FDA CRL - TherapeuticsMD, Inc.

The Food and Drug Administration (FDA) issued a Complete Response letter to TherapeuticsMD, Inc. for its New Drug Application (NDA 208564) for estradiol vaginal insert, 4, 10 \u00b5g, submitted on July 7, 2016. The application, filed under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, was not approved due to significant clinical safety deficiencies. The primary issues identified were the absence of long-term endometrial safety data for chronic use and insufficient characterization of the product's general safety profile over an extended duration. The FDA emphasized that given the chronic nature of treating moderate-to-severe dyspareunia and the increased risk of endometrial hyperplasia/cancer with unopposed estrogen in postmenopausal women, the existing 12-week safety data were inadequate. To address these concerns, TherapeuticsMD is required to conduct a long-term endometrial trial of sufficient size and duration. This trial must adequately characterize both the endometrial safety and the long-term general safety profile of the product. Additionally, a comprehensive safety update, including all new clinical and nonclinical data and a summary of worldwide safety experience, must be provided with the resubmission. The FDA also advised addressing differences between the product and the USP monograph for Estradiol Vaginal Inserts, either by petitioning the USP for revisions or clearly indicating deviations on product labels.