Report: More pediatric drug studies needed

April 4, 2012

By Mary Flynn
California Health Report

Newborns metabolize medications very differently, even when compared to small children or infants.

Laws intended to help our understanding of how drugs affect kids have increased our knowledge, but room for improvement remains, according to a recent Institute of Medicine report.

How drugs work in newborns and the long-term effects of drugs used on children are two of the areas that need more examination, the authors said.

The report evaluated two laws: the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). BPCA encourages more pediatric studies by offering economic incentives to drug companies who conduct studies requested by the Food and Drug Administration. PREA gave FDA the authority to require pediatric studies in specific circumstances. The laws, in place since 1997, are reviewed every five years.

“The laws themselves make it such that the FDA has to go back and look back at certain times, and say, ‘How well are these laws doing, are we getting labeling changes?’” said Dr. Jon Abramson, Chair of the Department of Pediatrics at Wake Forest Baptist Medical Center. “They’re doing pretty good, they’re doing a lot better than no laws when we had no laws, but they’re far from perfect.”

Many medications that doctors use in children – then and now – are not FDA-approved for use in kids.

Before the laws passed, very few of the drugs prescribed to kids had been studied in children, said Dr. Thomas Boat, University of Cincinnati College of Medicine and vice president for health affairs served as chairman of the committee.

“We were flying by the seat of our pants in a considerable way,” he recalled the early years of his practice in clinical medicine in the 1970s.

Using medications off-label has its consequences because many drugs affect children differently then they do adults. Medications that are generally safe and effective in adults can be harmful or completely ineffective – or both – for children.

“[Children] often metabolize the drug differently,” Abramson said. He explained that many drugs have a side effect in children that might not appear in an adult and vice versa.

A pediatric study conducted on Xolair, for instance, a drug used to treat moderate to severe asthma, determined that the risks of using the drug – including worsening their condition or severe allergic reaction – outweighed the benefits for children under twelve. Now the drug is recommended for use in children over twelve years old.

“If you’re going to use a drug, you want to be aware of what some of the potential side effects are in that age group,” Abramson said.

Newborns in particular metabolize medications very differently, even when compared to small children or infants. Chloramphenicol, for instance, an antibiotic that was widely used in adults and children in the 1950s, had toxic effects on newborns. Several newborns died after receiving the drug, and the case has become a classic example of the need for pediatric drug trials.

Conducting studies on newborn babies, or neonates, however, is especially difficult. The short neonatal period (28 days) is a brief window for research. Sample sizes are generally very small, and ethical issues complicate the study of sick or premature kids. Also, differences between newborns – including weight or their level of development – can significantly affect how a drug affects their body.

While recognizing these difficulties, the report still recommends more neonate studies.

We also continue to lack of information the long-term effects of drugs on kids. Treatment for young cancer patients, for instance, may create risks for later problems such as cognitive limitations, infertility, or even new cancers.

Abramson said that in some instances, it is even more necessary to do long-term studies in kids than adults, he said, because kids are still growing.

“Whether the drug is affecting their metabolic rate and the effect on them in terms growth, brain development, etc. – it takes years to figure out,” he said.

But long-term studies in children are difficult. “Let’s say you decide, ‘Alright, we’re going to study 100 kids with this drug.’ It’s easy to follow them during the time they’re getting the drug, that’s simple,” he said. “But to try to follow them for 10 years afterwards, it’s hard: these people move, and you can’t force the parents to bring the child back for the next 10 years.”

More timely planning, including the initiation and completion of the studies, would benefit children too, the report said. In the U.S. system, Boat explained, a pediatric drug studies aren’t initiated until nearly the end of clinical trials, when the drug company is applying for FDA approval.

Once approved in adults, Boat said, then the drug is also available to be used in children off-label. “So what you’re doing is protracting the period of time over which drugs will be used in kids without appropriate studies,” he said, creating an unnecessary delay that is likely disadvantageous to children.

On the other hand, it’s possible for studies to be initiated too soon. In Europe, for example, pediatric studies are happening from the beginning of the clinical trials, which Boat said might be wasteful if it is later discovered the drug does not work.

“Our feeling was that maybe the US is a little too late, maybe Europe is too early and maybe it’s somewhere in between that might be good, so we laid that out there as something for Congress to consider,” he said.

The committee also suggested the FDA might impose sanctions on studies that were unreasonably delayed or increase public access to information from pediatric studies might also further benefit children.

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