Guidance for Industry

Gingivitis: Development and Evaluation of Drugs for Treatment or
Prevention

#### DRAFT GUIDANCE

**This guidance document is being distributed for comment purposes
onl*y.***

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notice announcing the availability of the draft guidance.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 Registe*r.

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**

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**

Table of Contents

[**I.** **INTRODUCTION 1**](#i.-introduction)

[II. BACKGROUND 2](#ii.-background)

[A. Definition of Gingivitis 2](#definition-of-gingivitis)

[B. Antigingivitis Rulemaking 2](#antigingivitis-rulemaking)

[III. GENERAL CONSIDERATIONS 3](#iii.-general-considerations)

[A. Prescription vs. Over-The-Counter Status of the Drug
3](#a.-prescription-vs.-over-the-counter-status-of-the-drug)

[B. Prevention vs. Treatment Claim 3](#prevention-vs.-treatment-claim)

[C. Mechanism of Action 4](#mechanism-of-action)

[D. Dose-Response Relationship 4](#d.-dose-response-relationship)

[E. Combination Products 4](#e.-combination-products)

[F. Ethical Considerations of Conducting a Gingivitis Trial
4](#f.-ethical-considerations-of-conducting-a-gingivitis-trial)

[IV. NONCLINICAL CONSIDERATIONS 5](#nonclinical-considerations)

[V. CLINICAL PROTOCOL ISSUES AND ELEMENTS
9](#v.-clinical-protocol-issues-and-elements)

[A. Study Design 9](#a.-study-design)

[B. Randomization 9](#b.-randomization)

[C. Blinding 10](#c.-blinding)

[D. Length of Trial 10](#d.-length-of-trial)

[E. Standard of Care 10](#standard-of-care)

[F. Placebo or Active Control Formulation
11](#f.-placebo-or-active-control-formulation)

[G. Use of a No-treatment Group 11](#g.-use-of-a-no-treatment-group)

[VI. CONSIDERATIONS FOR SUBJECT RECRUITMENT
11](#vi.-considerations-for-subject-recruitment)

[A. Sample Size 11](#a.-sample-size)

[B. Inclusion and Exclusion Criteria
11](#inclusion-and-exclusion-criteria)

[C. Special Populations 14](#special-populations)

[D. Pediatric Populations 14](#d.-pediatric-populations)

[E. Geriatric Populations 14](#e.-geriatric-populations)

[VII. ASSESSMENT OF GINGIVITIS 15](#vii.-assessment-of-gingivitis)

[A. Calibrating Investigator Skills
15](#a.-calibrating-investigator-skills)

[B. Gingival Index 15](#gingival-index)

[C. Plaque Index 16](#c.-plaque-index)

[D. Bleeding on Probing 16](#d.-bleeding-on-probing)

[E. Calculus Formation 17](#e.-calculus-formation)

[F. Staining Index 17](#f.-staining-index)

[G. Microbiologic Sampling 17](#g.-microbiologic-sampling)

[VIII. CLINICAL AND STATISTICAL SIGNIFICANCE FOR DETERMINING AN EFFECT
17](#viii.-clinical-and-statistical-significance-for-determining-an-effect)

[A. Clinical Significance 17](#clinical-significance)

[B. Statistical Considerations 18](#statistical-considerations)

[IX. SAFETY CONSIDERATIONS 19](#safety-considerations)

[X. CONCLUDING COMMENTS 20](#x.-concluding-comments)

####### Guidance for Industry[^1]

Gingivitis: Development and Evaluation of Drugs for Treatment

or Prevention

This draft guidance, when finalized, will represent the Food and Drug
Administration\'s (FDA\'s) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternative approach, contact the
FDA staff responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number listed
on the title page of this guidance.

# I. INTRODUCTION

This guidance is intended to assist sponsors of new drug applications
(NDAs) with the development of drug products that treat or help prevent
gingivitis in adults and children. This document defines gingivitis and
clarifies the distinction between gingivitis and periodontitis. It
discusses general issues such as over-the-counter (OTC) versus
prescription status and prevention versus treatment. The bulk of this
guidance focuses on trial design issues and clinical assessments. The
document concludes with an examination of product safety determinations.

This document does not contain discussion of the general issues of
clinical trial design or statistical analysis. Those topics are
addressed in the ICH guidance documents, *E8* *General Considerations
for Clinical Trials* and *E9* *Statistical Principles for Clinical
Trials* (ICH-E9).[^2] This guidance focuses on specific trial design
issues that are unique to the study of gingivitis.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. BACKGROUND

## **Definition of Gingivitis**

Gingivitis is an inflammation of the soft tissue of the oral cavity that
immediately surrounds each individual tooth. This soft tissue, known as
the gingiva, consists of epithelial and connective tissues, which
support the teeth in the bone of the mandible or maxilla. The other
supporting structure that anchors the teeth is the periodontium, which
consists of connective tissue attachments and alveolar bone. Whereas
gingivitis is an inflammation confined to the gingival tissue,
periodontitis affects the ligaments and alveolar bone that support the
root of the tooth and provide its anchorage to the maxilla or mandible.

This guidance focuses on plaque-induced gingivitis, as it is the most
common form of gingivitis and responds well to oral hygiene and
antimicrobial products. Dental plaque is the aggregation of soft
deposits that form the biofilm adhering to the teeth or other hard
surfaces in the oral cavity, such as removable and fixed restorations.
In addition to plaque, other causes of gingivitis include viral, fungal,
or bacterial infection; endogenous sex steroid hormones; medication;
systemic diseases; and malnutrition. Sponsors interested in developing
products for gingivitis of nonplaque etiology can consult the Division
of Dermatologic and Dental Drug Products for advice that is specific to
that unique indication. In this guidance, the term *gingivitis* refers
specifically to plaque-induced gingival disease unless otherwise noted.

## **Antigingivitis Rulemaking**

During the past several decades, many products have entered the
marketplace as OTC products that purport to treat or prevent gingivitis.
As a result of the proliferation and promotion of those products, FDA
convened a subcommittee of the Dental Products Panel (Subcommittee) in
1993 to evaluate OTC products that make gingivitis claims and that were
in the marketplace without an NDA. The panel reviewed the data submitted
for the antigingivitis products and reported its findings on the safety
and effectiveness of OTC ingredients for the reduction or prevention of
gingivitis.

On May 29, 2003, the Subcommittee's final report was published in the
*Federal Register* (68 FR 32232) as an advance notice of proposed
rulemaking (ANPRM). The ANPRM established conditions under which OTC
drug products for the reduction or prevention of dental plaque and
gingivitis would be generally recognized as safe and effective and not
misbranded.

FDA is publishing this guidance document on the development of
antigingivitis drug products to aid drug sponsors in conducting clinical
trials either to submit additional information to the antigingivitis
rulemaking, or to obtain approval for a new antigingivitis drug through
the NDA process.

# III. GENERAL CONSIDERATIONS

## **A. Prescription vs. Over-The-Counter Status of the Drug**

One early consideration in drug development is whether the drug product
is to be marketed as a prescription medication (including drugs
available only to practitioners) or as an over-the-counter (OTC)
preparation. An expert panel convened by FDA in 1991 determined that the
general public is able to recognize and self-treat gingivitis. Drugs
that the public can use appropriately in the absence of supervision by a
physician, dentist, or other health care practitioner are marketed
OTC.[^3] OTC status is not appropriate for antigingivitis products that
call for supervised use.

Unlike a prescription drug label, an OTC label should contain
indications, directions for use, and warnings that are understood by the
general public. Comprehension studies can demonstrate that consumers
will be able to understand and follow labeled directions and warnings.
Sponsors of OTC products should demonstrate that consumers can use these
products safely since there will be no health professional monitoring
for adverse events or symptoms of more serious conditions, such as
periodontitis. Safety considerations for both prescription and OTC
antigingivitis drugs will be discussed in detail in section IX of this
document.

## **Prevention vs. Treatment Claim**

Another consideration is whether the therapy is intended to prevent or
to treat gingivitis. Many studies begin with subjects receiving a
professional scaling and polishing that alone may restore gingival
health. The endpoint then may be the reappearance of gingivitis after a
set period of time. If the test group develops significantly less
gingivitis than the placebo group in appropriately designed studies, it
is reasonable to conclude that the drug has reduced the incidence of
gingivitis. In the case of a chronic disease such as gingivitis,
*prevention* is more explicitly stated as "reduces the incidence of
disease" or "reduces the incidence of severe disease." Wording that
conveys this message would vary, depending on whether the product is
intended for prescription or OTC use. Wording for a prescription product
could include scientific language such as "reduction of disease
incidence." To convey this message on a level more appropriate for
consumers of nonprescription drugs, the Subcommittee has recommended
that OTC products carry the language "helps prevent gingivitis."

Subjects who already have measurable gingivitis before treatment may
experience a significant reduction in the mean gingivitis score or in
the number of gingivitis sites in the test group compared to placebo
group (scoring systems are described in section VII of this document).
This reduction would allow for a claim of "reduces the severity of
gingivitis" or some other treatment claim as appropriate for
prescription or OTC status.

## **Mechanism of Action**

Understanding a drug's mechanism of action is desirable but not required
for FDA approval for marketing. There is a safety concern in treating
gingivitis without removing one well-established causal factor, plaque
accumulation. Therefore, if the mechanism of action of the sponsor's
drug were other than plaque reduction (e.g., anti-inflammatory), the
sponsor would be asked to address the issue of masking underlying
periodontitis before approval. Further discussion on this topic can be
found in sections VII and IX of this document.

## **D. Dose-Response Relationship**

We strongly encourage the sponsor to explore the dose-response
relationship early in product development. It is always desirable to
identify the lowest effective dose for a drug. In the case of topical
antigingivitis products, not only should the lowest concentration of the
drug be identified, but also both the lowest effective frequency of
dosing and the shortest duration of therapy. As gingivitis is not a
life-threatening disease and other treatments for gingivitis are
available, an unfavorable adverse events profile for a new
antigingivitis drug could jeopardize approval, depending on the severity
and seriousness of the events. A lower dose of the drug might be
effective and provide an appropriate safety profile.

## **E. Combination Products**

Two or more drugs can be combined into a single dosage form when each
component makes a contribution to the claimed effect or effects (21 CFR
300.50 and 330.10(a)(4)(iv)). To demonstrate the contribution of each
component, we recommend that the combination product be shown to have a
greater effect than either component separately in the same vehicle, if
the product is for topical use. For example, if two antimicrobials are
combined into one topical drug product for the treatment of gingivitis,
the following arms should be included in the efficacy studies: vehicle,
antibiotic A only in vehicle, antibiotic B only in vehicle, antibiotics
A and B combined. To successfully demonstrate the efficacy of A and B
together, the A+B arm should be significantly better at gingivitis
reduction than both A alone and B alone.

## **F. Ethical Considerations of Conducting a Gingivitis Trial**

It is important that study subjects not be exposed to permanent
detrimental health outcomes as a result of their participation in a
clinical trial, and that subjects understand the risks and benefits
involved in their participation. As long as the group receiving the
vehicle also receives standard oral care, there is no ethical concern
because gingivitis is reversible. Gingivitis trials often begin with a
professional oral hygiene appointment, which will benefit subjects in
both the vehicle and test groups.

An example of a clinical trial with a potential ethical concern is a
study of individuals with either severe gingivitis or gingivitis in
conjunction with periodontitis. In these cases, a delay in treatment may
cause irreversible damage. To avoid this possibility, the sponsor may
wish to employ an active control and test for equivalence or
non-inferiority to the active control. Rather than statistical testing
for superiority to a placebo, confidence interval testing for
equivalence would be used. Refer to ICH-E9 for a discussion of the
statistical considerations of this trial design. Also refer to
subsection VIII.B of this document.

In the past, experimental gingivitis models have been used to accelerate
the development of gingivitis to shorten the trial. Although this may be
valuable during early phases of drug development to determine if the
test product has the potential to be effective, the ethics of this
approach raise concern. We recommend that sponsors carefully consider
factors such as the health of the subjects, duration of the proposed
trial, and possibility of irreversible damage. Also, these experimental
gingivitis studies do not represent the natural history of gingivitis
and may produce misleading results.

# NONCLINICAL CONSIDERATIONS

This section of the document concerns nonclinical development issues
related to products that are intended for administration within the oral
cavity for the treatment or prevention of gingivitis. These comments are
intended to supplement the applicable FDA guidance documents that
pertain to nonclinical development and should be considered within the
context of those documents.

The safety assessment of antigingivitis products should include
consideration of the potential to cause both local (inside the mouth or
gastrointestinal tract) and systemic toxicity. Even if the product is
not intended to be swallowed, the sponsor should assume that a portion
of each dose will be swallowed, and many compounds are absorbed buccally
or sublingually. Evaluation of the systemic toxicology of compounds that
are proposed for the treatment or prevention of gingivitis should follow
the same precepts that apply to development of the nonclinical safety
database associated with most other systemically administered compounds.
The ICH guidance, *M3 Nonclinical Safety Studies for the Conduct of
Human Clinical Trials for Pharmaceuticals*,[^4] provides an overview of
the general types of nonclinical data that may be important to support
various stages of clinical development and marketing of drug products.
It also gives information about the recommended durations of the
exposures of the animals to the test materials and the time at which
certain nonclinical data should be available relative to clinical
development. For details concerning general toxicological issues, refer
to the appropriate CDER guidance documents.[^5]

Systemic toxicity issues that concern these products are usually best
assessed through toxicology studies of appropriate duration and design
in which the drug substance (not necessarily the drug product) is
administered orally (usually by gavage, but in some instances in the
diet or drinking water). The studies should include thorough clinical
pathology (i.e., clinical chemistry, hematology, and urinalysis),
histopathological examination of a full range of tissues, and
toxicokinetic analysis. The gastrointestinal tract is an area of
particular concern since it may be exposed to the materials in
relatively undiluted form. Toxicokinetic data from these studies should
be compared to pharmacokinetic data obtained in suitable clinical
studies conducted with the drug product to ensure that systemic exposure
in the nonclinical studies was adequate to qualify the clinical
exposure. If acute studies are performed, we recommend that the studies
include animals that are sacrificed at an early time point (e.g., 24
hours post-treatment), since mucosal lesions heal rapidly. Development
of sustained-release products should include studies in which the intact
product is administered by gavage to a suitable species, with emphasis
on determining whether or not the product causes erosions or ulcers.

For products that are intended for direct administration within the
mouth, such as mouthwashes, dentifrices, and intraoral sustained-release
products, we recommend that sponsors consider the products' potential to
induce irritation or erosion of the oral tissues. The most appropriate
means of addressing this issue depends on the circumstances associated
with a particular product and clinical proposal; data from an oral
irritation study conducted in animals may be unnecessary. For example,
if a product is very similar to a formulation that has been studied
previously (in animals or humans) without excessive local irritation,
then additional oral irritation data may not be warranted. Another
factor that should be considered when assessing the importance of oral
irritation data in support of a given clinical proposal is the design of
the proposed clinical study. That is, what steps would be taken to
detect oral irritation at an early stage, and what measures would be
taken if irritation is observed? For example, the clinical protocol may
call for a qualified individual to examine the oral cavity at
appropriate time points (e.g., following 1, 3, 7, and 14 days of
treatment), with termination of dosing if signs of irritation are
evident. In this instance, carefully collected data from patients makes
an oral irritation study in animals less relevant, compared to a trial
with less frequent or less comprehensive oral examinations. These
matters should be considered on a case-by-case basis, and the review
division can be contacted for specific guidance.

If it is deemed important to evaluate a product for potential to induce
oral irritation in an animal model, then we suggest that the following
points be considered during the design of an oral irritation study:

-   **Test material.** The material that is tested should be the same
    formulation (including inactive ingredients) that is proposed for
    use in humans. Sponsors should recognize that inactive ingredients
    (e.g., alcohol, flavoring agents, surfactants) in drug products are
    often irritating to the oral tissues.

-   **Animals.** Rats or hamsters are generally used, although other
    species, such as dogs, may be appropriate in certain instances. It
    is recommended that animals of both genders be studied.

-   **Abrasion of the mucosa.** One of the goals of an oral irritation
    study should be to assess the product for potential to delay healing
    of lesions within the oral cavity. This goal can be accomplished by
    comparing the rates at which mechanically induced oral lesions heal
    in treated and control animals. Therefore, a portion of the oral
    mucosa of each animal should be abraded shortly before the first
    application of the test and control materials. The buccal mucosa
    should be abraded on only one side of the mouth, permitting
    examination of both intact and abraded mucosa in each animal.
    Abrasion can be accomplished with a variety of instruments (e.g.,
    file, brush, needle). It is important that the location, size, and
    depth of the abrasions be as uniform as possible within a study. The
    abrasion should be sufficiently severe that a lesion extending into
    the sub-epithelial connective tissue is observable in tissue
    sections from animals sacrificed 24 (or more) hours after treatment.
    Ideally, the abrasion procedure, including the time course of the
    healing process, should be histologically characterized before
    initiation of a definitive oral irritation study.

-   **Method of application.** The test material should be applied to
    the oral tissues in a manner that is reproducible in terms of (1)
    the quantity of test material that is applied to the oral
    cavity, (2) the oral tissues to which the test material is directly
    applied, and (3) the amount of application-induced abrasion of the
    oral tissues. The duration and pattern of each application should be
    consistent. The test material is usually applied with a cotton swab.
    In general, the animals should not be anesthetized during treatment,
    since many anesthetics impair salivation. Placement of the test
    material within the cheek pouch of a hamster is not particularly
    recommended, because the amount of time that the test material is
    retained within the pouch may vary substantially among animals (or
    between control and active materials). An exception to this
    statement pertains to situations in which a solid dosage form (e.g.,
    an osmotic tablet) should be retained in the mouth for a substantial
    period, in which case it may be appropriate to place the test
    material in the cheek pouch of an anesthetized hamster and suture
    the pouch partially closed to prevent expulsion.

-   **Dosage level.** A dosage of 1 milliliter or 1 gram of test or
    control material per kilogram of body weight per application is
    generally used, although different dosage volumes may be deemed
    appropriate on the basis of toxicity or the clinical dosage. If it
    is considered important to examine the effect of a range of exposure
    levels (i.e., evaluate the dose-response relationship associated
    with irritation of the oral tissues), the intensity or magnitude of
    the daily exposure to the test materials should be regulated through
    modulation of the dosing frequency. For example, a study might
    include a group of animals that were treated once daily, a second
    group that were treated twice daily, and a third group that were
    treated four times daily. The exposure level should not be modulated
    through variation of the quantity of material administered per
    application, since excess test material is usually swallowed or
    expelled without genuinely increased exposure of the oral cavity to
    the material.

-   **Dosing frequency.** The number of daily applications should at
    least equal, and preferably exceed, the maximum anticipated clinical
    dosing frequency for the product (although generally the maximum
    feasible number of applications per day in an animal study is four,
    at 2-hour intervals).

-   **Duration of application.** We recommend that the animals be
    treated for 28 consecutive days; a study of this duration should
    adequately support an NDA for a product that is proposed for chronic
    use (with respect to oral irritation), since local effects will be
    apparent within that time frame.

-   **Controls.** The study should include a negative control group
    consisting of animals treated with room temperature distilled water
    or 0.9 percent sodium chloride (NaCl). The vehicle of the drug
    product should *not* be used as a negative control article, as some
    inactive ingredients may be irritating.

-   **Sacrifice schedule.** We recommend that the oral tissues be
    histopathologically evaluated at selected intervals during the study
    following interim sacrifices. For example, in a study in which
    animals are to be treated for 28 days, with the day on which
    abrasion and the first treatments are performed being designated day
    1, animals might be sacrificed on days 2, 5, 29, and 43. The
    sacrifice on day 2 (approximately 24 hours after the abrasion of the
    mucosa) would permit assessment of the adequacy and uniformity of
    the abrasion technique, and might involve only a small number of
    randomly selected negative-control animals (e.g., three animals per
    sex). We recommend that an interim sacrifice of animals in each
    treatment group be conducted at a time point when the abraded mucosa
    in the negative control animals is partially (but not completely)
    healed. The purpose of this interim sacrifice is to provide
    information concerning the potential of the test material to delay
    healing of lesions of the oral mucosa, which could be accomplished
    through comparison of the abraded areas from test and control
    animals. Although it is suggested in this document that sacrifice on
    day 5 *may* be appropriate for assessment of effect on healing, the
    optimum time point will depend on various factors, including the
    nature of the initial abrasion. The time point that is selected
    should be based on data from previous studies that used an identical
    abrasion technique and evaluated the time course of healing of the
    lesion. Animals sacrificed on day 43 (14-day recovery group) could
    provide information about the reversibility of any lesions observed
    in animals sacrificed on day 29.

-   **Number of animals.** A typical study design might involve 18
    animals per gender in the negative control group and 15 animals per
    gender in each group that is to be treated with a test material.
    Such a study could involve sacrifice of 3 negative-control animals
    per gender 24 hours following abrasion (for assessment of the
    abrasion technique) and 5 animals per gender from each group on the
    date of the interim sacrifice (see the previous bulleted item above)
    and on days 29 and 43.

-   **Parameters to be evaluated.** The oral cavity of each animal
    should be visually inspected at least once daily, including
    evaluation of the colors of the oral tissues (including the teeth),
    signs of edema, erythema, sloughing, bleeding, or ulceration, and
    the presence of dryness, roughness, cracking, or bleeding of the
    lips. Terminal studies should include gross examination of the oral
    cavity, esophagus, stomach, small and large intestine, and any
    apparent lesions, and histopathology of the oral cavity and adjacent
    structures, including the labial junctions, the buccal and gingival
    tissues (including the area that was abraded), the tongue, the
    palate (hard and soft), the parotid salivary gland, the
    submandibular lymph nodes, the nasopharynx and nasal passages, the
    larynx, the esophagus, the stomach, and any tissues that appear
    abnormal during gross examination. Particular emphasis should be
    placed on the integrity and thickness of the epithelial barriers,
    signs of hyperplasia or keratinization, examination of the area that
    was abraded for signs of delayed healing (relative to the negative
    control animals), and examination of the soft tissues for
    infiltration of inflammatory cells and/or edema.

# V. CLINICAL PROTOCOL ISSUES AND ELEMENTS

## **A. Study Design**

Parallel group designs are commonly employed and generally recommended.
We advise sponsors to exercise caution with the use of crossover and
split-mouth designs, which rarely offer any advantage. A split-mouth
design, in which one side of the mouth is untreated and is used as a
control and the other side treated, may be difficult to execute. Test
agent from the treated side may contaminate the untreated side and
compromise the results. In a crossover design, a sufficient wash-out
period is important to eliminate any residual effects from prior
treatments.

## **B. Randomization**

A clear description of the method by which subjects are randomized to
treatment groups, as well as identification of stratification variables
and blocking factors, will demonstrate whether group allocation is
unbiased.

Age, gender, and disease severity are important factors in consideration
of the adequacy of randomization. Proper randomization of subjects will
create balanced groups with respect to demographic and baseline
characteristics. Enrollment of a diverse population may allow for
detection of racial, gender, or age differences in response to
treatment. For further information on this topic, refer to section VI.C
of this document as well as the following guidance documents:[^6]

-   *Study and Evaluation of Gender Differences in the Clinical
    Evaluation of Drugs*

-   *Study of Drugs Likely to be Used in the Elderly*

-   ICH *E11 Clinical Investigation of Medicinal Products in the
    Pediatric Population*

-   ICH *E-7* *Studies in Support of Special Populations: Geriatric*

In the case of an important potential confounder, such as baseline
gingivitis or smoking, it may be prudent to stratify the groups by this
factor before randomization. In some cases, adjustments for baseline
characteristics may be accomplished statistically after the trial, to
correct for differences. If that is anticipated, characteristics should
be prespecified in the statistical plan. For multicenter trials,
randomization of subjects within each center will help to ensure that
none of the centers is unbalanced in its assignment of subjects to
groups. More detailed information on randomization can be found in the
ICH guidances, *E9* *Statistical Principles for Clinical Trials* and
*E10* *Choice of Control Group and Related Issues in Clinical
Trials*.[^7]

## **C. Blinding**

We recommend a double-blinded trial design whenever possible. Should
blinding be compromised, the resultant bias may potentially invalidate
the results. In the case of a topical product, differences in packaging
or discernable characteristics, such as appearance (including viscosity,
color, and opacity), smell, taste, or texture, may compromise blinding.

## **D. Length of Trial**

Trial length may affect the demonstration of both safety and efficacy.
In terms of efficacy, sponsors should allow sufficient time to
demonstrate a significant effect, should it exist, and in the case of a
chronic-use product, to demonstrate that the effect is not transient. A
description of what constitutes a significant effect is discussed in
detail in section VIII of this document. Data from Phase 2 dose-ranging
studies can guide sponsors in determination of trial length. The review
division generally recommends studies of 6 months duration or longer. In
addition, 6 months is the typical interval between routine dental visits
and therefore corresponds to clinical practice. In terms of safety, the
ICH guidance, *E1A* *The Extent of Population Exposure Required to
Assess Clinical Safety for Drugs Intended for Long-Term Treatment of
Non-Life-Threatening Conditions* (ICH-E1A),[^8] suggests the number of
subjects that should be exposed to the drug for 6 months or longer to
adequately detect uncommon adverse events. OTC drugs may call for
additional safety testing because of their wider use and lack of
professional oversight.

## 

## **Standard of Care**

During a chronic study (6 months or longer), subjects should receive the
standard of care for gingivitis. This care consists of regular brushing
and use of dental floss between professional dental visits to maintain
oral health and reduce the incidence and severity of gingivitis.
Subjects should be instructed to continue these measures throughout the
trial. As would be typical of a dental visit, hygiene instruction should
be provided at the baseline visit. In addition, unless the trial is
specifically designed to measure gingivitis reduction in individuals who
do not receive regular dental care, a professional scaling and
prophylaxis should be performed at baseline.

## 

## **F. Placebo or Active Control Formulation**

To produce valid conclusions about the results of a clinical trial, we
prefer that the trial be designed so that the test and placebo (or
active control) groups differ only in the presence or absence of the
active ingredient or ingredients. Differences in inactive ingredients,
such as abrasives, sweeteners, and even dyes (which may have
antimicrobial properties), may confound the data.

## **G. Use of a No-treatment Group**

Use of a no-treatment arm in addition to the placebo and the test
product groups allows for not only comparing the gingivitis effects
between the test product and placebo, but also for examining any
therapeutic effect of the vehicle. Subjects in this no-treatment arm
would be instructed only to maintain their normal home oral hygiene
regimen. This study is ethical only for study of gingivitis that is not
severe or gingivitis not accompanied by periodontitis. For further
discussion on ethical concerns, refer to subsection III.F of this
document.

# VI. CONSIDERATIONS FOR SUBJECT RECRUITMENT

#  

## **A. Sample Size**

This subsection gives a brief discussion of some points the sponsor
should consider regarding sample size. For further discussion on sample
size, refer to the ICH guidance, *E9 Statistical Principles for Clinical
Trials* (ICH-E9). Note that the power calculations used to choose a
sample size are affected by the duration of the gingivitis trial.
Choosing a time period shorter than the recommended 6 months allows less
time for a significant difference between the treatment and nontreatment
groups to develop and may call for a larger sample size. Also, note that
ICH-E9 focuses on the sample size a sponsor would choose to demonstrate
efficacy. As discussed in section IX of this document, the number of
subjects that adequately demonstrate safety may be greater than the
number that would demonstrate efficacy.

### 

## **Inclusion and Exclusion Criteria**

Carefully chosen inclusion and exclusion criteria will allow for
enrollment of the appropriate population to test the product for the
target group. Of special consideration is the degree of gingivitis
appropriate for enrollment, which will depend on the intended claim for
the drug product and whether it would be marketed by prescription or
OTC. A product intended to be marketed only with a prescription from a
dentist would be appropriate for a population with gingivitis of a
severity that would warrant a dentist's intervention. Testing for that
product would focus on enrollment of subjects with this same level of
severity. A product intended to be marketed OTC would be labeled for
patients with a lower level of severity that may range from very mild to
moderate disease. We recommend that a product intended to be marketed
OTC be studied in a population which includes a full range of gingivitis
within the indication for nonprescription users to reflect the
population that will ultimately use the product.

Another consideration in OTC drug testing is the influence of
confounding factors such as pregnancy, diabetes, smoking, and presence
of orthodontic brackets or removable prosthetic appliances. Many
sponsors prefer to exclude individuals with these conditions to
eliminate the difficulty of recording accurate measurements on them and
the confounding effect of their conditions on gingivitis. Excluding
these individuals in a trial for an OTC product is discouraged because
those individuals will have access to the product in the marketplace,
and the study population should reflect the population that will
ultimately use the product. There is somewhat more flexibility in the
trial of a drug that will be limited by prescription status, as the
prescription label can convey information to the health professional,
who can then make a decision about prescribing. Even in studies for
prescription products, a rationale should be provided for excluding some
patients (e.g., known lack of efficacy, safety issues, and ethical
issues).

> *1. Recommended Inclusion Criteria*

Basic conditions that are common to all gingivitis trials would include
recruitment of subjects who are in good general health and who have the
ability to provide written informed consent. Below are examples of
possible inclusion criteria for gingivitis trials:

-   a specified minimum number of teeth present

-   a qualifying baseline plaque index

-   a qualifying baseline gingival index (GI)

-   presence of bleeding site or sites upon probing

The plaque and gingival indices are discussed in section VII of this
document.

*2. Recommended Exclusion Criteria*

General exclusion criteria for clinical trials can include known
hypersensitivity to any component of the test product or a closely
related product, concomitant participation in any other clinical study,
or a positive urine test for drugs of abuse. Because residence in the
same household as a subject already enrolled in the study may create
blinding and compliance issues, this also may warrant exclusion from the
trial.

For typical gingivitis trials, we do not recommend exclusion of subjects
based on age, race, or gender. Representation of special populations is
expected (see section VI.C of this document entitled *Special
Populations*). There may be cases where pregnant subjects would be
excluded because of safety considerations or concerns about the
confounding effect of pregnancy on gingivitis; however, we discourage
automatic exclusion because of pregnancy. Other exclusions would depend
on the drug product (e.g., gastrointestinal bleeding for an
antigingivitis drug that is a nonsteroidal anti-inflammatory). As was
discussed earlier in this section of the document, trials for OTC
products might have fewer exclusion criteria because it is important
that the products be tested in a wider range of subjects. Below are
examples of typical exclusion criteria for gingivitis trials:

-   Gross oral pathology, including widespread caries or chronic
    neglect, extensive restoration, pre-existing gross plaque or
    calculus, or soft or hard tissue tumor of the oral cavity.

-   Chronic disease with concomitant oral manifestations.

-   Medical conditions or significant laboratory abnormalities that the
    investigator considers significant and that may compromise the
    subject\'s safety.

-   Medical conditions that may affect the evaluability of the study
    results, such as clinically significant organic disease, including
    heart murmur, history of rheumatic fever, or valvular disease.

-   Treatment with antibiotics within the 1-month period before the
    screening examination, or having a condition that is likely to call
    for antibiotic treatment over the course of the trial. This list
    includes cardiac conditions requiring antibiotic prophylaxis, such
    as heart murmurs, pacemakers, or prosthetic heart valves, as well as
    non-oral prosthetic implants.

-   Orthodontic appliances or removable partial dentures.

-   Periodontitis as indicated by clinical attachment loss, radiographic
    alveolar bone loss, or periodontal pockets greater than 5
    millimeters.

-   Concomitant pharmacotherapy with drugs that may interact with test
    drug.

-   Chronic treatment (2 weeks or more) with any medication known to
    affect periodontal status (including phenytoin, calcium antagonists,
    cyclosporin, coumarin, nonsteroidal anti-inflammatory drugs, and
    aspirin) within 1 month of the screening examination. All other
    medications for chronic medical conditions have been initiated at
    least 3 months before enrollment.

-   History of early-onset periodontitis or acute necrotizing ulcerative
    gingivitis.

-   Concomitant endodontic or periodontal therapy other than prophylaxis
    in the last 6 months.

## **Special Populations**

It is important to examine the effects of gender, race, and age in the
clinical trials by enrolling sufficient numbers of subjects with a
diverse demographic background. Although there is no evidence to
demonstrate that individuals of certain races are predisposed to
gingivitis, factors such as access to health care, nutritional status,
and socioeconomic status may be confounding factors that affect the
validity of results obtained through uneven distribution. Age and gender
may affect gingivitis both physiologically and psychosocially. For
example, frequency of professional visits is greater in adult women than
men, and oral hygiene habits are highly inconsistent in children and
adolescents. In addition, during puberty and pregnancy,
hormone-associated gingivitis becomes a confounder. Furthermore ---
depending on the proposed therapy --- drug absorption, distribution,
metabolism, and excretion may be different in different races or between
men and women, or between children and adults.

Smoking and diabetes are both significant risk factors for gingivitis,
and it is important that they be considered in the clinical trial
design. Excluding subjects with these conditions in Phase 3 studies
based on lack of efficacy in these groups in Phase 2 is a possibility.
The labeling may then reflect that these groups were not studied in
Phase 3 after negative results in Phase 2. Stratifying by these factors
is preferred because this allows study of these groups but protects
against bias. Another possibility is to include all subjects but enroll
a sufficient number so that they can be analyzed separately. If smokers
and diabetics respond more slowly or to a lesser extent than others in
the trial, this would be valuable clinical information for labeling.

## **D. Pediatric Populations**

Gingivitis can be found in all age groups. In a comprehensive 1989
national survey conducted by the National Institute of Dental and
Craniofacial Research, 47 percent of adult males and 39 percent of
females exhibited at least one gingivitis site as demonstrated by
bleeding on probing. Like adults, children are susceptible to
plaque-induced gingivitis. The prevalence of gingivitis among
school-aged children in the United States has ranged from 40 to 60
percent in national surveys. Adolescents have the highest prevalence and
greatest severity of gingivitis of any age group.

Conducting clinical trials in children is challenging. Nonetheless, §
201.57(f)(9) (21 CFR 201.57(f)(9)) charges the sponsor with the
provision of safety and efficacy information on children before drug
approval. The pediatric plan can be tailored to the individual drug in
question. If safety and/or efficacy in children cannot be extrapolated
from studies in adults, it should be specifically demonstrated through
enrollment of children in the same trials as adults or by conducting
separate trials in children.

## **E. Geriatric Populations**

A *Geriatric Use* section in labeling has been a requirement for
approval since August 27, 1997 (21 CFR 201.57(10)(ii)). Gingivitis
affects individuals older than age 65 in significant numbers, and these
individuals may respond differently to the drug product than younger
adults. We encourage sponsors to (1) study a sufficient number of
geriatric subjects to uncover any age-related differences in safety or
efficacy, and (2) describe these differences in the drug labeling. For
further information, including recommended labeling language, refer to §
201.57(f)(10) entitled *Geriatrics Use*.

# VII. ASSESSMENT OF GINGIVITIS

We recommend that primary and secondary endpoints be clearly identified
before initiation of the trial and prospectively described in the
protocol, along with the statistical analysis methodology. The most
common primary endpoint is a change in the gingival index (GI), which is
a categorical scale to which values are assigned for degrees of
gingivitis. Since the most common form of gingivitis is plaque-induced,
a co-primary endpoint for most antigingivitis drugs is plaque index (PI)
reduction. A common secondary outcome variable is the bleeding index.
These indexes are discussed in greater detail later in this section of
the document, and the condition under which a PI can be used as a
secondary endpoint is discussed in section VIII of this document.

## **A. Calibrating Investigator Skills**

Proper staff training helps to ensure consistency in recording of data
and use of instruments. Reducing examiner variability is beneficial, as
a decrease in measurement error can reduce the sample size that would be
appropriate for a clinical trial. To the greatest extent possible, we
suggest that examiner skills be calibrated to consistently perform
reliable and accurate readings. As most trials employ several examiners,
inter-observer variability may be an issue. With proper randomization
and blinding, individuals in the test group and those in the placebo
group will be fairly evenly divided between examiners. Scheduling a
reasonable number of examinations per session with adequate rest periods
will help maintain examiner efficiency. It has been noted in clinical
trials that examiners trained at the beginning of an investigation adopt
this new training initially but revert to their original methods by the
end of the trial. Therefore, we recommend that training programs use
reinforcement lessons throughout the duration of the study.

## **Gingival Index** 

Several gingival indexes have been used over the years. One gingival
index that was developed in 1963 and is widely used today is the Loe and
Silness Gingival Index. This index has proved useful in controlled
clinical trials because it (1) is fairly sensitive to small changes, (2)
is simple to administer, and (3) permits calibration of the examiners to
minimize inter- and intra-examiner error. In this index, the gingival
tissues surrounding each selected tooth are divided into four areas for
scoring: distofacial papilla, facial margin, mesiofacial papilla, and
the entire lingual margin. Each of these units is scored for gingivitis
according to criteria that categorize each surface as 0 for normal
gingiva, 1 for mild inflammation, 2 for moderate inflammation, or 3 for
severe inflammation. Literature is available that describes the details
of this index, including those characteristics that accompany each
score. The scores from the four gingival units are averaged to obtain a
score for each tooth, and these scores are combined and averaged to
determine a score for each individual. The index is sometimes scored on
the entire dentition; literature is also available that supports using
certain *index* teeth that are representative of the entire dentition.
In this index, a periodontal probe is used to determine the bleeding
tendency of the tissues. It is important that standardized pressure be
exerted during the probing. Automated periodontal probes may improve the
accuracy and precision of probing depth measurements.

## 

## **C. Plaque Index**

When plaque accumulates along the tooth surface, the gingiva responds to
the bacterial insult with varying degrees of redness, edema, and
bleeding. Regular removal of plaque through good oral hygiene maintains
healthy gingiva and reduces the incidence of associated gingivitis.

It is the Agency's current thinking that antigingivitis drugs using a
mechanism other than plaque reduction, such as anti-inflammation, could
be approved as prescription drugs. However, without adequate
professional oversight, chronic use of an anti-inflammatory drug that
does not concomitantly reduce plaque has the potential to mask
underlying infection. Therefore, antigingivitis drugs intended for OTC
use would assign PI outcome as a co-primary, rather than a secondary,
endpoint. This subject is discussed further in section VIII of this
document.

Most trials employ a method of supragingival, rather than subgingival,
plaque measurement because of the difficulties in accurately observing
subgingival plaque. The Turesky modification of the Quigley and Hein
Plaque Index has received considerable use in measuring plaque changes
during clinical trials. In this index, plaque is identified using a
disclosing solution and scored using a 0 to 5 scale in which a score of
0 corresponds to no plaque present, and a score of 5 designates plaque
covering more than two-thirds of the tooth surface. Each tooth receives
mesial, middle, and distal scores for both the facial and lingual
surfaces. An individual's score is derived by adding the scores at each
site and dividing by the number of sites evaluated. The Loe and Silness
Plaque Index is also used in clinical trials. It employs a scoring scale
from 0 to 3 and evaluates four sites on each tooth.

Sampled plaque is often weighed, either dry or wet. Note, however, that
neither the PI nor quantification of dry or wet plaque weight correlates
strongly with gingivitis. No single measurement can relate the various
aspects of plaque accumulation, such as surface area of plaque, mass of
the plaque, density of plaque, bacterial composition, and location on
the tooth. The effect of plaque is most likely a combination of all
these factors, which have not been captured in a single index or
measurement.

## **D. Bleeding on Probing**

Bleeding on probing is a cardinal sign of gingivitis. Some GI's include
an assessment of bleeding. For those that do not, a categorical
evaluation (yes or no) of bleeding on probing can add valuable
information. Bleeding can be an appropriate secondary outcome variable.
It would not be sufficient as a stand-alone primary outcome variable.

### 

## **E. Calculus Formation**

The FDA views calculus reduction as a cosmetic claim rather than a drug
indication; cosmetic claims are not included in prescription labeling.
Certain topical dental drugs increase calculus formation, which is
considered an adverse event. We encourage the sponsor of an
antigingivitis product to include calculus examinations in both the
baseline and the end-of-the-study evaluations. The labeling for a
product that increases calculus formation would reflect this risk.

## **F. Staining Index**

Improvement of extrinsic staining of teeth, like calculus reduction, is
regarded as a cosmetic claim. Also, like calculus formulation, some
antigingivitis products are known to result in increased staining on
teeth. Increased staining is an adverse event that should be
communicated to consumers. For products thought to cause staining, it is
important to obtain measurements on a staining index, at least at
baseline and at final examination, and evaluate the data during the
analysis of the study results.

## **G. Microbiologic Sampling**

Because of the complexity of the microbial community associated with
gingivitis and the difficulty in accurately ascribing causality to
specific species, the FDA currently accepts microbiological data only as
descriptive evidence that can be included in the *Microbiology* section
of product labeling. Reductions in specific microorganisms in plaque or
in the mouth cannot be a surrogate for treatment of gingivitis. However,
the oral flora should be monitored to determine whether there is an
increase in opportunistic or resistant organisms.

# 

# VIII. CLINICAL AND STATISTICAL SIGNIFICANCE FOR DETERMINING AN EFFECT

## **Clinical Significance**

As is the case with all new drug products, the data from gingivitis
studies should demonstrate that (1) the outcomes seen are unlikely due
to chance (statistical significance), and (2) the magnitude of the
outcomes is such that some therapeutic benefit has been established
(clinical significance). In the case of gingivitis, improvement in the
GI score would be a primary outcome measure (seeeee the last paragraph
in this subsection for a discussion of a meaningful improvement). To
gain approval for an OTC drug claiming antigingivitis activity, the drug
should also successfully demonstrate a significant PI reduction, coupled
with the significant GI improvement.

For those products that treat nonplaque-induced gingivitis,
demonstration of reduction in plaque may not be important. However,
those products should provide convincing evidence that the underlying
disease is not progressing despite abatement of the signs and symptoms.
Those products probably would not be approved as OTC antigingivitis
drugs. Secondary claims regarding gingival bleeding can be used in
labeling if the outcomes are significant and the claims are both
truthful and relevant. To avoid the bias that may result from post hoc
analysis, the protocol's statistical plan should include the planned
analysis of secondary outcome variables.

The Agency concurs with the consensus of the expert dental community
regarding therapeutically significant improvements in plaque-induced
gingivitis (see Imrey, PB, NW Chilton et al., July 1994, *Recommended
Revisions to American Dental Association Guidelines for Acceptance of
Chemotherapeutic Products for Gingivitis Control,* J Periodontal Res,
29(4): 299-304). Accordingly, FDA recommends that an application
demonstrate the following for approval of an antigingivitis drug
product:

1.  The estimated proportionate reductions for the GI measurements
    should be no less than 15 percent in favor of the active treatment
    and statistically significant in each of at least two studies.

2.  The arithmetic mean of the estimated proportionate reductions for
    the GI measurements across the studies, referred to in item #1
    above, should be no less than 20 percent.

> Proportionate reduction refers to a comparison of the active therapy
> to the control at the end of the study, rather than to reductions from
> an initial baseline level, and presumes that randomization has
> produced initially comparable active and control clinical samples, or
> that fully-appropriate statistical adjustment has been used for
> randomization failures (Imrey and Chilton et al., 1994).
>
> It is reported as a percentage and defined as:
>
> [(mean endpoint GI of control minus mean endpoint GI of
> active)]{.underline}
>
> mean endpoint GI of control.

3.  Plaque reductions should be statistically significant in at least
    two studies. Because the exact amount of plaque reduction that is
    recommended for gingivitis reduction has not been established,
    demonstrating a statistically significant difference in plaque
    levels between the test group and placebo group through comparison
    of PI numbers is usually sufficient.

## **Statistical Considerations**

In this section of the guidance document, some specific statistical
considerations for gingivitis trials will be discussed. For more detail,
as well as general statistical considerations in clinical trials, refer
to the ICH-E9 guidance. As discussed in the previous section, the
primary efficacy variables for gingivitis trials are the GI and the PI.
Statistical testing for both of these variables is usually performed
with a comparison of means test through analysis of covariance.

In addition to the test of means for the GI, the sponsor can also
perform a responder analysis (i.e., evaluate the GI results as a
proportion of subjects or sites that achieve gingival health, as defined
by a predetermined definition). For example, the number of sites at the
end of the trial that measure 0 or 1 in the test group, compared to the
number in the placebo group, is an outcome measure that can be
evaluated. Since the goal of an antigingivitis product is to maintain
gingival health, this number has a direct clinical significance that is
fairly easy to interpret. If a test product can achieve 80 percent
healthy sites, as compared to a placebo that only achieves 55 percent,
the average practitioner may have a better understanding of the ability
of the drug to maintain gingival health than would be apparent from an
overall mean reduction in GI scores from 1.5 to 1.0. The traditional
statistical testing for this outcome measure is a comparison of
proportions of a dichotomous variable in subjects employing the Cochran
Mantel Haenszel test. For comparison of sites, it may be important to
conduct more complex testing, such as a repeated measures approach.

Additional indexes used as secondary outcome variables or to monitor
adverse events will follow the same recommendations. Staining and
calculus indexes are each evaluated as a difference in means in a
similar fashion to the GI and PI, and as such are analyzed with analysis
of covariance. For a site-specific dichotomous variable such as bleeding
upon probing, a repeated measures approach may be appropriate.

If ethical constraints call for use of an active agent (e.g., standard
of care) rather than placebo in the control arm, equivalence or
non-inferiority testing can be used to compare the test product to a
known effective gingivitis treatment. Non-inferiority testing is
discussed in section 3.3.2 of ICH-E9. Equivalence testing is not based
on a nonsignificant test result of the null hypothesis of two treatment
responses being equal. An equivalence margin (i.e., the largest
difference that is considered to be clinically insignificant) would be
chosen.

It is generally preferable to conduct both all-randomized subjects and
per protocol analyses to substantiate the study results. In superiority
studies, the all-randomized subjects analysis is often more conservative
than a per protocol analysis, since the noncompliers will diminish the
overall treatment effect. In equivalence or non-inferiority trials, the
all-randomized analysis is not conservative and may not be appropriate.

# SAFETY CONSIDERATIONS

Safety concerns for antigingivitis products fall into two main
categories: (1) adverse events associated with the drug, and (2) masking
of underlying periodontitis. Adverse events may be local events such as
oral irritation or systemic events resulting from ingestion or
absorption of drug. Because periodontitis may occur concurrently with
gingivitis, it is important to ascertain that treatment of the
gingivitis does not conceal the more serious periodontitis from either
the patient or the health care provider.

All noxious and unintended responses related to any dose of a medicinal
product should be considered adverse drug reactions (see ICH guidance
*E2A* *Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting*).[^9] Refer to ICH-E2A for a precise definition of
terms, such as mild, moderate, or severe, to describe the intensity of a
specific event as well as the medical significance. Also, ICH-E1A
describes the safety database for prescription products. Because OTC
products usually are more widely used than prescription products and are
used without professional supervision, these products may warrant a
larger safety database.

We advise sponsors to develop recommendations before initiating a trial,
including a policy for review of adverse events and circumstances under
which a trial might be discontinued. The sponsor has an obligation to
recommend and allow treatment under certain circumstances and to make
provisions for emergency treatment or withdrawal from the study in the
event of serious adverse reactions. In some cases, it may be appropriate
to continue the subject in the trial but to modify the dosage. In the
case of patient death or serious adverse events, the sponsor has
specific reporting requirements, which are outlined in 21 CFR 312.32.

Since drugs are readily absorbed through the oral mucosa, the
investigator should address pharmacokinetic monitoring of the drug's
absorption, distribution, metabolism, and excretion at baseline and the
end of the trial. It may also be advisable to consider routine
laboratory screenings such as complete blood count, and measures of
hepatic and renal function.

Examples of specific local adverse events associated with antigingivitis
products include mucosal irritation, staining of teeth, and excessive
calculus formation. Conduct of a thorough intraoral examination is
desirable, beginning early in the trial to identify drug-related
irritation as soon as it develops. Staining can be measured with a
staining index, such as the Lobene Index done visually, or
instrument-assisted colorimetric recording. Likewise, calculus can be
recorded with one of several indexes. In addition, baseline and
end-of-study measurement of attachment level is worthwhile in assessing
whether the product has a potential to adversely affect attachment.

# X. CONCLUDING COMMENTS

This guidance is not meant to be a substitute for meetings between the
Agency and the drug sponsor, which are tailored to discuss a specific
drug product and its precise indication. We strongly encourage the drug
sponsor to take advantage of pre-investigational new drug meetings,
general guidance meetings, and, particularly, end-of-phase-2 meetings
before proceeding with essential clinical trials. Sponsors also can
request special protocol assessments after an end-of-phase-2 meeting,
which may clarify regulatory issues that were discussed during that
meeting. As regulatory interpretation and drug development are dynamic
processes and every drug product may have unique attributes, important
issues may arise that have not been addressed in this document. The
procedure for scheduling and preparing for a meeting with the Agency can
be found in the CDER guidance document entitled *Formal Meeting with
Sponsors and Applicants for PDUFA Products.*[^10] Meeting requests and
requests for procedural clarification should be directed to the
Supervisory Project Manager in the Division of Dermatologic and Dental
Drug Products.

[^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.

[^3]: 21 U.S.C. 503(b)(1)(A) of the Federal Food, Drug, and Cosmetic
    Act.

[^4]: Available on the Internet at
    http://www.fda.gov/cder/guidance/index.htm.

[^5]: Available on the Internet at
    http://www.fda.gov/cder/guidance/index.htm.

[^6]: Available on the Internet at
    htttp://www.fda.gov/cder/guidance/index.htm.

[^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.

[^9]: Available on the Internet at
    http://www.fda.gov/cder/guidance/index.htm.

[^10]: Available on the Internet at
    htttp://www.fda.gov/cder/guidance/index.htm.