Somatic Cell Therapy Medicinal Products Research Articles

Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004-2022): Experience and Challenges for the Future.

Clinical investigation is the basis for establishing how useful advanced therapy investigational medicinal products (ATiMP) are for the treatment of serious diseases.In Spain, clinical trials (CT) on ATiMP need to follow the general European legislation on CT with medicinal products plus some specific legislation and guidance depending on the type of ATiMP.This chapter describes the characteristics of CT on ATiMP authorized in Spain in the period 2004-2022 and the legislation applicable along this period. There are clear differences in the clinical trials conducted by non commercial and commercial sponsors: the first have been more involved in CT on somatic cell therapy medicinal products (sCTMP) and tissue-engineered products (TEP), while the second drive more the CT on gene therapy medicinal products (GTMP) in the last years. Difficulties of budget and resources especially by non-commercial sponsors to meet the regulatory requirements are highlighted. The importance of complying with transparency rules with respect to CT on ATiMP is also discussed.

Treatment of Inherited Retinal Dystrophies with Somatic Cell Therapy Medicinal Product: A Review.

Inherited retinal dystrophies and retinal degenerations related to more common diseases (i.e., age-related macular dystrophy) are a major issue and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and the possibilities raised by gene-editing techniques opened a new era for clinicians and patients due to feasible possibilities of treating disabling diseases and the reduction in their complications burden. The scope of this review is to focus on the state-of-the-art in somatic cell therapy medicinal products as the basis of new insights and possibilities to use this approach to treat rare eye diseases.

Advanced therapy medicinal products: Regulatory framework, hospital and pharmaceutical circuits in Europe and France

Advanced therapy medicinal products (ATMPs) represent a new class of biological medicines. The European regulation has classified ATMPs into three categories: gene therapy medicinal products, somatic cell therapy medicinal products, and Tissue-Engineered products. If one of these categories incorporates a medical device, the medicine is defined as a Combined ATMP. The specificity and complexity of these innovative drugs have required a complete reorganization of hospital and pharmaceutical circuits, from patient eligibility to drug administration. Indeed, increased interaction and collaboration between different healthcare professionals are essential in order to guarantee quality and safety of these innovative medicines.

Novel cell-based therapies in inflammatory bowel diseases: the established concept, promising results.

Inflammatory bowel diseases (IBDs) are chronic and relapsing disorders that affect the quality of life in many individuals around the world. Over the past few years, the prevalence of IBDs is substantially rising which might pose a considerable social and economic burden on health systems. Progresses in the management of chronic inflammatory diseases lead to prolonged remission phase and decreased hospitalization rate. However, during treatment, many patients become refractory to conventional therapies. Recently, advanced approaches using somatic cell therapy medicinal products (SCTMPs) including immune and stem cell-based therapies have drawn many researchers’ attentions. Promising results from recent trials, alongside with the emerging market indicated that these therapeutic approaches could be an alternative and promising treatment to conventional therapies. In this review, we will discuss recent advances in cell-based therapies, which have been developed for treatment of IBDs. In addition, the global emerging market and the novel products in this field are highlighted.

Advanced Therapy Medicinal Products for the Eye: Definitions and Regulatory Framework.

Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous three categories combined with one or more medical devices. During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that today have no cure or are just subjected to symptomatic treatments. Therefore, it is important for all professionals working in this field to be familiar with the regulatory principles associated with these types of innovative products. In this review, we outline the legal framework that regulates the development of ATMPs in the European Union and other international jurisdictions, and the criteria that each type of ATMP must meet to be classified as such. To illustrate each legal definition, ATMPs that have already completed the research and development stages and that are currently used for the treatment of eye diseases are presented as examples.

Challenges for Cell-Based Medicinal Products From aPharmaceutical Product Perspective.

Advanced therapy medicinal products (ATMPs), such as somatic cell-therapy medicinal products or tissue-engineered products for human use, offer new and potentially curative opportunities to treat yet untreatable diseases or disorders. For cell-therapy medicinal products (CBMPs), multiple stability and quality challenges exist and relate to the cellular composition and unstable nature of these parenteral preparations. It is the aim of this review to discuss open questions and problems associated with the development, manufacturing and testing of CBMPs from a pharmaceutical drug product perspective. This includes safety, storage and handling, particulates, the choice of container closure systems and integrity. Analytical methods commonly used to evaluate the quality of the final CBMP to ensure patient's safety will be discussed. Particulate contamination in final products deserve special attention since CBMPs cannot be sterile filtered. Visible and sub-visible particles may represent environmental contaminations or may form during storage. They may be introduced from processing materials such as single use product contact materials, ancillary materials, or any components such as primary packaging used for the final product. Currently available analytical methods for detecting particulates may not be easily applicable to CBMPs due to their inherent particulate nature and appearance.

Characterizations of molecularly distinct subpopulations of conditioned medium derived extracellular vesicles prior to be used as medicinal product

Background & Aim Somatic cell therapy medicinal products is the largest group of advanced therapy medicinal products used in clinical trials which also resulted in routinely production of huge amount of conditioned medium. With its capacity to be used as therapeutics agents, cell-conditioned medium derived extracellular vesicles (EVs) play an explosive role in the realm of regenerative medicine or pharmaceutical science. However, the heterogeneity of EVs usually resolved by isolation of different sub-populations has sparked a heated debate. The introduction of quantifiable features assessed by reproducible and standardized assays is necessary to render EVs potentially promising options to be used as “commercial off-the-shelf product”. Methods, Results & Conclusion Therefore, in this report, following the isolation of EVs by different methods (ultracentrifuge, sucrose gradient, and 20,000g centrifugation only), we confirmed that all of them met MISEV2018 criteria (size, morphology, and presence of 3 positive markers and absence of 1 negative marker). Further assessments have been done to find out the purity (based on albumin contaminant), vesicular membrane perfectness (phosphatidylserine exposure), lipid content as well as their functions in in-vitro tests (cellular uptake and proliferation) and ex-vivo test of angiogenesis. Large scale proteome analysis of EVs sub-populations has also provided us with some important clues to choose between tests and functions. In conclusion, we demonstrate that molecularly distinct EV subpopulations can be evaluated by quantifiable methods. Further assessments to correlate some functions to each subpopulation prior to designing clinical trials can accelerate the development of EV-based therapeutics.

Médicaments de thérapie innovante : réglementation et applications cliniques

The European regulation introduced in 2007 a new class of biological products, named “Advanced Therapy Medicinal Products” (ATMPs) in order to clarify and harmonize the authorization rules of these products in Europe as well as to facilitate their availability for the patients. ATMPs include somatic cell therapy and gene therapy medicinal products, products derived from cellular and tissue engineering, possibly combined with medical devices. The classification of tissue or cell-based therapeutic approaches as medicinal products introduces specific legislation concerning their development and clinical trials, manufacture and marketing authorization. Most of the ATMPs come from the progress made in recent years in biotechnology and also in the knowledge of stem cell biology. The clinical applications are numerous, mainly in hematology and oncology, but also in the field of regenerative medicine.

Advanced therapies push regulatory boundaries: Novel therapeutic approaches require more regulatory flexibility and transparency.

The regulation of new medical applications has always been lagging behind the science that enabled these therapies in the first place, but emerging therapeutic approaches are pushing the boundaries harder than ever. Although fundamental principles around safety, efficacy and quality are cast in stone, new interpretations and greater flexibility are required for the clinical use of advanced medicines and treatments without introducing unacceptable risks. There are also ethical considerations that, although not new, are amplified by the potential of emerging therapies to address previously untreatable conditions. All major regulatory bodies, such as the US Food and Drug Administration (FDA) and the European Medical Agency (EMA), have for some years been aware of the challenges posed in particular by Advanced Therapy Medicinal Products (ATMPs). These roughly include three categories: gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (SCTMPs) and tissue‐engineered products (TEPs), many of which have emerged from the “omics” revolution and stem cell research. > All major regulatory bodies […] have for some years been aware of the challenges posed in particular by Advanced Therapy Medicinal Products ### Advanced Therapy Medicinal Products Both GTMPs and SCTMPs involve ex vivo manipulation of cells, but with a crucial difference in terms of manufacture and function. GTMPs deliver recombinant DNA to specific target cells in the body, whereas SCTMPs are whole cells or tissues genetically manipulated to change their biological characteristics or functions for preventing, diagnosing or treating disease. These cells can be autologous, coming from the patient, allogeneic from another human being or xenogeneic from animals. One recent example of GMTP is recombinant viral vaccines against cancer engineered from an immunogenic virus particle to express tumour antigens, cytokines or both [1]. SCTMPs were the first AMPs to be tested clinically in 1997 for corneal epithelial stem cell transplantation. Since then, the technique has been …

Specific requirements for somatic cell therapy medicinal products and tissue engineered products

Advanced-therapymedicinal products (ATMPs) are medicines for human use that are based on genes (gene therapy), cells (somatic-cell therapy) or tissues (tissue engineering) and include autologous, allogeneic, or xenogenic origin products. They are new therapeutic strategies and their development will contribute to providing opportunities for some diseases that so far lack effective treatments. The main objective of the pharmaceutical industry is to introduce on the market effective medications that increase hope and quality of life of the population, not to mention the safety criteria. To do this, it is important to know well the existing advanced therapies regulation allowing you to more easily perform the translation of basic research carried out in research laboratories and that decision making is quality. Definitions from a point of view regulatory of these medications are in the Regulation (EC) N◦ 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy (Chapter 1, article 2) drugs and the Directive 2001/83/CE of the European Parliament and of the Council of 6 November 2001 by establishing a community relating to medicinal products for human use code (annex I part IV, according to its last modification).

Creating Conditions for the Success of The French Industrial Advanced Therapy Sector

Although the European Union merely followed the initiatives of the United States and Japan by introducing special regimes for orphan medicinal products, it has introduced a special status for a new category of biological medicinal products, advanced therapy medicinal products (ATMPs), adopting specific associated regulations. European Regulation (which constitutes the highest legal instrument in the hierarchy of European law texts) [EC] No. 1394/2007, published in 2007, uses this term to define somatic cell therapy medicinal products, tissue-engineered products, and gene therapy medicinal products, possibly combined with medical devices. The stated objective was two-fold: both to promote their industrialization and market access, while guaranteeing a high level of health protection for patients. Since publication of the regulation, few marketing authorizations have been granted in Europe, and these have not been accompanied by commercial success. However, certain recent studies show that this is a growing sector and that France remains the leading European nation in terms of clinical trials. This round table brought together a panel of representatives of French public and private protagonists from the advanced therapy sector. The discussions focused on the conditions to ensure the success of translational research and, more generally, the French advanced therapy sector. These enabled a number of obstacles to be identified, which once lifted, by means of recommendations, would facilitate the development and success of this sector.

THE PROBLEMATIC ASPECTS OF THE HOSPITAL EXEMPTION REGULATION FOR ADVANCED THERAPY MEDICINAL PRODUCTS

Advanced therapy medicinal products – new category of biological pharmaceutical products, which covers somatic cell therapy, gene therapy, tissue-engineered products and combined advanced therapy medicinal products. Regulation (EC) No 1394/2007 defined advanced therapy medicinal products and set up special rules for advanced therapy medicinal products intended to be placed on the market in Member States and prepared industrially or manufactured by a method involving an industrial process. The scope of Regulation (EC) No 1394/2007 is not applicable for advanced therapy medicinal products which are prescribed under the exclusive professional responsibility of a medical practitioner, prepared on a non-routine basis according to specific quality standards and used within the same Member State in a hospital, but at the same time it is stressed that Comunity rules related to quality and safety should not be breaked for these products. For this purpose Member States should provide

The Evolution of Nonclinical Regulatory Science: Advanced Therapy Medicinal Products as a Paradigm

Advanced therapy medicinal products (ATMPs) comprise gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (CTMPs), and tissue-engineered products (TEPs). So-called combined ATMPs incorporate one or more medical devices as an integral part of the product. Because of their complexity and innovative nature, ATMPs pose new scientific and regulatory challenges to both developers and regulators.1 Many developers of such products request scientific advice from the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA). We have repeatedly been asked by stakeholders to analyze the scientific advice provided by the CHMP with regard to the identification of common principles that might be useful to share with product developers. Here we comprehensively analyze the scientific advice provided by the CHMP following implementation of the 2009 legislation on ATMPs, in which the Committee for Advanced Therapies (CAT) plays an integral role. This analysis allowed us to conclude that, for these innovative medicines, a classic guideline-based approach is insufficient owing to the complexity of the products. Regulators must employ a more tailored approach that includes principles of risk identification and mitigation. In the current analysis, we focus on the translational aspects of ATMPs (i.e., nonclinical issues) because these are a direct measure of developmental complexity of innovative treatments and often constitute a bottleneck for ATMP development. ATMPs are pharmaceuticals with a high level of complexity linked to their composition, development, manufacturing, characterization, and administration. Such products can serve as a paradigm for any innovative medicinal product or personalized medicine because of their high specificity, particularly with regard to how regulators provide guidance to accommodate the needs of stakeholders. The current regulatory framework was fully implemented in the European Community in 2009.2 Central to this regulatory framework for ATMPs was the establishment of a multidisciplinary expert scientific committee, the CAT, which is tightly integrated into the EMA procedure for CHMP scientific advice. In addition to the well-established procedures for the EMA's scientific advice and protocol assistance,3,4 classification and certification procedures have been established5,6,7,8 to facilitate discussions with developers. The CAT has published several guidelines for ATMPs to facilitate development of this complex class of therapy.9 However, the broad spectrum of ATMPs with regard to structure and mechanism of action means that such general guidance can be difficult to translate into product-specific requirements. These difficulties can be substantial for sponsors developing ATMPs, considering that the major stakeholders in Europe are academia, charities, and small companies, which often have limited financial resources or regulatory expertise when compared with large pharmaceutical companies.10

The Committee for Advanced Therapies' of the European Medicines Agency Reflection Paper on Management of Clinical Risks Deriving from Insertional Mutagenesis

In the European Union, the Committee for Advanced Therapies of the European Medicines Agency takes the lead in the scientific assessment for marketing authorization applications for advanced therapy medicinal products, which include gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products. The Committee for Advanced Therapies also takes the lead in defining the scientific framework for the quality, nonclinical and clinical development of such products. This reflection paper represents the Committee's current thinking on management of clinical risks deriving from insertional mutagenesis. A multidisciplinary approach to insertional mutagenesis is provided. This reflection paper has been adopted by the committee in its April 2013 meeting.

Clinical Development of Advanced Therapy Medicinal Products in Europe: Evidence That Regulators Must Be Proactive

Advanced therapy medicinal products (ATMPs), defined as gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products, and tissue-engineered products (TEPs),1,2 constitute a major class of innovative therapeutics that are being investigated as treatments for several diseases. Despite the success of many such products in animal studies, few have reached more advanced regulatory milestones in Europe (Figure 1), such as ATMP Certification from the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA),3 regulatory scientific advice from the EMA,4 or a marketing authorization application at the EMA.5 Therefore, there is a need to identify the major stakeholders in the development of such products and to investigate why they have been unable to move these products farther down the development pipeline. As members of the CAT and EMA, we analyzed the data in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database (https://eudract.ema.europa.eu). Analysis of 318 ATMP trials performed between 2004 and 2010 revealed that the main sponsors are academia, charities, and small companies. This may have implications for the further evolution of the regulatory framework for ATMPs given that such stakeholders often have limited financial resources or regulatory expertise, leading to a “translational gap” that must be proactively closed by regulators.

Advanced Therapy Medicinal Products and Exemptions to the Regulation 1394/2007: How Confident Can We be? An Exploratory Analysis

The market authorization procedure for medicinal products for human use is relying on their demonstrated efficacy, safety, and pharmaceutical quality. This applies to all medicinal products whether of chemical or biological origin. Since October 2009, the first advanced therapy medicinal product (ATMP) has been authorized through the centralized procedure. ATMPs are gene therapy medicinal products, somatic cell therapy medicinal products or tissue-engineered products. An appropriate ATMP – Regulation is dealing with ATMP requirements. Two exemptions are foreseen to the ATMP Regulation: (a) Products, which were legally on the Community market when the Regulation became applicable, should comply to the Regulation by December 30, 2012. (b) The hospital exemption rule for non-routine products for an individual patient. In this work we explored whether the actual application of the Regulation on ATMPs is in line with the aim of the Regulation in terms of guaranteeing the highest level of health protection for patients. Based on the analysis of the relative efficacy of the only EC authorized ATMP and its exempted alternatives, there is evidence against this Regulation 1394/2007 assumption.

Challenges with advanced therapy medicinal products and how to meet them

Advanced therapy medicinal products (ATMPs), which include gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products, are at the cutting edge of innovation and offer a major hope for various diseases for which there are limited or no therapeutic options. They have therefore been subject to considerable interest and debate. Following the European regulation on ATMPs, a consolidated regulatory framework for these innovative medicines has recently been established. Central to this framework is the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA), comprising a multidisciplinary scientific expert committee, representing all EU member states and European Free Trade Association countries, as well as patient and medical associations. In this article, the CAT discusses some of the typical issues raised by developers of ATMPs, and highlights the opportunities for such companies and research groups to approach the EMA and the CAT as a regulatory advisor during development.

Gene and Cell Therapy in Germany and the EU

Gene and somatic cell therapy medicinal products as well as tissue engineered products are summarized under the term advanced therapy medicinal products in the EU. The Paul-Ehrlich-Institut has established a specialized division with various sections providing scientific advice and clinical trial authorization to applicants, thereby protecting patients’ health and supporting product development. Gene therapy medicinal products include products suitable for in vivo diagnostics, for the prevention of infectious diseases (such as vaccines) and the treatment of common diseases such as cancer, cardiovascular and infectious diseases, and of rare or orphan diseases such as inherited monogeneic diseases. Clinical trial authorization in Germany is provided by the Paul-Ehrlich-Institut and, if genetically modified organism-containing medicinal products are used, includes deliberate release authorization under consultation with the Federal Office for Consumer Protection and Food Safety (BVL). Firstmarketing authorization applications of gene therapy medicinal products developed for the treatment of cancer have been submitted to the European Medicines Agency (EMEA) and have been or are being reviewed by experts from national medicines agencies. Beneficial gene therapy treatment in clinical trials has been reported for infants suffering from adenosine deaminase deficiency-based severe combined immunodeficiency disease. Human somatic cell therapy medicinal products are mainly being developed for cancer immunotherapy; tissue engineered products contain viable cells able to replace, repair or substitute for human tissues or cells, e.g., after myocardial infarction. Chondrocytes are being used clinically for cartilage repair and an application for EU-wide marketing has been submitted to the EMEA. The main issues for cell-containing medicinal products are cell selection, differentiation, manipulation to obtain specific characteristics and avoiding pre-neoplastic alterations. In summary, special expertise is needed to develop advanced therapy medicinal products and has to be met by scientists specialized in regulatory aspects to support patient safety and product development. Consequently, the EMEA will establish the Committee for Advanced Therapies to review future marketing authorization applications.