http://www.newyorker.com/fact/content/?050110fa_factTHE PEDIATRIC GAP
by JEROME GROOPMAN
Why have most medications never been properly tested on kids?
Excerpts"
Strafford told me that the surgeon's decision to improvise with bupivacaine was not unusual. Although the Food and Drug Administration has long required that medications be screened for safety in adults, approximately seventy-five per cent of drugs approved for use in the United States have never been subjected to comprehensive pediatric studies. A physician, however, is allowed to use any F.D.A.-approved drug in whatever way he deems beneficial, and he isn't required to inform parents if it hasn't been
specifically tested on children. There is no single official repository of information about how to calibrate drug dosages for children. Since
pharmaceutical companies rarely collect data about the effects of their drugs on minors, there is scant information about pediatric dosing in the
Physicians' Desk Reference, a compendium of guidelines and warnings supplied by drug companies; pediatric handbooks are published by private companies, but they are not comprehensive and their data are not obtained through a
consistent methodology. In the absence of reliable information, doctors are frequently forced to engage in guesswork when administering drugs. Speaking of the three-year-old boy, Strafford said, "This is a perfect example of
what can happen to a healthy kid."
Children with certain illnesses can be especially sensitive to the side effects of a drug. For example, infants with meningitis are much more likely than adults to react poorly to chloramphenicol, an antibiotic that is a
common medication for the disease; newborns, especially premature babies, do not have the necessary enzyme in the liver to metabolize the drug. Symptoms such as vomiting, refusal to suck on a breast or a bottle, and diarrhea usually appear two to nine days after the initial treatment. When chloramphenicol accumulates at toxic levels, blood pressure drops precipitately, and the lack of oxygen in the blood causes the baby's lips and skin to take on a bluish tint. Ultimately, body temperature plummets and
the baby turns ashen. "Gray-baby syndrome" can be fatal unless the infant receives a blood transfusion.
In recent years, federal legislation has sought to give pharmaceutical firms financial incentives to pay for clinical studies targeted to children. Since 1997, a company that agrees to set up a pediatric trial to screen a new drug has received a six-month extension of market exclusivity for the medication. Yet such reforms don't address the larger problem of old drugs that have never been tested on children. Children's health advocates also complain that the F.D.A. does not require manufacturers of medical devices to create
variants that are designed for children; consequently, pediatric surgeons and cardiologists must perform procedures on children using equipment that was developed for adults. "It's what I call the reverse lifeboat
phenomenon," Maureen Strafford told me. "In medicine, children come last."
Testing drugs on children used to be a priority. Stuart Siegel, a pediatric hematologist-oncologist and the director of the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles, told me that in the nineteen-fifties and sixties children with cancer were typically given experimental drugs before adults. The logic was that sick children deserved to be the first to receive the latest treatments. These days, the situation is often reversed; important new therapies-for example, Gleevec and Avastin-have been tested on adults first. Siegel attributes this shift to "an ethical change in society." Doctors and parents are increasingly concerned about whether children can truly give informed consent to participate in potentially harmful research. Drug companies have equally strong misgivings; they fear legal liability and negative publicity. If a child dies during a clinical study and the parents sue, jury awards can be very high.
"I've had discussions with some leaders in the pharmaceutical industry," Siegel said. "The feedback is consistent. They'll cite the cost and then they'll also cite the risk, in terms of an adverse event and what that would do to their profits and their stock."
Indeed, Eli Lilly and Company recently received a tremendous amount of bad press when Traci Johnson, an Indiana college student, committed suicide during a clinical trial of Cymbalta, an antidepressant. She had initially been given high doses of Cymbalta, but a few days before her death she had been switched to a placebo. Scientists have found that hallucinations and
paranoid delusions can occur when a patient is in withdrawal from an antidepressant. A spokesman for Lilly has stated that it is unclear what led
to the girl's suicide; the F.D.A. officially cleared the company of wrongdoing and approved the drug.
Johnson's death occurred at the same time that the F.D.A. was analyzing a large set of data compiled from multiple clinical trials. The results, which were released in October, indicated that twice as many children taking
antidepressants in clinical trials considered or attempted suicide as children taking placebos. The agency will require pharmacists to include a
warning, to be released later this month, that cites this study when dispensing packages of antidepressants. Although antidepressants can still be legally administered to children, the children must now be stringently monitored by doctors.
One reason the F.D.A. was slow to identify this danger, critics say, is that individual clinical trials sponsored by drug companies involved small
numbers of children. (The more subjects involved in a study, the costlier it is.) Pfizer's pediatric studies of Zoloft, for example, involved fewer than four hundred children; according to Lawrence Scahill, a researcher in
pediatric psychopharmacology at the Yale Child Study Center, thousands of depressed children would need to be studied before researchers could
pinpoint a subtle difference in behavior, such as increased suicidal thoughts. The F.D.A. extended Pfizer's patent on Zoloft for six months because it conducted the trial, which will allow it to reap hundreds of millions of dollars in added revenue.
In 2003, Congress passed legislation that codified what is known as the Pediatric Rule. A drug company working on a new treatment for a disease that affects both adults and children is now required to conduct pediatric studies. (The rule does not slow the process of approving new drugs for adult use.) To make this regulation palatable, the F.D.A. continues to offer a six-month extension of market exclusivity for drug companies that perform pediatric studies.
Children's health advocates, who had fought for years to help pass this legislation, were dismayed to discover that there were significant loopholes in the 2003 law, as well as in other recent reforms. For example, Congress did not set a timetable for the completion of pediatric studies. Moreover, the reforms include a "sunset clause" that will cause them to expire in 2007. (This clause was added as a result of pressure from drug companies and groups that oppose government regulation.) Advocates worry that many drug companies will exploit the clause by agreeing to conduct a trial but allowing the study to languish until 2007, when a different Congress may decline to renew the reforms.
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Much more at the link. Educate yourself about your government, doctors, and big pharm. It's worth your time and effort.
