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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
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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
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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
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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
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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
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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.
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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
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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.
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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
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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
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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
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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
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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.
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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.
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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
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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.
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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
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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
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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
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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
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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.