Nearly four out five children in U.S. hospitals receive drugs, including morphine, that have not been tested and approved for pediatric use, according to a study that reviewed over 355,000 cases in 31 hospitals. Study leader Dr. Samir S. Shah, a pediatrician specializing in infectious diseases at the Children's Hospital of Philadelphia, says that over the past five years, the prescribing of so-called "off-label" adult drugs for children has been growing. "What we want is to shed light on the magnitude of this problem," says Shah.
The findings, published today in Archives of Pediatric and Adolescent Medicine, are the result of the largest-ever U.S. pediatric study of its kind. Researchers defined "off label" as the use of a specific drug in a patient younger than the Food and Drug Administration-approved age range. While some drugs, like acetaminophen, were found to be rarely used off label, powerful sedatives like Propofol, Midazolam and Fentanyl, says Shah, were commonly prescribed. Off-label morphine was used in 27.8 percent of all children in the study.
Nearly 8o percent of the 355,409 young patients discharged from the hospitals in the study had received at least one of the 90 most common drugs administered off-label, Shah told NEWSWEEK. "Off-label use ends up [accounting for] more than 14 percent of all money spent on children's medicine at these 31 hospitals," Shah says. "We're talking about a lot of money." In fact, Shah says, the hospitals in the study spent more than $270 million for off-label drugs for kids in 2004. Children most likely to receive off-label meds are those over 29 days of age, children who had undergone a surgical procedure and children who eventually died in the hospital. "It's possible that these kids were very sick, and that approved therapies for them had failed them. When kids are so sick you often have no choice," says Shah. None of the off-label use is illegal, he adds: "The FDA regulates drug companies, not physicians. Clearly there are ethical issues in testing drugs on children, but if it's not tested on kids and we use them anyway, is that ethical? It's a very grey area."
The study did not explore whether off-label use was beneficial or harmful, but the authors urge further research into the health effects of off-label use in kids. "Continued off-label use of drugs is not an acceptable alternative to documenting the safety and effectiveness of drugs used to treat infants and children," they conclude. Children fall into a category, coined in the late '60's, known as "therapeutic orphans"—most available drugs have simply never been tested for effectiveness and safety on them. "But if we didn't use off-label drugs we would be depriving children of therapeutic advances that many of them need to improve their lives and some may need simply to survive," says Dr. Jeffrey L. Blumer, a critical care specialist and pediatric pharmacologist at Rainbow Babies and Children's Hospital in Cleveland, Ohio. "It happens every single day. We can't say whether it's good or bad, but I can say it's essential." For example, says Blumer (who was not involved in the study), this time of year hundreds of thousands of children with respiratory problems are using a drug called albuterol, "but if you look at the package it is not labeled for them. It would be important to know what dose is effective and safe." One problem with off-label drug use in kids, he adds, is dosing. Without the ability to make precise calculations, children might not get an effective dose; they get the medicine and its risk but may not reap the benefit.
The new study is expected to add fuel to the ongoing debate over the FDA's process for approving drugs for use in children. "We don't want to overstate our findings," says senior author of the report, Anthony D. Slonim, executive director of the Center for Clinical Effectiveness at Children's National Medical Center, "but if nearly 80 percent of hospitals are using off-label medicine on kids then something is askew with policy." Slonim tells NEWSWEEK that all drugs in pediatrics are administered by weight, with premature babies being the most vulnerable to problems with medication—one reason why babies under 29 days old are least likely to be given off-label meds. "As a pediatrician, I'm opened up to liability for using drugs off-label," Slonim says, "but they might be all I've got." There has been some progress. The Best Pharmaceuticals for Children Act, which gives financial incentives to drug companies that voluntarily decide to test drugs in children, was passed by Congress in 2002. The Pediatric Research Equity Act, which requires drug manufacturers to test specific drugs for use in children, passed the next year. In a statement responding to the new study, an FDA spokesperson said the agency has "advocated for decades that sponsors need to study their product in the pediatric population if it is going to be used in that population." The statement said the two laws "have assisted us in the process of gathering this information."
But Slonim says that a recent petition sent to the FDA raising concerns about the safety of over-the-counter cough medicines for children is another sign of the failure to formulate an appropriate approval method for vulnerable, younger patients: "There are children who have died because of these cough medicines. These drugs are not put through the FDA process. This is not an indictment of the FDA, but this does call into the question the present approach to drug credentialing." In response to the petition, Dr. Charles Ganley, the Director of the FDA's Office of Nonprescription Products in the Center for Drug Evaluation and Research, said the agency has already been actively re-evaulating " the safety and efficacy of these products in children." He also said that, "In some situations, particularly less than two years of age, the FDA has not had data that would help us determine what the effective dose would be in that age group. And there are still issues I think related to the safety of those products in that age group."
The cough and cold syrup petition was filed with the FDA last Thursday by a group of 15 prominent pediatricians and public health officials. It urges the agency to force drug-makers to stop marketing cough and cold medicines for use by children under six, arguing that they are not effective and are actually harmful. Two months ago the Centers for Disease Control and Prevention reported that over a two year period, more than 1,500 toddlers and babies were taken to emergency rooms because of the medicines. The CDC advised parents not to give the syrups to children under two without first consulting a doctor. Last Thursday's petition, however, calls for an all-out ban on use of the medicines on toddlers and preschoolers. In higher than normal doses, cough and cold medicines can cause problems such as heart rhythm changes, seizures and cardiopulmonary arrest. The petition states that in Maryland alone, 900 children under the age of four overdosed on the medicines in 2004, and in Baltimore a medical examiner has linked the products to deaths of at least four children under the age of four in the past five years.
Baltimore's health commissioner and the author of the petition, Dr. Joshua Sharfstein, told NEWSWEEK that those deaths are what sparked his decision to pursue the petition: "Kid's cough and cold syrups are a billion dollar industry, but there is no data on what is a safe or effective dose for children. What little data there is show that the medicine is not effective." He says he is encouraged by the FDA's immediate response that it would begin a review of the medications. What is lacking across the board, in all types of medications—prescription and non-prescription—says Sharfstein, is basic research into the effects of these drugs on children: "The evidence-base could be a lot stronger for medicine in pediatrics. If a child has a life-threatening infection and there is an antibiotic that has never been tested in kids, I understand. You have to use it. But when there is no threat to a child's life, and when there is actually evidence that a medicine is not effective and not safe and yet it is still relentlessly marketed, then what you have is definitely a policy problem."