2005D-0240 Guidance for Industry on Development and Evaluation of Drugs for Treatment or Prevention of Gingivitis; Availability
FDA Comment Number : EC4
Submitter : Dr. Walter Bretz Date & Time: 10/27/2005 05:10:37
Organization : University of Pittsburgh
Category : Academia
Issue Areas/Comments
Here we make the point(s) that gingival bleeding is a tangible primary clinical endpoint for periodontal diseases. This notion receives support in the current literature for evidence-based dental practice. Moreover if the parameter is tangible to the patient (as bleeding is) than it can be readily assessed by the patient which is the ultimate goal of clinical trials to establish benefits provided by trials (Hujoel PP.Endpoints in periodontal trials: the need for an evidence-based research approach.Periodontol 2000. 2004;36:196-204

1.) One of the most sensitive measure of gingivitis
Gingival bleeding has been reported in clinical and histological studies to be an earlier and more sensitive sign of gingival inflammation relative to visual alterations, such as redness and edema. (Muhleman 1971) Other authors have reported both bleeding and redness to be early signs of gingivitis. In some indices, such as SBI bleeding precedes color changes (with 1 = bleeding with no color change and 2 = bleeding with reddening), while other combined indices such as LS GI color change proceeds bleeding (with 1 = redness and no bleeding and 2 = bleeding). The SBI and PBI indices have both been shown to statistically significantly positively correlate to number of inflammatory cells in gingival connective tissue upon histomorphometric analysis. (Engelberger 1983) In separate research, the percentage of inflamed area of total connective tissue is weakly correlated to LS GI scores, although minimal difference in area of inflamed tissue was observed between biopsies with GI = 1 and GI = 2 scores. (Oliver 1969) Collectively the data support that gingival bleeding is an early sign of gingivitis and may occur prior to or at the same time as color change and edema. Furthermore, there is little data to supporting that color changes are an earlier event than bleeding or that ordinal combined gingival indices like LS GI accurately represent the underlying biology.

2.) Most clinically relevant measure of gingivitis to both the clinician and the consumer
Gingival bleeding is a more relevant and understandable endpoint for both dentists and consumers. Examination of gingival bleeding points is a routine part of standard oral exams and a common question that dentists ask their patients as part of a medical/dental history. Importantly, reduction in the number of bleeding sites is a more interpretable result than a reduction observed in an index score based on color. It is both objective and ordinal in nature.

3.) Has been shown to be predictive of future disease risk
Presence or absence of gingival bleeding remains one of the most useful clinical predictors for future disease risk as measured by periodontal attachment loss. (Lang 1986) With respect to negative predictive value, absence of gingival bleeding over a 4 year maintenance period ensured periodontal health in 98.5% of sites. (Lang 1986). In contrast, sites that repetitively bled following probing had significant attachment loss in 30% of the instances.

4.) More objective and easier to calibrate/standardize than visual combined indices
In general, the use of bleeding instead of other visual signs of inflammation as the indicator of gingival change has the clinical advantage in that it is a more objective sign. (Polson 1985) Bleeding is either present or absent, while color changes require subjective estimation by the examiner. (Meitner, 1979). With combined indices like LS GI, as many as four distinct examiner styles have been documented reinforcing the conclusion that combined indices are quite subjective. (McClanahan 2001) This examiner subjectivity presents significant obstacles in effectively calibrating examiners for multicenter studies. In general bleeding indices are easier to control through the standardization of probing force, angulation and time to bleeding following soft tissue.
Here we make the argument that gingival bleeding is a tangible primary clinical e