Precarious hope: Ethical considerations for offering experimental fetal therapies outside of research after initial studies in humans.

OBJECTIVE: Risks and benefits of experimental fetal therapies can remain uncertain after initial clinical studies, especially long-term effects. Nevertheless, pregnant individuals may request them, hoping to benefit their future child. Guidance about offering experimental fetal therapies outside research (as "innovative therapy") is limited, despite their ethical complexity. We propose points for clinicians and reviewers to consider when deciding whether and how to offer experimental fetal therapies as innovative therapies after initial clinical studies. METHOD: We used conceptual analysis and a current case to develop points for consideration, grounded in broader debates on innovative therapy and the unique challenges associated with experimental fetal therapies. RESULTS: Clinicians should evaluate whether offering experimental fetal therapies as innovative therapy is appropriate for a pregnant individual and their fetus. The anticipated risk-benefit ratio for the fetus should be favorable. For the pregnant individual, risks may outweigh benefits, within reasonable limits. Medical resources should be sufficient to ensure appropriate care. Clinicians should support pregnant individuals in making informed choices. Clinicians offering innovative therapies with more than minimal risk should collect and report data on outcomes. Independent review should take place. CONCLUSION: Considering these points may advance the interests of fetuses, future children, and their families.

Returning Individual Research Results from Digital Phenotyping in Psychiatry.

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants' locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant's real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas.

"It's Pretty Sad If You Get Used to It": A Qualitative Study of First Responder Experiences with Opioid Overdose Emergencies.

BACKGROUND: First responders play a vital role in the United States opioid drug overdose crisis, a public health emergency that has claimed many lives. OBJECTIVE: We sought to investigate first responders' experiences and attitudes toward opioid overdose emergencies and the ongoing crisis, as well as emotional effects, coping strategies, and support systems. METHODS: A convenience sample of first responders (n = 18) at the Columbus Fire Division, with experience responding to opioid emergencies, participated in semi-structured telephone interviews between September 2018 and February 2019. Interviews were recorded, transcribed verbatim, and analyzed using content analysis for themes. RESULTS: While almost all participants described overdose emergencies as routine, they recalled some as memorable and emotionally impactful. Almost all respondents were frustrated by the high rates of overdose among their patients and the lack of sustainable improvements in outcomes, yet expressed a strong moral commitment to caring for patients and saving lives. Themes of burnout, compassion fatigue, and hopelessness emerged, as did themes of increased compassion and empathy. Support for personnel experiencing emotional difficulty was either lacking or underutilized. Further, many felt public policies should prioritize more permanent resources and improve access to care, and believed that people who use drugs should face greater accountability. CONCLUSION: First responders perceive a moral and professional duty to treat patients who overdose, despite their frustrations. They may benefit from additional occupational support to cope with the resultant emotional effects of their role in the crisis. Addressing macro-level factors contributing to the overdose crisis and improving patient outcomes could also positively affect first responder wellbeing.

Communication of patients' and family members' ethical concerns to their healthcare providers.

BACKGROUND: Little is known about communication between patients, families, and healthcare providers regarding ethical concerns that patients and families experience in the course of illness and medical care. To address this gap in the literature, we surveyed patients and family members to learn about their ethical concerns and the extent to which they discussed them with their healthcare providers. METHODS: We surveyed adult, English-speaking patients and family members receiving inpatient care in five hospitals in the Washington DC-Baltimore metropolitan area from July 2017 to March 2020. Descriptive statistics were used to determine the frequency, comfortableness, and helpfulness of discussions regarding ethical concerns experienced when sick or receiving medical care. Univariable and multivariable stepwise logistic regression models were used to identify associations between healthcare provider and respondent characteristics and attitudes and (1) the likelihood of speaking to a healthcare provider about their ethical concern and (2) their level of comfort during these discussions. RESULTS: Of 468 respondents who experienced ethical issues, 299 (64%) reported discussing the situation with a member of their healthcare team; 74% (197/265) of respondents who had such a discussion found the discussion comfortable, and 77% (176/230) of respondents found the discussion helpful. To make discussions more comfortable and helpful, respondents proposed suggestions in open-ended responses involving (1) content and quality of communication; (2) positive healthcare provider qualities such as empathy, open-mindedness, knowledge, honesty, and trustworthiness; and (3) other contextual factors including having adequate time and available resources. CONCLUSIONS: Patients and families often have ethical concerns that they discuss with clinicians, and they want clinicians to be routinely receptive and attentive to such discussions.

The value of nurse bioethicists.

BACKGROUND: The field of nursing has long been concerned with ethical issues. The history of the nursing profession has a rich legacy of attention to social justice and to societal questions regarding issues of fairness, access, equity, and equality. Some nurses have found that their clinical experiences spur an interest in ethical patient care, and many are now nurse bioethicists, having pursued additional training in bioethics and related fields (e.g., psychology, sociology). PURPOSE: The authors describe how the clinical and research experiences of nurses give them a unique voice in the field of bioethics. RESULTS: Authors present reasons for the relative invisibility of nurse bioethicists, compared with physician, theologian, or philosopher bioethicists, as well as current efforts to increase the visibility of nurse bioethicists. They also describe four specific areas where nurse bioethicists have made and continue to make important contributions: as ethics consultants to colleagues in hospitals and other settings; as bioethics researchers or as advisers to researchers conducting trials with human subjects; as educators of trainees, patients and families, healthcare providers, and the public; and in helping to draft humane and ethical policies for the care of vulnerable patients and underserved populations. CONCLUSION: Nurse bioethicists are central to the future goals of healthcare bringing a unique perspective to the day-to-day ethical challenges of both clinical care and research, as well as to the education of health professionals and the public.

A new ethical framework to determine acceptable risks in fetal therapy trials.

OBJECTIVE: Fetal therapy trials pose complex ethical challenges because risks and benefits to both fetuses and pregnant persons must be considered. Existing regulatory guidance is limited and many proposed ethical frameworks have unnecessarily restrictive criteria that would block the development and implementation of important new fetal therapies. We aimed to develop a new ethical framework for assessing the risks and benefits of fetal therapy trials. METHODS: We reviewed existing regulatory and ethical guidance on fetal therapy trials. We used conceptual analysis to design a new ethical framework, which is grounded in general ethical principles for clinical research. RESULTS: We propose a new framework for assessing the risks and benefits of fetal therapy trials. We suggest that the potential benefits of a fetal therapy trial - for the fetus, the pregnant person, and society - should outweigh the risks for the fetus and the pregnant person. Furthermore, the risk-benefit profile for just the fetus and the risk-benefit profile for just the pregnant person should be appropriate. CONCLUSIONS: We hope that this new framework will permit important studies while protecting pregnant persons and fetuses from disproportionate harms.

A New Ethical Framework for Assessing the Unique Challenges of Fetal Therapy Trials.

New fetal therapies offer important prospects for improving health. However, having to consider both the fetus and the pregnant woman makes the risk-benefit analysis of fetal therapy trials challenging. Regulatory guidance is limited, and proposed ethical frameworks are overly restrictive or permissive. We propose a new ethical framework for fetal therapy research. First, we argue that considering only biomedical benefits fails to capture all relevant interests. Thus, we endorse expanding the considered benefits to include evidence-based psychosocial effects of fetal therapies. Second, we reject the commonly proposed categorical risk and/or benefit thresholds for assessing fetal therapy research (e.g., only for life-threatening conditions). Instead, we propose that the individual risks for the pregnant woman and the fetus should be justified by the benefits for them and the study's social value. Studies that meet this overall proportionality criterion but have mildly unfavorable risk-benefit ratios for pregnant women and/or fetuses may be acceptable.

Ethical challenges for a new generation of early-phase pediatric gene therapy trials.

After decades of setbacks, gene therapy (GT) is experiencing major breakthroughs. Five GTs have received US regulatory approval since 2017, and over 900 others are currently in development. Many of these GTs target rare pediatric diseases that are severely life-limiting, given a lack of effective treatments. As these GTs enter early-phase clinical trials, specific ethical challenges remain unresolved in three domains: evaluating risks and potential benefits, selecting participants fairly, and engaging with patient communities. Drawing on our experience as clinical investigators, basic scientists, and bioethicists involved in a first-in-human GT trial for an ultrarare pediatric disease, we analyze these ethical challenges and offer points to consider for future GT trials.

Design of placebo-controlled randomized trials of anticancer agents: Ethical considerations based on a review of published trials.

BACKGROUND: Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen. METHODS: Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk-benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p ≤ 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise. RESULTS: Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk-benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials. CONCLUSION: A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.

Motivations and Decision-Making of Adult Sickle Cell Patients in High-Risk Clinical Research.

Potentially curative but high-risk trials of gene therapy or stem cell transplantation (PBSCT) for sickle cell disease (SCD) pose new opportunities for adults with SCD, many of whom experience significant disease burden and complications with few treatment options, as well as stigma and disparities in care. We explored motivations and decision-making processes of enrollees and decliners of such trials. Semistructured interviews were conducted with a purposive sample of 20 enrollees and 6 decliners. Interviews explored participants' SCD experiences, motivations, and decision-making about trial participation, understanding of research-related information, and retrospective reflections. Interviews were analyzed with content analysis. Most identified the purpose of research, risks, and uncertainties of participation. Both enrollees and decliners described deliberative weighing of study risks and potential benefits (especially the prospect of a cure), with heavy factoring of their SCD status, experiences, and desire for a better life. Despite the influence of spirituality/religion and support of family and friends, all described the decision about participation as their own. In some patients, the primary outcome status defined by the trial did not match the patients' perceived outcomes. Patients with negative experiences expressed a desire for greater emphasis on risks and possible outcomes during informed consent. This cohort of adults with SCD were thoughtfully deliberative in their decisions about gene therapy or PBSCT trials. Future participants' decision-making may be enhanced by emphasizing that "successful" scientific outcomes can still involve complications or symptoms and be facilitated by referrals to former research participants and anticipatory discussions.

Patient and Family Descriptions of Ethical Concerns.

Ethically challenging situations routinely arise in the course of illness and healthcare. However, very few studies have surveyed patients and family members about their experiences with ethically challenging situations. To address this gap in the literature, we surveyed patients and family members at three hospitals. We conducted a content analysis of their responses to open-ended questions about their most memorable experience with an ethical concern for them or their family member. Participants (N = 196) described 219 unique ethical experiences that spanned many of the prevailing themes of bioethics, including the patient-physician relationship, end-of-life care, decision-making capacity, healthcare costs, and genetic testing. Participants focused on relational issues in the course of experiencing illness and receiving medical care and concerns regarding the patient-physician encounters. Many concerns arose outside of a healthcare setting. These data indicate areas for improvement for healthcare providers but some concerns may be better addressed outside of the traditional healthcare setting.

Nurses confronting the coronavirus: Challenges met and lessons learned to date.

Registered nurses are an essential workforce group across the globe. They use their expertise and skill sets every day in clinical practice to protect, promote, and advocate on behalf of patients and families under their care. In this article we discuss the physical, emotional, and moral stresses that nurses are experiencing in their day-to-day practice settings created by the novel coronavirus. We consider the demands placed on nurses by unexpected patient surges within hospital environments and inadequate personal protective equipment and other critical resources, challenging nurses' ability to meet their professional and ethical obligations. We also share our thoughts on supporting nurses and others now, and ideas for needed healing for both individuals and organizations as we move forward. Finally, we argue for the need for substantive reform of institutional processes and systems that can deliver quality care in the future when faced with another devastating humanitarian and public health crises.

A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research.

Human genome and exome sequencing are powerful research tools that can generate secondary findings beyond the scope of the research. Most secondary genomic findings are of low importance, but some (for a current estimate of 1%-3% of individuals) confer high risk of a serious disease that could be mitigated by timely medical intervention. The impact and scope of secondary findings in genome and exome sequencing will only increase in the future. There is considerable agreement that high-impact findings should be returned to participants, but many researchers performing genomic research studies do not have the background, skills, or resources to identify, verify, interpret, and return such variants. Here, we introduce a proposal for the formation of a secondary-genomic-findings service (SGFS) that would support researchers by enabling the return of clinically actionable sequencing results to research participants in a standardized manner. We describe a proposed structure for such a centralized service and evaluate the advantages and challenges of the approach. We suggest that such a service would be of greater benefit to all parties involved than present practice, which is highly variable. We encourage research centers to consider the adoption of a centralized SGFS.

Enduring and emerging challenges of informed consent.

The author summarizes emerging standards for informed consent as the underpinning of ethical research in humans.

The ethics of uninsured participants accessing healthcare in biomedical research: A literature review.

Background/aims Sparse literature exists on the challenges and ethical considerations of including people with limited access to healthcare, such as the uninsured and low-income, in clinical research in high-income countries. However, many ethical issues should be considered with respect to working with uninsured and low-income participants in clinical research, including enrollment and retention, ancillary care, and post-trial responsibilities. Attention to the uninsured and low-income is particularly salient in the United States due to the high rates of uninsurance and underinsurance. Thus, we conducted a scoping review on the ethical considerations of biomedical clinical research with uninsured and low-income participants in high-income countries in order to describe what is known and to pinpoint areas of needed research on this issue. Methods MEDLINE/PubMed, Embase, and Scopus databases were searched using terms that described main concepts of interest (e.g., uninsured, underinsured, access to healthcare, poverty, ethics, compensation, clinical research). Articles were included if they met four inclusion criteria: (1) English, (2) high-income countries context, (3) about research participants who are uninsured or low-income, which limits their access to healthcare, and in biomedical clinical research that either had a prospect of direct medical benefit or was offered to them on the basis of their ill health, and (4) recognizes and/or addresses challenges or ethical considerations of uninsured or low-income participants in biomedical clinical research. Results The searches generated a total of 974 results. Ultimately, 23 papers were included in the scoping review. Of 23 articles, the majority (n = 19) discussed enrollment and retention of uninsured or low-income participants. Several barriers to enrolling uninsured and low-income groups were identified, including limited access to primary or preventive care; lack of access to institutions conducting trials or physicians with enough time or knowledge about trials; overall lack of trust in the government, research, or medical system; and logistical issues. Considerably fewer articles discussed treatment of these participants during the course of research (n = 5) or post-trial responsibilities owed to them (n = 4). Thus, we propose a research agenda that builds upon the existing literature by addressing three broad questions: (1) What is the current status of uninsured research participants in biomedical clinical research in high-income countries? (2) How should uninsured research participants be treated during and after clinical research? (3) How, if at all, should additional protections for uninsured research participants affect their enrollment? Conclusions This review reveals significant gaps in both data and thoughtful analysis on how to ethically involve uninsured research participants. To address these gaps, we propose a research agenda to gather needed data and theoretical analysis that addresses three broad research questions.

Autonomy and couples' joint decision-making in healthcare.

BACKGROUND: Respect for autonomy is a key principle in bioethics. However, respecting autonomy in practice is complex because most people define themselves and make decisions influenced by a complex network of social relationships. The extent to which individual autonomy operates for each partner within the context of decision-making within marital or similar relationships is largely unexplored. This paper explores issues related to decision-making by couples (couples' joint decision-making) for health care and the circumstances under which such a practice should be respected as compatible with autonomous decision-making. DISCUSSION: We discuss the concept of autonomy as it applies to persons and to actions, human interdependency and gender roles in decision-making, the dynamics and outcomes of couples' joint decision-making, and the ethics of couples' joint decision-making. We believe that the extent to which couples' joint decision-making might be deemed ethically acceptable will vary depending on the context. Given that in many traditional marriages the woman is the less dominant partner, we consider a spectrum of scenarios of couples' joint decision-making about a woman's own health care that move from those that are acceptably autonomous to those that are not consistent with respecting the woman's autonomous decision-making. To the extent that there is evidence that both members of a couple understand a decision, intend it, and that neither completely controls the other, couples' joint decision-making should be viewed as consistent with the principle of respect for the woman's autonomy. At the other end of the spectrum are decisions made by the man without the woman's input, representing domination of one partner by the other. CONCLUSIONS: We recommend viewing the dynamics of couples' joint decision-making as existing on a continuum of degrees of autonomy. This continuum-based perspective implies that couples' joint decision-making should not be taken at face value but should be assessed against the specific cultural, ethnic, and religious backgrounds and personal circumstances of the individuals in question.