When kids take the risks

Some physicians and medical ethicists are warning that a new push to include kids in drug trials could endanger the health of the children who sign up for them.

It’s been six weeks since President Bush signed into law the Pediatric Research Equity Act, but drug makers already are beating the drum to enroll children in clinical trials. Among studies sponsored by the National Institutes of Health, some 62 new trials are actively looking to enroll children. Compare that with the fact that the NIH lists just three studies using children as already underway. It’s a sign that boom times are ahead in pediatric research.

The law gives the Food and Drug Administration new powers to require drug makers to test experimental and existing medications on children. Politicians and government officials say it will help make medicines now intended for adults safe and effective for kids -- and will encourage the development of new and improved treatments for them. But others fear that drug companies and the physicians who test the drugs may not be protecting children who agree to participate in trials.

In Washington, the Institute of Medicine has convened a special committee to consider the ethical issues that arise when children participate in clinical trials. Made up of independent scientists and academics, the institute advises federal agencies such as the FDA and the Department of Health and Human Services on matters of health and medical practice. It is expected to recommend in the spring ways to protect children who serve as research subjects.

The ethics of using kids as guinea pigs also is expected to be debated in the Journal of the American Medical Assn. next month.

For Dr. Martha V. White, a physician who helped found the Allergy & Asthma Network/Mothers of Asthmatics, the Institute of Medicine’s deliberations are a chance to strike a better balance between the need for improved medicines for kids and the well-being of the kids who help make that happen.

“Parents of children with asthma recognize the crucial need for medical therapies that have been thoroughly studied and shown to be safe in pediatric populations,” White told the panel last summer. But “many parents are reticent to allow their own children to become ‘guinea pigs.’ ”

When a child and the child’s family join a clinical trial -- often at the urging of the family’s physician -- the big winners are typically other children who would benefit later from the findings of the experiment. These trials demonstrate the safety and effectiveness of a medicine; they help determine the correct dosage for different age groups; and they identify side effects and drug interactions that might be specific to children.

But drug companies also benefit, by building the evidence needed for government approval of their product. And so do the physicians and researchers who carry out the clinical trials, usually with funding from the medicine’s manufacturer. They get the recognition that comes with journal articles and money for new research and larger staffs.

Children, meanwhile, are frequently told their participation will “help other kids.” But most families clearly hope to reap some clear health benefit for their own child.

This is where science and a scientist’s responsibility to protect vulnerable subjects such as children can come into conflict. The traditional method of proving a drug safe and effective is to take a group of research subjects and divide it into two smaller groups that are similar. Those in the first group take the drug that is being tested. Group two is led to think it is taking the same drug, but instead it gets a dummy drug, called a placebo.

If, on average, the subjects in group one get better and those taking the dummy drug stay the same or get worse, the case for the new drug is made.

That may be good science, but it poses an ethical problem when a child is sick, and medicines that can help make him well or keep him from becoming sicker already are on the market. Getting assigned to the placebo group often means that child will get no medicine-- neither the new and perhaps improved therapy nor the reliable old standby.

Unmedicated, the child in group two might be helping to prove the effectiveness of the new drug, but also might be getting sicker in the process. Most sponsors of clinical trials promise to take responsibility for the care of a research subject who is harmed by the drug being tested. But no such promise is made to the subject whose illness gets worse while he is in the placebo arm of a clinical trial.

In the January issue of Pediatrics, a group of researchers from the University of Chicago and the National Institutes of Health contended that the practice of enrolling children with asthma in the placebo arm of a clinical trial -- in which the young asthma sufferer would, in effect, be left untreated -- is common, harmful and ethically unjustified.

University of Chicago pediatrics professor Lainie Friedman Ross and her colleagues examined 70 clinical trials for asthma drugs that involved children as subjects -- and found that 45 left participating asthma sufferers without the daily medicine recognized as the standard treatment for their condition. Of almost 25,000 subjects in the trials reviewed, the authors were able to identify 205 children who were assigned to placebo groups and had to withdraw from the trials because their asthma symptoms were exacerbated.

There probably were many more children whose asthma was made worse, the authors noted, but gaps in the data made it impossible to count them.

In a majority of the clinical trials, Ross said, the children risked dangerous asthma attacks and even lung damage to participate in studies in which data on children were not even being collected and analyzed separately. In these cases, the study designers were not using the children’s participation to elicit information about a drug of importance to children. Kids, who by custom are to be accorded special protections, were treated the same as adult enrollees.

Ross called most of the proposed asthma drugs being tested “me-too drugs,” or medications that enter a field already crowded with effective therapies. In cases in which children with moderate or severe asthma were placed in placebo groups, they were risking illness or death not to help a breakthrough treatment come to market, she said, but to help a pharmaceutical company capture some share of a huge and lucrative market -- an estimated 26 million Americans (4.5 million of them children) with asthma.

Those designing and running the clinical trials, said Ross, “knew they were putting these people at risk” but enrolled children anyway. “I think there’s a lot of money to be made” in bringing new drugs to market, she added.