Children Are Not Just Small Adults: The Urgent Need for High-Quality Trial Evidence in Children

Perspective C hildren are often touted as being very important members of society because they represent our future. Optimizing their health outcomes has the potential for a huge impact on public health because children are at an early stage in the life trajectory. But it is often unclear how society allocates its resources or creates policies to ensure that it invests in children's health. The under-investment in pediatric clinical trials is a good example of how our resource allocation may be insufficient. Over half of the pharmacological interventions we use for hospitalized children are off-label or unlicensed drugs [1,2]. The challenge for clinical care is that health care providers may fail to use medications that are indeed effective, or conversely, continue to use ineffective medications, or even those that bring unintended harm. Child health care providers must often rely on evidence that has been generated on adult populations [3]. However, both the safety and efficacy profiles of medications may be significantly different for children than adults due to differences in developmental physiology, disease pathophysiology, or developmental pharmacokinetics and pharmacodynamics [4,5]. History has shown that children may be exposed to serious unintended harms from medications if adequate research is not performed. Examples of such harm include the use of chloramphenicol for neonates producing the grey baby syndrome, the use of verapamil for treatment of infants with supraventricular tachycardia resulting in refractory hypotension and death, serious extrapyramidal dysfunction and bladder retention leading to hospitalization after domperidone, and many more [5–7]. To address the lack of randomized controlled trials (RCTs) and pharmacokinetic and pharmacodynamic evidence in children, Europe and the United States have enacted legislative and regulatory changes to encourage pharmaceutical companies to invest in research involving children, to provide the needed data on safety and efficacy of new agents [8,9]. The outcome of such legislative and regulatory changes has been an increase in the number of pediatric studies performed; however, a significant number of these studies have not yet been published [10]. An overall examination of the pediatric studies performed under this new legislation has shown that the types of drugs studied have tended to mirror those most commonly used by the adult market rather than drugs commonly used by children [11]. While there is evidence that children have been harmed by medication that has not been adequately studied, or by medication that has demonstrated differences in pharmacokinetics and pharmacodynamics in children …