Prioritization of high-cost new drugs for HCV: making sustainability ethical.

Hepatitis C virus (HCV) infection is a major health problem worldwide. Chronic HCV infection may in the long run cause cirrhosis, hepatic decompensation and hepatocellular carcinoma, with an ultimate disease burden of at least 350,000 deaths per year worldwide. The new generation of highly effective direct acting antivirals (DAA) to treat HCV infection brings major promises to infected patients in terms of exceedingly high rates of sustained virological response (SVR) but also of tolerability, allowing even the sickest patients to be treated. Even in the face of the excellent safety and efficacy and wide theoretical applicability of these regimens, their introduction is currently facing cost and access issues denying their use to many patients in need. Health systems in all countries are facing a huge problem of distributive justice, since while they should guarantee individual rights, among which the right to health in its broader sense, therefore not limited to healing, but extended to quality of life, they must also grant equal access to the healthcare resources and keep the distribution system sustainable. In the face of a disease with a relatively unpredictable course, where many but not of all chronically infected will eventually die of liver disease, selective allocation of this costly resource is debatable. In most countries the favorite solution has been a stratification of patients for prioritization of treatment, which means allowing Interferon-free DAA treatment only in patients with advanced fibrosis or cirrhosis, while keeping on hold persons with lesser stages of liver disease. In this report, we will perform an ethical assessment addressing the issues linked to access to new therapies, prioritization and eligibility criteria, analyzing the meaning of the term "distributive justice" and the different approaches that can guide us (individualistic libertarianism, social utilitarianism and egalitarianism) on this specific matter. Even if over time the price of new DAA will be reduced through competition and eventual patent expiration, the phenomenon of high drug costs will go on in the next decades and we need adequate tools to face the problems of distributive justice that come with it.

Ethical aspects of Fecal Microbiota Transplantation (FMT).

The importance of human microbiota in preserving human organism healthy is nowadays well acknowledged. The alteration of the microbiota can be the consequence of a persistent use of antibiotics or immunosuppressive medications or abdominal irradiation or surgery, wrong diet, or can be caused by surgery or anatomical condition. These alterations can cause many infections and diseases that today can be treated with Fecal Microbiota Transplantation (FMT), also called Bacteriotherapy, that is the administration of a fecal solution from a donor into the intestinal tract of a recipient. Although to date, FMT appears to be safe and without serious adverse effects, there are some ethical issues that are worthy to be investigated. The aim of this article is to highlight these issues in order to give some notes for a better implementation of this particular clinical practice.

E-recruitment based clinical research: notes for Research Ethics Committees/Institutional Review Boards.

Patient recruitment is a critical point of today's clinical research. Several proposals have been made for improving it, but the effectiveness of these measures is actually uncertain. The use of Internet (e-recruitment) could represent a great chance to improve patient enrolment, even though the effectiveness of this implementation is not so evident. E-recruitment could bring some advantages, such as better interaction between clinical research demand and clinical research supply, time and resources optimization, and reduction of data entry errors. It raises some issues too, such as sampling errors, validity of informed consent, and protection of privacy. Research Ethics Committees/Institutional Review Boards should consider these critical points. The paper deals with Internet recruitment for clinical research. It also attempts to provide Research Ethics Committees/Institutional Review Boards with notes for assessing e-recruitment based clinical protocols.

Research Ethics Committees and clinical research in Italy: where are we going?

Italian Ethics Committees (ECs) have entered a new phase because of the recent Law no. 189 of November 8 2012 and the Ministry of Health Decree of February 8 2013. The new norms have introduced important changes. In fact, ECs are now established not to serve a single hospital or research institution but to serve even Regions. Moreover, they are established on the basis of the number of inhabitants, research sites and expected amount of clinical trials. The implementation of the news norms into practice have produced a drastic reduction in the number of ECs. This fact could raise some issues but it could obtain some benefits. The paper explains the main steps of ECs and clinical research development in Italy. Special attention will be paid to recent trends. Moreover, the new norms will be illustrated, showing possible issues and benefits connected to their implementation.

The ethical and legal implications of nanotechnologies: a preliminary survey to picture the perceptions of law students and medical students.

PURPOSE: The aim of this preliminary survey was to picture the current knowledge and opinions of law students and medical students about nanotechnologies. MATERIALS AND METHODS: Data were collected in June 2012 by interviews with 60 students of the University of Camerino (Macerata, Italy) defined as "jurist population" and 159 medical students of the Università Cattolica del Sacro Cuore (Rome, Italy) defined as "medical population". RESULTS: The Authors found that both law and medical students have some knowledge on what nanotechnologies are; with regards to the ethical issues and risks perception, both categories indicated that nanotechnologies generate bioethical issues. Nevertheless, a high percentage of respondents believed that neither existing technologies nor nanotechnologies pose risks for human health. Opinions on regulation of nanotechnologies are instead different. CONCLUSIONS: These preliminary findings underlined the ambiguity surrounding nanotechnologies both concerning the bioethical dimension and risks perception and their regulation. These early data therefore showed a need of additional reflection on these technologies that should be investigated more in detail; moving from students, future scientists and regulators, these data could contribute to clarify the debate on them.

[Internet use in clinical trials]. / L'uso di Internet nei trial clinici.

Recruiting patients is a critical point of today's clinical research and, along the years, several solutions have been proposed, even if their efficacy seems to be doubtful. On the other hand, nowadays, Internet represents a great opportunity for improving clinical trial recruitments. Nevertheless, on-line recruitment services (e-recruitment) could ensure some advantages (such as facilitating interaction between supply and demand of clinical research, time and money savings/optimizations, data entry errors reduction), but also raise some issues (such as those related to sampling, information, consent, real identity of participants and risks for data breaches). The article debates on the difficulties to recruit patients for clinical research, in general, and e-recruitment particularly, discussing some ethical issues raised by internet enrolment.

The legislation on living organ donation in Western Europe: legal and ethical analysis and impact on clinical practice.

In Europe there are various directives on living organ donation (LOD) that are applied differently in member countries. The objectives of this study were as follows: (1) to identify the most relevant normative differences among the countries of Western Europe, and (2) to evaluate the evolution of LOD data in these countries. We performed comparative analysis of national legislations to identify the most significant common and different regulatory elements that were evaluated subsequently from an ethical-legal point of view. For data analysis on LOD, we used the EULOD database of donations in Europe. Relevant legislative differences emerged among European countries. Through legal and ethical analysis, it has possible to delineate two legal guidelines: on the one hand, based primarily on informed consent applying the principle of individual autonomy, and on the other hand, informed consent associated with legal and medical criteria. From 1992 to 2009, countries with standards based primarily on individual informed consent showed an increase in LOD from 5.5% to 25.3%, which was greater than those in countries that had additional legal requirements, namely, from 1.6% to 16.0.%. The distinct transpositions of the European Directives among singles countries related to LOD are based essentially only on the request for informed consent or for additional medical and legal requirements. The former practices which increases LOD, can facilitate "organ tourism."

Ethical evaluation of risks related to living donor transplantation programs.

The shortage of available cadaveric organs for transplantation and the growing demand has incresed live donation. To increase the number of transplantations from living donors, programs have been implemented to coordinate donations in direct or indirect form (cross-over, paired, and domino chain). Living donors with complex medical conditions are accepted by several transplantation programs. In this way, the number of transplants from living has exceeded that from cadaver donors in several European countries. No mortality has been reported in the case of lung, pancreas, or intestinal Living donations, but the perioperative complications range from 15% to 30% for pancreas and lung donors. In living kidney donors, the perioperative mortality is 3 per 10,000. Their frequency of end-stage renal disease does not exceed the United States rate for the general population. However, long-term follow-up studies of living donors for kidney transplantations have several limitations. The frequency of complications in live donor liver transplantation is 40%, of these, 48% are possibly life-threatening according to the Clavien classification. Residual disability, liver failure, or death has occurred in 1% of cases. The changes in live donor acceptance criteria raise ethical issues, in particular, the physician's role in evaluating and accepting the risks taken by the living donor. Some workers argue to set aside medical paternalism on behalf of the principle of donor autonomy. In this way the medical rule "primum non nocere" is overcome. Transplantation centers should reason beyond the shortage of organs and think in terms of the care for both donor and recipient.

Patient-reported outcomes (PROs): the significance of using humanistic measures in clinical trial and clinical practice.

Patient-reported outcome (PRO) is an "umbrella term" that covers a whole range of potential types of measurement but it is used specifically to refer to all measures quantifying the state of health through the evaluation of outcomes reported by the patient himself/herself. PROs are increasingly seen as complementary to biomedical measures and they are being incorporated more frequently into clinical trials and clinical practice. After considering the cultural background of PROs - that is the well known patient-centered model of medicine -, their historical profile (since 1914, the year of the first outcome measure) and typologies, the paper aims at debating their methodological complexity and implementation into practice. Some clinical trials and therapeutic managements utilizing patient-centered measures will be also analyzed.

[Patient-reported outcomes (PRO): historical profile, definitions, classifications and problems]. / Patient-reported outcomes (PRO): profilo storico, definizioni, classificazioni e criticità.

This contribution deals with the use, within healthcare systems, of patient-reported outcomes (PROs), i.e., all measures aimed at quantifying the state of health through the evaluation of outcomes reported by the patient himself. A survey of their cultural background, identified in the patient-centered model of medicine, is followed by a delineation of their historical profile (from 1914, the year of the first outcome measure, to the more recent examples of their use in clinical trial and practice), a classification based on the size they wish to detect and the reconstruction of the main lines of debate around their use in health care.