Studies originally used to support phenylephrine efficacy under the OTC cold/cough monograph were insufficient "to provide a convincing demonstration of effectiveness," according to briefing materials prepared by FDA researchers for a Dec. 14 meeting of the Nonprescription Drugs Advisory Committee.

The findings by reviewers at FDA's Division of Nonprescription Regulation Development are included in materials released in advance of an NDAC meeting in Silver Spring, Md.

The meeting is in response to a Feb. 1 citizen petition questioning the safety and effectiveness of PE hydrochloride and PE bitartrate in OTC decongestants (¹ [A#05150440005], p. 8).

DNRD researchers say seven of the 14 studies of PE efficacy at a 10 mg dose demonstrated a statistically significant effect on nasal airway resistance. Six of the 10 studies at 25 mg also showed significant effect on NAR, although the remaining four studies at that dosage showed "positive trends."

However, the studies had "known design and reporting limitations," DNRD researchers say. The studies "in general" were "small and lacking many details necessary" to conclusively show efficacy, they add.

The briefing materials also include reports by FDA's Office of Biostatistics and Division of Pulmonary and Allergy Drug Products, the Consumer Healthcare Products Association, Schering-Plough and the Schering-Plough/Merck joint venture.

S-P and the joint venture submitted studies showing PE as "not significantly different" from placebo for nasal decongestant outcomes. 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 on PE, pointed to that study as evidence a review was needed.

CHPA Finds Safety, Efficacy

An expert who will present the efficacy portion of CHPA's report at the NDAC meeting, Ken Dretchen, chairman of Georgetown University's Department of Pharmacology, told "The Tan Sheet" that multiple randomized, double-blind, placebo-controlled clinical trials "provide clear and convincing evidence that the 10 mg dose is safe and effective."

"The issue at hand is not one of the effectiveness of phenylephrine, but design limitations in some of the other studies. For instance, some studies didn't have an active comparator and one study even used a placebo pill that was a different color from the phenylephrine tablet. I am of the opinion that five positive trials is strong evidence of efficacy," Dretchen said in an e-mail.

PE hydrochloride was included in the OTC drug review initiated in 1972 and codified in 1994; PE bitartrate was added to the monograph in 2006 based on pharmacokinetic data demonstrating it has similar bioavailability to PE hydrochloride, according to DNRD's briefing materials.

A CHPA working group also reviewed the monograph studies. In its ² report, CHPA says its "assessment of available scientific evidence concurs with previous findings of the FDA and the OTC expert advisory review panel, that oral phenylephrine 10 mg is safe and effective as a nasal decongestant for over-the-counter use in adults."

Further, data are insufficient to support increasing PE dosing to 25 mg, as the petitioners request, the trade group says.

"There are no convincing data to support that increasing the dose of phenylephrine to 25 mg is necessary to produce clinically meaningful improvements in subjective symptoms of nasal congestion," according to CHPA's report.

The group says seven double-blind, randomized trials used as monograph studies "demonstrated a significant reduction in NAR at the doses tested, ranging from 5 mg to 25 mg."

Four of those studies included PE at 10 mg and each showed "a clinically meaningful reduction in NAR," according to CHPA's report. A fifth study at 5 mg PE also showed significant NAR reduction.

Biostatistics Questions Petitioners' Analysis

FDA's Office of Biostatistics researchers reviewed the monograph studies and the petitioners' analysis.

The researchers, part of FDA's Division of Biometrics, point out the end point of the petitioners' meta-analysis is the maximal reduction over time in nasal airway resistance, but that "more than likely was not ... used in the planning or analysis of the original studies."

While heterogeneity was found in NAR reduction among the studies cited by the petitioners, differences in maximal NAR reduction "might need larger sample size to show statistical significance," according to the Biostatistics staff's report.

As a result, "it is not surprising the meta-analysis mentioned in the [petition] did not show a statistically significant difference in maximal NAR reduction after a single dose of phenylephrine 10 mg," the staff says.

"Without the meta-analyses, then one is left with the examination of the individual studies. The majority of the studies were of very small size, and about equal numbers showing a significant reduction in NAR as not," the report says.

In her summary of FDA's briefing package, Office of Nonprescription Products Associate Director Susan Johnson explains the advisory committee will not address the petitioners' question of whether PE use by children under 12 years old is appropriate.

Johnson says FDA currently is "working to determine the actions that will be taken" from recommendations concerning pediatric use of PE made by a joint meeting of NDAC and the Pediatrics Advisory Committee on Oct. 18 and 19 (³ Also see "FDA Panel Narrowly Votes Against Cough/Cold Drugs For Children Up To Age 6" - Pink Sheet, 22 October, 2007., p. 3).

The joint advisory panel decided in split votes to recommend immediately that all OTC cough/cold medicines should not be used for 2- to 5-year-old children but are safe for 6- to 12-year-olds.

The panel also voted unanimously to recommend "no use" of OTC antitussive, expectorant, nasal decongestant, antihistamine and combination cough/cold products for children under 2.

Further, the committees recommended the extrapolation of data from adult studies should not be used to show efficacy of OTC cough/cold products for children under 12.

- Malcolm Spicer (m.spicer@elsevier.com)

Phenylephrine Efficacy Studies Inconclusive, FDA’s Monograph Division Says

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