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BACKGROUND: Adolescents in low- and middle-income countries (LMICs) have a high burden of HIV, increasing the importance of including adolescents in HIV research. Adolescence is a period of transition that introduces unique ethical challenges for HIV research. The aim of this paper is to describe the ethical-legal barriers to adolescent participation in HIV research studies and potential strategies for including adolescents in LMIC research studies. METHODS: We examined experiences from PATC3H, a research consortium focused on HIV prevention and treatment research in resource-constrained settings. The consortium includes studies in Brazil, Kenya, Mozambique, Nigeria, South Africa, Zambia, and Uganda. PATC3H researchers were asked to identify ethical and practical challenges for adolescent consent to research participation in these countries. We also used standardized scenarios to facilitate comparison of adolescent consent in these seven countries. Informed by our examination of PATC3H consortium experiences, we conducted a scoping review focused on solutions that could be used to enhance adolescent participation in LMIC HIV studies. FINDINGS: Our consortium experiences demonstrated many ethical challenges, including the following: inconsistent or absent guidance for the conditions under which adolescents can independently consent to research participation; guidelines that fail to account for the full array of adolescents’ lives; and substantial variation in how ethical review committees assess adolescent research studies. Our scoping review identified several potential consent-related strategies to expand adolescent access to HIV research, including waiving parental consent requirements, allowing adolescents to provide independent research consent, and clarifying surrogate decision-making processes. INTERPRETATION: While there are several ethical and practical challenges in adolescent consent to HIV research participation in LMICs, these challenges can be addressed by alternative consent strategies. Guidance on the ethics of adolescent HIV research is needed to increase adolescent participation in research.

We conducted an online experimental survey to evaluate attitudes toward an authorization for contact (AFC) program allowing researchers to contact patients about studies based on electronic record review. A total of 1070 participants were randomly assigned to 1 of 3 flyers varying in design and framing. Participants were asked to select concerns about and reasons for signing up for AFC. Logistic regression and latent class analysis were conducted. The most commonly selected concerns included needing more information (43%), privacy (40%), and needing more time to think (28%). A minority were not interested in participating in research (16%) and did not want to be bothered (15%). Latent class analysis identified clusters with specific concerns about privacy, lack of interest in research, and not wanting to be bothered. A novel flyer with simple and positive framing was associated with lower odds of both not wanting to be bothered (P = .01) and not being interested in research (P = .01). Many concerns about AFC programs appear nonspecific. Addressing privacy, lack of interest in research, and not wanting to be bothered warrant further study as ways to enhance recruitment.

Purpose One third of people newly living with HIV/AIDS are adolescents. Research on adolescent HIV prevention is critical owing to differences between adolescents and adults. Parental permission requirements are often considered a barrier to adolescent enrollment in research, but whether adolescents view this barrier as the most important one is unclear. Methods Adolescents were approached in schools in KwaZulu-Natal, South Africa, and at a sexually transmitted infection clinic at the Children’s Hospital of Aurora, Colorado. Surveys with a hypothetical vignette about participation in a pre-exposure prophylaxis trial were conducted on smartphones or tablets with 75 adolescents at each site. We calculated descriptive statistics for all variables, using 2-sample tests for equality of proportions with continuity correction. Statistical significance was calculated at p Results Most adolescents thought side effects (77%) and parental consent requirements (69%) were very important barriers to research participation. When asked to rank barriers, adolescents did not agree on a single barrier as most important, but the largest group of adolescents ranked parental consent requirements as most important (29.5%). Parental consent was seen as more of a barrier for adolescents in South Africa than in the United States. Concerns about being experimented on or researchers’ mandatory reporting to authorities were ranked much lower. Finally, most (71%, n = 106) adolescents said they would want to extra support from another adult if parental permission was not required. Conclusion Adolescents consider both parental permission requirements and side effects important barriers to their enrollment in HIV prevention research. Legal reform and better communication strategies may help address these barriers.

Background An understanding of acceptability among potential intervention participants is critical to the design of successful real-world financial incentive (FI) programs. The purpose of this qualitative study was to explore adolescent and parent perspectives on the acceptability of using FI to promote engagement in diabetes self-care in adolescents with type 1 diabetes (T1D). Methods Focus groups with 46 adolescents with T1D (12-17 years old) and 39 parents of adolescents with T1D were conducted in the Seattle metropolitan area. Semistructured questions addressed participants' current use of incentives to promote change in diabetes self-care and receptivity to a theoretical incentive program administered by a third-party. Qualitative data were analyzed and emergent themes identified. Results Three thematic categories informed participant views about the acceptability of FI programs: (a) the extent to which using FIs in the context of diabetes management fit comfortably into a family's value system, (b) the perceived effectiveness for FIs to promote improved diabetes self-care, and (c) the urgent need for improved self-care due to the threat of diabetes-related health complications. These factors together led most parents and adolescents to be open to FI program participation. Conclusions The results from this qualitative study suggest that well-designed FI programs to support diabetes management are acceptable to families with adolescents with T1D. Additionally, the use of FIs may have the potential to support adolescents with T1D in developing strong self-care habits and ease the often-turbulent transition to independent self-care.

HCV infections have increased in recent years due to injection drug use and the opioid epidemic. Simultaneously, HCV cure has become a reality, with the advent of direct-acting antivirals (DAAs) and expansion of treatment programs. As a result, HCV screening recommendations now include all adults, including pregnant individuals; and many countries have endorsed widespread DAA access as a strategy to achieve HCV eradication. However, almost universally, pregnant individuals have been systematically excluded from HCV clinical research and treatment programs. This omission runs counter to public health strategies focused on elimination of HCV but is consistent with a historical pattern of exclusion of pregnant individuals from research. Our systematic review of publications on HCV treatment with DAAs in pregnancy revealed only one interventional study, which evaluated sofosbuvir/ledipasvir in 8 pregnant individuals. Given the paucity of research on this issue of great public health importance, we aimed to appraise the current landscape of HCV research/treatment and analyze the ethical considerations for responsibly including pregnant individuals. We propose that pregnancy may be an opportune time to offer HCV treatment given improved access, motivation, and other health care monitoring occurring in the antenatal period. Moreover, treatment of pregnant individuals may support the goal of eliminating perinatal HCV transmission and overcome the established challenges with transitioning care after delivery. The exclusion of pregnant individuals without justification denies them and their offspring access to potential health benefits, raising justice concerns considering growing data on DAA safety and global efforts to promote equitable and comprehensive HCV eradication. Finally, we propose a path forward for research and treatment programs during pregnancy to help advance the goal of HCV elimination.

It is widely agreed that an effective response to the coronavirus disease 2019 pandemic needs to include a vaccine that is safe and effective for minors. However, many current vaccine trials have no plans for when to enroll minors. Others have recently proposed enrolling minors as young as 12 years old. This lack of a systematic approach raises 2 concerns. Waiting too long to enroll minors could unjustly deny minors and their families the benefits of a vaccine and has the potential to delay an effective response to the pandemic by a year or longer. At the same time, enrolling minors too soon runs the risk of exposing them to excessive risks. With these concerns in mind, in the present article, we propose recommendations for when and how to enroll minors in vaccine trials for the coronavirus disease 2019.

Highlights • Quickly finding a safe and effective vaccine against SARS Co-V-2 would be of great value. • Collecting rigorous safety and efficacy data without compromising ethical and scientific norms is critical. • The best approach is accelerated individually randomized controlled trials. • Premature distribution could hamper public health and finding safe, effective SARS CoV-2 vaccines., Background A sense of urgency exists to develop vaccines against SARS CoV-2, responsible for numerous global cases and deaths, as well as widespread social and economic disruption. Multiple approaches have been proposed to speed up vaccine development, including accelerated randomized controlled trials (RCT), controlled human challenge trials (CHI), and wide distribution through an emergency use authorization after collecting initial data. There is a need to examine how best to accelerate vaccine development in the setting of a pandemic, without compromising ethical and scientific norms. Methods Trade-offs in scientific and social value between generating reliable evidence about safety and efficacy while promoting rapid vaccine availability are examined along five ethically relevant dimensions: (1) confidence in and generalizability of data, (2) feasibility, (3) speed and cost, (4) participant risks, and (5) social risks. Results Accelerated individually randomized RCTs permit expeditious evaluation of vaccine candidates using established methods, expertise, and infrastructure. RCTs are more likely than other approaches to be feasible, increase speed and reduce cost, and generate reliable data about safety and efficacy without significantly increasing risks to participants or undermining societal trust. Conclusion Ethical analysis suggests that accelerated RCTs are the best approach to accelerating vaccine development in a pandemic, and more likely than other approaches to enhance social value without compromising ethics or science. RCTs can expeditiously collect rigorous data about vaccine safety and efficacy. Innovative and flexible designs and implementation strategies to respond to shifting incidence and test vaccine candidates in parallel or sequentially would add value, as will coordinated data sharing across vaccine trials. CHI studies may be an important complementary strategy when more is known. Widely disseminating a vaccine candidate without efficacy data will not serve the public health nor achieve the goal of identifying safe and effective SARS Co-V-2 vaccines.

Brain death, or the determination of death by neurological criteria, has been described as a legal fiction. Legal fictions are devices by which the law treats two analogous things (in this case, biological death and brain death) in the same way so that the law developed for one can also cover the other. Some scholars argue that brain death should be understood as a fiction for two reasons: the way brain death is determined does not actually satisfy legal criteria requiring the permanent cessation of all brain function, and brain death is not consistent with the biological conception of death as involving the irreversible cessation of the functioning of an organism as a whole. Critics counter that the idea that brain death is a legal fiction is deceptive and undemocratic. I will argue that diagnosing brain death as a hidden legal fiction is a helpful way to understand its historical development and current status. For the legal-fictions approach to be ethically justifiable, however, the fact that brain death is a legal fiction not aligned with the standard biological conception of death must be acknowledged and made transparent.

Human challenge trials (HCTs) deliberately infect participants in order to test vaccines and treatments in a controlled setting, rather than enrolling individuals with natural exposure to a disease. HCTs are therefore potentially powerful tools to prepare for future outbreaks of emerging infectious diseases. Yet when an infectious disease is emerging, there is often substantial risk and uncertainty about its complications, and few available interventions, making an HCT ethically complex. In light of the need to consider ethical issues proactively as a part of epidemic preparedness, we use the case of a Zika virus HCT to explore whether and when HCTs might be ethically justified to combat emerging infectious diseases. We conclude that emerging infectious diseases could be appropriate candidates for HCTs and we identify relevant considerations and provide a case example to illustrate when they might be ethically acceptable.

According to prominent bioethics scholars and international guidelines, researchers and sponsors have obligations to ensure that the products of their research are reasonably available to research participants and their communities. In other words, the claim is that research is unethical unless it has local social value. In this article, we argue that the existing conception of reasonable availability should be replaced with a social value obligation that extends to the global poor (and not just research participants and host communities). To the extent the social value requirement has been understood as geographically constrained to the communities that host research and the countries that can afford the products of research, it has neglected to include the global poor as members of the relevant society. We argue that a new conception of social value obligations is needed for two reasons. First, duties of global beneficence give reason for researchers, sponsors, and institutions to take steps to make their products more widely accessible. Second, public commitments made by many institutions acknowledge and engender responsibilities to make the products of research more accessible to the global poor. Future research is needed to help researchers and sponsors discharge these obligations in ways that unlock their full potential.

In many regions around the world, those at highest risk for acquiring HIV are young adults and adolescents. Young men who have sex with men (young MSM) in the USA are the group at greatest risk for HIV acquisition, particularly if they are part of a racial or ethnic minority group.1 Adolescent girls and young women have the highest incidence rates of any demographic subgroup in sub-Saharan Africa.2 To reverse the global AIDS pandemic’s toll on these high-risk groups, it is important to deploy the most effective HIV prevention tools to young MSM in the USA, to adolescent girls and young women in sub-Saharan Africa, and to any other adolescents and young adults at high risk for HIV as products are proven to be safe and efficacious. Although prevention interventions with proven efficacy, such as oral pre-exposure prophylaxis (PrEP), are available,3–8 they have not been sufficient to stem the tide and an expanded prevention toolkit is urgently needed to serve these populations. The field of HIV prevention continues to identify promising leads in the development of new biomedical prevention products, either delivering antiviral drug topically (eg, the dapivirine vaginal ring) or systemically (eg, injectable cabotegravir). The dapivirine ring has been shown to provide modest protection and is currently being tested in open label studies while injectable cabotegravir is being tested in a large efficacy trial for preventing HIV acquisition. Advances in the field of HIV prevention mean that scientists and regulators must plan for how they will bring prevention tools to populations at high risk for HIV as they conduct efficacy and effectiveness trials. For instance, safety data from younger age groups can also be used in combination with efficacy data from adult studies, where appropriate, as bridging studies to expand labelling to younger ages. If these …

Controlled human malaria infection (CHMI) studies deliberately infect healthy participants with malaria to test interventions faster and more efficiently. Some argue the study design and high payments offered raise ethical concerns about participants’ understanding of risks and undue inducement. We conducted baseline and exit interviews with 16 CHMI study participants to explore these concerns. Participants described themes including decision-making tension with friends and family, mixed motivations for participating, low study risks but high burdens, fair compensation, sacrificing values, deceiving researchers, and perceived benefits. Our findings do not support concerns that high payments limit understanding of study risks, but suggest participants may lack appreciation of study burdens, withhold information or engage in deception, and experience conflict with others regarding study participation.

BackgroundTo assess ethical concerns associated with participation in a financial incentive (FI) programme to help adolescents with type 1 diabetes improve diabetes self-management.MethodsFocus groups with 46 adolescents with type 1 diabetes ages 12–17 and 38 of their parents were conducted in the Seattle, Washington metropolitan area. Semistructured focus group guides addressed ethical concerns related to the use of FI to promote change in diabetes self-management. Qualitative data were analysed and emergent themes identified.ResultsWe identified three themes related to the ethical issues adolescents and parents anticipated with FI programme participation. First, FI programmes may variably change pressure and conflict in different families in ways that are not necessarily problematic. Second, the pressure to share FIs in some families and how FI payments are structured may lead to unfairness in some cases. Third, some adolescents may be likely to fabricate information in any circumstances, not simply because of FIs, but this could compromise the integrity of FI programmes relying on measures that cannot be externally verified.ConclusionsMany adolescents with type 1 diabetes and their parents see positive potential of FIs to help adolescents improve their self-management. However, ethical concerns about unfairness, potentially harmful increases in conflict/pressure and dishonesty should be addressed in the design and evaluation of FI programmes.

Ethical guidelines recommend that experimental interventions should be tested in adults first before they are tested and approved in children. Some challenge this paradigm, however, and recommend initiating paediatric testing after preliminary safety testing in adults in certain cases. For instance, commentators have argued for accelerated testing of HIV vaccines in children. Additionally, HIV cure research on the use of very early therapy (VET) in infants, prompted in part by the Mississippi baby case, is one example of a strategy that is currently being tested in infants before it has been well tested in adults. Because infants' immune systems are still developing, the timing of HIV transmission is easier to identify in infants than in adults, and infants who receive VET might never develop the viral reservoirs that make HIV so difficult to eradicate, infants may be uniquely situated to achieve HIV cure or sustained viral remission. Several commentators have now argued for earlier initiation of HIV cure interventions other than (or in addition to) VET in children. HIV cure research is therefore a good case for re-examining the important question of when to initiate paediatric research. I will argue that, despite the potential for HIV cure research to benefit children and the scientific value of involving children in this research, the HIV cure agenda should not accelerate the involvement of children for the following reasons: HIV cure research is highly speculative, risky, aimed at combination approaches and does not compare favourably with the available alternatives. I conclude by drawing general implications for the initiation of paediatric testing, including that interventions that have to be used in combination with others and cures for chronic diseases may not be valuable enough to justify early paediatric testing.

20-Hydroxyeicosatetraenoic acid (20-HETE) is formed by the ω-hydroxylation of arachidonic acid by cytochrome P450 4A and 4F enzymes, and it induces angiogenic responses in vivo. To test the hypothesis that 20-HETE increases endothelial cell (EC) proliferation via vascular endothelial growth factor (VEGF), we studied the effects of WIT003 [20-hydroxyeicosa-5(Z),14(Z)-dienoic acid], a 20-HETE analog on human macrovascular or microvascular EC. WIT003, as well as pure 20-HETE, stimulated EC proliferation by ∼40%. These proliferative effects were accompanied by increased VEGF expression and release that were observed as early as 4 h after 20-HETE agonist addition. This was accompanied by increased phosphorylation of the VEGF receptor 2. The proliferative effects of 20-HETE were markedly inhibited by a VEGF-neutralizing antibody. Polyethylene glycol-superoxide dismutase (PEG-SOD) markedly inhibited both the increases in VEGF expression and the proliferative effects of 20-HETE. In contrast, administration of the NAD(P)H oxidase inhibitor apocynin had no effect to the proliferative response to 20-HETE. The 20-HETE agonist markedly increased superoxide formation as reflected by an increase in dihydroethidium staining of EC, and this increase was inhibited by PEG-SOD but not by apocynin. 20-HETE also increased the phosphorylation of p42/p44 mitogen-activated protein kinase (MAPK) in EC, whereas an inhibitor of MAPK [U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] suppressed the proliferative and the VEGF changes but not the pro-oxidant effects of 20-HETE. These data suggest that 20-HETE stimulates superoxide formation by pathways other than apocynin-sensitive NAD(P)H oxidase, thereby activating MAPK and then enhancing VEGF synthesis that drives EC proliferation. Thus, 20-HETE may be involved in the regulation of EC functions, such as angiogenesis.

The revised Common Rule emphasizes the importance of comprehension as a goal of the informed consent process, requiring consent forms to “facilitate … the prospective subject's or legally authorize...

Krause and Gruber offer the U.S. Food and Drug Administration (FDA) as part of the solution to the problems we have identified. We agree that the FDA could helpfully assist with the review of specific protocols for Zika human challenge trials (HCTs), especially given the need to update our panel's

Two critical, recurring questions can arise in many areas of research with human subjects but are poorly addressed in much existing research regulation and ethics oversight: How should research risks to “bystanders” be addressed? And how should research be evaluated when risks are substantial but not offset by direct benefit to participants, and the benefit to society (“social value”) is context-dependent? We encountered these issues while serving on a multidisciplinary, independent expert panel charged with addressing whether human challenge trials (HCTs) in which healthy volunteers would be deliberately infected with Zika virus could be ethically justified ( 1 ). Based on our experience on that panel, which concluded that there was insufficient value to justify a Zika HCT at the time of our report, we propose a new review mechanism to preemptively address issues of bystander risk and contingent social value.

Clinical research with children generates special ethical concern, raising the need for additional protections beyond those for research with competent adults. Most guidelines permit research with children when it offers a prospect of direct benefit, or poses minimal risk. Unlike many other guidelines, the U.S. federal regulations also allow institutional review boards (IRBs) to approve pediatric research that does not offer a prospect of direct benefit when the risks are no greater than a minor increase over minimal risk. To approve research in this category, IRBs must find that two additional conditions obtain:1). The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and 2). The intervention or procedure is likely to yield generalizable knowledge about the subjects disorder or condition which is of vital importance for the understanding or amelioration of the subjects disorder or condition.