March 23, 2020
National Center for Health Research’s Public Comments on FDA’s Draft Guidance on Levonorgestrel
[Docket Number FDA-2007-D-0369]
We are pleased to have the opportunity to comment on the FDA Draft Guidance on Levonorgestrel IUD devices for the design of bioequivalence studies supporting abbreviated new drug applications.
The National Center for Health Research (NCHR) is a nonprofit think tank that conducts, analyzes, and scrutinizes research, policies, and programs on a range of issues related to health and safety. We do not accept funding from companies that make products that are the subject of our work.
We will focus our remarks on the need for demographic diversity in testing IUDs. Trials should include diverse demographics in order to accurately demonstrate the effectiveness and safety of a device for all the women likely to use it. Unfortunately, the inclusion criteria named in this guidance provide only limited information about the demographics of participants. A diverse participant population is necessary for the results to be relevant to women of different races, ethnicities, and BMI.
For example, previous research has suggested that, compared to white women, black women are more likely to discontinue use of an intrauterine device, for reasons that are not fully understood.1 Yet, this draft guidance does not discuss the need for separate subgroup analyses of women in different racial and ethnic groups in the clinical trial. It is imperative that researchers include sufficient numbers of women in major racial/ethnic groups and conduct subgroup analyses to determine how safe and effective these IUDs are for women in different racial/ethnic groups.
We also note that the draft guidance has no inclusion criteria regarding the weight or BMI of participants. There is research evidence that continuation of intrauterine device use differs by weight, and efficacy may differ according to BMI since hormonal contraceptive pills tend to be less effective for women with a higher BMI.2 The study of residual levonorgestrel and serum levonorgestrel must account for the BMI of participants, and as noted earlier, the only way to provide meaningful information is conduct subgroup analyses by BMI.
The recommended clinical trial outlines that participants must be between the ages of 18 and 45. We agree with that age range, but point out that analyzing women in all age groups all together is not adequate. There is mixed evidence regarding whether or not expulsion of intrauterine devices is more common among younger women.3 Expulsion raises safety concerns and may also increase a woman’s risk for unintended pregnancy. There should be enough participants in each age group to conduct subgroup analyses for each, to ensure that there is sufficient data to draw conclusions regarding the efficacy and safety of the intrauterine device for women in each age group.
The National Center for Health Research can be reached at firstname.lastname@example.org or at (202) 223-4000.
- Phillips, S. J., Hofler, L. G., Modest, A. M., Harvey, L. F., Wu, L. H., & Hacker, M. R. (2017). Continuation of copper and levonorgestrel intrauterine devices: a retrospective cohort study. American journal of obstetrics and gynecology, 217(1), 57-e1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810132/
- Saito-Tom, L. Y., Soon, R. A., Harris, S. C., Salcedo, J., & Kaneshiro, B. E. (2015). Levonorgestrel intrauterine device use in overweight and obese women. Hawai’i Journal of Medicine & Public Health, 74(11), 369. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642497/
- Jatlaoui, T. C., Riley, H. E., & Curtis, K. M. (2017). The safety of intrauterine devices among young women: a systematic review. Contraception, 95(1), 17-39. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511984/