What is in the literature?

Identified ethical-legal complexities in adolescent HIV vaccine + microbicide research

Zaynab Essack; Catherine Slack & Ann Strode HIV AIDS Vaccines Ethics Group (HAVEG)University of KwaZulu-Natalwww.saavi.org.za/haveg.htm

Background31 articles

5 on adolescent microbicide trials (4 on acceptability; 1 on trials)

Our access to reports was limited

Summarised i.t.o a popular framework (Emanuel et al, 2000; 2004)

Summary in your pack and on CD, plus the articles

Summary includes issue each time identified by an author long!

Draft for comment

Emanuel et al (2000,2004)Collaborative partnership/ community participation

Social value

Scientific validity

Fair selection of participants and communities

Favourable risk-benefit ratio

Review (ethical and regulatory)

Informed consent

Ongoing respect for enrolled participants

Community Participation: Issues

Mistrust, esp. minority communities

Misconceptions about trials and products

Inadequate health-care infrastructure

Cultural and religious norms

Negative media coverage

Poor awareness of rights

Community Ptn: RecommendationsEngage with organisations that serve adolescents

Educate potential participants, parents, community leaders

Establish CABs; involve them in protocol development

Involve adolescents on CABs

Develop a prevention and care infrastructure

Co-ordinate/ align with existing youth prevention programs

Research, understand and respect cultural and religious beliefs and taboos

Social value: Issues Adolescents are at high risk for HIV infection

Young women are at increased risk

Major biological, hormonal, and physiological differences exist between adults and adolescents

Vaccines may be most effective in adolescence and pre-adolescence (before sexual debut) If adolescents are not enrolled, timely access to prevention products will be denied them.

Social value: RecommendationsEnsure adolescent participation in order to provide data relevant to them

Focus on enrolment of young women to ensure products they can use

Ensure that funders (HVTN, IAVI) develop plans for adolescent inclusion

Ensure that product developers incorporate adolescents into their plans

Learn lessons from private sector experience w STD vaccines, e.g. Merck; GSK

Accelerate the study of promising candidates in adolescents with highest risk

Scientific validity: IssuesOlder and younger adolescents have different requirements both biologically and legally

In contexts where sex below a certain age is illegal, adolescents below this age cannot be enrolled in efficacy studies where HIV infection is an endpoint.

Scientific validity: Recommendations

Enrol adolescents in trials when there is sufficient data from phase I and II studies in adults, without waiting for completion of adult efficacy studies

Use different trial designs for younger and older adolescents

Initiate dialogue between sponsor/researchers and National Regulatory Authorities prior to finalising design of efficacy or bridging studies

Fair selection: Issues Adolescents are a vulnerable group

Some adolescents have additional vulnerabilities, e.g. no LG

Identifying and retaining high risk adolescents is challenging

There is a lack of established cohorts of youth

Perceptions that youth are not at risk or that they/ their parents are reluctant to take part

There has been limited adolescent and parental WTP

Fair selection: RecommendationsEnrol less vulnerable first

Develop sophisticated consent or assent processes

Customize the environments for adolescents i.t.o location; operating schedules (e.g. school hours); staff practices (e.g. gender and youth sensitivity)

Involve adolescents as advisers on recruitment, education, CFs

Provide skills-building/ support groups to help youth adhere

Consider other successes, e.g. Merck; GSK

Identify suitable cohorts

Conduct studies of HIV prevalence, incidence, WTP

Favorable risk-benefit ratio: IssuesPotential for adverse events

Potential for stigma

Risk of false-positive testing in HIV vaccine trials

Risk of therapeutic misconception and increased risk behaviour

Sero-conversion or HIV infection

Impact on school attendance and school work

The need to ensure fair payment to participants

The need to consider appropriate benefits for trial participation

Favorable risk-benefit ratio: RecommsCollect safety data and carefully evaluate adverse events

Collect data on social and biological risks to allow RECs to judge risks

Specify methods to identify + reduce harms in protocols

Mitigate stigma e.g. community sensitisation meetings

Mitigate false positivity: Differential testing; ID cards, a toll-free number, office for complaints, education

Ensure referral for treatment, social support and disclosure to trusted adult, if adolescent becomes infected

Provide risk-reduction counselling tailored to the needs and sub-culture of adolescents

Debate models for payment of adolescents

Ensure a range of care and prevention services.

Review (Ethical & Regulatory): IssuesNRAs will require data from adolescents before licensing a vaccine for use in this age-group

Different NRAs will require different data before permitting adolescent enrolment and may have different concerns

Some NRAs have not issued guidance on the data they would require for enrollment or liscensure

Variation between + within countries on the requirements for child research

Reluctance by RECs to enrol adolescents Limited reviewer capacity

Complexities with ethical-legal concepts like minimal risk

Additional review requirements in some countries.

Review (Ethical & Regulatory): RecommsUndertake ethical-legal audits

Lobby NRAs to issue guidance on their requirements

Meet with NRAs to better understand their requirements

Build REC capacity to review protocols

Document data on risks for RECs

Ensure adolescent or paediatric expertise on RECs

Promote networking between RECs for a standardized approach

Increase the acceptability of trials to local RECs

Ask international organizations like WHO IVR/ WHO HVI for advice

Informed consent: IssuesVariation between countries with regard to age of consent, e.g. to research

Within one countrys framework, there may be poor harmonisation Parental consent: parental consent was required/ important versus not feasible/ not ethically required Whether/ how to accommodate adolescents with no guardians

Inadequate education; complex concepts

Features of adolescent decision-making, e.g. short-term focus

Threats to voluntariness: undue pressure from peers/ parents.

Informed consent: RecommendationsAudit local laws and guidelines

Consider transfer of guardianship, if parents are not available

Consider if/ how other care-givers can be involved

Design means to assess understanding of adolescents and parents

Develop age-appropriate materials to promote understanding

Increase contact time with counsellors

Offset threats to voluntariness, e.g. advocates or cultural mediators

Ongoing respect: Issues Adolescents privacy and confidentiality for risk info + test results

Disclosures that trigger mandatory reporting responses Sexual disinhibition

Compensation for research-related injury

Ongoing respect: RecommendationsDelineate adolescent rights to privacy

Research mandatory reporting requirements

Explain confidentiality, and its limits, in the CF and process

Train trial site staff to recognise + meet legal obligations

Do ongoing monitoring

ConclusionsLittle published literature on adolescent microbicide trials

Little literature deals with both HIV vaccine and microbicide trials, or explicitly compares issues in both fields

In the articles we summarized, most identified issues are relevant for both fields (except false positivity)

There may be some differences between developed and developing countries in terms of comprehensiveness of the legal framework and capacity of stakeholders, or health-care infrastructure

In articles we summarized, few authors explicitly referred to tools, but many to success stories

Many commentators appeared to be arguing for the need to set norms and standards

Acknowledgements and thanks

Numerous persons sent literature, or directed us to literature; including but not limited to: Mitchell Warren, Mary Allen, Lori Heise, Quarraisha Abdool Karim and Craig Wilson

The literature identifies several issues applicable across developed and developing contexts, namely (1) there is minority mistrust, and even weariness, of research and research institutions; (2) health-care infrastructures in communities targeted for clinical trials are often inadequate; however this may be exacerbated in developing contexts; (3) numerous misconceptions about trials and prevention products are prevalent; (4) cultural norms and religious beliefs may impact on the acceptability of trials; (5) there is potential for negative media coverage, such as has been the case with media reporting of the Carraguard trial in South Africa; (6) community representatives may have poor awareness of their rights; (7) in addition community engagement in research is complex; and (8) there are often difficulties in attempts to align research with other relevant prevention initiatives.Issues pertaining to community participation were not expressly described as being unique to vaccine or microbicide research. However, it is possible that trials enrolling only female participants (like microbicides) may have to engage more explicitly with the added vulnerability of girl children, in terms of biological risk and social marginalisation. Community participation in microbicide and vaccine trials is particularly critical because of the vulnerability of the potential participants and the sensitivity of the research. This necessitates a special kind of community partnership, one that is more youth and gender focussed.Standard recommendations like education, CAB development, active co-ordination of the prevention trial with other prevention and treatment initiatives, and the need to develop a spectrum of prevention and clinical care/ services for adolescents were put forth. Although not explicitly identified by the literature, microbicide trials may have to be more gender-sensitive and involve gender organisations. While no tools to facilitate community participation were mentioned, historical success stories such as the advocacy power of mothers in the March of Dimes, were mentioned.Adolescents are at high risk for HIV infection due to sexual activity and injection drug use. Therefore, they should have a range of prevention options available to them. Young women are at increased risk, and in some parts of sub-Saharan Africa, their infection rates outnumber that of boys by a rates of 6 to 1 (Heise & Wood, 2005). This can be partially accounted for by transactional and coercive sex, and experiences of rape and assault. Adolescents are not younger adults and major biological, hormonal, and physiological differences between adults and adolescents make it difficult to predict responses to products without trials. Further, vaccines may be most effective in adolescence and pre-adolescence before sexual debut, especially where high risk sexual activity is occurring in youth as young as 11 (as indicated in the Jaspan et al. (2006) study on adolescent HIV prevalence). If adolescents are not enrolled, timely access to prevention products will be denied them.The literature is clear on the social value and necessity of involving adolescents in HIV vaccine and microbicide trials, and has highlighted the need to ensure adolescent participation in HIV prevention trials in order to provide data relevant to them, and to focus on enrolment of young women so that products are available for use by young girls. Commentators have also recommended that funders like HVTN, IAVI, and Eurovac develop plans for the inclusion of adolescents and product developers incorporate into their product development plans, how data will be collected from children and adolescents. Again, the valuable lessons that could be learnt from private sector experience with other STD vaccines, e.g. Merck and GSK was emphasized. Older and younger adolescents present different requirements both biologically and legally. Statutory rape laws that make sex below a certain age illegal pose major barriers to the enrolment of adolescent below that age in efficacy studies; however, these laws may be country-specific. Once sufficient data from adult phase I and phase II trials is available, adolescents should be enrolled in trials. Different trial design strategies have been proposed for younger and older adolescents, e.g. enrol older adolescents who can lawfully consent to sex, in test of concept/ phase IIb trials or phase III trials (where infection is an endpoint), but for younger adolescents, consider bridging studies to test safety and immunogenicity that do not include HIV infection as an endpoint. However, this approach relies on correlates of immunity which do not currently exist. (i) Adolescents are a vulnerable group because of their physical and emotional immaturity, their evolving autonomy and limited life experience (ii) with some adolescents subject to additional vulnerabilities, for example, they may be without parents or guardians, homeless or experiencing abuse (iii) Identifying and retaining high risk adolescents is challenging because they are a highly mobile population, trials involve uncomfortable procedures, multiple scheduled visits and long follow up periods (iv) There is a lack of established cohorts of youth for future involvement in trials (v) The perceptions that youth are not at risk, adolescents reluctance to participate, or their parents reluctance to allow their participation, pose barriers to adolescent participation (vi) Further there is limited data on adolescent willingness to participate and parents willingness to allow their adolescents to participate. The identified issues appear to cut across microbicide and vaccine trials and to apply across developed and developing contexts although issues of heightened vulnerability (e.g. homelessness) may be more pronounced in developing world contexts Several recommendations have been put forth ranging from global recommendations such as revising overly protective guidelines to more site specific recommendations like revisiting clinic operating hours. The literature did not identify specific tools, however, reference was made to previous recruitment and retention successes with adolescent participants such as Merck and GSK HPV trials and the GSK HSV2 trial which evidenced high levels of retention in studies involving extended and invasive procedures. The potential for adverse events, stigma, vaccine-induced seropositivity, therapeutic misconception and increased risk behaviour, HIV infection, negative impact on school attendance and school work, were identified as risks of trial participation. The literature also identified the need to ensure fair payment to participants and the need to consider appropriate benefits for trial participation. Given that adolescent participants may be subject to several risks, the literature suggests that special measures must be implemented to protect adolescents such as collecting data on safety, evaluating adverse events, specifying methods to identify and reduce harms in research protocols, mitigating against false positivity concerns by providing testing that can differentiate between vaccine-induced seropositivity and actual infection, ID cards, a toll-free number and an office for complaints, among others. With the exception of vaccine-induced sero-positivity, potential risks are not unique to vaccines. Many low and middle income countries may have inadequate legal protections to prohibit unfair discrimination, and ethics committees in developing countries may have less capacity to evaluate risks; however, the issues identified do not appear exclusive to developing country contexts. The literature identifies a range of recommendations to respond to risk-benefit concerns, including research, education and community sensitization, referral and debate. The key issues relating to the ethical/regulatory approval of adolescent microbicide and vaccine research relate to both the frameworks and the limited capacity of those within such frameworks to regulate research involving children. With regard to the framework issue, the nature and comprehensiveness of ethical-legal frameworks vary from country to country making multi-country studies complex for both vaccine and microbicide trials. In developing countries, more than developed countries, ethical-legal frameworks are less formalized. Also, in certain countries, the local framework may pose specific requirements that must be met in order to obtain approval for such research, for example, in South Africa consent from the Minister must be sought for non-therapeutic research with minors. Although this is a South Africa specific problem, it raises the principled questioned of what protections ought to be in place for certain categories of child research. With regard to the issue of capacity, the literature shows that the complex science of HIV prevention research coupled with unsophisticated ethical-legal frameworks may place reviewers in a difficult position, e.g. they may struggle to apply complex standards like minimal risk or the the best interests of the child. These capacity problems may be exacerbated in developing countries. The literature also identifies a lack of guidance from NRAs as problematic Recommendations included that ethical-legal frameworks be audited to obtain clarity on key issues, and ethics review capacity be enabled through detailed protocols, training and technical assistance by international agencies like WHO. It was also recommended that NRA clarity and capacity be enabled through lobbying for guidance and regional consultation between NRAs facilitated by WHO. Although no tools are expressly identified in the literature, the five country study by the African AIDS Vaccine Programme could be used as a model for other legal audits. The key issues relating to informed consent in adolescent microbicide and vaccine research relate to the ethical-legal framework for consent, the requirement for parental or legal guardian consent for minors, and perceived threats to consent like inadequate education and developmental characteristics of adolescent decision-making. These issues appear to affect both fields even-handedly. In some developing world settings, factors like poor education and illiteracy may be elevated as will be the case with child-headed households. t is also possible that in such settings, the ethical-legal framework for consent may be less well-specified or understood by important stakeholders like site staff or ethics reviewers.Recommendations included research into local laws, the development of tools and processes to impart information, assess understanding, and enhance the voluntariness of decisions. While some writers argued adolescents should consent independently, the majority appeared to agree that adolescents should be assisted in decision-making by a mature adult, in most jurisdictions, the parent of guardian. Recommendations seemed equally relevant for vaccine and microbicide trials.Commentators raised issues such as (i) Adolescents privacy and confidentiality for data needs to be maintained, even if parents consent to enrolment (ii) Adolescents may make disclosures during trial participation that will trigger mandatory reporting responses (iii) There needs to be ongoing monitoring of sexual risk behaviour through-out trials (iv) Compensation for research-related injury needs thought. The literature made the following recommendations: Outline limits to privacy and confidentiality during the consent process, use indirect method to screen adolescents for sexual activity such as enrolling adolescents at post-natal, research mandatory reporting requirements in the host country and train trial site staff to recognise and meet legal obligations.That brings me to the end of the presentation. Thank you for your time and attention.