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.

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.

Decentralized clinical trials (DCTs): A few ethical considerations.

Decentralized clinical trials (DCTs) are studies in which the need for patients to physically access hospital-based trial sites is reduced or eliminated. The CoViD-19 pandemic has caused a significant increase in DCT: a survey shows that 76% of pharmaceutical companies, device manufacturers, and Contract Research Organizations adopted decentralized techniques during the early phase of the pandemic. The implementation of DCTs relies on the use of digital tools such as e-consent, apps, wearable devices, Electronic Patient-Reported Outcomes (ePRO), telemedicine, as well as on moving trial activities to the patient's home (e.g., drug delivery) or to local healthcare settings (i.e., community-based diagnosis and care facilities). DCTs adapt to patients' routines, allow patients to participate regardless of where they live by removing logistical barriers, offer better access to the study and the investigational product, and permit the inclusion of more diverse and more representative populations. The feasibility and quality of DCTs depends on several requirements including dedicated infrastructures and staff, an adequate regulatory framework, and partnerships between research sites, patients and sponsors. The evaluation of Ethics Committees (ECs) is crucial to the process of innovating and digitalizing clinical trials: adequate assessment tools and a suitable regulatory framework are needed for evaluation by ECs. DCTs also raise issues, many of which are of considerable ethical significance. These include the implications for the relationship between patients and healthcare staff, for the social dimension of the patient, for data integrity (at the source, during transmission, in the analysis phase), for personal data protection, and for the possible risks to health and safety. Despite their considerable growth, DCTs have only received little attention from bioethicists. This paper offers a review on some ethical implications and requirements of DCTs in order to encourage further ethical reflection on this rapidly emerging field.

Nonurgent patients in the emergency department? A French formula to prevent misuse.

BACKGROUND: Overcrowding in emergency department (EDs) is partly due to the use of EDs by nonurgent patients. In France, the authorities responded to the problem by creating primary care units (PCUs): alternative structures located near hospitals. The aims of the study were to assess the willingness of nonurgent patients to be reoriented to a PCU and to collect the reasons that prompted them to accept or refuse. METHODS: We carried out a cross sectional survey on patients' use of EDs. The study was conducted in a French hospital ED. Patients were interviewed about their use of health services, ED visits, referrals, activities of daily living, and insurance coverage status. Patients' medical data were also collected. RESULTS: 85 patients considered nonurgent by a triage nurse were asked to respond to a questionnaire. Sex ratio was 1.4; mean age was 36.3 +/- 11.7 years.Most patients went to the ED autonomously (76%); one third (31.8%) had consulted a physician. The main reasons for using the ED were difficulty to get an appointment with a general practitioner (22.3%), feelings of pain (68.5%), and the availability of medical services in the ED, like imaging, laboratory tests, and drug prescriptions (37.6%). Traumatisms and wounds were the main medical reasons for going to the ED (43.5%).More than two-thirds of responders (68%) were willing to be reoriented towards PCUs. In the multivariate analysis, only employment and the level of urgency perceived by the patient were associated with the willingness to accept reorientation. Employed persons were 4.5 times more likely to accept reorientation (OR = 4.5 CI (1.6-12.9)). Inversely, persons who perceived a high level of urgency were the least likely to accept reorientation (OR = 0.9 CI (0.8-0.9). CONCLUSIONS: Our study provides information on the willingness of ED patients to accept reorientation and shows the limits of its feasibility. Alternative structures such as PCUs near the ED seem to respond appropriately to the growing demands of nonurgent patients. Reorientation, however, will be successful only if the new structures adapt their opening hours to the needs of nonurgent patients and if their physicians can perform specific technical skills.

Organ Transplantation From Nonstandard Risk Donors: Midway Between Rigid and Flexible Rules.

In order to bridge the gap between available organs and patients needing transplants, donor selection criteria for donors are increasingly being extended; the possibility of using organs from nonstandard risk donors has been introduced in many countries. This clearly poses considerable ethical issues that should be analyzed and taken into consideration by the competent bodies and institutions. In this article, we illustrate the Italian situation regarding the possibility of using organs from anti-hepatitis C virus (HCV) and HCV RNA-positive donors (anti-HCV+ve) in negative recipients (healthy subjects who have never come into contact with the hepatitis C virus) in light of the availability of new direct-acting antiviral drugs (DAAs) for hepatitis C treatment. We discuss the motivations behind the both favorable opinions of the Ethics Committee of the Italian National Institute of Health (Istituto Superiore di Sanità) and the Italian National Bioethics Committee (Comitato Nazionale per la Bioetica) discussing the main implications from an ethical point of view.

A personalist approach to public-health ethics.

First we give an overview of the historical development of public health. Then we present some public-health deontology codes and some ethical principles. We highlight difficulties in defining ethics for public health, with specific reference to three of them that concern: (i) the adaptability to public health of the classical principles of bioethics; (ii) the duty to respect and safeguard the individual while acting within the community perspective that is typical of public health; and (iii) the application-oriented nature of public health and the general lack of attention towards the ethical implications of collective interventions (compared with research). We then mention some proposals drafted from North American bioethics "principles" and utilitarian, liberal and communitarian views. Drawing from other approaches, personalism is outlined as being the theory that offers a consistent set of values and alternative principles that are relevant for public health.

Ethical models underpinning responses to threats to public health: a comparison of approaches to communicable disease control in Europe.

Increases in international travel and migratory flows have enabled infectious diseases to emerge and spread more rapidly than ever before. Hence, it is increasingly easy for local infectious diseases to become global infectious diseases (GIDs). National governments must be able to react quickly and effectively to GIDs, whether naturally occurring or intentionally instigated by bioterrorism. According to the World Health Organisation, global partnerships are necessary to gather the most up-to-date information and to mobilize resources to tackle GIDs when necessary. Communicable disease control also depends upon national public health laws and policies. The containment of an infectious disease typically involves detection, notification, quarantine and isolation of actual or suspected cases; the protection and monitoring of those not infected; and possibly even treatment. Some measures are clearly contentious and raise conflicts between individual and societal interests. In Europe national policies against infectious diseases are very heterogeneous. Some countries have a more communitarian approach to public health ethics, in which the interests of individual and society are more closely intertwined and interdependent, while others take a more liberal approach and give priority to individual freedoms in communicable disease control. This paper provides an overview of the different policies around communicable disease control that exist across a select number of countries across Europe. It then proposes ethical arguments to be considered in the making of public health laws, mostly concerning their effectiveness for public health protection.

Meeting Patients' Right to the Correct Diagnosis: Ongoing International Initiatives on Undiagnosed Rare Diseases and Ethical and Social Issues.

The time required to reach a correct diagnosis is a key concern for rare disease (RD) patients. Diagnostic delay can be intolerably long, often described as an "odyssey" and, for some, a diagnosis may remain frustratingly elusive. The International Rare Disease Research Consortium proposed, as ultimate goal for 2017⁻2027, to enable all people with a suspected RD to be diagnosed within one year of presentation, if the disorder is known. Subsequently, unsolved cases would enter a globally coordinated diagnostic and research pipeline. In-depth analysis of the genotype through next generation sequencing, together with a standardized in-depth phenotype description and sophisticated high-throughput approaches, have been applied as diagnostic tools to increase the chance of a timely and accurate diagnosis. The success of this approach is evident in the Orphanet database. From 2010 to March 2017 over 600 new RDs and roughly 3600 linked genes have been described and identified. However, combination of -omics and phenotype data, as well as international sharing of this information, has raised ethical concerns. Values to be assessed include not only patient autonomy but also family implications, beneficence, non-maleficence, justice, solidarity and reciprocity, which must be respected and promoted and, at the same time, balanced among each other. In this work we suggest that, to maximize patients' involvement in the search for a diagnosis and identification of new causative genes, undiagnosed patients should have the possibility to: (1) actively participate in the description of their phenotype; (2) choose the level of visibility of their profile in matchmaking databases; (3) express their preferences regarding return of new findings, in particular which level of Variant of Unknown Significance (VUS) significance should be considered relevant to them. The quality of the relationship between individual patients and physicians, and between the patient community and the scientific community, is critically important for optimizing the use of available data and enabling international collaboration in order to provide a diagnosis, and the attached support, to unsolved cases. The contribution of patients to collecting and coding data comprehensively is critical for efficient use of data downstream of data collection.

The RD-Connect Registry & Biobank Finder: a tool for sharing aggregated data and metadata among rare disease researchers.

In rare disease (RD) research, there is a huge need to systematically collect biomaterials, phenotypic, and genomic data in a standardized way and to make them findable, accessible, interoperable and reusable (FAIR). RD-Connect is a 6 years global infrastructure project initiated in November 2012 that links genomic data with patient registries, biobanks, and clinical bioinformatics tools to create a central research resource for RDs. Here, we present RD-Connect Registry & Biobank Finder, a tool that helps RD researchers to find RD biobanks and registries and provide information on the availability and accessibility of content in each database. The finder concentrates information that is currently sparse on different repositories (inventories, websites, scientific journals, technical reports, etc.), including aggregated data and metadata from participating databases. Aggregated data provided by the finder, if appropriately checked, can be used by researchers who are trying to estimate the prevalence of a RD, to organize a clinical trial on a RD, or to estimate the volume of patients seen by different clinical centers. The finder is also a portal to other RD-Connect tools, providing a link to the RD-Connect Sample Catalogue, a large inventory of RD biological samples available in participating biobanks for RD research. There are several kinds of users and potential uses for the RD-Connect Registry & Biobank Finder, including researchers collaborating with academia and the industry, dealing with the questions of basic, translational, and/or clinical research. As of November 2017, the finder is populated with aggregated data for 222 registries and 21 biobanks.

Recommendations for Improving the Quality of Rare Disease Registries.

Rare diseases (RD) patient registries are powerful instruments that help develop clinical research, facilitate the planning of appropriate clinical trials, improve patient care, and support healthcare management. They constitute a key information system that supports the activities of European Reference Networks (ERNs) on rare diseases. A rapid proliferation of RD registries has occurred during the last years and there is a need to develop guidance for the minimum requirements, recommendations and standards necessary to maintain a high-quality registry. In response to these heterogeneities, in the framework of RD-Connect, a European platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research, we report on a list of recommendations, developed by a group of experts, including members of patient organizations, to be used as a framework for improving the quality of RD registries. This list includes aspects of governance, Findable, Accessible, Interoperable and Reusable (FAIR) data and information, infrastructure, documentation, training, and quality audit. The list is intended to be used by established as well as new RD registries. Further work includes the development of a toolkit to enable continuous assessment and improvement of their organizational and data quality.

[A survey on some Italian doctors' opinions about errors in clinical medicine]. / Un confronto di opinioni di alcuni medici italiani sugli errori nella medicina clinica.

The paper discusses opinions on medical errors from the scientific literature and from a survey on 173 medical doctors working in a large hospital (> 500 beds) in Rome (Italy). The study is meant to explore doctors' opinions on professional and/or system responsibility in front of errors. In our hypothesis doctors are more favourable to attribute responsibility to individual carers rather than to institutions, and they are interested in solutions involving relational and communicational enhancements more than in technological or systemic innovations for risk management. The focus of the questionnaire is on errors' frequency, their principal causes and possible remedies, and their emotional impact. The main findings of the survey are presented. They confirm the idea of a medical culture essentially focused on individual responsibility rather than on system's responsibility. According to doctors the major causes of errors result from work overload and from a lack of communication inside medical teams and among different medical specialties. System errors, as well as technological solutions, are more quoted by doctors working in laboratories. Psychological consequences of errors vary by doctors' sex, length of exercise, and place of activity.

'You should at least ask'. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research.

Within the myriad articles about participants' opinions of genomics research, the views of a distinct group - people with a rare disease (RD) - are unknown. It is important to understand if their opinions differ from the general public by dint of having a rare disease and vulnerabilities inherent in this. Here we document RD patients' attitudes to participation in genomics research, particularly around large-scale, international data and biosample sharing. This work is unique in exploring the views of people with a range of rare disorders from many different countries. The authors work within an international, multidisciplinary consortium, RD-Connect, which has developed an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for RD research. Focus groups were conducted with 52 RD patients from 16 countries. Using a scenario-based approach, participants were encouraged to raise topics relevant to their own experiences, rather than these being determined by the researcher. Issues include wide data sharing, and consent for new uses of historic samples and for children. Focus group members are positively disposed towards research and towards allowing data and biosamples to be shared internationally. Expressions of trust and attitudes to risk are often affected by the nature of the RD which they have experience of, as well as regulatory and cultural practices in their home country. Participants are concerned about data security and misuse. There is an acute recognition of the vulnerability inherent in having a RD and the possibility that open knowledge of this could lead to discrimination.

Improving the informed consent process in international collaborative rare disease research: effective consent for effective research.

The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia - a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects.

The Quality of Rare Disease Registries: Evaluation and Characterization.

BACKGROUND: The focus on the quality of the procedures for data collection, storing, and analysis in the definition and implementation of a rare disease registry (RDR) is the basis for developing a valid and long-term sustainable tool. The aim of this study was to provide useful information for characterizing a quality profile for RDRs using an analytical approach applied to RDRs participating in the European Platform for Rare Disease Registries 2011-2014 (EPIRARE) survey. METHODS: An indicator of quality was defined by choosing a small set of quality-related variables derived from the survey. The random forest method was used to identify the variables best defining a quality profile for RDRs. Fisher's exact test was employed to assess the association with the indicator of quality, and the Cochran-Armitage test was used to check the presence of a linear trend along different levels of quality. RESULTS: The set of variables found to characterize high-quality RDRs focused on ethical and legal issues, governance, communication of activities and results, established procedures to regulate access to data and security, and established plans to ensure long-term sustainability. CONCLUSIONS: The quality of RDRs is usually associated with a good oversight and governance mechanism and with durable funding. The results suggest that RDRs would benefit from support in management, information technology, epidemiology, and statistics.

Rare disease registries classification and characterization: a data mining approach.

BACKGROUND: The European Commission and Patients Organizations identify rare disease registries (RDRs) as strategic instruments to develop research and improve knowledge in the field of rare diseases. Interoperability between RDRs is needed for research activities, validation of therapeutic treatments, and public health actions. Sharing and comparing information requires a uniform and standardized way of data collection, so levels of interconnection between RDRs with similar aims and/or nature of data should be identified. The objective of this study is to define a classification and characterization of RDRs in order to identify different profiles and informative needs. METHODS: Exploratory statistical analyses (cluster analysis and random forest) were applied to data derived from the EPIRARE project ('Building Consensus and Synergies for the EU Rare Disease Patient Registration') survey on the activities and needs of RDRs. RESULTS: The cluster analysis identified 3 main typologies of RDRs: public health, clinical and genetic research, and treatment registries. The analysis of the most informative variables, identified by the random forest method, led to the characterization of 3 types of RDRs and the definition of different profiles and informative needs. CONCLUSIONS: These results represent a useful source of information to facilitate the harmonization and interconnection of RDRs in accordance with the different profiles identified. It could help sharing the information between RDRs with similar profiles and, whenever possible, interconnections between registries with different profiles.

The EPIRARE proposal of a set of indicators and common data elements for the European platform for rare disease registration.

BACKGROUND: The European Union acknowledges the relevance of registries as key instruments for developing rare disease (RD) clinical research, improving patient care and health service (HS) planning and funded the EPIRARE project to improve standardization and data comparability among patient registries and to support new registries and data collections. METHODS: A reference list of patient registry-based indicators has been prepared building on the work of previous EU projects and on the platform stakeholders' information needs resulting from the EPIRARE surveys and consultations. The variables necessary to compute these indicators have been analysed for their scope and use and then organized in data domains. RESULTS: The reference indicators span from disease surveillance, to socio-economic burden, HS monitoring, research and product development, policy equity and effectiveness. The variables necessary to compute these reference indicators have been selected and, with the exception of more sophisticated indicators for research and clinical care quality, they can be collected as data elements common (CDE) to all rare diseases. They have been organized in data domains characterized by their contents and main goal and a limited set of mandatory data elements has been defined, which allows case notification independently of the physician or the health service. CONCLUSIONS: The definition of a set of CDE for the European platform for RD patient registration is the first step in the promotion of the use of common tools for the collection of comparable data. The proposed organization of the CDE contributes to the completeness of case ascertainment, with the possible involvement of patients and patient associations in the registration process.

How legislation on decisional capacity can negatively affect the feasibility of clinical trials in patients with dementia.

Antipsychotic drugs are widely used to treat behavioural and psychological disturbances associated with Alzheimer's disease (AD), although only modest evidence from randomized controlled trials supports their efficacy, and increasing evidence from post-marketing surveillance shows serious adverse events associated with their use, including increased mortality. The AdCare study, a non-profit, randomized, placebo-controlled, double-blind, multicentre, pragmatic trial coordinated by the Italian National Institute of Health, aimed to evaluate the long-term safety and efficacy profiles of three atypical antipsychotic drugs (risperidone, olanzapine and quetiapine) and one conventional antipsychotic drug (haloperidol) in treating psychosis, aggression and agitation in outpatients with AD. The study was planned to be carried out in 19 clinical centres and to enrol 1000 outpatients. According to Italian law, in the case where a patient is considered unable to give informed consent, a legal representative designated by the court has to provide it. Because of difficulties in the informed consent procedure, the study had to be prematurely interrupted. From February 2009 to April 2010, 83 patients gave informed consent to participate in the trial. Fifty-six patients (68%) were included with consent given by a legal representative, while 27 patients (32%) were considered to provide personal informed consent on the basis of the results from a specifically built procedure. Patients and caregivers were offered the opportunity to participate in the trial before the occurrence of behavioural disturbances, in order to provide them with enough time to consider their participation in the study. Twenty-three patients experienced behavioural, clinically relevant symptoms and were randomized to the study drug; all randomized patients except one had consent for inclusion in the study given by legal representatives. After trial interruption, all patients taking an active drug continued treatment with the same molecule in clinical practice. Randomized controlled trials are acknowledged as the gold standard source of evidence on drug safety and efficacy. The AdCare study showed that an excessively rigid regulation can become a major obstacle while carrying out therapeutic research with incapacitated persons.

A study of the Healthy Growth Charter in socially disadvantaged children.

The Healthy Growth Charter is an educational and health-promoting project aimed at an active involvement of the primary school children in health surveillance and protection. Being duly acquainted of the matter, scholars are asked to fill by their own a questionnaire on height, weight, sport attendance and other items of medical and demographic interest. According to the project, problems suitable of corrective measures, such as amblyopia, are signalled to the families and dealt individually. The project has been previously tested on about 1500 boys and girls from various Italian regions, showing that, despite the limits of self-reported data, it provides information in line with literature. Health inequalities in children remain an important problem also in Italy, and a second test of the Healthy Growth Charter was launched in a group of socially disadvantaged children. As reported in this paper, overweight, reduced physical activity, visual problems and other items markedly differed in this with respect to the previous study. These results provide some indication on the potential role of social disadvantage and poverty on health status of children. To better tackle the problem of health inequalities, the actual surveillance systems should be empowered, preferably with an active educational involvement of children, translating the information into public health intervention policies.