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

Maria Luisa Di Pietro,Maria Luisa Barbaccia,Adele Anna Teleman,Renato Cutrera

doi:10.1186/s13052-015-0118-6

Abstract

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.

Highlights

Until the end of the last century children were precluded from entering clinical trials, a resolution intended to shield vulnerable individuals from the unanticipated risks inherent to experimental drug exposure
The core instrument of the Pediatric Regulation is the obligation for the Marketing Authorization Applicant (MAA) of any new drug in development or for the Marketing Authorization Holder (MAH) of a drug still onpatent at the moment of the directive coming into effect, to submit a Pediatric Investigation Plan (PIP)
There may be several advantages associated with enrolling a lower number of patients in placebo-controlled pediatric randomized clinical trials (RCTs), for instance: a) the study’s feasibility may be greater, due to the limited number of pediatric patients affected by specific diseases, and when there is a need to acquire data on pharmacokinetics, efficacy and safety stratified by age groups, b) results on efficacy are obtained with a lower number of vulnerable patients exposed to the unpredicted adverse effects of the new drug

Summary

Introduction

Until the end of the last century children were precluded from entering clinical trials, a resolution intended to shield vulnerable individuals from the unanticipated risks inherent to experimental drug exposure. While the 8–10 weeks usually required to show efficacy in a placebo-controlled RCT may be deemed as a tolerable delay to start treatment in a child/adolescent with low-moderate severity depression that is drug-naïve or that has shown no response to existing medications, the comparison versus placebo would not be acceptable if randomization entails the withdrawal of a medication that, even if prescribed off-label, is of benefit to the patient.

Results

Conclusion