Abstract
:For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in “basket” trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.
Highlights
HIV-infected children differ from adults in that they acquire HIV around the time of birth when their immune system is still developing; if untreated, they experience more rapid disease progression and early mortality
It is recognized by regulatory agencies that when disease progression, drug response, and exposure response in children are similar to adults, efficacy can be extrapolated from adult trials and only dose-finding and safety studies are required for pediatric regulatory approvals.[3,4,5]
DESIGNING EFFICIENT TRIALS Below, we describe trial designs for pediatric HIV that illustrate how several questions can be addressed within a single trial
Summary
HIV-infected children differ from adults in that they acquire HIV around the time of birth when their immune system is still developing; if untreated, they experience more rapid disease progression and early mortality. The top priorities included determining “the safety, efficacy, acceptability, pharmacokinetics, and optimal dosing of existing and new antiretroviral drugs and formulations for children,” improving adherence in adolescents, and evaluating novel treatment delivery systems in children and adolescents.[11] Management and prevention of coinfections, tuberculosis (TB), viral hepatitis, and bacterial infections, is another area where data in children are largely limited to PK data on drug interactions. All these questions would benefit from more efficient study designs that can address multiple questions while minimizing the number of patients enrolled. A common approach is to power a multi-arm trial based on one global test across all treatment arms (usually of any difference between arms); only if this is significant, other comparisons are tested.[16,17]
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