Vulvovaginal 
Candidiasis: 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) 
 
August 2019 
Clinical/Antimicrobial 
   
Vulvovaginal 
Candidiasis: 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
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 ..................................................................................................................................4 
7. Choice of Comparators ....................................................................................................................5 
8. Efficacy Endpoints ............................................................................................................................5 
9. Trial Procedures and Timing of Assessments ..................................................................................5 
10.  Statistical Considerations ............................................................................................................6 
a.  Analysis populations ..................................................................................................................6 
b.  Sample size ................................................................................................................................7 
C.  Other Considerations .....................................................................................................................7 
1. Ethical Considerations .....................................................................................................................7 
2. Relevant Nonclinical Considerations ...............................................................................................7 
3. Pharmacokinetic/Pharmacodynamic Considerations ......................................................................7 
 
 
  Contains Nonbinding Recommendations 
Vulvovaginal Candidiasis: 
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 clinical development program 
and clinical trial designs to support drugs for treating vulvovaginal candidiasis (VVC).2 
 
In general, this guidance focuses only on treating VVC.  This guidance does not discuss clinical 
development programs focused on preventing or reducing the recurrence of VVC. Sponsors 
should discuss the clinical development of such programs with FDA. 
 
This guidance focuses on considerations that are specific to VVC drug development. This 
guidance does not discuss trial designs for development programs for nonprescription treatments 
of VVC, nor does it discuss 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, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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 at the Food and Drug Administration. 
 
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological 
products unless otherwise specified. 
 
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. 
1  Contains Nonbinding Recommendations 
 
II.  DEVELOPMENT PROGRAM 
 
A.  General Considerations 
This section discusses clinical development considerations, including the target population, 
efficacy, and safety in developing drugs for treating VVC. 
 
1.  Drug Development Population 
 
Sponsors should enroll postmenarchal females with a clinical diagnosis of VVC.  Sponsors 
should also discuss with FDA whether they plan to include in the trial population patients who 
have HIV/AIDS or diabetes mellitus. 
 
2.  Efficacy Considerations 
 
In general, FDA recommends two adequate and well-controlled trials to demonstrate efficacy 
(see 21 CFR 314.126).  If the drug is being developed for other indications, 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 indications.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 product. 
If the same or greater dose and duration of therapy for treating VVC were used in clinical trials 
for other infectious disease indications, sponsors should include the safety information from 
those clinical trials in the overall preapproval safety database.  Sponsors should also discuss the 
appropriate size of the preapproval safety database with FDA during clinical development, 
depending on the characteristics of the topical or systemic product. 
 
For drugs administered topically, human safety evaluations should focus on local toxicities in the 
cervicovaginal area in addition to systemic toxicities. 
 
B.  Specific Efficacy Trial Considerations 
 
1.  Clinical Trial Designs 
 
Trials should be randomized, double-blinded, and either placebo-controlled or active-controlled, 
using a superiority design. If a noninferiority trial is being considered, sponsors should discuss 
such a trial design with the Agency.5  
 
                                                 
4 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products (May 1998). 
 
5 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016). 
2  Contains Nonbinding Recommendations 
2.  Clinical Microbiology Considerations 
 
Sponsor should obtain an appropriate vaginal swab specimen for microbiologic evaluation.  
Sponsors should also collect, process, transport, and store specimens as needed before testing 
according to appropriate methods.6 
 
Specimens collected to aid diagnosing VVC in the clinical laboratory should be examined 
microscopically for the presence of yeast (e.g., a wet mount prepared in a potassium hydroxide 
solution (KOH)) and should be cultured using standard fungal media.7  Yeast grown in culture 
should be identified to species level and tested for susceptibility to appropriate antifungal drugs, 
using standard laboratory methods such as those recommended by the Clinical and Laboratory 
Standards Institute (CLSI).8 
 
3.  Enrollment Criteria 
 
Inclusion criteria should include postmenarchal females who have a clinical diagnosis of VVC 
defined as: 
 
  Two or more of the following signs and symptoms of VVC: itching, burning, irritation, 
edema, redness, or excoriation9 
 
  KOH or saline preparation from the inflamed vaginal mucosa or secretions demonstrating 
yeast forms (hyphae or pseudohyphae) or budding yeasts 
 
  Vaginal pH less than or equal to 4.5 
 
The following patients should be excluded: 
 
  Patients with other infectious causes of vulvovaginitis (e.g., bacterial vaginosis, 
Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex, 
or human papillomavirus) or with mixed infections 
 
  Patients who were treated for VVC within the past 14 days 
 
                                                 
6 See, for example, the American Society for Microbiology, 2010, Clinical Microbiology Procedures Handbook, 3rd 
Edition. 
 
7 Clinical and Laboratory Standards Institute (CLSI), 2008, Reference Method for Broth Dilution Antifungal 
Susceptibility Testing of Yeasts; Approved Standard  Third Edition, CLSI document M27-A3, Clinical and 
Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA. 
 
8 CLSI, 2012, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth 
Informational Supplement, CLSI document M27-S4, Clinical and Laboratory Standards Institute, 940 West Valley 
Road, Suite 2500, Wayne, Pennsylvania 19087, USA. 
 
9 In general, we recommend that at least two signs or symptoms be of at least moderate severity.  
3  Contains Nonbinding Recommendations 
  Patients who are currently receiving antifungal therapy unrelated to VVC 
 
4.  Randomization and Blinding 
 
Eligible patients should be randomized to treatment groups at enrollment.  All trials should be 
multicenter and double-blinded to control for potential biases. 
 
5.  Specific Populations 
 
Sponsors should include patients of all races, as well as geriatric patients, in the trials.10  
Additionally, sponsors can enroll patients with renal or hepatic impairment if appropriate dosing 
regimens have been defined for systemic products. 
 
Sponsors are encouraged to begin discussing their pediatric clinical development plan 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.11  VVC is 
unlikely to occur in healthy premenarchal girls.  Sponsors should include in phase 3 clinical trials 
postmenarchal adolescent girls with VVC, if appropriate.  Including adolescents in phase 3 
clinical trials may fulfill the required pediatric clinical development plans. 
 
In general, safe and effective treatments are available for pregnant women with VVC.  
Therefore, it is generally acceptable for sponsors to complete phase 3 clinical trials that establish 
safety and efficacy in nonpregnant women before initiating trials in pregnant women.  However, 
if current effective therapy is unavailable, such as for a pregnant woman who is allergic to all 
available drugs for treating VVC, it may be appropriate for sponsors to offer the pregnant woman 
the investigational drug.  Before considering using 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.  Additionally, sponsors should follow 
infants born to mothers who received the investigational drug for an appropriate period of time 
based on available nonclinical and clinical data. 
 
6.  Dose Selection 
 
Sponsors should integrate findings from nonclinical studies, pharmacokinetic and dose-ranging 
studies, and safety information from earlier stages of clinical development to select the dose or 
doses to be evaluated in phase 3 clinical trials.  Sponsors should also evaluate the 
pharmacokinetics of the drug in specific populations (e.g., adolescent patients, patients with renal 
                                                 
10 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). 
 
11 See the Pediatric Research Equity Act (Public Law 108-155; section 505B of the Federal Food, Drug, and 
Cosmetic Act; 21 U.S.C. 355c), as amended by the Food and Drug Administration Safety and Innovation Act of 
2012 (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 Pediatric Study Plans (March 2016).  When final, this 
guidance will represent FDAs current thinking on this topic. 
4  Contains Nonbinding Recommendations 
or hepatic impairment) before initiating phase 3 clinical trials to determine dosing in patients in 
those populations and to facilitate the patients inclusion in phase 3 clinical trials. 
 
7.  Choice of Comparators 
 
For most superiority trials, the control group should be an oral placebo for an oral drug or a 
vehicle control for a drug administered topically.  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 antifungal effect).  Appropriate active comparators can be used as a control provided 
superiority is demonstrated. 
 
8.  Efficacy Endpoints 
 
The primary efficacy endpoint should be clinical cure, defined as the absence of all signs and 
symptoms of VVC.12 
 
Sponsors should consider the following secondary endpoints: 
 
  Vaginal swab culture negative for growth of Candida species 
 
  Responder outcome, defined as absence of signs and symptoms plus vaginal swab 
culture negative for growth of Candida species 
 
9.  Trial Procedures and Timing of Assessments 
 
The following are the recommended trial procedures and the timing of assessments: 
 
  Entry visit:  Sponsors should collect appropriate demographic information, history and 
physical examination findings, a microbiological specimen, and safety laboratory tests 
(including pregnancy testing).  Sponsors should also randomize patients and give them 
the investigational or control treatment. 
 
  On-therapy assessment:  Sponsors should use telephone calls or diary card entries to 
assess symptom improvement/resolution and adverse effects. 
 
  Patient 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), sponsors should assess the primary efficacy endpoint at 
this visit (can serve as the test-of-cure visit).  For topical drugs that are administered for a 
short period of time (e.g., 1 to 2 days) and have antifungal activity for a short time, 
sponsors should assess the primary efficacy endpoint at this visit.  Sponsors should also 
collect adverse-event information and, if appropriate, safety laboratory tests. 
                                                 
12 Please refer to the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 
Development to Support Labeling Claims (December 2009) if sponsors would like to propose a more clinically 
relevant endpoint regarding symptom improvement/resolution. 
5  Contains Nonbinding Recommendations 
 
  Patient visit at 21 to 30 days after randomization:  For systemic drugs that are 
administered for a longer period of time (e.g., 1 week) and/or have a long half-life (e.g., 
greater than 24 hours), sponsors should assess the primary efficacy endpoint at this visit 
(can serve as the test-of-cure visit).  For topical drugs that are administered for a longer 
period of time (e.g., 1 week) and/or maintain antifungal activity for a longer time, 
sponsors should assess the primary efficacy endpoint at this visit.  If the test-of-cure visit 
occurs at the earlier time point (e.g., 7 to 14 days after randomization), then sponsors can 
assess at this (21 to 30 days) visit the continued clinical response to treatment and 
adverse-event occurrence.  In such a scenario, the 21- to 30-day visit can be conducted by 
telephone. 
 
FDA recommends a patient diary for collecting information about investigational drug 
administration, assessment of symptoms, and adverse events.  Sponsors can assign patients who 
have continued or worsening symptoms before the test-of-cure visit as a treatment failure and 
can offer them rescue therapy for VVC. 
 
10.  Statistical Considerations 
 
In general, sponsors should submit a detailed statistical analysis plan stating the trial hypotheses 
and the analysis methods before initiating trial.  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 who have Candida species 
isolated on culture of vaginal specimen at baseline 
 
  Per-protocol population:  Patients who qualify for the mITT population and who follow 
important components of the trial, which include patients who adhere to the treatment and 
follow up for the efficacy assessment within the prescribed time frame 
 
Sponsors should consider the mITT population the primary analysis population.  In general, 
sponsors should not consider analyses of the per-protocol populations as primary because 
postrandomization events or characteristics could potentially bias results in this population.  
However, sponsors should evaluate the consistency of the results in all patient populations.  
Sponsors should also make every attempt to limit the drop out of patients from the trial and 
should specify in the protocol the method for handling missing data. 
 
6  Contains Nonbinding Recommendations 
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 expected to 
be superior to the control.  A two-sided type I error rate of 0.05 and a type II error rate between 
0.10 and 0.20 are usually specified.  Expected success rates are typically based on results 
obtained in phase 2 clinical trials or other information. 
 
C.  Other Considerations 
 
1.  Ethical Considerations 
 
Rescue therapy can be incorporated into the placebo-controlled trial design so that individual 
patients are treated at the time a failure outcome is assigned, which may mitigate ethical 
concerns about including a placebo group in a trial.  All trials should provide appropriate 
provisions for patient safety. 
 
2.  Relevant Nonclinical Considerations 
 
Investigational drugs being studied for VVC should have nonclinical data documenting activity 
against Candida species.13 
 
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 infections may not be 
appropriate for drugs used for treating VVC.  However, sponsors should consider the following 
pharmacokinetic evaluations.  
 
For a drug administered topically into the vagina and/or the area surrounding the vagina, it is 
important that sponsors determine systemic drug exposure as part of the safety assessment.  
Sponsors can evaluate systemic exposure following topical vaginal administration in females 
with VVC or in healthy females without VVC because the extent of systemic drug absorption is 
not related to the presence or absence of VVC. 
 
For a drug administered systemically for treating VVC (e.g., oral), sponsors should adequately 
characterize the systemic/vaginal exposure and other relevant clinical pharmacology aspects of 
the drug (e.g., drug-drug interactions, QT prolongation,14 dosage adjustment in renal and/or 
hepatic impairment, food effect).  Sponsors should discuss with FDA the need to evaluate 
pertinent drug-drug interactions, particularly with oral contraceptives.  Additionally, sponsors 
                                                 
13 See the Pharmacology/Toxicology guidance web page at https://www.fda.gov/drugs/guidances-drugs/all-
guidances-drugs. 
 
14 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs (October 2005). 
7  Contains Nonbinding Recommendations 
should conduct in the early stages of development (e.g., phase 2) dose-ranging studies with 
exposure-response analyses for both efficacy and safety in VVC patients to inform dosage in 
later trials. 
8