We thank Drs. Azizi and Sinaeifar for their letter to the editor on our recent publication, “A phase 3, multicenter, randomized, placebo-controlled trial of monthly oral ibrexafungerp to reduce the incidence of recurrent vulvovaginal candidiasis”. Their comments on the analysis of outcomes rules reflect the complex considerations in designing an objective phase 3 clinical trial for a drug seeking a Food and Drug Administration (FDA) marketing approval. Although there is regulatory guidance by the FDA on the design of a clinical trial for acute vulvovaginal candidiasis, there is none for trials for recurrent vulvovaginal candidiasis. The protocol trial design and rules on patient outcomes in the study were agreed upon in discussions with the FDA and reflect the best design approach at this time for the approval of new drugs for the treatment of recurrent vulvovaginal candidiasis.
With regard to the first comment on consistency of outcomes in the various categories, the treatment effect of ibrexafungerp remains when the analysis is limited to culture-confirmed recurrences, as reported in the key secondary endpoint “Mycologically proven recurrence” in the publication. All the recurrences for this endpoint were culture-confirmed. Supplemental Table 2 provides the outcome for each of the different recurrent vulvovaginal candidiasis categories (overall, mycologically proven, presumed, and suspected).
In terms of the second comment on missing data imputed as drug failures, the handling of missing data in the study only included the 2 analyses listed in this letter. Patients with key missing assessments (ie, mycological data or clinical efficacy evaluation) were imputed as failures for the visits where this critical information was missing, and a sensitivity analysis was conducted removing participants with imputed clinical outcomes. Both analyses render similar conclusions. No other approaches to handling missing data were prospectively planned or conducted. Considering the limited number of participants for which clinical outcome was imputed as failure (ie, 6 in the ibrexafungerp group and 7 in the placebo group; Supplemental Table 5), it is unlikely that other missing data handling approaches would render a different conclusion.
Ibrexafungerp is the second drug ever approved in the United States for the reduction in the incidence of recurrent vulvovaginal candidiasis and we believe the study design for this publication is robust. We appreciate Drs Azizi and Sinaeifar’s interest in our recent publication and their insightful comments on patient stratification for study endpoints and patient outcomes.
O.G. is in the Editorial Board of Merck Professional Manual and Elsevier and topic contributor to UpToDate. P.N. and J.D.S. report no conflict of interest.
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