The Food and Drug Administration (FDA)’s Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) voted 14 to 1 (with 1 abstention) in favor of the approval of Twirla (Agile Therapeutics), an investigational combined hormonal contraceptive (CHC) patch (AG200-15).
The transdermal system is designed to deliver 120mcg of levonorgestrel and 30mcg of ethinyl estradiol per day and is applied once every 7 days for 3 consecutive weeks followed by 1 week without a patch. In their submission, the Company claimed that the Twirla patch was a “low-dose” contraceptive option, however the committee noted that it should not be given that distinction given that the data showed an ethinyl estradiol exposure similar to a product containing 35mcg.
While the panel agreed that use of Twirla would reduce the risk of pregnancy compared with no contraceptive use, they expressed concern over the efficacy results. Specifically, they found the Pearl Index (pregnancy rate per 100 women-years of drug exposure) and upper bound of the 95% confidence interval (CI) “unacceptable for a CHC product when considering alternative products available in the US market.”
A summary of efficacy results showed that the overall Pearl Index (PI) in the primary efficacy population (≤35 years old regardless of BMI or weight) was 5.83 (95% CI: 4.45, 7.21). In women with BMI <30kg/m2, the PI was 4.34 (95% CI: 2.86, 5.82), while in those with BMI ≥30kg/m2, the PI was 8.64 (95% CI: 5.79, 11.50). In a previous meeting held in October 2013, the Company was informed that the FDA would not approve a contraceptive product for which the upper bound of the 95% CI around the PI exceeds 5.
To address this issue, Agile proposed that a Limitation of Use statement be included in the product labeling regarding lower efficacy in women with BMI ≥30kg/m2 and weight ≥92kg. The panel shared concerns over this approach stating that the data clearly showed that the patch was not as effective in women with BMI ≥30kg/m2 and therefore would be better suited as a contraindication. In addition, they noted that the statement does not address concerns about the high PI observed in the overall population.
As for safety, the panel concluded that there was not enough data to determine whether use of Twirla patch was associated with improved safety with regard to venous thromboembolism when compared with other CHCs. In addition, in one study, 40% of women reported unscheduled vaginal bleeding after 13 cycles of treatment, raising concerns over tolerability and compliance.
Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act date of November 16, 2019 has been set for the application. Currently, the only other CHC transdermal system available on the market is a generic version of Ortho Evra (Xulane) that delivers 150mcg of a different progestin, norelgestromin, and 35mcg of ethinyl estradiol per day.
For more information visit fda.gov.