Pediatric Drug Labeling Slow to Follow Law, Study Finds

Ricki Lewis, PhD

December 10, 2013

Few drugs have labels reflecting safety and efficacy testing in neonates, and very few drugs that are studied are actually used in neonatal intensive care units (NICUs), according to results from a new study published online December 9 in JAMA Pediatrics.

Infants younger than 28 days are at elevated risk for catastrophic drug-related adverse effects. Novel trial designs and clinical endpoints may be necessary to evaluate drug safety and efficacy because pharmacokinetics and physiology in neonates differ from those in adults.

Programs and legislation designed to encourage drug testing in neonates began in 1998 and were reauthorized in 2012. However, half of drug labels still lack information on dosing, safety, or efficacy in this vulnerable age group.

Matthew M. Laughon, MD, MPH, from the Department of Pediatrics, University of North Carolina at Chapel Hill, and colleagues reviewed drug studies, using the US Food and Drug Administration (FDA) Web site, that included neonates and that were conducted from 1997 through 2010. They assessed whether studies, in response to legislation, included neonates, whether labeling changes resulted, and the nature of the information on the labels.

Legislation inspired 406 pediatric labeling changes, but only 24 included new neonatal information. Of these 24, 11 (46%) stated the drug was approved for neonates. Thirteen (54%) of the 24 labels included the statement that "safety and effectiveness have not been established."

Among the labeled drugs were 14 anti-infectives, 5 drugs for gastroesophageal reflux, 3 cardiovascular drugs, 3 anesthetics, and 1 drug for volume replacement, 1 pulmonary drug, and 1 analgesic/antipyretic.

Most of the 28 drugs that were studied were not used in 290 NICUs between 2005 and 2010. The researchers considered 446,335 hospitalized infants using 399 drugs (1,525,739 drug exposures). Thirteen (46%) of the 28 drugs were not used at all, and 6 of these were for HIV or HIV complications. Eight (29%) of the 28 identified drugs with labeling changes were used in fewer than 60 neonates.

Less than 0.5% of all drug exposures in the large sample of neonates were of drugs approved for neonatal use. Most drugs were prescribed off-label, even when studies had shown the drugs to not be safe or effective.

The researchers conclude that further studies must establish and validate the safety and efficacy of many drugs for neonates. Limitations of the analysis include not knowing the number of neonates in 6 of the studies, incomplete clinical information on the indications for some drugs, and underestimated exposures to drugs used during surgery.

In an accompanying editorial, Justin Stiers, MD, and Robert Ward, MD, both from the Division of Neonatology, University of Utah, Salt Lake City, call neonates "the last therapeutic orphans to be adopted." They review the history of legislation covering pediatric drug testing, pointing out that although the 500th pediatric label change was approved in 2013, neonates are severely underrepresented in label changes.

Dr. Stiers and Dr. Ward call the new report "the most comprehensive analysis of the effects of this legislation on the study and labeling of drugs for newborns." However, they disagree with the researchers' opinion that off-label prescribing could expose neonates to risk of adverse effects without benefit, pointing out that "many effective treatments for neonates are published but are not included in the drug label."

This study was supported by the National Institutes of Health. Dr. Laughon receives support from the US government and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. One coauthor has received support from Pfizer, Cempra, Diomorph, Aptiv Solutions, GlaxoSmithKline, Janssen Research and Development, Special Products Ltd, Tetraphase Pharmaceuticals, and The Medicines Company for neonatal and pediatric drug development, as well as the National Institutes of Health and the Thrasher Research Fund. One coauthor is supported by Astellas Pharma US, Cubist Pharmaceuticals, Johnson & Johnson, Pfizer, Pangen Biosystems Inc, and CV Therapeutics Inc for neonatal and pediatric drug development and by the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. The other authors and the editorialists have disclosed no relevant financial relationships.

JAMA Pediatr. Published online December 9, 2013. Article abstract, Editorial extract

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