Working Together to Address Women's Health in Research and Drug Development: Summary of the 2017 Women's Health Congress Preconference Symposium.

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

FDA Public Meeting Report on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implications".

Potential drug interactions with hormonal contraceptives are an important public health concern. A public meeting on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implication" was hosted by the United States Food and Drug Administration (FDA). The meeting endeavored to provide an opportunity for the FDA to seek input from experts on the public health concerns associated with the use of hormonal contraceptives and interacting drugs that might affect efficacy and safety, including pharmacokinetic/pharmacodynamic considerations, in the design of drug interaction studies of hormonal contraceptives for drug development and approaches to translating the results of drug interaction information into informative labeling and communication. The input received could be used to refine FDA's thinking on hormonal contraceptives drug interaction study design and interpretation and labeling communication of drug interaction risk. This meeting benefited from strong and diverse participation from the Center for Drug Evaluation and Research at the FDA, Centers for Disease Control and Prevention, National Institutes of Health, Swedish Medical Products Agency, pharmaceutical industry, and representatives of academia. This report provides a summary of the key discussion based on the presentations and panel discussion.

Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs.

BACKGROUND: Concerns exist that women are underrepresented in trials of cardiovascular medications. OBJECTIVES: The authors sought to examine women's participation and the reported safety and efficacy by gender for pivotal cardiovascular disease (CVD) trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. METHODS: On the basis of publicly available FDA reviews, the authors assessed enrollment of women in trials supporting 36 drug approvals from 2005 to 2015. Prevalence-corrected estimates for the participation of women were calculated as the percentage of women among trial participants divided by the percentage of women in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of women in the trial and disease population. Sex differences in efficacy and safety were assessed. RESULTS: The proportion of women enrolled ranged from 22% to 81% (mean 46%). The calculated PPR by disease area was within or above the desirable range for atrial fibrillation (0.8 to 1.1), hypertension (0.9), and pulmonary arterial hypertension (1.4); PPR was <0.8 for heart failure (0.5 to 0.6), coronary artery disease (0.6), and acute coronary syndrome/myocardial infarction (0.6). The authors found little indication of clinically meaningful gender differences in efficacy or safety. Gender differences in efficacy or safety were described in labeling for 4 drugs. CONCLUSIONS: Women were well represented in trials of drugs for hypertension and atrial fibrillation, and overrepresented for pulmonary arterial hypertension. Representation of women fell below a PPR of 0.8 for trials in heart failure, coronary artery disease, and acute coronary syndrome. Minimal gender differences in drug efficacy and safety profiles were observed.

The science of sex and gender in human health: online courses to create a foundation for sex and gender accountability in biomedical research and treatment.

BACKGROUND: Sex and gender differences play a significant role in the course and outcome of conditions that affect specific organ systems in the human body. Research on differences in the effects of medical intervention has helped scientists develop a number of sex- and gender-specific guidelines on the treatment and management of these conditions. An online series of courses, "The Science of Sex and Gender in Human Health," developed by the National Institutes of Health Office of Research on Women's Health and the U.S. Food and Drug Administration Office of Women's Health, examines sex and gender differences and their implications. Thus far, three online courses have been generated. The first course offers an overview of the scientific and biological basis for sex- and gender-related differences. The second course is focused on disease-specific sex and gender differences in health and behavior and their implications. Finally, the third course covers the influence of sex and gender on disease manifestation, treatment, and outcome. METHODS: Data were obtained using website analytics and post-course surveys. RESULTS: To date, over 1000 individuals have completed at least one course. Additionally, 600 users have received continuing education credit for completing a course in the series. Finally, the majority of respondents to the online course survey have indicated that the courses considerably enhanced their professional effectiveness. CONCLUSIONS: "The Science of Sex and Gender in Human Health" online courses are freely available sources of information that provide healthcare providers and researchers with the resources to successfully account for sex and gender in their medical practice and research programs.

The Food and Drug Administration Office of Women's Health: Impact of Science on Regulatory Policy: An Update.

The U.S. Food and Drug Administration Office of Women's Health (FDA OWH) has supported women's health research for ∼20 years, funding more than 300 studies on women's health issues, including research on diseases/conditions that disproportionately affect women in addition to the evaluation of sex differences in the performance of and response to medical products. These important women's health issues are studied from a regulatory perspective, with a focus on improving and optimizing medical product development and the evaluation of product safety and efficacy in women. These findings have influenced industry direction, labeling, product discontinuation, safety notices, and clinical practice. In addition, OWH-funded research has addressed gaps in the knowledge about diseases and medical conditions that impact women across the life span such as cardiovascular disease, pregnancy, menopause, osteoporosis, and the safe use of numerous medical products.

Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies.

BACKGROUND: Sulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations. METHODS: Mother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities. RESULTS: We first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20 064 (n = 6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects. CONCLUSIONS: First-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials.

The prevalence and trends of antiviral medication use during pregnancy in the US: a population-based study of 664,297 deliveries in 2001-2007.

To evaluate the prevalence, trends, timing and duration of exposure to antiviral medications during pregnancy within a US cohort of pregnant women and to evaluate the proportion of deliveries with a viral infection diagnosis among women given antiviral medication during pregnancy. Live-born deliveries between 2001 and 2007, to women aged 15-45 years, were included from the Medication Exposure in Pregnancy Risk Evaluation Program, a collaborative research program between the U.S. Food and Drug Administration and eleven health plans. They were evaluated for prevalence, timing, duration, and temporal trends of exposure to antiviral medications during pregnancy. We also calculated the proportion of deliveries with a viral infection diagnosis among those exposed to antiviral medications. Among 664,297 live births, the overall prevalence of antiviral exposure during pregnancy was 4 % (n = 25,155). Between 2001 and 2007, antiviral medication exposure during pregnancy doubled from 2.5 to 5 %. The most commonly used antiviral medication was acyclovir, with 3 % of the deliveries being exposed and most of the exposure occurring after the 1st trimester. Most deliveries exposed to antiviral medications were exposed for less than 30 days (2 % of all live births). Forty percent of the women delivering an infant exposed to antiviral medications had a herpes diagnosis. Our findings highlight the increased prevalence of women delivering an infant exposed to antiviral medications over time. These findings support the need for large, well-designed studies to assess the safety and effectiveness of these medications during pregnancy.

Methods of linking mothers and infants using health plan data for studies of pregnancy outcomes.

PURPOSE: Research on medication safety in pregnancy often utilizes health plan and birth certificate records. This study discusses methods used to link mothers with infants, a crucial step in such research. METHODS: We describe how eight sites participating in the Medication Exposure in Pregnancy Risk Evaluation Program created linkages between deliveries, infants and birth certificates for the 2001-2007 birth cohorts. We describe linkage rates across sites, and for two sites, we compare the characteristics of populations linked using different methods. RESULTS: Of 299,260 deliveries, 256,563 (86%; range by site, 74-99%) could be linked to infants using a deterministic algorithm. At two sites, using birth certificate data to augment mother-infant linkage increased the representation of mothers who were Hispanic or non-White, younger, Medicaid recipients, or had low educational level. A total of 236,460 (92%; range by site, 82-100%) deliveries could be linked to a birth certificate. CONCLUSIONS: Tailored approaches enabled linking most deliveries to infants and to birth certificates, even when data systems differed. The methods used may affect the composition of the population identified. Linkages established with such methods can support sound pharmacoepidemiology studies of maternal drug exposure outside the context of a formal registry.

Prevalence and trends in the use of antipsychotic medications during pregnancy in the U.S., 2001-2007: a population-based study of 585,615 deliveries.

This study aims to estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S. We identified live born deliveries to women aged 15-45 years in 2001-2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program. We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis. Among 585,615 qualifying deliveries, 4,223 (0.72%) were to women who received an atypical antipsychotic and 548 (0.09%) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33% (95% confidence interval: 0.29%, 0.37%) in 2001 to 0.82% (0.76%, 0.88%) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63%), followed by bipolar disorder (43%) and schizophrenia (13%). The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.

Validation of an algorithm to estimate gestational age in electronic health plan databases.

PURPOSE: To validate an algorithm that uses delivery date and diagnosis codes to define gestational age at birth in electronic health plan databases. METHODS: Using data from 225,384 live born deliveries to women aged 15-45 years in 2001-2007 within eight of the 11 health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program, we compared (1) the algorithm-derived gestational age versus the "gold-standard" gestational age obtained from the infant birth certificate file and (2) the prenatal exposure status of two antidepressants (fluoxetine and sertraline) and two antibiotics (amoxicillin and azithromycin) as determined by the algorithm-derived versus the gold-standard gestational age. RESULTS: The mean algorithm-derived gestational age at birth was lower than the mean obtained from the birth certificate file among singleton deliveries (267.9 vs 273.5 days) but not among multiple-gestation deliveries (253.9 vs 252.6 days). The algorithm-derived prenatal exposure to the antidepressants had a sensitivity and a positive predictive value of ≥95%, and a specificity and a negative predictive value of almost 100%. Sensitivity and positive predictive value were both ≥90%, and specificity and negative predictive value were both >99% for the antibiotics. CONCLUSIONS: A gestational age algorithm based upon electronic health plan data correctly classified medication exposure status in most live born deliveries, but trimester-specific misclassification may be higher for drugs typically used for short durations.

Validity of health plan and birth certificate data for pregnancy research.

PURPOSE: To evaluate the validity of health plan and birth certificate data for pregnancy research. METHODS: A retrospective study was conducted using administrative and claims data from 11 U.S. health plans and corresponding birth certificate data from state health departments. Diagnoses, drug dispensings, and procedure codes were used to identify infant outcomes (cardiac defects, anencephaly, preterm birth, and neonatal intensive care unit [NICU] admission) and maternal diagnoses (asthma and systemic lupus erythematosus [SLE]) recorded in the health plan data for live born deliveries between January 2001 and December 2007. A random sample of medical charts (n = 802) was abstracted for infants and mothers identified with the specified outcomes. Information on newborn, maternal, and paternal characteristics (gestational age at birth, birth weight, previous pregnancies and live births, race/ethnicity) was also abstracted and compared to birth certificate data. Positive predictive values (PPVs) were calculated with documentation in the medical chart serving as the gold standard. RESULTS: PPVs were 71% for cardiac defects, 37% for anencephaly, 87% for preterm birth, and 92% for NICU admission. PPVs for algorithms to identify maternal diagnoses of asthma and SLE were ≥ 93%. Our findings indicated considerable agreement (PPVs > 90%) between birth certificate and medical record data for measures related to birth weight, gestational age, prior obstetrical history, and race/ethnicity. CONCLUSIONS: Health plan and birth certificate data can be useful to accurately identify some infant outcomes, maternal diagnoses, and newborn, maternal, and paternal characteristics. Other outcomes and variables may require medical record review for validation.

Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007.

OBJECTIVE: To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance before and during pregnancy in a large U.S. cohort of insured pregnant women. METHODS: Pregnancies resulting in live births were identified (N=437,950) from 2001 to 2007 among 372,543 females 12-50 years of age at delivery from 10 health maintenance organizations participating in the Medication Exposure in Pregnancy Risk Evaluation Program. Information for these descriptive analyses, including all antidiabetic medications dispensed during this period, was extracted from electronic health records and newborn birth certificates. RESULTS: A little more than 1% (1.21%) of deliveries were to women dispensed antidiabetic medication in the 120 days before pregnancy. Use of antidiabetic medications before pregnancy increased from 0.66% of deliveries in 2001 to 1.66% of deliveries in 2007 (P<.001) because of an increase in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%), whereas only 13.6% had a diagnosis code for diabetes. The use of antidiabetic medications during the second or third trimester of pregnancy increased from 2.8% of deliveries in 2001 to 3.6% in 2007 (P<.001). Approximately two thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy. CONCLUSIONS: Antidiabetic medication use before and during pregnancy increased from 2001 to 2007, possibly because of increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance. LEVEL OF EVIDENCE: III.

Trends in the use of antiepileptic drugs among pregnant women in the US, 2001-2007: a medication exposure in pregnancy risk evaluation program study.

BACKGROUND: Little is known about the extent of antiepileptic drug (AED) use in pregnancy, particularly for newer agents. Our objective was to assess whether AED use has increased among pregnant women in the US, 2001-2007. METHODS: We analysed data from the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) database, 1 January 2001 to 31 December 2007. We identified liveborn deliveries among women, aged 15-45 years on delivery date, who were members of MEPREP health plans (n=585615 deliveries). Pregnancy exposure to AEDs, determined through outpatient pharmacy dispensing files. Older AEDs were available for clinical use before 1993; other agents were considered newer AEDs. Information on sociodemographic and medical/reproductive factors was obtained from linked birth certificate files. Maternal diagnoses were identified based on ICD-9 codes. RESULTS: Prevalence of AED use during pregnancy increased between 2001 (15.7 per 1000 deliveries) and 2007 (21.9 per 1000 deliveries), driven primarily by a fivefold increase in the use of newer AEDs. Thirteen per cent of AED-exposed deliveries involved a combination of two or more AEDs. Psychiatric disorders were the most prevalent diagnoses, followed by epileptic and pain disorders, among AED users regardless of AED type, year of conception or gestational period. CONCLUSIONS: AED use during pregnancy increased between 2001 and 2007, driven by a fivefold increase in the use of newer AEDs. Nearly one in eight AED-exposed deliveries involved the concomitant use of more than one AED. Additional investigations of the reproductive safety of newer AEDs may be needed.

Medication Exposure in Pregnancy Risk Evaluation Program.

To describe a program to study medication safety in pregnancy, the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). MEPREP is a multi-site collaborative research program developed to enable the conduct of studies of medication use and outcomes in pregnancy. Collaborators include the U.S. Food and Drug Administration and researchers at the HMO Research Network, Kaiser Permanente Northern and Southern California, and Vanderbilt University. Datasets have been created at each site linking healthcare data for women delivering an infant between January 1, 2001 and December 31, 2008 and infants born to these women. Standardized data files include maternal and infant characteristics, medication use, and medical care at 11 health plans within 9 states; birth certificate data were obtained from the state departments of public health. MEPREP currently involves more than 20 medication safety researchers and includes data for 1,221,156 children delivered to 933,917 mothers. Current studies include evaluations of the prevalence and patterns of use of specific medications and a validation study of data elements in the administrative and birth certificate data files. MEPREP can support multiple studies by providing information on a large, ethnically and geographically diverse population. This partnership combines clinical and research expertise and data resources to enable the evaluation of outcomes associated with medication use during pregnancy.

Outpatient use of cardiovascular drugs during pregnancy.

PURPOSE: To provide information on the prevalence of use of cardiovascular drugs, some of which may have fetotoxic or teratogenic effects, in the outpatient setting among pregnant women in the United States. METHODS: A retrospective study was conducted using the automated databases of seven health plans participating in the HMO Research Network Center for Education and Research on Therapeutics (CERT). Women who delivered an infant from 1 January 2001 to 31 December 2005 were identified. Cardiovascular drug use was evaluated assuming a gestational duration of 270 days. RESULTS: During the period 2001 through 2005, 118,935 deliveries were identified that met the criteria for study; 3.1% of women (N = 3672) were dispensed an antihypertensive medication and 0.12% of women (N = 146) were dispensed an antihyperlipidemic medication at any time during pregnancy. The most common antihypertensive drugs dispensed during pregnancy were nifedipine (1219 deliveries; 1.0%), methyldopa (961 deliveries; 0.8%), atenolol (593 deliveries; 0.5%), and labetalol (576 deliveries; 0.5%). Overall, 134 women (0.11%) received an angiotensin converting enzyme (ACE) inhibitor and 7 women (0.006%) received an angiotensin II receptor blocker (ARB) during pregnancy. Statins were the most commonly dispensed antihyperlipidemic drugs (71 deliveries; 0.06%). CONCLUSIONS: The prevalence of use of cardiovascular drugs that are suspected to be fetotoxic or teratogenic (ACE inhibitors, ARBs, and statins) was low in this cohort of pregnant women. Differing patterns of use across health plans suggests that further research is needed to evaluate the potential differential effects of cardiovascular drugs to assist prescribers and patients in making informed treatment decisions.

The Food and Drug Administration Office of Women's Health: impact of science on regulatory policy.

In 1994, the Food and Drug Administration Office of Women's Health (FDA-OWH) was created to provide leadership and policy direction for the Agency regarding issues of women's health. Within its first year, the FDA-OWH established a science program for women's health research, promoting the development of sound policy and regulation. In a little over a decade, the program has provided approximately 14 million dollars to fund more than 100 women's health research studies covering a broad range of health topics affecting women across their lifespan. Some studies, such as those elucidating drug effects on QT prolongation in women and drug-dietary supplement interaction, have had significant influence on regulatory decisions. Other studies have provided sound scientific data on sex and gender differences supporting FDA guidelines to protect women's health. This paper describes the science program at the FDA-OWH, providing examples of how funded research impacts regulatory policy.