Guidance for Industry
Gingivitis: Development and Evaluation of Drugs for Treatment or
Prevention
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version of this document)
DRAFT GUIDANCE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being distributed for comment purposes only.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the notice announcing the availability of the draft guidance.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
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
Guidance for Industry
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draft guidance, when finalized, will represent the Food and Drug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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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,
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.
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.
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.
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:
·
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.
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.
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),
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 (see 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)
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.
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 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).
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.
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.
Meeting requests and requests for procedural clarification
should be directed to the Supervisory Project Manager in the
Division of Dermatologic and Dental Drug Products.
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Date created: June 27, 2005 |