Challenges in conducting clinical trials in children: approaches for improving performance

Abstract

Recent legislative changes in both Europe and the USA have increased the responsibility of drug developers to purposefully study the agents they market in children so that specific dosing recommendations can be made to assist clinicians in their use. Typically, clinicians use empiricalor experiential-based rationales for selecting the dose to use in children, generally in a manner that attempts to achieve the same dose-exposure or pharmacokinetic profile in children as in adults. However, whether this approach achieves the necessary dose exposure or exposure effect needed may not be systematically explored during off-label use. This creates the opportunity for under-or over-exposure in children, particularly in very young children (i.e., less than 2 years old) where a combination of factors during development can effect both pharmacokinetics and pharmacodynamics. The ethical, physiological and statistical differences of studying new therapeutic agents in children present economic challenges that may create unintended incentives -both positive and negative -for any individual developer who tries to meet the requirements of new legislation to study pharmaceutical agents in children. There should be a continued emphasis in academic clinical pharmacology programs towards creative methods and approaches to better understand these differences in children compared with adults. The ability to use information from knowledge obtained from adult studies, from preclinical studies, from studies of compounds with similar chemistry or pharmacology, or from known physiological differences between children and adults is essential to choosing a suitable dose for children and achieving these regulatory aims.

Pharmacokinetics of a Novel Sublingual Spray Formulation of the Antimalarial Drug Artemether in African Children with Malaria

“…However, the present study, utilizing a greater number of plasma concentration-time coordinates across doses and absorption phases offers support for a reduction in F through increased FP metabolism via the induction of enzymatic activity in the liver and intestines (18,22). Pharmacokinetic studies with intensive sampling schedules are challenging in small children because of the relatively large volume of blood that might need to be taken and the difficulty in obtaining, and the discomfort associated with, venous access and/or repeated venesections (23). The use of sparse sampling and a population modeling approach is a better alternative.…”

Neonatal seizures: controversies and challenges in translating new therapies from the lab to the isolette

“…Clinical trials in children and neonates are complicated by ethical, physiological, pharmacological, neurodevelopental and economic concerns (Kern, 2009). Consent, beneficence, confidentiality and equipoise are important considerations in the design of all trials, but may be particularly challenging in neonates who are often critically ill.…”

Clinical pharmacology in neonates and young infants: the benefit of a population-tailored approach

“…Similar to the expansion of biomarker research in adult human medicine, there is an active search for robust biomarkers to evaluate the effects and side effects of interventions in neonates and infants [10–12]. In essence, a biomarker is a characteristic or quantitative indicator that reflects either normal biological processes, pathological processes or pharmacological responses.…”

“…There are different add-on treatments or interventions (e.g., xenon, more aggressive treatment of nonclinical convulsions, argon and melatonin) that have the potential to further improve this outcome. Small focused studies combined with the use of such early available biomarkers are first needed to ensure that both the number of cases and the study time needed for subsequent large-scale pivotal studies remains feasible [12].

“…there is an active search for robust biomarkers to evaluate the effects and side effects of interventions in neonates and infants.”

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