What do we know about HIV trial design for

adolescents?

Sinéad Delany-Moretlwe, MBBCh PhD, DTM&H

International Workshop on HIV & Adolescence,

Cape Town, October 2018

Outline

• Why include adolescents in HIV trials?

• Where is the current status of adolescent trials?

• What are the barriers to inclusion of adolescents in HIV trials?

• What can be done in ensure inclusion of adolescents in HIV trials?

Three-quarters of new HIV infections in sub-Saharan Africa

Countries with HIV prevalence in young women >1%

UNAIDS, 2016; UNAIDS, 2017

Youth bulge in Sub-Saharan Africa

By 2030, the youth population will have doubled since the start of the HIV epidemic

Expanded range of prevention options required to control the epidemic

340 000 fewer HIV infections in the region without the youth bulge

UNAIDS Explainer, 2018

Hepatitis B vaccine experience

Licensed in 1981

Indication for minors 1991

Slide courtesy L-G Bekker

Why adolescent and youth needs may be different from adults?

Adolescence is a period of biological and behavioural transition

Biological changes can affect responses to drugs or vaccines

e.g. changes in body composition during puberty

Age related changes in drug absorption, metabolism and clearance

Age related differences in vaccine responses

Rudy, 2010; WHO, 2017

Adolescence is a period of biological and behavioural transition

Behavioural changes can affect responses to drugs or vaccines

e.g. pill-taking behaviour, risk disinhibition, other behaviours

Can’t simply extrapolate from adults

DiClemente, 2010; WHO, 2017

Risks of excluding adolescents from trials

• Off-label prescribing

• Wrong dose may be associated with toxicity or be sub-therapeutic

• Wrong formulation - ↓ bioavailability

• Accidental poisoning because package inserts inadequate

• Particular concerns if background substance use or use in overdose

WHO, 2007

What is the current status of adolescent trials?

“Everyone deserves medicines that meet their needs. All medicines need to be given at the correct dose, with an acceptable risk benefit profile. Medicines should be of good pharmaceutical quality with legally enforceable quality assurance of all aspects of their development and use.”

Turner, 2014

Regulatory requirements to include paediatric development plans

• Systematic search of 2 trial registries

• 111 unique studies

• 9 % included minors

• Under-represented in early phase studies, but over-represented in treatment trials

Barriers to enrolment of adolescents in

trials

Individual-level barriers

• Cognitive maturity

• Stigma associated with disclosure of sexual activity or orientation

• Peer acceptance important in this age group

• Potential for greater social harms

• “Self-presentation bias”

Diclemente, 2010

Familial barriers

• Parents are required to consent

• Parents or guardians may not be available

• Privacy of adolescent

• Parents may not understand research

• May have concerns about harms or stigma

• May not understand risk benefit ratio

• May have concerns about disclosure of own status

Diclemente, 2010; Kapagiannis, 2010, Slack, 2007

Community barriers

• Mistrust of research

• Reimbursement

• No obvious benefits of participation

• Concerns about risk behaviour/stigma

• Ethico-legal frameworks• Age of consent

• Laws on mandatory reporting

• Inconsistent, contradictory

Diclemente, 2010; Kapagiannis, 2010, Slack, 2007

Experiences from HPV vaccination: Process for approval

Department of Education

(GP, NW)

School principal

(n=4 schools)

Parental consent

Adolescent assent/consent

if>18

Challenges with consent

• Forms not returned or poorly completed

• Related to literacy and knowledge levels of care-givers

• Absent or working care-givers in some instances

• No parent contact details to follow up and make corrections

Opt in vs. Opt out

• Many favoured the approach adopted during the measles catch up campaigns

• Parents felt very strongly that they should be involved in the consent process

• Many adults believed that 18 was the legal age of consent and used this as a default

• Younger adolescents felt that parents should be involved

• Educators saw this as an educational opportunity for parents

• Policy experts identified opt out approach as a way to maximise coverage

• Some felt that young people are independent and should be allowed to make own decisions

• Some community members pointed to other areas of reproductive health where young people make decisions e.g. contraception

• Decision-making within traditional families might be complex

“That means she [my mother] does not love me. She would not love me if she does not want me to be vaccinated. If I am infected, she is going to cry.’”

Taung learner

“Their parents have to know” -views on vaccine decision-making

“I’m not yet old enough to make my own decision because I might make a decision that I might regret. Plus the parents, sometimes you wouldn’t like the choices they make, but when you grow up you will realise that those choices are for our own good” Johannesburg learner.

“I think that the opt-out consent should probably be considered. You know, because of the age that it needs to be administered […] they need to get consent and that’s really going to be really complicated.

... As the numbers go up you also have herd immunity, so effectively if you get a high enough uptake, you’re protecting the people who opted out as well.”

Investigator barriers

• Trial requirements e.g visit schedule and costs

• Biases about adolescent adherence and retention behaviours

• Trial sites may not be accommodating to young people

• Inadequate materials

What can be done?

Articulating the justification

• Trials in adolescents are

• Required AND are

• Feasible

• Acceptable

Plus increasing evidence from open-label PrEP studies

Trials are feasible and acceptable

• Does PrEP work in adolescents?

Yes – if taken consistently

…but daily pill taking is a challenge

6052,4 55

31,522,7 28,2

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

WK 4 WK 8 WK 12 WK 24 WK 36 WK 48

>700 (4 or

more days)

350-699 (2-3

days)

<350 (<2

days)

BLQ

Source: Hosek, JAMA Pediatrics 2017

Collaborative partnerships

• Early engagement with • ethics and regulatory groups

• Youth and youth cabs

• Parents

• Communities

• Generate evidence around presence or absence of harms

Trial designsApproach (1): determine what data are required

Consider role for the drug

• Age• Setting• Its place in current and future treatment• Specific safety concerns

Identify what data can be extrapolated from adults:

• Disease progression similar?• Response to treatment• Exposure-response

Use extrapolation algorithm to determine what studies are required:

• Pharmacokinetic+safety• Pharmacokinetic/pharmacodynamic +safety• Pharmacokinetic/pharmacodynamic

+safety+efficacy

Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

Approach (2): use efficient trial designs and consider innovative options

• Physiologically-based pharmacokinetic modelling can improve accuracy of test dose selection

• Study multiple ages and weight bands simultaneously

• Study adolescents alongside adults or include them in adult late phase trials

• Take advantage of “washout” data to design trials for neonates

• Assess acceptability and feasibility within the initial dose-finding and safety studies

Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

Approach(3): start trials as early as possible• Study agents in children as

soon as reassuring safety data are available from adult trials

• Risks to children from exposure to new agents can be mitigated with careful safety monitoring in the context of a clinical trial

• Bioequivalence of paediatric-appropriate formulations can be first studied in adults

Clinical trials for development and evaluation of drugs for children can be planned when phase II adult studies are underway and start while adult phase III trials are underway

Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

The Truvada experience

… recommended for adults and adolescents at risk for HIV-1 infection

weighing at least 35 kg…

Recommendation based on trial in 15-17 year olds

Summary

• Inclusion of adolescents in HIV trials is essential if we are to understand safety, efficacy and use in populations

• Progress on inclusion of adolescents is slow

• Adolescents have specific needs that must be addressed when designing trials; many other barriers can be overcome

• There are already many lessons learned from early vaccine trial development and now PrEP open-label studies

• Collaboration and stakeholder involvement is essential

Acknowledgements

Linda-Gail Bekker

Sybil Hosek

Bill Kapogiannis

Young trial participants

Their families and communities