As FDA embarks on a lengthy rulemaking process to address pediatric OTC cough/cold products, the agency has strategies outside the regulatory framework available to effect any more immediate changes it deems necessary.

"Whenever FDA has had a significant safety question about an OTC ingredient, it has been in the position to get the industry to make the changes it wants," Richard Kingham, a partner with Washington-based Covington & Burling, told agency executives at a Part 15 public hearing Oct. 2 in Beltsville, Md.

A panel made up mainly of officials from FDA's Center for Drug Evaluation and Research heard arguments for and against the continued marketing of cough/cold products for use in children between ages 2 and 6.

Industry representatives stressed the safety profile of the products and outlined planned and ongoing clinical trials to demonstrate the safety and efficacy of monograph ingredients in children.

Some industry stakeholders, medical experts and citizens pressed for collaborative and pragmatic approaches to reconciling concerns about pediatric use of cough/cold products covered in the OTC monograph.

Food and drug attorney Kingham, who appeared at the request of the Consumer Healthcare Products Association, suggested the agency could work with industry to remove any products with a serious safety problem, without pursuing a rulemaking.

John Jenkins, director of CDER's Office of New Drugs, said the agency will amend the monograph and the next step in the process will be to draft and publish a proposed final rule. It could be years before a final rule is promulgated.

Pressing The Agency

The meeting is one step in an ongoing review prompted by a citizen petition filed in March 2007 that questioned the safety and efficacy of the products in a pediatric context (¹ Also see "FDA Review Of Children’s Cough/Cold OTCs Has Broader Implications" - Pink Sheet, 5 March, 2007., p. 3).

At the meeting, petitioner Joshua Sharfstein, Baltimore commissioner of health, suggested a four-step process with deadlines that FDA and the industry should use to obtain the safety and efficacy data.

As part of his plan, he advised that by January 2009 FDA should announce OTC pediatric cough/cold products "must meet the same modern safety and efficacy standards as the agency has applied to prescription medications."

Sharfstein also recommended the agency engage in interim rulemaking by publishing a list of ingredients known to be dangerous in pediatric use - what he referred to as "the lowest hanging fruit."

He cited phenylpropanolamine as an example, although FDA has said it is unaware of products currently containing the substance (² Also see "Official PPA Removal From Market Sought In FDA Proposed Rule" - Pink Sheet, 2 January, 2006., p. 11).

Sharfstein raised a point of contention that continues to dog pediatric studies of cough/cold remedies: the lack of suitable efficacy endpoints (see ³ Also see "FDA Faces “Conundrum” In Determining Efficacy Of Children’s Cold Products" - Pink Sheet, 6 October, 2008.).

"Ultimately, if there's data for products that passed the test, then sure, they should be allowed to be marketed," he said. "But it seems like they're a ways from that."

The advocacy group Public Citizen provided comments during the meeting in support of a full ban on OTC cough/cold drugs for children younger than 12, and also details in an Oct. 2 release how the majority of products on pharmacy shelves appear to lack warnings about use in infants.

Unintended Consequences Of Removal

Sharfstein and other petitioners presenting at the hearing differed with CHPA and the industry over how the removal of pediatric cough/cold remedies from shelves would affect consumer behavior.

CHPA said a ban could lead caregivers to provide potentially dangerous and ineffective alternative treatments with greater frequency. A survey conducted for CHPA in January showed a quarter of parents would use adult formulations on their children if pediatric versions were not available, and more than half would try herbal remedies (⁴ Also see "Removing Pediatric OTC Cold Drugs Would Create New Problems – CHPA" - Pink Sheet, 3 March, 2008., p. 3).

Phillip Walson, a CHPA consultant and formerly a professor of pediatrics and pharmacology at the University of Cincinnati, enumerated the adverse events associated with antibiotics, the ineffectiveness of corticosteroids and the toxicity concerns linked to home remedies such as camphor, comfrey and chamomile.

Sharfstein testified that he was confident that most caregivers would not put children through "therapeutic misadventures" with inappropriate products or remedies.

Office of Nonprescription Products Director Charles Ganley closely questioned several presenters who suggested that unintended consequences were not relevant, implying he has concerns about the choices consumers would make in the absence of OTC cough/cold products for children.

Industry Initiative

Representatives from several makers of OTC drugs, appearing under the umbrella of CHPA, detailed the industry-sponsored pharmacokinetics research already being conducted on eight monograph ingredients.

The draft analysis of a PK study on proper dosing for pseudoephedrine was completed by Wyeth and McNeil in August and pediatric PK studies of phenylephrine and diphenhydramine began recruiting subjects in September.

Analyses of other ingredients are slated to follow, with the ultimate goal being to "confirm or refine" pediatric monograph doses.

CHPA members highlighted the industry's commitment to making appropriate changes to product labels in advance of formal FDA regulations. Firms voluntarily withdrew marketing of cough/cold products for children under the age of 2 in October 2007, following a unanimous vote by a joint FDA advisory panel against using the products in that age range (⁵ Also see "Firms Stop Cough/Cold Product Promotions For Use By Infants – CHPA" - Pink Sheet, 8 October, 2007., p. 9).

CHPA members also pointed to steps being taken to protect against misdosing, including the need for customized product-specific rather than standardized dosing devices.

Panel member Michael Levy, director of new drugs and labeling compliance in CDER's Office of Compliance, has supported the use of specialized devices to reduce consumer confusion (⁶ Also see "Tailored Dosing Devices Could Improve Compliance, FDA's Levy Says" - Pink Sheet, 2 June, 2008., p. 5).

The Mind Of FDA

Following the hearing, Jenkins provided some insight into the possible timeframe separating the public hearing from a final rule on the revised monograph.

The agency is collecting comments through Dec. 2. Jenkins said officials would be "working internally to try to get [a proposed rule] out for clearance within the agency and within the administration within the next few months."

Jenkins added that a "rapid process" of rulemaking could mean completion within a year, but it could take several years before final approval, especially with the transition to a new presidential administration in 2009.

Achieving clearance can be a drawn-out process with an unknown completion date, Jenkins noted. Fellow panelist Ganley has criticized clearance delays for hindering new regulations (⁷ Also see "FDA Clearance May Thwart Monograph Goal; Ganley Talks Turkey About ONP" - Pink Sheet, 27 November, 2006., p. 3).

In the near term, Jenkins said FDA is "considering whether there's any additional communications that we want to bring forward" to clarify safe dosing in pediatric usage. He cited the agency's advisory issued in January, warning consumers not to use the products on children under 2 (⁸ Also see "Parents’ Confusion Leads FDA To Repeat Advisory On Cough/Cold OTCs" - Pink Sheet, 21 January, 2008., p. 5).

A short-term action could be less likely though, since Jenkins noted, "We don't see a public health emergency as far as an inherent risk of the products."

While industry studies of the monograph ingredients may be years from completion, Jenkins said the agency is working with the data it has at present and will re-evaluate the direction of the rulemaking should new information be submitted.

- Dan Schiff (d.Schiff@elsevier.com)

Calls For Cough/Cold Collaboration As FDA Inches Toward Rulemaking

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