Health groups say most drugs not tested for use on children

By David Kohn, Baltimore Sun, 5/18/2003

ince it was first marketed in 1989, Propofol has been prescribed to thousands of American children. In many pediatric intensive care units, it was the first choice for sedation.

But it wasn't until 2000 that researchers looked carefully at the drug's effects. The drug worked well in young patients, but scientists discovered that 9 percent of those who received it died, more than twice the mortality rate of children given a similar anesthetic. Doctors now use the drug much less often.

What happened with Propofol, prescribing a drug that never had been tested on children, is common. Most health specialists say that about three-quarters of the drugs prescribed to America's children have not had adequate pediatric trials. Children have almost certainly suffered harmful side effects, and some probably died, many pediatricians said.

A group of doctors, children's health advocates, and government officials are pushing for more pediatric drug testing. They want the Food and Drug Administration to require drug companies to test all new drugs likely to be commonly used for children. Now moving through Congress, this bill would complement a 1997 measure that gave drug companies incentives to do more tests.

''We should not have two different classes in medical care,'' said Dr. Kwang Kim, a pediatric infectious disease specialist and Johns Hopkins University professor. ''It seems now that kids are second-class citizens.''

Increasingly, scientists realize that tests on adults often do not predict how a drug will affect children.

''We always say that children are not miniadults,'' said Dr. George Giacoia, who oversees the pediatric testing program at the National Institutes of Health. ''But it goes beyond that; newborn babies are not minichildren, and premature babies are different from all of them.''

Health specialists said children metabolize many drugs differently from adults and have distinct vulnerabilities. To treat children safely and effectively, doctors must see exactly how a given drug works on them.

''Most parents assume that if the pediatrician tells them to give a certain dose, or if the label gives certain advice, then that must be right,'' said Dr. Jeffrey Blumer, director of the Pediatric Intensive Care Unit at Rainbow Babies and Children's Hospital in Cleveland. ''But in many cases we have no basis for that information.''

Instead, doctors usually extrapolate from adult data, decreasing the dose based upon the child's weight. Health specialists said this approach is woefully crude.

The number of pediatric trials is on the rise. In 1994, NIH created a drug testing program affiliated with top medical centers. Known as Pediatric Pharmacology Research Units, these centers -- there are now 13 -- conduct a large proportion of children's drug trials.

Mostly, it was the 1997 incentive law -- which gives a six-month patent extension for conducting a pediatric trial -- that triggered the testing surge. Since then, more than 37,000 children have taken part in drug tests, according to the FDA.

Companies have tested 116 drugs and made 51 label changes. Many of these adjustments are minor. Others were not: Tests on the acne drug Accutane, for example, revealed that the drug might decrease bone density in children.

Among those being studied is Zuriel Smith, a 14-year-old who suffers from the autoimmune disease lupus. He also has osteoporosis, a side effect of the antilupus drugs he takes. Two months ago, he enrolled in a study of an antiosteoporosis drug, Alendronate, which has been studied only in adults.

Smith, who lives 60 miles east of San Francisco, said being a test subject doesn't worry him. ''They're watching me so closely,'' he said of the researchers who call every two weeks and examine him every month.

Pediatric trials also let researchers focus on questions relevant only to children. Doctors testing a drug in adults, for example, do not need to worry whether it will impede development.

Dr. Richard Gorman of Ellicott City, Md., a pediatrician, points to a small trial of Prozac, released last year, that showed that while the drug works well for depressed children, it may also stunt growth. Those who took it grew a half-inch less on average than those who did not. Researchers are doing follow-up studies to find out why.

''This information would only have come from a clinical trial,'' said Gorman, who chairs the Committee on Drugs for the American Academy of Pediatrics.

Some critics object to testing children, but proponents argue that without these studies children become test subjects by default. ''When you don't have data, you're doing an inadvertent experiment anyway,'' said Blumer, the pediatrician from Cleveland. Others contend that pediatric trials include only those who might be helped by the medicine being tested; control groups of healthy children are not used.

Children taking untested medicines usually suffer no harm. But some drugs have caused problems. In 1999, seven babies in Tennessee with whooping cough were given the antibiotic erythromycin, which had not been tested on that age group. The drug contributed to a stomach obstruction that required surgery.

Supporters point to the antibiotic chloramphenicol as the worst-case scenario. Released in 1947, it soon was widely used to treat children. But in 1959, doctors realized that the drug often killed infants. Those less than 6 months old did not have the correct enzymes to break down chloramphenicol. Hundreds of infants likely died as a result, the supporters of drug trials contended.

''If we had tested the drug, we would have found the problem right away,'' Gorman said.

''One day, we'll look back at the days before testing and say, `How did we ever let something this dangerous go on?' ''

This story ran on page A16 of the Boston Globe on 5/18/2003.
© Copyright 2003 Globe Newspaper Company.