Study finds safety test results on children's drugs not always reaching physicians

September 12, 2006

DURHAM, N.C. -- Hundreds of drugs that have been prescribed for children may not be safe or effective for pediatric use or may require different doses than currently suggested, but some of this information may not be reaching the medical community, according to a study by Duke University Medical Center researchers. Such drugs include antidepressants, antiseizure medications and sedatives.

The study team examined drugs covered by a congressionally mandated program known as "pediatric exclusivity," through which the Food and Drug Administration (FDA) may extend the period of time that a company holds exclusive marketing rights for a drug -- thereby delaying the entry of competing generic drugs -- if the manufacturer conducts FDA-requested trials on its use in children.

The researchers looked at how often the results of such studies were published in peer-reviewed scientific journals, often cited as among the most effective ways to communicate information to the medical community. Fewer than half of the pediatric exclusivity studies were published, the researchers found, and the results were less likely to be published if the drug was deemed unsafe or ineffective in children.

"Because children have different physiologies than adults, they often absorb drugs differently or experience different side effects," said the study's lead investigator, Daniel K. Benjamin, M.D., Ph.D., a pediatrician at the Duke Clinical Research Institute who also holds an appointment at the FDA's Office of Pediatric Therapeutics. "Much of pediatric drug use is done 'off label,' meaning that children are often treated based on what has been shown to be effective in older patients, and the results can be beneficial, harmful or not effective, depending on how much information about use of the drug in the pediatric population is known."

The FDA designed the pediatric exclusivity program to increase knowledge about how children may react differently to commonly used drugs that have not been previously studied in the pediatric population. Based on their study the Duke researchers suggest that the results of these pediatric exclusivity studies are not being widely disseminated outside mandated changes to label information.

The team reports its findings in the Sept. 13, 2006 issue of the Journal of the American Medical Association. There was no grant funding for this study.

Between 1998 and 2004, manufacturers conducted 253 studies through the pediatric exclusivity program on drugs indicated for the treatment of conditions such as pain, diabetes, gastroesophageal reflux, seizures and psychiatric disorders, among others. According to Benjamin, the studies resulted in key labeling changes -- defined as a significant finding related to dosing, safety or efficacy that is different from adults -- on 100 drugs. But of those studies, only 37 were published in peer-reviewed journals, the researchers found.

Studies could result in more than one key labeling change. In cases where there was a dosing change, only 49 percent of studies were published in peer-reviewed journals. When there was a change to safety information, only 43 percent were published, and when the drug was found to be ineffective in children, only 38 percent were published, the study found.

The FDA publishes label change information on its Web site (http://www.fda.gov/cder/pediatric/labelchange.htm), but users must know what they are looking for and where to look in order to find it, Benjamin said.

"The pediatric exclusivity program has been extremely successful in bringing about labeling changes where indicated, but additional efforts are needed to better inform the medical community about these changes and the studies behind them," he said. "Not having this information can be detrimental to patient care."

Examples of drugs that were tested through the pediatric exclusivity program and received labeling changes include more than a dozen products -- including antiseizure medications and some psychiatric drugs -- that required dosing adjustments for use in children, according to Benjamin.

In another study, the drug Propofol, while effective when used to induce or maintain anesthesia in critically ill patients, proved to have an increased mortality rate among pediatric patients when used as a sedative, compared with patients who received standard sedative agents. As a result of this study, a labeling change was made.

The researchers found that if a study resulted in a "positive" labeling change, meaning a drug's safety and effectiveness in children was established, it was more likely to be published. Fifty-four percent of such studies were published, compared with 36 percent of studies that resulted in a negative labeling change, which might include a finding that the drug showed no meaningful clinical effect in children or that it was associated with a worse outcome than the comparison therapy.

Though the pediatric exclusivity program itself has been a useful tool in making drugs safer for children through labeling changes, more can be done to make sure this information is getting into the right hands, said Benjamin.

"Physicians are used to using peer-reviewed journals as a source for the latest medical information, so it makes sense to get this information in there," he said.
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Other researchers involved in this study were Robert M. Califf and Jennifer S. Li of Duke and Philip Brian Smith, Dianne Murphy, Rosemary Roberts, Lisa Mathis and Debbie Avant of the FDA.

Duke University Medical Center

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