John N. van den Anker, MD, PhD, Guest Editor

Max J. Coppes, MD, PhD, MBA, Guest Editor

Gideon Koren, MD, FRCPC, FACMT, Guest Editor

However, even in the so-called developed world, there are still significant unmet medical needs for children. Moreover, the history of drug development is clearly one of neglecting the specific needs of children, by incorrectly assuming that data generated in adults can be applied directly to children. For decades, the needs of infants, children, and adolescents have been ignored in the process of drug development.

In adults, ischemic heart disease, hypertension, Alzheimer’s disease, and many types of cancer and other conditions have a high prevalence. If a drug is developed to treat one of these conditions, there are many patients to enroll in clinical trials, and once the drug is approved, the marketplace is large and profitable. For children, there are relatively few patients with any specific diagnosis and thus fewer patients to study, making clinical trials challenging. Furthermore “children” are not one group. Studies might be needed in newborns, infants, toddlers, older children, and adolescents. Each of these subgroups may have different dosing needs, different responses to medications, and different adverse reaction profiles, necessitating different dosage forms for safe and accurate administration. The cost and complexity of studies go up and, once the studies are completed, the marketplace may be so small that it is economically not viable to produce and distribute the product.

Traditionally, this process rendered children as “therapeutic orphans,” and pediatricians have been forced to use medicines with little evidence-based data to support a proper choice of medicines and doses, and without information of what to expect in terms of efficacy and side effects. Tragic outcomes from gray baby syndrome from chloramphenicol and deaths from drug excipients, such as diethylene glycol in elixir of sulfanilamide and benzyl alcohol in intravenous drugs used in newborns, are well-documented examples of the need for scientifically sound and ethically driven pediatric drug development and therapeutics.

In pediatric medicine, the patient may be a preterm infant weighing 400 g or a morbidly obese adolescent weighing as much as 250 kg. Drug doses for these children are often derived by scaling from adult dosages after adjusting for body weight. However, it is well known that the pharmacokinetics of a drug, including drug absorption, distribution, metabolism, and excretion, are substantially different in children as compared to adults, and that the pharmacokinetics change with growth and maturation.

Legislative actions such as the Best Pharmaceuticals for Children Act have raised the priority of pediatric studies through financial incentives and have been remarkably successful over the years. There has been a major response to the Act by the pharmaceutical industry, working in collaboration with academic pediatricians and the FDA. Much needed new data about medicines in children have been developed and old assumptions about doses, efficacy, and side effects of many drugs were shown to be incorrect. Efforts by the Eunice Kennedy Shriver National Institute of Child Health and Development to plan and support pediatric investigation as part of the National Institutes of Health roadmap initiative in Clinical and Translational Science Awards and in creating the Pediatric Pharmacology Research Unit Network, and more recently the Specialized Centers in Research in Pediatric Developmental Pharmacology, have been vital in advancing the field of developmental and pediatric pharmacology. Similarly, efforts within the FDA to improve pediatric drug development have been pivotal to move the agenda forward.

One of the critical elements in all human investigation is the assurance of the very highest ethical standards. Indeed, some of the critical elements of human investigation ethical assurance, particularly those related to respect for persons and human autonomy leading to concepts of voluntary informed consent, had been viewed as impediments to having children participate in clinical trials. Issues were raised especially in trials where the prospect of direct benefit to the child has been absent or unlikely. While there always should be an ongoing discussion and consideration of ethical issues as context, science, and society change, there is now a reasonable grounding to allow for pediatric investigation both in the United States and internationally. In fact, as the science of clinical investigation has advanced to allow us to address key issues in therapeutics in children, we have come to realize that the use of medicines in clinical practice not guided by data from good studies in children places children at greater risk than participation in well-designed, ethically conducted clinical trials. The advances in outcomes of children with cancer are a tribute to the value of capturing clinical results of therapies in structured clinical trials.

The future of pediatric therapeutics will depend on our expanding knowledge of disease pathogenesis, the discovery of new drug targets leading to new medicines, the skillful and ethical evaluation of those medicines in children, and the evolution of innovative approaches to support the development of medicines specifically for pediatric diseases. There is clearly a need for more and better trained pediatric clinical investigators, including clinical pharmacologists.

We have entered the era of increased emphasis on “personalized medicine,” providing the right drug for the right child based on improved diagnostic specificity and understanding of the net benefit of a specific therapy for a specific patient. A gradual move away from the traditional development of “blockbuster” drugs to more targeted therapeutics is needed, but the costs of drug development will keep on rising and there will be a demand for regulatory change too.

This issue of the Pediatric Clinics in North America is devoted to the topic of Neonatal and Pediatric Clinical Pharmacology. The same topic was covered by an issue of Pediatric Clinics in North America more than 15 years ago. The increase in knowledge in this area has shown an unprecedented growth in these years, and scientific contributions in this discipline have been published in numerous journals. This underscores the fact that the field of neonatal and pediatric clinical pharmacology has reached adulthood and in the coming years will continue to improve pharmacotherapy further in neonates, infants, children, and adolescents. All articles in this volume have been written by authors who published their pivotal work in this field in recent years.

However, although many important topics are dealt with, it is not possible to cover all aspects of this rapidly expanding field in a single volume. The articles cover a wide area of concerns for those who deal with neonatal and pediatric clinical medicine including updates on pharmacological treatments of HIV, pulmonary hypertension, opioid addiction, infectious diseases in the newborn, and pain-related issues, but also will present state-of-the-art updates on developmental pharmacology, developmental pharmacogenomics, new ways in detecting ADRs, the impact of new treatments such as hypothermia and ECMO on drug disposition, the importance of biomarkers, the emerging field of metabolomics, and ethical issues in neonatal and pediatric clinical trials.

It is clear that the worldwide collaboration among academicians, pharmaceutical industry, and regulatory authorities is critical for the future success of the discipline of neonatal and pediatric clinical pharmacology, but, more importantly, for the health and normal development of neonates, infants, children, and adolescents. All authors have provided not only the latest information in their areas of expertise but also presented the readers with food for thought on the directions their areas are moving toward. We are very grateful to all the authors for the time and effort they have put into writing these in-depth contributions.