FDA's review of children's over-the-counter cough/cold products will address the broader issue of whether extrapolating pediatric doses from adult dosing data is appropriate.

FDA is "relooking at this issue" of extrapolation as part of a data review begun in 2006, Charles Ganley, M.D., Ph.D., director of the agency's Office of Nonprescription Products said during a March 2 conference call to outline the initiative.

FDA initiated the review last year following deaths related to the unapproved prescription antihistamine ingredient carbinoxamine, which focused the agency's attention to pediatric respiratory products, Ganley said. The product was linked to 21 deaths in children under 2 years old (¹ Also see "CDC Expects Media To Spread Message About Infant Use Of Cough/Cold OTCs" - Pink Sheet, 15 January, 2007., p. 3).

A citizen petition filed March 1 seeking the relabeling of pediatric cough/cold products as not safe and effective for children under age 6 has spotlighted the issue of extrapolation as well as expanded the scope of FDA's review.

The products FDA is reviewing include monographed decongestants, antihistamines, cough suppressants and expectorants, Ganley said, estimating a majority of OTC cough/cold products are included. Dozens of ingredients, including dextromethorphan, guaifenesin, phenylephrine and brompheniramine maleate, fall under the review.

Ganley hopes the review will be completed in several months. Parents and pediatricians should "just continue following the dosing that is on the products right now," he said.

"I think given the information we have right now, if we thought if there was a need to come out with an immediate statement, we would do so. But I don't think that we've reached that level right now," he said.

In addition to reevaluating extrapolation from adult data, FDA will look at internal reports through its adverse event reporting system and available literature, he said.

"I'm not sure how this is going to work its way out, whether this will eventually make its way to a public discussion of this issue, but that's certainly a possibility. But I think within the next few months we'll have a clear understanding of where we're headed with it," Ganley said.

The citizen petition was submitted by 16 pediatricians and health care experts, including Baltimore's health commissioner, Joshua M. Sharfstein, M.D. and pediatrician and frequent Nonprescription Drugs Advisory Committee panelist Wayne R. Snodgrass, M.D., Ph.D.

The citizen petition requests FDA amend labeling for OTC antitussive, expectorant, nasal decongestant and combination cough/cold products to carry the statement that they should not be used in children under 6.

The petition also asks FDA to issue a public statement that would be in line with the relabeling.

Manufacturers who use the term "infant" or "baby" on their products or display images of children should be notified their marketing is not supported by scientific evidence and that they will be subject to enforcement action at any time, the petitioners say.

The authors of the petition cite several studies including a January 2006 guideline issued by the American College of Chest Physicians that says cough/cold products can be harmful to children and a Morbidity and Mortality Weekly Report from the CDC saying parents should consult a physician before administering cough/cold drugs to children under 2 (² Also see "Most OTC Cough Meds Dismissed By Chest Physicians Guidelines" - Pink Sheet, 16 January, 2006., p. 4 and ³ Also see "CDC Expects Media To Spread Message About Infant Use Of Cough/Cold OTCs" - Pink Sheet, 15 January, 2007., p. 6).

Ganley said the petition inadvertently asks the broader question of "whether these ingredients are effective in any children" through age 12.

"The petition is contending for the 2- to 6-year of age group that the efficacy data does not demonstrate that the drugs are effective in that age group. If they're going to make that contention you'd have to make the same contention for the 6- to 12-year of age group" because the method of dose extrapolation through pharmacokinetic information is the same for that group, he said.

"That gets into the whole issue of whether the agency should continue to extrapolate the efficacy data from adults to children."

The Consumer Healthcare Products Association says in a March 2 release current FDA assessment of the safety and efficacy of approved children's products "is based on scientific studies in children and/or on extrapolation from extensive data in adults."

"This process of extrapolation follows internationally recognized recommendations for diseases which are similar in adult and pediatric patients and applies to the symptoms and conditions for these medicines," CHPA says.

A change in the approach to extrapolation would likely affect prescription drugs as well, Ganley noted.

"If we're going to apply this standard to over the counter drug products, it has to be applied to other products that treat respiratory symptoms, whether they be prescription or OTC," he said.

"The mechanism by which, for example, prescription antihistamines are approved is also based - if they have a claim for allergic rhinitis - that the efficacy data for the adults was extrapolated to children based on pharmacokinetic data," he said.

Ganley said the problem is rooted in the fact that cough/cold studies are "incredibly difficult to do. ... They depend on subjective symptom scores and they're very difficult to do in adults and they are just as difficult to do in children."

"You're invariably going to come up with negative studies," he said. "If you're going to require that they have to have a study in children that statistically shows a significant difference between an active drug and a placebo, then you're essentially going to have no products available to treat respiratory symptoms in children," he added.

The implications of the petitioner's proposed labeling go farther when the population under age 2 is considered, Ganley said. Current labeling generally advises parents to ask a doctor before using the product with that age group.

"They're asking us to do a very different thing where it's, rather than referring to a doctor, is to say that there's no efficacy and safety information available on this."

"Historically, when we've not had data, we've left it to the discretion of a healthcare provider to determine whether they want to prescribe it and at what dose," he said. The proposal "raises that question of whether that should no longer be allowed here."

The elimination of the doctor's discretion is an issue with potential to "go across products and product classes," he said.

- Rebekah Moan (r.moan@elsevier.com)

FDA Review Of Children’s Cough/Cold OTCs Has Broader Implications

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