All authors are at the Centre for AIDS Programme of Research in South Africa, Congella, South Africa, and at the Nelson R. Mandela School of Medicine, University of KwaZulu–Natal, Durban, South Africa. Jerome Amir Singh is in the Department of Public Health Sciences and in the Joint Centre for Bioethics, University of Toronto, Ontario, Canada, and at the Howard College School of Law, University of KwaZulu–Natal, Durban, South Africa. Salim S. Abdool Karim and Quarraisha Abdool Karim are in the Division of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, United States of America. Salim S. Abdool Karim is also at the Weiss School of Medicine, Cornell University, New York, New York, United States of America. Carolyn Williamson is in the Department of Virology, University of Cape Town. Rondebosch, South Africa. Clive Gray is at the National Institute of Communicable Diseases, Johannesburg, South Africa. Michelle Govender is part of the AIDS Law Project, Johannesburg, South Africa.
The authors have declared that no competing interests exist.
Jerome Singh and colleagues present the ethical and legal challenges surrounding the enrollment of adolescents in HIV observational studies and other types of sensitive research.
With more than 6 million HIV positive individuals—the highest of any country in the world—South Africa is the epicentre of the HIV/AIDS pandemic. In much of sub-Saharan Africa, especially South Africa, the HIV/AIDS epidemic is growing fastest in teenagers, especially young girls (see sidebar) [
The current candidate HIV vaccines that are being considered for efficacy trials are likely to act principally by reducing viral loads, hence reducing both transmission to sexual partners and progression to AIDS [
The Joint United Nations Programme on HIV/AIDS notes that children, including infants and adolescents, should be eligible for enrolment in HIV preventive vaccine trials, both as a matter of equity and because young adolescents and children are at high risk of HIV infection [
The Centre for the AIDS Programme of Research in South Africa (CAPRISA), which is funded by the US National Institutes of Health, recently proposed a follow-up study of adolescents and young adults with acute HIV infection to obtain the essential information on subtype C viral set point, prognostic viral load measurements, and disease outcome—all important biological outcome markers in HIV vaccine efficacy trials. The study proposed to enrol, as one of its groups, adolescents as young as 14 years old from a prenatal and family planning clinic, where those who volunteered could do so without parental consent when parents or legal guardians were not available. Three ethics committees supported the enrolment of this cohort, although a fourth did not. As a result, the study protocol was amended to include participants only above the age of 18.
Several works have highlighted the ethico-legal challenges implicit in enrolling adolescents in South African HIV vaccine trials [
The Human Sciences Research Council reports an almost 2-fold increase in South African households headed by children or consisting only of children (referred to as “child-headed households”, i.e., orphans or children without resident adult guardians) between 2002 [
Our data supports these findings and show that many of the adolescents attending the prenatal and family planning clinics do not live with their parents [
(Photo: Arjen van de Merwe/Population Concern)
According to the Council for the International Organisation of Medical Sciences Guidelines, “In some jurisdictions, individuals who are below the general age of consent are regarded as ‘emancipated’ or ‘mature’ minors and are authorized to consent without the agreement or even the awareness of their parents or guardians” (see commentary on guideline 14 in [
Prenatal and family planning clinic attendees are often selected for enrolment into HIV studies because they are sexually active, often times have multiple partners, and are already familiar with clinical procedures. Given the observations on child-headed households above, there are good grounds to consider such adolescents as “mature minors”, as this recognises the social reality of the study population. Acknowledgment of this reality makes it unnecessary to seek supplemental parental consent for adolescent participation in studies.
On the issue of mature minors and the need to obtain additional parental informed consent, the Council for the International Organisation of Medical Sciences Guidelines state the following: “Some studies involve investigation of adolescents' beliefs and behaviour regarding sexuality or use of recreational drugs; other research addresses domestic violence or child abuse. For studies on these topics, ethical review committees may waive parental permission if, for example, parental knowledge of the subject matter may place the adolescents at some risk of questioning or even intimidation by their parents” (see commentary on guideline 14 in [
An HIV-positive test result often carries a negative connotation and stigma. Discrimination, violence, and social ostracism are often experienced by those, especially women, who disclose their HIV status to partners and family members. There is also the concern that adolescents are not willing to participate if their HIV status will be disclosed to their parents. In such cases, parents may want to be informed of their children's HIV status by researchers and health-care providers even if it is against their children's wishes, thereby violating the study participant's right to confidentiality. As a serious consequence of violating this right, participants could be inadvertently deterred from seeking necessary treatment, a decision that would have adverse consequences for their health.
The researcher's willingness to respect an adolescent participant's autonomy and right to confidentiality will likely determine that adolescent individual's willingness to participate in research. Adolescent participants would enrol in such studies on the legitimate expectation that their confidentiality would be respected. Requiring these participants to seek parental consent for their participation in the study would effectively nullify this obligation to assure confidentiality. Moreover, researchers or health-care providers who breach the adolescent participant's confidentiality to parents could violate section 14 of South Africa's Constitution [
In some countries, such as the US, ethical review committees have the authority to waive a requirement for parental permission for adolescent participation when there are compelling reasons warranting this action. Yet, despite the merits of doing so, ethical review committees in South Africa have been hesitant, not only for adolescents of 14 years of age, but even for adolescents of 16 and 17 years of age. This is compounded by the current ethico-legal position in South Africa, where the current South African Medical Research Council (MRC) research ethics guidelines (General Principles) prescribe 14 years of age as the autonomous age of consent for therapeutic research but not observational studies [
The General Principles also contain many other flaws and inconsistencies in regard to research on adolescents [
Our work in a rural part of South Africa has revealed that adolescents, some as young as 12 years old, routinely seek antenatal care, treatment for sexually transmitted infections, or family planning at district clinics. They do so autonomously, despite the legal age for consent to treatment being 14 years of age, and, perhaps, they do so because they do not have parents or legal guardians or because they perceive that confidentiality is assured. These factors no doubt motivate adolescents to present at clinics for treatment in other settings, too. Following the guidance of the General Principles for adolescent research attached to such clinics will make such research impossible. Although the General Principles are, strictly speaking, only binding on MRC-sponsored studies, they are generally considered influential among members of South Africa's research ethics community.
Adolescents' best interests will be served by their autonomous participation.
Matters will be compounded when the country's newly promulgated National Health Act (NHA) becomes operational. The NHA mandates the solicitation of parental consent for adolescent enrolment in therapeutic and nontherapeutic studies, as well as ministerial consent in the case of nontherapeutic studies. The NHA does not prescribe definitions for the terms “child” and “minor”, although it uses both terms interchangeably in relation to both types of studies, which is problematic since there is no uniform definition for these terms in South African law [
In May 2005, South Africa issued its first national health research ethics guidelines intended to govern all health-related research in the country. Entitled Ethics in Health Research: Principles, Structures and Processes (EHR), the document describes itself as the country's “national policy on the ethical practice of research”, and makes explicitly clear that its principles should guide “all research involving animals and human participants in any discipline relating to health” [
Paragraph 5.1 of the EHR governs research on minors. It begins by declaring that minors should participate in research “only where their participation is indispensable to the research and where participation is not contrary to the individual minor's best interests”. In terms of the EHR, “child” is taken to mean a person who has not yet reached puberty, while “adolescent” means a person who has reached puberty. The EHR's glossary section, which bases its definitions on the Canadian Code of Ethical Conduct for Research Involving Humans (1996) and the International Conference on Harmonisation Guidelines for Good Clinical Practice, defines “child” slightly differently. It provides that a child “is a minor who lacks the legal ability to make a decision whether or not to participate in research”. Despite its explicit reference to the law, the EHR, like the NHA, steers clear of providing a legal definition of the term “minor”. However, unlike the NHA, which does not recognise the rights of children to autonomously participate in research in any circumstance, the EHR adopts a flexible approach that seemingly puts it at odds with the NHA. It recognises that “adolescents may be capable of consenting themselves to certain types of research participation and that, for particular types of research, it may be desirable that they do so unassisted”. In this regard, the EHR can be said to be more responsive to South Africa's increasing social reality of “mature minors” and child-headed households.
The EHR also seems to have heeded the concerns of investigators participating in sensitive research involving adolescents, who voiced their concerns about the inflexibility of the NHA on this issue. Paragraph 5.3.1 of the EHR accordingly advises research ethics committees (RECs) that research involving adolescents who may consent unassisted should be approved only if (1) the research, including observational research, places the adolescent at no more than minimal risk, and only if (2) the nature of the research is such that, in the opinion of the REC, the parents or legal guardians or community at large are unlikely to object to the adolescent autonomously consenting to participation in the investigation. The opinion of the REC must be informed by information gathered from the community concerned and by contributions from the lay members of the committee.
“Minimal risk research”, according to the EHR, is that which “anticipates that the probability and magnitude of harm or discomfort to be experienced in the research will not be greater than those ordinarily encountered in daily life”. This resonates with the understanding of the term in the American Code of Federal Regulations (45 CFR 46.102). The EHR stipulates that in all cases, the protocol must provide sufficient information to justify clearly why adolescents should be included as participants and must justify clearly why the adolescent participants should consent unassisted.
Given that the NHA and EHR take different stances on the autonomous participation of children in research, how should RECs deal with this apparent conflict? Conventional wisdom dictates that provisions of law take precedent over provisions in policy or guidance documents. However, there are at least five important reasons why a REC should embrace the stance of the EHR, in regards to research on minors, over that of the NHA, notwithstanding the latter's legal nature.
First, adhering to the flexible stance of the EHR will make it possible to investigate valuable and necessary sexuality-related research on adolescents, of the type outlined above.
Second, a REC's primary mandate should be to make decisions based on ethical considerations versus exclusively legal considerations. Blindly following ill-considered law could evidence unethical and unconstitutional outcomes.
Third, the EHR was launched by the minister of health in the aftermath of the promulgation of the NHA and the numerous concerns that were raised about its provisions pertaining to research on minors. It should be assumed that the minister applied her mind to the issue, realised the inconsistency between the NHA and the EHR, but gave her unreserved endorsement to the latter because doing so was in the best interests of adolescent minors. To assume otherwise would imply that the minister did not apply her mind to the implications of the EHR before approving it.
Fourth, as in other countries, South African law holds that the best interests of the child must dictate what approach to follow in matters pertaining to a child. Given the invaluable biological, sociological, behavioural, and clinical data that the inclusion of an adolescent cohort will generate in HIV studies, the enrolment of this cohort is crucial for future prevention and treatment interventions in this group. Accordingly, the best interests of adolescents will be served by their autonomous participation in such studies. The NHA is intended to protect the interests of children. RECs should respect the spirit of the law rather than merely the letter of the law. The interests of children will be protected and promoted by their participation in minimal risk HIV observational studies.
Fifth, in growing recognition of the autonomous decision-making abilities of young individuals, South Africa's draft Children's Bill [
As adolescents are bearing the brunt of the AIDS epidemic in much of sub-Saharan Africa, we believe studies in this group are critical. We have argued that it is ethically justifiable to enrol adolescents in certain cases without seeking parental consent for adolescent participation in HIV research. The same might apply to certain types of sensitive non-HIV research involving adolescents who could be compromised if parental consent was made mandatory (for example, research on child abuse, teenage pregnancy, and teenage sexuality). We accordingly encourage local RECs to exercise their discretion to authorise the waiver of additional parental consent in studies involving adolescents on a case-by-case basis.
The research regulatory framework of the US—which is much more comprehensive than that of South Africa or the rest of sub-Saharan Africa—could prove instructive. The American Code of Federal Regulations (45 CFR 46.408c) endorses the waiver of parental consent in instances where the pursuit of consent could be detrimental to the minor (as we have argued is applicable in South Africa). Ethical review committees should also note that regardless of South Africa's lack of uniformity on the legal age of majority, the World Health Organization Guidelines for Research on Reproductive Health Involving Adolescents [
While it is difficult to establish truly representative community structures for consultation on research issues, the approach of engaging with the communities where the research is being conducted could be one part of the solution [
We do not believe that the challenges that face South African researchers in enrolling adolescent participants in HIV studies, such as the CAPRISA study, are unique to the country. The challenges probably apply to much of sub-Saharan Africa, where future vaccine and microbicide efficacy trials will need to be conducted if we are to fast track efforts to find a vaccine or microbicide to reduce the spread of HIV in this important population. Moreover, we also believe that the factors we argued for in favour of the autonomous participation of adolescents in HIV-related studies apply equally to certain types of sensitive non-HIV research. We recommend that investigators involved in such research endeavours urge the ethics committees that oversee their research to embrace the stance of the EHR over that of the NHA for the reasons we outlined above.
The need to protect adolescents from harm in research needs to be carefully balanced with the need to undertake research in this population to find solutions to this epidemic. To this end, rigid legislation and/or ethical guidelines that pertain to adolescent participation in research and their uncritical application are counterproductive. We need to be cognizant of this inherent conflict and create an enabling ethico-legal framework to avoid inadvertently doing more harm than good to the intended study population.
The rapid spread of HIV among young women, and particularly among adolescent girls in South Africa, has been described as “explosive” [
In one rural South African district, the prevalence of HIV infection in pregnant women increased from 26% in 2001 to 34% in 2002 [
Centre for the AIDS Programme of Research in South Africa
Ethics in Health Research: Principles
South African Medical Research Council
National Health Act
Research Ethics Committee