Tamara van Donge

Introduction 17 1 In 1975, only 22% of the drug labels contained pediatric information and almost 25 years later, in 1999, no improvement was observed and the percentage even dropped to 20%. 22,23 Due to the increased regulations and legislation in the second millennium, 46% of drug labels did incorporate pediatric information as assessed in 2009. 24 Although this is an constructive development, still 44% of children at the pediatric intensive care unit receive off-label drugs. 25 For newborns at the neonatal intensive care unit, this percentage more than doubled and 96% will receive at least one off-label prescription (Figure 1). 25 The causes why newborns and infants are still exposed to so many off-label drugs are multifactorial. PK data of drugs commonly used in the pediatric populations were mainly lacking when these drugs entered the market. This is because pediatric clinical trials were subjected to ethical constrains as infants and children, especially newborns were considered vulnerable and should be protected from (clinical) research. 26 In 1997 and in 2000 the European Union (EU) produced guidance documents on clinical investigation of medicines which encouraged the manufacturers to investigate their products in children when appropriate, although these guidance documents were not legally binding. 27 In was not until 2007 that a new EU regulation was implemented and ensured that the law became binding in all the EU countries. 28 This Pediatric Regulation aimed to stimulate the development of pediatric drugs and provide more information on their use. 29 This new regulation ensured that pediatric drug development regulation was comparable between the EU and the US (US Best Pharmaceutical for Children Act [2002] and US Pediatric Research Equity Act [2003]). 27 In one decade (period between January 2007 and December 2016), a total of 273 new medicines and 43 additional pharmaceutical forms appropriate for the use in children were authorized in the EU. In total, 950 pediatric investigation plans were agreed by the European Medicines Agency (EMA) and 486 waivers were granted. 29 Currently, the Pediatric Regulation has become an integral part of the early development of drugs across the EU. Pediatric pharmacometrics to bridge the gap Although these new regulations promoted the inclusion of newborns, infants and children in clinical trials, new and innovative approaches are needed to account for the (practical) challenges related to the conduction of pediatric clinical trials. Decades ago, treatment of newborns with new therapies based on solely adult information resulted in the grey- baby syndrome after chloramphenicol treatment or the gasping syndrome after exposure to benzyl alcohol. 30-32 Despite the fact that these examples are often recited, they still demonstrate the extreme vulnerability of the newborn and reflect the fundamental need to understand the underlying (patho-) physiology of neonatal diseases, the ontogeny of