FreshBurst Listerine Study Must Exhibit 20% Gingivitis Reduction – FDA

A six-month study of FreshBurst Listerine with Fluoride will need to show "a 20% reduction in gingivitis" over a control to merit agency sign-off, FDA told Pfizer execs at an OTC "feedback" meeting Aug. 27.

The 20% reduction criteria established by the independent Dental Task Force on Design and Analysis has been consistently used by FDA when reviewing new drug applications, Division of Dermatologic & Dental Drug Products Dental Officer Fred Hyman noted.

Although the proposed product would be covered under two monographs, FDA is still "more or less treating this as an NDA," he added.

In response to Pfizer's requests that the proposed product only be required to show a 15% gingivitis reduction over control because of the variability typically seen in studies, Hyman said "it would be a little unfair" to other firms to change the criteria.

Despite his insistence on the 20% standard, the FDAer implied there may be room for flexibility. When asked what Pfizer should do if the study yields an 18%-19% reduction, Hyman said the firm should still submit the data to FDA. "It is going to be a review issue, it certainly would not be a categorical 'no,'" he noted.

The "feedback" meeting in Rockville, Md. was held to discuss the design of Pfizer's six-month, double-blind, parallel-group, gingivitis clinical study on FreshBurst Listerine with Fluoride.

The study aims to demonstrate that the mouthwash is "at least as effective as" regular Listerine and significantly better than a hydroalcohol solution (¹ (Also see "Listerine With Fluoride Development Continues With “Feedback” Meeting" - HBW Insight, 10 Jun, 2002.), p. 5). Mean scores on the Modified Gingival Index and Plaque Index will serve as primary efficacy variables of the trial.

Reiterating FDA's stance that "this should be a trial that is equal with any NDA for any other new drug," Hyman also stressed the need for a multicenter design rather than the single site initially proposed by Pfizer.

In addition, the study should not include too many exclusion criteria, because a large number of restrictions would suggest the product is inappropriate for OTC use, Hyman maintained. If Pfizer opens up the trial to all types of potential users, the firm may be able to avoid labeling warnings against use by certain population sub-groups, he noted.

Pfizer said it could "handle" removing its exclusionary criteria for pregnant women, diabetics and people with partial dentures. However, Pfizer Consumer Healthcare Senior Director, Clinical Product Development-Oral Care Lori Kumar, PhD, agreed with FDA that subjects with oral piercings still would be excluded because of the "complications that go along with that...[such as] the damage they cause to...teeth."

If the study meets FDA's approval, it will prompt the agency to change both the anticaries and antiplaque/antigingivitis monographs by adding a combination product section to both.

"Assuming the data are sufficient at some point," FDA will create a "permitted combination section" in the anticaries monograph that allows sodium fluoride to be combined with Listerine's essential oils in a hydroalcohol solution, FDA Division of OTC Drug Products Regulatory Counsel Gerald Rachanow said.

The antiplaque/antigingivitis monograph also will include the combination product section when it is published as an advanced notice of proposed rulemaking in approximately six months, he added.

Creating a new section to each of the monographs is preferable to adding the fluoride component to their respective active ingredient sections, because doing so would allow the fluoride solution "without the Listerine component to be marketed as an anticaries product, [and] we are not sure that we have got sufficient data to do that," Rachanow commented.

"We believe that your study here is primarily on a combination product," he noted. Pfizer reps agreed with FDA's proposed handling of the monographs.

The combination product section also would contain specific labeling requirements. As a result, the agency advised Pfizer to consider minor details on FreshBurst Listerine with Fluoride's proposed label, such as whether it plans to tell consumers to "rinse" with the product or "swish vigorously."

Under the anticaries monograph, traditional Listerine must direct consumers to "swish vigorously," but Pfizer's proposed label for the combination product would tell consumers to "rinse."