Listerine comparability clinicals requirement urged by Warner-Lambert.

LISTERINE COMPARABILITY CLINICALS REQUIREMENT URGED by Warner-Lambert for products containing the same essential oil combination. At a May 27 meeting of FDA's Dental Plaque Subcommittee in Gaithersburg, Md., Warner-Lambert Consumer Healthcare R&D Dental Affairs Director Michael Barnett, DDS, suggested all marketers using the same essential oil active ingredients as Listerine be required to conduct six-month effectiveness studies because antimicrobial ingredients can be "adversely affected by excipients in a formulation."

Barnett reminded the subcommittee, part of FDA's Nonprescription Drugs Advisory Committee, that it has recommended final formulation testing in the antigingivitis monograph be mandated to demonstrate that new vehicle formulations have not compromised the active ingredients. The testing requirements Barnett proposed were developed to ensure that mouthrinse products containing the Listerine essential oil combination "provide a level of effectiveness comparable to" Listerine, he said.

Warner-Lambert recommended an in vitro kill time determination, which assesses the antimicrobial effectiveness of oral formulations, as well as a short-term clinical trial in humans. The proposed kill time assay would compare the new mouthrinse formula to Listerine Antiseptic and a sterile water negative control. Testing would be conducted with an exposure time of 30 seconds in the presence of serum and would determine the effect on specific bacteria.

The in vivo test, to be conducted if the kill time test were positive, would be based on the "experimental gingivitis" model, which assesses antiplaque and antigingivitis activities of different mouthrinse formulations, independent of the variable introduced by mechanical plaque control procedures, Barnett explained. The two-week study should "comply with the statistical requirements to demonstrate a formulation to be at least as good as another formulation," Barnett suggested.

The subcommittee agreed with Barnett's proposal, but some members said they felt flexibility should be incorporated into the protocol.

For example, prescribing specific bacteria for the in vitro assay might be unnecessary, the subcommittee said. The panel also noted a need for some leeway with statistical requirements so companies would not have to reproduce Warner-Lambert's tests for Listerine to demonstrate product equivalence. Although final language has yet to be drafted, the subcommittee agreed in principle to require the kill time and the two-week in vivo studies for "copycat" Listerine products. The committee also discussed labeling for the monograph.

Procter & Gamble presented a protocol for products using stannous fluoride or cetylpyridinium chloride, the latter found in Scope, as well as a number of other oral rinses. To evaluate other products using CPC, the company proposed its plaque glycolysis regrowth method, an ex vivo test that can be performed in a 24-hour period, and the disk retention assay, an in vitro method developed to measure the available level of CPC ("The Tan Sheet" June 17, 1996, p. 6). To measure stannous fluoride's plaque and gingivitis capacity, the company recommended using the PGRM. The company also recommended testing for the levels of available stannous ions and fluoride ions.

There was some discussion by the subcommittee that the P&G test protocol might not deliver results as exact as a two-week or a six-month clinical trial. P&G Health Care Product R&D Associate Director/Senior Researcher Matthew Doyle, PhD, noted the company has used the tests for over 10 years. In addition, P&G's Donald White, PhD, noted the PGRM was as predictive as a two-week study, and reminded the panel extensive clinicals have been conducted on stannous fluoride and CPC already, so the PGRM should serve as an adequate model to demonstrate if another finished formulation is substantially comparable to the P&G products on which the original tests were conducted.