Views of adults living with sickle cell disease on the theoretical return of secondary genomic findings.

PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.

Layered vulnerability and researchers' responsibilities: learning from research involving Kenyan adolescents living with perinatal HIV infection.

BACKGROUND: Carefully planned research is critical to developing policies and interventions that counter physical, psychological and social challenges faced by young people living with HIV/AIDS, without increasing burdens. Such studies, however, must navigate a 'vulnerability paradox', since including potentially vulnerable groups also risks unintentionally worsening their situation. Through embedded social science research, linked to a cohort study involving Adolescents Living with HIV/AIDS (ALH) in Kenya, we develop an account of researchers' responsibilities towards young people, incorporating concepts of vulnerability, resilience, and agency as 'interacting layers'. METHODS: Using a qualitative, iterative approach across three linked data collection phases including interviews, group discussions, observations and a participatory workshop, we explored stakeholders' perspectives on vulnerability and resilience of young people living with HIV/AIDS, in relation to home and community, school, health care and health research participation. A total of 62 policy, provider, research, and community-based stakeholders were involved, including 27 ALH participating in a longitudinal cohort study. Data analysis drew on a Framework Analysis approach; ethical analysis adapts Luna's layered account of vulnerability. RESULTS: ALH experienced forms of vulnerability and resilience in their daily lives in which socioeconomic context, institutional policies, organisational systems and interpersonal relations were key, interrelated influences. Anticipated and experienced forms of stigma and discrimination in schools, health clinics and communities were linked to actions undermining ART adherence, worsening physical and mental health, and poor educational outcomes, indicating cascading forms of vulnerability, resulting in worsened vulnerabilities. Positive inputs within and across sectors could build resilience, improve outcomes, and support positive research experiences. CONCLUSIONS: The most serious forms of vulnerability faced by ALH in the cohort study were related to structural, inter-sectoral influences, unrelated to study participation and underscored by constraints to their agency. Vulnerabilities, including cascading forms, were potentially responsive to policy-based and interpersonal actions. Stakeholder engagement supported cohort design and implementation, building privacy, stakeholder understanding, interpersonal relations and ancillary care policies. Structural forms of vulnerability underscore researchers' responsibilities to work within multi-sectoral partnerships to plan and implement studies involving ALH, share findings in a timely way and contribute to policies addressing known causes of vulnerabilities.

'Guidance should have been there 15 years ago' research stakeholders' perspectives on ancillary care in the global south: a case study of Malawi.

BACKGROUND: Medical researchers in resource-constrained settings must make difficult moral decisions about the provision of ancillary care to participants where additional healthcare needs fall outside the scope of the research and are not provided for by the local healthcare system. We examined research stakeholder perceptions and experiences of ancillary care in biomedical research projects in Malawi. METHODS: We conducted 45 qualitative in-depth interviews with key research stakeholders: researchers, health officials, research ethics committee members, research participants and grants officers from international research funding organisations. Thematic analysis was used to analyse and interpret the findings. FINDINGS: All stakeholders perceived the provision of ancillary care to have potential health benefits to study participants in biomedical research. However, they also had concerns, particularly related to the absence of guidance to support it. Some suggested that consideration for ancillary care provision could be possible on a case-by-case basis but that most of the support from research projects should be directed towards strengthening the public health system, emphasising public good above individual or personal benefits. Some researchers and ethics committee members raised concerns about potential tensions in terms of funding, for example balancing study demands with addressing participants' additional health needs. CONCLUSION: Our findings highlight the complexities and gaps in the guidance around the provision of ancillary care in Malawi and other resource-constrained settings more generally. To promote the provision of ancillary care, we recommend that national and international guidelines for research ethics include specific recommendations for resource-constrained settings and specific types of research.

A chronological discourse analysis of ancillary care provision in guidance documents for research conduct in the global south.

INTRODUCTION: Numerous guidelines and policies for ethical research practice have evolved over time, how this translates to global health practice in resource-constrained settings is unclear. The purpose of this paper is to describe how the concept of ancillary care has evolved over time and how it is included in the ethics guidelines and policy documents that guide the conduct of research in the global south with both an international focus and providing a specific example of Malawi, where the first author lives and works, as a case study. METHODS: Discourse analysis was conducted on 34 international ethics guidelines and policy documents. Documents were purposively selected if they contained a set of key terms that reflect the concept of ancillary care. Following a process of inductive discourse analysis, five key interrelated text phrases relating to ancillary care were extracted from the documents. The evolution of these phrases over time was explored as they represented the development of the concept of ancillary care as a component of ethical health research guidance and practice. RESULTS: We found key interrelated phrases that represent discourses regarding the evolution of ancillary care including participant protection; provide care as appropriate; supererogation; patient needs prevail over science; and ancillary care as an obligation. Arguments for the provision of ancillary care were characterised by safeguarding the safety, health rights and well-being of study participants. However, despite the evolution of discourse around ethical obligations to provide ancillary care, this is rarely made explicit within guidance documents, leaving interpretive space for differential application in practice. CONCLUSION: While there have been major changes to the ethics guidance that reflect significant evolution in the ethical conduct of research, the specific vocabulary or language used to explain the ethics of researchers' ancillary care obligations to the health needs of their research participants, lacks clarity and consistency. As a result, the concept of ancillary care continues to be under-represented in local ethical guidelines and regulations, with no clear directives for country-level research ethics committees to apply in regulating ancillary care responsibilities.

Objective monitoring of mosquito bednet usage and the ethical challenge of respecting study bystanders' privacy.

Insecticide-treated bednets are among the most prevalent and cost-effective tools for preventing malaria throughout the world. Consistent bednet use is crucial for effectiveness, but assessing adherence is challenging due to limitations in current measurement tools. Recent technologies have introduced methods for remote electronic bednet use monitoring. While valuable for researchers, these monitoring tools create potential ethical concerns for study bystanders because the monitors are typically unable to discriminate between individuals who are or are not study participants. Considerations related to study bystanders, including privacy, ancillary care obligations, and community perceptions, are discussed.

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.

An Open-Label Phase II Randomized Trial of Topical Dexamethasone and Tacrolimus Solutions for the Treatment of Oral Chronic Graft-versus-Host Disease.

The objective of this study was to evaluate the safety and efficacy of single-agent dexamethasone or tacrolimus topical solution as first-line treatment for symptomatic oral chronic graft-versus-host disease (cGVHD). This was a prospective, single-center, open-label, randomized phase II trial of patients with symptomatic oral cGVHD without prior topical therapy. Subjects were randomly assigned 1:1 to either topical dexamethasone (.5 mg/mL) or tacrolimus (.5 mg/mL) solution and instructed to rinse with 5 mL for 5 minutes, 4 times a day, for 4 weeks. Oral cGVHD assessments (National Institutes of Health [NIH] criteria) were completed at baseline and end of treatment (NIH criteria, global response, and tolerability). The primary endpoint was the response rate defined as ≥3-point reduction in patient-reported sensitivity score (range, 0 to 10). A parallel 2-stage design was employed so that a less efficacious arm could be terminated early. The accrual goal was 60 evaluable patients; 30 in each arm), accruing 14 in the first stage and 16 in the second stage. If both arms were regarded as efficacious, a "pick-the-winner" method would be employed to choose a better treatment for future investigation. Forty-six subjects were randomized to receive either dexamethasone (n = 28) or tacrolimus (n = 18). Six subjects were excluded from the analysis because of changes in systemic immunosuppression (dexamethasone = 1, tacrolimus = 3) or lack of end-of-treatment visit (1 per arm). After the first stage evaluation, the tacrolimus arm was terminated because of lack of activity (3 of 14 responses; response rate, 21%). Twenty-six subjects in the dexamethasone arm completed both study visits and were included in the response analysis, with a 58% (15 of 26) response rate, compared with 21% (3 of 14) in the tacrolimus arm (P = .05). The response rates according to the NIH score in the dexamethasone and tacrolimus arms were 50% (13 of 26) and 2% (2 of 14), respectively (P = .04). From the onset of therapy, 31% versus 21% patients reported feeling "much better" and 38% versus 36% reported feeling "slightly better," giving an overall global response rate ("much better" or "slightly better") of 81% (21 of 26) versus 71% (10 of 14), in the dexamethasone and tacrolimus arms, respectively. Dexamethasone rinses were well tolerated and taste was reported as "very pleasant" or "tolerable" in most subjects (96%). Intensive topical therapy with dexamethasone solution is effective for managing patients with new-onset symptomatic oral cGVHD and should be considered for first-line therapy. Topical tacrolimus solution appears less effective, at least for first-line therapy.

Medical Researchers' Ancillary Care Obligations: The Relationship-Based Approach.

In this article, I provide a new account of the basis of medical researchers' ancillary care obligations. Ancillary care in medical research, or medical care that research participants need but that is not required for the validity or safety of a study or to redress research injuries, is a topic that has drawn increasing attention in research ethics over the last ten years. My view, the relationship-based approach, improves on the main existing theory, Richardson and Belsky's 'partial-entrustment model', by avoiding its problematic restriction on the scope of health needs for which researchers could be obligated to provide ancillary care. Instead, it grounds ancillary care obligations in a wide range of morally relevant features of the researcher-participant relationship, including the level of engagement between researchers and participants, and weighs these factors against each other. I argue that the level of engagement, that is, the duration and intensity of interactions, between researchers and participants matters for ancillary care because of its connection to the meaningfulness of a relationship, and I suggest that other morally relevant features can be grounded in researchers' role obligations.

Can the Research Team-Participant Relationship Ground Ancillary-Care Obligations?

Discussion of medical researcher teams' ancillary-care obligations has long been dominated by partial-entrustment theory, developed in 2004 by the author of this article, in collaboration with Leah Belsky. Critics of the limited scope of the special ancillary-care obligations defended by that theory, however, argue that a better theory would take fuller account of the relationship that develops between individual research participants and members of the research team. Nate W. Olson and Thaddeus Metz have each put forward well worked-out versions of such a relationship-based account of ancillary-care obligations. This article critically evaluates these accounts, concluding that while each of them is vulnerable to various criticisms, each also crucially facilitates understanding of this relationship: Olson brings out well how research participants can find that role not just beneficial but also deeply meaningful, and Metz, drawing on African ethical traditions, emphasizes that when things go well, participants are involved as partners in the research effort. Yet the article closes by arguing that the partial-entrustment theory, surprisingly, can take on board each of these lessons. As so enhanced, it may actually be the best available relationship-based theory of this subject.

Managing ancillary care in resource-constrained settings: Dilemmas faced by frontline HIV prevention researchers in a rural area in South Africa.

BACKGROUND: We describe the findings from a research ethics case study, linked with a team evaluating a package of intervention services to prevent HIV infection in adolescent girls and young women (AGYW) living in a rural and poor setting of KwaZulu-Natal, South Africa. METHODS: We conducted qualitative interviews (n=77) with members of the linked research team evaluating the intervention programme, programme implementing staff, AGYW enrolled in the intervention programme, caregivers, ethics committee members, Public Engagement officers, community advisory board members and community stakeholders. Data were analysed iteratively using thematic framework analysis. Themes were determined by the study aims combined with an inductive development of codes emerging from the data. RESULTS: The findings show that the burden of providing ancillary care fell primarily on the shoulders of frontline researchers and programme staff. Dilemmas around responding to gender-based violence illustrated the limits of 'referral to services' as a solution for meeting ancillary care obligations in contexts with barriers to basic health and social services. CONCLUSION: Our findings show important gaps in meeting ancillary care needs. Participants' needs required social and economic support which frontline researchers and implementing partners were not able to meet, causing moral distress.

Dementia Care Work in Singapore: Embodied Relations and Power Dynamics.

Based on research at a dementia day-care center in Singapore, I discuss how embodied care relations proceed amidst cultural expectations on aging, dementia, and care work. Engaging with approaches that conceptualize "care" as either empathy or control, I argue that care between older people with dementia, their families, and care workers can be understood as a reiterative, dialogic process whereby care participants strive to keep pace with each other, however briefly, due to cognitive decline, care workers' own limitations, and particular family difficulties. Care vacillates between practices of control, surveillance, and recognition, and comprises dynamic rather than enduring power relations.

Ancillary care obligations in light of an African bioethic: from entrustment to communion.

Henry Richardson recently published the first book ever devoted to ancillary care obligations, which roughly concern what medical researchers are morally required to provide to participants beyond what safety requires. In it, Richardson notes that he is presenting the 'only fully elaborated view out there' on this topic, which he calls the 'partial-entrustment model'. In this article, I provide a new theory of ancillary care obligations, one that is grounded on ideals of communion salient in the African philosophical tradition and that is intended to rival and surpass Richardson's model, which is a function of Western considerations of autonomy. I argue that the relational approach of the former has several virtues in comparison to the basic individualism of the latter.

Planning for Ancillary Care Provision: Lessons From the Developing World.

As part of a study designed to assess a new strategy for increasing health research participation by members of underrepresented populations in the United States, we explored expectations about volunteering for research among people from lower income and largely minority communities in Madison, Wisconsin. Members of these communities often saw research participation as a means to access health care that might otherwise be unavailable to them. In light of persistent structural barriers to access, and the resulting health disparities, we argue that one cannot assume the existence of a "fair exchange" in which a community is likely to benefit from the results of research conducted with members of that community. We use ethical analysis and empirical research conducted in the developing world to explore how investigators in the United States might think about their obligations to provide ancillary care.

The unintended implications of blurring the line between research and clinical care in a genomic age.

While the development of next-generation sequencing technology has had a paradigm-changing impact on biomedical research, there is likely to be a gap between discovery of therapeutic benefits in research and actual adoption of the new technology into clinical practice. This gap can create pressure on the research enterprise to provide individualized care more typical of the clinic setting because it is uniquely accessible in research. This blurring of the line between research and clinical care is understandable, and perhaps even inevitable. But even if the gap is only transitory, such a blurring can have lasting implications, both by expanding obligations imposed on researchers, but also by challenging long-held ethical views. We explore this idea, focusing on how the dissolving distinction between research and clinical care has influenced the vigorous debate around how researchers should manage genetic findings (sometimes separated into primary and incidental or secondary findings) resulting from research.