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Objective Research recruitment through patient portals (ie, patient-facing, web-based clinical interfaces) has the potential to be effective, efficient, and inclusive, but best practices remain undefined. We sought to better understand how patients view this recruitment approach. Materials and Methods We conducted 6 focus groups in Atlanta, GA and Seattle, WA with members of patient advisory committees and the general public. Discussions addressed acceptability of patient portal recruitment and communication preferences. Focus groups were audio-recorded, transcribed, and analyzed using deductive and inductive codes. Iterative team discussions identified major themes. Results Of 49 total participants, 20 were patient advisory committee members. Participants’ mean age was 49 (range 18–74); 59% identified as non-Hispanic White and 31% as Black/African American. Participants were supportive of patient portal recruitment and confident that messages were private and legitimate. Participants identified transparency and patient control over whether and how to participate as essential features. Concerns included the frequency of research messages and the ability to distinguish between research and clinical messages. Participants also discussed how patient portal recruitment might affect diversity and inclusion. Discussion Focus group participants generally found patient portal recruitment acceptable and perceived it as secure and trustworthy. Transparency, control, and attention to inclusiveness were identified as key considerations for developing best practices. Conclusion For institutions implementing patient portal recruitment programs, continued engagement with patient populations can help facilitate translation of these findings into best practices and ensure that implemented strategies accomplish intended goals.

The US Food and Drug Administration (FDA) has issued emergency use authorizations (EUAs) for monoclonal antibodies (mAbs) for nonhospitalized patients with mild or moderate coronavirus disease 2019 (COVID-19) disease and for individuals exposed to COVID-19 as postexposure prophylaxis. EUAs for oral antiviral drugs have also been issued. Due to increased demand because of the Delta variant, the federal government resumed control over the supply and asked states to ration doses. As future variants (eg, the Omicron variant) emerge, further rationing may be required. We identify relevant ethical principles (ie, benefiting people and preventing harm, equal concern, and mitigating health inequities) and priority groups for access to therapies based on an integrated approach to population health and medical factors (eg, urgently scarce healthcare workers, persons in disadvantaged communities hard hit by COVID-19). Using priority categories to allocate scarce therapies effectively operationalizes important ethical values. This strategy is preferable to the current approach of categorical exclusion or inclusion rules based on vaccination, immunocompromise status, or older age, or the ad hoc consideration of clinical risk factors., Existing proposals for allocating scarce monoclonal antibodies and other treatments for coronavirus disease 2019 (COVID-19) focus on vaccination/immunocompromise status and older age; by contrast, we propose that fair allocation requires application of ethical principles that yield different priority categories.

ImportanceMinoritized groups are less likely to receive COVID-19 therapeutics, but few studies have identified potential methods to reduce disparities.ObjectiveTo determine whether screening plus outreach, when compared with referral alone, increases identification of vulnerable pediatric patients at high risk for severe disease eligible for COVID-19 therapeutics from low-resourced communities.Design, Setting, and ParticipantsA retrospective cohort study of COVID-19 medication allocation between January 1, 2022, and February 15, 2022, at Lurie Children’s Hospital, a quaternary care children’s hospital, in Chicago, Illinois. The cohorts were pediatric patients referred for COVID-19 therapeutics or with a positive SARS-CoV-2 polymerase chain reaction within the hospital system followed by outreach. Screening involved daily review of positive cases of SARS-CoV-2, followed by medical record review for high-risk conditions, and communication with clinicians and/or patients and families to offer therapy.ExposuresDiagnosis of COVID-19.Main Outcomes and MeasuresThe primary measure was difference in child opportunity index (COI) scores between the 2 cohorts. Secondary measures included presence and duration of symptoms at diagnosis, medication uptake, race and ethnicity, insurance type, qualifying medical condition, sex, primary language, and age.ResultsOf 145 total patients, the median (IQR) age was 15 (13-17) years, and most were male (87 participants [60.0%]), enrolled in public insurance (83 participants [57.2%]), and members of minoritized racial and ethnic groups (103 participants [71.0%]). The most common qualifying conditions were asthma and/or obesity (71 participants [49.0%]). From 9869 SARS-CoV-2 tests performed, 94 eligible patients were identified via screening for COVID-19 therapeutics. Fifty-one patients were identified via referral. Thirty-two patients received medication, of whom 8 (25%) were identified by screening plus outreach alone. Compared with referred patients, patients in the screening plus outreach group were more likely to have moderate, low, or very low COI composite scores (70 patients [74.5%] vs 27 patients [52.9%]); public insurance (65 patients [69.1%] vs 18 patients [35.3%]); and asthma or obesity (60 patients [63.8%] vs 11 patients [21.6%]). Patients in the referral group were more likely to be non-Hispanic White (23 patients [45.1%] vs 19 patients [20.2%]) and receive medication (24 patients [47.1%] vs 8 patients [8.5%]).Conclusions and RelevanceCompared with referral patients, screening plus outreach patients for COVID-19 medications were more socially vulnerable, with lower COI scores, and more likely to have asthma or obesity. Future studies should investigate communication strategies to improve uptake of these medications after outreach.

Research in rapidly evolving policy contexts can lead to the following ethical challenges for sponsors and researchers: the study’s standard of care can become different than what patients outside the study receive, there may be political or other pressure to move ahead with unproven interventions, and new findings or revised policies may decrease the relevance of ongoing studies. These ethical challenges are considerable, but not unprecedented. In this article, we review the case of a multinational, randomized, controlled perinatal HIV prevention trial, the “PROMISE” (Promoting Maternal Infant Survival Everywhere) study. PROMISE compared the relative efficacy and safety of interventions to prevent mother to child transmission of HIV. The sponsor engaged an independent international ethics panel to address controversy about the study’s standard of care and relevance as national and international guidelines changed. This ethics panel concluded that continuing the PROMISE trial as designed was ethically permissible because: (1) participants in all arms received interventions that were effective, and there was insufficient evidence about whether one intervention was more effective or safer than the other, and (2) data from PROMISE could be useful for a diverse range of stakeholders. In general, trials designed to inform rapidly evolving policy issues should develop mechanisms to revisit social value while recognizing that the value of research varies for diverse stakeholders with legitimate reasons to weigh evidence differently. We conclude by providing four reasons that trials may depart from the standard of care after a change in policy, while remaining ethically justifiable, and by suggesting how to improve existing trial oversight mechanisms to address evolving social value.

Background: Providing individuals with immediate, consistent inducements for health behaviors that do not provide proximal tangible benefits may promote adherence to diabetes self-management behaviors. Objective: To evaluate whether financial incentives lead to improvement in glycemic control and self-management behaviors in adolescents with type 1 diabetes. Methods: We conducted a randomized controlled crossover study with 12-18 year olds with type 1 diabetes. Adolescents self-selected target self-management behaviors (e.g., increase continuous glucose monitor [CGM] sensor wear time) and outcome goals (e.g., improve time in range [TIR]) and could earn up to $180 in each 3-month intervention cycle. Adolescents cycled through 3 study arms every 3 months: gain-framed payment where adolescents earned money for meeting behavioral goals, loss-framed payment where adolescents lost a portion of a weekly payment for not meeting behavioral goals, and usual care. Adolescents earned or lost $1.75 per day in the financial incentives arms, and a $2.75 weekly bonus for meeting their outcome-based goal. Goals were modeled against study arms with generalized linear mixed models to account for the longitudinal nature of the crossover design. Results: Out of 39 participants (mean age 16.1 years, 54% male, mean baseline HbA1c 9.42%, 38% insulin pump use, 95% CGM use) , 34 completed the trial. Mean HbA1c aggregated over all interventions was lower compared to baseline at 9.07% (p=0.13) and there was no difference in HbA1c among the 3 arms. Compared to the mean TIR for those under usual care of 39%, mean TIR under gain- and loss-frames were 45% (p Conclusions: Financial incentives can improve adolescent self-management behaviors and time in range in the short term and merits further longitudinal study to evaluate the effects on glycemic control and health care utilization. Disclosure F. Malik: n/a. T. Chen: None. M. Manzueta: None. J. Yi-frazier: None. C. Pihoker: None. J. L. Leblanc: None. S. K. Shah: None. D. Wright: None. Funding American Diabetes Association (1-18-ICTS-100)

Coronavirus disease 2019 (COVID-19) vaccines are being developed and implemented with unprecedented speed. Accordingly, trials considered ethical at their inception may quickly become concerning. We provide recommendations for Data and Safety Monitoring Boards (DSMBs) on monitoring the ethical acceptability of COVID-19 vaccine trials, focusing on placebo-controlled trials in low- and middle-income countries.

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.

There is limited guidance on how to assess the ethical acceptability of research risks that extend beyond research participants to third parties (or "research bystanders"). Community or stakeholder engagement has been proposed as one way to address potential harms to community members, including bystanders. Despite widespread agreement on the importance of community engagement in biomedical research, this umbrella term includes many different goals and approaches, agreement on which is ethically required or recommended for a particular context. We analyse the case of a potential Zika virus human challenge trial to assess whether and how community engagement can help promote the ethical acceptability of research posing risks to bystanders. We conclude that, in addition to having intrinsic value, community engagement can improve the identification of bystander risks, effective approaches to minimizing them, and transparency about bystander risks for host communities.

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.

Background The rising prevalence of hepatitis C virus (HCV) infection and the availability of direct acting antivirals for HCV treatment has prompted a public health goal of HCV eradication. Despite the availability of treatment for HCV, treatment programs have generally excluded pregnant individuals. Our objective was to query patients and clinicians to identify barriers to including pregnant individuals in HCV treatment programs. Methods and findings This qualitative investigation included obstetricians and previously/currently pregnant individuals with HCV. Participants completed interviews regarding knowledge of and attitudes towards HCV treatment and perceived barriers to treatment during pregnancy. Data were analyzed using the constant comparative method. Obstetricians (N = 18) and patients (N = 21) described concerns about equity, access, and cost. Both expressed uncertainty about safety and confirmed a need for clinician education. Obstetricians emphasized the lack of professional guidelines. Although some clinicians expressed concern about patient adherence and engagement, patients were largely desirous of treatment; both groups identified potential benefits of antenatal treatment. Conclusions Both patients and obstetricians were generally receptive to HCV treatment in pregnancy and recognized pregnancy as an important window of opportunity for treatment. Our findings suggest the need for further research on maternal-fetal safety of HCV treatment as well as on interventions to ensure fair and appropriate access to HCV treatment for pregnant individuals.

In human challenge trials (HCTs), volunteers are deliberately infected with an infectious agent. Such trials can be used to accelerate vaccine development and answer important scientific questions. Starting early in the COVID-19 pandemic, ethical concerns were raised about using HCTs to accelerate development and approval of a vaccine. Some of those concerns pertained to potential exploitation of and/or lack of truly informed consent from volunteers. Specific areas of concern arose around individuals who may be unusually risk-seeking or too economically vulnerable to refuse the payments these trials provide, as opposed to being motivated primarily by altruistic goals. This pre-registered study is the first large-scale survey to characterize people who, early in the pandemic, expressed interest and intention to volunteer to participate in COVID-19 HCTs. We found that individuals expressing interest in SARS-CoV-2 HCTs exhibit consistently altruistic motivations without any special indication of poor risk perception or economic vulnerability. In finding that, early in the pandemic, COVID-19 HCTs were able to attract volunteers whose values align with the nature of these trials, and who are not unusually vulnerable to exploitation, this study may allay some ethical concerns about the volunteers interested in participating in such trials.

IntroductionAdolescents and youth living with HIV (AYLHIV) have lower retention in care, adherence to treatment, and viral suppression compared with adults. Stepped care is a process by which clients are assigned to increasingly intensive services or ‘steps’ according to level of need. Differentiated care, in which stable clients access less frequent services, can be combined with stepped care to align needs and preferences of youth to promote optimal engagement in care.Methods and analysisThis hybrid type I effectiveness implementation cluster randomised trial aims to evaluate a data-informed stepped care (DiSC) intervention for AYLHIV. AYLHIV ages 10–24 receiving care at 24 HIV treatment facilities in Kisumu, Homabay and Migori counties in Kenya will be enrolled. Twelve facilities will be randomised to the DiSC intervention, and 12 will provide standard care. A clinical assignment tool developed by the study team will be used at intervention sites to assign AYLHIV to one of four steps based on risk for loss to follow-up: differentiated care, standard care, counselling services or intensive support services. The primary clinical outcome is retention in care, specifically missed visits (failure to return within 30 days for any visit) and 12-month loss to follow-up. Implementation outcomes are based on the Reach, Effectiveness, Adoption, Implementation and Maintenance framework. Proportions of missed visits will be compared using mixed effect models clustered by facility and participant.Ethics and disseminationThis study has been approved by the University of Washington Institutional Review Board (STUDY00011096), Maseno University Ethical Review Committee (MUERC/00917/20) and the Kenya National Commission for Science, Technology and Innovation (444824). AYLHIV provide written informed consent when legally permitted, or assent with caregiver permission for minors. Study staff will work with a Community Advisory Board, including youth members, to disseminate results via discussions, presentations, journal publications and local or international conferences.Trial registration numberNCT05007717.

Purpose: Adolescents with type 1 diabetes (T1D) often struggle with diabetes self-care tasks and achieving optimal glycemic control. Financial incentive (FI) programs may improve T1D self-care and health outcomes. We aimed to quantify adolescent preferences for the structure of FI. Methods: We performed a discrete choice experiment with 12-18 year-olds with T1D from two pediatric hospital endocrinology clinics in Seattle (n = 185) and Boston (n = 141). We used a literature review and focus groups to identify key attributes of FI: (1) monthly value of the reward, (2) payment structure (positive vs. negative reinforcement), and (3) difficulty of behaviors being incentivized. Using these three attributes, we generated a balanced set of profiles representing hypothetical FI using a fractional factorial design. In twelve choice questions, adolescents were shown a pair of profiles and chose the FI option more likely to motivate them to increase adherence to recommended self-care. The options presented were tailored to adolescents’ modes of insulin administration and glucose monitoring and to adolescents’ individual rating of the difficulty of completing each behavior. We used a multinomial logit choice model to analyze data. Results: The value of the reward was the primary driver of preferences, accounting for 50% of preferences. Adolescents significantly preferred FI with a positive vs. negative reinforcement payment structure ($5.17 (95% CI: $4.11, $6.25)) and preferred higher FI for performing hard vs. easier behaviors ($6.95 (95% CI: $4.57, $8.33)). Preferences were associated with respondent age and HbA1c (p Conclusions: Adolescent stated preferences should inform the design of a T1D FI intervention, which can then be tested in randomized controlled trials to determine the impact of FI on T1D self-care adherence and health outcomes. Latent class analyses can identify subgroups with differential preferences and will explore subgroup characteristics. Disclosure D. Wright: None. K. Chalmers: None. J. L. Leblanc: None. J. Yi-frazier: None. S. K. Shah: None. K. Garvey: None. K. Senturia: None. C. Pihoker: None. F. Malik: None. Funding American Diabetes Association (1-18-ICTS-100 to D.W.)

To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial.This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision.In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status.Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

In human challenge trials, volunteers are deliberately infected with a pathogen to accelerate vaccine development and answer key scientific questions. In the U.S., preparations for challenge trials with the novel coronavirus are complete, and in the U.K., challenge trials have recently begun. However, ethical concerns have been raised about the potential for invalid consent or exploitation. These concerns largely reflect worries that challenge trial volunteers may be unusually risk-seeking or too economically vulnerable to refuse the payments these trials provide, rather than being motivated primarily by altruistic goals. We conducted the first large-scale survey of intended human challenge trial volunteers and found that SARS-CoV-2 challenge trial volunteers exhibit high levels of altruistic motivations without any special indication of poor risk perception or economic vulnerability. Findings indicate that challenge trials with the novel coronavirus can attract volunteers with background conditions, attitudes, and motivations that should allay key ethical concerns.

ispartof: VACCINE vol:39 issue:7 pages:1028-1029 ispartof: location:Netherlands status: published

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.

Development of an effective vaccine is the clearest path to controlling the coronavirus disease 2019 (COVID-19) pandemic. To accelerate vaccine development, some researchers are pursuing, and thousands of people have expressed interest in participating in, controlled human infection studies (CHIs) with severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) (1, 2). In CHIs, a small number of participants are deliberately exposed to a pathogen to study infection and gather preliminary efficacy data on experimental vaccines or treatments. We have been developing a comprehensive, state-of-the-art ethical framework for CHIs that emphasizes their social value as fundamental to justifying these studies. The ethics of CHIs in general are underexplored (3, 4), and ethical examinations of SARS-CoV-2 CHIs have largely focused on whether the risks are acceptable and participants could give valid informed consent (1). The high social value of such CHIs has generally been assumed. Based on our framework, we agree on the ethical conditions for conducting SARS-CoV-2 CHIs (see the table). We differ on whether the social value of such CHIs is sufficient to justify the risks at present, given uncertainty about both in a rapidly evolving situation; yet we see none of our disagreements as insurmountable. We provide ethical guidance for research sponsors, communities, participants, and the essential independent reviewers considering SARS-CoV-2 CHIs.

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.

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.

Controlled human infection (CHI) models have been developed for numerous pathogens in order to better understand disease processes and accelerate drug and vaccine testing. In the past, some researchers conducted highly controversial CHIs with vulnerable populations, including children. Ethical frameworks for CHIs now recommend vulnerable populations be excluded because they cannot consent to high risk research. In this paper we argue that CHI studies span a wide spectrum of benefit and risk, and that some CHI studies may involve minimal risk. The categorical exclusion of children from CHIs therefore departs from the standard approach to evaluating research risks, as international regulations and ethical guidance for pediatric research generally permit non-beneficial research with low risks. The paradigm in research ethics has also shifted from focusing on protecting vulnerable participants to recognizing that inclusion can be important as a matter of justice, providing new reasons to question this default exclusion of children from CHIs. Recognizing that pediatric CHIs can raise complex ethical issues and are easy to sensationalize in ways that may threaten the public's trust in research and sponsor institutions, we conclude by describing additional complexities that must be addressed before pediatric CHIs beyond licensed vaccine studies might be ethically acceptable.

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.

Shared decision-making (SDM) has emerged as the preferred decision-making model in the clinician-patient relationship. Through collaboration, SDM helps to facilitate evidence-based medical decisions that are closely aligned with patient or surrogate preferences, values, and goals. How to implement SDM in clinical pediatric practice, however, remains elusive, in part because SDM in pediatrics is complicated by the involvement of parents as a special class of surrogate decision-maker. A provisional framework for the process of SDM in pediatrics was recently proposed by Opel to help facilitate its implementation. To identify aspects of the framework that require refinement, we applied it across a diverse range of clinical cases from multiple pediatric specialties. In doing so, several questions surfaced that deserve further scrutiny: (1) For which medical decisions is consideration of SDM required? (2) What is considered medically reasonable when there is variability in standard practice? (3) Can an option that is not consistent with standard practice still be medically reasonable? (4) How should public health implications be factored into SDM? (5) How should variability in preference sensitivity be approached? (6) How should the developing autonomy of adolescents be integrated into SDM?; and (7) How should SDM address parental decisional burden for emotionally charged decisions? We conduct a brief analysis of each question raised to illustrate key areas for future research.

Importance It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation. Objective To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial. Design, Setting, and Participants This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020. Exposure Parental choice of enrollment in neonatal clinical trial. Main Outcomes and Measures Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child’s medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant’s illness, (3) study comprehension, and (4) trust in clinicians and researchers. Results Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%];P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%];P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant’s medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment. Conclusions and Relevance In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.

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.

Key Points Question Is the timing of parents' decision on whether to enroll their children in research associated with review of the informed consent form? Findings This online survey study of 88 parents who either enrolled (n = 67) or declined to enroll (n = 21) their child in a weight management intervention study revealed that 67% decided whether to enroll before receiving the consent form. Twenty-five percent who remembered receiving the consent form reported that it taught them new information. Meaning The findings of this study suggest that regulatory review and interventions to improve decision-making should focus on early engagement throughout the recruitment and consent process rather than just consent forms to affect decision-making., Importance Obtaining informed consent is an important ethical obligation for clinical research participation that is imperfectly implemented. Research on improving consent processes often focuses on consent forms, but little is known about consent forms’ influence on decision-making compared with other types of engagement. Objective To evaluate whether parents decide whether to enroll their children in research before or after they receive the consent form. Design, Setting, and Participants An online survey of 88 parents who enrolled or declined to enroll their child in a weight management intervention study between January 2, 2018, and June 24, 2019, was conducted; surveys were completed between February 2, 2018, and July 9, 2019. A 31-item survey asked about impressions of the study throughout the enrollment process, timing of enrollment decisions, and decision-making factors. Responses were summarized descriptively and subgroups were compared using the Fisher exact test or χ2 test. Main Outcomes and Measures Self-reported timing of enrollment decision. Results A total of 106 parents were approached and gave permission for their contact information to be shared with the study team; 22 additional parents declined to allow their information to be shared, and 24 lost contact with the partner study before they could be asked for permission. A total of 88 parents (67 enrollees, 21 decliners) completed the survey (83% participation rate); 79 of 88 reporting gender (instead of sex, as biological sex was not relevant to survey) information were women (91%), 66 participants (75%) were non-Hispanic White, and 63 participants (72%) had annual household incomes greater than or equal to $70 000. No significant differences in respondent characteristics between enrollees and decliners were identified. Fifty-nine parents (67%) responded that they decided whether to enroll in the weight management study before receiving the consent form. Only 17 of 69 parents (25%) who remembered receiving the consent form responded that it taught them new information. Conclusions and Relevance The findings of this study suggest that interventions to improve informed consent forms may have limited influence on decision-making because many research decisions occur before review of the consent form. It appears that regulatory review and interventions to improve decision-making should focus more on early engagement (eg, recruitment materials). Future studies should test timing of decisions in other types of research with different populations and clinical settings., This survey study examines use of the informed consent form in decision-making by parents on enrollment of their children in a weight management study.

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.

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.

In 2013, researchers announced that a newborn child from Mississippi, USA might have been functionally cured of HIV by being given combination antiretroviral therapy within hours of birth. Public and media attention has since been captured by the possibility of finding a cure for HIV transmitted from mother to child. Research into the strategy used for the Mississippi patient is crucially important to establish whether it can be replicated and shown to work in diverse populations. At the same time, any ethical issues likely to arise in such studies should be addressed and not ignored in the pursuit of a functional cure. In this Personal View we identify ethical issues that could arise in research towards achievment of a functional cure for HIV in neonates, including difficult trade-offs associated with choosing the study population and questions about the broader social implications of the research, and propose ways to resolve them.

IMPORTANCE: California implemented 3 interventions to increase uptake of vaccines. In 2014, Assembly bill 2109 tightened requirements for obtaining a personal belief exemption. A 2015 campaign provided educational materials to school staff on the proper application of conditional admission for kindergartners who were not up to date on required vaccinations. In 2016, Senate bill 277 eliminated personal belief exemptions. Prior research has not evaluated these 3 interventions together with regard to the vaccination status of students. OBJECTIVE: To assess the changes in the yearly rates of kindergartners who were not up to date on required vaccinations who were entering school during the period of the interventions, by focusing on geographic clustering and the potential contacts of these kindergartners. DESIGN, SETTING, AND PARTICIPANTS: Observational study that used cross-sectional school-entry data from 2000-2017 to calculate the rates of kindergartners attending California schools who were not up to date on required vaccinations. EXPOSURES: Assembly bill 2109, a conditional admission education program, and Senate bill 277. MAIN OUTCOMES AND MEASURES: The primary outcome was the yearly rate of kindergartners without up-to-date vaccination status. The secondary outcomes were (1) the modified aggregation index, which was used to assess the potential within-school contacts among kindergartners without up-to-date vaccination status, (2) the number of geographic clusters of schools with rates for kindergartners without up-to-date vaccination status that were higher than the rates for schools located outside the cluster, and (3) the number of schools located inside the geographic clusters. RESULTS: In California between 2000 and 2017, 9 323 315 children started attending kindergarten and 721 593 were not up to date on required vaccinations. Prior to the interventions, the statewide rate of kindergartners without up-to-date status for required vaccinations increased from 7.80% during 2000 to 9.84% during 2013 and then decreased after the interventions to 4.87% during 2017. The percentage chance for within-school contact among kindergartners without up-to-date vaccination status decreased from 26.02% during 2014 to 4.56% (95% CI, 4.21%-4.99%) during 2017. During 2012-2013, there were 124 clusters that contained 3026 schools with high rates of kindergartners without up-to-date vaccination status. During 2014-2015, there were 93 clusters that contained 2290 schools with high rates of kindergartners without up-to-date vaccination status. During 2016-2017, there were 110 clusters that contained 1613 (95% CI, 1565-1691) schools. CONCLUSIONS AND RELEVANCE: In California, statewide legislative and educational interventions were associated with a decrease in the yearly rates of kindergartners without up-to-date vaccination status. These interventions also were associated with reductions in the number of schools inside the clusters with high rates of kindergartners without up-to-date vaccination status and the potential for contact among these kindergartners.

The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria.

In rapidly evolving medical fields where the standard of care or prevention changes frequently, guidelines are increasingly likely to conflict with what participants receive in research. Although guidelines typically set the standard of care, there are some cases in which research can justifiably deviate from guidelines. When guidelines conflict with research, an ethical issue only arises if guidelines are rigorous and should be followed. Next, it is important that the cumulative evidence and the conclusions reached by the guidelines do not eliminate the need for further research. Even when guidelines are rigorous and the study still asks an important question, we argue that there may be good reasons for deviations in three cases: (1) when research poses no greater net risk than the standard of care; (2) when there is a continued need for additional evidence, for example, when subpopulations are not covered by the guidelines; and (3) less frequently, when clinical practice guidelines can be justified by the evidence, but practitioners disagree about the guidelines, and the guidelines are not consistently followed as a result. We suggest that procedural protections may be especially useful in deciding when studies in the third category can proceed.

Advances in life-saving technologies in the past few decades have challenged our traditional understandings of death. Traditionally, death was understood to occur when a person stops breathing, their heart stops beating and they are cold to the touch. Today, physicians determine death by relying on a diagnosis of 'total brain failure' or by waiting a short while after circulation stops. Evidence has emerged, however, that the conceptual bases for these approaches to determining death are fundamentally flawed and depart substantially from the established biological conception of death. We argue that the current approach to determining death consists of two different types of unacknowledged legal fictions. These legal fictions were developed for practices that are largely ethically legitimate but need to be reconciled with the law. The considerable debate over the determination of death in the medical and scientific literature has not informed the public that vital organs are being procured from still-living donors and it seems unlikely that this information can remain hidden for long. Given the instability of the status quo and the difficulty of making the substantial legal changes required by complete transparency, we argue for a second-best policy solution: acknowledging the legal fictions involved in determining death to move in the direction of greater transparency. This may someday result in more substantial legal change to directly confront the challenges raised by life-sustaining and life-preserving technologies without the need for fictions.

Many guidelines for international research require that studies be responsive to host community health needs or health priorities. Although responsiveness possesses great intuitive and rhetorical appeal, existing conceptions are confusing and difficult to apply. Not only are there few examples of what research the responsiveness requirement permits and what it rejects, but its application can lead to contradictory results. Because of the practical difficulties in applying responsiveness and the danger that misapplying responsiveness could harm the interests of developing countries, we argue that responsiveness should be refocused in three ways: in terms of (1) who enforces it, (2) under what standard, and (3) in what cases. We conclude that responsiveness should be applied by host country officials at the policy level with the exercise of judgment when externally funded research threatens to displace scarce local resources.

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.

There is wide agreement that communities in lower-income countries should benefit when they participate in multinational research. Debate now focuses on how and to what extent these communities should benefit. This debate has identified compelling reasons to reject the claim that whatever benefits a community agrees to accept are necessarily fair. Yet, those who conduct clinical research may conclude from this rejection that there is no reason to involve communities in the process of deciding how they benefit. Against this possibility, the present manuscript argues that involving host communities in this process helps to promote four important goals: (1) protecting host communities, (2) respecting host communities, (3) promoting transparency, and (4) enhancing social value.