MODULE 1: TRIAL DESIGN ©WHO/Christopher Black 15 1. INTRODUCTION The overarching goal of this toolkit is to facilitate where most children with HIV live (1). To generate the treatment of children with HIV with the most the timely data about modern ARV drugs needed efficacious medications. The selection of the for children in the fast-changing landscape of right drugs and formulations given priority for the ARV drug pipeline and dynamic treatment development is based on target product profiles guidelines, clinical trials must be strategic, (see the module on target product profiles). forward-thinking and efficient in implementation. Nevertheless, before an agent can be approved for use by regulatory bodies or included in national and global guidelines, data about dosing, 1.1 General considerations for HIV drug safety and efficacy must be considered adequate trials involving children in the intended population of children. This module reviews issues in selecting a clinical trial Clinical trials for drug development are classically design to generate the necessary data about a divided into four phases: I to IV (Fig. 1.1). After candidate antiretroviral (ARV) drug for children preclinical study in the laboratory, a drug is as quickly and efficiently as possible. generally first tested in humans in Phase I trials that generate key safety and pharmacokinetic The development and evaluation of ARV drugs and pharmacodynamic data for small numbers for children has historically been slow, with some of participants. Phase I trials are generally dose- agents being approved for children as long as finding trials that might aim to establish the a decade after they were approved for adults maximally tolerated dose for adults or identify (1,2). The limited number of agents with age- the dosing for children that yields exposure appropriate ARV drug dosing and formulations for equivalent to that of adults. Phase II trials children has remained a key barrier to simplifying, confirm safety and explore efficacy to facilitate harmonizing and implementing WHO treatment decisions about further development. Phase III guidelines in low- and middle-income countries, trials are pivotal trials that confirm safety and Figure 1.1. Phases of clinical trials Preclinical Phase I Phase II Phase III Phase IV Pharmacology Evaluate short- Confirm safety Establish efficacy Evaluate long- (pharmacokitetic term safety Explore efficacy versus standard term safety and and care effectiveness Generate Hundreds of pharmacodynamic) pharmacokinetic participants Confirm safety Diverse groups, data and including those Demonstrate the Acceptability Toxicity pharmacodynamic excluded from benefits of the Hundreds to data for humans early trials In vitro and in vivo new treatment thousands of studies in animal Tens of participants Support additional models participants indications Support licensing Identify the safe Identify optimal and change starting dose for dose for a larger practice trials in humans trial 16 establish efficacy among a larger number of submit plans to study the agent among children participants; Phase III data are generally required or request a waiver (3,4). The EMA calls a plan for for regulatory approval of a new drug for adults. study among children a paediatric investigation Phase IV trials generate data on long-term safety plan and the FDA calls it a paediatric study and/or efficacy for a new drug after it has been plan. Stringent regulatory authorities require licensed in real-world conditions across different a paediatric investigation plan or paediatric populations. Developing drugs for children and study plan for every new drug being developed treatment optimization trials often combine for adults that is considered to be relevant features of different phases, commonly blending for children. Paediatric investigation plans Phases I and II and Phases II and III. or paediatric study plans are required to be submitted early in drug development (3,4) Clinical drug trials can also be classified into two and must be established before filing for the broad categories: regulatory and strategy trials. marketing authorization (Fig. 1.2 and the module Regulatory trials are conducted for licensing on regulatory filing). Trials for developing and applications that seek approval by stringent evaluating drugs for children are usually started regulatory authorities and may include features once trials involving adults show substantial of Phase I–III trials (dose-finding, safety and evidence of the efficacy and safety of the drug efficacy), depending on the extent to which of interest. Waivers are difficult to obtain but can the relevant data from adult studies can be be granted if an agent is not thought to have a extrapolated (see below). These trials generally role in care for children and/or because it would focus on pharmacokinetics and safety and use be logistically impossible to study (such as finding age-appropriate drug formulations for children eligible child participants being too difficult). already tested in adults for bioequivalence with In determining which data are needed to support the adult formulations. regulatory approval of an agent for use among To secure approval for an agent for adults, children, it is critical to first ask what data can be stringent regulatory authorities such as the extrapolated from adult trials and what data must United States Food and Drug Administration be generated de novo in trials involving children. (FDA) or European Medicines Agency (EMA) Fig. 1.3 summarizes FDA guidance on this topic. require pharmaceutical companies to either Depending on evidence-based assumptions on Fig. 1.2. Timing of the development pathway for HIV drugs for children Adult drug development Marketing authorization for adults Preclinical Phase 1 Phase 2 Phase 3 Phase 4 Submit paediatric investigation Yes Clinical trials among children Is the drug plan or paediatric Deferral if neededa relevant for HIV study plan among children? No Apply for waiver aAdditional efficacy and safety data for adults are needed before initiating studies among children. Source: reprinted from The Lancet Oncology, 14, Vassal G, Zwaan CM, Ashley D, Le Deley MC, Hargrave D, Blanc P et al., New drugs for children and adolescents with cancer: the need for novel development pathways, e117–24, Copyright (2013), with permission from Elsevier. (5) 17 the appropriateness of extrapolating efficacy from treatment and exposure–response relationships adult trials, the regulatory trials can differ in design, are similar for children and adults, and efficacy ranging from non-comparative studies evaluating evidence from adult Phase III trials can therefore pharmacokinetics and safety (extrapolation be extrapolated to children. In other words, Phase possible) to a randomized controlled trial, I/II pharmacokinetic and safety non-comparative evaluating pharmacokinetics, safety and efficacy trials are generally considered sufficient to support (no extrapolation possible). Some agents, such regulatory approval of ARV drugs for children if as immunomodulatory agents designed for cure the same exposure as for adults can be achieved. strategies, may rely on mechanisms that cannot be reasonably extrapolated to children; these agents In contrast to regulatory trials, strategy trials are require more study, probably including evidence of used to evaluate various treatment approaches, efficacy for children, to be approved. Nevertheless, such as the sequence of regimens for first-, for studies of most ARV drugs that target the second- and third-line therapy, treatment viral life cycle among children, it is generally simplification and use of more pragmatic dosing accepted that progression of HIV, response to compared with the standard of care and focus on Fig. 1.3. Algorithm for planning and extrapolating studies for children Do children have similar (1) disease progression and (2) response to treatment to adults? No to either Yes to both Do children have similar exposure response to adults? No Yes Is there pharmacodynamic measurement to predict efficacy in children? No Yes No extrapolation Partial extrapolation Full extrapolation Conduct among Conduct among children: Conduct among children: children: 1. Pharmacokinetic and pharmacodynamic 1. Pharmacokinetic studies 1. Studies to studies to establish exposure response among aimed at achieving establish dosing children for pharmacodynamic measurement exposure similar to that for adults 2. Safety and efficacy 2. Pharmacokinetic studies to achieve target studies at the exposure based on exposure response 2. Safety studies among identified dose(s) children at the 3. Safety studies among children at the identified dose(s) identified dose(s) Sources: adapted from General clinical pharmacology considerations for pediatric studies for drugs and biological products: guidance for industry 2014 (4) and Dunne et al. (6). 18 effectiveness (efficacy in the real world). Strategy possible. Strategy trials are usually Phases III–IV trials aim to optimize drug delivery and uptake, and use randomized controlled designs, although to improve safety, adherence, acceptability or single-arm designs can be also used when a quality of life and to explore potentially better randomized controlled trial is not feasible and the treatment options for children with coinfections. assumptions for thresholds for success or failure These trials can nest pharmacokinetic substudies can be prespecified (12). to evaluate dosing differing from the licensed dosing, such as once-daily