On the normativity of evidence - Lessons from philosophy of science and the "VALIDATE" project.

"Evidence" is a key term in medicine and health services research, including Health Technology Assessment (HTA). Randomized clinical trials (RCTs) have undoubtedly dominated the scene of generating evidence for a long period of time, becoming the hallmark of evidence-based medicine (EBM). However, due to a number of misunderstandings, the lay audience and some researchers have sometimes placed too much trust in RCTs compared to other methods of investigation. One of the principal misunderstandings is to consider RCTs findings as isolated and self-apparent pieces of information. In other words, what has been essentially lacking was the awareness of the value-context of the evidence and, in particular, the value- and theory-ladenness (normativity) of scientific knowledge. This paper aims to emphasize the normativity that exists in the production of scientific knowledge, and in particular in the conduct of RCTs as well as in the performance of HTA. The work is based on some lessons learned from Philosophy of Science and the European project "VALIDATE" (VALues In Doing Assessments of healthcare TEchnologies"). VALIDATE was a three-year EU Erasmus+ strategic partnerships project (2018-2021), in which training in the field of HTA was further optimized by using insights from political science and ethics (in accordance with the recent definition of HTA). Our analysis may reveal useful insights for addressing some challenges that HTA is going to face in the future.

Ethics of digital therapeutics (DTx).

Digital therapeutics (DTx) are a subset of digital health which are often coupled with artificial intelligence (A.I.) techniques and machine learning systems. DTx differ from common wellness apps or medication reminder tools in that they require "rigorous" clinical evidence. They are emerging as a new treatment option and are being applied in a variety of areas, including type II diabetes, hypertension, chronic respiratory problems, obesity, insomnia, Alzheimer's disease, various types of dementia or addiction (smoking, alcohol, drugs), anxiety, depression, autism, learning disabilities, and attention deficits. Today, there are roughly 35 to 40 products on the market, 8 of which approved by regulatory agencies. The value of the global DTx market was estimated at USD 1.8 billion in 2018, and it is expected to reach USD 8.9 billion by 2027. Implementing DTx across healthcare systems raises a number of ethical concerns. The present article aims to provide an overview of the main ethical issues pertaining the assessment, implementation, and use of this emerging technology. The final purpose is to support and facilitate an open and transparent deliberation with regard to DTx.

Factors affecting safe and healthy diet in older adults in Italy: results of a preliminary study performed in a community-dwelling sample.

OBJECTIVE: To investigate, through a questionnaire, older adults' demographic and socio-economic characteristics, knowledge, attitudes and practices in terms of food safety and healthy diet; and to develop dietary and hygiene indices able to represent participants' nutritional and food safety behaviour, exploring their association with demographic and socio-economic factors. DESIGN: One-year cross-sectional study. SETTING: Gemelli Teaching Hospital (Rome, Italy). PARTICIPANTS: People aged ≥65 years, Italian speaking, accessing the Centre of Ageing Medicine. RESULTS: Mean age of the sample was 74 (sd 7·7) years. Subjective perception of a safe diet was high: 64·2 % of respondents believed they have a balanced diet. Interviewees got informed about proper nutrition mainly from television, magazines, newspapers, Internet (29·9 %) and from health professionals (34·8 %) such as dietitians, whereas 15·4 % from general practitioners. Regarding food safety, 33·8 % of participants reported to consume expired food, even more than once per month; between 80 and 90 % of participants reported to follow food safety practices during preparation and cooking, even though 49·3 % defrosted food at room temperature. Calculated dietary and hygiene indices showed that the elderly participants were far from having optimal nutritional and food safety behaviours. CONCLUSIONS: These results suggest it is necessary to increase the awareness of older adults in the matter of healthy diet and food safety. Specific and targeted educational interventions for the elderly and their caregivers could improve the adoption of recommended food safety practices and safe nutritional behaviours among older adults.

Prevalence and determinants of resistance mutations in HIV-1-infected patients exposed to integrase inhibitors in a large Italian cohort.

OBJECTIVES: The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)-experienced HIV-1-infected patients and its predictors. METHODS: We selected HIV-1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI-experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ2 test and predictors of resistance were analysed by logistic regression. RESULTS: We included 462 genotypes from INSTI-exposed individuals: 356 'INSTI-failing' patients and 106 'previously INSTI-exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17-110 weeks]). Overall, at least low-level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non-B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008-2009. CONCLUSIONS: The results support integrase resistance testing in INSTI-experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation.

Why is it so difficult to integrate ethics in Health Technology Assessment (HTA)? The epistemological viewpoint.

Ethics has been identified as a key element in Health Technology Assessment (HTA) since its conception. However, ethical issues are still not frequently addressed explicitly in HTA. Several valuable reasons have been identified. The basis of the article is the claim that ethics is often not part of HTA for "epistemological reasons". Hence, the main aim of the contribution is to explore in more details and emphasize them by using the fact/value dichotomy. Our conclusion is that current HTA configuration is predominantly based on the comparison among objective and empirically testable "facts", whilst ethics is not empirically testable. In this sense, there is a sort of "epistemological gap", which can explain why it is so difficult to integrate ethics in HTA. We suggest that the epistemological differences among the various domains of HTA are addressed more explicitly.

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.

Male fertility and reduction in semen parameters: a single tertiary-care center experience.

Background. Infertility is both a clinical and a public problem, affecting the life of the couple, the healthcare services, and social environment. Standard semen analysis is the surrogate measure of male fertility in clinical practice. Objective. To provide information about the relationship between semen parameters and spontaneous conception. Methods. We evaluated retrospectively 453 pregnancies that occurred among 2935 infertile couples evaluated at an infertility clinic of a tertiary-care university hospital, between 2004 and 2009. Results. Normal semen analysis was present only in 158 patients; 295 subfertile patients showed alterations in at least one seminal parameter. A reduction in all seminal parameters was observed in 41 patients. Etiological causes of male infertility were identified in 314 patients. Conclusion. Our data highlights the possibility of a spontaneous conception with semen parameters below WHO reference values. Therefore, we support the importance of defining reference values on a population of fertile men. Finally, we analyzed the related ethical issues.

Informed consent.

Informed consent (IC) in clinical experimentation is a process by which a subject voluntarily and freely confirms his/her willingness to participate in a trial, after having been informed of all involved aspects. IC is a concept enough recent within medical tradition. Unquestionably, Nuremberg trials (1945-1947) influenced thought about consent in Medicine. When the idea of IC evolved, discussion for appropriate guidelines moved increasingly from a narrow focus on the physician's/researcher's obligation. IC shall be obtained in writing and documented before a subject is enrolled into clinical investigation. , Particularly in the case of medical devices, it is necessary an adequate information to the patient on possible incidents occurring following placing of devices.

Observational protocol.

An observational study (OS) is a non-interventional/non-experimental survey. In the OSs, the investigator observes and evaluates results of ongoing medical care without 'controlling' the therapy beyond normal medical practice. An OS is aimed: 1. to the evaluation of the safety profile of any medical procedure (drug, device, surgical procedure, radiotherapy, diagnostics, etc.) under the normal conditions of use and on great numbers of patients, 2. for close examinations on the effectiveness in the clinical practice, 3. for the verification of the prescriptive appropriateness and 4. for pharmacoeconomic evaluations. For their characteristics OPs don't involve additional risks for the patients to which the best conditions of clinical assistance are offered. Consequently they do not need further or different ethical procedures/ requirements in comparison to the experimental clinical studies Particularly it is necessary to avoid that an interventional trial could be introduced as an OP.