Zaynab Essack; Catherine Slack & Ann Strode HIV AIDS Vaccines Ethics Group (HAVEG)

1. 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-Natal www.saavi.org.za/haveg.htm

2. Background • 31 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

3. 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

4. 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

5. Community Ptn: Recommendations • Engage 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

6. 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.

7. Social value: Recommendations • Ensure 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

8. Scientific validity: Issues • Older 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.

9. 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

10. 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

11. Fair selection: Recommendations • Enrol 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

12. Favorable risk-benefit ratio: Issues • Potential 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

13. Favorable risk-benefit ratio: Recomms • Collect 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.

14. Review (Ethical & Regulatory): Issues • NRAs 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.

15. Review (Ethical & Regulatory): Recomms • Undertake 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

16. Informed consent: Issues • Variation between countries with regard to age of consent, e.g. to research • Within one country’s 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.

17. Informed consent: Recommendations • Audit 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

18. 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

19. Ongoing respect: Recommendations • Delineate adolescent rights to privacy • Research mandatory reporting requirements • Explain confidentiality, and it’s limits, in the CF and process • Train trial site staff to recognise + meet legal obligations • Do ongoing monitoring

20. Conclusions • Little 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

21. 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