FDA does not go far enough with its recent public health advisory on pediatric cough/cold OTCs to address the potential severe adverse events described in a citizen petition recommending labeling changes to the products, according to one of the petitioners.

"I think the new public health advisory shows that FDA is worried about the ongoing reports of serious injuries and deaths associated with these products. But the advisory is more or less consistent with the current labeling, and is not responsive to the reasonable requests made in the petition," Baltimore Health Commissioner Dr. Joshua M. Sharfstein told "The Tan Sheet."

In an Aug. 15 public health advisory, FDA included a reminder to parents and caregivers to ask a health care professional before using cough/cold medications in children under 2 years old, not to give children adult medications and to read and follow all labeling information, among other recommendations.

Sharfstein and 15 other health care experts in March filed a citizen petition that, in part, requests FDA re-label OTC antitussive, expectorant, nasal decongestant, antihistamine and combination cough/cold products as not safe or effective in children under 6 years old (¹ Also see "FDA Review Of Children’s Cough/Cold OTCs Has Broader Implications" - Pink Sheet, 5 March, 2007.. p. 3).

The petition also asks the agency to issue a public statement announcing the label changes to explain "the lack of evidence for use of cough and cold preparations in children under 6 years of age," notify manufacturers of children's cough/cold medications of the changes and warn of enforcement action if the products continue to be marketed with pediatric indications.

The medications' use, and misuse, in children under 6 years old has been tied to significant adverse effects, say Sharfstein and the other petitioners, including Dr. Wayne R. Snodgrass, of the pediatrics and pharmacology-toxicology departments at the University of Texas Medical Branch in Galveston and a frequent FDA Nonprescription Drugs Advisory Committee member.

They add current evidence suggests the products are not effective in alleviating children's cough/cold symptoms.

FDA will discuss the issues raised in the petition during a joint meeting of the NDAC and Pediatric Advisory Committee at the National Labor College in Silver Spring, Md. on Oct. 18 and 19. The agency outlined the discussion topics for the meeting in a Federal Register notice published Aug. 16 (see chart: " ² Pediatric OTC Cough/Cold Discussion Topics ").

Extrapolation Not "One-Size-Fits-All"

A key argument the petitioners make against the use of cough/cold OTCs in children is the lack of successful clinical efficacy studies in children, which therefore makes any risk presented by the medications too great.

However, in a response it submitted to the petitioners March 28, FDA cites the inherent difficulty in assessing the products' efficacy in children "because of the limited ability of children to subjectively quantify the severity of their symptoms."

The agency says this difficulty led it to extrapolate efficacy data from adult to children.

However, the outcome of the meeting's discussions may affect how FDA approves pediatric indications for adult medicine by forcing the agency to reevaluate this practice of data extrapolation.

In a May 7 letter to the agency, the petitioners said extrapolating data for cough/cold OTCs is inappropriate. They assert the data extrapolation was unnecessary because randomized controlled trials on the medicines "have successfully used parent questionnaires as a surrogate measure for symptom severity."

"These studies have found negative results, suggesting that extrapolation is not necessary for this drug class," they say.

The petitioners also cite underlying differences in the physiology and respiratory anatomies of children and adults, and those differences' effects on the development of respiratory illnesses, as additional reasons why extrapolation is inappropriate in this case.

Diagnostic differences between adults and children who suffer from cough/cold symptoms also complicate data extrapolation, Sharfstein and colleagues tell FDA.

"In one recent study on children with chronic cough, the authors reported that common causes of adult cough were found in less than 10 percent of children," the petitioners say in their response.

Additionally, "extrapolation is an inappropriate basis for aggressive marketing," they say, adding marketing for children's products should be based on pediatric data.

"I think the key point about extrapolation is that it is not one-size-fits all," Sharfstein told "The Tan Sheet." "Labeled instructions for this group of children direct parents to consult their doctor appropriate dosing information, creating an expectation that physicians have access to evidence-based dosing information," according to the petitioners' May letter to FDA.

They contend because children's cough/cold OTC products have shown little or no benefit in the few clinical trials conducted in children, the products present an unreasonable risk of harm.

"There may be good reasons to do so in certain circumstances that reflect physiology, pathophysiology, and clinical need. We don't find that case compelling for cough and cold products," he added.

Risk/Benefit Analysis Not Favorable

The petitioners also argue the lack of dosing information on the product labeling for children under age 2 is an inherent safety risk.

The studies of OTC cough/cold products in children cited by Sharfstein et al. show no differences between children's OTC cough/cold medications, such as antitussives, antihistamine-decongestant combinations, antihistamines and dextromethorphan, and placebo.

"We recognize that safety is a relative concept and that the risk of adverse effects must be balanced against efficacy in the drug approval process," the petitioners say.

"In the case of cough and cold preparations for young children, the lack of efficacy means there is no justification to tolerate real risk of severe side effects," they state in the petition.

FDA's Ongoing Data Review

The agency, meanwhile, continues a review of data concerning extrapolating pediatric doses from adult dosing it initiated in 2006 following reports of young children's deaths linked to the unapproved prescription antihistamine ingredient carbinoxamine (³ Also see "FDA Employs Carrot, Stick Under Unapproved Drug Enforcement Strategy" - Pink Sheet, 12 June, 2006., p. 3).

In March, FDA Office of Nonprescription Products Director Dr. Charles Ganley said the data review included the majority of OTC cough/cold product ingredients including dextromethorphan, guaifenesin, phenylephrine and brompheniramine maleate. Ganley said then he expected the review would be completed in several months.

The agency has not yet completed the review, but anticipates it will be released to the advisory committees "at least one month prior to the advisory meeting, although any actions will not take place until after we have input from the advisory committee," FDA told "The Tan Sheet."

Over the last few months, FDA has sent letters to health care organizations and industry groups - such as the American College of Emergency Physicians and the Consumer Healthcare Products Association - asking for comments on the petition.

The agency asked the groups to submit responses by Sept. 10 so it can include their comments with material for the advisory meeting. It had not received responses from any of the organizations through Aug. 16.

- Jessica Lake (j.lake@elsevier.com)

Pediatric Cough/Cold OTC Safety Review Continues With Joint Panel Planned

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