Placebo-controlled trials in pediatrics and the child’s best interest

For too long children have received medicines not sufficiently studied for their needs and, in fact, being considered as small replicas of adults, it was deemed sufficient to adjust the dosage of a drug approved for adults. Together with the limited availability of appropriate drug formulations, especially for neonates and toddlers, this approach has caused increased iatrogenic risk and/or suboptimal adherence to treatment. With the aim of encouraging the development of more efficacious and safer medicines for children, the Regulatory Agencies in Europe and U.S.A. commendably issued directives to promote adequate and well controlled pediatric clinical trials. In compliance with the agenda of the Pediatric Regulation, in the past decade the number of pediatric patients enrolled in double-blind randomized clinical trials (RCTs) is markedly increased. In order to establish the efficacy of new medicines, RCTs frequently include a placebo-control group that carries the burden of additional, and to some extent underestimated, ethical concerns with respect to trials in adults. Six years into the Pediatric Regulation implementation, off-patent drugs, most of which at present are extensively used off-label, are underrepresented in ongoing/proposed pediatric RCTs. We debate this status quo to assess what might be the child’s best interest. In fact, we argue that well-designed studies, in which efficacy and safety of new drugs are compared to off-patent drugs that are currently prescribed off-label, would achieve the aim of the Pediatric Regulation better and more ethically than placebo controlled RCTs.