# Presentation: 522097

## Bacterial Vaginosis Guidance Document

- Daniel Davis, MD, MPH
- ODE IV
- DAVISD@CDER.FDA.GOV

## Current Clinical Background

- Bacterial Vaginosis (BV) causes 40-50% of all vaginal infections.
- Risk factors include prior pregnancy and sexual activity.
- Associated with:
- Recurrent UTI
- Pelvic Inflammatory Disease (PID)
- Post-op Gyn & postpartum infections

- July 1998

## BV and Pregnancy

- 15-20% of US pregnant women have BV
- BV is associated with:
- chorioamnionitis
- preterm labor
- prematurity
- FDA approved regimens in pregnancy:
- metronidazole
- clindamycin

- July 1998

## History of BV Therapy

- 1960-70’s: Poor efficacy with:
- triple-sulfa creams
- erythromycin and tetracycline
- povidone-iodine
- douches
- 1970’s: Moderate cures with:
- ampicillin
- amoxicillin

- July 1998

## History of BV Therapy (contd.)

- 1980’s: metronidazole and clindamycin used off-label, oral and topical.
- 1990’s: FDA-approved regimens for:
-  3, 5, & 7 days
- oral or topical
- prescription only
- metronidazole & clindamycin

- July 1998

## Document Objectives

- The intent of this guidance document is to present guidelines regarding:
- clinical trial design
- evaluability criteria
- endpoints
- statistical considerations

- July 1998

## Study Considerations

- The Division recommends 2 trials:
- statistically adequate and well-controlled
- multi-center
- establishing equivalence or superiority
- comparator drug product
- the standard of care, _and_
- already approved by the FDA for BV

- July 1998

## Study Considerations (contd.)

- Randomization : all patients meeting the inclusion/exclusion criteria.
- Follow-up: try to maximize
- Blinding : at least investigator blinded
- Double blinded where possible
- Both arms: same routes of administration
- NO intravaginal placebo (where Rx arms differ)

- July 1998

## Study Considerations (contd.)

- Microbiological:
- Cultures for BV are not recommended:
- NO clearly established pathogen
- Cultures for common STDs recommended:
- R/O concomitant infections
- Pregnancy: may be included after 1st trimester, unless drug safety is an issue.

- July 1998

## Inclusion Criteria

- Postmenarchal females with a Dx of BV based on _all_ four findings:
- Homogeneous thin adherent discharge with minimal or absent inflammation
- Vaginal pH >4.5
- >20% “clue cells” on wet mount
- Positive “whiff” or amine test (10% KOH)

- July 1998

## Clue cell

- July 1998

## Exclusion Criteria

- Other causes of vulvovaginal pathology:
- infectious
- non-infectious
- Patients who received antifungal / antimicrobial Rx within 14 days of entry.
- Pregnant women in the first trimester.
- Later pregnancy:
- if drug safety concerns exist

- July 1998

## Drug Compliance

- Evaluability depends on treatment duration in the study arm.
- Single dose should receive all drug
- 3 day therapy should receive all drug
- 5 to 7 day Rx should receive at least first 3 consecutive days of drug

- July 1998

## Evaluation Visits 

- Previously, 3 visits recommended for evaluability.
- Now recommend:
- 2 visits
- patient diary
- interim telephone contact

- July 1998

## Evaluation Schedule 

- Entry Visit:
- Focused history and physical:
- contraception, past BV, sexual activity
- Pap, “wet mount,” 10% KOH “whiff test”
- Gram stain: goes to central reference lab
- STD cultures: GC, Chlamydia, Trich
- Patient diary card + instructions

- July 1998

## Interim phone call: 
(7-10 days after study Day 1)
Not critical for evaluability
Patient protocol and diary compliance 
Response to treatment
Record adverse events (AEs)

- (7-10 days after study Day 1)
- Not critical for evaluability
- Patient protocol and diary compliance
- Response to treatment
- Record adverse events (AEs)

- Evaluation Schedule (contd.)

- July 1998

## Evaluation Schedule  (contd.)

- Test-of-Cure (TOC) visit:
- (Days 21-30 of study)
- “Wet mount,” 10% KOH “whiff test”
- Gram stain: goes to same reference lab
- Patient diary card + Sn/Sx evaluation
- STD cultures, if clinically indicated
- Investigator’s clinical assessment

- July 1998

## Therapeutic Outcome (contd.)

- In the past: 3 categories
- Clinical Cure
- Clinical Improvement
- Clinical Failure
- Now recommend composite dichotomous outcome of:
- Therapeutic Cure or Failure

- July 1998

## Therapeutic Outcome (contd.)

- Based on combination of:
- Clinical Outcome (Cure/Failure)                   _AND_
- Nugent Scoring System (Cure/Failure)
- Gram stain results
- Central reference lab
- Standardized criteria

- July 1998

## Clinical Outcome

- Clinical Cure
- Return to “normal” physiological discharge
- Negative “whiff” test
- Saline wet mount negative for “clue cells”
- Vaginal pH <4.7
- Clinical Failure
- Does _not_ meet definition of cure
- Investigator determination
- Use of other BV Rx during study

- July 1998

## Nugent Scoring System

- July 1998

## Nugent Score Outcome

- Total score = the sum of the 3 weighted scores based on the quantification of 3 different bacterial morphotypes.
- Normal = score of 0-3
- “Intermediate” = score of 4-6
- BV = score of 7 or more
- Division recommendations:
- >3 to be abnormal (entry criteria)
- 0-3 to be normal (cure criteria)

- July 1998

## Overall Therapeutic Outcome at TOC

- July 1998

## Evaluability

- As a Cure
- TOC visit between Days 21-30 of study
- No other antimicrobial drug used
- Rx started within 48 hours of randomization
- No protocol violations
- No other intravaginal products Days 1-7

- July 1998

## Evaluability (contd.)

- As a Failure
- Assessment between Days 4-30
- Additional antimicrobial drug used
- Investigator’s clinical determination

- July 1998

## Non-Evaluability

- Entry Nugent score <4
- Did not comply with minimum days Rx
- Started drug > 48 hours after randomization
- Used other vaginal interventions Days 1-7
- Missing clinical or Gram stain data

- July 1998

## Analytical Considerations

- Recommend analyses be performed on two populations:
- Per protocol (strictly evaluable)
- Intent-to-treat (anyone randomized)
- Primary Efficacy Variable
- Therapeutic cure rate at TOC visit

- July 1998

## Statistical Considerations

- Two multicenter trials
- Each trial should be adequately powered to demonstrate therapeutic equivalence of the  test drug to the comparator for the _per protocol_ evaluable population.
- Using a 95% CI around the difference in the two therapeutic cure rates

- July 1998

## Past, Present, and Future...

- New entry criteria:
- Nugent’s score >3
- Number of visits:
- 2 instead of 3
- Add interim phone call
- New therapeutic outcome:
- Based on clinical + Nugent’s score
- NO “improvement” category

- July 1998

## Questions for the Committee#1

- Does the AC agree with the proposed use of the Nugent scoring system, and the criteria that an overall therapeutic cure is based on a combination of clinical outcome + Nugent scoring system ?
- Standardized; comparative; central lab
- Allows outside “unbiased” interpretation
- Allows strict criteria for both Dx and cure
- “Improvement” category eliminated

- July 1998

## Questions for the Committee#2

- Does the AC agree with the recommendation that the TOC visit occur between Days 21-30?
- BV is a derangement of the “normal” polymicrobial vaginal flora.
- Literature is unclear as to the time for the vaginal flora to “normalize” following antibiotic usage.

- July 1998

## Questions for the Committee#3

- Does the AC believe placebo-controlled trials are ethical and desirable for BV (in contrast with blinded active-controlled studies)?
- BV is a very common infection with mild symptoms
- Better AE evaluation
- Can measure placebo effect
- Unknown efficacy rates if the new proposed guidance is followed

- July 1998