Drug Advances Leave Children Out in the Cold : Health: Few new medicines are being tested on youngsters. Pediatricians want drug makers to provide better guidelines.
Nancy Sander was elated when she read of a new allergy medicine that did not cause drowsiness. Her 15-year-old son, Michael Gregory, suffered terribly from hay fever-type symptoms in the spring and fall, but all of the antihistamines his doctor recommended made him too groggy to concentrate in school.
Sander immediately called the pediatric group near her home in Fairfax, Va., to request a prescription for the drug, Seldane. But the doctor on duty refused.
“Seldane was not approved by the (U.S. Food and Drug Administration) for children my son’s age,” Sander recalls. “I was really irritated.”
Sander’s experience is typical.
The last 50 years have seen a virtual explosion in new drugs to combat disease and alleviate suffering. But children have largely been excluded from these medical advances.
Most new prescription drugs have never been tested on children, leaving pediatricians with a limited FDA-approved drug arsenal. Some pediatricians are also concerned about the possibility of civil lawsuits should they prescribe drugs lacking FDA approval, even though the agency does not prohibit the use of such drugs.
Nancy Sander, however, is not one easily put off by such technicalities.
She is the founder of Mothers of Asthmatics, a 5,000-member educational and advocacy organization born of experiences with her daughter, Brooke, a severe asthmatic since infancy. Brooke’s life had been saved several times by drugs lacking FDA approval for use in children, so Sander was not about to let such a restriction on Seldane deny her son its potential benefits.
She waited until the family’s regular pediatrician returned from a trip, and she made a convincing case for at least trying the drug.
“Every year since, Seldane has prevented his allergies and he’s just fine,” Sander says.
Sander’s experience ended happily, but such is not always the case.
The history of drug development in the 20th Century is pocked with disasters resulting from inadequately tested drugs. Ironically, most victims of these mistakes were children, among them the thousands of babies in Western Europe maimed in utero when the drug Thalidomide was given to pregnant women.
The FDA, as we know it today--a screening agency to which drug companies must prove their products are safe and effective--was born out of a tragedy in 1937 involving the early antibacterial drug sulfanilamide. Seeking to capitalize on its popularity, one company sought to market a more easily administered liquid form, unaware that the company chemist used as his solvent diethylene glycol, an ingredient of antifreeze and a deadly poison.
The error was never picked up in the company’s pre-marketing tests, which looked only at fragrance, texture and appearance, according to Wallace F. Janssen, the FDA’s historian. One hundred and seven people died, most of them children whose parents had been advised to administer the syrup for sore throats.
There were smaller-scale catastrophes in newborn nurseries when drugs used successfully in adults were discovered to be toxic to babies with immature kidneys and livers.
“You have to understand that children are not little adults, when it comes to calculating doses or anticipating side effects,” says Dr. Edwin N. Forman, professor of pediatrics at Brown University and director of the children’s cancer center at Rhode Island Hospital in Providence.
Most cancer drugs--powerful agents with a host of potentially lethal side effects--are marketed for adults before they are tested on children. Forman uses these adult drugs very cautiously, sharing observations and experiences with counterparts at about 50 other pediatric cancer centers.
Known as the Pediatric Oncology Group, his is one of several such cooperative organizations nationally that maintain a data bank that doctors can use to guide their use of cancer drugs on children.
Unfortunately, this sort of monitoring system for the use of adult drugs in children is the exception rather than the rule.
Many drugs that clear the FDA without scientific studies in children will eventually be used on them in isolated, experimental situations when conventional treatment fails.
The results eventually may be shared at professional meetings or through medical journals, but the delay in delineating a drug’s therapeutic value--or harmfulness--in children is often counted in years, according to Dr. Ralph E. Kauffman, director of clinical pharmacology at Children’s Hospital of Michigan in Detroit and chairman of the American Academy of Pediatrics’ committee on drugs.
Kauffman is at the forefront of a growing movement to improve children’s access to pharmacological advances, and he has a lot of support from pediatricians such as Forman, who has spent 30 years struggling with inadequate data from drug manufacturers to guide use of their products in his patients.
“New drugs are constantly being developed because the standard therapy is inadequate,” Forman says. “But children are left out of these advances. As pediatricians, we are always behind and always dependent on guesswork.”
Only about 20% of new drugs are evaluated in children before they get FDA approval. The rest usually end up described this way in the Physicians Desk Reference--the standard text that provides doctors with pharmaceutical manufacturers’ instructions--”Safety and effectiveness in children have not been established.”
“It does not mean physicians can’t use the drugs, but that they have no data to guide their use,” says Dr. Wayne R. Snodgrass, chief of clinical pharmacology at the University of Texas Medical Branch in Galveston. Like Kauffman, he is among about a dozen specialists nationally in pediatric pharmacology.
Under such circumstances, doctors will adjust for a child’s size and factor in differences in infant metabolism and physiology to cut the recommended adult dosage. They may consult by telephone with doctors more experienced in using the drug. They may search the pediatric medical journals for an account of the drug’s performance under similar circumstances in young patients. But it is a rough calculation at best.
Most of the inhaled asthma drugs, for example, are not approved for use by young children, yet thousands of youngsters depend upon them for relief of wheezing and coughing--and have for more than a decade, according to Dr. Gary Rachelefsky. The Los Angeles allergy specialist says he has been studying the use of inhaled steroids in asthmatic children since 1974.
And virtually all of the drugs used to treat the life-threatening conditions of premature babies have not been approved for use in children, Snodgrass says.
Why pharmaceutical companies market drugs without adequate testing in children is the subject of a long-running debate. Several medical conferences were held on the issue as far back as 1974, but the situation has changed little since then.
Lately, though, the debate has taken on greater urgency as more children with serious, long-term illness such as acquired immune deficiency syndrome, certain cancers and other immune-compromising conditions confront the dearth of drugs scientifically evaluated for pediatric use.
In addition, the relatively small numbers of children with chronic heart problems, high blood pressure or other diseases more commonly seen in adults have always had to depend on adjusted dosages of adult medications.
But requiring pediatric testing as a condition of approval raises a different set of problems, FDA spokesman Mike Shaffer says.
First, the FDA is not authorized to require such tests, Shaffer says. Congress would have to give the agency additional muscle, Shaffer says, to order pediatric drug tests as a condition for marketing approval.
Second, long delays already characterize the progress of new drugs from test tube to market--a journey averaging seven to 10 years, according to Jeffrey L. Trewhitt, spokesman for the Pharmaceutical Manufacturers Assn. The association represents about 100 drug companies that develop most of the new drugs in the United States and Europe.
Drug development does not come cheaply, either, averaging $125 million in up-front costs for each drug that clears the FDA, Trewhitt says.
The agency worries that a pediatric testing requirement would further slow the process. And since new drug development depends greatly upon a drug company’s willingness to absorb the costs, the FDA is reluctant to discourage the industry with additional regulation.
“The population (of seriously ill children) is so small that it doesn’t justify a drug company’s trouble and expense to seek approval in this area,” says the FDA’s Shaffer.
For its part, the pharmaceutical industry plays down the profit factor, justifying decisions not to test certain drugs on children on ethical and legal grounds.
“From the ethical standpoint, the concern is that children can be more vulnerable,” Trewhitt says. “They raise more cancer concerns than adults because they are still growing. There is also a concern that testing experimental drugs in children could affect growth in a key body organ. And legally, product liability lawsuits abound in this country.”
But Kauffman decries such justifications as a disingenuous cop-out.
“You can see that when there is an economic incentive, they have done the work,” Kauffman says, pointing to drugs commonly used to treat conditions that affect large numbers of children. In order to get FDA approval for pediatric use, drug companies have voluntarily tested antibiotics for the ear and respiratory infections that occur frequently in childhood as well as over-the-counter preparations for fever and colds.
But for the most part, the drug companies don’t voluntarily test more specialized drugs that might be used by a smaller group of children.
“To me,” Kauffman says, “the most unethical thing to do is to subject kids to drugs that have not been tested in children, so that each child becomes an individual experiment.”
His cause is gaining momentum.
“The FDA isn’t ignoring the problem and neither are we,” Kauffman says. “The committee on drugs (of the pediatrics academy) now has a contract with the FDA, and we are working with them to identify information from medical journals and other sources on drugs used in children and compile it to include in drug labeling.”
Also, the Institute of Medicine of the National Institutes of Health has been sufficiently aroused to convene a conference on the subject next April.
“We have a long way to go,” says Kauffman, “but there are some things happening that give us hope.”
