Federal incentive has increased number of pediatric drug studies

Pharmacists play crucial role in encouraging further trials

Federal incentive for pharmaceutical companies to study drugs in children has led to improved labeling for several medications. More needs to be done, though, and pharmacists can play a key role in encouraging the process, says one pediatrician.

About 50%-75% of the drugs used in pediatric patients have not been studied to provide appropriate labeling information, say researchers from the U.S. Food and Drug Administration (FDA). Pediatric clinicians are left to use the literature and their clinical judgment to prescribe these drugs "off-label," which means the medications are given to a population not approved by the FDA.

Until the last few years, little was done to study pharmaceuticals in children, says John C. Ring, MD, FAAP, associate professor of pediatrics at the University of Tennessee Health Sciences Center in Memphis. He specializes in cardiology and critical care, and also is a member of the American Academy of Pediatrics’ (AAP) National Committee on Drugs.

Pediatric drug trials are complicated in their consent issues and traditionally have provided little financial incentive for the pharmaceutical companies. The federal government decided to offer more encouragement through the Food and Drug Administration Modernization Act (FDAMA), which became law in 1997. The FDAMA provided an additional six months of marketing exclusivity if drug companies voluntarily would undertake and complete studies of certain therapies important to the pediatric population.

The FDA researchers, including one registered pharmacist, decided to identify new-drug labeling information from pediatric studies submitted to the FDA under the FDAMA in response to the FDA’s written requests. The researchers’ report, published in the Aug. 20 issue of the Journal of the American Medical Association (JAMA), found that the FDA requested studies on 242 drugs between July 1998 and April 1, 2002, and 53 drugs were granted exclusivity as the result of completed studies. The report includes data as of April 2002 from the studies of the first 33 drugs with new pediatric information on the label.

Significant new dosing information and/or safety information was identified for 12 drugs, the report found. New dosing information was determined for seven of these drugs. Safety information was defined for gabapentin, propofol, sevoflurane, the combination of ribavirin and interferon alfa-2b, and various betamethasone-containing dermatologic preparations. For example, a higher percentage of deaths has been reported with patients who received propofol compared with controls in the pediatric intensive care unit. Seizures have been seen in patients administered sevoflurane. Patients receiving a combination of ribavirin and interferon alfa-2b have experienced an increased incidence of suicidal ideation when compared with adults. In addition, an unexpectedly high percentage of those receiving betamethasone-containing dermatologic preparations had documented hypopituitary-adrenal axis suppression.

The FDA researchers concluded from their findings that the FDAMA has "stimulated pediatric clinical studies resulting in improved understanding of the pharmacokinetics of drugs prescribed in pediatric medicine, important dose changes, and improved safety for children taking certain drugs."

Ring is encouraged by the numbers of drug studies in pediatrics that have been conducted even after the report’s end. The FDA, as of the beginning of September 2003, has requested a total of 660 studies, and has approved 59 label changes that address a pediatric population.

He points to the contrast of how little was actually known about pediatric pharmacotherapy before the FDAMA (only 11 studies of marketed drugs were completed in the seven years prior to FDAMA, according to published reports) against the large volume of good science that has come about in a short period with both the FDAMA and the 1998’s Pediatric Rule. The Pediatric Rule required pediatric studies of certain new and marketed drug and biological products. A lawsuit, however, resulted in a federal court enjoining the FDA in 2002 from enforcing the rule.

"As a society, there is nothing more crucial than optimizing the health of our children and making our pharmacopoeia for children more scientific," Ring says. "We have a means to bring that about, which clearly in a short period of time has been of considerable benefit. The data show that the benefit is escalating."

A drop in the bucket

In an editorial accompanying the JAMA report, however, one physician says the federal effort has far to go. "[The] current approach has yielded this critical information for only a fraction of the medications commonly used for children," says Peter P. Budetti, MD, JD, a Bartlett Foundation professor and chair at the department of health administration and policy at the college of public health at the University of Oklahoma Health Sciences Center in Oklahoma City.

The market exclusivity extension can lead manufacturers to focus on drugs with large adult markets but only limited application in children, he says. In addition, the approach provides no incentive for pediatric studies of drugs with expired patents and does not address the need for trials of drugs now predominantly used to treat relatively small numbers of children.

This means that for most drugs, pediatric physicians must still "extrapolate from evidence and experience with adults and from fundamental principles of physiology and pharmacokinetics and try to make sound decisions with respect to dosage and usage of drugs for children," Budetti says.

Prescribing medications with even the best clinical judgment nonetheless remains uncontrolled, undocumented, and unsystematic, he adds.

In his editorial, Budetti endorses the Senate’s Pediatric Research Equity Act of 2003, which would provide the FDA with additional authority to require pediatric studies of pharmaceutical products when they are needed to ensure their safe and effective use in children. Ring agrees and says pharmacists could track the progress of such legislation and encourage their legislators — through pharmacists’ AAP contacts, congressional representatives, or professional associations — to support it.

Pharmacists also can help to push along the pediatric labeling process by regularly logging on to both the AAP and FDA web sites to see what labeling changes have been added that address pediatrics. In addition, pharmacists can notify the AAP or the FDA of medications they feel would most benefit from pediatric studies and improved labeling.

Some pharmaceutical companies and other organizations may consider additional studies for pediatrics to be burdensome and expensive. Such studies, however, make sense even from a narrow economic point of view, Ring says. "Whether you endorse what I say, making interventions in childhood — especially early — is likely to pay lifelong health dividends."