Putting Children to the Test

Four weeks after the birth of their son, Ronnie and Michelle Higgins were stunned when they were asked to put him in a clinical trial for an antifungal drug.

Born 15 weeks premature, he had been expected to endure a long hospitalization crammed with drug treatments, tests and possibly surgery. And when he developed a fungal infection, they knew additional medication would be required. But an unproven drug?

“I found the idea of a clinical trial very scary,” Michelle Higgins says.

Letting a child participate in the testing of a drug does carry some risks--and it’s a decision that more parents are making.

A federal law passed in 1997 gave drug companies an incentive to test products in children by offering a six-month patent extension on drugs so tested. And in December, the Food and Drug Administration began requiring that new drugs deemed important to children--or even commonly used in children--include labeling on safe pediatric use.

As a result, the number of medications being tested in children has jumped from 114 in 1990 to 217 last year, according to the Pharmaceutical Research and Manufacturers of America. Most doctors agree there’s a need for such research--and have long pushed for it.

After all, about 400 drugs commonly used in children--and 70% of all medications--bear no labeling information on safety and efficacy for them, says Dianne Murphy, associate pediatrics director at the FDA. Doctors typically prescribe the drugs simply hoping they’ll work as they do in adults. With the new clinical trials, 120 medications could carry labeling for children within five to 10 years.

Still, “if a trial is for a new [drug], you can’t really give people a good idea of all the types of possible side effects,” says Jeff Goad, an assistant professor at the USC School of Pharmacy.

The possibility of serious harm became apparent during research on the drug Propulsid, for gastroesophageal reflux, in 1999. The FDA reported that 24 children being treated died of cardiac arrhythmia--some while involved in clinical trials. The drug’s manufacturer, Johnson & Johnson Co., withdrew it from the market last year, although there is dispute over how much of a role the drug played in the infants’ deaths.

But the case points to the agonizing choice facing doctors and parents: Test drugs in children or allow untested medications to be given to them. Even before the dangers of Propulsid were clear, doctors were enthusiastically prescribing the drug for babies despite the fact that the label carried no information on safety and effectiveness in children.

“There is this difficult dilemma as to which situation presents the most risk”--giving untested medications to children or doing clinical trials in children, says Christopher Milne, assistant director of the Tufts University Center for the Study of Drug Development. “But I think the evidence is coming down on the side of testing these medications in children.”

Prescribing “adult” drugs to children has its own dangers, experts note. In the 1960s, numerous newborns died from the antibiotic chloramphenicol. And many other drugs have proved to be harmful in children in ways that were not discovered during testing in adults. For example, sulfa drugs were found to cause jaundice in newborns; the painkiller fentanyl led to withdrawal symptoms in kids; and the antibiotic tetracycline was found to stain the teeth of young children.

Among the major proponents of pediatric drug testing in children have been AIDS advocates, including the late Elizabeth Glaser, who said children were dying of the disease because of the lack of pediatric drug data.

Moreover, several recent studies have indicated that dosage in children does not work as doctors had hoped--that many children are receiving too much or too little of various medications.

Some trials have actually had immediate benefits for their participants. For instance, the standard medication for the Higgins baby’s fungal infection can be toxic to the kidneys, particularly risky for such a young patient. The parents participated in the trial, and the baby is now doing well.

That antifungal drug study resulted in a change in treatment philosophy by demonstrating that the new medication was as effective but less toxic, according to a November paper in the journal Clinical Infectious Diseases.

“We’re relieved now,” his mother says, “because he could have been in another hospital where the experimental drug wasn’t available and he would have received the toxic drug.”

A Perception of Emphasis on Profit

Several U.S. children’s hospitals, Children’s Hospital of Orange County among them, are planning research centers to handle the growing demand for clinical trials.

While establishing separate pediatric research facilities is a lucrative business move on the part of many hospitals--CHOC, for example, has 59 trials going--officials at pediatric hospitals justify their centers by saying that they are better suited than general hospitals and other research centers to do studies in children.

“Pediatrics is a specialty, and you should have pediatricians doing these studies,” says USC’s Goad.

Still, many people believe that children are being used to make hospitals and drug companies money, acknowledges the Higgins baby’s doctor, Antonio Arrieta of Children’s Hospital of Orange County.

“The perception is that people are profiting off this and are luring children into research,” says Arrieta, an infectious diseases specialist. “But if there are two medications, wouldn’t you like to know which one is better?”

The knowledge gleaned from pediatric studies even goes beyond which drug is better, experts say. Research in children is also defining the differences in how infants, toddlers, preadolescent children and adolescents react to medication, says Dr. Greg Koski, director of the federal Office for Human Research Protections.

“Children are not little adults or even a homogenous population,” he says. “It makes a big difference whether it’s a teenager, preteen, toddler or infant.”

Among the findings of recent drug trials:

* Under common dosing guidelines, children under age 5 receiving the anti-seizure medication gabapentin may be getting too little of the drug. Further, a small number of children ages 3 to 12 experience hostility taking it.

* Girls ages 8 to 11 being treated for obsessive-compulsive disorder typically receive too much Luvox.

* Children with congenital heart disease or pulmonary hypertension need lower doses of the sedative midazolam than was previously believed.

Drug companies also are learning how to formulate medications so they’re easier for children to take. One antibiotic that was tested in children with ear infections and reformulated into a liquid even ended up aiding adults. Researchers found that the drug helped elderly people with urinary infections who also have difficulty swallowing.

In the case of the sedative midazolam, clinical trials in children led to the development of an oral medication. Previously, the drug had to be delivered through an injection.

And, last December, the first pill for type 2 diabetes, Glucophage, became available for children. For some young patients, it will be the only FDA-approved alternative to insulin shots. While doctors sometimes prescribe other diabetes medications for children, picking the correct dose is often guesswork.

“Sometimes it is difficult to change a drug’s formulation,” says Dr. Bert Spilker, senior vice president of scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America. “There can be many problems, and it can take months, if not years, to develop these dosage forms.”

The studies also are teaching investigators more about how to conduct research in children.

“They are advancing the science of pediatric clinical trials,” says Milne. “They’re coming up with new sampling techniques that are less invasive and new ways to measure [results] that are more applicable to children.”

For example, researchers worked diligently to produce a new rating scale to measure anxiety in children, Milne says.

“That had previously been a problem with getting drugs approved to treat pediatric anxiety,” he says. “You couldn’t measure efficacy because the ratings scales were designed for adults.”

But while there are benefits to conducting drug studies in children in terms of the knowledge gained, individual parents and doctors still struggle with the question: When is a clinical trial advantageous to a particular child?

Different Degrees of Risk and Benefit

That is the sticky question that investigators, parents and the people who monitor clinical trials must constantly ponder, says Denise Angst, director of pediatric research at Lutheran General Children’s Hospital in Chicago. “Most people believe these studies are important to do, but there is concern over how to do it,” she says.

There is general agreement that early-stage testing to determine if a drug is safe is not justified in children. Conversely, it’s often easier for parents of a seriously ill child who has exhausted all other therapeutic options to try an experimental drug. Studies offering less seriously ill children potential benefit, along with some risk, are sometimes controversial.

Other types of studies that need close scrutiny include studies in which an experimental drug is compared to a placebo (a harmless, dummy drug), although Koski says that type of research is rare in children. Parents can also face a difficult dilemma if they are asked to enroll a healthy child in a study that might present even a tiny degree of risk.

Moreover, more than a few headlines have been generated in recent years stemming from improperly conducted clinical trials in adults. In 1999, for example, the death of a man in a gene-therapy study led to the revelation that more than 600 adverse events had occurred in other gene-therapy studies but had not been reported to federal authorities as stipulated by law. “The same abuses that have happened with adult trials could happen with children,” Angst notes.

All clinical trials are overseen by a panel called an institutional review board. These committees consist of doctors, lawyers, chaplains, ethicists, nurses and parents and are charged with reviewing a study to protect the patients’ interests.

“As more trials are done in children, those conducting the trials as well as the IRBs looking at trials need to have experience with the unique issues related to children,” Angst says. For example, while parents must sign a document giving consent for a child to participate in a trial, children age 7 or older also should be asked to give verbal assent.

There is also concern among ethicists that some families may be persuaded to enter clinical trials due to incentives attached to trials. In clinical trials for people of all ages, it’s common for patients to be offered a small amount of money or gift certificates to compensate for their time and effort.

“The IRB will look to see if there is undue inducement,” Goad says. “If there is an impoverished patient, would the financial inducement cause them to take part in the study when they otherwise wouldn’t do it?”

Many of the ethical and safety issues related to research in children will be addressed in a report due out this month from the Office for Human Research Protections, says Koski. The document will even suggest how researchers should handle situations in which parents of a critically ill child consent to research but the child opposes the experimental treatment.

Parents should take their time before entering a child in a research program, experts say. The informed consent document should be written in clear, understandable language.

“We often give families a highlighter and say, ‘There are lots of things [in the informed consent] you won’t understand. Why don’t you highlight it, and we’ll answer your questions,’ ” says Angst.

The decision to enter a trial can be more complicated if a child is seriously ill, says Goad. “In that case, you may need a second opinion. Have another physician read the informed consent to make sure the study has benefit for your child,” he says.

When a child is ill, research typically involves a choice between the standard therapy and the drug under investigation, experts say.

A solicitation to enter a clinical trial should never be high-pressure, says Angst. “When the child and parent are vulnerable by virtue of the situation, we need to be careful in making sure that we present this as research,” she says. “It is voluntary. If they decide not to participate, there are alternatives. If they decide not to do it, it shouldn’t compromise their care. They shouldn’t feel obligated.”