Despite government efforts to promote research on medications used in children, huge gaps persist in knowledge about whether medications are safe and effective for the most vulnerable—newborns receiving care in neonatal intensive care units (NICUs)—according to a study published today in JAMA Pediatrics.
Matthew M. Laughon, MD, MPH, of the department of pediatrics at the University of North Carolina at Chapel Hill, and his colleagues found large gaps in the information available about medications used in neonates. They reported that medication use is very common in this population: in a cohort of nearly half a million hospitalized infants, 399 drugs were used and there were more than 1.5 million drug exposures in just the first 28 days of life for this group. Yet when the researchers reviewed US Food and Drug Administration (FDA) databases to identify medications studied in neonates and whether the studies resulted in new information on the drugs’ labels, they found that only 28 drugs had been studied in this population, resulting in labeling changes for only 24. Only 11 of the label changes provided information about the safety and efficacy of the drug for premature infants and 13 of the drugs studied were not used in NICUs, where most neonatal drug exposure occurs. Eight of the drugs were used in fewer than 60 preemies.
Laughon discussed the findings with news@JAMA.
news@JAMA: Why did you decide to do this study?
Dr Laughon: We knew anecdotally and experientially that federal legislation designed to increase the amount of information on drugs used to treat children didn’t do much to address the need for information on neonates. We wanted to quantify that.
news@JAMA: Which laws are you talking about?
Dr Laughon: Prior to 1997, there was very little incentive for drug companies to study pharmaceuticals in children. In 1997, the US Food and Drug Administration Modernization Act was passed and then the Best Pharmaceuticals for Children Act [BPCA] was passed in 2002. These laws helped increase the study of drugs in children, which is great. Last year, the Food and Drug Administration Safety and Innovation Act was passed, designating neonates as a special population. As a result the FDA has hired a neonatologist.
news@JAMA: What has been the effect of these laws on data about drugs for neonates?
Dr Laughon: Since the laws went into effect, there have been between 400 to 500 pediatric labeling changes on drugs, but only a minority related to neonates. A lot of the label changes related to neonates did not include safety and efficacy information. There were only 14 where safety and efficacy were established for neonates, but these drugs were hardly used in neonates, often not in the NICU. Even though the safety and efficacy of many drugs have not been established, physicians are still using these drugs on neonates without evidence of benefits, knowing there are side effects since all drugs have side effects.
news@JAMA: Why do you think information about neonatal medication use has lagged?
Dr Laughon: They are a real tough population to study. Parents are often reluctant to consent to participation. There are physiologic changes that occur in neonates that don’t occur at any other time of life. Over the first month of life, there may be rapid changes in drug metabolism in these neonates. That’s really challenging. You need special pharmacokinetic techniques to make sense of the data. There is not much expertise available, with fewer than 10 individuals in the United States who are true experts on drug metabolism in neonates. The National Institutes of Health [NIH] is trying to beef up expertise in pediatric pharmacokinetics, including neonatal pharmacokinetics.
Neonates also have low circulating blood volume, so you can’t take much blood. You need very sensitive assays to detect a drug in small amounts of blood.
news@JAMA: What can be done to promote more study of medication use in neonates?
Dr Laughon: On the industry side, new drugs are usually developed for adults, then passed down to children and then to neonates. Some federal programs give 6-month patent extensions to companies who study their new drugs in children. For old drugs that are off patent, there is not a lot of incentive for pharmaceutical companies to study the drugs in children. The BPCA has designated funding to NIH for the Pediatric Trials Network to study off-patent and off-label medication use in children. The network has done a wonderful job studying drugs in children, with a fair number of the studies in neonates.
news@JAMA: What do you hope your study contributes?
Dr Laughon: This article is about awareness. Very few physicians have read an FDA label; it is important to know where this information comes from. They should be willing to participate in studies to help generate new information. We need parents’ help to enroll their neonate child in studies. We are thankful to the parents who have agreed to enroll in past studies; they have helped us improve the care of neonates. We have learned, for example, that the doses of fluconazole we were giving neonates were not right, so now when we have neonates with candida [a fungal infection], we can give them the right dose.