By Rob Stein
Washington Post Staff Writer
Friday, October 26, 2007
For years, Joshua Sharfstein shuddered whenever he walked down a drugstore aisle lined with cough and cold products for babies and toddlers.
"It never ceased to aggravate me," said Sharfstein, a pediatrician and father of two young boys. "Kids with colds were getting these medicines that had never been shown to be either effective or safe."
So when Sharfstein became Baltimore's health commissioner, he launched a campaign that led an expert panel of the Food and Drug Administration to conclude last week that the products should not be used in children younger th6, shocking many parents and setting up a possible clash between the FDA and the pharmaceutical industry, which is vowing to continue selling the products.
The case has also raised many questions: How could the products remain on the market for so long without proof they work? Why didn't the FDA act sooner? Why didn't the medical establishment warn parents? Are there other medications in a similar situation?
Although there are other over-the-counter remedies of questionable effectiveness, no one could point to a specific product or class of products used as widely as the cough and cold medications that are a cause for obvious concern. But about two-thirds of drugs prescribed for pediatric use have not been tested in children.
"There are a huge number of drugs that are regularly given to children that have never been tested in children," said Michael W. Shannon, a professor of pediatrics at Harvard Medical School. "I'm very concerned many of these agents may also be inappropriate for children."
"It really is unbelievable," said Peter Lurie of Public Citizen's Health Research Group, a consumer group. "You're just left scratching your head about how this could go on for so long."
The answers lie in the history of drug regulation and the evolution in scientific thinking about how drugs work in adults and children: Many over-the-counter medications arrived on the market before government requirements for stringent testing, and it was long considered unethical and unnecessary to test drugs in children.
Over-the-counter cough and cold medications are among many products that have been sold for decades, since well before the FDA had the authority to regulate them closely. Once the FDA got that power in 1962, the agency began systematically reviewing broad classes of products.
"They had a massive job involving hundreds of products and hundreds of ingredients," said William B. Schultz, a former FDA deputy commissioner. "They gave priority to prescription drugs, for understandable reasons. The over-the-counter drug review was never made a priority in the agency, and so it dragged on for years and years."
The agency did, however, organize a panel of experts in 1972 to review nonprescription cough and cold medications, and the group concluded that there was enough evidence to endorse 35 of the 92 ingredients in the products. But the recommendation was based on studies in adults. So the panel made a crucial decision: recommending in 1976 that doses for children be extrapolated from data from adults.
"At that point in time, it was felt that was the best level of evidence we could have," said Marsha D. Rappley, a professor of pediatrics at Michigan State University who co-chaired last week's panel. "We now understand that we can organize studies in children and don't have to extrapolate from adults. But that wasn't the case back then."
Although the agency revisited adult dosing guidelines periodically in the ensuing decades as it finalized a series of monographs regulating the products, no significant changes were made for children and the products never again received any kind of detailed scrutiny.
But as researchers began testing some of the products directly in children, they slowly started to raise disturbing questions. The Journal of the American Medical Association published an analysis in 1993 that concluded there was no good evidence that the medications worked. The Cochrane Collaboration, an independent international project that regularly evaluates medical therapies, reached a similar conclusion in 2004.
Although many pediatricians were aware of the mounting doubts and began urging their patients not to use the products, some doctors continued to counsel their patients that they could, and the products remained a mainstay.
"Where do parents get a lot of their information? If you are a desperate parent at 10 or 11 o'clock at night on a Saturday and your kid has a cold, what do you do? You go to the drugstore and see all this stuff on the shelves with pictures of babies and assume it must work," said Wayne R. Snodgrass, a professor of pediatrics at the University of Texas Medical Branch, who co-signed Sharfstein's petition.
The American Academy of Pediatrics adopted a policy in 1997 stating that cough products are ineffective, and the American College of Chest Physicians produced a similar statement in 2006. But other groups, such as the American College of Family Physicians, never issued any formal guidance to doctors, and no major medical groups ever officially questioned the class of products or campaigned against their use.
"I think there was a vacuum in leadership on this issue by the professional societies," Lurie said. "You can justify the argument that doctors can make up their own minds, but that's a much harder argument to make for parents, who have never seen any of these studies."
Some experts defend the medical groups, saying policy statements from doctors' groups can do only so much, especially against the aggressive marketing by large pharmaceutical companies, which spend more than $50 million a year to sell the products.
"For the past 25 or 30 years, we've been warning about violence on TV," said Snodgrass, who also chairs the American Academy of Pediatrics committee on drugs. "What has that done? In this case, we're up against a multibillion-dollar industry. The American Academy of Pediatrics is not a multibillion-dollar industry. We try to do what we can, but there's only so much we can do. Where are the companies in this? Where was the FDA in this?"
But Sharfstein and others wonder whether the medical profession could have been more aggressive.
"When I was trained as a pediatrician, it was just accepted that these products had no role. This was known in the profession," Sharfstein said. "It's a fair question why there wasn't a strong regulatory challenge by the profession. They could have justified one. But what really stunned us was that this was never really looked at from the legal-regulatory side."
Using powers it received from two new laws, the FDA has begun demanding that some prescription drugs be tested in children before being approved, and it has enticed drug companies to conduct pediatric studies of some of those medications already on the market.
Officials at the agency said they acted quickly on Sharfstein's petition because they had become alarmed by the studies questioning the cold products' effectiveness and by mounting reports of possible dangers. The federal Centers for Disease Control and Prevention reported in January, for example, that more than 1,500 children, including three who died, had suffered adverse reactions to the medications in 2004 and 2005.
The FDA is reviewing last week's recommendations, but because of the history of the products, it says any formal action could take years. In the meantime, the agency, which stresses that any adverse reactions are relatively rare, might offer advice to parents, officials said, and plans to work with the drugmakers to organize studies of the products. The industry has voluntarily withdrawn products designed for children younger than 2, but it maintains that the remedies are both safe and effective for older children when used properly, blaming the problems primarily on overdoses.
"If the industry decides to dig in its heels against the clear guidance of the advisory committee, I hope the FDA has the ability to stop them," Sharfstein said. "It's a very small risk, unquestionably. But if you don't have evidence that the products work and you have kids who have died from taking them, I don't think there's a role for them."