FDA's Nonprescription Drugs Advisory Committee recommends additional studies on phenylephrine efficacy for treatment of nasal congestion, although members say current data support the efficacy of the OTC cough/cold ingredient.

The committee on Dec. 14 voted 10-2 to say additional studies are needed on PE 10 mg in an immediate release formulation dosed every four hours, as indicated in FDA's current monograph; however, the panel voted nearly unanimously, 11-1, the current data support efficacy.

FDA convened the advisory committee meeting in Silver Spring, Md., in response to a Feb. 1 citizen petition asserting available data does not support the adult and pediatric doses of PE-hydrochloride and PE-bitratrate included in the current monograph (¹ Also see "Citizen Petition On Phenylephrine Requests Pulling OTC Status For Children" - Pink Sheet, 12 February, 2007., p. 3).

The petitioners found "insufficient" data from an eight-study meta-analysis to support PE efficacy at the 10 mg dose. They recommended FDA increase the maximum dose of PE-hydrochloride to 25 mg and the maximum dose of PE-bitratrate to 40 mg from 15.6 mg. They also recommended additional studies to identify the most effective dose.

The advisory panel agreed additional PE efficacy studies are necessary to identify the most effective dose, even though it also said current studies support the safety and efficacy of PE 10 mg doses.

"We need to understand a lot more in terms of benefits - is [10 mg] the best dose, or would a higher dose be more effective without leading to greater risks?" asked Mary Tinetti, NDAC chairwoman and chief of the geriatrics division at Yale University's medical school.

She explained the original efficacy studies FDA reviewed when it added PE to the monograph "would not meet today's standard of evidence," because they "were extremely small."

The NAR methodology that some of the original studies used is "not state-of-the-art" and "does translate into symptom relief, which is really the indications we want to measure," Tinetti added.

Linda Suydam, president of the Consumer Healthcare Products Association, said at a briefing following the meeting that "the industry is committed to working with the FDA on expanding the data and adding to the body of evidence" for the efficacy of the 10 mg dose.

However, firms would need to study the efficacy of the 25 mg dose "individually," and "apply to the FDA for an NDA so they can have a product on the market at a higher dose, if it turns out to be safe and effective," she adds.

"Twenty-five milligrams is really not relevant at this point because 10 mg was considered to be effective," Suydam said.

FDA has not decided whether it will consider changing the monograph or order more studies. However, in the event the agency would issue recommendations to amend the monograph, it would prefer that the industry initiate the studies on its own, the officials said.

Products formulated with 10 mg of PE will continue to be available, which Suydam said is a "good thing."

She added that consumer data show 89 percent of people who use products with 10 mg of PE are satisfied.

Additional studies should include a broader range of variables than previous research, said NDAC member Ralph D'Agostino, a professor at Boston University's Department of Mathematics and Statistics and a former chairman of the committee.

"I think at the 10 mg dose we need to have better understanding of generalizablity. I think we need multi-center studies with age, gender, race, and severity, and the plethora and the spectrum of those variables covered," he said.

The panel members also agreed that subjective symptom measures are a more effective way to study PE efficacy. However, researchers should not "jettison objective measures," said Garret FitzGerald, chairman of the University of Pennsylvania School of Medicine's pharmacology department.

Rather, studies should use objective measures, such as NAR, as secondary measures to support their subjective findings, FitzGerald added.

Ruth Parker, a pediatrician and a professor of medicine at the Emory University School of Medicine, said studies on PE and other individual ingredients do not provide accurate pictures of the safety and efficacy of multi-ingredient products more commonly used by consumers.

"I'm concerned that it's easier and clearer for us to talk about a single-ingredient and the safety and efficacy of single-ingredient, but it does not reflect the reality of the actual marketplace and what the average person faces," Parker said during the committee's discussion.

Schering-Plough and a Schering-Plough/Merck joint venture submitted studies showing PE as "not significantly different" from placebo for nasal decongestant outcomes (² Also see "Phenylephrine Efficacy Studies Inconclusive, FDA’s Monograph Division Says" - Pink Sheet, 10 December, 2007., p. 12).

S-P, which positions its pseudoephedrine-containing Claritin-D against competitors that reformulated with PE, released one of the studies in 2006.

Rep. Henry Waxman, D-Calif., who called for an NDAC meeting on PE, pointed to that study as evidence a review was needed (³ Also see "Phenylephrine “Not Significantly Different From” Placebo – Schering Study" - Pink Sheet, 13 November, 2006., p. 6).

"I am surprised that they discounted the new Schering-Plough studies, and only looked at this old . . . stuff. To me these old studies are junk," petitioner Leslie Hendeles, a University of Florida pharmacy and pediatrics professors, said after the meeting.

"I think that I got what I was looking for. The committee asked for additional studies to look at the 25 mg and in the process they will have to look at the efficacy of the 10 mg dose," he said.

"I think that those studies will show that the 10 mg dose does not relieve a stuffy nose and they will find out if a higher dose is better," Hendeles added.

- Jessica Lake (j.lake@elsevier.com) and Elizabeth Crawford (e.crawford@elsevier.com)

Data Support Phenylephrine Efficacy, But More Studies Needed – NDAC

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