Claudia Nunez-Eddy, MS, National Center for Health Research, October, 30 2019
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. My name is Claudia Nunez-Eddy. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug and medical device companies, so I have no conflicts of interest.
When choosing a method of birth control, patients weigh many factors including, safety, efficacy, convenience, and personal preference. Patients use contraceptives more consistently when they are satisfied with their chosen method. A variety of safe, effective, and convenient contraceptive methods are needed to meet the needs of patients.
We would like to commend Agile for conducting several studies with racial and BMI diversity that reflects the US population seeking contraception. Women with obesity are often excluded from clinical trials, even though they comprise a substantial percentage of the US population.
We share FDA’s concerns about the efficacy of this product. The Pearl Index of 5.83 reported in Study 23 is higher than other combined hormonal contraceptives approved by the FDA. However, we agree that cross-study comparisons of effectiveness can be misleading, especially when the study populations and design are different. There are several factors, aside from product efficacy that could explain an increase in Pearl Indices between the sponsor’s product and previously approved contraceptives.
When looking at the Pearl Index in Study 23 for women with normal BMI, the Pearl Index of 3.46 with a 95% Confidence Interval upper bound of 5.16 does not seem to be substantially higher than other recently approved contraceptives that were tested in primarily thin, white women.
In addition, the sponsors initially conducted active-controlled trials that demonstrated a similar Pearl Index between AG200-15 and a combined hormonal oral contraceptive. Though the confidence interval was wide and FDA noted concerns about data collection and quality, this adds to the evidence that the real-world failure rates of previously approved contraceptives may be higher than the rates provided in the original clinical trials.
Unfortunately, because Study 23, which FDA focused on to determine efficacy, was a single armed trial, it is impossible to tell whether the study’s Pearl Indices are substantially different from other combined hormonal contraceptives had those studies included a similar demographic population with a similar study design.
There are major problems with directly comparing the results from Study 23 to previous contraceptive clinical trials submitted to the FDA. Differences in how the clinical trials determine the pearl index, such as excluding cycles where no sexual activity occurred, as well as improved accuracy of pregnancy testing may make these comparisons inaccurate.
A particularly important point is that increases in women’s BMI also make using historical controls inadequate, because most contraceptive clinical trials have included only a limited number of overweight and obese women. As a result, there may be a wide gap between clinical trial efficacy and real-world effectiveness. Without comparative effectiveness trials, it is impossible to evaluate whether a new hormonal contraceptive is as safe and effective as one or more other hormonal contraceptives already on the market.
We are concerned that 51% of subjects dropped out of the study. While only 11% discontinued due to an adverse event, this raises questions about compliance, high user failure, and patient acceptability of the product. The FDA and sponsors state that this is comparable to rates of discontinuation in other recently approved combined hormonal contraceptives. However, that raises concerns about the data on which regulatory and clinical decisions are based for all combined hormonal contraceptives.
Lastly, we would like to address the safety and efficacy of AG200-15 for patients with obesity. For these women, the serious risks of thromboembolic events outweigh the benefits, given the reduced efficacy. We support the FDA’s conclusion that the data presented warrants a contraindication for patients with BMI greater than or equal to 30. We also strongly recommend that FDA require that all previously approved combined hormonal contraceptives be tested in patients with obesity and a contraindication included on the label for those that also find limited efficacy in those patients.
In summary, it is crucial that clinical trials include participants who are representative of the patients that would consider using the product. Such studies provide more comprehensive, generalizable data that can better inform patients and providers as they make decisions about contraceptives. The FDA has acknowledged that it is unclear whether the higher Pearl Index reflects differences in study population and design or truly indicates sub-optimal effectiveness of AG200-15. The FDA should always require that manufacturers conduct comparative effectiveness trials or active-controlled trials when differences between previous studies make it difficult to directly compare the efficacy and safety of new products with previously approved hormonal contraceptives.
The Bone, Reproductive and Urologic Drugs Advisory Committee voted on one question related to the Agile contraceptive patch. On the question of whether the benefits of AG200-15 (the Agile patch) outweigh its risks to support the drug’s approval for the prevention of pregnancy, the committee voted 14 to 1 that the benefits outweigh the risks, with one abstention.