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By Francesca Lunzer Kritz
Special to The Washington Post
Tuesday, September 10, 2002; Page HE05

Wendy Goldberg of Bethesda wonders each day if some of the many drugs her 11-year-old daughter, Abby, has taken for severe asthma since she was 8 weeks old may have done more harm than good.

While all the drugs were approved by the Food and Drug Administration (FDA) as safe and effective, most of their testing was done in adults, not kids. Of the seven drugs Abby now takes, only four have dosing information, relatively new to their labels, that addresses children in Abby's age group. Three of the four, however, don't have information for children under 6, though asthma is common in very young children.

What prompted the label changes are recent findings that resulted from a series of federal directives that new drugs (as well as some older ones) that may be taken by children be tested in the age groups that use them. Previously, say experts, dose recommendations for children were based largely on guesswork.

New information about dosing for children is beginning to appear on drug labels only now, says Mark Schreiner, head of pediatric clinical trials at the Children's Hospital of Philadelphia and a leading expert on drug use in children, because clinical trials take several years to complete and be evaluated by the FDA. William Rodriguez, an expert on pediatric testing at the FDA, says label changes have now been made for nearly 60 drugs, with additional changes expected for 100 more within the next few years. (See chart on Page F5.)

In the case of Flonase, one of the allergy and asthma drugs taken by Abby Goldberg, research showed that the drug could be taken safely and effectively in children as young as 4.

The rationale for not studying children's dosing of drugs until now has been, ironically enough, child protection. Because of ethics and liability concerns prompted by the drugs' potential for side effects, researchers have traditionally been reluctant to test drugs on children or women of childbearing age. In recent years, however, patient advocates have argued that such considerations may put members of these and other groups at heightened risk if it stymies research.

"At times, children have been harmed and maybe even killed because of a lack of knowledge of how drugs would affect them," says Robert Ward, a former chairman of the American Academy of Pediatrics (AAP) Committee on Drugs. He cites as an example the deaths in the 1950s of several newborns after they were given an antibiotic called chloramphenicol. Because the babies' livers were unable to break down the drug, toxic levels of it built up, leading to their deaths.

Other drugs that have caused side effects -- some serious -- in children, according to the FDA, include sulfa drugs (antibacterials that caused jaundice in some newborns), the painkiller fentany (which caused withdrawal symptoms for some patients after long-term use) and the antibiotic tetracycline (which stained teeth in some children)

Richard Gorman, chairman of the AAP committee, calls the requirement to test drugs in children one of the most important developments in pediatric medicine. Until now, he says, no more than a third of all drugs used in children were actually studied in kids. Vaccines widely used in children were among those drugs previously tested.

For other drugs, doctors have done their best to extrapolate the best children's dose based on body weight and some understanding of how particular drugs work, says Schreiner, "but what we have discovered through the clinical trials is that sometimes we overdosed, risking serious side effects, and sometimes we underdosed and therefore gave drugs [in doses] that weren't sufficiently effective."

Course Corrections

 

One example of a misjudgment prior to expanded child testing is the epilepsy drug Neurontin, for which dosing was increased after tests showed that higher doses controlled seizures better in children without causing more severe side effects.

In some cases, clinical trials have shown that a drug should not be used at all in children below certain ages. That has been the case with the eczema drug Elidel, which poses a risk of infections and diarrhea in children younger than 2. Testing on Diprolene, which is used to treat certain rashes, found that the drug could cause endocrine problems in younger children. Its label now recommends that the cream not be used in children 12 and younger.

Conditions for which much more pediatric drug information is still needed, according to the FDA, include depression, epilepsy, severe pain, gastrointestinal problems, allergic reactions and high blood pressure. Safety and efficacy information is especially sparse on many drugs used in children under 2, according to the agency.

Recent congressional moves, as well as pending action, suggest that testing in children will continue. The Best Pharmaceuticals for Children Act, which gives a financial incentive -- a six-month patent extension -- to pharmaceutical companies that test drugs in kids, was signed into law earlier this year and applies through 2007. An attempt by some Democratic senators to cut the benefit to three months failed. Drugs that owe their expanded information to this law include children's pain and fever relievers Advil and Motrin. Both drug labels now carry information on dosing for babies 6 months to 2 years.

The Senate Appropriations Committee is also expected this year to consider a funding request that would allow the National Institutes of Health to conduct pediatric testing of some drugs whose patents have expired, since the drug companies often have no incentive to do so. Also pending is congressional legislation to codify an FDA rule empowering the agency to force companies to test certain drugs. After the FDA considered shelving the rule earlier this year, an outcry from groups such as the AAP led Secretary of Health and Human Services Tommy Thompson to promise to retain it. Not satisfied, three Democratic senators have written legislation to make the rule federal law.

A tight legislative calendar could keep the bill from becoming law this year, but Sen. Christopher Dodd (D-Conn.), chairman of a Senate subcommittee on children and families and one of the bill's authors, says he will reintroduce the measure early next year if Congress does not pass it before the current session concludes.

Francesca Lunzer Kritz is a regular contributor to the Health section.