1. Toolkit for research and development of paediatric antiretroviral drugs and formulations
In collaboration with experts from the Paediatric Antiretroviral Working Group

2. Module 1: Trial design Authors: Anna Turkova1 and Theodore Ruel2
1University College London, United Kingdom
2University of California, San Francisco, USA
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

3. Role of trials in the development of antiretroviral drugs for children
Development and evaluation of antiretroviral drugs for children has historically been slow
This module focuses on designing clinical trials involving children, aiming to facilitate and accelerate the generation of needed data in the fast-changing landscape of antiretroviral therapy
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

4. Regulatory and strategy trials in drug development and evaluation
For an agent to be approved by regulatory bodies and later included in national and global guidelines, data about dosing, safety and efficacy must be adequate
Developing drugs and optimizing treatment for children living with HIV
Regulatory trials
Conducted for licensing applications
Features of Phase I-III trials (dose-finding, safety and efficacy)
Strategy trials
Evaluate different treatment approaches (Phase III- IV)
Often bridge a gap from regulatory approval to optimised clinical use
Address the existing knowledge gaps in pharmacokinetic and pharmacodynamic and long- term age-specific toxicity
Usually carried out after a drug is approved, but may overlap with regulatory trials
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

5. Challenges for clinical trials of antiretroviral drugs for children
Pharmaceutical companies have limited incentives to support trials in children (small market)
It is more difficult to recruit and enrol children than adults
Difficult decisions about sample size
Staggered approach (from older to younger children) for dose- finding studies can slow down completion
Landscape of antiretroviral drug options is rapidly changing
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

6. 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

7. Approach(2): 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

8. Approach (3): 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

9. Approach (3): use efficient trial designs and consider innovative options
Trials should be carefully designed to generate the key data efficiently
Use innovative statistical methods and designs to increase efficiency
Adaptive trial designs such as multi-arm multistage trials (MAMS)
Bayesian methods
Design trials to maximize evidence generation with efficient use of financial and patient resources
Multi-arm randomized controlled trials, crossover designs, factorial and basket trials
Embed substudies
Note: not yet used for antiretroviral drugs for children
Bayesian methods: Evidence from previous studies, including adult studies, can be ‘borrowed’ to inform predictions and reduce the sample size. Interim analyses can be prespecified to incorporate new data, adjusting sample size and design while the trial is in motion (E.g. PHPT-5).
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

10. Approach (4): coordination with other stakeholders
Collaboration between research networks
Study designs should be:
aligned so that results can be easily compared
complementary, addressing different data gaps
E.g. IMPAACT P1093 (Phase I/II) and ODYSSEY (Phase II/III trials) focus on different aspects of drug evaluation to accelerate development of dolutegravir for children
Alignment of requirements for trials involving children and harmonization of approval process
Drug development companies should consult with stringent regulatory authorities (FDA and EMA) and external paediatric clinical trial experts to optimize their paediatric investigation/study plan design and generate clinically relevant data (advisory groups, WHO- led PAWG/PADO group)
Alignment of regulatory requirements between the main stringent regulatory authorities (e.g. FDA, EMA) can help to accelerate drug development for children
FDA=US Food and Drug Administration, EMA=European Medicines Agency
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

11. Key considerations
Identify the key data needed for regulatory approval and to inform clinical guidelines
Start antiretroviral drug trials in children as soon as possible, while Phase III trials in adults are underway
Use innovative trial designs and procedures for efficient data generation
Apply physiologically-based pharmacokinetic modelling to help with dose selection
Study multiple ages and weight bands simultaneously
Study adolescents alongside adults or include them in adult late phase trials
Use “washout” data from neonates
Include acceptability and feasibility study within the initial dose-finding and safety studies
Consider innovative statistical methods and trial designs to increase efficiency
Ensure early and ongoing collaboration between paediatric antiretroviral research community, innovator and generic pharmaceutical companies, regulatory authorities and policy makers
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design

12. Acknowledgements
Module reviewers: Deborah Ford, Ellen Chadwick, Diana Gibb and Elaine Abrams
The Toolkit for research and development of paediatric antiretroviral drugs and formulations was developed under the leadership of the Treatment and Care team in the HIV Department, WHO, and with the financial support of Unitaid, the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network and the PENTA Foundation. It was supported by the WHO Paediatric Antiretroviral Working Group (PAWG), led by Martina Penazzato (WHO Paediatric HIV Lead, Geneva, Switzerland) and coordinated by Claire Townsend (WHO Consultant, Geneva, Switzerland).
Partner organizations: WHO, Drugs for Neglected Diseases initiative (DNDi), Clinton Health Access Initiative (CHAI), United Nations Children's Fund (UNICEF), ICAP at Columbia University (ICAP), Elizabeth Glaser Pediatric AIDS Foundation (EGPAF), Industry Liaison Forum (ILF), President's Emergency Plan for AIDS Relief (PEPFAR), Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), Medicines Patent Pool (MPP).
Toolkit for research and development of paediatric antiretroviral drugs and formulations – Module 1: Trial design