WASHINGTON, D.C. - Only 42% of U.S. drugs widely used in pediatric patients have been tested in children, and the percentage of drugs being tested in that group decreased by over one-third between 1992 and 1996, according to the Food and Drug Administration (FDA).
To address this problem, President Clinton announced a proposed FDA ruling in August 1997, which was soon followed by the detailed FDA Modernization Act passed in November 1997. The two FDA policies focused on resolving the issue of lacking pediatric dosage information.
When the proposed regulations were announced, the idea appeared as a plain and simple benefit to children - that is until questions arose about how to address the ethical and moral issues that surround testing drugs in children.
The issue of studying drugs in children evokes a strong reaction from everyone surrounding the issue - especially the practicing pediatrician who worries each time he/she prescribes a necessary medication despite its lack of pediatric labeling.
In these situations, each child becomes an individual experiment. Without proper dosing information from clinical trials, the dosage prescribed is a pediatrician's best guess.
Kathryn Edwards, MD, professor of pediatrics, Vanderbilt University Medical Center, Nashville, Tenn., said she believes for this reason it is important to study drugs in children. But finding children to participate in the study is not always easy. She has heard practitioners say they don't want to participate because they don't want the children in their practice used for an experiment.
"Unless we do careful and well conceived experiments, we will never learn anything. We can't discover new things about children and about how medications should be used unless there are studies," she said. "But we need pediatricians to help with the recruitment of patients. It can't be a `we' and a `they.'"
The American Academy of Pediatrics (AAP) also supports the studies and is working with the FDA to help implement the pediatric portion of the FDA Modernization Act.
Several members of the AAP are working with the FDA and others to create a list of approved drugs for which additional pediatric information may produce health benefits in the pediatric patients. The official list of drugs to be submitted in May is the first step in achieving the goal of having as much data on children as on adults, said Jon S. Abramson, MD, chairman and Weston M. Kelsey professor of pediatrics, Wake Forest University School of Medicine, Wake Forest University, Winston-Salem, N.C.
"I think parents would be shocked if they knew most of the drugs being used on their children are not approved in children," he said.
However, he stressed that most pediatricians aren't as worried about the more commonly used drugs like penicillin and ampicillin simply because they have been used for so long with few any serious adverse events. The draft list of over 400 drugs submitted to the FDA in March focused on newer drugs.
"There are drugs that haven't been around as long [as penicillin] that we are using and we need to know if the dosages we are using are truly correct for those populations," he explained.
"We're using all these drugs - new ones coming out and others that we've been using for a number of years - without sufficient data and that is an overwhelming argument compared to problems with liability, etc.," Abramson said. "We use these drugs because we don't have good alternatives."
Although the AAP is working with the FDA to implement this plan, the proposed list of drugs to be studied is not officially endorsed by the AAP.
"This list is not an official recommendation from the American Academy of Pediatrics," said Abramson, who added that the AAP pushed for this ruling. Abramson is also a member of the AAP Committee on Infectious Diseases.
The initial draft list was published in the March 16 issue of the Federal Register. The first official list will be updated annually.
Philip A. Pizzo, MD, Thomas Morgan Rotch professor of pediatrics at Harvard University and physician in chief and chairman of the department of medicine at Boston Children's Hospital, agrees that the Modernization Act is a step forward, but expressed concern about the lack of phase 3 trials that would normally be required for a pediatric indication.
"It is important to recognize that these new regulations don't carry with them a mandate to conduct large phase 3 clinical trials in pediatric populations for drugs also being tested in adults for similar indications. This is good news. Rather, it is expected that a pediatric drug approval will be based on phase 1/2 clinical trials that assess pharmacokinetics, toxicity and limited activity data," he said. "Thus, approval for drugs in children could be based on limited pediatric data when a drug is being used for similar indications, as in adults. Of course, if my use of an agent is specific to a pediatric disease, more extensive testing may be required."
Pizzo said part of the pharmaceutical industry's reluctance in the past to study drugs in children was based on concerns over adverse events, which might have affected the approval process for adults.
John Siegfried, MD, deputy vice president of science and regulatory affairs for the Pharmaceutical Research and Manufacturers of America (Phrma), said that when President Clinton initially made the announcement, he underestimated the difficulties involved.
He explained that Phrma wasn't opposed to the idea, but the officials involved in making the decision underestimated the cost and the ethical and legal considerations that had to be addressed.
"Pharmaceutical manufacturers are apprehensive. It will take more money and it may cost more in terms of time, but they also know that we will have better labeling for pediatricians and for families who need drugs for children," said Siegfried, a practicing pediatrician for more than 20 years. "Over the next five to 10 years, we will begin to see the fruits of this effort, and there will be better labeling for kids. If it cost a little more and takes a little more time, so be it."
Siegfried added that with the incentive of increased marketing exclusivity that is now offered to manufacturers through the Modernization Act, and the penalty of clinical hold of the proposed rule, no company would begin a project without including pediatric studies. However, the studies should first be conducted in older children and adults.
"It is unethical to expose the most vulnerable population if you don't have information about what happens in older children," he said. "The exception to that is if you are dealing with a drug that is specifically intended for small children and neonates."
The FDA developed a section on pediatrics in the Modernization Act because the 1994 FDA ruling that called for voluntary pediatric studies was not effective.
Although the ruling allowed pharmaceutical manufacturers to use existing data to assess labeling for children, most existing studies did not produce sufficient data. If the data wasn't available, the drug's labeling was then simply required to state that the drug was not studied in pediatric populations.
"Many pediatricians felt that was the problem with that ruling. It didn't have enough `teeth' in it to make the manufacturers go and do the studies that we need," Abramson said.
However, Siegfried defended the manufacturers and said it wasn't necessarily because of opposition to the voluntary rule. "The expectations of the FDA and their disappointment is unfounded because they didn't put the rule out until December 1994 and drug development cycles take 10-15 years. To expect a big response in that short amount of time is unrealistic," Siegfried said.
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