JAIDS Journal of Acquired Immune Deficiency Syndromes:
Ethical Issues in Adolescent HIV Research in Resource-Limited Countries
Bekker, Linda-Gail MD, PhD*; Slack, Catherine BA, MA†; Lee, Sonia PhD‡; Shah, Seema JD§; Kapogiannis, Bill MD‡
*The Desmond Tutu HIV Centre, University of Cape Town, Cape Town;
†HIV AIDS Vaccines Ethics Group, School of Applied Human Sciences, College of Humanities, UKZN, Pietermaritzburg, South Africa;
‡Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; and
§NIH Department of Bioethics, Clinical Center and Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD.
Correspondence to: Linda-Gail Bekker, MBChB, DCH, PhD, The Desmond Tutu HIV Centre, University of Cape Town, South Africa (e-mail: Lindafirstname.lastname@example.org).
This research was supported in part by the Intramural Research Program of the NIH Clinical Center and by NIAID, and received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The opinions expressed are the views of the authors. They do not represent any position or policy of the US National Institutes of Health, the Public Health Service, or the Department of Health and Human Services.
Funding was also provided to C. Slack by the South African AIDS Vaccine Initiative (SAAVI) and by the National Institutes of Health award (1RO1 A1094586) CHAMPS (Choices for Adolescent Methods of Prevention in South Africa).
Prior presentation: This work will be presented in part in an online training module on the Training and Resources in Research Ethics Evaluation (TRREE) website (http://elearning.trree.org).
The authors have no conflicts of interest to disclose.
Abstract: Globally, there are 5 million young people aged 15–24 years living with HIV, and many more millions are at risk for HIV acquisition. Compelling research questions exist that require the involvement of young people and other vulnerable populations in HIV-related research in diverse settings around the world. Despite this, there remains a reluctance to involve adolescent participants, including young women, in clinical research. Complex and, at times, contradictory legal and ethical requirements can be a challenge. Ethical benchmarks can be applied to ensure that research meets high-level standards and is planned for appropriately.
In an HIV epidemic that has manifested throughout the world, youth continue to be at considerable risk. Adolescence and young adulthood are the periods when various behaviors put individuals at an increased risk for HIV acquisition: sexual debut occurs, sexual and gender orientation is explored and established, and experimentation with intravenous drugs and sex work careers may occur.1 The World Health Organization estimates that 5 million youth aged 15–24 years are living with HIV/AIDS (most without knowing that they are infected); 39% of all new infections are occurring among young people on a global basis,2 highlighting the need to expand HIV research in general in this population. In keeping with the global burden, an expansion of biomedical HIV research is occurring in most parts of the world, including in low- and middle-income countries. Given the unequal burden of disease, it is both likely and appropriate that more biomedical HIV research will occur in research sites outside of the United States and Europe.3,4
The literature on vulnerable populations in biomedical HIV research, especially in children and adolescents, has undergone a relatively recent shift in thinking, and there is now an important amount of information gained from ethically appropriate and scientifically rigorous research with adolescents.5–14 Despite this, in many parts of the world, there remains reluctance to involve adolescent participants, including young women, in clinical research testing experimental products.15,16 Research that involves human subjects, and especially clinical trials, has come under intense scrutiny by various bodies, including the Office for Human Research Protections, The US Food and Drug Administration, the National Institutes of Health, and Institutional Review Boards and/or Research Ethics Committees. Understanding the complex and, at times, contradictory legal and ethical requirements and harmonizing their application so that research meets high-level standards continues to be a challenge.5
In 2004, scholars developed an ethical framework for research in low- and middle-income countries.17 The benchmarks identified help identify and systematize the ethical issues relevant to the conduct of research with adolescents in such settings: social value, scientific validity, fair subject selection, collaborative partnership, acceptable risk/benefit ratio, independent review, informed consent, and ongoing respect for enrolled participants.17 Table 1 summarizes these principles and benchmarks, and the relevant applications to adolescents and other vulnerable populations.
The social value and scientific validity of the proposed study must be clearly articulated and justified. The study should be designed to answer a compelling question or set of questions addressing an important health problem in the vulnerable population by yielding valid and reliable answers to these questions.18 For example, adherence to prescribed regimens is a particular problem for adolescents.34 This is critically important in research on combination antiretroviral therapy for treatment and for preexposure prophylaxis. Poor adherence may result in a failed regimen, and a trial may or may not find a difference between regimens when 1 exists. Researchers must develop adherence objectives, or the data may be compromised and, importantly, suboptimal adherence may place participants at an increased risk of developing resistance to antiretroviral therapy.35 To justify enrolling adolescents, it is important to determine whether the scientific objectives cannot be achieved through the enrollment of adult participants alone.5 Critical stakeholders, such as participating community representatives, may need these justifications set out persuasively, and meaningful stakeholder engagement makes success of the clinical trial more likely.
In terms of fair selection of participants, scientific selection criteria should ensure that the study produces generalizable knowledge relevant to the youth population.17 Also given the vulnerability of youth and young women in particular, these populations should only be considered for enrollment when adult populations are insufficient or inappropriate. Further, efforts to enroll adolescents must be conducted with community input and cultural competence in mind as further explained below with respect to Collaborative Partnership. When such reasoning is disseminated to critical stakeholders, it may offset mistrust about unfair selection practices.
Collaborative partnerships are crucial to building a successful research infrastructure, especially for studies involving adolescent participants.18,19 Investigators should engage key stakeholders for adolescent studies, including the participating community, to offset power differentials and mistrust, increase transparency, and improve identification of risks that may be hidden to investigators who are less familiar with the sociocultural setting.18 Many stakeholders in resource-limited settings (RLSs) may be vigilant about adolescent research, and their concerns should be appropriately canvassed. Effective strategies to engage stakeholders and harness their expertise should be implemented including, but not limited to, Community Advisory Boards and especially those involving adolescent participants. Such youth engagement and perspectives are critical to the success of any research endeavor involving this population. In multisite adolescent trials, efforts to help Community Advisory Boards coordinate with one another should be encouraged, and there should be investment in their ability to critically engage with any controversial or challenging substantive issues.
The determination of an acceptable risk–benefit ratio is of paramount importance to the design of research that has special relevance for vulnerable youth populations. Investigators will need to be familiar with the risk–benefit ratio legally permitted in the host setting(s) for adolescent research procedures that carry the possibility of direct benefit, and the allowable ratio of risk to scientific knowledge gained from research procedures that do not.20 Most international guidelines permit research with children when it offers a prospect of direct benefit or when it poses minimal risk.21 Investigators should consider the factors that may increase the risk of research-related harm for adolescents in that setting, and take steps to minimize the risks.
More complex are the instances where the research proposed does not carry the prospect of direct benefit to the youth, because there are varying approaches taken by different countries to determine what risk level exposure is permissible, and how it is further categorized and defined.5 Although 1 commonly accepted definition of minimal risk is “the risks of daily life,” there is considerable debate over what counts as minimal risk and whether it should be a relative or absolute standard. In other words, should adolescents who face higher risks on a daily basis be able to enroll in higher risk research given that the risks of their daily lives are higher than average? Although there are some who have advocated for this view in HIV prevention research,22 there is good reason to think it would be unfair to have a relative standard of risk and thereby compound existing disparities, many of which may be in part due to global injustice.23 Adolescents in RLSs may also take on critical tasks such as care for others in the home that may be disrupted by study participation, and unreliable transport in such settings may increase the inconvenience of study visits. In many RLSs, substantial resources may be needed to capacitate sites and site staff to become “adolescent friendly.”16,24 Clinical and research providers who are accustomed to conducting research and care with adults will need additional training to bolster their competence.24
An additional component of the risk–benefit ratio relates to the fact that, in many countries, the onset of puberty and age of sexual debut are in early adolescence, which makes adolescents vulnerable to becoming infected with HIV and also raises the possibility that female adolescents will become pregnant. When HIV prevention or treatment interventions have teratogenic or mutagenic risks to fetuses, it is important to build in protections to minimize these risks. At 1 time, the dominant approach to managing risks of reproductive toxicity was to exclude women of reproductive potential from research altogether.36 This approach has been widely criticized,37 and there is a new call for enrolling pregnant women in research to collect much needed data.38 Pregnant adolescents may pose special challenges in terms of obtaining informed consent, optimizing adherence to medications and other health-seeking behaviors, and a host of other factors, but stakeholders should work together to ensure that these issues do not block access to important benefits available only in research that could help adolescents and their infants.
In obtaining independent review, researchers may encounter contradictory or ambiguous ethical and legal requirements that different countries have for the enrollment of children. Such complexities should be identified early in a thorough audit of international, national, and local laws and ethical guidelines.25 Some frameworks may require that additional bodies review adolescent protocols. Ethics committees may interpret guidance and have different judgments regarding levels of risk. Less experienced ethics committees tend to be conservative when applying research standards to research involving children, pregnant women, and other vulnerable populations, so it is important to ensure that ethics committees have the relevant expertise. Encouraging discourse among reviewing ethics committees may reduce conflicting judgments in multisite studies.26 Investigators should show how they have anticipated the ethical–legal complexities and build in safeguards when they submit protocols for review.27
Obtaining informed consent from adolescents may pose challenges not only because different countries will have different legal or ethical requirements regarding when adolescents can consent independently for HIV-related research but also because of the logistic challenges of adolescent and guardian consent.28,29 Relevant considerations in the ethical–legal framework will likely include the anticipated level of risk and the age or cognitive capacity and developmental maturity of the adolescent. Investigators will need to be familiar with these requirements, which may differ across countries or within countries with poorly harmonized internal frameworks. Even where parental consent is required for trial enrollment, adolescents in all settings are likely to have increasing expectations of involvement in decision making. Therefore, consent materials and interactions should be tailored to assist them to understand key study concepts in a familiar language and appropriate literacy level, and with culturally appropriate references. Additional time in discussion with study staff should be planned to help adolescents, and as necessary their parents, to comprehend unfamiliar scientific concepts and their implications.30
To show ongoing respect for enrolled participants, investigators should be familiar with the laws in the country (or countries) hosting the study that may impact on the confidentiality assurances that can be offered adolescent participants, for example, laws requiring the mandatory reporting of children experiencing abuse, neglect, or living in vulnerable circumstances (e.g., child-headed households) and possibly engaging in underage sexual activity. Such familiarity is necessary because study tests and questionnaires may cause investigators to become aware of sensitive information with mandatory reporting implications.25,27 Where parental consent for study enrollment is required, parents need to be aware of these legal requirements and how study staff will manage them, including how parents will be notified and engaged if such incidents arise. The management of such requirements should be developed in collaboration with Research Ethics Committee members, where possible. Adolescents themselves should understand these matters because they are likely to represent “deal breakers” in the consent process.29,30 Consent materials and operating procedures should be designed to help investigators manage these complex scenarios.
Further, compensation for time, inconvenience, and expenses needs to be carefully considered based on the knowledge of local rates for comparable activities and local expenses31 to ensure equity while avoiding the potential for undue inducement.32 In addition, investigators should consider the likely medical conditions they will identify during the course of study, and consider the responses they will implement to help address such potential ancillary care needs, even when such responses will not advance the scientific objectives of the study. They should anticipate that in many settings, there might be limited alternatives for health care outside of the research. They should implement appropriate budgeting and planning steps in particular circumstances, such as those studies requiring intensive engagement with participants, and those which require participants to assume nontrivial research-related risks and burdens.33 These include designing-assisted referral procedures to ensure that participants have access to adolescent-appropriate care, and where possible, the research should help to build capacity in such care facilities.
In conclusion, adolescent research—even in high-income settings—is complex because adolescent participants are undergoing transitions in cognitive, psychosocial, and physical domains, and they have features that complicate study enrollment and retention and factors that may heighten study-related risk and compromise decision making.10,39,40 Adolescent research in RLSs has an additional layer of complexity brought–in part–by resource disparities between research collaborators, cultural complexities, and involvement of multiple sites. The issue will be the subject of an online training module for researchers and Research Ethics Committee members to be posted on the Training and Resources in Research Ethics Evaluation website (http://elearning.trree.org). Because adolescents in RLSs are critical participatory stakeholders in HIV-related research, the complexities must be faced head-on with appropriate planning, budgeting, partnership formation, and capacity development, and the complexities can be systematically anticipated using familiar ethical frameworks.
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adolescents; ethics; informed consent
© 2014 by Lippincott Williams & Wilkins
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