A Gap in Knowledge About Kids, Medication

By Rob Stein
Washington Post Staff Writer
Friday, November 23, 2007

A decade after the government began trying to ensure that prescription drugs used to treat children work and are safe, doctors still have scant information to guide them when they administer many medications to kids.

Although federal regulators have enticed or forced pharmaceutical companies to conduct hundreds of studies that have produced vital results about more than 200 drugs, perhaps two-thirds of the thousands of medications given to children remain untested on them.

"Are there children dying because of this? I don't know. Are there children being less effectively treated because of this? Probably yes. But I can't tell you because I don't know," said Richard L. Gorman of the American Academy of Pediatrics. "That's the problem: We don't know what we don't know."

What researchers have discovered has been disturbing. A highly effective adult migraine drug, for example, turned out to be worthless in children, while sometimes causing serious side effects, including strokes. An asthma inhaler could inhibit growth. A narcotic patch routinely used to relieve pain, such as after tonsil surgery, could cause fatal overdoses. Doctors were giving far too little of a medicine used to prevent seizures.

The alarming gap in medical knowledge is the legacy of many factors. The testing of drugs in children was shunned for decades as unnecessary and unethical; Congress and the pharmaceutical industry did not provide adequate funding; and conducting medical experiments on children is difficult.

"We're chipping away at the problem, but we still have a long way to go," Gorman said. "It's like trying to turn an oil tanker: It takes a long time to get it moving in the right direction. And even when it's moving in the right direction, there's a big ocean it has to get across. There's still a big ocean of unstudied drugs that we have to sail across before we complete them all."

The quandary stems from the same dynamics that left over-the-counter pediatric cold remedies on drugstore shelves despite little evidence that they helped and mounting evidence that they could be dangerous. Pharmaceutical companies, regulators and researchers long thought that doctors could safely extrapolate the results of studies in adults and simply scale down the doses.

"Up to the late 1990s, children were mostly left out of new drug development," said Ralph E. Kauffman, an emeritus professor of pediatrics at the University of Missouri School of Medicine in Kansas City. "It just wasn't thought necessary."

At the same time, pharmaceutical developers had little incentive to focus on children.

"Pediatric patients were always the orphans. People didn't pay enough attention to them. They're just not a big enough market share," said Lisa Mathis, associate director for the pediatric and maternal health staff at the Food and Drug Administration's office for new drugs.

But researchers started to realize that children react to many drugs in surprising ways.

"Children are different; they are not just small adults," said Gregory L. Kearns, a professor of pharmacology and pediatrics at the University of Missouri at Kansas City. "They are not just fractions of adults."

In 1997, Congress began to address the problem. The FDA Modernization Act gave the agency a crucial tool: It could offer companies six precious extra months to sell a drug without competition if they studied it in children. The prospect of millions if not billions of dollars of extra sales stimulated a willingness and the necessary infrastructure to do such testing on a wide scale.

Congress renewed the FDA's authority in 2002 with the Best Pharmaceuticals for Children Act, which also established mechanisms for the FDA to work with the National Institutes of Health to start scrutinizing some drugs that companies ignored or had no incentive to study because they already had generic competitors.

The legislation called for Congress to appropriate $200 million for the NIH to study the highest-priority medications. And in response to criticism that the pharmaceutical industry was getting a windfall from profitable patent extensions, the legislation established a fund to help finance studies that companies would not at the Foundation for the National Institutes of Health, a private nonprofit entity.

"There was a lot of horse-trading going on, and the pharmaceutical companies implied they would also step up to the plate," Gorman said.

Advocates pushed for a written commitment from the industry to provide $6 million a year, said Elaine Vining, who was the chief lobbyist of American Academy of Pediatrics at the time. Then-Rep. W.J. "Billy" Tauzin (R-La.) chaired the House committee that negotiated the legislation.

"Unfortunately for children, that money never materialized," Vining said. Tauzin subsequently took over as the head of the Pharmaceutical Research and Manufacturers of America (PhRMA).

The foundation has raised $4.2 million -- barely enough to pay for half of one study of one drug.

Industry representatives said there was never a formal obligation to contribute to the fund. Noting that companies are spending tens of millions of dollars sponsoring studies of patented drugs, they blamed the shortfall primarily on the failure of Congress to appropriate the promised money.

"The expectation was that NIH funding would come into play to help conduct those studies," said Alan Goldhammer of PhRMA.

In the absence of the congressional funding, the NIH has spent $25 million a year in each of the past three years to study a handful of the drugs identified as the biggest concerns.

"We've sort of cobbled together studies as best we can based on the resources we have available," said Donald R. Mattison, chief of the obstetric and pediatric pharmacology branch of the National Institute of Child Health and Human Development.

Of about 50 drugs that have been deemed high priority, the NIH has managed to launch studies of 14, including Ritalin, lithium and morphine. But only preliminary steps have been completed.

"It takes time, and it's complicated," Mattison said. "We've made substantial progress in terms of identifying drugs that need to be tested and the appropriate testing that we need to do to better understand how to use them in children. But these are very difficult studies to do."

Physically collecting and analyzing blood samples and other data from children is often harder, for example. Drugs usually need to be evaluated separately in four age groups. And parents can be wary about letting their children participate.

"When they hear the word 'study,' parents are often very reluctant," said Robert M. Ward, director of the pediatric pharmacology program at the University of Utah. "They don't want their child to be thought of as a guinea pig or a rat in a study. What I try to explain is that if they are receiving a medication that hasn't been studied, then they are essentially participating in an experiment anyway."

One big help was the 2003 Pediatric Research Equity Act, which authorized the FDA to require companies to test new drugs on children before they are approved for sale. That has stimulated more than 200 studies, resulting in 64 drugs carrying specific information about how to use them in children.

But the most successful part of the effort remains the initial program offering incentives to drug companies. The FDA has requested more than 800 studies of nearly 300 drugs, and pharmaceutical companies have agreed to do most of them, enabling the FDA to give doctors specific advice about 138 drugs, so far.

"It's been highly successful," said Dianne Murphy, head of the FDA's office of pediatric drug development. "We've really begun to learn how much we don't know."

In about a fifth of the cases, drugs that work in adults were found ineffective in children. In about another fifth, the doses being used had to be changed. Another third caused unexpected side effects, including some that were potentially fatal.

"We have been humbled by the knowledge we have gained from these studies," Mathis said.

Surprisingly, the dosages were often too low. Children's bodies, it turns out, often process drugs more quickly than adult bodies do.

At the same time, one of the major concerns is that drugs may adversely affect development.

"Unlike adults, children are growing. So there are a lot more things that can be adversely affected in a child than in an adult. Their growth could be stunted. Their emotional or cognitive development could be adversely affected," Mattison said.

Researchers have identified broad categories of drugs that should be a priority for testing, including those used to treat cancers, infections, asthma, high blood pressure and hyperactivity, as well as individual drugs including the antibiotic ampicillin, the autism drug clonidine, the blood thinner heparin and the sedative ketamine.

"You're always treading water," Murphy said.

"We've made a dent over the past 10 years. We've gotten more than 200 drugs studied. But we know that, in that time, there have probably been at least that many new products that have come onto the market that haven't been studied."

In September, Congress reauthorized and strengthened the laws empowering the FDA to require that drugs be tested, making it somewhat easier to require pediatric testing.

It also called again for $200 million more in funding.

"When's the next dangerous drug going to be found? That's what keeps me up at night," said Wayne R. Snodgrass, a professor of pediatrics at the University of Texas Medical Branch. "It's what we can't predict that worries me."

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