NCHR Comment on FDA’s Draft Guidance to Industry on Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy

National Center for Health Research, September 10, 2019

National Center for Health Research’s Public Comments on the FDA’s Draft Guidance for Industry; Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy

Thank you for the opportunity to comment on the draft guidance for industry “Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy.” The National Center for Health Research is a nonprofit research center staffed by scientists, medical professionals, and health experts focused on research, policies, and programs that affect public health. Our Center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from companies that make medical products, so we have no conflicts of interest.

We support FDA’s efforts to be transparent in the recommendations provided to sponsors guiding the development of hormonal drug products for preventing pregnancy. With dozens of different hormonal contraceptives on the market, it is essential that FDA’s guidance document persuade sponsors to use the most rigorous study design possible for establishing safety and efficacy. Currently, FDA’s standards for hormonal contraceptives do not ensure that only the safest, most effective hormonal contraceptives are on the market.

#1. We disagree with the guidance’s outdated standard that clinical trials should be single-armed studies compared to a historical control. There are major problems with the use of historically controlled trials. For example, as noted in the draft guidance, there have been significant changes in patient demographics, pregnancy testing, determinations of conception date, and dosing directions. These changes, including increases in women’s BMI, make using historical controls inadequate, since contraceptive clinical trials have historically excluded women who were greater than 130% of their ideal body weight.1 Instead, comparative effectiveness trials are needed to evaluate whether a new hormonal contraceptive is better than or at least as safe and effective as one or more other hormonal contraceptives already on the market.

#2. It is essential that studies include a representative sample of women who are likely to use the product. We strongly urge the FDA to specify the enrollment criteria in order to ensure sufficient diversity to scientifically evaluate safety and efficacy. As noted in the draft guidance, patient demographics have changed substantially over the years. For example, now more than two-thirds of reproductive-aged women in the U.S. are overweight and more than 30% of women are obese.1,2 Therefore, it is not sufficient to include only a small number of women with high BMI. While the guidance states that products should be tested using subgroup analysis to determine if they are effective for obese women, subgroup analyses should also be conducted for both safety and efficacy for overweight women, major racial/ethnic demographic groups, women who vape, women who smoke, and women with diagnosed health problems. What matters is not whether the contraceptive is better for one subgroup than another; what matters is that analyses of each subgroup determine to what extent the benefits outweigh the risks for that specific group.

#3. We strongly urge the FDA to be more explicit about safety evaluations in the guidance. As written, the guidance focuses on efficacy rather than safety. While contraceptives are generally safer than pregnancy, that is not the appropriate standard. Premarket studies should assess the likelihood of potentially serious adverse events, including ectopic pregnancy, deep vein thrombosis, migraines, and depression, as well as more common adverse events such as heavy bleeding, cramping, acne, and weight gain. While less serious adverse events may be tolerated by patients who are focused on preventing pregnancy, patients want to know if some hormonal contraceptives are less likely to cause these adverse events than others before choosing a method of contraception.

In summary, we strongly urge the FDA to convey to industry the need for a comparison group instead of historical controls, the need to conduct subgroup analyses of the safety and efficacy of their product for each of several major patient populations, and the importance of premarket studies that quantify the likelihood of adverse events for different subpopulations.

Thank you for the opportunity to comment on this important issue.