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

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

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

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

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

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

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

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

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

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

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

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