Bacterial Vaginosis: Developing Drugs for Treatment Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Bacterial Vaginosis:
Developing Drugs for
Treatment
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2019
Clinical/Antimicrobial

Bacterial Vaginosis:
Developing Drugs for
Treatment
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2019
Clinical/Antimicrobial

TABLE OF CONTENTS
I. 	INTRODUCTION..................................................................................................1
II. 	DEVELOPMENT PROGRAM ............................................................................2
A. 	General Considerations .................................................................................................... 2
1. Drug Development Population ............................................................................................ 2
2. Efficacy Considerations ...................................................................................................... 2
3. Safety Considerations .......................................................................................................... 2
B. 	Specific Efficacy Trial Considerations ............................................................................ 2
1. Clinical Trial Designs ......................................................................................................... 2
2. Clinical Microbiology Considerations ................................................................................ 3
3. Enrollment Criteria ............................................................................................................. 3
4. Randomization and Blinding ............................................................................................... 4
5. Specific Populations ............................................................................................................ 4
6. Dose Selection ..................................................................................................................... 5
7. Choice of Comparators ....................................................................................................... 5
8. Efficacy Endpoints............................................................................................................... 6
9. Trial Procedures and Timing of Assessments ..................................................................... 6
10. 	Statistical Considerations ............................................................................................... 7
a. 	Analysis populations..................................................................................................... 7
b. 	Sample size ................................................................................................................... 7
C. 	Other Considerations ........................................................................................................ 8
1. Ethical Considerations ........................................................................................................ 8
2. Relevant Nonclinical Considerations .................................................................................. 8
3. Pharmacokinetic/Pharmacodynamic Considerations ......................................................... 8

Contains Nonbinding Recommendations
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Bacterial Vaginosis: Developing Drugs for Treatment
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
The purpose of this guidance is to assist sponsors in the overall development program and
clinical trial designs to support development of topical and systemic drugs and biological
products for the treatment of bacterial vaginosis (BV).2
This guidance focuses on considerations that are specific to BV drug development. This
guidance does not contain discussion of the general issues of statistical analysis or clinical trial
design. Those topics are addressed in the ICH guidances for industry E9 Statistical Principles
for Clinical Trials (September 1998) and E10 Choice of Control Group and Related Issues in
Clinical Trials (May 2001), respectively.3
In general, FDA’s guidance documents 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.
1 This guidance has been prepared by the Division of Anti-Infective Products in the Center for Drug Evaluation and
Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug
Administration.
2 For purposes of this guidance, references to drugs includes drugs approved under section 505 of the Federal Food,
Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355) and biological products licensed under 351 of the Public
Health Service Act (42 U.S.C. 262) that are drugs.
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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II. 	DEVELOPMENT PROGRAM
A. 	General Considerations
1. 	Drug Development Population
FDA considers postmenarchal females with clinical and laboratory-based criteria for diagnosis of
BV (see sections II.B.2., Clinical Microbiology Considerations, and II.B.3., Enrollment Criteria)
to be eligible for enrollment.
2. 	Efficacy Considerations
In general, FDA recommends two adequate and well-controlled trials to support effectiveness
(see 21 CFR 314.126). If the drug is being developed for other infectious disease indication(s) in
addition to BV, sponsors should discuss with FDA the potential situations in which one trial
would provide evidence of effectiveness, supported by evidence of effectiveness for the other
infectious disease indication(s).4
3. 	Safety Considerations
The recommended size of the safety database depends on whether the drug is administered
systemically or topically, and the level of systemic absorption expected with the topical drug. If
the same or greater dose and duration of therapy for treatment of BV were used in clinical trials
for other infectious disease indications, typically sponsors should include the safety information
from those clinical trials in the overall preapproval safety database. Sponsors should discuss the
appropriate size of the preapproval safety database with FDA during clinical development,
depending upon the characteristics of the topical or systemic drug.
For drugs administered topically, human safety evaluations should focus on local toxicities of the
cervicovaginal area in addition to systemic toxicities.
B. 	Specific Efficacy Trial Considerations
1. 	Clinical Trial Designs
The sponsor should conduct randomized, double-blind, and either placebo-controlled or active-
controlled trials, with the hypothesis that the investigational drug is superior to the control
treatment. Trials can be multicenter and multinational in scope; however, particular
considerations may apply to such trial designs. These issues are addressed in the ICH guidance
for industry E5 Ethnic Factors in the Acceptance of Foreign Clinical Data (June 1998) and the
guidance for industry and FDA staff FDA Acceptance of Foreign Clinical Studies Not Conducted
Under an IND: Frequently Asked Questions (March 2012).
4 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological
Products (May 1998).

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2. 	Clinical Microbiology Considerations
An appropriate vaginal swab specimen should be obtained for microbiologic evaluation.
Specimens should be collected, processed, transported, and stored before testing according to
appropriate methods.5
The following tests should be performed on vaginal secretion specimens collected to aid in the
clinical laboratory diagnosis of BV: (1) measurement of pH; (2) the addition of a drop of 10-
percent solution of potassium hydroxide (KOH) to evaluate for the presence of a characteristic
fishy amine odor; (3) the examination for the presence of clue cells using a microscope at 400-
times magnification of a normal saline wet mount; (4) measurement of pH of vaginal secretions;
and (5) the examination by Gram stain for specific bacterial morphologic types (e.g., large gram-
positive rods suggestive of Lactobacillus species, small gram-variable rods suggestive of
Bacteroides species, curved gram-variable rods suggestive of Mobiluncus species, and gram-
positive cocci).
3. 	Enrollment Criteria
The recommended enrollment criteria are outlined below:
• 	FDA recommends the following inclusion criteria: Postmenarchal females should have
the presence of all four Amsel criteria:6
(1) Off-white (milky or gray), thin, homogeneous discharge with minimal or absent
pruritus and inflammation of the vulva and vagina
(2) The presence of clue cells greater than 20 percent of the total epithelial cells on
microscopic examination of the saline wet mount7
(3) Vaginal secretion pH of greater than 4.5
(4) A fishy odor (i.e., a positive whiff test) of the vaginal discharge with the addition of a
drop of KOH
5 See, for example, the American Society for Microbiology, 2010, Clinical Microbiology Procedures Handbook, 3rd
Edition.
6 Amsel R, PA Totten, CA Spiegel, KC Chen, D Eschenbach, and KK Holmes, 1983, Nonspecific Vaginitis:
Diagnostic Criteria and Microbial and Epidemiologic Associations, Am J Med, 74(1):14–22.
7 Diagnostic clue cells should have Gardnerella-like organisms (small, nonmotile, coccobacilli) covering not only
the surface of the squamous epithelial cells but also spreading out past the cell boundaries, obscuring the
cytoplasmic margins and thus creating a shaggy appearance. The entire cell need not be covered with bacteria, but
cells with organisms simply sticking to the surface without extending past the cytoplasmic margins should not be
considered clue cells. Both the saline mount and the Gram stain can be easily and accurately used to determine clue
cells.

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To enhance the reliability for the clinical laboratory diagnosis of BV at enrollment, the
Gram stain of the vaginal specimen should have a Nugent score of greater than or equal
to 7.8
• 	FDA recommends the following exclusion criteria:
‒ 	Patients with other infectious causes of vulvovaginitis (e.g., vulvovaginal candidiasis,
Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes
simplex, or human papillomavirus)
‒ 	Patients with another vaginal or vulvar condition, which would confound the
interpretation of clinical response
‒ 	Patients who are currently receiving antibacterial therapy unrelated to BV
4. 	Randomization and Blinding
Eligible patients should be randomized to treatment groups at enrollment. Treatment assignment
should be blinded to the patient, investigator, and microbiologist performing assessments.
5. 	Specific Populations
The trials should include patients of all races, as well as geriatric patients.9 Patients with renal or
hepatic impairment should be enrolled, provided pharmacokinetics of a systemic drug have been
evaluated in these patients and appropriate dosing regimens have been defined, or a topically
administered drug demonstrated minimal or no systemic absorption.
FDA encourages sponsors to begin discussions about pediatric clinical development plans as
early as is feasible because pediatric studies are a required part of the overall drug development
program and sponsors are required to submit pediatric study plans no later than 60 days after an
end-of-phase 2 meeting or such other time as may be agreed upon by FDA and the sponsor.10
BV is unlikely to occur in healthy premenarchal females. Inclusion of postmenarchal adolescent
females in phase 3 trials may be capable of fulfilling the required pediatric clinical development
plans.
8 Nugent RP, MA Krohn, and SL Hillier, 1991, Reliability of Diagnosing Bacterial Vaginosis Is Improved by a
Standardized Method of Gram Stain Interpretation, J Clin Microbiol, 29(2):297–301.
9 See the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics (August 1994) and
E7 Studies in Support of Special Populations: Geriatrics; Questions and Answers (February 2012).
10 See the Pediatric Research Equity Act (Public Law 108-155; section 505B of the FD&C Act; 21 U.S.C. 355c), as
amended by the Food and Drug Administration Safety and Innovation Act (Public Law 112-144), and the draft
guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans
and Amended Initial Pediatric Study Plans (March 2016). When final, this guidance will represent FDA’s current
thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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In general, safe and effective treatments are available for pregnant women with BV. Therefore,
in general, it is appropriate to complete phase 3 clinical trials that establish safety and efficacy in
nonpregnant women before trials in pregnant patients are initiated. However, if current effective
treatments are unavailable, such as for a pregnant woman who is allergic to all available
therapies for BV, it may be appropriate to characterize safety and pharmacokinetics of the
investigational drug in pregnant women who have the potential to benefit from the
investigational drug. Before sponsors consider clinical evaluations of an investigational drug in
pregnant women, sponsors should complete nonclinical toxicology studies, reproductive and
developmental toxicology studies, and phase 1 and phase 2 clinical trials.11 If a woman becomes
pregnant during the clinical trial, appropriate monitoring through the pregnancy and pregnancy
outcome data should be collected. Infants born to women who received the investigational drug
should be followed for an appropriate period of time based on available nonclinical and clinical
data.
6. 	Dose Selection
Sponsors should conduct dose-ranging studies in BV patients in the early stages of development
to help determine an adequate dosage regimen or regimens for phase 3 trials.
Specifically, sponsors should integrate findings from nonclinical studies, pharmacokinetic
studies, and safety information from earlier stages of clinical development to select the dose or
doses to be evaluated in phase 3 clinical trials. For systemic drugs, sponsors should evaluate
information regarding pharmacokinetics in specific populations (e.g., adolescent patients,
patients with renal or hepatic impairment) before initiating phase 3 trials to determine dosing in
patients in those populations and to facilitate the patients’ inclusion in phase 3 clinical trials.
7. 	Choice of Comparators
The control group for superiority trials can be a placebo or another antibacterial drug. If a
vehicle control is used as the placebo for a drug administered topically, then the vehicle control
should not influence the safety or efficacy evaluations (e.g., the vehicle control should not cause
irritation and should not have an antibacterial effect). Appropriate active comparators can be
used as a control provided superiority is demonstrated.
11 See the draft guidance for industry Pregnant Women: Scientific and Ethical Considerations for Inclusion in
Clinical Trials (April 2018). When final, this guidance will represent the FDA’s current thinking on this topic.

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8. 	Efficacy Endpoints
FDA characterizes the recommended primary efficacy endpoint as follows:
• 	Clinical cure: Resolution of the abnormal vaginal discharge, a negative whiff test, and
the presence of clue cells at less than 20 percent of the total epithelial cells on
microscopic examination of the saline wet mount.12, 13
Sponsors also can consider the following supportive secondary endpoints:
• 	Nugent score of less than 4
• 	Responder outcome defined as clinical cure plus Nugent score of less than 4
9. 	Trial Procedures and Timing of Assessments
FDA recommends the following trial procedures and the timing of assessments; however,
sponsors should discuss the timing of assessments for their systemic drugs with the Division of
Anti-Infective Products or with the appropriate review division in CBER for CBER-regulated
products:
• 	Entry visit: Appropriate demographic information, history and physical examination
findings, a microbiological specimen, and pregnancy and safety laboratory tests should
be collected at this visit; patients should be randomized and receive the study drugs at
this visit.
• 	Visit at approximately 7 to 14 days after randomization: For systemic drugs that are
administered for a short period of time (e.g., 1 to 2 days) and have a relatively short half-
life (e.g., less than 24 hours), the primary efficacy endpoint should be assessed at this
visit. For topical drugs that are administered for a short period of time (e.g., 1 to 2 days)
and have antibacterial activity for a short time, the primary efficacy endpoint should be
assessed at this visit. Adverse event information and, if appropriate, safety laboratory
tests should also be collected.
• 	Visit at 21 to 30 days after randomization: For systemic drugs that are administered for a
longer period of time (e.g., for 1 week) and/or have a long half-life (e.g., greater than 24
hours), the primary efficacy endpoint should be assessed at this visit. For topical drugs
that are administered for a longer period of time (e.g., for 1 week) and/or maintain
antibacterial activity for a longer time, the primary efficacy endpoint should be assessed
at this visit. If this visit assesses the continued clinical response to treatment and adverse
12 Note that there are four entry criteria, yet only three of the four criteria are used as the primary efficacy endpoint.
The pH inclusion criteria are included for the purpose of enrichment of a clinical trial population most likely to have
a true diagnosis of BV. Vaginal pH is not included as a component of the clinical cure for BV.
13 For assistance with developing and using an appropriate patient-reported outome tool to assess symptoms of BV,
see the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to
Support Labeling Claims (December 2009).

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events following an earlier test-of-cure clinical visit, contact with the patient by telephone
may be sufficient for this visit.
FDA recommends a patient diary for the collection of information regarding drug administration,
assessment of symptoms, and assessment of adverse events. Patients who have continued or
worsening symptoms before the test-of-cure visit can be considered treatment failures and be
offered rescue therapy for BV.
10. 	Statistical Considerations
In general, before initiating trials, the sponsor should submit a detailed statistical analysis plan
stating the trial hypotheses and the analysis methods. The primary efficacy analysis should be
based on a comparison of the proportions of patients achieving a successful efficacy outcome.
a. 	Analysis populations
Sponsors should consider the following definitions of analysis populations:
• 	Safety population — All patients who received at least one dose of the investigational
drug during the trial
• 	Intent-to-treat population — All patients who were randomized
• 	Modified intent-to-treat (mITT) — All randomized patients, excluding those who
subsequently demonstrate a positive test result for other concomitant vaginal or cervical
infections at baseline (e.g., C. trachomatis, N. gonorrhoeae), which may interfere with
the efficacy assessment for BV, or who have a baseline Nugent score less than 7.
• 	Per-protocol population — The population of patients who qualify for the mITT
population and who follow important components of the trial (important components of
the trial include adhering to the treatment and follow-up for the efficacy assessment
within the prescribed time frame)
Sponsors should consider the mITT population as the primary analysis population. In general,
sponsors should not consider analyses of the per-protocol populations as primary because after-
randomization events or characteristics could potentially bias results in this population.
However, consistency of the results should be evaluated in all patient populations. Every attempt
should be made to limit the loss of patients from the trial and to follow all randomized patients
for the study outcome so that the ITT analysis can be performed and there should be specific
protocol-specified plans for handling missing data.
b. 	Sample size
The sample size is influenced by several factors including the prespecified type I and type II
error, the expected success rate, and the amount by which the investigational drug is superior to
the control in a superiority trial. A two-sided type I error rate of 0.05 and a type II error rate

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between 0.10 and 0.20 are usually specified. Expected success rates are typically based upon
results obtained in phase 2 trials or other information.
C. 	Other Considerations
1. 	Ethical Considerations
The occurrence of adverse events from antibacterial drugs can be relevant in assessing the
benefit-risk to patients in a placebo-controlled trial. Rescue therapy can be incorporated into the
trial design so that individual patients are treated at the time when a failure outcome is assigned;
this may serve to mitigate concerns regarding inclusion of a placebo group in a trial. All trials
should provide appropriate provisions for patient safety.
2. 	Relevant Nonclinical Considerations
Investigational drugs being studied for BV should have nonclinical data documenting activity
against the implicated pathogens associated with BV. Guidances for industry provide
information for sponsors on nonclinical considerations for drug development in general and also
nonclinical considerations for drugs administered topically.14
3. 	Pharmacokinetic/Pharmacodynamic Considerations
Pharmacokinetic/pharmacodynamic approaches typically used to identify appropriate dosing
regimens for evaluation in phase 2 and phase 3 clinical trials for systemic bacterial infections
may not be appropriate for drugs used for the treatment of BV. However, sponsors should
consider the following pharmacokinetic evaluations.
For a drug administered topically in the vagina and/or the area surrounding the vagina, it is
important to determine systemic drug exposure as part of the safety assessment. Evaluation of
systemic exposure following topical vaginal administration can be performed in females with BV
or in healthy females without BV because the extent of systemic drug absorption is not related to
the presence or absence of BV.
For a drug administered systemically for treatment of BV (e.g., oral), the systemic exposure and
other relevant clinical pharmacology aspects of the drug (e.g., drug-drug interactions, QT
prolongation,15 dosage adjustment in renal and/or hepatic impairment, food effect) should be
adequately characterized. Sponsors should discuss with FDA the need to evaluate pertinent
drug-drug interactions, particularly with oral contraceptives.
14 See the FDA Drug guidance web page at https://www.fda.gov/drugs/guidances-drugs/all-guidances-drugs for all
guidances listed in that category.
15 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic
Potential for Non-Antiarrhythmic Drugs (October 2005).