The debate over infant cough and cold medicines has brought to light an open secret in medical circles: Most drugs given to children have never been tested for them, forcing physicians to sometimes use a best guess in determining dosing, efficacy and even safety.

Federal regulators and physicians have recognized the need for more pediatric drug research, realizing that children are not just small adults. Their bodies process medication differently - sometimes faster, sometimes slower, sometimes turning it into poison. Yet, adult drugs are routinely prescribed for children despite the lack of scientific evidence.

"If you extrapolate from an adult dose to a pediatric dose, you may be right ... you may be wrong," said Dr. Joseph M. Wiley, chief of pediatrics at Sinai Hospital in Baltimore.

Federal reform legislation passed a decade ago - and reauthorized this summer - made strides toward ensuring that new drugs entering the marketplace for children would be fully investigated before being prescribed. But it has failed to completely fill the gap in research, particularly in older medications. The Government Accountability Office, the investigative arm of Congress, said this year that only one-third of the drugs prescribed for children have been studied and labeled for pediatric use.

The pediatric research that has been done includes some startling results: Of the older drugs newly studied in children, 87 percent were being improperly prescribed. Children were getting medicine that didn't work, being overdosed, underdosed or exposed to previously unknown side effects.

"We found out that you can't predict how kids are going to handle things," said Dr. Dianne Murphy, director of the Food and Drug Administration's office of pediatric therapeutics.

Once a medication is FDA-approved for use in adults, it can be legally prescribed to anyone. Yet the data drawn from rigorous work determining safe doses, effectiveness and possible side effects applies only to full-grown adults, not children whose brains are still developing, who are still growing and whose body chemistry is immature.

The practice is called prescribing off-label, and it is done safely by physicians every single day. Some argue that if doctors stuck to what is approved for children, many sick kids would die and others would suffer unnecessarily.

Doctors say they prescribe drugs that haven't been studied in children because they have no alternative. They choose doses based on the child's weight, what they know about the drug and how it is metabolized in the body, and on what they know about the disease. Often, they have to rely on the experiences of others who have used the drug in children to make determinations. It's not all guesswork, they say.

A study published in the March issue of the Archives of Pediatrics & Adolescent Medicine showed that off-label drugs were used in nearly 80 percent of patients at major children's hospitals in 2004.

Dr. Anthony D. Slonim, an intensive-care specialist at Carilion Clinic Children's Hospital in Roanoke, Va., and one of the study's authors, said off-label drugs are a vital part of what he does. Morphine, for example, is the best thing he has to soothe severe pain while also calming patients.

In emergency situations, he administers medicines to children, including some that aren't approved for them, without asking parents.

"I don't have time when a child is critically ill in the ICU to talk about the numerous drugs I'm going to give to the child to save his life. We're left with, 'Do the right thing for the child. The heck with the off-label use,'" Slonim said.

In nonemergencies, parents can ask doctors and pharmacists about a drug's approval history.

Slonim thinks that off-label has a bad connotation. He says it just means that a drug hasn't gone through the FDA approval process for that use. He says that for certain medications that have been used for such a long time - such as morphine - perhaps they should be able to get some sort of secondary approval based on real-life experience: "Shouldn't we just give them a bye?"

Failure to test medications before prescribing them is what led to the law that created the FDA in 1938. Sulfanilamide, a drug used to treat strep infections, had shown great success as a cure in the 1930s and was used safely in tablet and powder form. Doctors wanted a liquid form, primarily for children. Because the sulfa drug did not dissolve easily in water, a drug company chemist created an elixir with diethylene glycol, a chemical normally used as an antifreeze. More than 100 people, mostly children, died.

Safety studies had not previously been required.

New laws meant improved testing for drugs in adults, not children.

"People worried about 'experimenting' on kids by putting them in trials," Murphy said. But as long ago as 1977, the American Association of Pediatrics issued a statement saying that it was unethical not to enroll children in clinical trials. "What the AAP said is, 'If you don't do trials, every child becomes an experiment of one,'" she said.

Pediatricians say that studying drugs in children can be difficult. Some diseases, while more common in adults, are rarer in children, making it harder to study. There are ethical issues with studying drugs in healthy children and other questions about giving sugar pills to sick kids in studies. These studies can take a long time to pull together and can be expensive.

Federal legislation passed in 1997 and updated in 2002 pushed drug companies to do pediatric clinical trials. It was primarily focused on new drugs coming to market, but it also included provisions to study drugs that had been around for a while and older drugs whose patents have expired.

The legislation gives financial incentives to drug manufacturers to do the tests by granting an added six months of patent protection for doing so. Murphy called it "the engine driving pediatric drug development."

"Without it, there are a lot of children that wouldn't have access to these medicines or physicians that would be left to guess as to how to appropriately dose children," said Lori Reilly, vice president for policy and research at Pharmaceutical Research and Manufacturers of America. "It's been tremendously successful."

The problem is this: Pharmaceutical companies do not have to study every drug the FDA requests of them. They can say no - and they do. Drug companies agreed to 173 of the 214 requests for studies of on-patent drugs from January 2002 to December 2005, according to the Government Accountability Office.

To cover the studies that drug companies would not do, Congress authorized the Foundation for the National Institutes of Health to cover them. But the amount of money raised by the foundation as of December 2005 was just $4.13 million, enough to pay for half of one pediatric study out of the nine deemed most important by the FDA, according to the GAO.

Medications that the FDA wants studied in children include morphine, bupropion (for depression) and eletriptan (for migraines).

There is little incentive for drug companies to pay for studies on drugs that are no longer under patent. Of those drugs, not a single pediatric study has been completed, the FDA's Murphy said - drug companies have not agreed to do them and the government has yet to pay for them.

"For the older drugs, we really don't have that much information," said Mark Riddle, a Johns Hopkins doctor who studies psychiatric drugs in children.

Congress has authorized the National Institutes of Health to pay for studies of these older drugs, said PhRMA's Reilly, but has not yet funded them. With study costs in the tens of millions of dollars, she said, drug companies lack the incentive to pay, especially when they would be required to come up with new preparations - such as liquid formulations - just for children.

"When that drug is off patent, most companies lose 90 percent of the market share in the first month," she said. "They're hardly selling any of their product anyway."

Most of the time when pediatric studies are done, drug labels are found to be insufficient - occasionally dangerously so. In one case involving the migraine drug sumatriptan - sold under the brand-name Imitrex - five studies did not establish safety and effectiveness, and post-marketing experience showed that children had suffered adverse effects such as stroke and vision loss. The FDA now says the product is not recommended for children younger than 18.

Even over-the-counter medications can prove to be problematic. FDA panels will hear discussions this week on the safety and effectiveness of cough and cold formulas for young children, responding to critics who say that some kids have been harmed.

Murphy said about 200 older drugs have been studied in children but new products come on the market all the time - and their studies, while under way, will take time to complete. It adds up to a lot of untested medications for kids.

Still, she said, things are on the right track: "I never thought ignorance was good public health policy."

stephanie.desmon@baltsun.com

This week

WHAT: Joint meeting of the Food and Drug Administration's Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee

WHEN: 8 a.m., Thursday and Friday

WHERE: The National Labor College, Lane Kirkland Center, Solidarity Hall, 10000 New Hampshire Ave., Silver Spring

AGENDA: The committees will discuss the safety and efficacy of over-the-counter cough and cold products marketed for pediatric use. Speakers will include Dr. Joshua M. Sharfstein, Baltimore's health commissioner.