The FDA Office of Women’s Health (OWH) awards research grants for 1-2 year studies to address regulatory research questions related to women's health issues and the impact of sex differences on product safety and efficacy.
Intramural, Extramural and Special Funding Research Initiatives by Funding Year
Evaluating Inferior Vena Cava Filter Performance in Women Using Patient-Specific Computational Modeling - Brent Craven, PhD/CDRH
Pulmonary embolism, the blockage of blood flow to the lungs by blood clots, is a leading cause of maternal death. Blood clots originate from the legs and pass through a large vein called the inferior vena cava (IVC) on their way to the heart and lungs. IVC filters are medical devices placed in the IVC to capture clots before they reach the lungs. Approximately 100,000 filters are placed in US patients each year, with filter placement commonly performed in pregnant women because of their 5-fold increased risk of developing clots during pregnancy and 60-fold increased risk postpartum. Commercial IVC filters come in a single size that is meant to accommodate both women and men. Women, however, have a shorter IVC with a smaller diameter compared to men. Additionally, filters are typically placed in a different location in the IVC of pregnant women to avoid potential complications. Such anatomical differences—and placement location in pregnant women—likely influence device performance. Typical laboratory testing performed to evaluate device safety and effectiveness, however, does not account for differences between women and men. In the proposed study we will: (i) develop a free and publicly available database of patient-specific IVC models in women and men, (ii) quantify sex-dependent anatomical differences, and (iii) use patient-specific computational modeling to determine if IVC filter performance (mechanics, blood flow, clot trapping) is sex-specific. We will focus on adult women of childbearing age since they are at an especially high risk of developing clots due to pregnancy and use of oral contraceptives, a group of age-matched men, and a pregnant woman. Our findings will be used to update recommended laboratory testing for IVC filters, and to explore recommendations for IVC filter design, use, and selection criteria for improved performance in women.
Development of an artificially intelligent virtual pregnant woman modeling suite to support regulatory decisions - Annie Lumen, NCTR
Efficacy and safety testing remains a challenge in pregnant women as deliberate experimentation for every compound of regulatory interest is not feasible or ethical. This hinders regulatory agencies from providing authoritative guidance for the use of a range of products such as drugs and vaccines that could promote or protect pregnant women’s health. Computational models, which have the unique ability to assimilate available information (e.g. animal model findings) and make appropriate inferences in humans are invaluable tools to guide regulatory decisions for pregnant women.
Such models are developed on a case-by-case basis and can be a time- and labor-intensive process driven by the expertise of an individual modeler. No unified computational tool exists to support regulatory evaluations in pregnant women that is accessible by both modeling experts and novices and adaptable for any products to be tested. This presents an unmet need for a scientific methodology across the agency limiting the widespread use of modeling and simulations; i.e., to do the best available science to protect pregnant women’s health. Our project’s goal is to address this need.
We, a team of modelers and regulators across the FDA Centers in global collaboration with computer programmers from academia and research institutes, propose to develop a prototype for a virtual pregnant woman modeling suite. The novel aspect of this suite is that it will be developed to be ‘artificially intelligent’. The time- and labor-intensive part of model development process will be pre-built in the suite using advanced computer algorithms. Such that the suite interactively gathers available data from the end-user and the type of regulatory question to be addressed as input and automatically generates the most appropriate computational model for testing. Such a flexible tool will increase the overall regulatory capacity of the FDA to efficiently evaluate products for pregnant women.
Evaluation of women’s-targeted dietary supplements for labeling compliance and potential contamination, containing live microbes in the U.S. market with special emphasis on pregnant and lactating women, and infants - Carmen Tartera/CFSAN
Many products available to the consumer, such as dietary supplements and foods contain intentionally added live microorganisms that may provide a human health benefit. This has led to an increased production of these commodities to meet the demand for these new health related supplements. However, identification and characterization of the microbes in these products is lacking and pre-market requirements are limited to general safety concerns. Consumers rely on product labels, that report identity and viability, to be accurate and true. However, species are often misclassified or absent, and products are occasionally contaminated, in some instances with a pathogen. Our interest focuses on dietary supplements that target women at various stages of life, especially pregnancy and lactation, as well as infants. Products designed for women contain microbes associated with support of vaginal, urinary tract, breast and gut health, among others. Newborns, especially those prematurely born, are considered at-risk populations due to their underdeveloped immune system. They can be particularly susceptible to contaminants and pathogenic microorganism that may be present in the final product through the manufacturing and handling processes. High-throughput next generation sequencing (NGS) can support metagenomic investigations as a feasible means to analyze these products and eliminate any bias of culture-based sampling, or the inability to isolate all microbes present in foods. The challenge remains to identify microbes present in low amounts in the presence of predominantly beneficial microbes. The aim of this project is to create an analytical pipeline that will incorporate the use of specific phages and antibodies to reduce the product’s indigenous microorganisms and allow detection of low level microbial constituents and contaminants by metagenomics. This approach will provide a better understanding of the content and purity of dietary supplements available to women and infants in the U.S. market.
Utilizing Model-Informed Drug Development to Facilitate Antimalaria Dosing in Pregnant Women - Luning Zhuang/CDER
Malaria infection during pregnancy, particularly Plasmodium falciparum (P. falciparum) malaria, has been linked to increased morbidity and mortality. It is vital for pregnant women infected with malaria to receive prompt and effective treatment. However, current dosing strategies of antimalarial drugs in pregnant women are not guided by physiologic changes during pregnancy and are typically the same as those for non-pregnant adults. The objective of the current project is to evaluate the recommended dosing of approved antimalarial drugs and proposed dosing of investigational antimalarial drugs in pregnant women infected with malaria. Model-informed drug development (MIDD) approaches will be used to characterize physiologic changes during pregnancy and the potential effect of those changes on efficacy and safety. The results of this project will support regulatory decision making on dose recommendations for approved and investigational antimalarial drugs in pregnant women and provide guidance for clinical study design to expedite antimalarial drug development in this population.
Patient Reported Outcomes (PRO) Symptom Data to Complement Traditional Exposure-Response (ER) Analysis for Dose optimization during Breast Cancer Drug Development - Jeanne Fourie Zirkelbach/CDER
In the US, breast cancer is the second leading cause of cancer death among women. Its treatment is with systemically administered drugs in combination with surgery and radiation. Metastatic breast cancer remains incurable, and existing drug therapies have significant symptomatic toxicities that adversely impact health-related quality of life.
Drug-associated toxicity is currently evaluated using physician-based toxicity reporting using Common Terminology Criteria for Adverse Events (CTCAE), which lacks systemic assessment of symptomatic adverse events (AEs). Increasingly, there is interest in enhancing assessment of symptomatic AEs using patient self-reporting. A patient-reported outcome (PRO) is a measure of a patient’s health status obtained directly from the patient. The National Cancer Institute has developed the PRO version of the CTCAE (PRO-CTCAETM) to complement our understanding of therapeutic side-effects.
FDA’s Office of Hematology and Oncology Products identified the use of PRO libraries like the PRO-CTCAE as a complementary tool to characterize safety and tolerability from the patient perspective. PRO-CTCAE assesses expected symptomatic AEs systematically over time, providing a rich source of longitudinal data to better understand their trajectory.
A standard component of clinical trials is to determine relationships between drug concentrations and drug-associated toxicities [exposure-response (ER) safety analyses]. ER analysis is critical in cancer drug development to inform selection of the dosage that maximizes the risk-benefit ratio, and can be used to design rational dose adjustment strategies to manage drug associated symptomatic adverse events. ER analysis that incorporates real-time PRO data for common symptomatic toxicities may be an important new regulatory decision making tool to improve characterization of the relationship between drug exposure and treatment outcome.
With this project, we propose to integrate PRO endpoints into ER analysis and to evaluate its performance to complement and enhance the current methodologies for dose selection and dose adjustment strategies in breast cancer drug development.
Evaluating the clinical comparability of U.S. vs. non-U.S. clinical trial data for FDA-regulated medical devices for obesity treatment - Dongyi (Tony) Du, PhD/CDRH
In the U.S., obesity is of epidemic proportions and has been on the rise increasing from 20.9% of the population being obese to 33.8% in the last ten years. Obesity has been combatted using various methods including bariatric surgery, drugs, behavior modification, as well as medical devices. As one of the treatment options for weight loss, medical devices intended for obesity treatment must be deemed to be safe and effective, which is often assessed in clinical studies, in which participants are assigned to receive one or more treatments. These studies would enable the direct comparison of different treatment options. However, they can also be time consuming and costly. ClinicalTrials.gov contains information on clinical trials, many of which take place in the U.S. However, there are other sources of data on clinical trials that are not U.S. based, which may provide additional information on the safety and effectiveness of FDA-regulated medical devices. The proposed study aims to compare clinical trials from U.S. vs. non-U.S. clinical trials (specifically participant characteristics) to potentially identify supplementary information to what is known and potentially aid in regulatory decisions. Data will be used from ClinicalTrials.gov for U.S. clinical trials and from 22 foreign and international clinical trial registries previously identified by the U.S. Department of Health and Human Services (HHS). Specifically, we will examine clinical trials for the following obesity treatment devices that have received FDA approval: gastric bands, vagus nerve modulator, intragastric balloons, and gastric emptying systems.
Computational models to evaluate the safety and effectiveness of vaginal heat therapy devices - David Birsen/CDRH
Vaginal heating devices are energy-based devices consisting of laser, radiofrequency (RF), and ultrasound technologies that apply heat to the vagina. Vaginal heating devices have become increasingly popular in recent years for use as a non-hormonal treatment for symptoms of menopause, as well as for women seeking aesthetic vaginal rejuvenation procedures. The aim of these devices is to heat the vaginal tissue within a therapeutic range to stimulate a wound healing response, but below the thermal dose at which permanent tissue damage occurs. However, the heating effects of laser, ultrasound, and RF devices on vaginal tissue have not been robustly studied or characterized. Device manufacturers evaluate vaginal tissue heating using computer simulations and/or bench testing, but these test methods have not been validated and their clinical utility is not established. This raises safety concerns regarding unintended thermal injury when these devices are used in humans, as well as significant regulatory obstacles when evaluating these devices for marketing submissions. The goal of this project is to develop and validate test methods that can be used to reliably assess the safety and performance of vaginal heating devices. Specifically, this project will develop computational models to simulate vaginal heating in the human anatomy due to the heat produced from laser, RF, and ultrasound devices. This study will provide tools to aid FDA reviewers in assessing the safety of vaginal heating devices prior to use in humans, as well as provide device manufacturers with validated methods to conduct non-clinical testing.
Plasma Biomarkers in Perimenopause-Onset Depression - Gioia Guerrieri, DO/CDRH
The transition into menopause can be a time when a woman is at risk for a first episode of depression or when a depression might recur in a woman who had a depression when she was younger. There are multiple theories about what might cause that risk. One of those theories considers that increased blood levels of inflammation, called biomarkers, or other metabolic biomarkers might contribute to that increased risk of depression. The aim of this study was to evaluate those markers of inflammation in two groups of women: women who enter the menopause transition and have no mood symptoms of depression symptoms (and never had them) and women who enter the menopause transition who are starting to have symptoms of depression. These women are between the ages of 40 and 60 years and started having irregular menstrual cycles but haven’t stopped having menstrual cycles completely. This study included 150 women with confirmed depression symptoms and were in the menopause transition and 100 women without depression who were also in the menopause transition. All women were medically healthy. By trying to find differences in the biomarkers of the two groups, scientists might be able to better determine the triggers of depression in women as they get older.
Sex differences in Drug-Induced QT Prolongation and Torsades De Pointes Establishing an Invitro Model for High-Throughput Screening and Risk Assessment of Torsadogenic Drugs (Special Funding Initiative) - Li Pang, MD/NCTR
Numerous drugs have the potential adverse effect of lengthening the heart’s electrical cycle and cause the heart to stop beat accidently (torsade de pointes /TdP). Women are at a much higher risk than men for experiencing drug-induced irregular beats. Due to the absence of appropriate tools, few studies have investigated whether genetic differences between men and women have any effects on drug-induced arrhythmia (irregular rhythm). Several clinical and animal studies suggest that sex hormones may play an important role in determining the sex differences of drug-induced irregular beats. Recent progress in induced pluripotent stem cell (iPSC) technology (a technology that can induce stem cells directly from adult cells and make them capable of giving rise to several different types of cells) has made it possible in utilizing human heart muscle cell (iPSC-hCMs) model to investigate influences of both genetic and sex hormones on heart ion channel gene expression and heart muscle cell function. In our previous study supported by the FDA Office of Women’s Health (OWH), we found that genetic-based differences in male and female iPSC-hCMs alone were sufficient to determine bigger responses of female cells to drugs that are known to cause TdP. We would like to confirm the result found in our pilot study with additional iPSC-hCMs lines derived from other healthy male and female donors. The success of the study will provide valuable information in understanding the mechanisms of sex differences in human heart muscle cell beating process and risk assessment of drug-induced arrhythmia in both men and women.
Development of a Standardized Protocol for Screening and Detection of ALCL and implant Rupture through High Resolution 3D MRI Imaging of Silicone breast Implants - Sunder Rajan, PhD/CDRH
The advent of newer silicone gel breast implants has led to longer life, due to better shell design. Despite the improvement in design, Post-market clinical studies have demonstrated a significant prevalence of silicone breast implant (SBI) ruptures. Ironically, the longer life of the implants has also contributed to an increase in the incidence of Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). BIA-ALCL is suspected of being caused by the texture design of the newer implant shells and there is a significant concern that the incidence will continue to increase. It is believed that public awareness of BIA-ALCL will also lead to an increased need to imaging based diagnostic screening.
FDA recommends that women with SBI, be screened regularly for implant failure. Magnetic resonance imaging (MRI) is the preferred diagnostic technique for the evaluation of implant rupture. Currently, the MRI clinical scan protocols involve several complex individual scans that provide two-dimensional images in different orientations which are also difficult to interpret because of the complex folds and structure around a breast implant. We hypothesize that a simple volume scan which allows for high definition image slices in any desired orientation, will allow for better and easier diagnosis. It will also allow for better visualization of the wall of the implant and any surrounding liquid (seroma). We recently conducted a pilot study using such a 3D protocol, which provided additional diagnostic information and confidence. However, for robust clinical translation this method needs to be implemented and standardized by the MRI instrument vendors. Standardization of the 3D method will allow for reproducible MRI image quality from site to site. We propose to use a custom test object which contains components to mimic a human breast with implants. The phantom will be utilized to implement the 3D protocol with the collaboration of MRI vendor scientists to generate comparable signal behavior. This quality controlled protocol will be implemented in approximately 10 MRI facilities in preparation for a multicenter clinical trial.
Identifying the Impact of Surface-Texturing on the Pathogenesis of Breast Implant Associated- Anaplastic Large Cell Lymphoma - Hainsworth Shin, PhD/CDRH
This proposal explores a possible explanation for incidence of breast implant associated-large cell lymphoma (BIA-ALCL). BIA-ALCL is a rare lymphoma that afflicts women with breast implants (BIs). FDA recently released safety communications linking BIs with BIA-ALCL. While the risk for BI recipients to contract BIA-ALCL is estimated to be low at 0.1-0.3 per 100,000 women per year, this estimate represents a troubling trend especially since it may be based on incomplete data. At minimum, FDA must respond to this risk estimate to protect women from this disease. Very little is known about how BIs cause BIA-ALCL. Recently, FDA with the American Society of Plastic and Reconstructive Surgery (ASPRS) reported a significant correlation between BIA-ALCL and BI surface texturing. Most, if not all, cases of BIA-ALCL were for women with textured BIs. Surface texturing increases the BI surface area and introduces pockets that encourage tissue ingrowth. This can have two effects. First, it anchors BIs in host tissues differently than smooth implants, which causes them to a move differently due to bodily activity (e.g., walking, breathing). These different movement patterns create a unique mechanical force environment for the cells in the implant site, which may enhance the body’s inflammatory response. Second, texturing increases the contact area and numbers of protective pockets for bacteria to grow. Bacterial biofilms also enhance inflammation. This research tests the possibility that chronically high levels of inflammation resulting from either of these two effects or both results in BIA-ALCL. We expect to learn key information about the origins of BIA-ALCL, which can be shared with the public, including the device industry and medical communities. This information will also help FDA develop new assessment approaches to help with the regulatory review of BIs, as well as other implants that incorporate surface texturing.
Analysis of Sex Specific Differences in Quality of Life Measures for Heart Failure - Anindita Saha, BS/CDRH
Cardiovascular disease is the number one cause of death for women in the world. In recent years, approximately 1 in every 4 deaths in the United States results from heart disease, with similar rates among men and women. Therefore, it is critical for patient care and regulatory decisions that valuable tools such as patient-reported outcomes (PROs) be properly developed and calibrated for both male and female patients. In this study, we will evaluate gender differences in responses to the Kansas City Cardiomyopathy Questionnaire (KCCQ), a PRO measure of symptoms and functioning in heart failure patients. If the observed response differences warrant, we will provide a recommendation to analyze scores for female and male patients so that all individuals receive proper care, and the FDA makes regulatory decisions based on analyses that account for female-male differences. PROs are the report of a patient’s health condition that comes directly from the patient, without interpretation by others. These instruments can be formatted as items, questionnaires, or event diaries and can deliver information on a patient’s function, activities of daily life, symptom severity, or quality of life. PRO measures provide essential information in clinical care and regulatory decisions by evaluating health status from the patient’s perspective. In this way, PROs compliment other clinical measures to provide the full picture of a patient’s health status. PROs are often used in heart failure clinical trials to provide the patient’s perspective of a treatment and to predict adverse events. The KCCQ is a widely used PRO measures for heart failure patients in clinical trials. The KCCQ was scientifically developed and evaluated based on study samples that were historically majority male. However, male and female patients have different heart failure presentations. Male and female patients with the same disease stage and severity can respond systematically differently to questions, yielding different overall scores [1, 2]. Ultimately, the goal of this research is to facilitate accurate measurement of important outcomes in clinical trials for heart failure patients to ensure the best care for all patients.
1. Berg, S.K., et al., DenHeart: Differences in physical and mental health across cardiac diagnoses at hospital discharge. J Psychosom Res, 2017. 94: p. 1-9.
2. Comin-Colet, J., et al., Health-related Quality of Life of Patients With Chronic Systolic Heart Failure in Spain: Results of the VIDA-IC Study. Rev Esp Cardiol (Engl Ed), 2016. 69(3): p. 256-71.
Evaluation of the Safety and Effectiveness of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) for Atrial Fibrillation in Underrepresented Subgroups in Premarket Clinical Trials Using Combined Clinical and Statistical Modeling Approaches. (Special Funding Initiative) - Robbert Zusterzeel, MD/CDER
Irregular heartbeat, more commonly called “atrial fibrillation (AF)”, can cause blood clots formed in the heart to spread to the brain and cause a stroke. To prevent this, doctors usually prescribe a drug called “warfarin”. However, due to its association with high bleeding risk, warfarin requires frequent dose adjustment and monitoring by a specialist and is thus cumbersome to use. In the last 7 years, a new set of drugs, known as Non-Vitamin K Antagonist Oral Anticoagulants (NOACs), were approved by FDA for use in AF as a possible alternative to warfarin. This project will evaluate sex and race specific risks of stroke, bleeding and death associated with NOAC therapy by combining data from multiple clinical trials. New computational modeling methods and statistical approaches will be implemented to estimate the risks of outcomes in demographic subgroups.
Improving FDA Health Communications with Older Women Regarding FDA-Regulated Products. (Cross-Center Collaboration Project) - Marc Kusinitz, MS, PhD/CBER
Nearly one-third of the current U.S. population is aged 50 years or older, and this proportion is expected to increase dramatically by 2050. Half of these older adults are women. Unlike younger women, older women face the increasing burden of chronic health conditions, for which they often use FDA-regulated medical products and recommended diet modifications to maintain their health, or treat or prevent health complications. Many older women also have dual roles, as both patient and caregiver, which compounds the challenges of making health-related decisions. These challenges are further complicated in those 68% or more of older adults who have difficulty using print materials, interpreting numbers, and performing basic calculations. Such limited health literacy among these older adults contributes to health disparities, worse health outcomes, increased use of healthcare facilities and products, and more medication errors. Yet, there has been no research to identify the difficulties that older adults – specifically older women – might face in understanding and using information provided by FDA. Therefore, it is critical for FDA to produce easily understood materials that teach older women how to use FDA-regulated products safely and effectively.
This study aims to collect data that FDA Centers can use to inform the development of more effective health communications related to FDA-regulated products that target older women, defined here as US women aged 50 years and older. In Phase 1 of the proposed study, the investigators will collect information from focus groups composed of older women to better understand the perceptions, including how older women view the adequacy, appropriateness, usefulness, and relevance of health communications associated with FDA-regulated products. In Phase 2, the investigators will conduct a national survey of older women to explore their perceptions of FDA health communications and their health-information seeking behaviors and intentions.
If successful, the proposed research will support efforts to provide effective and easily understood information about FDA-regulated products to older women that can help them use such products appropriately.
Gender differences related to Alzheimer’s disease as revealed by Exome sequencing and RNA sequencing – Sherry Ferguson/NCTR
Alzheimer’s disease (AD) is a devastating neurological disorder and the 5th leading cause of death for those 65 years of age and older. Women have a higher incidence of AD at later ages. Among those that are 71 years of age or older, 16% of women have AD but only 11% of men. Better understanding of sex differences involved in the cause and progression of AD could contribute to better drugs and other types of interventions to slow the disease progression. Given that there are 5.3 million people in the U.S. with AD and this number is expected to rise to 16 million by 2050, increased knowledge of potential biomarkers and molecular pathways that may be specific to women with AD is important. Here, we will sequence the DNA that encodes the expressed genes via a technique known as Exome sequencing which is a less expensive, yet efficient, alternative to whole genome sequencing. This technique enables the determination of potential genetic variants that may be causal for AD and that may show gender-specific differences. We have received preliminary datasets for the Exome sequencing. NCTR biostatisticians are currently working with these datasets to analyze the data. The second assay, RNA Seq, may identify differences in gene expression between men and women. Although these assays will be conducted in post-mortem brain tissue, they serve as a starting point for identifying gender-specific biomarkers of AD. Identifying such biomarkers will greatly enhance the FDA’s ability to determine potential toxicities and/or efficacies of regulated or proposed treatments for this shattering disease.
Translational Regulatory Science to Advance Drug Safety in Women Combining in silico Modeling and Clinical Approaches - David Strauss, MD, PhD/CDER
The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative is a novel proposal to screen a new drug’s potential to cause Torsade de Pointes (TdP), a potentially fatal abnormal heart rhythm, before the drug is on the market. Using a computer model of the heart, CiPA will analyze the effects of the new drug on the molecular level to predict its potential to cause TdP. To validate this proposal, we will test 28 drugs with different levels of risks for causing TdP. This project will integrate computer modeling and clinical assessments from post-market databases to investigate whether there are differences in TdP risk between men and women. If such sex-differences are found, then this information will be used to improve and implement sex-specific models of the human heart cell for regulatory assessment of TdP risk for new drugs.
In silico research on sex differences in the biological responses and adverse events elicited by implantable devices/biomaterials - Yelizaveta (Lisa) Torosyan, PhD/CDRH
The current project is aligned with the CDRH’s regulatory science initiatives and it serves the Center’s vision for the National System for Medical Device Evaluation that can provide access to safe and effective devices by accurately characterizing real-world performance throughout the total product life cycle and by delivering “the right device to the right person.” As part of the CDRH's regulatory research efforts aimed at strengthening medical device evaluation, new evidentiary approaches are needed to individualize risk-benefit assessment and facilitate more predictive evaluation of real-world performance. The approaches proposed in this project will utilize a novel in silico framework which harnesses recent advances in bioinfomatics, translational epidemiology, and genetics/genomics. In addition to employing conventional data sources such as device registries, the open-access and other pre-existing biomedical data sources will be explored for possibilities of identifying device-related genetic/genomic evidence and discovering new reliable and measurable study endpoints (e.g., molecular biomarkers) that are more indicative of device performance in patient subsets (e.g., sex-stratified subpopulations). As a result, the project's is expected to enhance regulatory decision-making on long-term device performance and to promote Precision Medicine applications, thereby improving device-related patient outcomes.
Virtual model of a female human subject with large body habitus for use in MR Radiofrequency safety assessments - Angelone Leonardo, PhD/CDRH
The goal of this project is to generate a computational anatomical model of a human female adult subject of large body habitus. The model, proposed initially for analysis of radiofrequency induced heating during MRI, will be freely available to stakeholders in the scientific and industry. More than 35 million Magnetic Resonance Imaging (MRI) scans are performed in the US each year, making MRI an important diagnostic tool. MRI’s energy is tightly controlled by international regulatory standards, and well-established guidelines bolster patient safety. In addition, unlike computer tomography scanning (CT scanning), MRI does not use ionizing radiation, but rather makes images of the internal structures of the body by using specialized coils to send and receive RF energy. All medical devices carry some risk—for MRI, one possible risk is excessive RF-induced heating of tissue with possible thermal damage. RF-induced heating depends on several variables, including geometry of the coil, the patient’s position (imaging landmark or body posture), and the patient’s anatomy. Computational modeling has been largely used over the past decade to investigate RF-induced heating of patient tissue undergoing. Several human body models, such as the Virtual Family (Christ et al. 2008), the Visible Human Male and Visible Human Female (Visible Human Project) are currently available to the scientific community for analysis of RF-induced heating. However, there are no models validated against direct experimental data that represent the anatomy of a female subject of large body habitus. Because RF heating depends on the patient dimensions and body posture, the project aims to fill such gap and generate a computational model of a human female subject of large body habitus for RF-induced heating analysis. The model will also be validated experimentally with measurements in MRI, ultimately allowing for the assessment of the potential risk of injury over a broader sample of patient population.
Sex-specific analysis of percutaneous left atrial appendage closure (LAAC) device for stroke prevention in patients with atrial fibrillation - Hongying (Helen) Jiang, PhD/CDRH
Atrial fibrillation (AF) is a cardiac arrhythmia that manifests as irregular heartbeat. According to the U.S. Centers for Disease Control, AF affected approximately 2.66 million people in the United States in 2010, and the numbers are expected to increase over time. AF is the most common arrhythmia in the US, and its prevalence increases with aging. Patients with AF are at increased risk of having blood clots, stroke, and heart failure. More than 30% of strokes in individuals over the age of 75 years are due to AF, presumably due to thromboembolism from the left atrial appendage (LAA). Oral anticoagulation therapy with warfarin or more recently approved novel anticoagulants are the standard of care to reduce risks of blood clots and stroke. Emerging new technologies in stroke prevention have been undergoing development rapidly. One new technology is the percutaneous LAA closure (or occlusion) device. The LAA is a small pouch, often shaped like a windsock, which connects and empties into the left atrium, the top chamber of the left side of the heart. This structure is prone to form and collect blood clots, in particular in patients with AF. When a blood clot travels from the LAA to the systemic blood circulation and travels to the brain, it may result in stroke. The percutaneous LAA closure device is a novel technology that closes the LAA via percutaneous vascular access, and thus prevents blood clots from entering the systemic circulation and reduces stroke risk. It is recognized that there are sex-specific differences in the pathophysiology of stroke and AF. Moreover, women (particularly elderly women) often have more challenging vascular anatomies (e.g. smaller blood vessels and heart sizes) for percutaneous procedures vs. men, and more often have higher rates of surgical complications. It is unknown whether these sex differences impact the effectiveness and safety of this new LAA closure device for stroke prevention. Our goal is to answer this question by pooling and analyzing both pre-market and post-market data available at the FDA on this type of device via an in-depth statistical analysis. This study will help us better understand sex difference in stroke prevention and increase the assurance the safety and effectiveness of the LAA closure device in women.
Population-based computational framework for assessing xenobiotic disposition and interaction effects in pregnant women - Annie Lumen, PhD/NCTR
Women are sensitive to thyroid disturbances during crucial life-stages, such as pregnancy, which can lead to pregnancy-related complications. Pregnant women are normally excluded from clinical trials because of ethical concerns. Given the lack of available data, there is a need for better approaches to characterize the dose-response relationships for drugs and chemicals in pregnant women to guide regulatory decisions. Recently, we developed a first-of-its-kind computational model to evaluate the effects of iodide deficiency and exposure to a single dietary contaminant, perchlorate, on the thyroid function of an ‘average’ pregnant woman1. In a pilot study, the average model was extended to a population-based model to capture successfully the dose-response relationship for perchlorate in a population of pregnant women. Our work also highlighted the prevalence of iodine inadequacy among late-gestation pregnant women in the U.S., which will further predispose women to thyroid disruption. Current efforts aim to continue the expansion of this generalized computational pregnancy modeling framework for addressing the issue of co-exposure to mixtures of thyroid-active chemicals that reflects better real world exposure scenarios. Specifically, thiocyanate, a thyroid-disruptor, predominantly found in food and to which pregnant women are exposed at high levels is being evaluated in our ongoing work as a constituent of a ternary mixture. The complete population-based risk assessment framework, including model components addressing the issue of chemical mixtures, will provide regulatory agencies with a valuable and robust tool for the quantitative assessment of health risks of exposure to thyroid-active chemicals by a population of pregnant women. Such computational tools have high regulatory relevance in line with the FDA’s strategic plan for modernizing toxicology and advancing regulatory science. In addition, the development and implementation of such computational approaches to evaluate women’s health outcomes and address emerging public health concerns contributes directly to the Office of Women’s Health mission.
Stimulate innovation in clinical evaluations and personalized medicine to improve patient outcomes with triple negative breast cancer - Beverly Lynn-Cook, PhD/NCTR
Triple negative breast cancer is an aggressive form of breast cancer that frequently strikes young women. Due to its aggressive nature, its spreads to other parts of the body quickly. Unlike other breast cancers where targets have been identified for drug treatment, triple negative breast cancer lacks targets and, therefore, lacks treatment. This cancer, in addition to striking young women, has a high prevalence in women of color, particularly African American and Hispanic/Latina women. This cancer lacks hormone receptors in which targeted therapies have been developed. Although clinical trials are ongoing for new treatments for this aggressive type of breast cancer, understanding and discovering biomarkers and molecular signatures will aid in predicting risk and improve prognosis and treatment for this fatal disease. This study will investigate novel signaling pathways in women at high risk for triple negative breast cancer to identify early biomarkers. Furthermore, this study will track response to target agents in high risk women with mammary atypia. Our current “one-size-fits-all” approach to prevention is not working. While progress has been made in understanding the diverse biology of estrogen-receptor negative (ER-) breast cancer subtypes, we have little information on how breast cancer starts in an individual woman. Without this understanding, it is almost impossible to develop effective targeted prevention, particularly for triple negative breast cancer. We need a better understanding of the biology of triple negative breast cancer initiation in individual women. This collaborative transdisciplinary team between FDA, City of Hope and the University of Tennessee Health Science Center brings together expertise in women’s health, breast cancer biology, and epigenetic analyses to identify activated signaling networks in precancerous changes in high-risk women tissues. Together this transdisciplinary team aims to identify early signaling changes in high-risk women and deliver individualized targeted prevention strategies. Furthermore, identifying early signaling pathways will aid in developing strategies for chemoprevention and life-style changes.
Evaluation of the Extent and Impact of Gender Sensitive Advertising and Promotional Labeling of Health Products - Oluchi Elekwachi, PharmD/CBER
Health literacy and comprehension of health-related materials play an important role in mitigating morbidity and mortality caused by improper use of health care products and services. This is particularly true in elderly patients who often take more prescription medications and who generally require more health services. Although development of culturally competent messages, suitable for individuals of a specific ethnicity, is recognized as an essential factor in reducing health disparities, little attention has been focused on producing materials that are gender-sensitive. In this study, gender sensitive messaging in promotional material will be examined, along with the barriers preventing consistent production of gender-sensitive messages. Promotional material submitted to the FDA as intended for use in populations aged 65 and older, will be examined to determine the degree to which it exhibits age appropriate, gender specific messaging at appropriate health literacy levels. Focus groups will be used to evaluate the comprehension and acceptance of promotional labeling and advertising for health services and products targeting older women. The data gathered from this study will be used to create healthcare professional and consumer educational materials, intended to increase awareness of the importance of gender-sensitive health messaging, and to develop best practices for gender-sensitive health messaging in advertising and promotional labeling.
Evaluation of thromboembolic events following C1-inhibitor therapy - Paul Buehler, PharmD, PhD/CBER
Hereditary angioedema (HAE) is a rare potentially life threatening disorder associated with a deficiency of functional C1-esterase inhibitor (C1INH), and it is more severe and frequent in female population than in men. Until recently, there was no HAE-targeted therapy available in the United States, and only fresh-frozen plasma or attenuated androgens were used to provide some relief during acute attacks. Since 2008, DHRR/CBER approved three C1INH products for replacement therapy in patients with HAE for the treatment of acute attacks and for prophylaxis. According to the available database and recent publications, C1INH therapy in HAE patients is associated with a risk of thromboembolic events. Thrombosis also has been predominantly reported in women and appears to depend on hormonal status. This project will focus on the evaluation of a risk of thromboembolic events due to C1INH administration at supraphysiological levels and elucidation of possible underlying mechanisms. Secondly, to assure safety and effectiveness of C1INH treatment in case of recently proposed concomitant administration of C1INH and pharmaceutical heparins, this project will focus on the evaluation of the C1INH potentiation by heparin and the impact of various compositions and conditions on possible thrombotic events. The proposed studies, both in vitro and in animal models, are essential for the development of reliable biomarkers to evaluate and predict thromboembolic events in women during C1INH therapies, as well as for elucidating the mechanisms for possible enhancement of currently available C1INH therapies by pharmaceutical heparins and its impact on a risk of thrombosis.
Developing biomarkers for trastuzumab-induced cardiotoxicity - Wen Jin Wu, MD, PhD/CDER
Trastuzumab (also known as Herceptin®) is a humanized monoclonal antibody directed against extracellular domain of human epidermal growth factor receptor 2 (HER2) and is approved for the treatment of breast cancers that are HER2-positive. Trastuzumab provides considerable therapeutic benefits in HER2-positive breast cancers and improves disease free and overall survival after adjuvant chemotherapy. However, trastuzumab treatment is also associated with cardiac dysfunction. There are no clinically approved biomarkers that can be used to predict the cardiac dysfunction induced by trastuzumab. Furthermore, several large clinical trials have shown that cardiomyopathy induced by trastuzumab maybe potentially irreversible in some patients. Therefore, it is important to develop biomarkers and sensitive and specific testing methods that could be used to detect cardiotoxicity induced by trastuzumab. Using echocardiography, we recently found that trastuzumab significantly reduced left ventricular performance in mice. Importantly, this trastuzumab-induced cardiac dysfunction was associated with elevated level of cardiac myosin light chain 1 (cMLC-1) in mice sera, suggesting that cMLC1 could be a potential biomarker for trastuzumab-induced cardiotoxicity. The goal of this study is to further investigate the mechanisms of trastuzumab-induced cardiotoxicity and to collaborate with clinical investigators at Massachusetts General Hospital (MGH), Harvard University to validate the potential biomarker that we identified based on our preclinical studies. This proposed collaborative study may yield biomarkers that could be used to predict trastuzumab-induced cardiac dysfunction and to help define the risks and the benefits of trastuzumab treatment.
Tool development of modeling and simulations for metastatic breast cancer - Jingyu Yu, PhD/CDER
Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. Although survival rate is high for women with breast cancer, the five-year survival rate after diagnosis for metastatic (stage 4) breast cancer patients is 40 percent based on MD Anderson researchers. The Critical Path Initiative of the US Food and Drug Administration calls for leveraging existing knowledge from clinical data through the use of quantitative modeling to improve the drug development process. We therefore propose to quantify the relationship between early tumor size after treatment and clinical outcome (e.g., patient survival, progression free survival) in women with metastatic breast cancer using the pooled clinical data submitted to the Food and Drug Administration by multiple pharmaceutical companies. Our proposal aims at demonstrating how data mining of drug registration trials for metastatic breast cancer agents enables us to develop a pharmacostatistical model that can capture the time course tumor size change and link time of death or disease progression to risk factors and the tumor size information after start of therapy. The disease model we propose here may reduce the failure rate of drugs by selecting the right dose for right candidate compounds that are highly efficacius on the basis of a predicted survival benefit for women with metastatic breast cancer.
Bacteria and virus migration through latex condoms in the presence of personal lubricants - Srilekha Das, PhD/CDRH
In the 1990s, studies were undertaken in CDRH to address the critical public health concern related to the possibility of passage of pathogenic viruses, such as HIV, hepatitis virus, and human papilloma virus, through natural rubber latex condoms. To more easily conduct the experiments, a bacteriophage, ΦX 174, of similar size and shape to the pathogenic viruses was used as a non-pathogenic test surrogate. Results of this investigation confirmed the effectiveness of intact condoms in preventing the passage of small molecules and thus, protecting consumers from sexually transmitted infections (STI). As a result, a modified version of the method was introduced in FDA guidance and an ISO standard. This method, however, did not account for the presence of personal lubricants that are often used in conjunction with condoms. Over–the–counter personal lubricants are comprised of an assortment of various chemicals; major components are usually water, glycerol, sorbitol, polyethylene or poly propylene glycol, and silicone oils, and also include a number of minor chemical components for smell, taste, and color. The presence of a personal lubricant may promote the transmission rate of small biological molecules through the thin layer of a condom by either increasing the pore size in the condom material or increasing the chemical affinity of the molecule in the external environment. In this investigation, we plan to determine if the presence of personal lubricants that may swell the latex material and change its elasticity by relaxing the polymer network, change the permeability of the membrane to ΦX 174, as well as of two of the smallest known pleomorphic (capable of changing shape) bacteria, Ureaplasma urealyticum and Mycoplasma hominis, compromising the ability of the condom to prevent transmission of STI.
Sex and racial difference in prosthetic aortic valve selection and risk factors for patient outcome—an observational study of Medicare beneficiaries - Dongyi Du, MD, PhD/CDRH
Preservation of relevant clinical information in lossy compressed digital mammograms using objective image quality metrics - Aria Pezeshk, PhD/CDRH
Capture and storage of medical images are becoming increasingly demanding for both screening and diagnostic purposes, resulting in the production of several petabytes of medical image data annually. With widespread use of screening mammography, and emergence of new modalities such as digital breast tomosynthesis (DBT) and breast CT that produce large numbers of images, efficient storage of such a vast amount of data has become a significant challenge. Moreover, the large size of images is the primary limiting factor in accessing patient data in telemedicine, electronic health records, and viewing medical images on mobile devices. While lossless image compression produces no risk to the interpretation of data and diagnosis, it does not allow for high compression rates. Lossy image compression and the associated higher compression ratios are therefore more desirable. The FDA currently interprets the Mammography Quality Standards Act (MQSA) as prohibiting lossy compression of digital mammograms for primary image interpretation, image retention, or transfer to the patient or her designated recipient. Reader studies are the most common type of study for discovering proper usage criteria of lossy compression algorithms across different organs and modalities. Such studies are often limited in size and scope, use different definitions of medical image quality as well as different study endpoints, and therefore arrive at conflicting conclusions. In this project we will use objective numerical image quality metrics to find proper limits that control the adverse effects of lossy image compression on both detection and estimation tasks in digital mammography. This project is expected to have a substantial regulatory impact by identifying proper study designs and metrics that can be used by the industry and users to assess the impact of lossy compression. In addition the results of this study can lead to updates to current MQSA guidance regarding usage of lossy image compression in mammography.
Development of test methods to evaluate the risk of cancer-cell permeation through tissue containment bags during laparoscopic power morcellation of uterine fibroids - Matthew Myers, PhD/CDRH
Laproscopic power morcellators are medical devices used to excise uterine fibroids in to small fragments which could then be removed from the abdomen through small incisions as a minimally invasive procedure. However, in recently published safety communications, FDA has pointed out that power morcellators carry the risk of spreading cancer cells within the abdomen and pelvic regions while fragmenting the fibroid tissue. To minimize the risk of spreading the cancerous tissue, some studies have recommended the use of a tissue containment bag, which surrounds the power morcellator and forms a barrier between the tissue and the abdomen. The tissue-containment bags are made out of polymers which are supposedly packed tight to prevent any penetration of the cancer cell through the pores present in the membrane. The device manufacturers evaluate the performance of these devices by testing them in a static environment which does not mimic the forces experienced by the tissue bags during power morcellation. The goal of is study is to develop new test methods that could test the integrity of the tissue containment bag in the presence of forces imparted by the power morcellator. This study will also develop computational models to assess whether cancer cells can permeate tissue containment bags during the surgical procedure. The results published by this study will aid FDA reviewers in the development of a new guidance document for testing the safety and performance of tissue-containment bags.
Calcium and material characterization in women using dual-energy CT: Phase II - Nicholas Petrick, PhD/CDRH
Cardiovascular disease is the leading cause of death for American women and women have higher cardiovascular mortality rates compared with men. Large numbers of cardiovascular events occur in asymptomatic people who do not belong to high risk groups. Risk-based markers, such as coronary artery calcium score, have been suggested as methods for identifying candidates for primary prevention of coronary artery disease (CAD) through risk-factor modification. The calcium score, related to the amount of calcium found in coronary vessels, is used as a summary measure of coronary health, with higher scores indicating higher risk of CAD. Women have smaller, faster beating hearts, smaller arteries, and different anatomy than men. While research in standardizing CT quantification of coronary calcium has been carried out, little has been done to 1) address gender differences, 2) develop methods for systematically quantifying measurement error or 3) validate the performance of calcium scoring and plaque material characterization in dual-energy CT. In Phase I (OWH funded 2014-15), we are evaluating the accuracy and precision of calcium scoring in single- and dual-energy CT scans through static phantom studies. Our initial results show that vessel size and gender-based anatomy are significant factors that strongly influence calcium scoring. In Phase II, we propose to investigate how quantitative coronary calcium scoring and plaque material characterization are affected by gender difference and CT acquisition techniques with a special focus on measuring and optimizing performance of dual-energy CT in women. We will build on our initial static phantom studies by developing a dynamic motion controller that allows the impact of heart motion to be accounted for. We are also proposing a substantial expansion to evaluate the potential of dual-energy CT for characterizing the material composition of coronary plaques and in particular to validate how well dual-energy CT can differentiate hard from soft plaques. While the phantoms developed are specific to coronary vessel measurements, the general approaches and validation methods developed will generalize to the assessment of technical performance for other quantitative imaging biomarkers.
Mammographic CAD device testing using computationally inserted microcalcification clusters and masses - Berkman Sahiner, PhD/CDRH
Breast cancer is the second leading cause of cancer death and the most prevalent cancer type among American women. There is considerable evidence that early diagnosis with screening imaging modalities improves the chance of survival for patients with breast cancer. Many breast imaging techniques benefit from computer-aided diagnosis (CAD) devices, which help radiologists detect cancerous lesions by automatically prompting suspicious locations identified through advanced computerized image analysis methods. Most CAD devices used for breast cancer screening are first developed and assessed for a specific “original” acquisition system, e.g., a specific image detector, or a specific image acquisition methodology in digital breast tomosynthesis (DBT). When CAD developers are ready to apply their CAD device to a new acquisition system, they are typically expected to assess their CAD device with the new system. The acquisition of a large and representative set of abnormalities for the new acquisition system can be a bottleneck, since the prevalence of breast cancer in the screening population is low. Our project aims to address this problem by using an innovative technique called lesion blending. Using well-defined imaging characteristics of the original and new acquisition systems, this technique will allow its users to blend lesions imaged under the original acquisition system into normal images acquired with the new system. Since normal images are easier to collect, this will allow CAD developers to assess their CAD device using fewer resources and expeditiously for the new acquisition system. In this project, this concept will be demonstrated with mammographic CAD devices, because previous data exists to validate our approach. However, the general idea is applicable to other current breast cancer screening modalities, such as DBT, and future screening modalities, such as breast CT. By allowing timely and proper assessment of devices for improved breast cancer detection, our project is expected to make a significant impact on women’s health.
Improving assessment of spinal device subsidence by incorporating female anatomy and density - Srinidhi Nagaraja, PhD/CDRH
Patients with severe neck or low back pain are often treated with spinal medical implants such as interbody cages or total disc replacement devices. Although these are relatively successful procedures, it is possible for the device to push into the top or bottom of the vertebra. This is referred to as device subsidence. If severe, the patient may experience more pain or loss of back flexibility. This is an important issue for women’s health as many older women have neck and low back pain that may require implantation of spinal devices. It is unknown, however, if implant subsidence occurs more frequently in women because of osteoporotic changes leading to lower bone density and poorer bone quality than men. Therefore, the goal of this study is to better understand factors that put a patient at risk for implant subsidence. By using experiments and computer simulations, our goal is to develop a method that can better predict if this adverse event may occur when a spinal device is used to treat these patients.
Spectral photoacoustic tomography (PAT) for breast tumor oximetry: Test method development, in vivo validation, and computational modeling - Brian Garra, MD/CDRH
Breast cancer is the second leading cause of cancer–related death in American women. A new imaging modality called Photoacoustic Tomography (PAT) can potentially help with detection and classification of breast cancers. In PAT, a laser pulse stimulates tissue to generate and send back sound waves from which images are created by an ultrasound machine. PAT can not only image abnormal small blood vessels due to absorption of the laser pulse by hemoglobin, but can also measure the amount of oxygen in the hemoglobin (called oximetry). Both of these features can be used to distinguish cancers from benign tumors and can help identify aggressive cancers. Despite great scientific interest and development of new PAT products intended for commercial use, no standard methods for testing PAT oximetry systems exist. This lack of proper test methods has hampered FDA regulatory review of new systems. We propose using tissue simulating materials and phantoms we previously developed for PAT imaging testing, to construct new phantoms and tests for PAT oximetry performance testing. A custom research-grade PAT system will be tested for its ability to measure hemoglobin oxygenation using these new phantoms, and the test results will be validated against measurements obtained using the same PAT system on rats. These results will be used to devise a simple but scientifically rigorous phantom and test methods for testing of new commercial systems during design, production and regulatory review. The results will also be used to complete development of a computational model of PAT system performance that, in the future, could be used in place of the phantom tests. Together all of these methods will markedly reduce the time and expense of performance testing and regulatory evaluation of new PAT systems for breast cancer evaluation.
The role of epigenetic mechanisms in re-expression of ER, PR, and HER receptors in triple negative breast cancer: effects of FDA approved epigenetic drugs and dietary agents - Beverly Lyn-Cook, PhD/NCTR
Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. About 15% of breast cancers falls into this category. TNBC often strikes premenopausal women. TNBC patients generally have a poorer prognosis and early relapse that often results in death. This subtype of cancer lacks targeted therapies receptors, such as the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor-2 (HER2). TNBC patients cannot, thereby, be treated with targeted therapies that blocks the action of these receptors, such as tamoxifen and Herceptin. Therefore, these patients are limited to cytotoxic chemotherapies with harsh side effects. Risk factors for TNBC include: being of African descent, BRCA1 mutation, a strong family history of breast cancer, lifestyle and environmental factors. Although mutations are involved in the initiation of TNBC, research has revealed that individuals are controlled by factors other than DNA sequences; these factors are termed epigenetics. Epigenetics refers to changes in gene expression that do not directly affect DNA sequences. In humans, these epigenetic mechanisms involve DNA methylation, histone modifications, and noncoding RNAs that control tissue-specific gene expression. This study will examine whether an epigenetic drug (vorinostat) and a dietary agent (indole-3-carbinol), which have been shown to exert their effects through epigenetic mechanisms, can re-express critical targeted receptors (ER, PR and HER2) in TNBC cells and render these resistant cells sensitive to approved FDA cancer drugs such as tamoxifen, raloxifene or Herceptin.
Hepatotoxicity database for herbal/dietary supplements - Weida Tong, PhD/NCTR
Herbal and Dietary Supplements (HDS) are considered by the public to be safe. Estimates suggest HDS usage by approximately 80% of the population. In the US, herbs are defined as dietary supplements. Therefore, manufacturers are not requested to demonstrate safety as it would be required for drugs. Recent research is highly suggestive for different, due to inappropriate controls, serious side effects most notable hepatotoxicity. From 2004-2013, CDER received over 400 botanical Investigational New Drug (IND) applications and pre-IND meeting requests. Most INDs were allowed to enter Phase 2 clinical trials for evaluation of preliminary safety and efficacy of the investigational botanical products in patients. HDS are more frequently used by women than men and the same applies to minority populations. In order to avoid risk to the public health, it is the interest of the FDA to identify the hepatotoxic potential of HDS prior to market release and to protect populations at high risk including women and minority groups. In this study, we will investigate and provide a comprehensive assessment of hepatotoxic potential of HDS. We will research all available data relating to HDS consumption with emphasis on women and minority populations from various sources (i.e., public databases, literature and data from the regulatory agencies worldwide) and the data will be organized using the standard terminologies so that the information from diverse sources can be compared and analyzed. The outcome of the study is a database that could be a resource to support the FDA review to reduce the health disparities for women and minority groups. Having a database of hepatotoxicity findings for commercially available dietary supplements could enhance our understanding of the safety profiles of those botanicals and thus help us to make more informed decision for botanical IND reviews.
Drug-delivery nanoparticle immunological effects on induction of pro-inflammatory responses to Candida albicans in mice - Doug Wagner, PhD/NCTR
Delivery of drugs to women by direct application to the vaginal tract may be improved by use of very small chemical structures called nanoparticles. In previous research, we have found that certain dissolving drug-delivery nanoparticles are toxic to vaginal cells and cause the cells to recruit inflammation. When the same material is used in medical devices larger than 1 micrometer in size inserted into the body, it is not toxic. These drug-delivery nanoparticles may be used to provide medicines into a women’s vaginal tract when she has a yeast infection. Vaginal yeast infections often cause inflammation. We propose to conduct experiments in a mouse model of inflammatory vaginal yeast infections to determine whether the nanoparticles make the inflammation during yeast infections worse. This will provide important knowledge for FDA to make regulatory decisions regarding when it will be appropriate to use these kinds of drug-delivery nanoparticles. In the experiments, mice will be given vaginal yeast infections by an established method and given nanoparticles into their vaginal tracts at doses similar to those that would be used to treat women with drugs, such as those that prevent viral infections. We will measure the damage to DNA and cellular machinery of the vaginal tissue by the nanoparticles as well as the inflammation that occurs with or without yeast infections. We will also determine whether the nanoparticles cause the yeast infections to spread into the body. Vaginal drug delivery in nanoparticles is a promising new technology to improve women’s health, but the risks of their use during a common yeast infection have not been determined. This project will allow us a better understanding of those risks.
Evaluating the migration and toxic potential of silver nanoparticles in feminine hygiene products into vaginal tissue: In vivo rodent and human in vitro 3D mucosal models - Yongbin Zhang, DVM, PhD/NCTR
There is increasing manufacturing and market interest in the development of more effective feminine hygiene products. These developments are usually based on improvements in manufacture or fiber/polymer technology, and lately, the ability to manufacture nanoscale materials that reportedly have bacteriostatic/bactericidal properties. Some feminine hygiene products (e.g. cleansers and pads) currently available on the market claim to include nanoscale silver. Nanomaterials in feminine hygiene products potentially could migrate into vaginal tissue and become a hazard to the consumer. A key challenge for biomedical research on nanomaterials is understanding the biological fate of nanomaterials (where do the materials go; do they have any effect) and the cumulative risk following daily use/exposure (does the effect accumulate/increase with continued use; does the material and effect go away when use stops). This study will use both in vitro cell culture and a rodent model to examine the penetration/permeation of different species of silver (nanoparticles, nanoparticle agglomerates, and silver ions) into vaginal mucosal tissue. In addition the toxic potential of the silver species will be examined on vaginal mucosal tissue and the microbiota found in the vaginal environment. This project takes advantage of the outstanding facilities available at the collaborating laboratories, and the NCTR-ORA Nanotechnology Core Facility at FDA’s Jefferson Laboratories campus.
Cardiovascular Risk of Testosterone Treatment in Women (Special Funding) - Lai-Ming Lee, PhD/CDER
A variety of testosterone products are used off-label for the treatment of female sexual dysfunction (FSD). Due to the chronic nature of FSD, these products are anticipated to be used as long-term therapy in women. Therefore, assessment of cardiovascular risk will be an important factor in the risk/benefit determination. The Framingham General Cardiovascular Risk Score predicts the 10-year risk of all cardiovascular events including coronary heart disease, stroke, transient ischemic attacks, and heart failure. The variables used in the formula are age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein, use of hypertension medication, smoking status, and history of diabetes. We hypothesize that the Framingham General Cardiovascular Risk Score will be useful in estimating cardiovascular risk of drug products in Phase 3 trials. We will use available data to determine the utility of the Framingham General Risk Score to estimate the cardiovascular risk in women exposed to drug products with a likelihood of a cardiovascular signal. If successful, this formula would be applied to androgens and androgen-like products being evaluated for the treatment of female sexual dysfunctions in women.
Assessment of Placental Transmission of Zika Virus Glycoprotein E Immunogen (Special Funding) - Evi Struble, PhD/CBER
Zika virus infection has reached epidemic proportions in Latin America. Based on the geographical distribution of its mosquito carriers, it is likely that Zika virus will spread to the U.S. Zika infections during pregnancy have been associated with increased number of severe neurologic birth defects in newborn babies. Treatment with human antibodies against Zika virus may become a likely treatment option during pregnancy. Given the limited scientific data on Zika disease and treatment during pregnancy, it is very important to collect and analyze safety and efficacy data for this potential medical intervention. Toward this goal, we propose to use our expertise on placental transfer studies to investigate whether circulating non-neutralizing ZIKV antibody complexes contribute to fetal infection and the potential for interaction with pre-existing immunity to other flaviviruses.
We will use monoclonal antibodies and antibodies from individuals that have recovered from the Zika infection in complex with the virus envelope protein E, the viral component that mediates both viral infection of human cells and the host immune response to the Zika virus. Experiments will be performed to evaluate whether Zika protein E/antibody complexes are required for the passage of E protein across a laboratory model of the placental barrier. In addition, we will determine if differences in antibodies produced by different recovered individuals or individuals with antibodies against other mosquito borne viruses can have an effect in the placental transfer of Zika. Our study should provide critical information on what constitutes an efficacious and safe immunoglobulin therapy during pregnancy to benefit the mother and her baby.
Optimization of an in silico cardiac cell model for predicting sex differences in drug-induced proarrhythmia risk (Special Funding) - Wendy Wu, PhD/CDER
The FDA is generating computer models of human heart cells to improve the prediction of drug safety, specifically the risk of a drug inducing a life-threatening ventricular arrhythmia called Torsade de Pointes (TdP). These models will be used by both drug developers and FDA reviewers to define the appropriate drug candidates for human use and to inform clinical trial design strategies. It is known that women are at higher risk of developing TdP than men, and so two computer models - a male and a female human heart cell - will be needed for drug-induced TdP risk prediction. The proposed project uses single-cell electrophysiology recording techniques and an animal model to generate the data needed to create a male and a female heart cell model in which drug effects can be simulated. This research will contribute to protecting and advancing women’s health by ensuring that future drug safety evaluations take into account biological differences between women and men.
Background: Historically, scientific questions that uniquely affect women (e.g. pelvic floor disorders, uterine fibroids, female sterilization) have been evaluated in stand‐alone studies. When targeted registries were created, linkage to other data sources was not possible, missing the opportunity to create infrastructure to advance women’s health in the continuum of routine clinical practice. Therefore, we propose to create a “Coordinated Registries Network” (CRN), which will serve as the national infrastructure for the evaluation of medical devices in clinical areas unique to women.
Specific objectives: to, (1) establish a Public‐Private‐Partnership (PPP) with stakeholders; (2) identify/prioritize clinical conditions and devices unique to women; (3) convene an “Expert Core Working Group”; (4) establish convener group within MDEPINet; (5) hold stakeholders workshops at FDA Campus; (6) create a robust consortium of registries that can incorporate IDE and postmarket mandated studies into their infrastructure.
Methods: Key stakeholders will be identified and invited to join the Expert Core Working Group, which will be charged with: (1) identification of clinical conditions and device areas to prioritize, (2) evaluation of existing efforts and models that can be applied in the realm of women specific devices/health issues, and (3) selection of the convener group within MDEpiNet. The convener group will coordinate CRNs work per identified priority areas, and will develop the business and sustainability model. CRNs will allow for data involving diagnostic and treatment modalities to be captured in a “Suite” of registries. The individual registries would operate under the auspices of health care professional societies (e.g. ACOG, AUGS, ASPS, etc.), ideally sharing a common platform, analytical and support infrastructure, while maintaining the flexibility necessary to address specific questions unique to the clinical conditions covered by the respective registries. The infrastructure will also incorporate premarket (IDE) and postmarket mandated studies, which will limit startup costs and implementation time of clinical trials as well as review time for FDA to evaluate premarket applications or postmarket submissions.
FDA has preliminarily identified the following areas of concern: uterine fibroids, abnormal uterine bleeding (non‐fibroid related), contraception methods, stress and urge urinary incontinence, fecal incontinence, pelvic organ prolapse, urinary retention, outcomes for breast implants, cosmetic surgery, obesity, infertility, reproductive cancer detection and treatment, labor and delivery, pregnancy and postpartum, menstruation, sexual function, and TMJ disorders. Collaboration has already begun with the COMPARE‐UF Registry, and discussions have taken place to adapt the registry for collection of data on medical devices used during treatment of uterine fibroids.
Advancing Methods for Assessment and Prediction of Clinical Performance of High Intensity Therapeutic Ultrasound Systems (Special Funding) - Keith Wear, PhD/CDRH
High Intensity Therapeutic Ultrasound (HITU) is a new minimally-invasive alternative to surgery. HITU shows great promise for many women's health conditions including uterine fibroids, breast cancer, breast fibroadenoma, uterine adenomyosis, tubal pregnancy, fetal surgery and polycystic ovary syndrome. HITU can destroy diseased or unwanted tissue but can also destroy healthy tissue because of the difficulty of precise dosage and localization of HITU energy in the body. The proposed project aims to develop computational and experimental methodology to improve standardization and objective characterization of HITU systems. The project contains five parts: 1) development and validation of software (to be made publically available) for modeling HITU systems, 2) development and validation of radiation force balance methods for measuring HITU acoustic output power, 3) development and validation of methods for broadband characterization of tissue-mimicking materials used in HITU system characterization, 4) investigation into dependence of HITU output measurements on the type of hydrophone used, and 5) development and validation of a model for correcting needle and fiber optic hydrophones for low-frequency distortion.
Non-clinical mechanistic studies in addressing ovarian cancer risk from talc use in cosmetics (Special Funding) - Nakissa Sadrieh, PhD/CFSAN
Talc is an important industrial chemical, that is widely used in plastic surfaces, especially in surgical gloves, various plastic apparatus, and gynecologic services, and women are commonly known to use products containing talc for hygiene and cosmetic purpose. Although some studies have examined the relation between talc and ovarian cancer, its effects on female genital system tissues have not been adequately investigated. A study published by Keskin et al (2009), aimed to examine carcinogenic effects of long-term talc exposure on the genital system of female Sprague -Dawley rats. The preliminary results showed that in rats, talc given intravaginally to the animals (100 mg in 0.5 ml saline) daily for 3 months, had unfavorable effects on the female genital system. However, these effects seemed to be in the form of foreign body reaction or infection short of neoplastic changes, suggesting the need for studies with longer exposure periods and more detailed evaluation of the early events in genital system tissue transformation. This proposed research will help to fill some of the existing data gaps, in the molecular and genetic events associated with early ovarian oncogenesis, as these are largely unknown. Specifically, the association of such oncogenesis, with respect to exposure to a cosmetic ingredient used by women (talc), is of particular interest to women's health, and our studies could prove to be useful as possible experimental models for further mechanistic studies in ovarian carcinogenesis.
Bayesian demographic subgroup analyses for pregnant women - Judy X. Li, PhD/CBER
This project is a statistical study of the effects of pre-eclampsia therapies in subgroups of pregnant women. Pre-eclampsia (PE) affects pregnant women in different subgroups, e.g., different ages and ethnic groups. Therefore, it is important to be able to make accurate safety and efficacy assessments of pre-eclampsia therapies among different demographic subgroups. Standard statistical analysis could yield inaccurate results if these nonhomogeneous populations were simply combined and treated as a single population. On the other hand, individual standard statistical analysis of each small, diverse population could yield erroneous results because some or all of the sample sizes might be too small, that is, they might have low statistical power. To solve the problem of having too few individuals in subgroups, this project will use Bayesian statistics to analyze clinical trial data, which enables borrowing information across data from different subgroups. This approach will enable FDA regulators to make more informed regulatory assessments about the safety and effectiveness of new treatments based on data from clinical trials that are composed of different subgroups that might each respond somewhat differently to the treatment. This project will help healthcare providers and patients make more informed treatment decisions.
Capturing Sex-Specific Data in Regulatory Submissions and National Vascular Quality Initiative Registry - Danica Marinac-Dabic, MD, PhD/CDRH
This project examines pre- and postmarket OB/GYN device studies to assess the quality and transparency of demographic information reported on device labeling, and to identify barriers and potential solutions to minority groups’ access to enrollment and participation in clinical trials. Congress passed federal law in 2012 (Food and Drug Administration Safety Innovation Act) that emphasized the importance of diverse subject populations in forming a more complete knowledge base about the safety and effectiveness of medical devices. Patient demographic subgroups such as African Americans have historically been underrepresented in clinical research, which can decrease the generalizability and applicability of the research results. This is especially problematic for certain conditions in the OB/GYN specialty, such as uterine fibroids, where disease prevalence, severity, and methods of treatment have been shown to vary by race/ethnicity.
Treating the pregnant patient: pharmacokinetic and mechanistic studies of antiviral IGIV preparations at different stages of gestation in an animal model of pregnancy - Evi Struble, PhD/CBER
Pregnant women are at high risk for infection by pathogens. Vertical transmission of infectious agents, such as hepatitis B (HBV), hepatitis C (HCV), and cytomegalovirus (CMV) during pregnancy remains a public health problem, associated with dire outcomes for the neonate. Thus, a safe prophylactic and therapeutic approach for protecting the mother and the neonate from infection remains a high priority. This project is focused on ensuring the safety and efficacy of hyperimmune preparations of immune globulin intravenous (IGIV) when used to combat infectious diseases during pregnancy. The results of previous studies using the guinea pig model suggested that transplacental transfer of human antibodies given at the end of pregnancy contributes to lower half life and faster clearance of antibody biologics, compared to non-pregnant age-matched controls. In addition, it was demonstrated that transplacental transfer in guinea pigs increases exponentially with gestation age. This study aims to investigate 1) the pharmacokinetics of IGIV preparations in different stages of pregnancy; 2) how the differences in transplacental transfer at different gestation ages correlate to the differences in antibody pharmacokinetics in pregnancy; 3) mechanism for these differences, especially regarding placenta structure and IgG receptor (FcRn) expression. Data from this study will provide information that can inform dosing decisions during pregnancy that are efficacious for the pregnant woman and her baby.
Effect of procoagulant impurity on coagulation in plasma from pregnant women - Mikhail Ovanesov PhD/CBER
This project will study the mechanisms of thrombotic adverse events (TAE) in pregnant women who receive treatment with immune globulin (IG) products. This study is important because IGs are often used to prevent recurrent pregnancy loss and for other indications in pregnant women, despite evidence that some IG products cause thrombotic complications due to the presence of a procoagulant impurity, activated coagulation Factor XI (FXIa). Researchers hypothesized that pregnant women are at increased risk for thrombosis after IG because: 1) they are at up to 50x higher risk than non-pregnant women even in the absence of IG; 2) TAE risk is further elevated under most known procoagulant conditions, such as surgery, history of thrombotic events, or genetic anticoagulant deficiency. In the absence of results from human studies, researchers have investigated increased thrombogenicity of IG products in pregnant mice using vascular injury, ex vivo pharmacodynamics, and pharmacokinetics approaches. This study used the findings and methodology of the animal study to design a study on human plasma from pregnant women spiked with procoagulant impurities in vitro. This study will help to bridge the gap between animal and human studies. The results of this study will enhance the FDA regulatory science base in facilitating the product review.
Modulatory effects of progesterone on maternal immunity and their implications in pregnancy-associated susceptibility to avian influenza infections- Hang Xie, PhD/ CBER
This study will use a mouse model to investigate how female hormones modulate maternal immune responses to avian influenza viruses. The epidemiological data suggest that pregnant women are highly susceptible to severe influenza infections, including the highly pathogenic avian influenza (HPAI) H5N1 viruses. Babies born to women with severe influenza illness are at higher risk for premature birth and low birth weight. However, many pregnant women are reluctant to get vaccinated because they are unaware of the potentially severe complications of influenza infections and have misconceptions about the safety of vaccines. Furthermore, research in this area is lagging because: 1) HPAI H5N1 viruses and associated biological materials are strictly controlled by federal regulations; 2) Pregnant women have been traditionally excluded from clinical investigations studying human disease pathogenesis and new drug and vaccine development because of the concerns about fetal safety. To fill this gap, this project will develop a mouse model to mimic responses of pregnant women to H5N1 infections. Using this model, this project aims to elucidate how female hormones, particularly progesterone, affect maternal immunity during H5N1 infections. The study will help us to better understand the susceptibility of pregnant women to H5N1 infections.
Addressing the unmet medical needs for cardioprotection in women receiving chemotherapy - Ashutosh Rao, PhD/CDER (Supplementary funds)
The FDA regulates several oncology agents, including anthracyclines, monoclonal antibodies and cytokines that are known to induce oxidative damage and cardiac dysfunction. Younger women appear to be sensitive to cardiac dysfunction from chronic exposure to chemotherapy. Taken together with the fact that heart disease is the number one killer of women in the US, cardioprotection in women remains an unmet medical need. A preclinical model was designed and validated to test both anticancer potential and cardiac safety, where spontaneously hypertensive rats (SHRs) were implanted with a syngeneic breast cancer cell line (SST-2). Using this model the researchers identified an inverse correlation between cardiac stress and circulating reproductive hormone levels using doxorubicin for proof-of-principle studies. The researchers are currently investigating reproductive hormone supplementation with doxorubicin for potential chemoprotection. The researchers will leverage the SHR/SST-2 preclinical model to investigate a mechanistic link between hormone levels, oxidative stress, and cardiac health in females, as a means to provide critical, missing information on the mechanism behind female cardiac sensitivity. The results of this study may potentially enable the development of personalized therapies that can provide a mechanistically-sound treatment window to maximize anticancer activity while minimizing cardiotoxicity in women receiving chemotherapy.
Sex-specific modeling and analysis of ACL injury susceptibility- James Coburn/CDRH
More than 130,000 anterior cruciate ligament (ACL) repairs are performed each year. Athletes are the primary recipients, with female athletes 3-6 times more likely to suffer from ACL tears than males. Non-athletes may also require ACL repair due to an accident or a condition that increases their risks. Tests that screen for susceptibility to ACL injury are made for athletes and involve high impact activities. For those with compromised movement or other risk factors (e.g. elderly), they may not be an option. This research project has two aims. The first is to use existing and new data gathered from subjects performing specific activities to develop a low impact metrics to assess ACL injury susceptibility. The second is to develop a computational model of the knee ligaments to aid the regulatory review of medical devices to repair the ACL.
Individual patient-data meta-analysis and postmarket analysis as a method for improving data quality in demographic subgroups - Daniel Canos, PhD/CDRH (Support for implementation of FDASIA Section 907 Action Plan)
Women have been underrepresented in clinical trials for medical devices and cardiovascular devices in particular. Therefore, the results of these trials primarily reflect outcomes in men. Directly addressing the FDASIA 907 Action Plan priorities of improving the quality and public availability of demographic subgroup data the current project will combine clinical trial data submitted to the FDA as part of pre-market approval applications. This allows for the analysis of sex-differences in medical devices, hereby leveraging existing clinical data and improving methodology for performing sex-specific analysis as individual clinical trials are often underpowered to detect potential sex-differences. Furthermore, a second step this project will pool pre-market and post-market data to assess sex-differences in real-world use thereby strengthening the system to make better use of data once medical products are available on the market. By combining already existing pre-market clinical trial data and assessing post-market real-world performance this study will be able to quickly evaluate device performance in demographic subgroups. Next to recommendations for future individual-patient data meta-analyses as a result of this project, this will also lead to rapid implementation into the regulatory review process and guidance documents, better clinical trial designs, and improve women’s health supporting multiple FDASIA priorities and action items.
Preclinical test methods for percutaneously implanted heart valves - effect of non-circular valve configuration after implantation on valve leaflet dynamics - Terry Woods, PhD/CDRH
Thousands of elderly American women suffer from narrowing of the aortic heart valve each year. Transcatheter aortic valve replacement (TAVR) has become a life-saving therapy for many of these patients in recent years. FDA has approved five TAVR devices. TAVR devices are typically manufactured to have a circular shape. However, imaging has shown that TAVR devices can take on a non-circular shape, like a triangle or the letter “D”, after implantation. These changes can affect how the valve leaflets open and close when the heart is beating and could impact how the device functions long-term. This project aims to address the research question – How does the non-circular shape affect how TAVR devices function long-term? The research findings will help guide industry in developing appropriate testing and aid reviewers in assessing the test results provided in applications for new TAVR devices. Thus the outcomes from the study will help ensure that TAVR devices function appropriately for the expected device lifetime, directly supporting the CDRH vision of delivering safe, effective, and high quality medical devices for the American public first in the world.
Sex-specific outcomes with cardiac resynchronization therapy - Daniel Canos, PhD/CDRH (Support for implementation of FDASIA Section 907 Action Plan)
The effects of gender differences in adverse events for integrated fixation spinal implants - Srinidhi Nagaraja, PhD/CDRH
Integrated Fixation (IF) interbody spinal cages are medical devices used to treat patients with degenerative disc disease, radiculopathy, and/or myelopathy. As a new approach to spinal fusion, these devices have the potential to reduce complications and morbidity. However, the safety of these devices may be a concern where adverse events such as endplate subsidence (i.e. the device migrates into the vertebral body), device loosening, and bone fracture resulting in pain and revision surgery have been observed clinically. This is of particular importance in women as adverse events in females occur at a greater rate than in males (Lastfogel et al. 2010). This study has direct regulatory impact and relevance to women as it identifies how sex differences in bone quality and spinal flexibility affect the mechanical integrity of these devices after implantation. This coincides precisely with the Agency’s mission to provide safe and effective medical devices to all patients in the US, particularly for subgroups such as women who may have higher rate of adverse events due to these gender specific differences.
Identifying and characterizing key mechanical characteristics of surgical meshes used for pelvic organ prolapse repair and treatment of stress urinary incontinence in women - Terry Woods, PhD/CDRH (Supplementary Funds)
Over 300,000 American women each year have surgery to treat conditions like leaking of urine that you cannot control and organs in the pelvis falling out of place. Many of these surgeries include mesh implants. Both conditions have considerable women’s health impact, including reduced sexual, urinary, and bowel movement function. There has been an increase in reported adverse events with numbers approaching 1000 per year. Mesh exposure through adjacent tissue is the most commonly reported mesh-specific problem. Researchers believe mesh stiffness influences exposure through tissue, thus, development of improved methods to evaluate stiffness is crucial. When sponsors of new surgical mesh applications submit stiffness information, the test methods used vary between devices, making comparison of devices difficult. There is also a general lack of understanding of the effects of stiffness and mesh properties on device function. This study will develop standardized test methods to describe mesh behavior. These methods will be included in revised guidance documents, leading to more consistent and timely reviews. This should reduce device development time for industry by better defining required preclinical testing. This will support the CDRH vision of providing safe, effective, and high-quality medical devices to the American public first in the world.
Bacterial colonization and biofilm formation in dermal fillers implants: An in vivo model to confirm in vitro findings and pathogenesis leading to adverse events - Kenneth Phillips, PhD, CDRH
The use of dermal fillers (DF) to address contour defects resulting from aging, disease, and trauma is increasing exponentially (over 1.7mil. in 2011, >91% in women). Infections are a concern for permanent DF and can lead to disfiguring necrosis/scarring or result in bacteremia. Removal of DF can damage tissue and long-term antibiotic therapy can lead to multi-drug resistant infections. Patients suffer social and psychological trauma. This work sought to understand how to make DF use safer by targeting two intervention areas: 1)Novel simulated skin and pigskin models were developed to study how to reduce contamination during injection; 2)A novel flow cell insert was developed to how study how chemical and mechanical properties of DF affected S. aureus adhesion and 24h biofilm formation. The results can be used to develop evidence-based regulatory and clinical recommendations, and show how infection rates might be lowered by developing improved DF.
Gender differences in neuronal reward circuit activation by nicotine and tobacco smoke using magnetic resonance spectroscopy - Serguei Liachenko, PhD/NCTR
The decreased effectiveness of the remedies to quit smoking and increased incidence of unwanted effects after discontinuing smoking in women is a significant public health issue. However, at present little is known about the exact reasons for that, which underlines the need for further research in the area of the sex differences in addictive and harmful properties of cigarette smoking. In this project we will be using novel imaging method to evaluate the existence and strength of ‘soft’ connections between different parts of the animal brain, which are responsible for the development of addiction to cigarettes and nicotine. This evaluation will be done before, during, and after the animals will be given the course of 28 days of nicotine injections or cigarette smoke inhalations. As a result of this project new information will be gathered about how differently internal brain connections are changing during nicotine administration or cigarette smoking in both male and female rats. This information may shed a new light on how differently smoking addiction develops in males and females and what major parts of the brain are involved in most different way. Such information may lead to the discovery of novel approaches to correct the disturbances to which women are more prone than men after quitting the cigarette smoking.
A pilot study for evaluating genetic influences on sex differences of drug-induced – proarrhythmia - Li Pang, MD/ NCTR
Drug-induced proarrhythmia (irregular heartbeat) is a major safety issue in drug development. Women are at a higher risk than men for drug-induced QT prolongation and Torsades de Pointes (TdP), a rare but lethal heart rhythm problem, which can cause the heart to stop beating. Due to the absence of appropriate tools, few studies have investigated whether genetic differences between men and women have any effects on drug-induced irregular beats. Sex hormones are believed to play predominant roles in determining the sex differences of drug-induced TdP. Recently, progresses in induced pluripotent stem cell (iPSC) technology have made it possible in utilizing an in vitro iPSC-derived cardiomyocytes (iPSC-CMs) model to test influences of both genetic and sex hormones on heart ion channel gene expression and heart cell function. In this pilot study, we will use subject-specific iPSC-CMs from both men and women to investigate genetic influences on sex-differences of drug-induced TdP. This study is supplementary to another OWH-funded project in evaluating effects of sex hormones on drug-induced TdP. The combination of the two studies will provide valuable information in understanding the mechanisms of sex differences in heart cell beating process and risk assessment of drug-induced TdP in both men and women.
Oncomutation profile of triple negative breast cancer: Additional studies in African American women - Meagan Myers, PhD/NCTR
Breast cancer is the second most deadly cancer in American women, with an estimated 40,000 deaths each year. Breast cancers in African American women display different characteristics than in Caucasian women, such as an earlier onset, more aggressive tumor characteristics, and a less favorable outcome. Many differences have been attributed to these disparities, most notably the higher prevalence of triple-negative breast cancer (TNBC) in women of African American decent. While differences in epidemiology and prognosis between African American and Caucasian women with breast cancer, and specifically TNBC, have been described in the literature, little if any data is available regarding possible differences in somatic gene mutations found in the breast tumors from African American compared to Caucasian women. To this end, utilizing the sensitive and quantitative Allele-Specific Competitor Blocker PCR, point mutations in the PIK3CA, HRAS and BRAF genes will be quantified in African American normal breast and 4 different subtypes of breast cancer, including TNBC. Data generated from this study will be compared to our OWH FY12 study, titled “Oncomutation Profile of Triple Negative Breast Cancer”, which was comprised mostly from Caucasian women. Completion of this project will promote women's health by facilitating the development of personalized approaches to treat breast cancer, including TNBC for which there are currently limited treatment options. The data generated from increasing the sample diversity in our dataset will strengthen current knowledge of the molecular differences between breast cancers of different ethnic origins. Furthermore, research into potential differences in low frequency somatic point mutations in these unfavorable tumors of women of African origin may further progress towards the ultimate goal of individualized cancer therapy.
Population-based computational framework for assessing xenobiotic disposition and interaction effects in pregnant women - Annie Lumen, PhD/NCTR (Supplementary Funds)
Women are sensitive to thyroid function disturbances during crucial life-stages, such as pregnancy, which can lead to pregnancy-related complications. Pregnant women are normally excluded from clinical trials because of ethical and legal concerns. Given the lack of available data, there is a need for better approaches to characterize the dose-response relationships for drugs and chemicals in pregnant women to guide regulatory decisions. Recently, researchers developed a first-of-its-kind computational model to evaluate the effects of iodide deficiency and exposure to a single dietary contaminant, perchlorate, on the thyroid function in the pregnant women. The model captured the dose-response of an ‘average’ pregnant woman. In a pilot study, the average model was extended to a population-based model and was able to capture successfully the dose-response relationship of a population of pregnant women. Current efforts aim to expand this generalized computational pregnancy modeling framework for addressing the issue of pregnant women’s exposure to mixtures of thyroid-active chemicals that reflects better the real world exposure scenarios. The model developed in this work provides regulatory agencies with a valuable and robust tool for the quantitative assessment of health risks of exposure by pregnant women to thyroid-active chemicals in food.
Ensuring accessible supply of safe and effective drugs: Quantifying women-specific pro-arrhythmia risk of drug therapies - David Strauss, MD/PhD/CDER (OWH Women’s Health Cardiovascular Research Fellowship)
Prolongation of the heart rate corrected QT (QTc) interval by drugs has been used as a surrogate for developing Torsade de Pointes (Torsade), a cardiac arrhythmia that can cause sudden cardiac death. Women are disproportionally affected by pro-arrhythmic effects of certain drugs compared to men. While some studies have suggested that women have greater drug-induced QTc prolongation compared to men, recent work has found that there is no sex difference in QTc prolongation for certain drugs. This indicates that QTc prolongation is likely not the best marker for actual Torsade risk and does not explain sex-differences in Torsade risk on its own. Instead of evaluating the effects of drug-induced QTc prolongation, this project will quantify real-world sex-specific risk of Torsade using multiple pre-market and post-market databases. The data will be used to develop Torsade risk models based on multiple predictors in women and men separately.
Bayesian assessment of safety profiles for pregnant women-From animal study to human clinical trial - Judy X. Li, PhD/CBER
Evaluation of pharmacokinetics of thrombogenic impurity following different routes of immune globulin administration during pregnancy - Mikhail Ovanesov, Ph.D./CBER
Novel therapeutic approaches to prevent drug-induced torsade de pointes - Norman Stockbridge, MD, PhD/CDER
Develop animal and cellular models to investigate the mechanisms of cardiotoxicity induced by trastuzumab, trastuzumab/pertuzumab, and ado-trastuzumab emtansine to support post-marketing surveillance of these antibody-based HER2-targeted therapies, and characterize novel serum biomarker of cardiotoxicity induced by trastuzumab, trastuzumab/pertuzumab, and ado-trastuzumab emtansine - Wen Jin Wu, MD, PhD/ CDER
Disease systems analysis: towards a generic framework for characterizing disease progression and treatment effects in osteoporosis - Li Li Ph.D./CDER
Phantom-based evaluation of photoacoustic imaging systems for breast tumor vasculature quantification - Brian Garra, M.D/ CDRH
Calcium and material characterization in women using dual-energy computed tomography - Nicholas Petrick/CDRH
Follicle-stimulating hormone (FSH) may exacerbate local and systemic effects of wear particles released from metal-on-metal hip implants: Implications for women - Steven C. Wood Ph.D./CDRH
Simulation of realistic masses on mammograms and digital breast tomosynthesis images for system assessment and CAD development/testing - Berkman Sahiner PhD/CDRH
Blood pressure threshold for cardiovascular disease risk: an assessment of sex-based criterion - Ching-Wei Chang/NCTR
Evaluation of methods used to measure growth of staphylococcus aureus and the production of toxic shock syndrome toxin-1 as influenced by menstrual tampons - Mark E. Hart, Ph.D./ NCTR
Sex differences in drug-induced QT prolongation and torsade de pointes: establishing an in vitro model for high-throughput screening and risk assessment of torsadogenic drugs - Li Pang, MD/ NCTR
Detection of synthetic drugs as adulterants in natural and herbal slimming products by UPLC-mass spectrometry - Phyllis Wilson/ORA
Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products - Anne Pariser, MD/CDER (Support for implementation of FDASIA Section 907 Action Plan)
Evaluation of HSV-2 co-infection and hormonal contraceptive use on HIV acquisition and pathogenesis using patient-derived clinical specimens - Indira Hewlett, PhD, CBER
Assessing Passive Prophylaxis of Infection at Different Stages during Gestation in a Pregnant Animal Model - Evi Struble, PhD, CBER
Use of innate immune response modulators in women: The perfect storm to trigger autoimmune disease? - Daniela Verthelyi, MD, PhD, CDER
MRI Safety Testing of Breast Tissue Expanders used in Mastectomy Patients - Sunder Rajan, PhD, CDRH
Sex differences in biomarkers of kidney injury in patients with metal-on-metal hip implants - Ronald Brown, MS, CDRH
The Effects of Gender Differences in Revision Rates for Spinal Total Disc Replacement Procedures - Srinidhi Nagaraja, PhD, CDRH
Incremental Values of Sequential Procedures for Diagnosing Breast Cancer - Zhiwei Zhang, PhD, CDRH
Effect of Injection Techniques, Materials Chemistry and Physical Properties of Dermal Fillers on Potential for Bacterial Colonization and Infection - Kenneth Phillips, PhD, CDRH
Mechanical causes of higher hip implant failure rates in women - James Coburn, MS, CDRH
Photo-Thermal Safety in Laser-based Devices for Detection and Treatment of Breast Cancer: Effect of Endogenous Absorbers and Gold Nano-Particles - Do-Hyun Kim, PhD, CDRH
Nanoparticle Effects on Induction of Pro-inflammatory Responses to Candida albicans by Cultured Vaginal Epithelial Cells - Robert Wagner, PhD, NCTR
Population-Based Computational Framework for Assessing Xenobiotic Disposition and Interaction Effects in Pregnant Women-Pilot Study - Annie Lumen, PhD, NCTR
Clinical and Biological Significance of Three Identified Targets in Systemic Lupus Erythematosus Patient PBMCs: IL-18, TNFSF13B, and FOXP3 - Beverly Lyn-Cook, PhD, NCTR
Population-Based Computational Framework for Assessing Xenobiotic Disposition and Interaction Effects in Pregnant Women-Pilot Study - Annie Lumen, PhD, NCTR, (Special Initiative)
OWH supplemental funds to Dr. Strauss to do the PK analysis of the samples for a study funded by CDER Critical Path - David Strauss, MD, PhD, CDRH, (Special Funding)
Pharmacokinetic Sample Analysis from Ranolazine, Dofetilide, Verapamil and Quinidine Clinical Study - Norman Stockbridge, MD/CDER (Supplement to CDER Critical Path-Special Funding)
Gender-Specific Predictors of Heart Failure Hospitalization and Death in Cardiac Resynchronization Therapy - David Strauss, MD, PhD, CDRH
Safety and Efficacy of Iron Oxide Nanoparticles Used as MRI Contrast Agents for Breast Cancer Imaging - Peter Goering, PhD, CDRH
Novel Electrocardiographic Device Algorithms to Assess Cardiac Safety of Investigational Drugs - David Strauss, MD, PhD, CDRH
Abdominal Aortic Aneurysms: analysis of patient Characteristics and Anatomy Related to EVAR treatment and outcomes- AAA CARE - Tina Morrison, PhD, CDRH
Sex differences in kidney biomarker response following exposure to an orthopedic alloy: Implications for the safety assessment of metal-on-metal hip implants - Ronald Brown, MS, CDRH
Development, validation and dissemination of computational modeling tools to estimate radiation dose and image quality of emerging imaging technologies for the diagnosis and staging of breast cancer - Andreu Badal-Soler, PhD, CDRH
MRI in pregnant patients: A systematic analysis of Radio-frequency heating with multi-transmit technology - Leonardo Angelone, PhD, CDRH
Comparitive Analysis of Adverse Events Between Conventional Tube Ligation and Transcervical Occlusive Devices of the Fallopian Tube for Female Sterilization: A Cohort Study
Quantitative oncomutation profile of triple negative breast cancer - Colin Anderson-Smits, MPH, CDRH
Identifying drugs that cause women-biased hepatotoxicity by reviewing FDA drug approcal packages/labels and FDA maintained databases and conducting comparitive studies in primary hepatocytes of rats. - Qiang Shi, PhD, NCTR
Gender differences in neuronal reward circuit activation by nicotine and tobacco smoke using magnetic resonance spectroscopy - Serguei Liachenko, PhD, NCTR
Improving safety of blood products administered during pregnancy - Mikhail Ovanesov, PhD, CBER
Development of a mouse model to mimic the response of female and pregnant human subjects to avian influenza infections and to evaluate the protective efficacy of pandemic H5N1 vaccines against highly pathogenic avian influenza - Zhiping Ye, PhD/ Xie Hang, PhD, CBER
Investigate the mechanisms of trastuzumab-induced cardiotoxicity and cardiotoxicity and cardio protective role of antioxidants in trastuzumab-mediated cardiac dysfunction - Wen Jin Wu, MD, PhD, CDER
Investigation of Drug-Drug Interactions with Hormonal Contraceptives - Chongwoo Yu, PhD, CDER
Gender effect on PK/PD of hypnotic drug: Driving impairment and dosing recommendations - Jagan Mohan Parepally, PhD, CDER
Exploring Potential Safety Issues of PPIs on Osteoporosis in Elderly Women Using the PPI Legacy Database - Zhongjun Luo, MD, PhD, CDER
Quantification of drug retained in the skin after removal of estradiol transdermal drug delivery systems used in hormone replacement therapy - Sri Rama Krishnaiah Yellela, PhD, CDER
Applications of Clinical Pharmacology Principles in Pharcotherapy of Diseases in Pregnancy - Srikanth Nallani, Ph.D, CDER
Sex Disparities in Autoimmune Treatment Response - Lanyan Fang, PhD, CDER
A Mechanistic Study of the Capacity of Silicone to Present (Self) Antigens to the Immune System - Jack Ragheb, PhD, CDER
Prophylaxis of HBV infection with HBIGIV in a pregnant animal model - Pei Zhang, MD, CBER
The Role of Estrogen in Controlling Hepatitis C Virus Replication - Deborah Taylor, CBER
An investigation of sexual dysfunction in depressive trials - Peiling Yang, PhD, CDER
Effects of body mass index (BMI)/body weight (BW) on effectiveness of hormonal contraceptive products for women - Chongwoo Yu, PhD, CDER
Nuclear Uptake of Transcription Co-Activator JTV1 Induces p53-Meadiated Apoptosis of Ovarian Cancer (OC) Cells – Implications for the Development of New Ovarian Cancer Biomarkers and Therapeutic Targets - Juhong Liu, PhD, CDER
Addressing the unmet medical needs for cardioproctection in women receiving chemotherapy - Rao, Ashutosh, CDER
Pharmacokinetics (PK) and biomarkers of the medications used to treat multiple sclerosis (MS) – any gender difference? - Ta-Chen Wu, PhD, CDER
Evaluation of safety and effectiveness of mesh implantation in surgical interventions for the treatment of pelvic floor disorders, Phase III - Cara Krulewitch, CNM, PhD, CDRH
Evaluating radiation risks and benefits of breast CT for diagnosing breast cancer - Robert Jennings, PhD, CDRH
Reproducibility in the quantitative assessment of multiple tissue-based biomarkers for breast cancer using light and digital microscopy - Nicholas Petrick, PhD, CDRH
Sex-based differences in the molecular mechanisms of polymer degradation in drug eluting stents (DES) - Dinesh Patwardhan, PhD, CDRH
Preclinical Test Methods for Percutaneously Implanted Heart Valves: Effect of Non-Circular Valve Configuration After Implantation On Valve Leaflet Dynamics - Terry Woods, CDRH
MRI and Ultrasound imaging of silicone filled breast implants - Rajan Sunder, PhD, CDRH
Integrated analysis of single nucleotide polymorphism and copy number variation in genome association of breast cancer - Ching-Wei Chang, PhD, NCTR
Sex and ethnic differences in expression of Toll-like receptors (TLR-3, TLR-7, and TLR-9) in systemic lupus erythematous (SLE): new targets for emerging therapeutics - Beverly Lyn-Cook, PhD, NCTR
Development of a targeted microRNA-based epigenetic therapeutic approach for breast cancer treatment - Igor Pogribny, PhD, NCTR
Genetic and epigenetic mechanisms for sex differences in the kidney of a rat model system: developing safety biomarkers for FDA regulated products - James Fuscoe, PhD, NCTR
Detection of Nanoscale Materials in Products Targeted to Women: Feminine Hygiene Products and Dietary Supplements - Sean Linder, PhD, ORA
Studies of gluten-mediated cell signaling and immune modulation in Caco-2 intestinal epithelial cells: impact on women’s health and celiac disease - Rallabhandi, Prasad, PhD, CFSAN
Lupus Workshop - Shashi Amur, Special funding/CDER
Prospective assessment of clinical and health status outcomes for female patients undergoing Percutaneous Coronary Intervention (PCI) procedures via femoral and radial access - Katie O'Callaghan, Special funding/CDRH
Sex-Specific Left Bundle Branch Block Criteria and ECG Scar Quantification to Predict Benefit from Cardiac Resynchronization Therapy (CRT) - David Strauss, MD, Special funding/CDRH
Continuation of a pilot study on performing sex analysis on a vaccine database - Jingyee Kou, PhD, Special funding/CBER
Treatment of progressive vaccinia in a pregnant immunocompromised mouse model - Dorothy Scott, M.D. (CBER)
Evaluation of Safety and Effectiveness of Mesh Implantation in Surgical Interventions for the Treatment of Pelvic Floor Disorders, PHASE II and PHASE III - Cara Krulewitch, PhD (CBER)
Atrial Fibrillation Ablation Registry Study (SAFARI) - Ellen Pinnow, PhD (CBER)
A pilot study on on performing sex analysis on a vaccine database - Jingyee Kou, PhD (CBER)
Assessment of Risk Factors Associated with Exposure to Proton Pump inhibitors and Fracture and CV outcomes in post-menopausal osteoporosis woman - Antonio Paredes, PhD (CDER)
Applications of clinical pharmacology principles in pharmacotherapy of diseases in pregnancy - Srikanth Nallani, PhD (CDER)
Sex and age related differences in baseline QT, QT prolongation, and TdP risk - Christine Garnett, Pharm D (CDER)
Women in HIV trials: a comprehensive review and meta-analysis for safety - Guoxing (Greg) Soon, Ph.D (CDER)
Evaluation of gender-related clinical pharmacology information in the labelings on adverse events and outcomes - Lei Zhang, PhD (CDER)
An analysis of safety signal detection methods for pregnancy exposure registries - Paul Schuette, PhD (CDER)
Development of standard color management methods for assessment of immunohistochemical HER2 expression in breast cancer using digital microscopy - Aldo Badano, PhD (CDRH)
The swan-ganz balloon flotation pulmonary artery catheter: possible racial and sex discrepancies - Daniel Canos, PhD (CDRH)
Assessment of outcomes and bleeding complications following implantation of drug eluting stents (DES) and dual anti-platelet therapy (DAPT) - Hesha Duggirala, PhD (CDRH)
Dose and image quality optimizations in various full-field digital mammography systems - Kish Chakrabarti, PhD (CDRH)
Safety and efficacy of biomarkers using gene expression data for breast cancer patient treatment and care - Subok Park, PhD (CDRH)
Risk of Adverse Events following Cardiac Catheterization by Hemostasis Device Use – Phase III - Dale Tavris, PhD (CDRH)
Quantum mechanical and NMR spectral approaches for the rapid prediction of estrogen activity or new drugs and environmental documents - Jon Wilkes, PhD (NCTR)
Effects of phytoestrogens on gene expression responses of vaginal epithelial cells after contact with candida albicans - Doug Wagner, PhD (NCTR)
In vitro studies to assess impact of gender and co-infection with Herpes Simplex virus type 2 on the replication and transmissibility of major emerging HIV-1 variants - Indira Hewlett, Ph.D. (CBER)
The role of estrogen in enhancing innate immunity during viral infection - Deborah Taylor, Ph.D. (CBER)
Computational human health effects study to assess the safety of botanical extracts widely used by women in the United States for treatment of menopausal symptoms - Luis Valerio, Ph.D. (CDER)
Ethics roundtable: the ethics of studying drugs and biologics in pregnant women - Karen Feibus, M.D. (CDER)
Do vertebroplasty procedures increase the risk of adjacent level vertebral fractures in osteoporotic women - Srinidhi Nagaraja, Ph.D. (CDRH)
Quality of life and significant symptoms after LASIK - Malvina Eydelman, M.D. (CDRH)
Analysis of sex-differences in cardiac resynchronization therapy devices: inclusion, adverse events, and outcomes - Katie O’Callaghan, MS. (CDRH)
Sex-based differences in the safety of drug-eluting stents containing bioresorbable materials - Dinesh V. Patwardhan, Ph.D. (CDRH)
Development of a tissue-mimicking physical phantom and quantitative, assessment tools for standardizations, optimization, and NSF risk reduction in dynamic contrast-enhanced MRI of the breast - Aldo Badano, Ph.D. (CDRH)
Women’s radiation dose and excess cancer risk associated with x-ray computed tomography scans: quantification and risk-mitigation strategies - Iacovos S. Kyprianou, Ph.D. (CDRH)
Application of co-culture and simulated vaginal models to elucidate the inhibitory properties of naturally occurring and bioengineered strains of lactobacillus toward toxic shock syndrome toxin-1 producing strains of staphylococcus aureus - Mark Hart, Ph.D. (NCTR)
Development of an FDA resource for sex difference-related pharmacogenomics data review-Phase II - Weida Tong, Ph.D. (NCTR)
Women’s health initiative seminar series and workshop at NCTR - Beverly Lyn-Cook, Ph.D. (NCTR)
Inactivation of UDP-Glucuronosyltransferases (UGTs) in human breast and endometrial tissues: accessing cancer risk, tamoxifen safety and toxicity - Beverly Lyn-Cook, Ph.D. & Athena Davenport, Ph.D. (NCTR)
Genome wide methylation arrays for detecting markers of increased susceptibility to mammary cancer caused by in utero exposures to endocrine disruptors - Cecilia Aguila D.V.M. (CVM)
The Role of Vaccine Adjuvant Mediated TACI Up regulation in SLE - Mustafa Akkoyunlu M.D., Ph.D. (CBER)
Effects of B-Estradiol on the Safety of Anti-HIV Drugs - Andrew Dayton, Ph.D. (CBER)
Gender-Related Differences in QT Effects and Torsade de Pointes Potential of Drugs - Christine Garnett, Ph.D., Philip Dinh, Ph.D. (CDER)
Qualifying Imaging Biomarkers to Monitor Neoadjuvant Chemotherapy in Breast Cancer Patients to Identify Responders Using Positron Emission Tomography (PET) - Christy John, Ph.D. (CDER)
The Asthma and Allergy Medications in Pregnancy Surveillance System (AAMPSS) Demonstration Project - Sandra Kweder, M.D. (CDER)
Evaluating the Effects of Over-the-Counter Skin Products, such as Sunscreen, on the Absorption of Dermally Applied Estradiol, in an In- Vitro and an In-Vivo Model - Nakissa Sadrieh, Ph.D. (CDER)
Detection and Confirmation of Gender Related Safety Signals Using the Electronic Healthcare Data from the Department of Defense - Ana Szarfman, Ph.D. (CDER)
Safer use of Narcotics in Pregnant and Lactating Women - Lei Zhang Ph.D. (CDER)
Dose and Image Quality Optimization in Full Field Digital Mammography - Kish Chakrabarti, Ph.D. (CDRH)
The Safety and Effectiveness of Surgical Mesh Implant Use in Uro-Gynecologic Surgery for Soft Tissue Augmentation - Cara Krulewitch, CNM, Ph.D. (CDRH)
Workshop: Guidance for the Study and Analysis of Sex Differences in the Clinical Evaluation of Cardiovascular Medical Devices - Kathryn M. O’Callaghan, B.S. (CDRH)
Patient Safety and Imaging Performance of Three-Dimensional (3D) X-Rays Systems for Detection of Breast Cancer -Subok Park, Ph.D. (CDRH)
Gender Differential in National Estimates for Medical Device-Associated Adverse Events (MDAEs) from Emergency Departments - Cunlin Wang, M.D., Ph.D. (CDRH)
Evaluation of Inflammation and Sex Hormones as Biological Factors that May Contribute to Gender Differences in Susceptibility to Chemical-Induced Liver Injury – Studies Using Human Liver Cells in Culture - Thomas Flynn, Ph.D. (CFSAN)
Risk Assessment of Human Skin Microflora Metabolism of Synthetic Azo Colorants used in Women’s Cosmetics - Huizhong Chen, Ph.D. (NCTR)
Genotyping of Transporter Genes Associated with Gender Differences and Promoter Methylation Profile of UGT1A1 in Human Liver: A Mean of Assessing Safety and Toxicity of Chemotherapeutic Drugs - Beverly Lyn-Cook, Ph.D. (NCTR)
Gene Expression Responses of Estrogen-Primed Vaginal Epithelial Cells After Contact With Candida albicans and Probiotic Lactobacilli - Doug Wagner, Ph.D. (NCTR)
Effects of Proposed Revisions to the Regulations Implementing the Mammography Quality Standards Act - Steven Tucker, Ph.D, (OC)
Evaluation of Gender Differences in Detection, Replication and Transmissibility of Emerging HIV-1 Variants - Indira Hewlett, Ph.D. (CBER)
The Role of Estrogen in Enhancing Innate Immunity During Viral Infection - Deborah Taylor, Ph.D. (CBER)
Gender, Ethnicity and Pharmacogenomics in Systemic Lupus Erythematosus (SLE) - Shashi Amur, Ph.D. (CDER)
Workshop: Drugs in Pregnancy - Audrey Gassman, M.D. (CDER)
Identification of Sex Differences in Adverse Outcomes for New Molecular Entities (NMEs) Approved from 2000-2002 - Yongsheng Yang, Ph.D. (CDER)
Factors Accelerating the Progression of Heart Failure (HF) in Women: Implications for Drug Interactions with Medical Devices - Soma Kalb, Ph.D. (CDRH)
The Impact of Sex-Based Differences in Atherosclerotic Plaque on the Response to Drug Eluting Stent Implantation - Dinesh Patwardhan, Ph.D. (CDRH)
Real-World Outcomes of Drug-Eluting Stents - Art Sedrakyan, MD, Ph.D. (CDRH/AHRQ)
Understanding Consumer Behavior Associated with Changing Messages on Listeria monocytogenes and Food Safety - Elizabeth Calvey Ph.D., Marjorie Davidson, Ph.D. (CFSAN)
Sex differences in Systemic Lupus Erythematosus (SLE): Effects of a single nucleotide polymorphism (SNP) in the prolactin (PRL) gene on individual response to prasterone therapy - Neera Gopee, Ph.D. (NCTR)
Mechanisms of Gender Differences in Aspirin Effects: Metabolizing Enzymes and Therapeutic Targets - Baitang Ning, Ph.D. (NCTR)
Development of a FDA Resource for Improved Efficiency of Sex Difference Related Pharmacogenomic Data Analysis and review - Weida Tong, Ph.D. (NCTR)
Development of a Rapid Version of the Tampon Test Method Based on 21CFR801.430 - Lesley Kerr, Ph.D. (ORA)
Development and Validation of an HPLC Method for the Simultaneous Determination of Estradiol, Estriol, Estrone and Progesterone in Pharmaceutical Preparations - Phyllis Wilson, Ph.D. (ORA)
Drug Eluting Stent (DES)/Thrombosis - Bram Zukerman PhD, Norman Stockbridge, PhD, Duke Clinical Research Institute
HIV SELECTEST A Novel Assay for Diagnosis of HIV Infections in the Presence of Antibodies Induced by Candidate HIV Vaccines: Evaluation of Gender Bias in Sensitivity and Specificity - Hana Golding, Ph.D., Surender Khurana, Ph.D. (CBER)
Gender Differences and Impact of Pharmacogenomics in Rheumatoid Arthritis - Shashi Amur, Ph.D. (CDER)
Impact of Gender Analysis and Pharmacogenomics on Clinical Efficacy, Safety, and Pharmacokinetics of Drugs Used for the Treatment of Alzheimer’s Disease. - Angela Men, Ph.D., Shashi Amur, Ph.D. (CDER)
Quantitative Tumor Size - Survival Relationship in Oncology Clinical Trials - Jogarao Gobbura, PhD. (CDER)
Statistical Analysis of Gender Specific Data from New Drug Application (NDA) Submissions - Ohidul Siddiqui, Ph.D. (CDER)
Women in HIV Trials: A Comprehensive Review and Meta-Analysis - Guoxing (Greg) Soon, Ph.D. (CDER)
Drug Use in Pregnancy - Mary Willy, Ph.D. (CDER)
Research on the Effects of Drug Exposure in Pregnancy - Anne Trontell, MD, MPH., (CDER/AHRQ)
Participation of Women in Clinical Trials and Gender Analysis of Data in Original NDAs Approved 2000-2002 - Yongsheng Yang, Ph.D. (CDER)
Evaluating the Effectiveness of Vertebroplasty for Improving the Mechanical Properties of the Spine in Patients with Osteoporosis. - Jove Graham, Ph.D. (CDRH)
Evaluation of Availability and Quality of Information Available on Females Included in Mechanical Device Implant Trials. - Kathryn O’Callaghan B.S. (CDRH)
Molecular Mechanisms Underlying Gender-associated Differences in the Adverse Reactions to the Anti-retroviral Agent, Zidovudine (AZT) Role of Mitochondrial Toxicity - Varsha Desai, Ph.D. (NCTR)
Protective Effect of Vaginal Lactobacillus Species Against Staphylococcus Aureus-mediated Toxic Shock Syndrome - Christopher Elkins, Ph.D., Mark Hart, Ph.D. (NCTR)
Sex Differences in Chemotherapeutic Toxicity: Profiling of Transporter Genes in Human Liver - Beverly Lyn-Cook, Ph.D. (NCTR)
Phase I - II Mental Modeling Research of how best to communicate to health care providers about the risks and benefits of prescription drug use for pregnant or Lactating Women with Chronic Conditions - Kara Morgan, Ph.D. (OC)
ECG Warehouse - Duke Clinical Research Institute and Duke University - Christopher Cabell, M.D., MHS, Duke Clinical Research Institute (DCRI)
ECG Warehouse - Mortara Instruments Inc. - Justin Mortara, Mortara Instrument Inc.
The Molecular Assays and Targeted Therapies (MATT) Consortium - Ray Woosley, MD, Ph.D., The Critical Path Institute
Pharmacokinetics and Pharmacodynamics of Selected Antibiotics during Pregnancy - Gloria Sarto, MD., University of Wisconsin
Sex Difference Dependent Drug-drug Interactions of Anti-HIV Therapeutics - Hyojong Kwon, Ph.D., Robert Lionberger, Ph.D. (CDER)
Implications of Gender-based Differences in Cardiovascular Disease on Imaging for Treatment and Diagnosis - Iacovos Kyprianou, Ph.D., Kyle Myers, Ph.D. (CDRH)
Assessment of the Accuracy of the Troponin Assay and the Diagnosis of Myocardial Infarction by Gender/ How Gender Influences Treatment - Azadeh Shoaibi, M.S., MPH, Dale Tavris M.D. MPH (CDRH)
Systems Biology Approach to Evaluate Sex Differences in the Heart of a Rat Model - James Fuscoe, Ph.D. (NCTR)
Use and Outcomes of Coronary Stents in Women: Use of a National Medicare Database - Karen Freund, MD, Boston University
CYP2B6 Genotype-Phenotype and the Influence of Sex and Ethnicity - Erin G. Schuetz, Ph.D.
Gender Based Differences in the Vascular Response to Anthrax Toxin: Investigation of the Role of Hormones in an In Vitro Human Endothelial Cell Culture System - Felice D’Agnillo, Ph.D. (CBER)
Gender Dimorphism in HIV Infection in Primary Macrophages and T-Lymphocytes Kinetics of HIV Replication and Efficacy of Anti-Retroviral Agents - Andrew Dayton, Ph.D. (CBER)
Gender Differences in the Willingness to Read and Follow Patient Information - Ellen Tabak, Ph.D, Leslie Wheelock, Ph.D. (CDER)
Development of Guidelines for Evaluating the Appropriateness of Vertebroplasty Surgery for Patients with Osteoporosis - Jove Graham, Ph.D. (CDRH)
Do Phytoestrogens Modify the Allergic Response to Food Allergens in the Newly Validated, Highly Sensitive, In-Bred Asthmatic Rat Model? - Maria Lorenzo, DVM, Mona S. Calvo, Ph.D. (CFSAN)
Developmental Toxicity of Androstenedione in Rats - Robert Sprando, Ph.D. (CFSAN)
Pharmacokinetics and Pharmacodynamics (PK/PD) of Atenolol in Lactating Women - Mary Hebert, Pharm D, University of Washington
Drug Metabolism in Women - Stephen Hall, PhD, Indiana University
Transmission Attenuation Correction for Female Patients Undergoing Myocardial Perfusion Imaging: Correction for Confounding Breast Tissue Artifact - Michelle Dew, MD, University of Arizona
Pilot Study: Combined Beta1 Arg 389 and Alpha 2c Del 322-325 Adrenergic Receptor Polymorphisms and Heart Failure with Preserved Left Ventricular Ejection Fraction in African American Women - Thierry LeJemtel, MD, Tulane University
Are Women at Higher Risk from Proarrhythmic Drugs? - Jogarao Gobburu, Ph.D. (CDER)
Discovery and Evaluation of Interspecies Biomarkers to Monitor the Early Onset and the Progression of Cardiovascular Toxicity Associated with Tiazolidinedione Compounds Used in the Treatment of Type 2 Diabetes - Eugene Herman, Ph.D. (CDER)
Electrophysiological Characterization of Several Torsadogenic Drugs in Isolated Rabbit Hearts - John. Koerner, Ph.D.(CDER)
Cardiovascular Effects of Ultrasound Contrast Agents in Intact and Ovariectomized Female Animals - Melvin Stratmeyer, Ph.D. (CDRH)
Assessment of Maternal Effects Infant Outcomes Using Large Automated Healthcare Data Systems in Women Exposed to Prescription Medications During Pregnancy - William Cooper, MD MPH, Vanderbilt University
Self-Monitoring of Blood Glucose with Finger-Tip versus AST: Effect on Long term Glycemic Control - Caroline Apovian, MD, Boston University
Maternal Antidepressent Drug Research and Evaluation (Madre): Pharmacokinetics and Pharmacodynamics of Sertraline in Pregnant and Postpartum - Marlene Freeman, MD, Arizona Health Science Center
Effect of Sex Hormones on the Immune Response to CpG ODN - Daniela Verthelyi, Ph.D. (CBER)
Gender Effect on the Assessment of Bioavailability and Bioequivalence Gender Differences in Intestinal Levels of CYP3A4, CYP 3A5, P-gP and MRP - Mei Ling Chen, Ph.D. (CDER)
Incidence and Attributable Risk of Serious Adverse Events and Death Associated with the Use of Homeostasis Devices by Gender - Dale Tavris, M.D. MPH (CDRH)
Characterization of the Effect of Pre-pubertal and Pubertal Exposure of Androstenedione on Female Reproductive Health - Robert Sprando, Ph.D. (CFSAN)
Development and Characterization of Conditionally Immortalized Human Primary Hepatocyte Cell Lines From Female And Male Donors -- Phase I - Angela Harris, Ph.D. (NCTR)
Pharmacokinetics and Pharmacodynamics (PK/PD) of Atenolol in Pregnancy - Mary Hebert, Pharm D, University of Washington
Ciprofloxacin and Doxycycline in lactating women and in the elderly - Raymond Galinsky, Indiana School of Medicine
Thymic Regeneration and Immune Function Reconstitution in Babies Born to HIV-infected Mothers - Hana Golding, Ph.D., Marina Zaitseva, Ph.D. (CBER)
Discovery and Evaluation of Interspecies Biomarkers to Identify and Characterize the Cardiotoxic Effects of Herceptin, a Novel Antibody Used in the Treatment of Breast Cancer - Eugene A. Herman, Ph.D., Frank Sistare Ph.D. (CDER)
The Effects of Echinacea on Cytochrome P450 Enzymes and Oral Contraceptives - Shew-Mei Huang, Ph.D., Steven Hall Ph.D. (CDER)
Drug Update in Human Mammary Gland Epithelia - Shinya Ito, M.D., Gerald Fetterly, Ph.D. (CDER)
Development of a General Approach for the Investigation of Drug Transfer in Breast Milk: In Vitro Assessment of Drug Distribution into Breast Milk - Patrick J. McNamara, Ph.D., Gerald Fetterly, Ph.D. (CDER)
Developing a Diagnostic Gene Expression Profile for Latex Sensitivity Using Microarrays - Rosalie Elespuru, Ph.D., Roselie Bright, Sc.D. (CDRH)
Optimization of UV Exposure Patterns Maximizing Perceived Benefits While Minimizing Photocarcinogenic/photo-aging Effects - Sharon Miller M.S., Janusz Beer, Ph.D. (CDRH)
Labetalol and Hypertension in Pregnancy: Pharmacokinetics and Pharmacodynamics - James Fischer, Pharm D, University of Illinios
The PK of Amoxicillin during Pregnancy and Postpartum - Mary Hebert, Pharm D, University of Washington
Vaginal Volume: Optimizing Vaginal Deployment of Topical Microbicides - Debra Birnkrant, M.D., Ajaz Hussain, Ph.D. (CDER)
Women's Participation in Clinical Drug Trials for Unstable Angina and Myocardial Infarction - Ann Farrell, M.D., Lilia Talarico, M.D. (CDER)
Evaluation of the Tg.AC Transgenic Mouse as a Model for Predicting the Photocarcinogenicity of Pharmaceuticals and Cosmeceuticals - Ronald Honchel, Ph.D., Frank Sistare, Ph.D. (CDER)
Surveillance of Sex-specific Utilization, Morbidity, and Mortality Associated with Transmyocardial Revascularization - Ronald Kaczmarek, M.D. (CDRH)
A Study to Evaluate the Consistency of T-scores Among Ultrasound Bone Measurement Devices and the Usefulness of these Devices for Monitoring Bone Status - Richard Kotz, Ph.D. (CDRH)
Teratogenic Potential of Cosmetic Products Containing Retinol (Vitamin A) and Retinyl Palmitate-Phase I - Jeffrey Yourick, Ph.D. (CFSAN)
Use of a Unique Animal Model to Study Placental Milk Transfer of Ciprofloxicin from the Dam to the Offspring During the Perinatal Period - Jurgen von Bredow, Ph.D. (CVM)
Evaluation of the Effects of Daidzein And Genistein on The Genotoxic and Carcinogenic Activity of the Model Mammary Carcinogen 7,12-Dimethylbenz(A) Anthracene (DBMA) in Ovariectomized Transgenic Big Blue Rats - Anane Aidoo, Ph.D. (NCTR)
Evaluation of the Tk Knockout Mouse as a Model of Systemic Lupus Erythematosus - Vasily Dobrolovsky, Ph.D. (NCTR)
Analysis of Dioxins/Furnas (17 congeners) Levels in Tampons - Jeffery Archer, M.S. (ORA)
Pattern of botanical dietary supplement usage in menopausal women - Gail Mahady, PhD, University of Illinois at Chicago
Effects of dietary soy and calcium supplementation on lipid levels, brachial artery function, biochemcial markers of bone turnover, inflammatory markers of atherosclerosis and menopuasal symptioms in postmenopausal women - Francine Welty, MD PhD, Beth Israel Deaconess Medical Center and Harvard U
The effects of St Johns Wort on the efficacy of oral contraception - Stephen Hall, PhD, Indiana University
Review of herbal weight loss product experiences and adverse events. - Sara Warber, MD, University of Michigan
Use and interaction of dietary supplements in the SEA Trial. - Mara Vitolins, DrPH, Wake Forest University
Phytoestrogens: Drug interaction potential in women - Gail Anderson, PhD, University of Washington
Improving the Evaluation of Ovarian Cancer Treatment - Vance Berger, Ph.D. (CBER)
Hormone Effects on Pathogenesis & Host Cell Interactions of N. Gonnorrhea - Carolyn Deal, Ph.D. (CBER)
Evaluation of In-vitro Mechanistic Basis for Gender Dependant Differences in Pharmacokinetics - Chandra Sahajwalla, Ph.D. (CDER)
Post-marketing Drug Risk Assessment Using the ARAMIS Database in RA Patients - Mary Willy, Ph.D. (CDER)
Active Postmarketing Surveillance Methods: A Hospital Pilot - Rosalie Bright, Sc.D. (CDRH)
Assessment of Consumer Understanding of Barrier Contraception and Tampon Labeling: Focus Group Studies - Robert Navario, Ph.D, S.L.Brown, M.D. (CDRH)
Potential Exposure of Women to Estrogens, Phytoestrogens and Xenoestrogens through Cosmetic Products - Robert Bronaugh, Ph.D. (CFSAN)
Antigenic Biomarkers of Estrogen Catechol Metabolism for Post-Market Surveillance of Oral Contraceptives and HRT's - Dean Roberts, Ph.D. (NCTR)
Silicone Gel-filled Breast Implant Capsules: A Molecular Histologic and Immunophenotypic Study - Frederick Miller, M.D., Ph.D. (CBER)
Improve the Efficacy of Chemotherapeutic Drugs for the Treatment of Breast Cancer - Emily Shachter, Ph.D. (CBER)
Pregnancy Labeling Taskforce Focus Group testing (co-funded by NIH ORWH) - Kathryn Aiken, Ph.D. (CDER)
Gender Differences in P450 Activities and their Implications (co-funded by NIH ORWH) - Shiew Mei Huang, Ph.D., Robert Branch, Ph.D. (CDER)
Chemical Characteristics of Conjugated Estrogens - Thomas Layloff, Ph.D. (CDER)
Adverse Events Reporting System (AERS): Risk assessment, Compliance & Management - Ralph Lillie, RPh (CDER)
Teratogen Surveillance - Carolyn McCloskey, M.D., MPH (CDER)
Data Mining Techniques for Identifying Potential Serious Drug Interactions in Women - Ana Szarfman, M.D., Ph.D. (CDER)
Variations in the Drug-induced QT Interval Prolongation During the Menstrual Cycle (Co-funded by NIH ORWH) - Ana Szarfman, M.D., Ph.D., Raymond L. Woosley, M.D., Ph.D. (CDER)
CFSAN's Internet Initiative: Infra-structure Support - Kenneth T. Durham, Ph.D. (CFSAN)
Contaminants in Dietary Supplements Frequently Used in Women - Nancy Slifman, M.D., MPH (CFSAN)
Abrasion Testing of Breast Implants - Patricia Dubill, Ph.D. (CDRH)
Ovarian Steroids and Cardiovascular Disease the Role of Gender in the Effectiveness of Interventional Medical Devices - James Karanian, Ph.D. (CDRH)
Accelerated Aging Studies of Condoms/condom Materials - Harvey Rudolph, Ph.D. (CDRH)
Flow Studies and the Use of a Waveguide in Cardiovascular Devices - Harvey Rudolph, Ph.D. (CDRH)
Development and Validation of Ultrasonic Backscatter Measurement for Bone Density Assessment - Keith Wear, Ph.D. (CDRH)
In-Vivo Modeling Of Steroid-Mediated Gender Effects in Drug Metabolism (Phase I and II) - Patricia Thompson, Ph.D. (NCTR)
Development and Validation of a Universal Water Leak Test Method for Barrier Contraceptives - Lesley Kerr, Ph.D. (ORA)
Antigenic Characteristics and Immunogenicity of Synthetic Peptide Vaccines for the Pathogenic Neisseria: Neisseria meningitides and Neisseria gonorrhea - Margaret Bash, M.D., MPH (CBER)
Sexual transmission of HIV-1 in Women and Mother to Infant Transmission: The Importance of HIV-1 Co-receptor Expression on Cerviovaginal Cells and on Cord Blood Cell Subsets - Hana Golding, Ph.D. (CBER)
Contribution of Estrogen Components to the Efficacy of Conjugated Estrogens - Preliminary Analytical Chemistry - John Strong, Ph.D. (CDER)
Visualization Tools for Studying Gender Differences - Ana Szarfman, M.D., Ph.D. (CDER)
Institute of Medicine Study: A Study of Safety of Silicone Breast Implants - S. Lori Brown M.D. (IOM/CDRH)
Protocol for a Study of Breast implant rupture - S. Lori Brown, M.D. (CDRH)
Mammography Breast Cancer Screening Rates Among Disadvantaged Women within a Pre-Paid Health Care System - Rosalie Bright, Sc.D. (CDRH)
Optimization of mammography - Robert Jennings, Ph.D. (CDRH)
A Comparison of Gender Specific Utilization of Implantable Cardioverter Defibrillator Therapy and Post-implantation Survivability - Steven Lascher, DVM, MPH (CDRH)
Epidemiology of Medical Devices in Women (conference) - Danica Marinac-Dabic, M.D. (CDRH)
Obesity: Its Effect on Antioxidant and Estrogen Metabolism - Shirley R. Blakely, Ph.D. (CFSAN)
Vitamin K Status of Non-Hispanic Black and White Girls and Young Adult Women: Direct Measure of Serum Phylloquinone Levels and Measurement of a New Functional Endpoint in Serum Samples from NHANES III - Mona S. Calvo, Ph.D. (CFSAN)
Breast Cancer in African-American Women: Metabolic Modification of Dietary and Hormonal Risk Factors - Christine B. Ambrosone, Ph.D. (NCTR)
Molecular and Metabolic Determinants of Maternal Risk and Progression of Down's Syndrome Potential for Nutritional Intervention - S. Jill James, Ph.D. (NCTR)
Development Of In Vitro Human Cell Culture Systems to Screen Compounds Suspected To Have Estrogenic or Anti-Estrogen Activity - William H. Tolleson, Ph.D. (NCTR)
A Novel Approach to the Treatment of Lupus Nephritis - Dennis Klinman, M.D., Ph.D. (CBER)
Human Cytotoxic T Lymphocyte Recognition of Papilloma Virus - Penelope Robbins, Ph.D. (CBER)
Administration of Thrombolytic Therapy to Women with Acute Myocardial Infarction: Is It Too Late? - Emily B. Shachter, Ph.D. (CBER)
IP-10: A Potential New Therapeutic for Breast Cancer - Giovanna Tosato, M.D. (CBER)
In Vitro Prediction of Time to Neutropenic Nadir: Anti-neoplastic Alkylating Agents as Prototype Drugs - Donna A. Volpe, Ph.D. (CDER)
Development of a Safe, Economical Assay for Silicone Containment in Blood and Tissue - Marwood N. Ediger, Ph.D. (CDRH)
The Transfer of Defense, Intelligence and Space Technologies for the Early Detection and Control of Cancers in Women (conference) - Melvyn Greberman, M.D., MPH (CDRH)
A Computer Model for Simulating Virus Transport through Barriers - Matthew R. Myers, Ph.D. (CDRH)
CFSAN’s Women's Health Internet Initiative - Phase II - Kenneth T. Durham, Ph.D. (CFSAN)
Screening for Nervous System Dysfunction in Offspring of Dams Exposed to Natural Food Contaminates During Pregnancy - Thomas J. Sobotka, Ph.D. (CFSAN)
Women’s Health Information Line - Ruth A. Welch, Ph.D. (CFSAN)
DNA Adducts of Tamoxifen - Frederick A. Beland, Ph.D. (NCTR)
Development of an Estrogen Knowledge Base for Research and Regulation - Darnell Carlton Jackson, Ph.D. (NCTR)
Experimental Assessment of Environmental Estrogens - Daniel M. Sheehan, Ph.D. (NCTR)
Cytokine Induced Activation of the Jak Kinase/STAT Transcription Factor Pathway in Immune Cells (Monocytes and Lymphocytes) of Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus - David S. Finbloom, M.D. (CBER)
Induction of Mucosal Immunity to Protect Females from HIV-1 - Basil Golding, M.D. (CBER)
Hormonal Regulation of Cytokine-producing Cells in Women with Systemic Lupus Erythematosus - Dennis Klinman, M.D., Ph.D. (CBER)
Development of a Method to Evaluate the Effect of Vaccines and Antiviral Therapy on Latent Viral Burden in an Animal Model of Genital Herpes - Philip R. Krause, M.D. (CBER)
The Effect of Thalidomide on the Pharmacokinetics of Ethinyl Estradiol and Norethindrone - Carol B. Trapnell, M.D. (CDER)
Estimation of Reproductive Toxicity of Pharmaceuticals Using QSAR Software Programs - Edwin J. Matthews, Ph.D. (CDER)
Hormone Replacement Therapy in Women with a Previous Diagnosis of Endometrial Cancer - Bruce V. Stadel, M.D. (CDER)
Gender Differences in Perception of Risks Communicated by Prescription and Over-the-counter Drug Labels, Phase I and II - Ellen R. Tabak, Ph.D. (CDER)
Thalidomide: Are There Gender Disparities in Treatment Outcome and Non-teratogenic Adverse Effects? - Brenda Vaughan, M.D. (CDER)
Profile of Drug Use in Pregnancy - Sheila Weiss, Ph.D. (CDER)
Gender Differences in Early and Long-term Results of Coronary Angioplasty with Palmaz/Schatz Stent - Danica Marinac-Dabic, M.D. (CDRH)
Non-invasive Assessment of Silicone Migration from Gel-filled Breast Implants - Kyle Myers, Ph.D. (CDRH)
Contraceptive Efficacy Table for Uniform Contraceptive Labeling-- a Consumer Focus Group Study - Part I and II - Paula G. Silberberg, M.D. (CDRH)
Application of Ultrasonic Tissue Characterization to Diagnosis of Bone Disease - Keith A. Wear, Ph.D. (CDRH)
CFSAN’s Women's Health Internet Initiative - Phase I - Kenneth T. Durham, Ph.D. (CFSAN)
Rapid Method for Detection and Enumeration of Listeria Monocytogenes in Foods - Mary L. Tortorello, Ph.D. (CFSAN)
Osteoporosis Prevention in Adolescent Girls - Ruth Welch Ph.D., Carole Schiffman Ph.D. (CFSAN)
A Novel Molecular Approach to Risk Assessment of Hormonally Active Compounds - John Leighton, Ph.D. (CVM)
Research Involving Human Subject Committee (RIHSC) - Peter Rheinstein, M.D., JD (OEA)
Development and Expansion of a Pilot Tracking System for Monitoring the Barriers to the Enrollment of Women in Clinical Trials - Teresa Toigo, RPh, MBA (OEA)
Mechanism of Immunotoxicity and Carcinogenicity Associated With Silicone Breast Implants - S. Jill James, Ph.D. (NCTR)
Mechanism of Tamoxifen Development Toxicity and Neoplasia Tamoxifen Effects on the Rat Uterine Insulin Like Growth Factor System - Randal Streck, Ph.D. (NCTR)
Mammography Quality Standards Act Facilities Workshop - Barbara Ward-Groves, MPH (ORA)
Immunogenetic Risk Factors for Silicone-associated Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance - Frederick W. Miller, M.D., Ph.D. (CBER)
Women and AIDS Transmission - Michael A. Norcross, M.D. (CBER)
An Open-label, Randomized, Cross-over, Feasibility Study to Quantify the Retention of Vaginally Administered Nonoxynol-9 (N-9) Foam in Premenopausal Women - Carol B. Trapnell, M.D. (CDER)
Women in Clinical Trials Terfenadine/Oral Contraceptive Study - Lou Cantillina, M.D. (CDER)
Comparison of the Beta-adrenergic Antagonist Actions of Propranolol in Men and Women - David Flockhart, M.D., Ph.D. (CDER)
Comparison of the Potassium Channel Blocking Actions of Quinidine in Men and Women - Raymond L. Woosley, M.D., Ph.D. (CDER)
Silicone Gel Alternatives Workshop - John Langone, Ph.D. (CDRH)
Consumer Brochure on MammographyDevelopment of MQSA Speaker Kits - Carol Sierka, B.S. (CDRH)
Cosmetics Initiatives Alpha Hydroxy Acids (AHAs) - John E. Bailey, Ph.D. (CFSAN)
AHA Literature Search - John E. Bailey, Ph.D. (CFSAN)
Infant Feeding Practices Study - Sara B. Fein, Ph.D. (CFSAN)
Effects of Toremifene and ICI 182,780 on Rat Uterine Growth and Differentiation - Dan Sheehan, Ph.D. (NCTR)
Conference on STD Clinical Trials Workshop (NIH and OEA) - April 6-8, 1994
Workshop: FDA-regulated Products and Pregnant Women - OWH Small Grants Program (OC)