Center for Drug Evaluation and Research



Draft Questions

August 20, 2003

Holiday Inn, Versailles Ballroom, 8120 Wisconsin Avenue, Bethesda, MD 20814


Clinical Trial Design Issues

in the Development of Topical Microbicides

for the Reduction of HIV Transmission




1.     Currently no definitive biological correlates of effectiveness against HIV have been determined for topical microbicides.  Therefore the conventional clinical development approach of conducting Phase 2 ‘proof-of-concept’ trials before embarking on Phase 3 trials has become problematic. Please comment on the following alternative approaches for clinical development of topical microbicides.


A.    A phase 2-run in phase 3 trial design, with safety monitoring emphasized in the phase 2 portion.


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.  


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 comment on whether to


A.    include a third no-treatment (condom-only) arm, or

B.    exclude a third no-treatment (condom-only) arm.


3.     If the committee is in favor of including a no-treatment arm in a phase 3 trial design, does the committee agree with FDA’s definition of a ‘win’?


4.     If the Committee is in favor of a 2-arm trial design, which control should be used? Placebo or no-treatment (condom-only) control?




5.     High drop-out rates are a major concern when determining the length of follow-up for microbicide phase 3 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



          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




6.     Given the urgent public need for effective topical microbicides and that it may be difficult to conduct a second confirmatory trial in the setting of positive results from an initial phase 3 trial, the Agency has considered 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?