FDA Office of New Drugs Director John Jenkins is uncertain the efficacy of OTC cough/cold ingredients can be accurately assessed in a pediatric population.

"It really leaves us in the conundrum of how to move forward in developing that evidence," Jenkins said at an FDA meeting Oct. 2 after hearing presentations about topics including determining endpoints for assessing cold symptoms in children.

"Where does that leave us on our ability to do trials on the common cold for these products to show that they work? Assuming there is a benefit, how are we going to be able to show it?" Jenkins asked.

A panel of FDA officials heard presentations from a trade group, OTC firms, pediatric doctors and related experts and the public at the Part 15 hearing in Beltsville, Md. The agency conducted the hearing to gather information for establishing a final rule amending for the OTC cough/cold monograph.

Officials from the Center for Drug Evaluation and Research on the panel included Jenkins, Associate Director for Policy Jane Axelrad and Director of the Office of Surveillance and Epidemiology Gerald Dal Pan.

Also from CDER were Office of Nonprescription Products Director Charles Ganley and OND's Associate Director of Pediatric and Maternal Health Staff and Michael Levy, director of New Drugs and Labeling Compliance in the Office of Compliance. Other panelists were Robert "Skip" Nelson, a pediatric ethicist in the commissioner's office and Dan Budnitz, a medical officer from the Centers for Disease Control.

The meeting was a follow-up to an October 2007 joint meeting of FDA's Pediatric and Nonprescription Drugs advisory committees to gain insight on whether there is adequate safety and efficacy data for OTC cough/cold drugs in children.

That meeting was sparked by a March 2007 citizen petition authored by 16 pediatric experts and other medical researchers asking FDA to review the products, noting there is no data confirming the ingredients' safety or efficacy in pediatric use (¹ Also see "FDA Panel Narrowly Votes Against Cough/Cold Drugs For Children Up To Age 6" - Pink Sheet, 22 October, 2007., p. 3).

Consumer Healthcare Products Association staff and representatives from member firms presented the industry's clinical work already underway - "a comprehensive and scientifically rigorous efficacy and safety program for children age 2 to 12," including pediatric pharmacokinetic studies for eight of the most common ingredients.

The group says it will develop its efficacy studies following completion of its PK studies.

During their presentation, CHPA representatives said the group has yet to design the efficacy studies, but it recognizes the importance of tailoring efficacy endpoints to children. Further, they said the studies would be large and focused on both rare and common events.

Pediatrician Ronald Turner, a University of Virginia School of Medicine professor who spoke at the hearing at the request of CHPA, recognized determining efficacy of cough/cold products in children is difficult.

He said it is possible that there is not a "good way to assess efficacy" in children. Because cold symptoms can develop and leave quickly, it is difficult to determine whether symptoms naturally dissipate or whether a drug has an effect.

In a separate presentation, Birgit Winther, of the Department of Otolaryngology at the University of Virginia Health System, discussed objective measures, such as using tympanometry - examining the inside of a child's ear to detect changes in congestion - as a possibility for determining endpoints.

While Winther explained that researchers would not soon develop alternative measurements, but the first step in implementing new methods in the field would be figuring out how to use tympanometry to diagnose the cold.

Jenkins said he was concerned that CHPA's program did not offer concrete methods for efficacy studies or measuring cold symptoms.

"Even assuming these products do work for the common cold, we've also heard it may be very difficult, if not impossible, to show that in controlled, clinical trials," Jenkins observed.

Randy Juhl, a former NDAC chair who is a professor of pharmacy at the University of Pittsburgh, also acknowledged cold symptoms are difficult to measure.

Juhl, who was not present at the meeting, noted with antibiotics, it is easy to measure if an infection goes away. With a cold, though, it is more difficult to measure "if the sniffles are clearing up," he said.

He pointed that out while measuring efficacy in children appears unsolvable so far, it is more likely that no one has "worked on it hard enough."

"I guess you go under the assumption that bright people can come up with something and you are able to make it work," he said.

"All science is finding something to measure and that is what we lack in assessing the common cold. We all know what it is when we see it, but there is no way to grade the severity that is reproducible and applicable to one person versus another," he said. "And especially in a patient population where they are not trustworthy to tell us what the answer is."

In January 2008, FDA issued a public advisory not to administer the products to children under 2 (² Also see "FDA Working Group Considering Changes To OTC Cough/Cold Monograph" - Pink Sheet, 21 January, 2008., p. 3).

Firms recalled the products for children under 2 prior to the October 2007 advisory committee meeting (³ Also see "Infant Cold Products Pulled; Waxman Looks For More OTC Risks" - Pink Sheet, 15 October, 2007., p. 6).

At the Oct. 2 hearing, lead petitioner and Baltimore Commissioner of Health Joshua Sharfstein called on FDA to set an April 2009 deadline for the industry to propose studies.

Sharfstein also asked FDA to call for a voluntary recall of the products for children under 6.

He said judging from the CHPA presentation during the hearing, it seems that OTC firms "are a ways" from getting data to prove the products safe and effective.

The presentations did not give him a sense that "good evidence" is on the way, Sharfstein said in an interview. The industry's plan was possibly a "bridge to nowhere," he added

FDA says it will use the information from the Oct. 2 hearing as it decides what it will do next.

- Katie Stevenson (k.stevenson@elsevier.com)

FDA Faces “Conundrum” In Determining Efficacy Of Children’s Cold Products

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