Most drugs never tested for safety in children

Children seen facing risks from medicines

By Christopher Rowland, Globe Staff, 8/20/2003

Pediatricians are forced to engage in risky "trial-and-error" medicine when they give drugs to children because two-thirds of all drugs they routinely prescribe have never been adequately studied on kids, according to a study by Food and Drug Administration researchers to be published today in the Journal of the American Medical Association.

 

What's more, when certain drugs developed for adults were methodically tested in children, researchers found previously unknown safety risks, including higher incidences of death, seizures, and suicidal thoughts, according to new data contained in the study.

"Most people don't have any idea that such a low proportion of prescription medicines have never been approved as safe and effective for kids," said Dr. Peter P. Budetti, a professor at the University of Oklahoma College of Public Health who wrote an editorial accompanying the study.

"You can't treat children merely as small adults," he said. "Just because a child weighs one-tenth the amount of an adult, it doesn't mean they can take one-tenth of that drug. They may not be able to take that drug at all."

The lack of trials is a growing concern in Washington, where the Senate last month unanimously approved a bill that would give the FDA authority to require drug companies to test new drugs for safety, efficacy, and dosing information in children. The measure is pending in the House.

It's both legal and common for doctors to prescribe drugs for children that haven't been fully tested on them, as long as the drugs have shown to be effective in limited studies. But with major differences in physiology between adults and children, doctors have long worried that relying on these so-called "off-label" indications is inadequate.

The study bolstered those concerns with drugs doctors had been using for years. After full trials were performed on children given an anesthesia drug called Diprivan in intensive care units, for example, researchers found a statistically higher risk of deaths than for children given different forms of anesthesia. Another anesthetic, Ultane, triggered rare cases of seizures in young adults and children with no history of seizures. An antiviral therapy called Rebetron was associated with suicidal thoughts in 2.4 percent of children, compared with 1 percent for adults given the drug, according to the FDA.

In an interview, Dr. Richard Gorman, a Baltimore pediatrician and chairman of the American Academy of Pediatrics' committee on drugs, said an epilepsy medication called Neurontin prescribed to control pain in some children was ineffective because the dose was too small. Once clinical trials were performed, it turned out that the dosing schedule had been improperly recalculated for children. The original dosing was based on children's weight alone, without taking into account their faster metabolism.

"We were giving it to kids in good faith to help their pain, and it didn't work," he said. "You have kids who suffered needlessly because the data wasn't there."

Dr. Richard Parad, a specialist in neonatal intensive care at Brigham and Women's Hospital in Boston, said none of the drugs he uses to treat premature infants for potentially deadly pulmonary disorders has FDA approval for pediatric uses. He said he has picked up expertise in off-label dosing for these drugs by reading medical journals.

"Most of the tools we use as pediatricians are kind of hand-me-downs that have been tested and tried in adults," he said.

The pace of trials did not pick up significantly until Congress approved the Food and Drug Administration Modernization Act of 1997. That gave drug companies an additional six months of market exclusivity, with no generic competition, if they voluntarily performed pediatric clinical trials. There have been risks associated with the accelerated trials, including deaths and lawsuits relating to alleged ethical lapses.

The FDA researchers who wrote the study published today did not discuss those concerns. They pointed to the benefits of the government's incentive: 53 drugs have won the exclusivity provision and 49 drugs have new labels updated with pediatric information. Thirteen of the findings or labeling changes were considered "significant" by the FDA, meaning they revealed improper recommendations for dosage that affected safety or effectiveness.

In 1998, the FDA imposed a requirement that all drugs with possible pediatric indications be tested on children, but that was thrown out by a US District Court judge in Washington last year after a legal challenge by several groups that lobby for fewer regulations, including the Competitive Enterprise Institute and the Association of American Physicians and Surgeons. The bill passed by the Senate in July would restore the rule legislatively.

Opponents say requiring pediatric clinical trials will slow down new drug approvals and make it more difficult for companies to bring drugs to market. Sam Kazman, general counsel of the Competitive Enterprise Institute, said the measure would discourage drug companies from researching new uses for drugs if they believed off-label pediatric uses might trigger FDA requirements for expensive, full-blown clinical trials.

The drug-industry trade group, the Pharmaceutical Research and Manufacturers of America, backs the voluntary provisions of the 1997 law.

Budetti, who wrote the journal editorial, said the FDA needs to wield a regulatory stick because drug companies on their own aren't performing enough trials, in part because there are fewer child patients than adults. "Just in terms of the financial incentive, there is not the same kind of gain for pharmaceutical companies to be spending the money that it costs to run the tests in children, because the market isn't going to be there," he said. Until the climate improves for pediatric clinical trials, he added, parents must be advocates for their children.

"It is fair to ask questions like, `How widely is this drug used in children,' and `Is it approved or not by the FDA,' " he said.

Christopher Rowland can be reached at crowland@globe.com.