U.S. Department of Health and Human Services
Center for Drug Evaluation and Research (CDER)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
Comments on Guidance for Industry for
Low Sexual Interest, Desire, and/or Arousal in Women: Developing Drugs for Treatment
[Docket No. FDA-2016-D-2817]
The National Center for Health Research is a nonprofit think tank that analyzes and reviews research on a range of health issues, with a focus on determining safe and effective treatments for diverse patient groups.
Low sexual interest, desire, and/or arousal are problems for many women in the United States, and there are numerous possible causes for this condition. Flibanserin was approved by the FDA in August 2015, despite substantial concerns about the efficacy and safety of the drug. In fact, some of our concerns regarding the research data for flibanserin are addressed in the proposed guidance, such as the reliance on patients’ monthly reports, which raised questions of accuracy compared to daily diaries, and safety studies conducted primarily on men rather than the target population (pre-menopausal women).
We support the FDA’s efforts to provide a guidance to stimulate stronger evidence of efficacy and safety. However, we have several concerns about the draft guidance.
We agree that it is important to study subgroups that represent the target populations for whom the drug is intended for use. The guidance suggests inclusion of both premenopausal and postmenopausal women and recommends subgroup analysis according to the cause of menopause, hormonal contraceptive use for premenopausal women, hormone therapy use for postmenopausal women, age and race. However, there are other key subgroups that were not included. For example, women with hormone disorders such as Polycystic Ovarian Syndrome and women who are severely overweight or underweight may differ in etiologies and treatment responses. These differences may affect the generalizability of the efficacy and safety data from the clinical trials. Therefore, the guidance should also recommend subgroup analysis based on the presence of hormone disorders and BMI. Furthermore, the guidance should emphasize the importance of providing sufficient and reliable data of safety and efficacy for each subgroup separately, rather than comparing the subgroups. It does not really matter if one group benefits more than another; what matters is whether the benefits outweigh the risks for each specific subgroup. Approval should be specifically indicated only for those subgroups where benefits are most likely to outweigh the risks.
Other common drugs, such as over-the-counter medications or alcohol, can interact with the drug under study, and these interactions should be assessed. These potential interactions can be identified by pharmacology or because the drugs are commonly used together. For instance, flibanserin was found to interact with alcohol to cause hypotension and temporary loss of consciousness caused by a drop in blood pressure.
While the guidance’s suggestion that trials lasting at least 24 weeks may be sufficient to establish efficacy, a much longer trial is needed to establish long-term safety. This is especially true if the drug under study is intended to be used indefinitely, such as flibanserin. The guidance instructs sponsors to follow the International Council of Harmonisation (ICH) guideline information, which suggests that, in order to observe the frequency of adverse events over this time period, a larger cohort size is necessary. However, if the drug shows indications of rare or slow-developing adverse events, it will be important to also increase the length of trial, to evaluate the clinical significance of these potential adverse events and to conduct a risk/benefit analysis based on the findings. For instance, in the case of flibanserin, there were some indications in animal studies that showed a possible increase in malignant mammary tumors. Although it was considered to be an unlikely adverse event, there was enough concern for it to be included in the label. When signals like this occur, studies longer than 24 weeks should be required.
In conclusion, there is a need to find treatments for low sexual interest, desire, and/or arousal in women, as those conditions affect women’s quality of life. However, the scientific standards should be solid, and consistent with long-term use, if that is the intent. If a sponsor does not want to conduct a large enough study to carefully evaluate safety and efficacy for all the known subgroups, the FDA should approve the drug only for those subpopulations that have been found to have benefits that outweigh the risks.
- Addyi Tablets. U.S. Food and Drug Administration. (18 August, 2015). Retrieved December 20, 2016, from http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/022526Orig1s000SumRedt.pdf.
- ICH Harmonised Tripartite Guideline. The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions E1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. (27 October, 1994). Retrieved December 20, 2016, from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E1/Step4/E1_Guideline.pdf.