Drugs for Children

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The off‐label use of drugs is prevalent in children. In my institution in Canada, which is a university‐affiliated children's hospital with highly specialized patient care functions, approximately half of the drugs in the formulary are off‐label in their indications, doses, patient ages, or other factors. In the intensive care units (ICU), including the neonatal ICU, the percentage becomes even higher (probably 80% or more is off‐label), even if research uses are excluded. This is a common phenomenon in most pediatric programs in the world. In the US, the implementation of regulatory changes including the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) have steadily increased the amount of labeling information for pediatric drug use. Still, more effort needs to be made, particularly in neonates.1 The elimination of the therapeutic orphan status is a long and winding process.
As the American Academy of Pediatrics (Committee on Drugs) defines it,2 the “off‐label” use of drugs does not necessarily mean inappropriate use, malpractice, or contraindication, although such uses may constitute “off‐label use.” Figure1 illustrates the concepts of off‐label medication use, highlighting the notion that “labeling” information is one piece of evidence for clinical use, scrutinized through regulatory processes, but there exists another category of knowledge outside labeling information in the public domain. This “on‐evidence but off‐label” use is not based on labeling information by definition, meaning it lacks regulatory approval but it may be sufficient to guide clinical management decisions for the benefit of the patients. Although sufficient levels of evidence may differ among drugs and the clinical context, no drug must be used clinically in the absence of knowledge and evidence to support its clinical use (i.e., off‐evidence). Rigorous research frameworks are required for the generation of new knowledge and evidence before clinical use. In clinical settings, however, off‐label uses of drugs are often off‐evidence at the same time; one study demonstrated that nearly three‐quarters of off‐label drug usage in US clinics were without evidence, namely, off‐evidence.3 This is highly disturbing.
The off‐label use of drugs goes hand in hand with adverse drug reactions (ADR). This is probably due to a combination of a lack of evidence for its use and the increased complexity of the patients' disease conditions. Both of these circumstances are common in infants and children. Moreover, developmental changes of key pharmacokinetics and pharmacodynamics factors pose challenges in extrapolating findings acquired in older children and adults to young infants. As Elzagallaai, Greff, and Rieder describe in this issue of the journal,4 such age‐dependent factors lead to ADR and its risk factors are relatively specific to children. However, acquiring such clinically important knowledge is not easy, as the pediatric patient population is limited in its size. In order to capture rare ADR signals in infants and children, such a system must be multi‐institutional at least, and hopefully worldwide across many jurisdictions.
The world's population of children is rapidly growing in resource‐challenged countries. As a result, unmet healthcare needs of infants and children in those countries remain greater than those in wealthier nations. Over the last decade, the World Health Organization has published updated Model Lists of Essential Medicines for Children, so that each country can modify it to develop their own lists of essential pediatric drugs that are relevant to their society, available in adequate amounts, affordable, effective and safe. In this issue, however, Hoppu5 argues that a sustained and stronger societal commitment is necessary even to begin evaluating the outcomes of such a program. Prioritizing essential drugs is no doubt a necessary step, but it is just a first step.
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