Guidance for Industry 
Gingivitis: Development and 
Evaluation of Drugs for Treatment 
or Prevention 
 
 
 
 
DRAFT GUIDANCE 
This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 
days of publication in the Federal Register of the notice announcing the availability of 
the draft guidance. Submit comments to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852. All comments should be identified with the docket number listed in the notice of 
availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact Fred Hyman, 301-827-2020. 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2005 
Clinical Medical 
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Guidance for Industry 
Gingivitis: Development and 
Evaluation of Drugs for Treatment 
or Prevention 
 
 
 
 
 
 
Additional copies of this Guidance are available from: 
 
Office of Training and Communications 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
5600 Fishers Lane, Rockville, MD 20857 
(Tel) 301-827-4573 
http://www.fda.gov/cder/guidance/index.htm. 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
June 2005 
Clinical Medical 
 
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TABLE OF CONTENTS 
 
I.  INTRODUCTION......................................................................................................................................1 
II.  BACKGROUND.........................................................................................................................................2 
A.  DEFINITION OF GINGIVITIS....................................................................................2 
B.  ANTIGINGIVITIS RULEMAKING..............................................................................2 
III.  GENERAL CONSIDERATIONS............................................................................................................3 
A.  PRESCRIPTION VS. OVER-THE-COUNTER STATUS OF THE DRUG........................3 
B.  PREVENTION VS. TREATMENT CLAIM...................................................................3 
C.  MECHANISM OF ACTION........................................................................................4 
D.  DOSE-RESPONSE RELATIONSHIP...........................................................................4 
E.  COMBINATION PRODUCTS......................................................................................4 
F.  ETHICAL CONSIDERATIONS OF CONDUCTING A GINGIVITIS TRIAL....................4 
IV.  NONCLINICAL CONSIDERATIONS..................................................................................................5 
V.  CLINICAL PROTOCOL ISSUES AND ELEMENTS........................................................................9 
A.  STUDY DESIGN........................................................................................................9 
B.  RANDOMIZATION....................................................................................................9 
C.  BLINDING..............................................................................................................10 
D.  LENGTH OF TRIAL................................................................................................10 
E.  STANDARD OF CARE.............................................................................................10 
F.  PLACEBO OR ACTIVE CONTROL FORMULATION................................................11 
G.  USE OF A NO-TREATMENT GROUP.......................................................................11 
VI.  CONSIDERATIONS FOR SUBJECT RECRUITMENT.................................................................11 
A.  SAMPLE SIZE........................................................................................................11 
B.  INCLUSION AND EXCLUSION CRITERIA...............................................................11 
C.  SPECIAL POPULATIONS........................................................................................14 
D.  PEDIATRIC POPULATIONS....................................................................................14 
E.  GERIATRIC POPULATIONS...................................................................................14 
VII. ASSESSMENT OF GINGIVITIS..........................................................................................................15 
A.  CALIBRATING INVESTIGATOR SKILLS.................................................................15 
B.  GINGIVAL INDEX..................................................................................................15 
C.  PLAQUE INDEX......................................................................................................16 
D.  BLEEDING ON PROBING........................................................................................16 
E.  CALCULUS FORMATION.......................................................................................17 
F.  STAINING INDEX...................................................................................................17 
G.  MICROBIOLOGIC SAMPLING................................................................................17 
VIII. CLINICAL AND STATISTICAL SIGNIFICANCE FOR DETERMINING AN EFFECT.......17 
A.  CLINICAL SIGNIFICANCE......................................................................................17 
B.  STATISTICAL CONSIDERATIONS...........................................................................18 
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X.  CONCLUDING COMMENTS..............................................................................................................20 
 
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1
Guidance for Industry  
1 
Gingivitis: Development and Evaluation of Drugs for Treatment  
2 
 
or Prevention
3 
4   
5   
6  This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 
7  thinking on this topic.  It does not create or confer any rights for or on any person and does not operate to 
8  bind FDA or the public.  You can use an alternative approach if the approach satisfies the requirements of 
9  the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 
10  staff responsible for implementing this guidance.  If you cannot identify the appropriate FDA staff, call 
11  the appropriate number listed on the title page of this guidance.  
12   
13   
14   
15   
16  I.  INTRODUCTION 
17  This guidance is intended to assist sponsors of new drug applications (NDAs) with the 
18  development of drug products that treat or help prevent gingivitis in adults and children.  This 
19  document defines gingivitis and clarifies the distinction between gingivitis and periodontitis.  It 
20  discusses general issues such as over-the-counter (OTC) versus prescription status and 
21  prevention versus treatment.  The bulk of this guidance focuses on trial design issues and clinical 
22  assessments.  The document concludes with an examination of product safety determinations. 
23   
24  This document does not contain discussion of the general issues of clinical trial design or 
25  statistical analysis.  Those topics are addressed in the ICH guidance documents, E8 General 
26  Considerations for Clinical Trials and E9 Statistical Principles for Clinical Trials (ICH-E9).2  
27  This guidance focuses on specific trial design issues that are unique to the study of gingivitis. 
28   
29  FDA's guidance documents, including this guidance, do not establish legally enforceable 
30  responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
31  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
                                                 
1 This guidance has been prepared by the Division of Dermatologic and Dental Products in the Center for Drug 
Evaluation and Research (CDER) at the Food and Drug Administration (FDA). 
 
2 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER 
guidance page at http://www.fda.gov/cder/guidance/index.htm. 
 
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32  cited.  The use of the word should in Agency guidances means that something is suggested or 
33  recommended, but not required. 
34   
35  II.  BACKGROUND 
36  A.  Definition of Gingivitis 
37   
38  Gingivitis is an inflammation of the soft tissue of the oral cavity that immediately surrounds each 
39  individual tooth. This soft tissue, known as the gingiva, consists of epithelial and connective 
40  tissues, which support the teeth in the bone of the mandible or maxilla. The other supporting 
41  structure that anchors the teeth is the periodontium, which consists of connective tissue 
42  attachments and alveolar bone. Whereas gingivitis is an inflammation confined to the gingival 
43  tissue, periodontitis affects the ligaments and alveolar bone that support the root of the tooth and 
44  provide its anchorage to the maxilla or mandible. 
45   
46  This guidance focuses on plaque-induced gingivitis, as it is the most common form of gingivitis 
47  and responds well to oral hygiene and antimicrobial products. Dental plaque is the aggregation of 
48  soft deposits that form the biofilm adhering to the teeth or other hard surfaces in the oral cavity, 
49  such as removable and fixed restorations.  In addition to plaque, other causes of gingivitis 
50  include viral, fungal, or bacterial infection; endogenous sex steroid hormones; medication; 
51  systemic diseases; and malnutrition. Sponsors interested in developing products for gingivitis of 
52  nonplaque etiology can consult the Division of Dermatologic and Dental Drug Products for 
53  advice that is specific to that unique indication.  In this guidance, the term gingivitis refers 
54  specifically to plaque-induced gingival disease unless otherwise noted. 
55   
56  B.  Antigingivitis Rulemaking 
57   
58  During the past several decades, many products have entered the marketplace as OTC products 
59  that purport to treat or prevent gingivitis.  As a result of the proliferation and promotion of those 
60  products, FDA convened a subcommittee of the Dental Products Panel (Subcommittee) in 1993 
61  to evaluate OTC products that make gingivitis claims and that were in the marketplace without 
62  an NDA.  The panel reviewed the data submitted for the antigingivitis products and reported its 
63  findings on the safety and effectiveness of OTC ingredients for the reduction or prevention of 
64  gingivitis.   
65   
66  On May 29, 2003, the Subcommittees final report was published in the Federal Register (68 FR 
67  32232) as an advance notice of proposed rulemaking (ANPRM).  The ANPRM established 
68  conditions under which OTC drug products for the reduction or prevention of dental plaque and 
69  gingivitis would be generally recognized as safe and effective and not misbranded.   
70  FDA is publishing this guidance document on the development of antigingivitis drug products to 
71  aid drug sponsors in conducting clinical trials either to submit additional information to the 
72  antigingivitis rulemaking, or to obtain approval for a new antigingivitis drug through the NDA 
73  process. 
74   
 
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75  III.   GENERAL CONSIDERATIONS 
76  A.  Prescription vs. Over-The-Counter Status of the Drug 
77  One early consideration in drug development is whether the drug product is to be marketed as a 
78  prescription medication (including drugs available only to practitioners) or as an over-the-
79  counter (OTC) preparation.  An expert panel convened by FDA in 1991 determined that the 
80  general public is able to recognize and self-treat gingivitis.  Drugs that the public can use 
81  appropriately in the absence of supervision by a physician, dentist, or other health care 
82  practitioner are marketed OTC.3  OTC status is not appropriate for antigingivitis products that 
83  call for supervised use. 
84   
85  Unlike a prescription drug label, an OTC label should contain indications, directions for use, and 
86  warnings that are understood by the general public.  Comprehension studies can demonstrate that 
87  consumers will be able to understand and follow labeled directions and warnings.  Sponsors of 
88  OTC products should demonstrate that consumers can use these products safely since there will 
89  be no health professional monitoring for adverse events or symptoms of more serious conditions, 
90  such as periodontitis.  Safety considerations for both prescription and OTC antigingivitis drugs 
91  will be discussed in detail in section IX of this document. 
92   
93  B.  Prevention vs. Treatment Claim 
94   
95  Another consideration is whether the therapy is intended to prevent or to treat gingivitis. Many 
96  studies begin with subjects receiving a professional scaling and polishing that alone may restore 
97  gingival health. The endpoint then may be the reappearance of gingivitis after a set period of 
98  time.  If the test group develops significantly less gingivitis than the placebo group in 
99  appropriately designed studies, it is reasonable to conclude that the drug has reduced the 
100  incidence of gingivitis.  In the case of a chronic disease such as gingivitis, prevention is more 
101  explicitly stated as reduces the incidence of disease or reduces the incidence of severe 
102  disease.  Wording that conveys this message would vary, depending on whether the product is 
103  intended for prescription or OTC use.  Wording for a prescription product could include 
104  scientific language such as reduction of disease incidence.  To convey this message on a level 
105  more appropriate for consumers of nonprescription drugs, the Subcommittee has recommended 
106  that OTC products carry the language helps prevent gingivitis. 
107   
108  Subjects who already have measurable gingivitis before treatment may experience a significant 
109  reduction in the mean gingivitis score or in the number of gingivitis sites in the test group 
110  compared to placebo group (scoring systems are described in section VII of this document).  This 
111  reduction would allow for a claim of reduces the severity of gingivitis or some other treatment 
112  claim as appropriate for prescription or OTC status. 
113   
                                                 
3 21 U.S.C. 503(b)(1)(A) of the Federal Food, Drug, and Cosmetic Act. 
 
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114  C.  Mechanism of Action 
115   
116  Understanding a drugs mechanism of action is desirable but not required for FDA approval for 
117  marketing.  There is a safety concern in treating gingivitis without removing one well-established 
118  causal factor, plaque accumulation.  Therefore, if the mechanism of action of the sponsors drug 
119  were other than plaque reduction (e.g., anti-inflammatory), the sponsor would be asked to 
120  address the issue of masking underlying periodontitis before approval. Further discussion on this 
121  topic can be found in sections VII and IX of this document. 
122   
123  D.  Dose-Response Relationship 
124   
125  We strongly encourage the sponsor to explore the dose-response relationship early in product 
126  development.  It is always desirable to identify the lowest effective dose for a drug.  In the case 
127  of topical antigingivitis products, not only should the lowest concentration of the drug be 
128  identified, but also both the lowest effective frequency of dosing and the shortest duration of 
129  therapy.  As gingivitis is not a life-threatening disease and other treatments for gingivitis are 
130  available, an unfavorable adverse events profile for a new antigingivitis drug could jeopardize 
131  approval, depending on the severity and seriousness of the events.  A lower dose of the drug 
132  might be effective and provide an appropriate safety profile. 
133   
134  E.  Combination Products 
135  Two or more drugs can be combined into a single dosage form when each component makes a 
136  contribution to the claimed effect or effects (21 CFR 300.50 and 330.10(a)(4)(iv)).  To 
137  demonstrate the contribution of each component, we recommend that the combination product be 
138  shown to have a greater effect than either component separately in the same vehicle, if the 
139  product is for topical use.  For example, if two antimicrobials are combined into one topical drug 
140  product for the treatment of gingivitis, the following arms should be included in the efficacy 
141  studies: vehicle, antibiotic A only in vehicle, antibiotic B only in vehicle, antibiotics A and B 
142  combined.  To successfully demonstrate the efficacy of A and B together, the A+B arm should 
143  be significantly better at gingivitis reduction than both A alone and B alone.   
144   
145  F.  Ethical Considerations of Conducting a Gingivitis Trial 
146  It is important that study subjects not be exposed to permanent detrimental health outcomes as a 
147  result of their participation in a clinical trial, and that subjects understand the risks and benefits 
148  involved in their participation.  As long as the group receiving the vehicle also receives standard 
149  oral care, there is no ethical concern because gingivitis is reversible.  Gingivitis trials often begin 
150  with a professional oral hygiene appointment, which will benefit subjects in both the vehicle and 
151  test groups. 
152   
153  An example of a clinical trial with a potential ethical concern is a study of individuals with either 
154  severe gingivitis or gingivitis in conjunction with periodontitis.  In these cases, a delay in 
 
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155  treatment may cause irreversible damage.  To avoid this possibility, the sponsor may wish to 
156  employ an active control and test for equivalence or non-inferiority to the active control.  Rather 
157  than statistical testing for superiority to a placebo, confidence interval testing for equivalence 
158  would be used.  Refer to ICH-E9 for a discussion of the statistical considerations of this trial 
159  design.  Also refer to subsection VIII.B of this document. 
160   
161  In the past, experimental gingivitis models have been used to accelerate the development of 
162  gingivitis to shorten the trial.  Although this may be valuable during early phases of drug 
163  development to determine if the test product has the potential to be effective, the ethics of this 
164  approach raise concern.  We recommend that sponsors carefully consider factors such as the 
165  health of the subjects, duration of the proposed trial, and possibility of irreversible damage.  
166  Also, these experimental gingivitis studies do not represent the natural history of gingivitis and 
167  may produce misleading results. 
168   
169  IV.  NONCLINICAL CONSIDERATIONS 
170   
171  This section of the document concerns nonclinical development issues related to products that 
172  are intended for administration within the oral cavity for the treatment or prevention of 
173  gingivitis.  These comments are intended to supplement the applicable FDA guidance documents 
174  that pertain to nonclinical development and should be considered within the context of those 
175  documents.   
176   
177  The safety assessment of antigingivitis products should include consideration of the potential to 
178  cause both local (inside the mouth or gastrointestinal tract) and systemic toxicity.  Even if the 
179  product is not intended to be swallowed, the sponsor should assume that a portion of each dose 
180  will be swallowed, and many compounds are absorbed buccally or sublingually.  Evaluation of 
181  the systemic toxicology of compounds that are proposed for the treatment or prevention of 
182  gingivitis should follow the same precepts that apply to development of the nonclinical safety 
183  database associated with most other systemically administered compounds.  The ICH guidance, 
184  M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals,4 
185  provides an overview of the general types of nonclinical data that may be important to support 
186  various stages of clinical development and marketing of drug products.  It also gives information 
187  about the recommended durations of the exposures of the animals to the test materials and the 
188  time at which certain nonclinical data should be available relative to clinical development.  For 
189  details concerning general toxicological issues, refer to the appropriate CDER guidance 
190  documents.5   
191   
192  Systemic toxicity issues that concern these products are usually best assessed through toxicology 
193  studies of appropriate duration and design in which the drug substance (not necessarily the drug 
194  product) is administered orally (usually by gavage, but in some instances in the diet or drinking 
195  water).  The studies should include thorough clinical pathology (i.e., clinical chemistry, 
                                                 
4Available on the Internet at http://www.fda.gov/cder/guidance/index.htm. 
5Available on the Internet at http://www.fda.gov/cder/guidance/index.htm.  
 
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196  hematology, and urinalysis), histopathological examination of a full range of tissues, and 
197  toxicokinetic analysis.  The gastrointestinal tract is an area of particular concern since it may be 
198  exposed to the materials in relatively undiluted form.  Toxicokinetic data from these studies 
199  should be compared to pharmacokinetic data obtained in suitable clinical studies conducted with 
200  the drug product to ensure that systemic exposure in the nonclinical studies was adequate to 
201  qualify the clinical exposure.  If acute studies are performed, we recommend that the studies 
202  include animals that are sacrificed at an early time point (e.g., 24 hours post-treatment), since 
203  mucosal lesions heal rapidly.  Development of sustained-release products should include studies 
204  in which the intact product is administered by gavage to a suitable species, with emphasis on 
205  determining whether or not the product causes erosions or ulcers.   
206   
207  For products that are intended for direct administration within the mouth, such as mouthwashes, 
208  dentifrices, and intraoral sustained-release products, we recommend that sponsors consider the 
209  products potential to induce irritation or erosion of the oral tissues.  The most appropriate means 
210  of addressing this issue depends on the circumstances associated with a particular product and 
211  clinical proposal; data from an oral irritation study conducted in animals may be unnecessary.  
212  For example, if a product is very similar to a formulation that has been studied previously (in 
213  animals or humans) without excessive local irritation, then additional oral irritation data may not 
214  be warranted.  Another factor that should be considered when assessing the importance of oral 
215  irritation data in support of a given clinical proposal is the design of the proposed clinical study.  
216  That is, what steps would be taken to detect oral irritation at an early stage, and what measures 
217  would be taken if irritation is observed?  For example, the clinical protocol may call for a 
218  qualified individual to examine the oral cavity at appropriate time points (e.g., following 1, 3, 7, 
219  and 14 days of treatment), with termination of dosing if signs of irritation are evident.  In this 
220  instance, carefully collected data from patients makes an oral irritation study in animals less 
221  relevant, compared to a trial with less frequent or less comprehensive oral examinations.  These 
222  matters should be considered on a case-by-case basis, and the review division can be contacted 
223  for specific guidance. 
224   
225  If it is deemed important to evaluate a product for potential to induce oral irritation in an animal 
226  model, then we suggest that the following points be considered during the design of an oral 
227  irritation study: 
228   
229    Test material.  The material that is tested should be the same formulation (including 
230  inactive ingredients) that is proposed for use in humans.  Sponsors should recognize 
231  that inactive ingredients (e.g., alcohol, flavoring agents, surfactants) in drug products 
232  are often irritating to the oral tissues.   
233   
234    Animals.   Rats or hamsters are generally used, although other species, such as dogs, 
235  may be appropriate in certain instances.  It is recommended that animals of both 
236  genders be studied.  
237   
238    Abrasion of the mucosa.  One of the goals of an oral irritation study should be to 
239  assess the product for potential to delay healing of lesions within the oral cavity.  
 
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240  This goal can be accomplished by comparing the rates at which mechanically 
241  induced oral lesions heal in treated and control animals.  Therefore, a portion of the 
242  oral mucosa of each animal should be abraded shortly before the first application of 
243  the test and control materials.  The buccal mucosa should be abraded on only one 
244  side of the mouth, permitting examination of both intact and abraded mucosa in each 
245  animal.  Abrasion can be accomplished with a variety of instruments (e.g., file, 
246  brush, needle).  It is important that the location, size, and depth of the abrasions be as 
247  uniform as possible within a study.  The abrasion should be sufficiently severe that a 
248  lesion extending into the sub-epithelial connective tissue is observable in tissue 
249  sections from animals sacrificed 24 (or more) hours after treatment.  Ideally, the 
250  abrasion procedure, including the time course of the healing process, should be 
251  histologically characterized before initiation of a definitive oral irritation study.  
252   
253    Method of application.  The test material should be applied to the oral tissues in a 
254  manner that is reproducible in terms of (1) the quantity of test material that is applied 
255  to the oral cavity, (2) the oral tissues to which the test material is directly applied, and 
256  (3) the amount of application-induced abrasion of the oral tissues.  The duration and 
257  pattern of each application should be consistent.  The test material is usually applied 
258  with a cotton swab.  In general, the animals should not be anesthetized during 
259  treatment, since many anesthetics impair salivation.  Placement of the test material 
260  within the cheek pouch of a hamster is not particularly recommended, because the 
261  amount of time that the test material is retained within the pouch may vary 
262  substantially among animals (or between control and active materials).  An exception 
263  to this statement pertains to situations in which a solid dosage form (e.g., an osmotic 
264  tablet) should be retained in the mouth for a substantial period, in which case it may 
265  be appropriate to place the test material in the cheek pouch of an anesthetized hamster 
266  and suture the pouch partially closed to prevent expulsion.  
267   
268    Dosage level.  A dosage of 1 milliliter or 1 gram of test or control material per 
269  kilogram of body weight per application is generally used, although different dosage 
270  volumes may be deemed appropriate on the basis of toxicity or the clinical dosage.  If 
271  it is considered important to examine the effect of a range of exposure levels (i.e., 
272  evaluate the dose-response relationship associated with irritation of the oral tissues), 
273  the intensity or magnitude of the daily exposure to the test materials should be 
274  regulated through modulation of the dosing frequency.  For example, a study might 
275  include a group of animals that were treated once daily, a second group that were 
276  treated twice daily, and a third group that were treated four times daily.  The exposure 
277  level should not be modulated through variation of the quantity of material 
278  administered per application, since excess test material is usually swallowed or 
279  expelled without genuinely increased exposure of the oral cavity to the material. 
280   
281    Dosing frequency.  The number of daily applications should at least equal, and 
282  preferably exceed, the maximum anticipated clinical dosing frequency for the product 
 
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283  (although generally the maximum feasible number of applications per day in an 
284  animal study is four, at 2-hour intervals).  
285   
286    Duration of application.  We recommend that the animals be treated for 28 
287  consecutive days; a study of this duration should adequately support an NDA for a 
288  product that is proposed for chronic use (with respect to oral irritation), since local 
289  effects will be apparent within that time frame. 
290   
291    Controls.  The study should include a negative control group consisting of animals 
292  treated with room temperature distilled water or 0.9 percent sodium chloride (NaCl).  
293  The vehicle of the drug product should not be used as a negative control article, as 
294  some inactive ingredients may be irritating. 
295   
296    Sacrifice schedule.  We recommend that the oral tissues be histopathologically 
297  evaluated at selected intervals during the study following interim sacrifices.  For 
298  example, in a study in which animals are to be treated for 28 days, with the day on 
299  which abrasion and the first treatments are performed being designated day 1, animals 
300  might be sacrificed on days 2, 5, 29, and 43.  The sacrifice on day 2 (approximately 
301  24 hours after the abrasion of the mucosa) would permit assessment of the adequacy 
302  and uniformity of the abrasion technique, and might involve only a small number of 
303  randomly selected negative-control animals (e.g., three animals per sex).  We 
304  recommend that an interim sacrifice of animals in each treatment group be conducted 
305  at a time point when the abraded mucosa in the negative control animals is partially 
306  (but not completely) healed.  The purpose of this interim sacrifice is to provide 
307  information concerning the potential of the test material to delay healing of lesions of 
308  the oral mucosa, which could be accomplished through comparison of the abraded 
309  areas from test and control animals.  Although it is suggested in this document that 
310  sacrifice on day 5 may be appropriate for assessment of effect on healing, the 
311  optimum time point will depend on various factors, including the nature of the initial 
312  abrasion.  The time point that is selected should be based on data from previous 
313  studies that used an identical abrasion technique and evaluated the time course of 
314  healing of the lesion.  Animals sacrificed on day 43 (14-day recovery group) could 
315  provide information about the reversibility of any lesions observed in animals 
316  sacrificed on day 29. 
317   
318    Number of animals.  A typical study design might involve 18 animals per gender in 
319  the negative control group and 15 animals per gender in each group that is to be 
320  treated with a test material.  Such a study could involve sacrifice of 3 negative-control 
321  animals per gender 24 hours following abrasion (for assessment of the abrasion 
322  technique) and 5 animals per gender from each group on the date of the interim 
323  sacrifice (see the previous bulleted item above) and on days 29 and 43.   
324   
325    Parameters to be evaluated.  The oral cavity of each animal should be visually 
326  inspected at least once daily, including evaluation of the colors of the oral tissues 
 
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327  (including the teeth), signs of edema, erythema, sloughing, bleeding, or ulceration, 
328  and the presence of dryness, roughness, cracking, or bleeding of the lips.  Terminal 
329  studies should include gross examination of the oral cavity, esophagus, stomach, 
330  small and large intestine, and any apparent lesions, and histopathology of the oral 
331  cavity and adjacent structures, including the labial junctions, the buccal and gingival 
332  tissues (including the area that was abraded), the tongue, the palate (hard and soft), 
333  the parotid salivary gland, the submandibular lymph nodes, the nasopharynx and 
334  nasal passages, the larynx, the esophagus, the stomach, and any tissues that appear 
335  abnormal during gross examination.  Particular emphasis should be placed on the 
336  integrity and thickness of the epithelial barriers, signs of hyperplasia or keratinization, 
337  examination of the area that was abraded for signs of delayed healing (relative to the 
338  negative control animals), and examination of the soft tissues for infiltration of 
339  inflammatory cells and/or edema.   
340   
341  V.  CLINICAL PROTOCOL ISSUES AND ELEMENTS 
342  A.  Study Design 
343   
344  Parallel group designs are commonly employed and generally recommended.  We advise 
345  sponsors to exercise caution with the use of crossover and split-mouth designs, which rarely 
346  offer any advantage.  A split-mouth design, in which one side of the mouth is untreated and is 
347  used as a control and the other side treated, may be difficult to execute.  Test agent from the 
348  treated side may contaminate the untreated side and compromise the results.  In a crossover 
349  design, a sufficient wash-out period is important to eliminate any residual effects from prior 
350  treatments. 
351   
352  B.  Randomization 
353   
354  A clear description of the method by which subjects are randomized to treatment groups, as well 
355  as identification of stratification variables and blocking factors, will demonstrate whether group 
356  allocation is unbiased. 
357   
358  Age, gender, and disease severity are important factors in consideration of the adequacy of 
359  randomization. Proper randomization of subjects will create balanced groups with respect to 
360  demographic and baseline characteristics.  Enrollment of a diverse population may allow for 
361  detection of racial, gender, or age differences in response to treatment.  For further information 
362  on this topic, refer to section VI.C of this document as well as the following guidance 
363  documents:6  
364   
365    Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs 
366    Study of Drugs Likely to be Used in the Elderly  
367    ICH E11 Clinical Investigation of Medicinal Products in the Pediatric Population  
                                                 
6Available on the Internet at htttp://www.fda.gov/cder/guidance/index.htm.  
 
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368    ICH E-7 Studies in Support of Special Populations: Geriatric 
369     
370  In the case of an important potential confounder, such as baseline gingivitis or smoking, it may 
371  be prudent to stratify the groups by this factor before randomization.  In some cases, adjustments 
372  for baseline characteristics may be accomplished statistically after the trial, to correct for 
373  differences.  If that is anticipated, characteristics should be prespecified in the statistical plan.  
374  For multicenter trials, randomization of subjects within each center will help to ensure that none 
375  of the centers is unbalanced in its assignment of subjects to groups.  More detailed information 
376  on randomization can be found in the ICH guidances, E9 Statistical Principles for Clinical Trials 
377  and E10 Choice of Control Group and Related Issues in Clinical Trials.7 
378   
379  C.  Blinding 
380   
381  We recommend a double-blinded trial design whenever possible.  Should blinding be 
382  compromised, the resultant bias may potentially invalidate the results.  In the case of a topical 
383  product, differences in packaging or discernable characteristics, such as appearance (including 
384  viscosity, color, and opacity), smell, taste, or texture, may compromise blinding. 
385   
386  D.  Length of Trial 
387  Trial length may affect the demonstration of both safety and efficacy.  In terms of efficacy, 
388  sponsors should allow sufficient time to demonstrate a significant effect, should it exist, and in 
389  the case of a chronic-use product, to demonstrate that the effect is not transient.  A description of 
390  what constitutes a significant effect is discussed in detail in section VIII of this document. Data 
391  from Phase 2 dose-ranging studies can guide sponsors in determination of trial length.  The 
392  review division generally recommends studies of 6 months duration or longer.  In addition, 6 
393  months is the typical interval between routine dental visits and therefore corresponds to clinical 
394  practice.  In terms of safety, the ICH guidance, E1A The Extent of Population Exposure Required 
395  to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening 
396  Conditions (ICH-E1A),8 suggests the number of subjects that should be exposed to the drug for 6 
397  months or longer to adequately detect uncommon adverse events.  OTC drugs may call for 
398  additional safety testing because of their wider use and lack of professional oversight. 
399   
400  E.  Standard of Care 
401   
402  During a chronic study (6 months or longer), subjects should receive the standard of care for 
403  gingivitis.  This care consists of regular brushing and use of dental floss between professional 
404  dental visits to maintain oral health and reduce the incidence and severity of gingivitis.  Subjects 
405  should be instructed to continue these measures throughout the trial.  As would be typical of a 
406  dental visit, hygiene instruction should be provided at the baseline visit.  In addition, unless the 
                                                 
7 Available on the Internet at http://www.fda.gov/cder/guidance/index.htm. 
8 Available on the Internet at http://www.fda.gov/cder/guidance/index.htm. 
 
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407  trial is specifically designed to measure gingivitis reduction in individuals who do not receive 
408  regular dental care, a professional scaling and prophylaxis should be performed at baseline. 
409   
410  F.  Placebo or Active Control Formulation 
411  To produce valid conclusions about the results of a clinical trial, we prefer that the trial be 
412  designed so that the test and placebo (or active control) groups differ only in the presence or 
413  absence of the active ingredient or ingredients.  Differences in inactive ingredients, such as 
414  abrasives, sweeteners, and even dyes (which may have antimicrobial properties), may confound 
415  the data. 
416   
417  G.  Use of a No-treatment Group 
418  Use of a no-treatment arm in addition to the placebo and the test product groups allows for not 
419  only comparing the gingivitis effects between the test product and placebo, but also for 
420  examining any therapeutic effect of the vehicle.  Subjects in this no-treatment arm would be 
421  instructed only to maintain their normal home oral hygiene regimen.  This study is ethical only 
422  for study of gingivitis that is not severe or gingivitis not accompanied by periodontitis.  For 
423  further discussion on ethical concerns, refer to subsection III.F of this document. 
424     
425  VI.  CONSIDERATIONS FOR SUBJECT RECRUITMENT 
426    
427  A.  Sample Size 
428   
429  This subsection gives a brief discussion of some points the sponsor should consider regarding 
430  sample size.  For further discussion on sample size, refer to the ICH guidance, E9 Statistical 
431  Principles for Clinical Trials (ICH-E9).  Note that the power calculations used to choose a 
432  sample size are affected by the duration of the gingivitis trial.  Choosing a time period shorter 
433  than the recommended 6 months allows less time for a significant difference between the 
434  treatment and nontreatment groups to develop and may call for a larger sample size.  Also, note 
435  that ICH-E9 focuses on the sample size a sponsor would choose to demonstrate efficacy.  As 
436  discussed in section IX of this document, the number of subjects that adequately demonstrate 
437  safety may be greater than the number that would demonstrate efficacy. 
438   
439  B.  Inclusion and Exclusion Criteria 
440   
441  Carefully chosen inclusion and exclusion criteria will allow for enrollment of the appropriate 
442  population to test the product for the target group.  Of special consideration is the degree of 
443  gingivitis appropriate for enrollment, which will depend on the intended claim for the drug 
444  product and whether it would be marketed by prescription or OTC.  A product intended to be 
445  marketed only with a prescription from a dentist would be appropriate for a population with 
446  gingivitis of a severity that would warrant a dentists intervention. Testing for that product would 
447  focus on enrollment of subjects with this same level of severity.  A product intended to be 
448  marketed OTC would be labeled for patients with a lower level of severity that may range from 
 
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449  very mild to moderate disease.  We recommend that a product intended to be marketed OTC be 
450  studied in a population which includes a full range of gingivitis within the indication for 
451  nonprescription users to reflect the population that will ultimately use the product. 
452   
453  Another consideration in OTC drug testing is the influence of confounding factors such as 
454  pregnancy, diabetes, smoking, and presence of orthodontic brackets or removable prosthetic 
455  appliances.  Many sponsors prefer to exclude individuals with these conditions to eliminate the 
456  difficulty of recording accurate measurements on them and the confounding effect of their 
457  conditions on gingivitis.  Excluding these individuals in a trial for an OTC product is 
458  discouraged because those individuals will have access to the product in the marketplace, and the 
459  study population should reflect the population that will ultimately use the product.  There is 
460  somewhat more flexibility in the trial of a drug that will be limited by prescription status, as the 
461  prescription label can convey information to the health professional, who can then make a 
462  decision about prescribing.  Even in studies for prescription products, a rationale should be 
463  provided for excluding some patients (e.g., known lack of efficacy, safety issues, and ethical 
464  issues). 
465   
466  1.  Recommended Inclusion Criteria 
467   
468  Basic conditions that are common to all gingivitis trials would include recruitment of subjects 
469  who are in good general health and who have the ability to provide written informed consent.  
470  Below are examples of possible inclusion criteria for gingivitis trials: 
471   
472    a specified minimum number of teeth present 
473    a qualifying baseline plaque index 
474    a qualifying baseline gingival index (GI) 
475    presence of bleeding site or sites upon probing 
476   
477   The plaque and gingival indices are discussed in section VII of this document. 
478   
479      2.  Recommended Exclusion Criteria 
480   
481  General exclusion criteria for clinical trials can include known hypersensitivity to any 
482  component of the test product or a closely related product, concomitant participation in any other 
483  clinical study, or a positive urine test for drugs of abuse.  Because residence in the same 
484  household as a subject already enrolled in the study may create blinding and compliance issues, 
485  this also may warrant exclusion from the trial. 
486   
487  For typical gingivitis trials, we do not recommend exclusion of subjects based on age, race, or 
488  gender.  Representation of special populations is expected (see section VI.C of this document 
489  entitled Special Populations).  There may be cases where pregnant subjects would be excluded 
490  because of safety considerations or concerns about the confounding effect of pregnancy on 
491  gingivitis; however, we discourage automatic exclusion because of pregnancy.  Other exclusions 
492  would depend on the drug product (e.g., gastrointestinal bleeding for an antigingivitis drug that is 
 
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493  a nonsteroidal anti-inflammatory).  As was discussed earlier in this section of the document, 
494  trials for OTC products might have fewer exclusion criteria because it is important that the 
495  products be tested in a wider range of subjects.  Below are examples of typical exclusion criteria 
496  for gingivitis trials: 
497   
498    Gross oral pathology, including widespread caries or chronic neglect, extensive 
499  restoration, pre-existing gross plaque or calculus, or soft or hard tissue tumor of the 
500  oral cavity. 
501   
502    Chronic disease with concomitant oral manifestations. 
503   
504    Medical conditions or significant laboratory abnormalities that the investigator 
505  considers significant and that may compromise the subject's safety. 
506   
507    Medical conditions that may affect the evaluability of the study results, such as 
508  clinically significant organic disease, including heart murmur, history of rheumatic 
509  fever, or valvular disease. 
510   
511    Treatment with antibiotics within the 1-month period before the screening 
512  examination, or having a condition that is likely to call for antibiotic treatment over 
513  the course of the trial.  This list includes cardiac conditions requiring antibiotic 
514  prophylaxis, such as heart murmurs, pacemakers, or prosthetic heart valves, as well as 
515  non-oral prosthetic implants. 
516   
517    Orthodontic appliances or removable partial dentures. 
518   
519    Periodontitis as indicated by clinical attachment loss, radiographic alveolar bone loss, 
520  or periodontal pockets greater than 5 millimeters. 
521   
522    Concomitant pharmacotherapy with drugs that may interact with test drug. 
523   
524    Chronic treatment (2 weeks or more) with any medication known to affect 
525  periodontal status (including phenytoin, calcium antagonists, cyclosporin, coumarin, 
526  nonsteroidal anti-inflammatory drugs, and aspirin) within 1 month of the screening 
527  examination.  All other medications for chronic medical conditions have been 
528  initiated at least 3 months before enrollment. 
529   
530    History of early-onset periodontitis or acute necrotizing ulcerative gingivitis. 
531   
532    Concomitant endodontic or periodontal therapy other than prophylaxis in the last 6 
533  months. 
 
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534   
535  C.  Special Populations 
536   
537  It is important to examine the effects of gender, race, and age in the clinical trials by enrolling 
538  sufficient numbers of subjects with a diverse demographic background.  Although there is no 
539  evidence to demonstrate that individuals of certain races are predisposed to gingivitis, factors 
540  such as access to health care, nutritional status, and socioeconomic status may be confounding 
541  factors that affect the validity of results obtained through uneven distribution.  Age and gender 
542  may affect gingivitis both physiologically and psychosocially.  For example, frequency of 
543  professional visits is greater in adult women than men, and oral hygiene habits are highly 
544  inconsistent in children and adolescents.  In addition, during puberty and pregnancy, hormone-
545  associated gingivitis becomes a confounder.  Furthermore  depending on the proposed therapy 
546   drug absorption, distribution, metabolism, and excretion may be different in different races or 
547  between men and women, or between children and adults. 
548   
549  Smoking and diabetes are both significant risk factors for gingivitis, and it is important that they 
550  be considered in the clinical trial design.  Excluding subjects with these conditions in Phase 3 
551  studies based on lack of efficacy in these groups in Phase 2 is a possibility.  The labeling may 
552  then reflect that these groups were not studied in Phase 3 after negative results in Phase 2.  
553  Stratifying by these factors is preferred because this allows study of these groups but protects 
554  against bias.  Another possibility is to include all subjects but enroll a sufficient number so that 
555  they can be analyzed separately.  If smokers and diabetics respond more slowly or to a lesser 
556  extent than others in the trial, this would be valuable clinical information for labeling. 
557   
558  D.  Pediatric Populations 
559  Gingivitis can be found in all age groups. In a comprehensive 1989 national survey conducted by 
560  the National Institute of Dental and Craniofacial Research, 47 percent of adult males and 39 
561  percent of females exhibited at least one gingivitis site as demonstrated by bleeding on probing.  
562  Like adults, children are susceptible to plaque-induced gingivitis. The prevalence of gingivitis 
563  among school-aged children in the United States has ranged from 40 to 60 percent in national 
564  surveys.  Adolescents have the highest prevalence and greatest severity of gingivitis of any age 
565  group. 
566   
567  Conducting clinical trials in children is challenging.  Nonetheless,  201.57(f)(9) (21 CFR 
568  201.57(f)(9)) charges the sponsor with the provision of safety and efficacy information on 
569  children before drug approval.  The pediatric plan can be tailored to the individual drug in 
570  question.  If safety and/or efficacy in children cannot be extrapolated from studies in adults, it 
571  should be specifically demonstrated through enrollment of children in the same trials as adults or 
572  by conducting separate trials in children. 
573   
574  E.  Geriatric Populations 
575   
 
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576  A Geriatric Use section in labeling has been a requirement for approval since August 27, 1997 
577  (21 CFR 201.57(10)(ii)).  Gingivitis affects individuals older than age 65 in significant numbers, 
578  and these individuals may respond differently to the drug product than younger adults.  We 
579  encourage sponsors to (1) study a sufficient number of geriatric subjects to uncover any age-
580  related differences in safety or efficacy, and (2) describe these differences in the drug labeling.  
581  For further information, including recommended labeling language, refer to  201.57(f)(10) 
582  entitled Geriatrics Use. 
583    
584  VII.  ASSESSMENT OF GINGIVITIS 
585  We recommend that primary and secondary endpoints be clearly identified before initiation of 
586  the trial and prospectively described in the protocol, along with the statistical analysis 
587  methodology.  The most common primary endpoint is a change in the gingival index (GI), which 
588  is a categorical scale to which values are assigned for degrees of gingivitis.  Since the most 
589  common form of gingivitis is plaque-induced, a co-primary endpoint for most antigingivitis 
590  drugs is plaque index (PI) reduction.  A common secondary outcome variable is the bleeding 
591  index.  These indexes are discussed in greater detail later in this section of the document, and the 
592  condition under which a PI can be used as a secondary endpoint is discussed in section VIII of 
593  this document. 
594   
595  A.  Calibrating Investigator Skills 
596   
597  Proper staff training helps to ensure consistency in recording of data and use of instruments.  
598  Reducing examiner variability is beneficial, as a decrease in measurement error can reduce the 
599  sample size that would be appropriate for a clinical trial.  To the greatest extent possible, we 
600  suggest that examiner skills be calibrated to consistently perform reliable and accurate readings.  
601  As most trials employ several examiners, inter-observer variability may be an issue.  With proper 
602  randomization and blinding, individuals in the test group and those in the placebo group will be 
603  fairly evenly divided between examiners. Scheduling a reasonable number of examinations per 
604  session with adequate rest periods will help maintain examiner efficiency.  It has been noted in 
605  clinical trials that examiners trained at the beginning of an investigation adopt this new training 
606  initially but revert to their original methods by the end of the trial.  Therefore, we recommend 
607  that training programs use reinforcement lessons throughout the duration of the study. 
608   
609  B.  Gingival Index  
610   
611  Several gingival indexes have been used over the years.  One gingival index that was developed 
612  in 1963 and is widely used today is the Loe and Silness Gingival Index.  This index has proved 
613  useful in controlled clinical trials because it (1) is fairly sensitive to small changes, (2) is simple 
614  to administer, and (3) permits calibration of the examiners to minimize inter- and intra-examiner 
615  error. In this index, the gingival tissues surrounding each selected tooth are divided into four 
616  areas for scoring: distofacial papilla, facial margin, mesiofacial papilla, and the entire lingual 
617  margin.  Each of these units is scored for gingivitis according to criteria that categorize each 
618  surface as 0 for normal gingiva, 1 for mild inflammation, 2 for moderate inflammation, or 3 for 
 
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619  severe inflammation.  Literature is available that describes the details of this index, including 
620  those characteristics that accompany each score.  The scores from the four gingival units are 
621  averaged to obtain a score for each tooth, and these scores are combined and averaged to 
622  determine a score for each individual.  The index is sometimes scored on the entire dentition; 
623  literature is also available that supports using certain index teeth that are representative of the 
624  entire dentition.  In this index, a periodontal probe is used to determine the bleeding tendency of 
625  the tissues.  It is important that standardized pressure be exerted during the probing.  Automated 
626  periodontal probes may improve the accuracy and precision of probing depth measurements.   
627   
628  C.  Plaque Index 
629   
630  When plaque accumulates along the tooth surface, the gingiva responds to the bacterial insult 
631  with varying degrees of redness, edema, and bleeding.  Regular removal of plaque through good 
632  oral hygiene maintains healthy gingiva and reduces the incidence of associated gingivitis.   
633   
634  It is the Agencys current thinking that antigingivitis drugs using a mechanism other than plaque 
635  reduction, such as anti-inflammation, could be approved as prescription drugs.  However, 
636  without adequate professional oversight, chronic use of an anti-inflammatory drug that does not 
637  concomitantly reduce plaque has the potential to mask underlying infection.  Therefore, 
638  antigingivitis drugs intended for OTC use would assign PI outcome as a co-primary, rather than a 
639  secondary, endpoint.  This subject is discussed further in section VIII of this document. 
640   
641  Most trials employ a method of supragingival, rather than subgingival, plaque measurement 
642  because of the difficulties in accurately observing subgingival plaque.  The Turesky modification 
643  of the Quigley and Hein Plaque Index has received considerable use in measuring plaque 
644  changes during clinical trials.  In this index, plaque is identified using a disclosing solution and 
645  scored using a 0 to 5 scale in which a score of 0 corresponds to no plaque present, and a score of 
646  5 designates plaque covering more than two-thirds of the tooth surface.  Each tooth receives 
647  mesial, middle, and distal scores for both the facial and lingual surfaces.  An individuals score is 
648  derived by adding the scores at each site and dividing by the number of sites evaluated.  The Loe 
649  and Silness Plaque Index is also used in clinical trials.  It employs a scoring scale from 0 to 3 and 
650  evaluates four sites on each tooth. 
651   
652  Sampled plaque is often weighed, either dry or wet.  Note, however, that neither the PI nor 
653  quantification of dry or wet plaque weight correlates strongly with gingivitis.  No single 
654  measurement can relate the various aspects of plaque accumulation, such as surface area of 
655  plaque, mass of the plaque, density of plaque, bacterial composition, and location on the tooth.  
656  The effect of plaque is most likely a combination of all these factors, which have not been 
657  captured in a single index or measurement. 
658   
659  D.  Bleeding on Probing 
660   
661  Bleeding on probing is a cardinal sign of gingivitis.  Some GIs include an assessment of 
662  bleeding.  For those that do not, a categorical evaluation (yes or no) of bleeding on probing can 
 
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663  add valuable information.  Bleeding can be an appropriate secondary outcome variable.  It would 
664  not be sufficient as a stand-alone primary outcome variable. 
665   
666  E.  Calculus Formation 
667   
668  The FDA views calculus reduction as a cosmetic claim rather than a drug indication; cosmetic 
669  claims are not included in prescription labeling. Certain topical dental drugs increase calculus 
670  formation, which is considered an adverse event.  We encourage the sponsor of an antigingivitis 
671  product to include calculus examinations in both the baseline and the end-of-the-study 
672  evaluations.  The labeling for a product that increases calculus formation would reflect this risk. 
673   
674  F.  Staining Index 
675   
676  Improvement of extrinsic staining of teeth, like calculus reduction, is regarded as a cosmetic 
677  claim.  Also, like calculus formulation, some antigingivitis products are known to result in 
678  increased staining on teeth.  Increased staining is an adverse event that should be communicated 
679  to consumers.  For products thought to cause staining, it is important to obtain measurements on 
680  a staining index, at least at baseline and at final examination, and evaluate the data during the 
681  analysis of the study results. 
682   
683  G.  Microbiologic Sampling 
684   
685  Because of the complexity of the microbial community associated with gingivitis and the 
686  difficulty in accurately ascribing causality to specific species, the FDA currently accepts 
687  microbiological data only as descriptive evidence that can be included in the Microbiology 
688  section of product labeling.  Reductions in specific microorganisms in plaque or in the mouth 
689  cannot be a surrogate for treatment of gingivitis.  However, the oral flora should be monitored to 
690  determine whether there is an increase in opportunistic or resistant organisms.   
691   
692  VIII.  CLINICAL AND STATISTICAL SIGNIFICANCE FOR DETERMINING AN 
693  EFFECT 
694   
695  A.  Clinical Significance 
696   
697  As is the case with all new drug products, the data from gingivitis studies should demonstrate 
698  that (1) the outcomes seen are unlikely due to chance (statistical significance), and (2) the 
699  magnitude of the outcomes is such that some therapeutic benefit has been established (clinical 
700  significance).  In the case of gingivitis, improvement in the GI score would be a primary 
701  outcome measure (see the last paragraph in this subsection for a discussion of a meaningful 
702  improvement). To gain approval for an OTC drug claiming antigingivitis activity, the drug 
703  should also successfully demonstrate a significant PI reduction, coupled with the significant GI 
704  improvement. 
705   
 
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706  For those products that treat nonplaque-induced gingivitis, demonstration of reduction in plaque 
707  may not be important.  However, those products should provide convincing evidence that the 
708  underlying disease is not progressing despite abatement of the signs and symptoms.  Those 
709  products probably would not be approved as OTC antigingivitis drugs.  Secondary claims 
710  regarding gingival bleeding can be used in labeling if the outcomes are significant and the claims 
711  are both truthful and relevant.  To avoid the bias that may result from post hoc analysis, the 
712  protocols statistical plan should include the planned analysis of secondary outcome variables. 
713   
714  The Agency concurs with the consensus of the expert dental community regarding 
715  therapeutically significant improvements in plaque-induced gingivitis (see Imrey, PB, NW 
716  Chilton et al., July 1994, Recommended Revisions to American Dental Association Guidelines 
717  for Acceptance of Chemotherapeutic Products for Gingivitis Control, J Periodontal Res, 29(4): 
718  299-304).  Accordingly, FDA recommends that an application demonstrate the following for 
719  approval of an antigingivitis drug product: 
720   
721  1.  The estimated proportionate reductions for the GI measurements should be no less 
722  than 15 percent in favor of the active treatment and statistically significant in each of 
723  at least two studies. 
724   
725  2.  The arithmetic mean of the estimated proportionate reductions for the GI 
726  measurements across the studies, referred to in item #1 above, should be no less than 
727  20 percent. 
728   
729  Proportionate reduction refers to a comparison of the active therapy to the 
730  control at the end of the study, rather than to reductions from an initial 
731  baseline level, and presumes that randomization has produced initially 
732  comparable active and control clinical samples, or that fully-appropriate 
733  statistical adjustment has been used for randomization failures (Imrey and 
734  Chilton et al., 1994).  
735   
736  It is reported as a percentage and defined as: 
737   
738  (mean endpoint GI of control minus mean endpoint GI of active) 
x 100 
739  mean endpoint GI of control. 
740   
741  3.  Plaque reductions should be statistically significant in at least two studies. Because 
742  the exact amount of plaque reduction that is recommended for gingivitis reduction has 
743  not been established, demonstrating a statistically significant difference in plaque 
744  levels between the test group and placebo group through comparison of PI numbers is 
745  usually sufficient. 
746   
747  B.  Statistical Considerations 
748   
749  In this section of the guidance document, some specific statistical considerations for gingivitis 
750  trials will be discussed.  For more detail, as well as general statistical considerations in clinical 
 
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751  trials, refer to the ICH-E9 guidance.  As discussed in the previous section, the primary efficacy 
752  variables for gingivitis trials are the GI and the PI.  Statistical testing for both of these variables 
753  is usually performed with a comparison of means test through analysis of covariance. 
754   
755  In addition to the test of means for the GI, the sponsor can also perform a responder analysis 
756  (i.e., evaluate the GI results as a proportion of subjects or sites that achieve gingival health, as 
757  defined by a predetermined definition).  For example, the number of sites at the end of the trial 
758  that measure 0 or 1 in the test group, compared to the number in the placebo group, is an 
759  outcome measure that can be evaluated.  Since the goal of an antigingivitis product is to maintain 
760  gingival health, this number has a direct clinical significance that is fairly easy to interpret.  If a 
761  test product can achieve 80 percent healthy sites, as compared to a placebo that only achieves 55 
762  percent, the average practitioner may have a better understanding of the ability of the drug to 
763  maintain gingival health than would be apparent from an overall mean reduction in GI scores 
764  from 1.5 to 1.0.  The traditional statistical testing for this outcome measure is a comparison of 
765  proportions of a dichotomous variable in subjects employing the Cochran Mantel Haenszel test.  
766  For comparison of sites, it may be important to conduct more complex testing, such as a repeated 
767  measures approach. 
768   
769  Additional indexes used as secondary outcome variables or to monitor adverse events will follow 
770  the same recommendations.  Staining and calculus indexes are each evaluated as a difference in 
771  means in a similar fashion to the GI and PI, and as such are analyzed with analysis of covariance.  
772  For a site-specific dichotomous variable such as bleeding upon probing, a repeated measures 
773  approach may be appropriate. 
774    
775  If ethical constraints call for use of an active agent (e.g., standard of care) rather than placebo in 
776  the control arm, equivalence or non-inferiority testing can be used to compare the test product to 
777  a known effective gingivitis treatment.  Non-inferiority testing is discussed in section 3.3.2 of 
778  ICH-E9.  Equivalence testing is not based on a nonsignificant test result of the null hypothesis of 
779  two treatment responses being equal.  An equivalence margin (i.e., the largest difference that is 
780  considered to be clinically insignificant) would be chosen.   
781   
782  It is generally preferable to conduct both all-randomized subjects and per protocol analyses to 
783  substantiate the study results.  In superiority studies, the all-randomized subjects analysis is often 
784  more conservative than a per protocol analysis, since the noncompliers will diminish the overall 
785  treatment effect.  In equivalence or non-inferiority trials, the all-randomized analysis is not 
786  conservative and may not be appropriate. 
787   
788  IX.  SAFETY CONSIDERATIONS 
789   
790  Safety concerns for antigingivitis products fall into two main categories: (1) adverse events 
791  associated with the drug, and (2) masking of underlying periodontitis.  Adverse events may be 
792  local events such as oral irritation or systemic events resulting from ingestion or absorption of 
793  drug.  Because periodontitis may occur concurrently with gingivitis, it is important to ascertain 
 
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794  that treatment of the gingivitis does not conceal the more serious periodontitis from either the 
795  patient or the health care provider. 
796   
797  All noxious and unintended responses related to any dose of a medicinal product should be 
798  considered adverse drug reactions (see ICH guidance E2A Clinical Safety Data Management: 
799  Definitions and Standards for Expedited Reporting).9  Refer to ICH-E2A for a precise definition 
800  of terms, such as mild, moderate, or severe, to describe the intensity of a specific event as well as 
801  the medical significance.  Also, ICH-E1A describes the safety database for prescription products.  
802  Because OTC products usually are more widely used than prescription products and are used 
803  without professional supervision, these products may warrant a larger safety database.   
804   
805  We advise sponsors to develop recommendations before initiating a trial, including a policy for 
806  review of adverse events and circumstances under which a trial might be discontinued.  The 
807  sponsor has an obligation to recommend and allow treatment under certain circumstances and to 
808  make provisions for emergency treatment or withdrawal from the study in the event of serious 
809  adverse reactions.  In some cases, it may be appropriate to continue the subject in the trial but to 
810  modify the dosage.  In the case of patient death or serious adverse events, the sponsor has 
811  specific reporting requirements, which are outlined in 21 CFR 312.32. 
812   
813  Since drugs are readily absorbed through the oral mucosa, the investigator should address 
814  pharmacokinetic monitoring of the drugs absorption, distribution, metabolism, and excretion at 
815  baseline and the end of the trial.  It may also be advisable to consider routine laboratory 
816  screenings such as complete blood count, and measures of hepatic and renal function. 
817   
818  Examples of specific local adverse events associated with antigingivitis products include 
819  mucosal irritation, staining of teeth, and excessive calculus formation.  Conduct of a thorough 
820  intraoral examination is desirable, beginning early in the trial to identify drug-related irritation as 
821  soon as it develops.  Staining can be measured with a staining index, such as the Lobene Index 
822  done visually, or instrument-assisted colorimetric recording.  Likewise, calculus can be recorded 
823  with one of several indexes.  In addition, baseline and end-of-study measurement of attachment 
824  level is worthwhile in assessing whether the product has a potential to adversely affect 
825  attachment. 
826   
827  X.  CONCLUDING COMMENTS 
828  This guidance is not meant to be a substitute for meetings between the Agency and the drug 
829  sponsor, which are tailored to discuss a specific drug product and its precise indication. We 
830  strongly encourage the drug sponsor to take advantage of pre-investigational new drug meetings, 
831  general guidance meetings, and, particularly, end-of-phase-2 meetings before proceeding with 
832  essential clinical trials.  Sponsors also can request special protocol assessments after an end-of-
833  phase-2 meeting, which may clarify regulatory issues that were discussed during that meeting.  
                                                 
9 Available on the Internet at http://www.fda.gov/cder/guidance/index.htm. 
 
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834  As regulatory interpretation and drug development are dynamic processes and every drug 
835  product may have unique attributes, important issues may arise that have not been addressed in 
836  this document.  The procedure for scheduling and preparing for a meeting with the Agency can 
837  be found in the CDER guidance document entitled Formal Meeting with Sponsors and 
838  Applicants for PDUFA Products.10  Meeting requests and requests for procedural clarification 
839  should be directed to the Supervisory Project Manager in the Division of Dermatologic and 
840  Dental Drug Products. 
                                                 
10 Available on the Internet at htttp://www.fda.gov/cder/guidance/index.htm. 
 
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