Regulatory Decision Summary for Intrarosa

In this NDS the sponsor submitted reports of 6 clinical studies to support the proposed indication.

Four of the five Phase 3 trials conducted were randomized, placebo-controlled, double-blind studies of 12 weeks duration. The fifth Phase 3 trial was a single-arm 52-week study, which provided longer-term safety data.

Across the trials, the prasterone vaginal ovules induced favorable changes at the level of the vaginal mucosa, including improved pH and maturation index. Dose ranging studies defined the optimal dosage for complete transformation of the vaginal mucosa as prasterone vaginal ovules 6.5 mg (0.50%) daily. Improvement in the vaginal mucosa was evident following 7 days of treatment and was maintained through 52 weeks. Daily administration of the drug was necessary, since decreasing the frequency of application to twice weekly led to diminished improvement in vaginal atrophic changes. Consistent with the observed cytological changes, patient-reported efficacy parameters were improved, with decreases in the mean severity scores of dyspareunia, as well as vaginal dryness, and vaginal irritation / itching.

Endometrial biopsies performed after 52 weeks of Intrarosa treatment showed no evidence of hyperplasia. The most common reported adverse reaction to Intrarosa, reported in approximately 15% of patients, was application site discharge.

Cases of abnormal Pap smear cytology were observed in patients receiving Intrarosa, including cases of Atypical Squamous Cells of Unknown Significance (ASCUS), low grade squamous intraepithelial lesion, and a single case of a high grade squamous epithelial lesion. The relationship, if any, of these cytological changes to Intrarosa exposure is unclear. The Product Monograph describes the occurrence of abnormal cervical cytology in the clinical trials, and recommends that patients undergo regular gynecological examinations.

Review of the Chemistry and Manufacturing (C&M) portion of the original NDS identified several deficiencies and data gaps which precluded continuing review of the submission, leading to issuance of a Notice of Deficiency (NOD) on September 28, 2017. In the subsequent Response to NOD, further C&M deficiencies were identified, resulting in issuance of a Notice of Non-Compliance (NON) on February 8, 2019. With submission of a Response to the NON, these issues have been satisfactorily resolved.

A Risk Management Plan (RMP) for Intrarosa was submitted by the sponsor to the Marketed Health Products Directorate and was found to be acceptable with revisions.