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By Varsha Bhatt-Mehta

Varsha Mehta-finaltAccording to the American Academy of Pediatrics Committee on Drugs, the off-label (unapproved use of a drug that is not described in the package insert) use of medications in children has improved significantly since the passage of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 2002 and 2003. The report states that despite increased labeling information on drug use in pediatric patients, off-label use (often referred to as “off-evidence use”) of medications is still a common and important problem in this population. The issues are larger and more complex in premature and full term neonates, children younger than two years of age, and those with chronic and rare diseases. Why are pediatric patients still therapeutic orphans despite advances in basic sciences and clinical trial methodologies?

In 2008, the National Academy Press published the proceedings of an Institute Of Medicine workshop on addressing the barriers to pediatric drug development. Some of the barriers identified in this workshop exist even today (seven years later). The reasons for persistence of these barriers, despite federal regulations, are manifold. Lack of complete understanding of pediatric clinical pharmacology and the best use of tools that inform us about drug-body interactions (pharmacokinetics, pharmacodynamics, systems pharmacology, best modeling and simulation techniques etc.) in children who present as multiple patient population types within the various age ranges, and the disconnect between biomedical sciences and clinical sciences as well as true translation to a patient’s bedside are just a few reasons. There are many steps between each of these sciences that must be addressed well.

Appropriately sized, well designed clinical trials remain amongst the most challenging aspect of translation. Despite advances in pharmacometric methodologies and clinical trial designs to include larger sample sizes, why is my patient never a good fit for any data? True translation from phase 2 and 3 clinical (epidemiologic) studies remains a challenge as pediatric patients rarely fall within the inclusion/exclusion criteria of these relatively small clinical trials or the assumptions of models used to simulate large clinical trials.

The dynamic nature of the young bodies, including constant growth, continually challenges the clinical scientist in advancing understanding of the “little” body; it necessitates the inclusion of variability in drug disposition due to ontogeny of the developing organs in any clinical pharmacology study. Neonates present a major challenge in this regard. Most current pediatric labeling studies focus largely on clinical pharmacology (PK/PD). Even today, more than 50% of medications used in daily practice in children do not have appropriate dosing information on the label. During therapeutic decision making, evidence and experience, not label indication of a medication, remain the gold standard for a practicing clinician. Much work remains to be done to understand pharmacology in the pediatric patient who is not a small adult. Due to developmental ontogeny, many subpopulations exist within the pediatric age range. Consequently, even within pediatrics one size does not fit all!

Varsha Bhatt-Mehta is a clinical professor of pharmacy, pediatrics, and communicable diseases at the University of Michigan with nearly 26 years of clinical and research experience in Pediatric and Neonatal Intensive Care. Her clinical services are dedicated to the care of full term and premature newborn infants.