Clinical Pharmacology in Women's Health: Current Status and Opportunities.

Abstract

Women's health focuses on the treatment and diagnosis of diseases and conditions that affect a woman's physical and emotional well-being. Women experience many unique health issues related to reproduction and sexuality ranging from contraceptive methods to prevent pregnancy during reproductive age to postmenopausal symptoms such as hot flashes, sexual dysfunction, and osteoporosis after menopause. In addition, conditions that affect both men and women, such as cardiovascular disease and osteoporosis, manifest differently in women.1 For example, approximately 4 times more women suffer from osteoporosis than men.2 As another example, it has been reported that women experience more severe disease with a considerably lower remission rate than men with early rheumatoid arthritis,3 while men respond better to anti–tumor necrosis factor therapy in early diagnosis of rheumatoid arthritis.4 These unique aspects of disease conditions and treatment responses in women undoubtedly raise the important considerations that there should be more research activities and drug development opportunities to improve women's health. However, underrepresentation of women in clinical trials has been an ongoing problem and a challenge impacting overall women's health. Fortunately, there are many opportunities to overcome this obstacle, and we are moving in the right direction, as noted by the establishment of centers of excellence in women's health research, the Food and Drug Administration (FDA)’s active role in advancing women's health, and conducting large-scale clinical trials, such as the Women's Health Initiative. Given important gaps in current scientific knowledge of many relevant areas of women's health, including reproductive health and contraception, clinical research in pregnant women, and osteoporosis and hormone therapy in postmenopausal women, we highlight these specific topics in this supplement to present a comprehensive review of clinical pharmacology aspects of diseases and conditions affecting women. In addition, we provide an overview of current status and future opportunities to improve treatment options for women. Experts in specific topic areas have contributed 11 peer-reviewed articles to this supplement on topics including women's health initiatives, development of complex generic drug products delivered through the female reproductive tract, drug development for the treatment of uterine fibroids, pelvic floor hypertonic disorder, postmenopausal osteoporosis, rheumatoid arthritis, drug interactions with oral contraceptives, and clinical research in pregnant women. South et al5 introduce the mission of the FDA's Office of Women's Health (OWH) in protecting and promoting the health of women and highlight how they strive to achieve its mission. This is mainly attained through 3 program areas: scientific research, education, and outreach/communications. The authors provide a nice summary of OWH activities in these 3 program areas and showcase how OWH has continued to fulfill its public mission. In addition to promoting the participation of women in clinical trials, the authors highlight how OWH supports research needs to address knowledge gaps and advance science in women's health by providing research funding. Dinatale et al6 discuss the importance of clinical research in pregnant women to better inform prescription drug labeling. Given that pregnant women are often excluded from clinical trials during drug development, there is a lack of adequate information to guide informative decision making in terms of dose and regimen. Therefore, the authors advocate that pharmacokinetic (PK) studies in pregnant women should be incorporated into drug development programs and prioritized to obtain important information about safe and appropriate doses of a drug when used during pregnancy. Additionally, they suggest other alternative approaches such as physiologically based pharmacokinetic (PBPK) modeling as a useful tool to predict pregnancy-related changes in drug disposition. Finally, to improve how information for pregnant women is reflected in drug labeling, the Pregnancy and Lactation Labeling Rule requires that narrative summaries of the available data on the risks of a drug during pregnancy and lactation. Donnelly et al7 comprehensively review complex drug products delivered through the female reproductive tract, such as vaginal, intrauterine, and endocervical routes, and highlight the challenges faced in developing generic products due to lack of appropriate bioequivalence (BE) method for these locally acting drugs. The authors highlight FDA-funded research contract with the University at Buffalo (Buffalo, New York) to develop an open-source, generalized PBPK modeling and simulation platform for complex products delivered through the female reproductive tract. This research can be useful by potentially assisting generic complex product development, supporting alternative approaches to establish BE, and/or reducing the burden of comparative clinical end point BE studies. In another related article, Sharan et al8 report challenges faced during the development of generic drug products of the intrauterine system (IUS) in particular. This article discusses various internal and external research programs that are being pursued by the FDA to facilitate generic drug development of IUS products. Shon et al9 provide a comprehensive overview on key clinical pharmacology aspects of drug development for the treatment of uterine fibroids, a common gynecological disorder characterized by noncancerous growths of the uterus that generally develop in women of reproductive age. In addition to summarizing the currently available treatment options, the authors discuss the key issues to be considered in clinical pharmacology development program during drug development and focus on 2 emerging treatment options, selective progesterone receptor modulators and gonadotropin-releasing hormone antagonists. The key clinical pharmacology issues for consideration are categorized into 3 major areas: intrinsic factors, extrinsic factors, and safety. For intrinsic factors, the authors highlight how obesity may be associated with an increased risk of symptomatic uterine fibroids, while black women may have a greater prevalence and severity of uterine fibroids. For extrinsic factors, drug interaction potentials with hormonal contraceptives, add-back therapies, and mineral supplements such as iron or calcium are discussed. For safety, liver injury signals are highlighted for some selective progesterone receptor modulators and gonadotropin-releasing hormone antagonists. In conclusion, the authors suggest that these key clinical pharmacology issues be taken into consideration for successful drug development for treatment of uterine fibroids. The topic of drug interactions with oral contraceptives has a significant implication in drug development and in the women's health arena given the wide use of oral contraceptives for the prevention of pregnancy. For example, evaluation of drug interaction potential of a new molecular entity and oral contraceptives can pose a unique challenge to the drug developers, as there are many factors to consider. One of the major factors to consider in designing such a study to evaluate drug interaction potential is that combinations of estrogen and progestin components of hormonal contraceptives have a different strength of ethinyl estradiol and progestins with different metabolic pathways. Sun et al10 conducted a comprehensive systemic review and summarized the key aspects to consider in study design and conduct of oral contraceptive drug interaction studies. These include the role of new molecular entity properties with respect to whether they are teratogens, selection of progestins and their different metabolic pathways, choice of PK- or PK/pharmacodynamic (PD)-based study design and assessment on whether drug interaction findings with one oral contraceptive can be generalizable to other oral contraceptives. The article describes several limitations for the use of PD measurements, including its high variability and the challenge in data interpretation. While minimum therapeutic concentrations of estrogen and progestin components of combinational oral contraceptives have not been identified yet, the importance of understanding the relationship between PK/PD and efficacy and safety to better interpret the drug interaction study results is highlighted. The article introduces the emergence of new tools such as PBPK modeling approaches and how these tools may be useful to predict the magnitude of drug interactions with oral contraceptives. While reproductive health is one of the important elements to consider for women of reproductive age in general, providing and managing practical and effective contraceptive options to assist women with any substance use disorder is critical to achieve their desired fertility or reduce the risk of unintended pregnancy. The article by Stone et al11 summarizes several key aspects of reproductive health to consider for women with opioid use disorder. They state that women with opioid use disorder have a high risk for unintended pregnancy and low uptake of highly effective contraceptive methods, including long-acting removable contraceptives (ie, IUSs and subdermal implants). As contributing factors for these findings, the authors cite patient misconception or lack of reproductive health knowledge, cost, poor access to care, partner violence, fear of criminalization, comorbid conditions, and health care provider misconceptions or practice limitations. The authors discuss each of these factors in detail by describing the study findings or data and by citing the tools or guidelines from different professional organizations and domestic and international agencies. The authors suggest potential strategies or mitigation approaches to reduce the unintended pregnancy rate and increase the uptake of effective contraceptive methods. In addition, they call for additional research to identify and develop strategies to empower women with opioid use disorder to effectively access and use of all forms of contraceptive methods. In addition to bothersome vasomotor symptoms, postmenopausal women are at greater risk for genitourinary and sexual dysfunction, cognitive decline, cardiovascular disease, and significant bone loss. Hormone therapy has been shown to be the most effective treatment for problematic vasomotor symptoms of menopause while significantly decreasing the risk of postmenopausal bone loss. The article by Smith et al12 effectively reviews data from the newer studies since the publication of the Women's Health Initiative trials and discusses how hormone therapy formulation, timing of administration, mode of hormone therapy delivery, and combination of hormones used impacts a woman's risk. The authors emphasize new data that improves expert understanding, allowing for individualized hormone therapy regimens, and recommend ways to optimally balance risk and benefit using conventional and newer options for systemic and local hormone therapies. Osteoporosis is a chronic progressive disease that affects men and women above the age of 50 years and is responsible for millions of fractures annually. One of every 2 women in the United States is at risk for osteoporosis and fracture. Particularly postmenopausal women are more vulnerable because they suffer from a steep decline in endogenous estrogen production during menopausal transition. Clinical trials to develop drugs for the treatment of postmenopausal osteoporosis are based on fracture risk as the primary end point and are expensive and lengthy. Lien et al13 present an elegant mechanistic disease–drug trial model for postmenopausal osteoporosis that can predict phase 3 trial outcome based on short-term bone turnover marker data using a 2-year phase 3 clinical trial of zoledronic acid in 581 postmenopausal women. This model can be applied to other classes of drugs and potentially help speed up the development of safe and effective treatments for postmenopausal osteoporosis. Rheumatoid arthritis is an autoimmune disease that can cause joint pain and damage throughout the body, leading to significant disability and mortality. Sex is one of the risk factors of rheumatoid arthritis, and the prevalence is much higher in women than in men. With new treatment options such as biologic drugs available, it is important to identify whether men and women warrant different treatment regimens to ensure the best clinical response. Fang et al14 conducted a thorough meta-analysis of data from 11 clinical trials in patients with rheumatoid arthritis that supported FDA approval of 6 biologic products and address the question of whether women need a different dosing regimen compared to men. Stone et al15 performed a systemic review of intravaginal diazepam for the treatment of pelvic floor hypertonic disorder. Women with this nonrelaxing pelvic floor disorder often experience chronic pelvic pain and/or sexual dysfunction without any interventions such as a pelvic floor physical therapy and rehabilitation. However, for those who are not eligible or have no access to these nonpharmacological interventions, having an alternative option, such as pharmacological treatments, may provide benefits to women. Nevertheless, as noted by the authors, there is limited information on the use of pharmacological drug products to treat this disorder. To assess the potential utility of diazepam as one of the pharmacological treatments, the authors conducted a systemic review of intravaginal diazepam use in women with high-tone pelvic floor dysfunction. The authors identified 5 articles that met the inclusion criteria and assessed the heterogeneity in the studies in terms of study designs, sample size, what the diagnoses were, doses and duration of diazepam administered, use of different treatment modalities, and study outcomes. Based on positive findings in symptom relief, the authors conclude that use of intravaginal diazepam as adjuvant therapy should be further investigated in randomized placebo-controlled trials. In conclusion, the articles in the supplement comprehensively review current status of clinical pharmacology aspects of treatments in various reproductive and nonreproductive diseases and conditions of importance to women's health and highlight the future opportunities to improve therapies in these areas. We would like to express our sincere gratitude to the authors for contributing to this important and special supplement, especially during this challenging time. The authors declare no potential conflicts of interest. The authors received no financial support for the research, authorship, and/or publication of this article. The opinions expressed in this article are those of the authors and should not be interpreted as the position of the US Food and Drug Administration or Novartis Institutes for BioMedical Research.