Colgate-Palmolive Total triclosan dentifrice is "approvable".

COLGATE TRICLOSAN TOOTHPASTE ANTI-PLAQUE CLAIM QUESTIONED by the Dental Products Panel and some members of the Dental Drug Products Plaque Subcommittee at a Feb. 29 meeting in Bethesda, Md. Some panelists expressed reservations about whether the data submitted by Colgate-Palmolive in support of its NDA for the triclosan/sodium fluoride dentifrice were sufficient to support a plaque claim.

However, no clear consensus emerged. Some members of the group described the levels of plaque reduction demonstrated in Colgate's data as "modest," yet statistically significant.

Colgate's NDA for the toothpaste -- Total -- was designated as "approvable" by FDA, on Jan. 30. However, the plaque claim was one "approval issue" that the panel discussed at FDA's request. If approved, the toothpaste would be the first in the U.S. authorized to make anti-plaque, anti-gingivitis and anti-caries claims.

FDA Division of Dermatologic and Dental Drug Products Dental Officer Fred Hyman, DDS, said in introductory remarks to panel members that while the agency believes that Colgate "has provided support for the safety and efficacy of this product," the company is seeking advice on whether the "magnitude" of plaque reduction demonstrated by use of the product compared to an active fluoride control is "clinically significant."

The panel also voiced concern about the different indices used for plaque and gingivitis reduction and whether their correlation in Colgate's studies was appropriate. The plaque scale used is an accumulation scale, Colgate Clinical Dental Research VP Anthony Volpe, DDS, explained, and the gingivitis scale measures inflammation.

Colgate supported the anti-plaque claim with five published six-month clinical studies measuring plaque and gingivitis efficacy, submitted as part of the NDA. However, FDA determined that only two of the trials, conducted in West Palm Beach, Fla. and Buffalo, N.Y., used the same formulation as the product Colgate is trying to market and thus were pivotal. The remaining trials, cast in the "supporting" role by FDA, used test dentifrices with different ingredients and concentrations than Total.

The first pivotal study, Mankodi et al., recorded reductions in plaque and gingivitis of 11.9% and 19.3%, respectively, compared to placebo. The second, Bolden et al., found reductions of 17% for plaque and 29% for gingivitis versus the placebo. Additional data provided were results from three three-year clinical studies to demonstrate fluoride efficacy against caries and one six-month and two three-month clinical studies comparing the tartar reduction of Total with a traditional toothpaste. The NDA was filed in January 1993.

All five of the trials were randomized, double-blind, parallel and placebo-controlled. The subjects ranged in age from 18 to 65. There was a total of nearly 1,000 male and female participants. The study dentifrices were used for one-minute unsupervised brushings twice a day. Clinical examinations were performed at baseline, mid-study and at the end of the trial.

The panelists discussed at length whether the plaque claim is appropriate based on the fact that the studies linked plaque reduction with anti-gingivitis scores and, although plaque is widely known as a contributor to gingivitis, it is not the only factor.

"The relationship between plaque and gingivitis isn't always linear," panel member Robert Genco, DDS, State University of New York School of Medicine, noted. For example, he said, pregnant women, smokers and post-menopausal women on hormone replacement therapy do not exhibit the same association of plaque to gingivitis as other populations. However, Max Listgarten, DDS, University of Pennsylvania Microbiological Testing Laboratory, stated, "Plaque is still the major cause of gingivitis seen in clinical situations."

Dental Products Panel Chairman Paul Robertson, DDS, University of Washington School of Dentistry, concluded that some panel members "support...the notion that there's sufficient evidence to document a separate plaque claim based on very well-accepted, albeit crude, estimates of plaque." He added, however, that "equally understandable are those who think that a separate plaque claim is not important or not valid."

Colgate has proposed to FDA that clinically significant reductions of plaque must: "meet established criteria for statistically significant difference from placebo controls"; "demonstrate plaque reductions of at least 10% compared to a placebo control"; and "`be associated' with reductions of gingivitis which are minimally 15% for each study and 20% for all studies when combined."

FDA's Hyman commented that "although [Total] meets the...three conditions, the rationale for selecting these conditions is not provided, and it is unclear how these conditions are supportive of clinical significance, especially the `10%' value for reduction given in the second condition." FDA hoped that the panel's discussion would "help to establish a consensus concerning the significance of the plaque reduction demonstrated in these trials."

However, the panel did not come to a consensus on whether the three criteria for obtaining significant plaque reduction data are valid. Many of the members agreed with the first condition but were critical of the second and third. A number of panelists were skeptical of the 10% plaque reduction figure, stating that they would like to see the supporting data. Robertson predicted that the "debate" over the plaque issue "will continue."

Procter & Gamble, which markets a triclosan-containing toothpaste internationally, opposed Colgate's proposal at the meeting.

P&G Clinical Research Section Head Stephen McClanahan, PhD, said that there is a "lack of a direct correlation between numerical plaque reductions and gingivitis reductions reported for triclosan/gantrez dentifrices in the literature," adding that "the presence of a reduction in [either] plaque or gingivitis does not imply a reduction in the other." Each clinical entity "must be established separately," he stated.

P&G had planned to introduce Ultra Protection Crest with triclosan in the U.S. in 1991 but halted plans for the launch when FDA said that the product would require an approved NDA.