective related to equitable access to organ, tissue, and cell transplants in Brazil., Conclusion: The recommendations developed carry importance, as they are innovative and contribute to the establishment of priorities when shaping public policies. The report not only highlights indicators that were not satisfactorily met but also provides insights into the recommendations formulated to improve those indicators that have already been achieved and to work toward achieving those that have not yet been realized. Additionally, these recommendations can justify actions and establish priorities for research efforts in the field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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.)

Cell therapy has provided unprecedented opportunities for tissue repair and cancer therapy. Imaging tools for in vivo tracking of therapeutic cells have entered the clinic to evaluate therapeutic cell delivery and retention in patients. Thus far, clinical cell tracking studies have been a mere proof of principle of the feasibility of cell detection. This review centers around the main clinical queries associated with cell therapy: Have cells been delivered correctly at the targeted site of injection? Are cells still alive, and, if so, how many? Are cells being rejected by the host, and, if so, how severe is the immune response? For stem cell therapeutics, have cells differentiated into downstream cell lineages? Is there cell proliferation including tumor formation? At present, clinical cell tracking trials have only provided information on immediate cell delivery and short-term cell retention. The next big question is if these cell tracking tools can improve the clinical management of the patients and, if so, by how much, for how many, and for whom; in addition, it must be determined whether tracking therapeutic cells in every patient is needed. To become clinically relevant, it must now be demonstrated how cell tracking techniques can inform patient treatment and affect clinical outcomes., (© RSNA, 2018.)

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.

To encourage and maximise the use of human biological material in Europe, the European Commission instigated a main Directive in 2004 (Directive 2004/23/EC), four technical ones in 2006 (Commission Directives 2006/17/EC and 2006/86/EC) and in 2015 (Commission Directives (EU) 2015/565 and (EU) 2015/566). They encourage the donation of tissues and cells for transplant purposes in the safeguard of public health. Another major aim of Directive 2004/23/EC is to guarantee recipients' safety in transplantation. Hence, measures for accreditation of establishments storing, preparing and distributing tissues and cells are required to be implemented in Members States' jurisdictions. In addition, adequate training is required for the personnel directly involved in such activities. Despite the adoption of a ?full legislation,? the EU legal framework for cells cannot be seen as totally harmonized. In this article we first address the issues posed at the European level by the uses of human cells as therapeutic agent with regards to their qualification: body elements? Medicinal product? We study the ways to address these bioethical dilemmas at an EU level. Then we discuss the impact of this qualification in terms of safety through the definition of safety's measures and their limits regarding the directive's scope. We conclude with the emergence of an ?ethical safety?.

CD4 + CD25 high FoxP3 + T regulatory cells (Tregs) are immunodominant suppressors in the immune system. Tregs use various mechanisms to control immune responses. Preclinical data from animal models have confirmed the huge therapeutic potential of Tregs in many immune-mediated diseases. Hence, these cells are now on the road to translation to cell therapy in the clinic as the first clinical trials are accomplished. To date, clinical research has involved mainly hematopoietic stem cell transplantations, solid organ transplantations, and autoimmunity. Despite difficulties with legislation and technical issues, treatment is constantly evolving and may soon represent a valid alternative for patients with diseases that are currently incurable. This review focuses on the basic and clinical experience with Tregs with adoptive transfer of these cells, primarily from clinical trials, as well as on perspectives on clinical use and technical problems with implementing the therapy.

Introduction: Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation and organ transplantation are well-established treatments for different conditions. Graft versus host disease (GvHD) is a major complication in both methods. There has been a rapid increase in the application of nonhematopoietic somatic cells, such as mesenchymal stem cells and regulatory T cells in GvHD experimental therapy. According to current European Union (EU) law, human cells intended for human application can be considered either as cell grafts or as advanced therapy medicinal products (ATMPs)., Objective, Materials and Methods: The aim of the paper is an attempt to answer, based on GvHD experimental treatment data as well as existing EU and Polish law, whether cells cease to be cells (cell grafts) and becomes drugs (ATMPs); if yes, when; and what are the consequences of such situation both for patients as well as for physicians engaged in the treatment process in Poland., Results and Discussion: Data analysis confirmed the interest in the experimental GvHD cell therapy. In the vast majority of analyzed cases the in vitro culture step in the cell preparation protocols has been foreseen. Therefore, the answer to title question was unambiguous-expanded cells are recognized in EU as ATMPs. In borderline cases, a scientific recommendation by the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) can play an important auxiliary role; however, it is currently neither required by Polish law nor legally binding in Poland., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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.)

The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on "placing on the market of ATMPs," which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation.

The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials.

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.

Use of cellular products for therapeutic purposes has predominantly been unregulated in Australia until recently. Transplant of haemopoietic progenitor cells (HPC) for bone marrow regeneration is now a routine treatment for many disorders with an established mechanism of facility accreditation. However, other cellular therapies do not have any form of accreditation, are not well evaluated and may be associated with significant risks. On 31 May 2011 the Therapeutic Goods Administration (TGA) implemented a long heralded regulatory biologicals framework for cell and tissue based therapies. The framework currently excludes human HPC, organs for direct transplantation and reproductive materials which are already covered by various forms of existing peer review and accreditation. This new framework is a practical approach for applying regulation based on the risk of the product to the recipient with four classes of product. Class 1 is reserved for the least regulated products and currently does not contain any proposed products. Class 2 will be for minimally manipulated products which will only require manufacturing compliance and evaluation against product and other mandatory standards before entry onto the Australian Register of Therapeutic Goods (ARTG). Class 3 and 4 products will be more than minimally manipulated and these cells and tissues may be used in a non-homologous manner. Class 3 and 4 products will represent a spectrum of risk where Class 4 therapies will represent the highest potential risk to the recipient, with the same requirements for Class 2 approvals but with additional requirements for comprehensive evaluation of a dossier for quality, safety and efficacy of the product. The extent of this quality, safety and efficacy data will depend upon the nature of the product and its associated risks, but will be more comprehensive for Class 4 as opposed to Class 3 products. The only truly contentious feature of this framework is the extremely high cost for dossier evaluation and the puzzling absence of an orphan drug scheme for biologicals.

The European Union has a public health strategy and will generally ensure in all its policies and activities a "high level of human health protection". The new Regulation (EC) n 1394/2007 on advanced therapy medicinal products (ATMP), stems from this global policy and aims to harmonise access to the ATMP market. A real will for the harmonisation is clearly expressed in legal texts and enforced in the implementable procedures and requirements. However, several barriers remain. On the one hand, the scope of the ATMP Regulation is limited. On the other hand, Member States benefit from a wide margin of action.

The recent scientific development using stem or other differentiated cells has generated great hopes for treatment of various diseases. Major thrust has been given to formulate country specific laws and regulations considering international guidelines to conduct research and clinical applications of "Cell Based Therapy" (CBT) all over the world. Attempts have made in this review to discuss the current policies that are practiced by various countries in the areas related to CBT with special emphasis on CBT related research and development in India. The two major funding agencies of Government of India e.g. Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR), have jointly formulated the "Guidelines for Stem Cell Research and Therapy" in 2007 which requires update and revision. Based on the review of the current world scenario of CBT research and development, suggestions have been made for the development of a new CBT policy that will help in progress of research and patient treatment in India.

To be able to produce advanced therapy medicinal products, compliance with regulatory standards while maintaining flexibility is mandatory. For this purpose, careful planning is vital in the design or upgrade of a facility. Similarly, extensive foresight is elemental to anticipate upcoming needs and requirements. Failing this may lead to the facility's in-ability to meet the demands. In this chapter we aimed to outline the current issues with regards to the European Union Directives (EUD) and the proposal for Advanced Therapies, which are of importance to cellular and gene therapy facilities in Europe. This chapter is an attempt to elucidate what the minimum requirements for GMP facilities for cell and gene therapy products are and what is considered necessary to comply with the regulations in Europe.

Virus safety of advanced therapy medicinal products is a particular challenge. These products may consist of whole cells and the manufacture of these is performed using various human or animal-derived starting materials and reagents. Therefore, extensive testing of donors and of established cell banks is required. Furthermore, the virus safety of reagents such as bovine sera, porcine trypsin, and growth factors needs to be considered. Whenever possible, manufacturing steps for inactivation or removal of viruses should be introduced. However, it is not possible to introduce such steps for cell-based medicinal products as the activity and viability of cells will be compromised. Only in the production of small and stable non-enveloped viral gene vectors is it conceivable to implement steps to selectively inactivate or remove potential contaminating enveloped viruses.

On 15 December 2005, the European Medicines Agency (EMEA) launched an "SME Office" to provide financial and administrative assistance to micro-, small- and medium-sized enterprises (SMEs), with the aim of promoting innovation and the development of new human and veterinary medicinal products by SMEs. According to current EU definition of an SME, companies with fewer than 250 employees, and an annual turnover of not more than 50 million euro or an annual balance sheet total of not more than 43 million euro, are eligible for assistance from the SME Office. Incentives available from the EMEA for SMEs, include: Administrative and procedural assistance from SME Office within the Agency; Fee reductions (90%) for scientific advice and inspections; Fee exemptions for certain administrative services (excluding parallel distribution); Deferral of the fee payable for an application for marketing authorisation or related inspection until after the grant of the marketing authorisation; Conditional fee exemption where scientific advice followed and marketing application is unsuccessful; Assistance with translations of the product information documents. At the end of May 2009, more than 380 companies from 21 countries across the European Economic Area (EEA) had SME status assigned by the EMEA. The large majority of companies are developing medicinal products for human use, 16 are veterinary companies, 15 companies are developing products for both human and veterinary use and 38 are regulatory consultants. Since the SME initiative started the Agency has processed more than 130 requests for scientific advice with fee reductions totalling of 6.9 million euro. Regulatory assistance has been provided to more than 170 companies and 12 companies have benefited from the SME translation service. Stakeholders have acknowledged the significant role the SME Office now plays as a service provider. In the period between January 2006 and June 2009, 34 applications for marketing authorization from SME applicants were filed for medicinal products for human use. Current analysis shows SMEs to have a lower success rate compared to non-SME companies. Major objections for SMEs are particularly high in the area of quality. Although the SME initiative is still at an early stage, it is apparent from the experience gained with applications for marketing authorisation to date that it is important for companies to open up an early dialogue with the EMEA. Scientific advice should be sought early, proactively and comprehensively on key issues in development (quality, non-clinical, clinical) and follow-up advice should be sought as development proceeds. For advanced therapy medicinal products, the assistance available to SMEs will be reinforced in 2009, with the introduction of the certification process.

Maturity and applicability of a distinct field of science can be estimated, using a review of current filing statistics of patent applications. Therefore, hereby a search based on international classifications has been directed to the world intellectual property organization (WIPO) to determine the amount and content of patent applications related to the field of cell microencapsulation. The search was evaluated with regard to the distinct indications envisaged and an evaluation of possible technology gaps for fostering further progress was conducted.

The Regulation on Advanced Therapies (Regulation (EC) 1394/2007) establishes a new scientific committee, the Committee for Advanced Therapies (CAT), at the European Medicines Agency. The CAT is composed of experts in the field of Advanced Therapy Medicinal Products (ATMPs)--gene and cell therapy and tissue engineered products--and is responsible for the evaluation of the marketing authorisation applications for this novel class of products. The CAT is also involved in all scientific advice on ATMPs and in two new regulatory procedures for ATMPs, the classification and the certification procedures. The CAT will also play a key role in early contacts with developers of ATMPs.

The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

Many gene therapy medicinal products and also some vaccines consist of, or contain, genetically modified organisms (GMOs), which require specific consideration in the environmental risk assessment (ERA) before marketing authorisation or clinical trial applications. The ERA is performed in order to identify the potential risks for public health and the environment, which may arise due to the clinical use of these medicinal products. If such environmental risks are identified and considered as not acceptable, the ERA should go on to propose appropriate risk management strategies capable to reduce these risks. This article will provide an overview of the legal basis and requirements for the ERA of GMO-containing medicinal products in the context of marketing authorisation in the EU and clinical trials in Germany. Furthermore, the scientific principles and methodology that generally need to be followed when preparing an ERA for GMOs are discussed.

Advanced therapy medicinal products consist of gene therapy, somatic cell therapy and tissue engineered products. Due to their specific manufacturing process and mode of action these products require specially tailored legislation. With Regulation (EC) No. 1394/2007, these needs have been met. Definitions of gene therapy, somatic cell therapy and tissue engineered products were laid down. A new committee, the Committee for Advanced Therapies, was founded, special procedures such as the certification procedure for small- and medium-sized enterprises were established and the technical requirements for Marketing Authorisation Applications (quality, non-clinical and clinical) were revised.

Advanced therapy medicinal products (ATMPs) are an innovative treatment option. To promote timely access of the innovative medicinal product and to safeguard public health, new elements have been introduced into legislation. A key element of the ATMP regulation is the requirement for long-term follow-up on safety and efficacy of patients enrolled in clinical trials with ATMPs, which is beyond the routine requirements on pharmacovigilance. For gene therapy medicinal products, a guideline on long-term follow-up, which lays down the technical requirements, is available. A further key element of the ATMP regulation is the traceability of the starting materials used to manufacture the ATMP. A common European coding system is imperative to ensure the traceability of starting materials, especially across the borders of European Member States.

Today, sterility of parenteral drugs is practically guaranteed. Well-defined procedures in the pharmaceutical industry enable effective protection against contamination by bacteria and fungi. In contrast, problems regarding microbial safety of advanced therapy medicinal products (ATMPs), especially of cell therapeutics, are at best only partially solved. The latter should be understood as a challenge for manufacturers, regulators, and physicians. Many of the manufacturing principles mentioned above are not applicable in production of cell therapeutics. Sterility of source materials cannot be guaranteed and the hitherto known procedures for sterilization are, as a rule, not feasible. Thus, the sterility of the final product cannot be guaranteed. Considering the extremely short shelf life of many cell therapeutics, sometimes only a few hours, the results from established methods for sterility testing are often available too late. Furthermore, the sterility of a test sample does not indicate sterility of the whole product. In most cases, conventional methods for pyrogen testing are not applicable for ATMPs. This paper demonstrates relevant limitations regarding microbial safety and pyrogenicity. Possibilities to overcome these problems are discussed and some novel solutions are proposed.

Regulation (EC) No. 1394/2007 has created a new legal framework for advanced therapy medicinal products (gene therapy medicinal products, somatic cell therapy medicinal products and tissue engineered products). The Regulation is directly applicable in the Member States of the European Union and, in principle, requires no incorporation into national law. However, the amendment of Directive 2001/83/EC, which results from Regulation (EC) No. 1394/2007, has created a need for incorporation into and amendment of the German Medicinal Products Act. This is one of the objectives of the 15th amendment of the German Medicinal Products Act. In particular, the definition "advanced therapy medicinal products" and the special provisions for advanced therapy medicinal products prepared on a non-routine basis, which are based on the special provisions contained in Art. 28 No. 2 of Regulation (EC) No. 1394/2007, are to be incorporated into the German Medicinal Products Act. These special provisions will be explained in detail.

For advanced therapies, the same basic principles for assessment apply as for any other biotechnological medicinal product. Nevertheless, the extent of data for quality, safety, and efficacy can be highly specific. Until recently, advanced therapies were not uniformly regulated across Europe, e.g., tissue engineered products were regulated either as medicinal products or medical devices. Thus, for some products no data from clinical studies are available, e.g., for autologous chondrocyte products. The draft guideline on Good Clinical Practice for clinical trials with advanced therapies describes specific additional requirements, e.g., ensuring traceability. Most clinical studies with advanced therapies in Germany are still in early phase I or II trials with highly divergent types of products and clinical indications. The Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMEA) has been established to meet the scientific and regulatory challenges with advanced therapies.

Purpose of Review: This article reviews recent literature on regulatory issues of xenotransplantation, focusing primarily on current progress with transplantation of pancreatic islets for diabetic patients. The need for a global system that connects the national and international regulatory levels within a coherent framework is emphasized., Recent Findings: Recent progress in preclinical xenotransplantation of pancreatic islets has enhanced the hopes of providing patients with safe and effective treatments from animal cells and tissues in the near future. At the same time the increasing number of clinical trials proposed and sometimes authorized calls for attention from regulatory authorities., Summary: Although the main regulatory aspects of xenotransplantation have been identified since the early 1990s, regulatory problems connected to the promising scientific data published in the field of pancreatic islets still require attention. In fact most normative issues, such as criteria for patients' enrollment in clinical trials and the management of safety measures have been primarily explored in relation to solid organ transplantation. Also the issue of animal rights has become more compelling in relation to the treatment of nonhuman primates in preclinical trials. In these rapidly evolving conditions the establishment of agreed guidelines at both the national and international levels remains the most urgent goal to be achieved.

The author analyses the implications of cell therapy from a legal study that regulates the use of embryonic material: the regulation of the obtaining of cells, of research with embryos and their research and therapeutic use. There is a detailed look at the provisions in the Convention on Human Rights and Biomedicine of the Council of Europe and concludes that "therapeutic cloning" is not prohibited in our legal regulation.

This paper attempts to delineate the main tenets of Spanish interpretation of the Tissue Directive, which, arguably, constitute the "ideal" model traced by the Directive. The different ways in which ideals of altruism and solidarity have played out in the implementation or translation of the Directive are underlined. But it also highlights the difficulties and conflicts that the application of this pattern has already revealed, as for example, in the governance of private cord blood banking and oocyte donation.

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 transplantation of allogenic tissue (bone, cartilage, tendon, skin, amnion and special preparations such as demineralised bone matrix and acellular dermis) is an important component of the treatment of bone and soft tissue defects, particularly in traumatology and orthopaedic, reconstructive and plastic surgery. In Germany, the requirement for such tissue transplants is met by supply from local tissue banks (in particular bone banks) and a small number of regional and national tissue banks. These banks operate on the basis of the "Guidelines for Bone Banks" laid down by the German Chamber of Physicians, and of the German Drug Law (AMG). The 2004/23/EG guidelines issued by the European Parliament and ratified on 31/3/2004 define the quality and safety standards for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. These guidelines will have a major impact on all aspects of tissue banking and transplantation. In particular, the new guidelines will remove the possibility for local tissue banks to operate outside of national drug laws ( section sign 4 a [4]). The currently in draft law on "Quality and Safety of Human Tissues and Cells" ("Tissue Law") of the Federal Health Ministry seems to be heading in this direction, but it also includes possibilities for the continuation of local banks. An additional European guideline draft "Proposal for the regulation of advanced therapeutic medical products" is currently under discussion. This paper assesses the impact of these new pieces of legislation on the quality, safety and availability of human cell and tissue transplants in terms of the current situation and future prospects in Germany.

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.

This article describes the new Law on the removal, storage and transplantation of cells, tissues and organs of July 1, 2005, which entered into force on January 1, 2006.

Although therapeutics derived from biological sources have been subjected to regulatory oversight for some time, the products used in transplantation procedures have historically been exempt from this oversight. These products have been viewed as being part of medical practice rather than as the result of mainstream pharmaceutical manufacture. Furthermore, their unique source makes them difficult to assess in traditional regulatory systems based on the tenets of pharmaceutical quality control. With the increasing use of transplantation therapies to both replace dysfunctional organs and to influence genetic and metabolic processes, public health concerns on these therapies have increased. In addition, it is recognized that therapeutic claims for some of these interventions need to be properly assessed. These considerations have led the established regulatory agencies of the developed world to develop new regulatory paradigms for the products of transplantation practice. While a number of concerns have driven these developments, the minimization of infectious disease risk remains the paramount driver for introducing these regulatory systems. More than the regulation of medicines and medical devices manufactured in traditional pharmaceutical modes, the regulation of cell and tissue products is intimately linked to areas of public health policy and funding. This places regulators in a challenging position as they attempt to reconcile their roles as independent assessors with the needs of the overall public health framework. This is particularly difficult when considering measures which may affect access to life saving therapies. Regulators have recognized the need to assess these therapies through systems which incorporate consideration of risk-benefit ratios and include mechanisms for transparent and accountable release of products when full compliance to traditional concepts of manufacturing practice is not possible.