FOOD AND DRUG ADMINISTRATION
Center for Drug Evaluation and Research
ANTIVIRAL
DRUGS ADVISORY COMMITTEE (AVAC) MEETING
Questions to the Committee
Holiday
Inn,
Clinical Trial Design Issues
in the Development of Topical Microbicides
for the Reduction of HIV
Transmission
1. For topical microbicides, a conventional clinical development approach
of conducting Phase 2 ‘proof-of-concept’ trials before embarking on Phase 3
trials may require large numbers of participants. For antiretroviral
drugs, HIV RNA levels have been shown to be a valid surrogate marker for
predicting clinical outcome and short-term drug-induced changes in HIV RNA have
been employed in phase 2 proof-of-concept trials. However, biological correlates of the
effectiveness of topical microbicides for the
reduction of HIV transmission have not been determined. Please comment on the following alternative
approaches for clinical development of topical microbicides:
B. A stand-alone phase 2 trial
design targeted at high-risk populations (e.g. commercial sex workers) in
regions with high HIV seroincidence rates. If the
results of the phase 2 trial are promising, please comment on the feasibility
of conducting a subsequent phase 3 trial in general population. A phase 3
trial(s) of a microbicide conducted in a more
representative population of expected users is considered essential by FDA for
submission of a marketing application.
C. Does the Committee have
alternative design recommendations?
2. Given the advantages and
disadvantages of including a no-treatment arm (i.e. condom-only) in the design
of phase 3 trials, please discuss and rank the following design options:
A. 3-arm design (candidate microbicide, placebo, and no-treatment)
B. 2-arm design (candidate microbicide, placebo)
C. 2-arm design (candidate microbicide,
no-treatment)
3. If the committee is in favor
of the 3-arm design, does the committee agree with FDA’s definition of a ‘win’,
i.e., the microbicide arm has to show a significantly
better reduction in HIV seroconversion rate than both the placebo and ‘no-treatment’
arms?
4. High drop-out rates are a
major concern when determining the length of follow-up for phase 3 microbicide trials.
Factors such as mobility, adherence to product use, desire to be
pregnant, etc. can play a role. Please
discuss the following questions regarding on-treatment and off-treatment follow-up
duration.
A. How long should the
on-treatment evaluation be for a topical microbicide
product?
1).
12 months for every participant
2).
24 months for every participant
3). Follow-up continues until last patient
enrolled completes 12 or 24
months
4). Less than 12 months
B. Should there be an
off-treatment follow-up period after participants are off
the
study treatment (premature discontinuation or completed) in order to collect
efficacy
endpoints (with emphasis on HIV seroconversion)? If yes, then how
long?
5. Given the urgent public need for effective topical microbicides and the potential difficulty in conducting a second confirmatory trial in the setting of positive results from an initial phase 3 trial, the Agency considers that a single large well-controlled trial is an acceptable alternative to two adequate and well-controlled phase 3 trials. Under this approach, does the Committee agree with the range of p-values specified by the Division (< 0.01, 2-sided)? In interpreting results from a single large well-controlled trial, what other supportive evidence does the Committee like to have?