2005D-0240 Guidance for Industry on Development and Evaluation of Drugs for Treatment or Prevention of Gingivitis; Availability
FDA Comment Number : EC8
Submitter : Dr. Mark Putt Date & Time: 11/03/2005 10:11:27
Organization : Indiana University-Purdue University Fort Wayne
Category : Academia
Issue Areas/Comments
GENERAL
GENERAL
Dear Dr. Hyman:

I am concerned about the methods described for assessment of gingivitis in the draft guideline (Docket 2005D-0240). As written it describes use of the Gingival Index of Loe and Silness as the primary outcome measure, and it relegates bleeding on probing to secondary outcome status. In my opinion as a researcher who has conducted several dozen gingivitis clinical trials during the past couple decades, this approach does not accurately reflect the biology of the disease process. The GI is a composite index that combines visual symptoms of erythema and edema with bleeding upon stimulation (probing) and was introduced for use in epidemiologic studies. While the GI has been used successfully to differentiate between treatments in clinical trials, it is a relatively weak ordinal index that has been used more for its familiarity and historical acceptance than its scientific merit. Furthermore, comparisons between different examiners using the GI have demonstrated that this composite index is highly subjective. A more complete discussion of these factors is available in our publication: Van Dyke TE, Offenbacher S, Pihlstrom B, Putt MS, Trummel C: What is Gingivitis? Current Understanding of Prevention, Treatment, Measurement, Pathogenesis and Relation to Periodontitis. J Int Acad Periodontol 1(1):3-15, 1999.

Because visual symptoms and bleeding reflect different aspects of gingivitis initiation and progression, they really should be assessed and reported independently as primary outcome variables. In fact, based on both clinical and histological studies, I think the consensus among researchers in this area is that bleeding is an earlier and more sensitive sign of gingival inflammation than visual symptoms. Gingival bleeding also has been shown to be a predictor for future risk of periodontitis. Furthermore, it is a relevant and easily understood endpoint for both dental professionals and patients, and it tends to be more objective than indices involving visual symptomology (i.e. changes in appearance - color and swelling). Thus, it is evident that gingival bleeding merits the status of a primary outcome variable. I do not understand the sentence on page 18 of the draft that states, 'It would not be sufficient as a stand-alone primary outcome variable.' For the reasons described above there is no scientific basis for this statement.

The next generation of gingivitis measurements should include quantitative biochemical or biophysical assessments that yield continuous data on a ratio scale. Measurements of various cytokines and other biochemical mediators of inflammation have shown encouraging results and should be validated for use in gingivitis clinical trials. Continued use of indices that combine clinical signs (e.g. GI) should be discouraged, not encouraged as in the existing draft document.

In conclusion, to provide a more complete picture in the measurement of gingivitis given the current understanding of the disease process, I recommend that both visual symptoms and bleeding be regarded as primary outcome variables. Appropriate indices for these two methods are the Modified Gingival Index (Lobene et al., Clin Prev Dent 8:3-6, 1986) and the Gingival Bleeding Index (Saxton & van der Ouderaa, J Periodont Res 24:75-80, 1989) or the Angulated Bleeding Index (Van der Weijden et al., J Periodont Res 29:589-594, 1994). I also recommend the inclusion of biochemical and biophysical measurements as secondary outcome variables.

Respectfully,
Mark S. Putt, MSD, PhD,
Director and Research Scientist,
Health Science Research Center,
Indiana University-Purdue University,
2101 East Coliseum Boulevard,
Fort Wayne, IN 46805,

and
Director, Project Development,
University Park Research Center,
1220 Medical Park Drive, Building #2,
Fort Wayne, IN 46825