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 empirical- or 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.

Keywords::

• economics
• efficacy
• ethics
• modeling and simulation
• pediatric
• pharmacodynamics
• pharmacokinetic

Financial & competing interests disclosure

Partial funding received from NIH grant U10 HD045986 University of Utah Pediatric Pharmacology Research Unit grant. Steven Kern has served as a consultant to Novartis Pharma AG on the use of modeling and simulation in clinical trials. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.