Most of the committee members based their decisions on the need for additional contraceptive options for patients. However, most also expressed concerns about its efficacy and offered suggestions for product labeling that called attention to high rates of unintended pregnancies and increased risk of venous thromboembolism (VTE) in obese women.
The agency’s Bone, Reproductive and Urologic Drugs Advisory Committee reviewed safety and efficacy data for AG200-15, a combined hormonal contraceptive patch developed by Agile Therapeutics. The treatment regimen involves application of a patch to the abdomen, buttock, or upper torso, and the patch is changed weekly for 3 weeks, followed by 1 week without a patch.
, consultant and former chief medical officer of Agile, presented study data on safety and effectiveness of the patch. The key study (known as Study 23) considered by the FDA included 1,736 women aged 35 years and younger. The primary efficacy endpoint was the pregnancy rate in the women who used the patch. Women reported sexual activity and back-up contraception use in e-diaries.
A total of 68 pregnancies occurred in the study population after 15,165 evaluable cycles, yielding an overallof 5.83 across all weight and body mass index groups. Historically, a Pearl Index of 5 has been the standard measure for effectiveness in contraceptive products, with lower being better. The index is defined as the number of pregnancies per 100 woman-years of product use. For example, a Pearl Index of 0.1 means that 1 in 1,000 women who use the same contraceptive method for 1 year becomes pregnant.
A subgroup analysis showed reduced efficacy in women with a higher BMI. The Pearl Index for women with a BMI of less than 30 kg/m2 (defined as nonobese) was 4.34, whereas in women with a BMI of 30 kg/m2 and higher (defined as obese), the index was 8.64, nearly double that of nonobese women. No significant differences in the index were noted based on race/ethnicity.
The company described the patch as filling a niche and providing an additional alternative for women seeking a noninvasive method of contraception. It proposed a limitation of use (LOU) as part of the product label that would provide detailed information on efficacy based on the Pearl Index for the different categories of BMI and would suggest that the patch may be less effective for women with obesity. Most of the committee members favored use of a LOU statement on the label, but some noted that it might limit prescriptions to nonobese women.
The committee expressed concern over the Pearl data in the study. The FDA has never approved a contraceptive product with a Pearl Index of greater than 5, said Yun Tang, PhD, a statistical reviewer for the agency’s Office of Translational Sciences, who presented the evaluation of the effectiveness of AG200-15.
Key safety concerns raised in discussion included the risk of venous thromboembolism and the risk of unscheduled bleeding. Both of those issues were significantly more common among obese women, said, clinical reviewer for the FDA, who presented details on the safety profile and risk-benefit considerations for the patch.
Overall, in Study 23, the incidence rate of VTE was 28/10,000 women-years, with cases in five participants. Four of those were deemed related to the patch, and all occurred in obese women.
, of Oregon Health and Science University, Portland, voted no to recommending approval of the patch mainly because of efficacy concerns. “My goal is to do no harm, and I have concerns regarding efficacy and giving our patients a false sense of hope,” she said.
Even those members who voted yes expressed concerns about the efficacy data and VTE risk in obese women and recommended postmarketing studies and appropriate labeling to help clinicians in shared decision making with their patients.
, of the National Institutes of Health, noted that the patch fills a need, certainly for women with a BMI less than 30 kg/m2, and suggested that use be limited to women in that lower BMI category.
Other committee members suggested that the product not be restricted based on BMI, but rather that the LOU provide clear explanations of how effectiveness decreases as BMI increases.
, of the University of Pennsylvania, Philadelphia, opted to abstain from voting, in part based on concerns about the study design and a lack of additional data from the company.