What do we know about HIV trial design for adolescents?

Transcription

1 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

2 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?

3 Three-quarters of new HIV infections in sub-saharan Africa Countries with HIV prevalence in young women >1% UNAIDS, 2016; UNAIDS, 2017

4 Youth bulge in Sub-Saharan Africa By 2030, the youth population will have doubled since the start of the HIV epidemic

5 Expanded range of prevention options required to control the epidemic fewer HIV infections in the region without the youth bulge UNAIDS Explainer, 2018

6 Hepatitis B vaccine experience Licensed in 1981 Indication for minors 1991 Slide courtesy L-G Bekker

7 Why adolescent and youth needs may be different from adults?

8 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

9 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

10 Risks of excluding adolescents from trials Off-label prescribing Wrong dose may be associated with toxicity or be subtherapeutic Wrong formulation - bioavailability Accidental poisoning because package inserts inadequate Particular concerns if background substance use or use in overdose WHO, 2007

11 What is the current status of adolescent trials?

12 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

13 Regulatory requirements to include paediatric development plans

14 Systematic search of 2 trial registries 111 unique studies 9 % included minors Under-represented in early phase studies, but over-represented in treatment trials

15 Barriers to enrolment of adolescents in trials

16 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

17 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

18 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

19 Experiences from HPV vaccination: Process for approval Department of Education (GP, NW) School principal (n=4 schools) Parental consent Adolescent assent/consent if>18

20 Challenges with consent Forms not returned or poorly completed Related to literacy and knowledge levels of caregivers Absent or working caregivers in some instances No parent contact details to follow up and make corrections

21 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

22 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.

23 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

24 What can be done?

25 Articulating the justification Trials in adolescents are Required AND are Feasible Acceptable Plus increasing evidence from open-label PrEP studies

26 Trials are feasible and acceptable Does PrEP work in adolescents? 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 60 52,4 55 Yes if taken consistently 31,5 22,7 28,2 WK 4 WK 8 WK 12 WK 24 WK 36 WK 48 >700 (4 or more days) (2-3 days) <350 (<2 days) BLQ but daily pill taking is a challenge Source: Hosek, JAMA Pediatrics 2017

27 Collaborative partnerships Early engagement with ethics and regulatory groups Youth and youth cabs Parents Communities Generate evidence around presence or absence of harms

28 Trial designs Approach (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

29 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

30 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

31 The Truvada experience

32 recommended for adults and adolescents at risk for HIV-1 infection weighing at least 35 kg Recommendation based on trial in year olds

33 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

34 Acknowledgements Linda-Gail Bekker Sybil Hosek Bill Kapogiannis Young trial participants Their families and communities