Research opportunities and ethical considerations for heart and lung xenotransplantation research: A report from the National Heart, Lung, and Blood Institute workshop.

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance of immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including nonhuman primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include the appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potentially novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.

Medicare and Amyloid PET Imaging: The Battle Over Evidence.

We examine a recent dispute regarding the Centers for Medicare and Medicaid Services' (CMS) refusal to unconditionally pay for amyloid positron emission tomography (PET) imaging for Medicare beneficiaries being assessed for Alzheimer's disease. CMS will only pay for amyloid PET imaging when patients are enrolled in clinical trials that meet certain criteria. The dispute reflects CMS's willingness in certain circumstances to require effectiveness evidence that differs from the Food and Drug Administration's standard for pre-market approval of a medical intervention and reveals how stakeholders with differing perspectives about evidentiary standards have played a role in attempting to shape the Medicare program's coverage policies.

Evidence and Access to Biomedical Interventions: The Case of Stem Cell Treatments.

The controversy over patients' access to stem cell interventions is familiar to scholars of the drug regulatory system and the politics of evidence-based medicine. What counts as evidence of a biomedical intervention's safety and effectiveness? Who should define and assess safety and effectiveness, and how? In the first section of the paper we describe the types of stem cells that may be therapeutically effective. We then describe how the US Food and Drug Administration asserted regulatory authority over certain stem cell interventions and the legal challenge to the agency's actions. Next, we place the debate about patients' access to stem cell interventions in the broader context of efforts in the US to promote and implement health technology assessment and the debate about standards of evidence. We then review several proposed initiatives to get stem cell and other new biomedical interventions into the clinic faster and consider the extent to which these policies can resolve the underlying conflicts about evidentiary standards for clinical use. Finally, we consider whether efforts to expedite access to biomedical technologies may undermine countervailing efforts to improve the safety and effectiveness of stem cell interventions.

IRB practices and policies regarding the secondary research use of biospecimens.

BACKGROUND: As sharing and secondary research use of biospecimens increases, IRBs and researchers face the challenge of protecting and respecting donors without comprehensive regulations addressing the human subject protection issues posed by biobanking. Variation in IRB biobanking policies about these issues has not been well documented. METHODS: This paper reports on data from a survey of IRB Administrative Directors from 60 institutions affiliated with the Clinical and Translation Science Awards (CTSAs) about their policies and practices regarding secondary use and sharing of biospecimens. Specifically, IRB ADs were asked about consent for future use of biospecimens, assignment of risk for studies using biobanked specimens, and sharing of biospecimens/data. RESULTS: Our data indicate that IRBs take varying approaches to protocol review, risk assessment, and data sharing, especially when specimens are not anonymized. CONCLUSION: Unclear or divergent policies regarding biospecimen research among IRBs may constitute a barrier to advancing genetic studies and to inter-institutional collaboration, given different institutional requirements for human subjects protections.

All of Us and the Promise of Precision Medicine: Achieving Equitable Access for Federally Qualified Health Center Patients.

The United States National Institutes of Health's (NIH) All of Us (AoU) initiative recruits participants from diverse backgrounds to improve the makeup of biobanks, considering nearly all biospecimens used in research come from people of European ancestry. Participants who join AoU consent to provide samples of blood, urine, and/or saliva and to submit their electronic health record to the program. In addition to diversifying precision medicine research studies, AoU will return genetic results back to many participants, which may require further follow-up care (i.e., more frequent cancer screening or mastectomy after a BRCA result). To help achieve its goals, AoU has partnered with Federally Qualified Health Centers (FQHCs), which is a type of community health center whose patient base is comprised largely of people who are uninsured, underinsured, or on Medicaid. Our NIH-funded study convened FQHC providers involved in AoU to better understand precision medicine in community health settings. Drawing from our findings, we present barriers community health patients and their providers face when accessing diagnostics and specialty care after genetic results necessitate medical follow-up care. We also propose several policy and financial recommendations to help overcome the challenges discussed, stemming from a commitment to equitable access to precision medicine advances.

Editors' Statement on the Responsible Use of Generative AI Technologies in Scholarly Journal Publishing.

Generative artificial intelligence (AI) has the potential to transform many aspects of scholarly publishing. Authors, peer reviewers, and editors might use AI in a variety of ways, and those uses might augment their existing work or might instead be intended to replace it. We are editors of bioethics and humanities journals who have been contemplating the implications of this ongoing transformation. We believe that generative AI may pose a threat to the goals that animate our work but could also be valuable for achieving those goals. In the interests of fostering a wider conversation about how generative AI may be used, we have developed a preliminary set of recommendations for its use in scholarly publishing. We hope that the recommendations and rationales set out here will help the scholarly community navigate toward a deeper understanding of the strengths, limits, and challenges of AI for responsible scholarly work.

Managing incidental findings and research results in genomic research involving biobanks and archived data sets.

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using "biobank" here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.

Clarifying the Ethics and Oversight of Chimeric Research.

This article is the lead piece in a special report that presents the results of a bioethical investigation into chimeric research, which involves the insertion of human cells into nonhuman animals and nonhuman animal embryos, including into their brains. Rapid scientific developments in this field may advance knowledge and could lead to new therapies for humans. They also reveal the conceptual, ethical, and procedural limitations of existing ethics guidance for human-nonhuman chimeric research. Led by bioethics researchers working closely with an interdisciplinary work group, the investigation focused on generating conceptual clarity and identifying improvements to governance approaches, with the goal of helping scholars, funders, scientists, institutional leaders, and oversight bodies (embryonic stem cell research oversight [ESCRO] committees and institutional animal care and use committees [IACUCs]) deliver principled and trustworthy oversight of this area of science. The article, which focuses on human-nonhuman animal chimeric research that is stem cell based, identifies key ethical issues in and offers ten recommendations regarding the ethics and oversight of this research. Turning from bioethics' previous focus on human-centered questions about the ethics of "humanization" and this research's potential impact on concepts like human dignity, this article emphasizes the importance of nonhuman animal welfare concerns in chimeric research and argues for less-siloed governance and oversight and more-comprehensive public communication.

Regulating Gene Editing in the Wild: Building Regulatory Capacity to Incorporate Deliberative Democracy.

The release of genetically engineered organisms into the shared environment raises scientific, ethical, and societal issues. Using some form of democratic deliberation to provide the public with a voice on the policies that govern these technologies is important, but there has not been enough attention to how we should connect public deliberation to the existing regulatory process. Drawing on lessons from previous public deliberative efforts by U.S. federal agencies, we identify several practical issues that will need to be addressed if relevant federal agencies are to undertake public deliberative activities to inform decision-making about gene editing in the wild. We argue that, while agencies may have institutional capacity to undertake public deliberative activities, there may not be sufficient political support for them to do so. Advocates of public deliberation need to make a stronger case to Congress about why federal agencies should be encouraged and supported to conduct public deliberations.

Public Deliberation about Gene Editing in the Wild.

Genetic editing technologies have long been used to modify domesticated nonhuman animals and plants. Recently, attention and funding have also been directed toward projects for modifying nonhuman organisms in the shared environment-that is, in the "wild." Interest in gene editing nonhuman organisms for wild release is motivated by a variety of goals, and such releases hold the possibility of significant, potentially transformative benefit. The technologies also pose risks and are often surrounded by a high uncertainty. Given the stakes, scientists and advisory bodies have called for public engagement in the science, ethics, and governance of gene editing research in nonhuman organisms. Most calls for public engagement lack details about how to design a broad public deliberation, including questions about participation, how to structure the conversations, how to report on the content, and how to link the deliberations to policy. We summarize the key design elements that can improve broad public deliberations about gene editing in the wild.

Animals with Human Cells in Their Brains: Implications for Research.

In "Human-Animal Chimeras: The Moral Insignificance of Uniquely Human Capacities," Julian Koplin argues against the views that all uniquely human traits have moral significance or that all the traits humans have in common with other animals "are morally insignificant." He recommends instead the adoption of "a better framework for thinking about the moral status of part-human beings," one that emphasizes the "phenomenal value (or disvalue)" chimeric animals are likely "to enjoy (or suffer)." If the moral status of these chimeric animals is grounded in the phenomenal value of their interests-that is, their interests as nonhuman animals-current protections for animals used in research may be inadequate to protect those interests.

Patient-Centered Care, Yes; Patients As Consumers, No.

There are numerous calls for building health care delivery systems that are more patient centered. The focus on patient-centered care has increasingly begun to rely upon, and even merge with, the concept of patients as consumers. Early references to patients as consumers were made by patient advocates who were attempting to challenge professional and corporate dominance in health care. Today, "consumer-driven" health care has become associated with neoliberal efforts to emphasize market factors in health reform and deemphasize government regulation and financing. In our view, a narrow focus on consumerism is conceptually confused and potentially harmful. The consumer metaphor wrongly assumes that health care is a market in the usual understanding of that term, that the high cost of US health care is a function of excessive consumer demand, and that price transparency and competition can deliver on the promise of reducing costs or ensuring quality. Furthermore, a consumer metaphor places disproportionate burdens on patients to reduce health care costs, and it could erode professional obligations to provide appropriate and effective care.

Evidence and Human Genome Editing.

In July, the United Kingdom's Nuffield Council on Bioethics issued a report on human genome editing in which it said that editing a human embryo's genome to reduce the possibility that the future child will inherit a genetic disorder could be ethically acceptable when certain conditions are met: the intended use of genome-editing interventions secures and is consistent with the "welfare of the future person" and does not "increase disadvantage, discrimination or division in society." Yet the Council noted that if current legal restrictions on the use of heritable genome-editing interventions were lifted, the interventions should be used only in the context of "well-designed and supervised studies" to ensure that they are safe and effective. Some people might contend that it is premature to talk about what kind of evidence-and how much-will be needed to gauge the safety and effectiveness of genome-editing interventions since the United Kingdom, the United States, and several other countries currently prohibit clinical trials that involve transferring into a woman an embryo whose genome was edited. Yet based on an analysis of evidentiary disputes involving several medical technologies (an analysis that I conducted with my Hastings colleague Michael Gusmano for a forthcoming book, Debating Modern Medical Technologies: The Politics of Safety, Effectiveness, and Patient Access), I suggest that now is the time to start the conversation about evidentiary standards for the use of genome editing in reproductive medicine.

On Improving Oversight and Enhancing Protections.

For this theme issue, "Reflections on the Revised Common Rule," we invited leading experts and scholars in research ethics to identify and comment on some of the important changes that the U.S. Department of Health and Human Services made to the Common Rule in a final regulation the agency released in January 2017. The authors draw on their experience as institutional leaders, members of national research ethics advisory bodies and institutional review boards, and scholars with deep knowledge of the ethical issues that human biomedical and behavioral research raises. Carl Coleman addresses some of the implications of the definitional ambiguities that remain in the revision, including the distinction between research and quality assessment and quality assurance activities. Barbara Bierer argues that the generalizable knowledge definition of research should not be the criterion for distinguishing research from clinical care. Holly Fernandez Lynch, Emily Largent, and Deborah Zarin raise important issues about what kind of research could be conducted on and with the consent forms that the revised Common Rule requires be posted on a publicly accessible website. And Suzanne Rivera identifies several concerns about the new blanket requirement that multisite studies cede authority to one single IRB to review the protocols for all the study sites.

Breakthrough Cancer Treatments Raise Difficult Questions.

The approval of a first-of-its kind cancer therapy creates new challenges related to safety, access, and costs.

Innovation Promises and Evidence Realities.

Over the past year media outlets and scientific and bioethics journals have reported about several medical and scientific innovations touted as having the potential to fundamentally change not only how diseases and disorders are diagnosed and treated but even how to alter the genomes of future generations. The purported "miracle" blood-testing technology of Theranos and the potential use of the genome editing technology CRISPR-Cas9 to modify human and nonhuman organisms reflect dramatic advances in scientific understanding about the biological mechanisms of humans and other living organisms. Yet evidence about whether these and other innovative biomedical technologies are safe and effective and lead to improved health outcomes for patients young and old is often in dispute. How to assess the safety and effectiveness of innovative biomedical technologies, who should be involved in that effort, and how to define risks and benefits of those technologies are questions at the intersection of values, interests, and politics.

The Ethical Imperative And Moral Challenges Of Engaging Patients And The Public With Evidence.

Engaging patients and the public with evidence is an ethical imperative because engagement is central to respect for persons and will likely improve health outcomes, facilitate the stewardship of resources, enhance prospects for justice, and build public trust. However, patient and public engagement is also morally complex, because evidence alone is never definitive. As patients and the public engage with evidence, value conflicts will arise and must be managed to achieve trustworthy decision making. We outline value conflicts likely to emerge in the following five settings: clinical care, health care organizations, public health, the regulatory context, and among payers. Using a variety of examples, we offer suggestions about how such conflicts may be managed, including providing more opportunities for democratic deliberation and having more explicit community discussion of how to balance personal choice and community well-being, transparent discussions of cost and quality outcomes, and greater patient engagement in community-based participatory research and the governance of learning health systems.