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.

Genomic tools for health: Secondary findings as findings to be shared.

PURPOSE: Whether and how to disclose secondary finding (SF) information to children is ethically debated. Some argue that genetic testing of minors should be limited to preserve the child's future autonomy. Others suggest that disclosure of SFs can occur if it is in the best interests of the child. However, the ways that parents conceptualize and weigh their child's future autonomy against the interests of their child and other family members are unknown. METHODS: To explore how parents understand SF disclosure in the context of their child and other family members' lives, we conducted semistructured interviews with 30 families (40 parents in total). All parents had children who were enrolled in a genetic sequencing protocol that returned results by default. RESULTS: We found that parents did not routinely conceptualize SFs as distinctive health information. Rather parents saw this information as part of their child's overall health. To make decisions about disclosure, parents weighed their child's ability to understand the SF information and their other family member's need to know. CONCLUSION: Because most families desired SF information, we argue that disclosure of SF be reconceptualized to reflect the lived experiences of those who may receive this information.

Implementing Expanded Prenatal Genetic Testing: Should Parents Have Access to Any and All Fetal Genetic Information?

Prenatal genetic testing is becoming available for an increasingly broad set of diseases, and it is only a matter of time before parents can choose to test for hundreds, if not thousands, of genetic conditions in their fetuses. Should access to certain kinds of fetal genetic information be limited, and if so, on what basis? We evaluate a range of considerations including reproductive autonomy, parental rights, disability rights, and the rights and interests of the fetus as a potential future child. We conclude that parents should be able to access information that could be useful during pregnancy, but that testing for non-medical information should be limited. Next, we argue that the government lacks a compelling state interest in regulating prenatal genetic testing and propose that regulation should occur through medical professional organizations. Finally, we present a framework for determining what testing physicians should recommend, offer neutrally, or not offer at all.

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.

Autonomy concerns with using contracts to enhance patient adherence.

The failure of many patients with chronic conditions to correctly follow medical advice that they hope or intend to follow is a major concern, especially as effective long-term therapies for chronic conditions materialize. Some US healthcare providers have responded with strategies that involve implementing contracts with their patients, including provisions that may deny future treatments after continued nonadherence. This is among the first articles to explicitly discuss the ethics of patient contracts.

Reason-Based Abortion Bans, Disability Rights, and the Future of Prenatal Genetic Testing.

Recent advances in prenatal genetic testing have made testing for congenital disorders more accessible, with emerging technologies promising further expansion of available testing options. In particular, non-invasive prenatal testing ("NIPT") has allowed women to identify more fetal disorders earlier in pregnancy than was possible only a decade ago. In addition to allowing women to prepare for the birth of a child with a disability, prenatal diagnoses give women the ability to terminate a pregnancy to avoid raising a child with a disability, a choice driven by myriad factors.

When Not to Ask: A Defense of Choice-Masking Nudges in Medical Research.

In this article, we examine the legality and ethics of a controversial but widespread practice in clinical research: choice-masking nudges. A choice-masking nudge (CMN) exists when a research team explicitly obscures a meaningful choice from participants by presenting a default decision as the standard way forward. Even though an easy-to-use opt-out mechanism is available for participants who independently express concerns with the standard default, the fact that a default has been pre-selected is not made obvious to research participants. To opt out of the nudge, a participant must overtly request non-standard treatment. We argue that use of such nudges in medical research can be justified by their individual, collective, and social benefits, provided that they respect autonomy and satisfy our four further acceptability conditions. The structure of this Article is as follows. In Part II, we describe three controversial cases of CMNs in medical research. In Part III, we provide background on nudging and explain how our proposed CMNs fit into the existing literature on nudging and libertarian paternalism. In Part IV, we explain how the reasonable person standard as employed by United States research regulations can be used to support CMNs. In Part IV, we anticipate some of the strongest objections to CMNs by explaining how CMNs are compatible with a wide range of plausible accounts of autonomy. Finally, in Part VI, we discuss four additional core considerations an acceptable CMN must meet: legitimate policy goals; benefits outweighing harms; burdens distributed fairly; and absence of ethically superior feasible alternatives. We also analyze the three existing controversies explored in Part II and show how each would benefit from the conceptual clarity offered by our analytic framework. Medical research is complicated and can be difficult for participants to understand; thoughtfully designed CMNs can play an important role in gently guiding large numbers of research participants toward decision outcomes that really are best for them and their communities.

Exploring the motivations of research participants who chose not to learn medically actionable secondary genetic findings about themselves.

PURPOSE: Proposals to return medically actionable secondary genetic findings (SFs) in the clinical and research settings have generated controversy regarding whether to solicit individuals' preferences about their "right not to know" genetic information. This study contributes to the debate by surveying research participants who have actively decided whether to accept or refuse SFs. METHODS: Participants were drawn from a large National Institutes of Health (NIH) environmental health study. Participants who had accepted SFs (n = 148) or refused SFs (n = 83) were given more detailed information about the types of SFs researchers could return and were given an opportunity to revise their original decision. RESULTS: Forty-one of 83 initial refusers (49.4%) opted to receive SFs following the informational intervention. Nearly 75% of these "reversible refusers" thought they had originally accepted SFs. The 50.6% of initial refusers who continued to refuse ("persistent refusers") demonstrated high levels of understanding of which SFs would be returned postintervention. The most prominent reason for refusing was concern about becoming worried or sad (43.8%). CONCLUSION: This study demonstrates the need for a more robust informed consent process when soliciting research participants' preferences about receiving SFs. We also suggest that our data support implementing a default practice of returning SFs without actively soliciting preferences.

An ethical framework for genetic counseling in the genomic era.

The field of genetic counseling has grown and diversified since the profession emerged in the early 1970s. In the same period, genomic testing has become more complex, profitable, and widespread. With these developments, the scope of ethical considerations relevant to genetic counseling has expanded. In light of this, we find it helpful to revisit how ethical and relational variables are used to inform genetic counseling practice. Our specific focus is on whether, and to what extent, it is ethically acceptable for genetic counselors to make normative recommendations to patients. This article builds on prior literature that has critiqued nondirectiveness, a concept that has influenced and constrained the modern profession of genetic counseling since its origin. In it, we review scholarly efforts to move beyond nondirectiveness, which we believe privilege patient autonomy at the expense of other important values. We then argue that genetic counselors should favor a more explicit commitment to the principles of beneficence and non-maleficence, as well as a broader understanding of autonomy and the relational variables that impact genetic counseling. Finally, to translate our arguments into practice, we present a framework of six considerations that genetic counselors should take into account when deciding whether it is ethically acceptable, or even desirable, to make recommendations to patients in certain areas of their work.

Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.

In 1995, the American Society of Human Genetics (ASHG) and American College of Medical Genetics and Genomics (ACMG) jointly published a statement on genetic testing in children and adolescents. In the past 20 years, much has changed in the field of genetics, including the development of powerful new technologies, new data from genetic research on children and adolescents, and substantial clinical experience. This statement represents current opinion by the ASHG on the ethical, legal, and social issues concerning genetic testing in children. These recommendations are relevant to families, clinicians, and investigators. After a brief review of the 1995 statement and major changes in genetic technologies in recent years, this statement offers points to consider on a broad range of test technologies and their applications in clinical medicine and research. Recommendations are also made for record and communication issues in this domain and for professional education.

Development of a consensus approach for return of pathology incidental findings in the Genotype-Tissue Expression (GTEx) project.

The active debate about the return of incidental or secondary findings in research has primarily focused on return to research participants, or in some cases, family members. Particular attention has been paid to return of genomic findings. Yet, research may generate other types of findings that warrant consideration for return, including findings related to the pathology of donated biospecimens. In the case of deceased biospecimen donors who are also organ and/or tissue transplant donors, pathology incidental findings may be relevant not to family members, but to potential organ or tissue transplant recipients. This paper will describe the ethical implications of pathology incidental findings in the Genotype-Tissue Expression (GTEx) project, the process for developing a consensus approach as to if/when such findings should be returned, possible implications for other research projects collecting postmortem tissues and how the scenario encountered in GTEx fits into the larger return of results/incidental findings debate.

Recontacting participants for expanded uses of existing samples and data: a case study.

PURPOSE: Facilitating genomic research may require the use of samples and data collected via consent processes that did not include specific descriptions of secondary uses. We explore whether a waiver of consent with notification and the option to withdraw (WNOW) is a viable alternative to written informed consent for secondary uses of samples and data. METHODS: We developed a retrospective case study of a rare-disease protocol involving 1,978 participants that implemented WNOW for genomic data-sharing activities. We analyzed institutional review board and investigator records and conducted in-depth semistructured interviews with key staff members. RESULTS: WNOW was largely successful at achieving its goals in this case, although the recontact effort, relative to proceeding with a waiver, decreased participation in genomic data sharing by 13.8% (n = 253), primarily because 224 letters were returned as undeliverable. A small number of participants responded (n = 89), and some of them expressed confusion and frustration. In the pediatric arm of the study, the research may have been practicable without a waiver, given the relationship between the pediatric clinicians and families. CONCLUSION: The practicability of conducting research on existing specimens without a waiver of informed consent, and whether WNOW is a viable alternative, depend on contextual factors, including a reliable way to communicate with participants.Genet Med advance online publication 26 January 2017.