Regulatory Decision Summary for Duavive

The information submitted in this SNDS did not support the following proposed indication: Duavive is indicated for the maintenance of BMD in postmenopausal women.

Both constituents of Duavive (conjugated estrogens [CE] and bazedoxifene acetate [BZA]) demonstrated an increase in bone mineral density at 24 months in postmenopausal women. However data demonstrating the effect of the combination product (CE/BZA) on fracture reduction was not submitted.

Safety and efficacy of CE/BZA for the maintenance of BMD has been demonstrated in two Phase 3 studies 303 (SMART 1) and 3307 (SMART 5).

The SMART 1 study (2 years) included 2 substudies:

• Bone Substudy I assessed women >5 years from their last menstrual period: n = 182 women receiving CEs 0.45 mg/BZA 20 mg and n = 173 women receiving CEs 0.625 mg/BZA 20 mg.
• Bone Substudy II and Metabolic Substudy assessed women between 1 and 5 years post menopause, with at least one additional risk factor for osteoporosis: n = 111 women receiving CEs 0.45 mg/BZA 20 mg and n = 105 women receiving CEs 0.625 mg/BZA 20 mg.

The SMART 5 study (1 year) assessed the efficacy of CEs/BZA for the maintenance of BMD in postmenopausal women in a substudy in women who were <5 years postmenopausal (n = 512).

BMD and bone turnover markers (BTMs) together are not considered adequate surrogate markers to support the proposed indication. In order to use BMD as a surrogate endpoint to support the indication for the maintenance of BMD, data which demonstrate a correlation between the BMD and vertebral fracture are required. Vertebral fracture data were not provided in the original new drug submission (NDS) or in this SNDS.

The data provided did not support the proposed indication of "maintenance of bone mass in postmenopausal women". However, information about the maintenance of BMD was included in the actions and clinical pharmacology section of the PM.