Drug research and children: recent studies are providing important new information about drug safety and effectiveness for children. Pediatricians say it's about time

FDA Consumer, Jan-Feb, 2003 by Michelle Meadows

Most drugs prescribed for children have not been tested in children. Only 20 percent to 30 percent of drugs approved by the Food and Drug Administration are labeled for pediatric use. So by necessity, doctors have routinely given drugs to children "off label," which means the drug hasn't been studied in children in adequate, well-controlled clinical trials approved by the agency.

To be well-controlled, a study should have an adequate number of people and a control group--people who are similar to the group taking the drug being studied, but who are receiving some different type of treatment, such as another drug or an inactive pill (placebo).

Experts say the historical lack of pediatric drug testing is due to a combination of reasons. The primary reason is that pharmaceutical companies generally have viewed children as a market that would only bring small financial benefits. The drugs that have been adequately studied, in children--vaccines, some antibiotics, and some cough and cold medicines--have a large market.

"It's also harder to carry out studies in children," says Dianne Murphy, M.D., director of the FDA's Office of Pediatric Therapeutics. "You need child-friendly environments in every sense, from age-appropriate equipment and medical techniques to pediatric specialists who are sensitive to a child's fear."

Jeffrey Blumer, M.D., Ph.D., chief of pediatric pharmacology at Case Western Reserve University in Cleveland, says technical procedures that seem simple for adults, such as drawing blood or getting a urine sample, can be difficult with children.

The ethical issues are also stickier. For example, while adults can give informed consent to participate in a clinical trial, children can't because "consent" implies full understanding of potential risks and other considerations. Parents are involved in the decision to enroll children in a study, and children ages 7 or older can "assent" or "dissent," meaning they can agree or disagree to participate in a study.

Blumer says, "I've had parents who are enthusiastic about a study and then a 7-year-old who hears everything involved and says, `No way!'"

Children Aren't Small Adults

But rather than avoiding pediatric research because of the challenges, experts say it's more important to build the foundation and resources needed to conduct the studies. Without them, children face significant risks.

In the absence of data, doctors use their medical judgment to decide on a particular drug and dose for children. "Some doctors stay away from drugs, which could deny needed treatment," Blumer says. "Generally, we take our best guess based on what's been done before."

A common approach has been to use data from adults and adjust the dose according to a child's weight. Experimenting over the years has taught doctors to use many drugs in children safely and effectively. But this trial-and-error approach has also resulted in tragedy, indicating that adult experiences with a drug aren't always a reliable predictor of how children will react.

For example, in the 1950s, the antibiotic chloramphenicol was widely used in adults to treat infections resistant to penicillin. But many newborn babies died after receiving the drug because their immature livers couldn't break down the antibiotic.

"Experience has shown us that we need to study drugs in children because they aren't small adults," says Ralph Kauffman, M.D., director of medical research at Children's Mercy Hospital in Kansas City, Mo. "It's not just about smaller weight," he says. "There are dynamics of growth and maturation of organs, changes in metabolism throughout infancy and childhood, changes in body proportion, and other developmental changes that affect how drugs are metabolized."

Proof is in the Data

Fortunately, recent regulatory and legislative changes that give drug companies financial incentives to conduct drug studies in children have resulted in a dramatic increase in pediatric drug studies. "There have been more studies conducted in children in the last five years than in the previous 30 years combined," Kauffman says.

The information coming out of those studies has added pediatric information to the drug labeling for more than 40 drugs, and more changes are coming. Drug labeling is the guidance to doctors and other health-care providers on how to use a drug. "We knew that we needed science to determine proper dosing for children the same way we do with adults," says Dianne Murphy. "Now, we have confirmed it."

Ibuprofen, one of the most common over-the-counter drugs that parents rely on to reduce children's fevers, carried no dosing information for children younger than 2 years old until recently. Now, because of studies in thousands of young infants, the dose considered to be safe and effective for over-the-counter use has been established for children ages 6 months to 2 years.

The labeling has also been changed for Zantac (ranitidine), a drug used to treat gastroesophageal reflux. This condition can be life-threatening in infants. When reflux occurs, the stomach contents can flow up the esophagus and be aspirated into the lungs. This can harm the lungs of infants and result in breathing problems.