Liver transplantation from active COVID-19 donors: Is it ethically justifiable?

The debate on the opportunity to use organs from donors testing positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in recipients with naïve resolved or active COVID-19 is ongoing. We aim to present the ethical analyses underlying the decision to perform liver transplantation (LT) in selected patients with resolved or active COVID-19 in Italy. We used Jonsen, Siegler, and Winslade's Four-Boxes casuistic method, addressing the four topics considered as constitutive of the essential structure of single clinical cases for their ethical analysis (medical indications, patient preferences, quality of life, and contextual features) to enable decision-making on a case-by-case basis. Based on these topics, we elucidate the meaning and balance among the principles of biomedical ethics. Clinical ethics judgment based on the relation between the risk of acquiring SARS-CoV-2 along with its potentially negative effects and the expected benefits of transplant lead to consider LT as clinically appropriate. Shared decision-making allows the integration of clinical options with the patient's subjective preferences and considerations, enabling a valid informed consent specifically tailored to the patients' individual circumstances. The inclusion of carefully selected SARS-CoV-2 positive donors represents an opportunity to offer lifesaving LT to patients who might otherwise have limited opportunities to receive one. COVID-19 positive donor livers are fairly allocated among equals, and respect for fundamental rights of the individual and the broader community in a context of healthcare rationing is guaranteed.The ethical analysis of the decision to perform LT in selected patients shows that the decision is ethically justifiable.

Italian law n. 219/2017 on consent and advance directives: survey among Ethics Committees on their involvement and possible role.

BACKGROUND: On December 2017 the Italian Parliament approved law n. 219/2017 "Provisions for informed consent and advance directives" regarding challenging legal and bioethical issues related to healthcare decisions and end-of-life choices. The law does not contain an explicit reference to Ethics Committees (ECs), but they could still play a role in implementing the law. METHODS: A questionnaire-based survey was performed among the ECs of the Italian Institute for Research and Care belonging to the Network of neuroscience and neurorehabilitation, with the aim of (1) knowing whether the ECs participated and, if so, how in the process of implementation of law n. 219/2017 in the referring institutes; (2) investigating the point of view of the ECs regarding their possible involvement in the process; (3) exploring the contribution ECs can provide to give effective implementation to the law principles and provisions. RESULTS: Seventeen ECs out of thirty took part in the survey; the characteristics of the responding and non-responding committees are similar, so the responding ECs can be regarded as representative of all ECs in the Network. Nine ECs did not discuss the law in anyway: the main reason for this is that the referring institutions (6) and the health care professionals (3) did not ask for an EC intervention. Nevertheless, the large majority of the ECs believe that their involvement in the implementation of the law as a whole is appropriate (8) or absolutely appropriate (6), while 3 of them are neutral. No EC believes that the involvement is inappropriate. The aspect of the law on which the 14 ECs converge in considering the EC involvement appropriate/absolutely appropriate is the one related to the health facilities obligation to guarantee the full and proper implementation of the principles of the law. CONCLUSIONS: Our survey confirms that ECs believe they can play a role in the implementation of law n. 219/2017, although this does not entirely correspond to what the committees have actually done in reality. This role could be better exercised by ECs specifically established for clinical practice, which would have a composition, functioning and a mandate better suited to the purpose. This supports the call for a national regulation of ECs for clinical practice.

A few ethical issues in translational research for gene and cell therapy.

BACKGROUND: Although translational research for drug development can provide patients with valuable therapeutic resources it is not without risk, especially in the early-phase trials that present the highest degree of uncertainty. With the extraordinary evolution of biomedical technologies, a growing number of innovative products based on human cells and gene therapy are being tested and used as drugs. Their use on humans poses several challenges. METHODS: In this work, we discuss some ethical issues related to gene and cell therapies translational research. We focus on early-phase studies analysing the regulatory approach of Europe and the United States. We report the current recommendations and guidelines of international scientific societies and European and American regulatory authorities. RESULTS: The peculiarity of human cell- or tissue-based products and gene therapy has required the development of specific regulatory tools that must be continually updated in line with the progress of the research. The ethics of translational research for these products also requires further considerations, particularly with respect to the specificity of the associated risk profiles. CONCLUSIONS: An integrated ethical approach that aims for transparency and regulation of development processes, the support of independent judgment in clinical trials and the elimination of unregulated and uncontrolled grey areas of action are necessary to move gene and cell therapy forward.

The Role of Solidarity(-ies) in Rare Diseases Research.

Solidarity plays a relevant role in rare diseases (RDs) research to create and enable research in the field. In Europe RDs are estimated to affect between 27 and 36 million people even though single RDs can count very few patients, making the contribution of everyone essential to reach solid results. Often RD research is initiated by patient groups devoting substantial time and resources to the scientific enterprise. In RD research solidarity is often evocated and expressed, in different ways and on different levels, so that it is possible to talk about "solidarities" played by different stakeholders and sometimes conflicting with each other. In this paper we describe different contexts in which solidarity is expressed and embedded in RD research, in particular the context of tight relationships between individuals and their families or in small communities/ethnic groups; among individuals suffering from different RDs and researchers working on a specific RD or a group of RDs, and within society at large. In all these cases the different types of solidarity should be balanced against each other and also against conflicting values. The request to a patient to share data and samples to increase scientific knowledge on the basis of solidarity values needs to be balanced against the need to protect her privacy and autonomy; the duty for a researcher to allow fair access to RD sample and data collections which were donated in a spirit of solidarity is balanced against the need to be competitive in the research world. In the Report "Solidarity. Reflections on an emerging concept in bioethics", the Nuffield Council of Bioethics defines solidarity as "shared practices reflecting a collective commitment to carry 'costs' (financial, social, emotional or otherwise) to assist others". Therefore, if a solidarity framework has to be solid and ethically sound it needs to be framed as a shared value, reflected in the different practices by all the stakeholders and be based on reciprocity (not one sided). The context of solidarity(ies) provides a solid base for framing the research endeavor as collectively valuable, not only for possible results of the research, but as intrinsic valid societal practice. This paper tries to draw the lessons on solidarity that we can derive from the RD world where "solidarities" have been part of the game for long time and are declined on many different levels.

Bioethics of Clinical Applications of Stem Cells.

The clinical applications of stem cells pose a multitude of problems, including safety, efficacy, information and consent, the right to unproven treatments, the "right to try", costs, access, sustainability, scientific scrupulousness, patents and regulatory aspects, to name but a few. This article does not address individual issues, but rather introduces and discusses some of the possible approaches to solving the problems. The first part compares the consequentialist and deontological approaches, offering an overview of "top-down" and "bottom-up" models and proposing the principles of personalism as applied in clinical settings. The second part of the article suggests practical frameworks for organising the ethical issues, focusing in particular on the medical indications, patient preferences, quality of life, and contextual features.

Trials, Regulation and tribulations.

INTRODUCTION: Regulation EU 536/2014 EU introduces a separation between two parts (technical-scientific aspects and locally relevant ethical aspects) in the assessment of applications for approval of trials and provides for each 'Member State concerned' to arrive at 'one single decision' regarding the application for authorisation to conduct a trial. PROPOSALS: The Regulation should be implemented in such a way as to avoid a separation between scientific assessment and ethical assessment; guarantee the absence of conflicts of interest in the institutions responsible for decision-making; promote efficiency on the part of ethics committees. In particular, (i) it is not appropriate to assess Parts I and II of the application for approval to conduct a trial separately (scientific soundness is the principal requisite for ethical soundness); (ii) conflicts of interest should be avoided, especially as regards links with the national authority responsible for drugs regulation; (iii) decision-making in each state should be the responsibility of a single coordinating ethics committee divided into sections specialising in different therapeutic fields; (iv) local committees affiliated to institutions where trial participants are recruited should be able to interact with the coordinating committee, provide consultation services-including on issues of clinical ethics-and promote training in the field of biomedical ethics.

What is the role of ethics committees after Regulation (EU) 536/2014?

EU Regulation 536/2014 stipulates that when assessing applications for authorisation to conduct clinical trials, Member States should formulate a 'single decision'. This raises the problem of identifying: (1) the facility designated to express this 'single decision' and (2) the role of ethics committees in the decision-making process. The article addresses the consequences of the requirement that for each Member State the assessment of an application for approval to conduct a trial must take the form of a 'single decision' by the Member State concerned. Three possible approaches to the procedures for expressing that 'single decision' and to the role of ethics committees in the decision-making process are described, one of which is indicated as the preferred option.

Research involving subjects with Alzheimer's disease in Italy: the possible role of family members.

BACKGROUND: Alzheimer's disease is a very common, progressive and still incurable disease. Future possibilities for its cure lie in the promotion of research that will increase our knowledge of the disorder's causes and lead to the discovery of effective remedies. Such research will necessarily involve individuals suffering from Alzheimer's disease. This raises the controversial issue of whether patients with Alzheimer's disease are competent to give their consent for research participation. DISCUSSION: We discuss the case of subjects with Alzheimer's disease who may have impaired decision-making capacity and who could be involved in research protocols, taking into consideration aspects of the Italian normative framework, which requires a court-appointed legal representative for patients who are not able to give consent and does not recognise the legal value of advance directives. We show that this normative framework risks preventing individuals with Alzheimer's disease from taking part in research and that a new policy that favours research while promoting respect for patients' well-being and rights needs to be implemented. SUMMARY: We believe that concerns about the difficulty of obtaining fully valid consent of patients with Alzheimer's disease should not prevent them from participating in clinical trials and benefiting from scientific progress. Therefore, we argue that the requirement for patients to have a legal representative may not be the best solution in all countries and clinical situations, and suggest promoting the role of patients' family members in the decision-making process. In addition, we outline the possible role of advance directives and ethics committees.

[A framework for evaluating ethical issues of public health initiatives: practical aspects and theoretical implications]. / Uno strumento per la valutazione delle iniziative di sanità pubblica: aspetti operativi e implicazioni teoriche.

The "Framework for the Ethical Conduct of Public Health Initiatives", developed by Public Health Ontario, is a practical guide for assessing the ethical implications of evidence-generating public health initiatives, whether research or non-research activities, involving people, their biological materials or their personal information. The Framework is useful not only to those responsible for determining the ethical acceptability of an initiative, but also to investigators planning new public health initiatives. It is informed by a theoretical approach that draws on widely shared bioethical principles. Two considerations emerge from both the theoretical framework and its practical application: the line between practice and research is often blurred; public health ethics and biomedical research ethics are based on the same common heritage of values.

A policy for the disposal of autologous hematopoietic progenitor cells: report from an Italian consensus panel.

BACKGROUND: Autologous stem cell transplantation (ASCT) requires collection and cryopreservation of hematopoietic progenitor cells (HPCs), which in turn may be partially or never reinfused. Thus, HPC storage has become a logistic, ethical, and economic issue. SIDEM, GITMO, and CNT/ISS endorsed a project aimed to define national criteria for HPC disposal aimed to guarantee appropriateness and equity. STUDY DESIGN AND METHODS: A multidisciplinary panel was convened including HPC harvest and manipulation experts from apheresis units, hematologists with clinical expertise in ASCT, a representative of the national health authority, and a bioethicist. An analytic hierarchy process (AHP) was carried out to select disposal criteria. RESULTS: The AHP selected two criteria for prompt disposal of freshly collected HPCs: an abnormal freezing procedure causing highly reduced viability or major microbiology contamination. Moreover, AHP selected six major criteria, each one of them allowing for the disposal of stored HPC units: patient death, withdrawal of consent to ASCT, contraindications or loss of indications to ASCT, a damaged label that prevents correct identification of the unit, and time elapsed since harvest longer than 10 years. Three minor criteria were additionally identified that allowed to anticipate disposal only provided that viability levels are below the limit of acceptance: a documented cold chain interruption, loss of bag integrity, and total amount of stored CD34+ cells lower than 1 × 10(6) /kg or lower than 2 × 10(6)/kg in patients with a successfully completed stem cell transplantation program. CONCLUSIONS: A formal consensus process allowed SIDEM and GITMO to propose a policy for autologous HPC disposal that fulfills clinical, ethical, and economic criteria.

[Codes, guidelines and guidance of ethics of research: the issue of quality]. / Codici, linee guida e commentari di etica della ricerca: la questione della qualità

After an overview of the evolution of ethics laws for medical activities, we suggest a possible classification of documents regarding the ethical conduct of scientific research with human beings. The authors outline the necessity to define formal criteria for the development and the implementation of ethics standards.

[Neonatal screening and the right to know: ethical considerations]. / Screening neonatali e "diritto di sapere": alcuni spunti di etica.

Tandem mass spectrometry provides information on numerous metabolites and is widely used for neonatal screening of congenital metabolic disorders. The list of disorders covered by screening programmes in different nations and regions varies, leading to the dilemma of whether parents have an absolute "right to know" information that can be provided by technology but that is not included in the programme implemented by one's country/region. The article discusses some ethical points to consider: the right to know is not absolute, parents are not always the best judges, and it may be in the patient's interest not to provide some of the information.

Registries or non-pharmacological observational studies? An operational attempt to draw the line and to provide some suggestions for the ethical evaluation of rare disease registries.

Originally established to evaluate the ethical aspects of clinical trials, Ethics Committees (ECs) are now requested to review different types of projects, including, among others, observational studies and disease registries. In Italy, clinical trials on medicinal products for human use and on medical devices are regulated by EU Regulation 536/2014, EU Regulation 2017/745, and 2017/746 while pharmacological observational studies are regulated by the Italian Medicines Agency guidelines of 2008 and by Ministerial Decree of November 30th, 2021. The other types of studies are not strictly regulated, causing discrepancies in their definition and assessment by the ECs, and slowdowns in the start of projects. The present contribution aims to propose definitions and distinctions between non-pharmacological observational studies and disease registries, which constitute different entities but are often assimilated by ECs, and to formulate suggestions for the evaluation of rare disease registries, which are an expanding research area of interest.

Ethical issues in umbilical cord blood banking: a comparative analysis of documents from national and international institutions.

The issues of collection, storage, and use of cord blood (CB) stem cells have been addressed extensively in national and international guidelines, policies, and regulations. Many of these documents are not binding, but are nonetheless accorded considerable respect on account of the authority of the issuing organizations. Most discussion has to date focused on two topics: informed consent for collection, banking, and use and the debate between those who favor public storage for altruistic purposes and those who advocate private storage for autologous use. There is generally agreement or consensus in the guidelines that public storage for allogeneic transplants is preferable and that private storage should be discouraged. Given the consensus in national and international guidance on these two issues, it is time for other ethical issues to be examined in greater detail. These include additional uses of CB samples, for example, for research or for the production of blood-derived drugs, and the economic implications arising from the extensive international network for the exchange of CB for transplantation.

An ethical framework for the disposal of autologous stem cells.

The disposal of haematopoietic stem cells stored for autologous transplantation purposes becomes a problem for hospitals when the conditions for their preservation cease to exist. When these cells have been stored for a considerable time the problem often becomes an ethical one involving informed consent and is linked to at least two simultaneous circumstances: (i) the indications regarding disposal contained in available informed consent papers are either absent or too generic; (ii) the person who provided the sample can no longer be traced. This article proposes and discusses some of the ethical criteria for addressing this problem on the basis of the so-called "principles" of North American bioethics, and compares them with some of the principles and values proposed in other models of bioethics.

The ethics of paediatric trials: questions of procedure and of substance.

One of the more frequently debated questions about the ethics of research with children is that of informed consent. This raises a twofold problem: the legally valid consent given by the person or persons exercising parental authority, and the consent of the minor when he or she has adequate decision-making capacity. Another ethically important issue is the weighing of risks and benefits. Any assessment of the benefits will embrace the controversial problem of balancing the direct benefits to the individual and the social benefits to other children in similar medical circumstances deriving from increased knowledge. The highly significant questions of risk and of the advancement of knowledge are often - perhaps too emphatically - taken together with that of consent, as though the existence of legally valid consent and, where possible, the assent of the minor were sufficient to justify exposing a child to serious or probable risks.

Clinical trials with subjects unable to give consent: some ethical-legal paradoxes.

The Italian Data Protection Authority recently authorised a US pharmaceutical company and an Italian hospital to use the personal data of people without capacity to make their own decisions, including those with no legal representation, within the framework of a specific clinical trial although this is not legal under current Italian legislation. This action effectively acknowledged the validity of consent given by persons with family ties to patients, or those in hospitals caring for patients, in contrast with Italian legislation which regards as valid only consent that is given by a legally appointed guardian. This article considers the present state of the regulations governing trials involving incapacitated adults, the paradoxes generated by the discrepancy between the authorisation granted by the Authority and current legislation, and (possible) future developments.