Histological assessment of nanostructured fibrin-agarose skin substitutes grafted in burnt patients. A time-course study.

A previously developed fibrin-agarose skin model-UGRSKIN-showed promising clinical results in severely burnt patients. To determine the histological parameters associated to the biocompatibility and therapeutic effects of this model, we carried out a comprehensive structural and ultrastructural study of UGRSKIN grafted in severely burnt patients after 3 months of follow-up. The grafted epidermis was analogue to native human skin from day 30th onward, revealing well-structured strata with well-differentiated keratinocytes expressing CK5, CK8, CK10, claudin, plakoglobin, filaggrin, and involucrin in a similar way to controls, suggesting that the epidermis was able to mature and differentiate very early. Melanocytes and Langerhans cells were found from day 30th onward, together with a basement membrane, abundant hemidesmosomes and lack of rete ridges. At the dermal layer, we found an interface between the grafted skin and the host tissue at day 30th, which tended to disappear with time. The grafted superficial dermis showed a progressive increase in properly-oriented collagen fibers, elastic fibers and proteoglycans, including decorin, similarly to control dermis at day 60-90th of in vivo follow-up. Blood vessels determined by CD31 and SMA expression were more abundant in grafted skin than controls, whereas lymphatic vessels were more abundant at day 90th. These results contribute to shed light on the histological parameters associated to biocompatibility and therapeutic effect of the UGRSKIN model grafted in patients and demonstrate that the bioengineered skin grafted in patients is able to mature and differentiate very early at the epithelial level and after 60-90 days at the dermal level.

Regulation of advanced therapies in Europe: Are we on the right track?

Sixteen years after regulating advanced therapy medicinal products (ATMPs) in the European Union, few ATMPs have gained marketing authorization. Additionally, market withdrawals for commercial reasons and a lack of reimbursement are de facto blocking patient access. Here, we pinpoint the major factors underlying this roadblock and how to circumvent it.

International Society for Cell & Gene Therapy Position Paper: Key considerations to support evidence-based cell and gene therapies and oppose marketing of unproven products.

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.

Successful restoration of corneal surface integrity with a tissue-engineered allogeneic implant in severe keratitis patients.

OBJECTIVES: Corneal diseases are among the main causes of blindness, with approximately 4.6 and 23 million patients worldwide suffering from bilateral and unilateral corneal blindness, respectively. The standard treatment for severe corneal diseases is corneal transplantation. However, relevant disadvantages, particularly in high-risk conditions, have focused the attention on the search for alternatives. METHODS: We report interim findings of a phase I-II clinical study evaluating the safety and preliminary efficacy of a tissue-engineered corneal substitute composed of a nanostructured fibrin-agarose biocompatible scaffold combined with allogeneic corneal epithelial and stromal cells (NANOULCOR). 5 subjects (5 eyes) suffering from trophic corneal ulcers refractory to conventional treatments, who combined stromal degradation or fibrosis and limbal stem cell deficiency, were included and treated with this allogeneic anterior corneal substitute. RESULTS: The implant completely covered the corneal surface, and ocular surface inflammation decreased following surgery. Only four adverse reactions were registered, and none of them were severe. No detachment, ulcer relapse nor surgical re-interventions were registered after 2 years of follow-up. No signs of graft rejection, local infection or corneal neovascularization were observed either. Efficacy was measured as a significant postoperative improvement in terms of the eye complication grading scales. Anterior segment optical coherence tomography images revealed a more homogeneous and stable ocular surface, with complete scaffold degradation occurring within 3-12 weeks after surgery. CONCLUSIONS: Our findings suggest that the surgical application of this allogeneic anterior human corneal substitute is feasible and safe, showing partial efficacy in the restoration of the corneal surface.

Addressing Risks Derived From the Commodification of Substances of Human Origin: A European Proposal Applicable Worldwide.

In view of the public consultation recently launched by the World Health Organization on Regulatory Convergence of Cell and Gene Therapy Products and the Proposal for a Regulation on substances of human origin (SoHO) repealing the European Union Directives on Blood and on Tissues and Cells, an opportunity arises to define an ethical and transparent framework of collaboration between industry and authorities responsible for SoHO-derived products, comprising medicines, medical devices, transfusion, and transplantation. The commodification of SoHO-derived medicinal products and medical devices entails important risks to the sustainability of healthcare systems and threatens the equitable access of patients to innovative therapies. It may also jeopardize the principle of altruistic donation of SoHO that is required for the treatment and survival of thousands of patients every year. This article puts forward several proposals aimed at reconciling the ethical principles of voluntary and unpaid SoHO donation and the noncommercialization of the human body with obtaining a profit that allows business activities, while ensuring high quality, safety, and efficacy standards of tissues and cells for clinical use.

Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products.

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.

Mesenchymal Stromal Cells for Treating Steroid-Resistant Acute and Chronic Graft Versus Host Disease: A Multicenter Compassionate Use Experience.

Graft versus host disease (GVHD) is a severe complication after allogenic hematopoietic cell transplantation (HSCT). Several clinical trials have reported the use of mesenchymal stromal cells (MSCs) for the treatment of GVHD. In March 2008, the Andalusian Health Care System launched a compassionate use program to treat steroid-resistant GVHD with MSC. Clinical-grade MSC were obtained under GMP conditions. MSC therapy was administered intravenously in four separate doses of 1 × 106 cells/kg. Sixty-two patients, 45 males (7 children) and 17 females (2 children), received the treatment. Patients had a median age of 39 years (range: 7-66) at the time of the allogenic HSCT. The overall response was achieved in 58.7% of patients with acute (a)GVHD. Two years' survival for aGVHD responders was 51.85%. The overall response for patients with chronic (c)GVHD was 65.50% and the 2-year survival rate for responders was 70%. Age at the time of HSCT was the only predictor found to be inversely correlated with survival in aGVHD. Regarding safety, four adverse events were reported, all recovered without sequelae. Thus, analysis of this compassionate use experience shows MSC to be an effective and safe therapeutic option for treating refractory GVHD, resulting in a significant proportion of patients responding to the therapy.

[The regenerative medicine and stem cell business: confusion with legal implications]. / El negocio de la medicina regenerativa y las células madre: confusión con implicaciones legales.

The rise of regenerative medicine and the growth of the offer of autologous therapies, obtained from blood, cells or tissues of the patients, have been favoured by the current availability of an increasing number of commercial devices. Most of these devices are easy to use, allowing the elaboration of products and its application within the same procedure. Regardless of the questionable efficacy and safety of many of the treatments offered under the claim of stem cells or regenerative medicine, most of the centres and professionals offering these treatments are unaware of the legal requirements and implications of their use. A common confusion consists in not distinguishing between the authorization required by the equipment itself, considered a medical device, and the authorization for the use of the product obtained, usually considered a medicinal product (whether advanced therapy or not) or a transplant. Moreover, these treatments frequently have an experimental nature. In that case, in addition to requiring the corresponding ethical evaluation and the authorization of various regulatory bodies, their administration must be offered free of charge, obtaining the patient's informed consent and after contracting a specific insurance policy. In this article we present a brief summary of the main requirements for the application of these autologous biological products with the aim of serving as a guide both for the professionals who prescribe them and for those who inspect the centres where the products are administered. Finally, we include some recommendations for patients.

Promoting the ethical use of safe and effective cell-based products: the Andalusian plan on regenerative medicine.

With regard to regenerative medicine, the expectations generated over the last two decades and the time involved in developing this type of therapies, together with the availability of devices that allow point-of-care treatments through the rapid isolation of cellular or plasma products from patients in the operating theater, represent the perfect breeding ground for the offering of unproven or unregulated therapies on a global scale. A multidisciplinary approach-one based on the collaboration of institutions that, from the perspective of their area of competence, can contribute to reversing this worrying situation-to this problem is essential. It is a priority for local health authorities to take measures that are adapted to the particular situation and regulatory framework of their respective territory. In this article, the authors present the regenerative medicine action plan promoted by the Andalusian Transplant Coordination (i.e., the action plan for the largest region in Spain), highlighting the aspects the authors believe are fundamental to its success. The authors describe, in summary form, the methodology, phases of the plan, actions designed, key collaborators, important milestones achieved and main lessons they have drawn from their experience so that this can serve as an example for other institutions interested in promoting the ethical use of this type of therapy.

Transplant of Tissue-Engineered Artificial Autologous Human Skin in Andalusia: An Example of Coordination and Institutional Collaboration.

A new model of tissue-engineered artificial autologous human skin developed in Andalusia is currently being transplanted into patients suffering from large burns within the Andalusian Public Healthcare System. This product is considered an advanced therapy medicinal product (ATMP) in Europe, and its clinical use implies meeting transplant and medicinal product legal requirements, being the Guidelines of Good Manufacturing Practice for ATMPs of particular importance. The preclinical research and clinical translation of the product have represented a technical, regulatory, and organizational challenge, which has taken 10 years since the first preclinical experiments were designed. Twelve patients with large burns, including 3 pediatric patients, have hitherto received artificial autologous skin grafts with an overall survival rate of 75% and positive clinical, homeostatic, and histologic results. Achieving such a milestone within our Healthcare System was possible through a multidisciplinary approach and the joint efforts of multiple publicly funded institutions and units under the coordination of the Andalusian Initiative for Advanced Therapies. In this article, we present the organizational model set up to facilitate collaboration and logistics among the professionals involved, totaling more than 80 people. The similarities between the tissue-engineered artificial autologous human skin transplant and other organ and tissue transplants, in terms of logistic requirements, reveal how regional and hospital transplant coordination have played a crucial role.

Successful development and clinical translation of a novel anterior lamellar artificial cornea.

Blindness due to corneal diseases is a common pathology affecting up to 23 million individuals worldwide. The tissue-engineered anterior human cornea, which is currently being tested in a Phase I/II clinical trial to treat severe corneal trophic ulcers with preliminary good feasibility and safety results. This bioartificial cornea is based on a nanostructured fibrin-agarose biomaterial containing human allogeneic stromal keratocytes and cornea epithelial cells, mimicking the human native anterior cornea in terms of optical, mechanical, and biological behavior. This product is manufactured as a clinical-grade tissue engineering product, fulfilling European requirements and regulations. The clinical translation process included several phases: an initial in vitro and in vivo preclinical research plan, including preclinical advice from the Spanish Medicines Agency followed by additional preclinical development, the adaptation of the biofabrication protocols to a good manufacturing practice manufacturing process, including all quality controls required, and the design of an advanced therapy clinical trial. The experimental development and successful translation of advanced therapy medicinal products for clinical application has to overcome many obstacles, especially when undertaken by academia or SMEs. We expect that our experience and research strategy may help future researchers to efficiently transfer their preclinical results into the clinical settings.

Randomised, double-blind, placebo-controlled clinical trial for evaluating the efficacy of intracoronary injection of autologous bone marrow mononuclear cells in the improvement of the ventricular function in patients with idiopathic dilated myocardiopathy: a study protocol.

BACKGROUND: Cellular therapies have been increasingly applied to diverse human diseases. Intracoronary infusion of bone marrow-derived mononuclear cells (BMMNC) has demonstrated to improve ventricular function after acute myocardial infarction. However, less information is available about the role of BMMNC therapy for the treatment of dilated myocardiopathies (DCs) of non-ischemic origin. This article presents the methodological description of a study aimed at investigating the efficacy of intracoronary injection of autologous BMMNCs in the improvement of the ventricular function of patients with DC. METHODS: This randomised, placebo-controlled, double-blinded phase IIb clinical trial compares the improvement on ventricular function (measured by the changes on the ejection fraction) of patients receiving the conventional treatment for DC in combination with a single dose of an intracoronary infusion of BMMNCs, with the functional recovery of patients receiving placebo plus conventional treatment. Patients assigned to both treatment groups are monitored for 24 months. This clinical trial is powered enough to detect a change in Left Ventricular Ejection Fraction (LVEF) equal to or greater than 9%, although an interim analysis is planned to re-calculate sample size. DISCUSSION: The study protocol was approved by the Andalusian Coordinating Ethics Committee for Biomedical Research (Comité Coordinador de Ética en Investigación Biomédica de Andalucia), the Spanish Medicines and Medical Devices Agency (Agencia Española de Medicamentos y Productos Sanitarios), and is registered at the EU Clinical Trials Register (EudraCT: 2013-002015-98). The publication of the trial results in scientific journals will be performed in accordance with the applicable regulations and guidelines to clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02033278 (First Posted January 10, 2014): https://clinicaltrials.gov/ct2/show/NCT02033278 ; EudraCT number: 2013-002015-98, EU CT Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002015-98 . Trial results will also be published according to the CONSORT statement at conferences and reported peer-reviewed journals.

Cell, tissue and gene products with marketing authorization in 2018 worldwide.

Cell and gene therapies (CGTs) are progressively entering into clinical practice in different parts of the world. The International Society for Cell & Gene Therapy (ISCT), a global scientific society, has been committed since 1992 to supporting and developing knowledge on clinical applications of CGTs. Considering the number of products that have been progressively approved and, in some cases, withdrawn in recent years, the ISCT would like to present a brief annual report on CGTs with marketing authorization (MA) in different regions. This article reflects the dynamic momentum around authorized CGTs coinciding with the parallel increase of unproven approaches where cells are delivered without appropriate and rigorous scientific and regulatory assessment and authorization. This is intended to be a living document with a yearly update linked to a dedicated section of the ISCT website for faster adjustments. The aim is to ultimately inform, by periodic snapshots, the scientific community, healthcare stakeholders and patient associations on authorized CGT products as a way to increase communication around the approved therapeutic approaches charged with heightened expectations.

Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study.

BACKGROUND: Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. PATIENTS AND METHODS: In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. RESULTS: Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. CONCLUSION: Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.

A study protocol for a multicentre randomised clinical trial evaluating the safety and feasibility of a bioengineered human allogeneic nanostructured anterior cornea in patients with advanced corneal trophic ulcers refractory to conventional treatment.

INTRODUCTION: There is a need to find alternatives to the use of human donor corneas in transplants because of the limited availability of donor organs, the incidence of graft complications, as well as the inability to successfully perform corneal transplant in patients presenting limbal deficiency, neo-vascularized or thin corneas, etc. We have designed a clinical trial to test a nanostructured fibrin-agarose corneal substitute combining allogeneic cells that mimics the anterior human native cornea in terms of optical, mechanical and biological behaviour. METHODS AND ANALYSIS: This is a phase I-II, randomised, controlled, open-label clinical trial, currently ongoing in ten Spanish hospitals, to evaluate the safety and feasibility, as well as clinical efficacy evidence, of this bioengineered human corneal substitute in adults with severe trophic corneal ulcers refractory to conventional treatment, or with sequelae of previous ulcers. In the initial phase of the trial (n=5), patients were sequentially recruited, with a safety period of 45 days, receiving the bioengineered corneal graft. In the second phase of the trial (currently ongoing), subjects are block randomised (2:1) to receive either the corneal graft (n=10), or amniotic membrane (n=5), as the control treatment. Adverse events, implant status, infection signs and induced neovascularization are evaluated as determinants of safety and feasibility of the bioengineered graft (main outcomes). Study endpoints are measured along a follow-up period of 24 months, including 27 post-implant assessment visits according to a decreasing frequency. Intention to treat, and per protocol, and safety analysis will be performed. ETHICS AND DISSEMINATION: The trial protocol received written approval by the corresponding Ethics Committee and the Spanish Regulatory Authority and is currently recruiting subjects. On completion of the trial, manuscripts with the results of phases I and II of the study will be published in a peer-reviewed journal. TRIAL REGISTRATION: CT.gov identifier: NCT01765244 (Jan2013). EudraCT number: 2010-024290-40 (Dec2012).

Cell-based product classification procedure: What can be done differently to improve decisions on borderline products?

In June 2015, European Medicines Agency/Committee for Advanced Therapies (CAT) released the new version of the reflection paper on classification of advanced therapy medicinal products (ATMPs) established to address questions of borderline cases in which classification of a product based on genes, cells or tissues is unclear. The paper shows CAT's understanding of substantial manipulation and essential function(s) criteria that define the legal scope of cell-based medicinal products. This article aims to define the authors' viewpoint on the reflection paper. ATMP classification has intrinsic weaknesses derived from the lack of clarity of the evolving concepts of substantial manipulation and essential function(s) as stated in the EU Regulation, leading to the risk of differing interpretations and misclassification. This might result in the broadening of ATMP scope at the expense of other products such as cell/tissue transplants and blood products, or even putting some present and future clinical practice at risk of being classified as ATMP. Because of the major organizational, economic and regulatory implications of product classification, we advocate for increased interaction between CAT and competent authorities (CAs) for medicines, blood and blood components and tissues and cells or for the creation of working groups including representatives of all parties as recently suggested by several CAs.