Clinical Translation of Bio-Artificial Pancreas Therapies: Ethical, Legal and Psychosocial Interdisciplinary Considerations and Key Recommendations.

The field of regenerative medicine offers potential therapies for Type 1 Diabetes, whereby metabolically active cellular components are combined with synthetic medical devices. These therapies are sometimes referred to as "bioartificial pancreases." For these emerging and rapidly developing therapies to be clinically translated to patients, researchers must overcome not just scientific hurdles, but also navigate complex legal, ethical and psychosocial issues. In this article, we first provide an introductory overview of the key legal, ethical and psychosocial considerations identified in the existing literature and identify areas where research is currently lacking. We then highlight two principal areas of concern in which these discrete disciplines significantly overlap: 1) individual autonomy and 2) access and equality. Using the example of beta-cell provenance, we demonstrate how, by harnessing an interdisciplinary approach we can address these key areas of concern. Moreover, we provide practical recommendations to researchers, clinicians, and policymakers which will help to facilitate the clinical translation of this cutting-edge technology for Type 1 Diabetes patients. Finally, we emphasize the importance of exploring patient perspectives to ensure their responsible and acceptable translation from bench to body.

Access to effective but expensive treatments: An analysis of the solidarity argument in discussions on funding of medical treatments.

The development of new effective but expensive medical treatments leads to discussions about whether and how such treatments should be funded in solidarity-based healthcare systems. Solidarity is often seen as an elusive concept; it appears to be used to refer to different sets of concerns, and its interrelations with the concept of justice are not well understood. This paper provides a conceptual analysis of the concept of solidarity as it is used in discussions on the allocation of healthcare resources and the funding of expensive treatments. It contributes to the clarification of the concept of solidarity by identifying in the literature and discussing four uses of the concept: (1) assisting patients in need, (2) upholding the solidarity-based healthcare system, (3) willingness to contribute and (4) promoting equality. It distinguishes normative and descriptive uses of the concept and outlines the overlap and differences between solidarity and justice. Our analysis shows that the various uses of the concept of solidarity point to different, even conflicting, ethical stances on whether and how access to effective, expensive treatments should be provided. We conclude that the concept of solidarity has a role to play in discussions on the accessibility and funding of newly approved medical treatments. It requires, for instance, that healthcare policies promote and maintain both societal willingness to contribute to the care of others and the value of providing care to vulnerable patients through public funding.

Ethics of allocation of donor organs.

PURPOSE OF REVIEW: There is no widely accepted single ethical principle for the fair allocation of scarce donor organs for transplantation. Although most allocation systems use combinations of allocation principles, there is a particular tension between 'prioritizing the worst-off' and 'maximizing total benefits'. It is often suggested that empirical research on public preferences should help solve the dilemma between equity and efficiency in allocation policy-making. RECENT FINDINGS: This review shows that the evidence on public preferences for allocation principles is limited, and that the normative role of public preferences in donor organ allocation policy making is unclear. The review seeks to clarify the ethical dilemma to the transplant community, and draws attention to recent attempts at balancing and rank-ordering of allocation principles. SUMMARY: This review suggests that policy makers should make explicit the relative weights attributed to equity and efficiency considerations in allocation policies, and monitor the effects of policy changes on important ethics outcomes, including equitable access among patient groups. Also, it draws attention to wider justice issues associated not with the distribution of donor organs among patients on waiting lists, but with barriers in referral for transplant evaluation and disparities among patient groups in access to waiting lists.

Impact of incidental findings on young adult participants in brain imaging research: an interview study.

OBJECTIVES: The current study aims to investigate young adult research participants' experiences with and preferences regarding the disclosure of MRI incidental findings (IFs) in brain imaging research, and to elucidate the impact and long-term effects of IF disclosure on these participants. METHODS: We conducted 11 semi-structured interviews with 10 research participants to whom an IF was disclosed after they participated in brain MRI research at the Donders Institute, Centre for Cognitive Neuroimaging (DCCN) in the Netherlands. Interview transcripts were analyzed using the constant comparative method. RESULTS: The analysis yielded five themes regarding the impact of IF disclosure: the initial shock of disclosure, a period of uncertainty, results of the follow-up examination, long-term impact, and participants' biomedical background. Participants were primarily impacted by the uncertainty in the period immediately following IF disclosure. For our participants, disclosure has had no health benefits and some, albeit mostly temporary and limited, negative impact. CONCLUSIONS: Our study suggests that it is important to carefully consider IF disclosure in a population of young healthy participants and emphasizes the relevance of systematic, large-scale follow-up studies to monitor risks and benefits of IF disclosure in this population. The insights from this study can be of added value to improve current research procedures or frameworks for the management and disclosure of IFs in imaging studies. KEY POINTS: • Participants were primarily impacted by the uncertainty in the period immediately following IF disclosure. • Our study suggests that it is important to carefully consider IF disclosure in a population of healthy young adult participants. • Our study emphasizes the relevance of systematic, large-scale follow-up studies to monitor the risks and benefits of IF disclosure in this population.

Ethics of Early Clinical Trials of Bio-Artificial Organs.

Regenerative medicine is the new frontier in the field of organ transplantation. Research groups around the world are using regenerative medicine technologies to develop bio-artificial organs for transplantation into human patients. While most of this research is still at the preclinical stage, bio-artificial organ technologies are gearing up for first-in-human clinical trials in the not-too-distant future. What are the ethical conditions under which early-phase clinical research of bio-artificial organs can be conducted safely and responsibly? What lessons can be learned from prior experiences with early-phase clinical trials in adjacent fields of research? This is a Meeting Report of an online international workshop organised in the context of the Horizon 2020-funded VANGUARD project, which is developing a bio-artificial pancreas for the treatment of patients with type 1 diabetes.

Early-Phase Clinical Trials of Bio-Artificial Organ Technology: A Systematic Review of Ethical Issues.

Regenerative medicine has emerged as a novel alternative solution to organ failure which circumvents the issue of organ shortage. In preclinical research settings bio-artificial organs are being developed. It is anticipated that eventually it will be possible to launch first-in-human transplantation trials to test safety and efficacy in human recipients. In early-phase transplantation trials, however, research participants could be exposed to serious risks, such as toxicity, infections and tumorigenesis. So far, there is no ethical guidance for the safe and responsible design and conduct of early-phase clinical trials of bio-artificial organs. Therefore, research ethics review committees will need to look to related adjacent fields of research, including for example cell-based therapy, for guidance. In this systematic review, we examined the literature on early-phase clinical trials in these adjacent fields and undertook a thematic analysis of relevant ethical points to consider for early-phase clinical trials of transplantable bio-artificial organs. Six themes were identified: cell source, risk-benefit assessment, patient selection, trial design, informed consent, and oversight and accountability. Further empirical research is needed to provide insight in patient perspectives, as this may serve as valuable input in determining the conditions for ethically responsible and acceptable early clinical development of bio-artificial organs.

Inequitable Access to Transplants: Adults With Impaired Decision-Making Capacity.

Inequitable access to deceased donor organs for transplantation has received considerable scrutiny in recent years. Emerging evidence suggests patients with impaired decision-making capacity (IDC) face inequitable access to transplantation. The "Ethical and Legal Issues" working group of the European Society of Transplantation undertook an expert consensus process. Literature relating to transplantation in patients with IDC was examined and collated to investigate whether IDC is associated with inferior transplant outcomes and the legitimacy of this healthcare inequality was examined. Even though the available evidence of inferior transplant outcomes in these patients is limited, the working group concluded that access to transplantation in patients with IDC may be inequitable. Consequently, we argue that IDC should not in and of itself be considered as a barrier to either registration on the transplant waiting list or allocation of an organ. Strategies for non-discrimination should focus on ensuring eligibility is based upon sound evidence and outcomes without reference to non-medical criteria. Recommendations to support policy makers and healthcare providers to reduce unintended inequity and inadvertent discrimination are set out. We call upon transplant centres and national bodies to include data on decision-making capacity in routine reporting schedules in order to improve the evidence base upon which organ policy decisions are made going forward.

The 'false hope' argument in discussions on expanded access to investigational drugs: a critical assessment.

When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises 'false hope' among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients' hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients' hopes to be false, and hence, to deny them access to investigational drug based on that argument.

Toward a Framework for Assessing Privacy Risks in Multi-Omic Research and Databases.

While the accumulation and increased circulation of genomic data have captured much attention over the past decade, privacy risks raised by the diversification and integration of omics have been largely overlooked. In this paper, we propose the outline of a framework for assessing privacy risks in multi-omic research and databases. Following a comparison of privacy risks associated with genomic and epigenomic data, we dissect ten privacy risk-impacting omic data properties that affect either the risk of re-identification of research participants, or the sensitivity of the information potentially conveyed by biological data. We then propose a three-step approach for the assessment of privacy risks in the multi-omic era. Thus, we lay grounds for a data property-based, 'pan-omic' approach that moves away from genetic exceptionalism. We conclude by inviting our peers to refine these theoretical foundations, put them to the test in their respective fields, and translate our approach into practical guidance.

Ethical Considerations in Screening for Rapid Eye Movement Sleep Behavior Disorder in the General Population.

Clinical studies have shown that up to 90% of patients with idiopathic rapid eye movement sleep behavior disorder (RBD) will eventually be diagnosed with a clinical α-synucleinopathy. Because of this high conversion rate, screening for RBD is often performed to identify eligible participants for studies aimed at elucidating the prodromal phase of α-synucleinopathies. However, screening for RBD, especially in the general population, raises many ethical dilemmas. In light of the existing ethical literature and our experience in establishing a screening approach for RBD in the Rotterdam Study, we discuss ethical dilemmas when screening for RBD in population-based studies. We conclude that informing study participants about the reason for invitation and the possible trajectory that lies ahead when participating is essential. However, participants should not be troubled unnecessarily by giving them detailed information about possible diagnoses or associated disease risks. © 2020 International Parkinson and Movement Disorder Society.

Should pregnant women be charged for non-invasive prenatal screening? Implications for reproductive autonomy and equal access.

The introduction of non-invasive prenatal testing (NIPT) in healthcare systems around the world offers an opportunity to reconsider funding policies for prenatal screening. In some countries with universal access healthcare systems, pregnant women and their partners are asked to (co)pay for NIPT. In this paper, we discuss two important rationales for charging women for NIPT: (1) to prevent increased uptake of NIPT and (2) to promote informed choice. First, given the aim of prenatal screening (reproductive autonomy), high or low uptake rates are not intrinsically desirable or undesirable. Using funding policies to negatively affect uptake, however, is at odds with the aim of screening. Furthermore, copayment disproportionally affects those of lower socioeconomic status, which conflicts with justice requirements and impedes equal access to prenatal screening. Second, we argue that although payment models may influence pregnant women's choice behaviours and perceptions of the relevance of NIPT, the copayment requirement does not necessarily lead to better-informed choices. On the contrary, external (ie, financial) influences on women's personal choices for or against prenatal screening should ideally be avoided. To improve informed decision-making, healthcare systems should instead invest in adequate non-directive, value-focused pretest counselling. This paper concludes that requiring (substantial) copayments for NIPT in universal access healthcare systems fails to promote reproductive autonomy and is unfair.

Prevention in the age of personal responsibility: epigenetic risk-predictive screening for female cancers as a case study.

Epigenetic markers could potentially be used for risk assessment in risk-stratified population-based cancer screening programmes. Whereas current screening programmes generally aim to detect existing cancer, epigenetic markers could be used to provide risk estimates for not-yet-existing cancers. Epigenetic risk-predictive tests may thus allow for new opportunities for risk assessment for developing cancer in the future. Since epigenetic changes are presumed to be modifiable, preventive measures, such as lifestyle modification, could be used to reduce the risk of cancer. Moreover, epigenetic markers might be used to monitor the response to risk-reducing interventions. In this article, we address ethical concerns related to personal responsibility raised by epigenetic risk-predictive tests in cancer population screening. Will individuals increasingly be held responsible for their health, that is, will they be held accountable for bad health outcomes? Will they be blamed or subject to moral sanctions? We will illustrate these ethical concerns by means of a Europe-wide research programme that develops an epigenetic risk-predictive test for female cancers. Subsequently, we investigate when we can hold someone responsible for her actions. We argue that the standard conception of personal responsibility does not provide an appropriate framework to address these concerns. A different, prospective account of responsibility meets part of our concerns, that is, concerns about inequality of opportunities, but does not meet all our concerns about personal responsibility. We argue that even if someone is responsible on grounds of a negative and/or prospective account of responsibility, there may be moral and practical reasons to abstain from moral sanctions.

Rethinking counselling in prenatal screening: An ethical analysis of informed consent in the context of non-invasive prenatal testing (NIPT).

Informed consent is a key condition for prenatal screening programmes to reach their aim of promoting reproductive autonomy. Reaching this aim is currently being challenged with the introduction of non-invasive prenatal testing (NIPT) in first-trimester prenatal screening programmes: amongst others its procedural ease-it only requires a blood draw and reaches high levels of reliability-might hinder women's understanding that they should make a personal, informed decision about screening. We offer arguments for a renewed recognition and use of informed consent compared to informed choice, and for a focus on value-consistent choices and personalized informational preferences. We argue for a three-step counselling model in which three decision moments are distinguished and differently addressed: (1) professionals explore women's values concerning whether and why they wish to know whether their baby has a genetic disorder; (2) women receive layered medical-technical information and are asked to make a decision about screening; (3) during post-test counselling, women are supported in decision-making about the continuation or termination of their pregnancy. This model might also be applicable in other fields of genetic (pre-test) counselling, where techniques for expanding genome analysis and burdensome test-outcomes challenge counselling of patients.

Implementing non-invasive prenatal testing (NIPT) in the Netherlands: An interview study exploring opinions about and experiences with societal pressure, reimbursement, and an expanding scope.

The noninvasive prenatal test (NIPT) as the first trimester prenatal screening (FTS) for trisomies 21, 18, and 13 is offered to all pregnant women in the Netherlands. NIPT using genome sequencing allows for an expansion of the scope of FTS and the introduction of NIPT gives rise to ethical and societal concerns about deliberated decision-making, pressure to engage in screening, and possible lack of equal access due to the financial contribution (€175) to NIPT. We explored the opinions and experiences of pregnant women, who were offered FTS, about these concerns, and the possibility of a broadened scope. Nineteen pregnant women representing a diversity of backgrounds were interviewed using a semi-structured interview guide. Eight women did not opt for prenatal screening while 11 did (NIPT = 4, combined test = 7). Women experienced a free choice to accept or decline prenatal screening, despite sometimes receiving advice from others. Prior to pretest counseling, some women had already deliberated about what an abnormal test result would mean to them. Others accepted or declined FTS without deliberation. The current Dutch policy of requiring a co-payment was acceptable to some, who believed that it functioned as a threshold to think carefully about FTS. Others were concerned that a financial threshold would lead to unequal access to screening. Finally, pregnant women found it difficult to formulate opinions on the scope of FTS, because of lack of knowledge. Life expectancy, severity, and treatability were considered important criteria for the inclusion of a condition in NIPT.

The Impact of Incidental Findings Detected During Brain Imaging on Research Participants of the Rotterdam Study: An Interview Study.

This interview study investigates the short- and long-term implications of incidental findings detected through brain imaging on research participants' lives and their surroundings. For this study, nine participants of the Rotterdam Scan Study with an incidental finding were approached and interviewed. When examining research participants' narratives on the impact of the disclosure of incidental findings, the authors identified five sets of tensions with regard to motivations for and expectations of research participation, preferences regarding disclosure, short- and long-term impacts and impacts on self and others. The paper shows: (1) that the impact of incidental findings may be greater than participants at first let on; (2) incidental findings can have significant effects on participants' social environment; and (3) participants may not feel prepared for disclosure even if incidental findings have been discussed during the informed consent process. The authors call for investigators to be aware of research participants' experiences and these short- and long-term impacts when designing suitable courses of action for the detection and management of incidental findings in research settings.

What do patients with unmet medical needs want? A qualitative study of patients' views and experiences with expanded access to unapproved, investigational treatments in the Netherlands.

BACKGROUND: Patients with unmet medical needs sometimes resort to non-standard treatment options, including the use of unapproved, investigational drugs in the context of clinical trials, compassionate use or named-patient programs. The views and experiences of patients with unmet medical needs regarding unapproved, investigational drugs have not yet been examined empirically. METHODS: In this qualitative study, exploratory interviews and focus groups were held with patients with chronic or life-threatening diseases (n = 39), about topics related to non-standard treatment options, such as the search for non-standard treatment options, patients' views of the moral obligations of doctors, and the conditions under which they would or would not wish to use non-standard treatment options, including expanded access to unapproved, investigational drugs. RESULTS: Respondents had very little knowledge about and/or experience with existing opportunities for expanded access to investigational drugs, although some respondents were actively looking for non-standard treatment options. They had high expectations of their treating physicians, assuming them to be aware of non-standard treatment options, including clinical trials elsewhere and expanded access programs, and assuming that they would inform their patients about such options. Respondents carefully weighed the risks and potential benefits of pursuing expanded access, citing concerns related to the scientific evidence of the safety and efficacy of the drug, side effects, drug-drug interactions, and the maintaining of good quality of life. Respondents stressed the importance of education and assertiveness to obtain access to good-quality health care, and were willing to pay out of pocket for investigational drugs. Patients expressed concerns about equal access to new and/or non-standard treatment options. CONCLUSION: When the end of a standard treatment trajectory comes into view, patients may prefer that treating physicians discuss non-standard treatment options with them, including opportunities for expanded access to unapproved, investigational drugs. Although our respondents had varying levels of understanding of expanded access programs, they seemed capable of making well-considered choices with regard to non-standard treatment options and had realistic expectations with regard to the safety and efficacy of such options. Dutch patients might be less likely to fall prey to false hope than often presumed.

On the personal utility of Alzheimer's disease-related biomarker testing in the research context.

Many healthy volunteers choose to take part in Alzheimer's disease (AD) prevention studies because they want to know whether they will develop dementia-and what they can do to reduce their risk-and are therefore interested in learning the results of AD biomarker tests. Proponents of AD biomarker disclosure often refer to the personal utility of AD biomarkers, claiming that research participants will be able to use AD biomarker information for personal purposes, such as planning ahead or making important life decisions. In this paper, the claim that AD biomarkers have personal utility for asymptomatic individuals is critically assessed. It demonstrates that in the absence of clinical validity, AD biomarkers cannot have personal utility and do not serve research participants' autonomy. Over the next few years, many research groups will be confronted with participants' preferences to learn the results of AD biomarker tests. When researchers choose to make results available upon explicit request, they should ensure adequate information provision and education, notably on the uncertain clinical significance of AD biomarker information. Routine disclosure of AD biomarkers to cognitively unimpaired individuals in research settings cannot be justified with an appeal to the personal utility of AD biomarker information.

Ethics of routine: a critical analysis of the concept of 'routinisation' in prenatal screening.

In the debate surrounding the introduction of non-invasive prenatal testing (NIPT) in prenatal screening programmes, the concept of routinisation is often used to refer to concerns and potential negative consequences of the test. A literature analysis shows that routinisation has many different meanings, which can be distinguished in three major versions of the concept. Each of these versions comprises several inter-related fears and concerns regarding prenatal screening and particularly regarding NIPT in three areas: (1) informed choice, (2) freedom to choose and (3) consequences for people with a disability. Three of the strongest arguments raised under the flag of routinisation are assessed for their validity: the threat that NIPT poses to informed choice, the potential increase in uptake of first-trimester prenatal screening and its consequences for social pressure to participate in screening or terminate affected pregnancies, and the negative consequences for disabled people. These routinisation arguments lack empirical or normative ground. However, the results of this analysis do not imply that no attention should be paid to possible problems surrounding the introduction of NIPT. At least two problems remain and should be addressed: there should be an ongoing debate about the requirements of informed choice, particularly related to an expanded scope of prenatal screening. Also, reproductive autonomy can only be achieved when expecting parents' options are variegated, real and valuable, so that they can continue to choose whether or not to screen or to terminate a pregnancy.