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Vulvovaginal Candidiasis: Developing Drugs for Treatment Guidance for Industry - PharmaFacts
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Vulvovaginal Candidiasis: Developing Drugs for Treatment Guidance for Industry

Vulvovaginal

Candidiasis: Developing

Drugs for Treatment Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written 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 Shrimant Mishra, MD, at 301-796-1400.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

July 2016 Clinical/Antimicrobial

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15051dft.doc 06/28/16

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: This e-mail address is being protected from spambots. You need JavaScript enabled to view it http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

July 2016 Clinical/Antimicrobial

I. II.

A.

1. 2. 3.

B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 DEVELOPMENT PROGRAM ....................................................................................... 2 General Considerations .................................................................................................................2

Drug Development Population.........................................................................................................2 Efficacy Considerations ...................................................................................................................2 Safety Considerations.......................................................................................................................2 Specific Efficacy Trial Considerations .........................................................................................3

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

a.

b.

Clinical Trial Designs ......................................................................................................................3 Clinical Microbiology Considerations .............................................................................................3 Enrollment Criteria ..........................................................................................................................3 Randomization and Blinding ............................................................................................................4 Specific Populations.........................................................................................................................4 Dose Selection ..................................................................................................................................5 Choice of Comparators ....................................................................................................................5 Efficacy Endpoints............................................................................................................................5 Trial Procedures and Timing of Assessments ..................................................................................5

Statistical Considerations ............................................................................................................6

Analysis populations..................................................................................................................6

Sample size................................................................................................................................7

C. Other Considerations .....................................................................................................................7

1. Ethical Considerations .....................................................................................................................7 2. Relevant Nonclinical Considerations...............................................................................................7 3. Pharmacokinetic/Pharmacodynamic Considerations ......................................................................7

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  1. 1 Vulvovaginal Candidiasis:

  2. 2 Developing Drugs for Treatment

  3. 3 Guidance for Industry1

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I. INTRODUCTION 18

  1. 19  The purpose of this guidance is to assist sponsors in the overall clinical development program

  2. 20  and clinical trial designs to support drugs for the treatment of vulvovaginal candidiasis (VVC).2

  3. 21  This draft guidance is intended to serve as a focus for continued discussions among the Division

  4. 22  of Anti-Infective Products, pharmaceutical sponsors, the academic community, and the public.3

23

  1. 24  In general, this guidance focuses only on developing antifungal drugs for the treatment of

  2. 25  uncomplicated VVC, generally defined as a single episode of vaginal inflammation caused by

  3. 26 Candida yeast in an otherwise healthy female. For complicated VVC (e.g., patients who have

  4. 27  recurrent VVC, defined as having four or more episodes of VVC in a 1-year time frame), the

  5. 28  dose, duration, or formulation of antifungal treatment may be different in comparison to

  6. 29  uncomplicated VVC. Sponsors should discuss with FDA the clinical development programs for

  7. 30  treatment of complicated VVC.

31

  1. 32  This guidance does not discuss trial designs for development programs for nonprescription

  2. 33  treatments of VVC. This guidance also does not contain discussion of general issues in drug

  3. 34  development or general issues of statistical analysis or clinical trial design. Those topics are

    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 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that arise during the development of drugs for the treatment of VVC.

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This draft guidance, when finalized, will represent 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 staff responsible for this guidance as listed on the title page.

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  1. 35  addressed in the ICH guidances for industry E9 Statistical Principles for Clinical Trials and E10

  2. 36 Choice of Control Group and Related Issues in Clinical Trials, respectively.4

37

  1. 38  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 39  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 40  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 41  the word should in Agency guidances means that something is suggested or recommended, but

  5. 42  not required.

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II. 46
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  1. 51  Sponsors should enroll postmenarchal females with a clinical diagnosis of uncomplicated VVC.

  2. 52  Sponsors should discuss with FDA if the trial population plans to include patients who have

  3. 53  HIV/AIDS or diabetes mellitus.

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2. Efficacy Considerations 56

  1. 57  In general, two adequate and well-controlled trials are recommended for the demonstration of

  2. 58  efficacy (see 21 CFR 314.126). If the drug is being developed for other infectious disease

  3. 59  indications, sponsors should discuss with FDA the potential situations in which one trial would

  4. 60  provide evidence of effectiveness, supported by evidence of effectiveness for the other infectious

  5. 61  disease indications.5

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3. Safety Considerations 64

  1. 65  The recommended size of the safety database depends on whether the drug is administered

  2. 66  systemically or topically, and the level of systemic absorption. If the same therapy for treatment

  3. 67  of VVC were used in clinical trials for other infectious disease indications, the safety information

  4. 68  from those clinical trials typically can be included in the overall preapproval safety database.

  5. 69  Sponsors should discuss the appropriate size of the preapproval safety database with FDA during

  6. 70  clinical development.

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  1. 72  For drugs administered topically, human safety evaluations should focus on local toxicities of the

  2. 73  cervicovaginal area in addition to systemic toxicities.

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4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

5 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.

DEVELOPMENT PROGRAM
A. General Considerations
1. Drug Development Population

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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.

2. Clinical Microbiology Considerations

An appropriate vaginal swab specimen should be obtained for microbiologic evaluation. Specimens should be collected, processed, and transported according to appropriate methods.6

Specimens collected to aid in the diagnosis of VVC 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 methods such as those recommended by the Clinical and Laboratory Standards Institute (CLSI).8

3. Enrollment Criteria

Inclusion criteria for VVC trials should include postmenarchal females who have a clinical diagnosis of VVC, defined as having a white or creamy vaginal discharge plus the following findings:

Two or more of the following signs and symptoms of VVC that are characterized as moderate or severe: itching, burning, irritation, edema, redness, or excoriation9

KOH or saline preparation from the inflamed vaginal mucosa or secretions revealing yeast forms (hyphae or pseudohyphae) or budding yeasts

Normal vaginal pH (greater than or equal to 4.5)
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 There should be at least two signs or symptoms are of at least moderate severity. Signs and symptoms can be rated on a scale and evaluated using a score based on a numerical rating of severity (absent=0; mild=1; moderate=2; severe=3) for each symptom. The purpose of the qualitative evaluation of signs and symptoms at baseline is to establish a patient population with sufficient severity of uncomplicated VVC for trial enrollment. See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims.

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107 The following patients should be excluded from VVC trials: 108
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  1. 119  Eligible patients should be randomized to treatment groups at enrollment. All trials should be

  2. 120  multicenter and double-blinded to control for potential biases.

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5. Specific Populations 123

  1. 124  The trials should include patients of all races, as well as geriatric patients.10 Patients with renal

  2. 125  or hepatic impairment can be enrolled if appropriate dosing regimens have been defined.

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  1. 127  Sponsors are encouraged to begin discussions about their pediatric clinical development plan as

  2. 128  early as is feasible because pediatric studies are a required part of the overall drug development

  3. 129  program and sponsors are required to submit pediatric study plans no later than 60 days after an

  4. 130  end-of-phase 2 meeting or such other time as may be agreed upon by FDA and the sponsor.11

  5. 131  Uncomplicated VVC is unlikely to occur in healthy premenarchal girls. Postmenarchal

  6. 132  adolescent girls with VVC should be included in phase 3 trials, if appropriate. Inclusion of

  7. 133  adolescents in phase 3 trials is capable of fulfilling the required pediatric clinical development

  8. 134  plans.

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  1. 136  In general, safe and effective treatments are available for pregnant patients with VVC.

  2. 137  Therefore, it is generally acceptable to complete phase 3 clinical trials that establish safety and

  3. 138  efficacy in nonpregnant patients before trials in pregnant patients are initiated. However, if

  4. 139  current effective therapy is unavailable, such as a pregnant patient who is allergic to all available

  5. 140  drugs for treatment of VVC, it may be appropriate to offer the investigational drug in the

  6. 141  pregnant patient. Before sponsors consider use of an investigational drug in pregnant women,

  7. 142  nonclinical toxicology studies, reproductive and developmental toxicology studies, and phase 1

  8. 143  and phase 2 clinical trials should be completed. Infants born to mothers who received the

    10 See the ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics and E7 Studies in Support of Special Populations: Geriatrics; Questions and Answers.

    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. When final, this guidance will represent FDA’s current thinking on this topic.

Patients with other infectious causes of vulvovaginitis (e.g., bacterial vaginosis, Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex, or human papilloma virus) or with mixed infections

Patients who were treated for VVC within the past month
Patients who are currently receiving antifungal therapy unrelated to VVC
4. Randomization and Blinding

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investigational drug should be followed for an appropriate period of time based on available nonclinical and clinical data.

6. DoseSelection

Sponsors should integrate findings from nonclinical studies, pharmacokinetics, and safety information from earlier stages of clinical development to select the dose or doses to be evaluated in phase 3 clinical trials. The pharmacokinetics of the drug in specific populations (e.g., adolescent patients, patients with renal or hepatic impairment) should be understood before initiation of phase 3 trials to determine whether dose adjustments are necessary. This evaluation may prevent the exclusion of such patients from the phase 3 clinical trials.

7. Choice of Comparators

For most superiority trials, the control group for VVC should be an oral placebo 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.

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 bullet points outline the recommended trial procedures and the timing of assessments:

Entry visit: Appropriate demographic information, history and physical examination findings, a microbiological specimen, and safety laboratory tests (including pregnancy testing) should be collected at this visit; patients should be randomized and receive the investigational drug or control treatment at this visit.

On-therapy assessment: Telephone calls or diary card entries should be used to assess for adverse effects.

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Test-of-cure visit, approximately 7 to 14 days after randomization: This visit should assess the primary efficacy endpoint. Adverse effect information and, if appropriate, safety laboratory tests should also be collected. The timing of this visit depends on the total duration of antifungal therapy.

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  1. 198  A patient diary is recommended for the collection of information regarding investigational drug

  2. 199  administration, assessment of symptoms, and adverse events. Patients who have continued or

  3. 200  worsening symptoms before the test-of-cure visit can be assigned as a treatment failure and

  4. 201  offered rescue therapy for VVC.

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10. Statistical Considerations 204

  1. 205  In general, a detailed statistical analysis plan stating the trial hypotheses and the analysis

  2. 206  methods should be submitted before trial initiation. The primary efficacy analysis should be

  3. 207  based on a comparison of the proportions of patients achieving a successful efficacy outcome.

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  1. 226  The mITT population should be considered the primary analysis population. In general,

  2. 227  sponsors should not consider analyses of the per-protocol populations as primary because

  3. 228  postrandomization events or characteristics could potentially bias results in this population.

  4. 229  However, consistency of the results should be evaluated in all patient populations. Every attempt

  5. 230  should be made to limit the loss of patients from the trial. The method for handling missing data

  6. 231  should be specified in the protocol.

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Visit at 21 to 30 days after randomization: This visit should assess the continued clinical response to treatment and adverse events. Contact with the patient by telephone may be sufficient for this visit.

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 — The population of patients who qualify for the mITT population and who follow important components of the trial (important components of the trial include patients who adhere to the treatment and follow-up for the efficacy assessment within the prescribed time frame)

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233 b. Sample size 234

  1. 235  The sample size is influenced by several factors including the prespecified type I and type II

  2. 236  error, the expected success rate, and the amount by which the investigational drug is expected to

  3. 237  be superior to the control. A two-sided type I error rate of 0.05 and a type II error rate between

  4. 238  0.10 and 0.20 are usually specified. Expected success rates are typically based upon results

  5. 239  obtained in phase 2 trials or other information.

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C. Other Considerations 242
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1. Ethical Considerations 244

  1. 245  Rescue therapy can be incorporated into the placebo-controlled trial design so that individual

  2. 246  patients are treated at the time a failure outcome is assigned: this may serve to mitigate ethical

  3. 247  concerns regarding inclusion of a placebo group in a trial. All trials should provide appropriate

  4. 248  provisions for patient safety.

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2. Relevant Nonclinical Considerations 251

  1. 252  Investigational drugs being studied for VVC should have nonclinical data documenting activity

  2. 253  against Candida species. Guidance for industry provides information for sponsors on nonclinical

  3. 254  considerations for drug development in general and also nonclinical considerations for drugs

  4. 255  administered topically.12

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3. Pharmacokinetic/PharmacodynamicConsiderations 258

  1. 259  Pharmacokinetic/pharmacodynamic approaches typically used to identify appropriate dosing

  2. 260  regimens for evaluation in phase 2 and phase 3 clinical trials for systemic infections may not be

  3. 261  appropriate for drugs used for the treatment of VVC. However, the following pharmacokinetic

  4. 262  evaluations should be considered.

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  1. 264  For a drug administered topically into the vagina and/or the area surrounding the vagina, it is

  2. 265  important to determine systemic drug exposure as part of the safety assessment. Evaluation of

  3. 266  systemic exposure following topical vaginal administration can be performed in females with

  4. 267  VVC or in healthy females without VVC because it is deemed that the extent of systemic drug

  5. 268  absorption is not related to the presence or absence of VVC.

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12 See the Pharmacology/Toxicology guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065014.htm; for example, see the guidance for industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products; and, given the unique characteristics of a topical administration, sponsors of a topical drug may want to refer to the discussions of nonclinical safety evaluations in the guidance for industry Nonclinical Pharmacology/Toxicology Development of Topical Drugs Intended to Prevent the Transmission of Sexually Transmitted Diseases (STD) and/or for the Development of Drugs Intended to Act as Vaginal Contraceptives. See also the guidance for industry Vaginal Microbicides: Development for the Prevention of HIV Infection on the Clinical/Antimicrobial guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064980.htm.

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  1. 270  For a drug administered systemically for treatment of VVC (e.g., oral), the systemic/vaginal

  2. 271  exposure and other relevant clinical pharmacology aspects of the drug (e.g., drug-drug

  3. 272  interactions, QT prolongation,13 dosage adjustment in renal and/or hepatic impairment, food

  4. 273  effect) should be adequately characterized. Sponsors should discuss with FDA the need to

  5. 274  evaluate pertinent drug-drug interactions, particularly with oral contraceptives. In addition,

  6. 275  dose-ranging studies in VVC patients can be considered as an option in the early stages of

  7. 276  development to help determine an adequate dosage regimen to bring forth in later trials.

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13 See the ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.

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