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OWH Research Program Awards by Funding Year

From the FDA Office of Women's Health

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

202520242023, 20222021 20202019, 2018, 2017, 2016, 2015, 2014, 2013, 2012, 2011, 2010 and before

OWH-Funded Research - by Topic Area


Pregnancy Exposure Registry Enrollment Project: A survey of health care providers to advance pregnancy safety data collection and improve health communications – Katherine Kratz, Miriam Dinatale, CDER

Pregnant individuals are not usually enrolled in clinical trials for investigational drugs or biologics during development; therefore, animal data are used to assess perinatal toxicity and inform prescription drug labeling. Human data are collected post-approval, using three approaches: pregnancy exposure registries (registries), complementary studies, and pharmacovigilance. Registries are typically operated by the pharmaceutical industry, often as a result of a post-marketing requirement (PMR) or commitment (PMC) issued by FDA at the time of drug approval. Complementary studies are frequently issued as a PMR or PMC as well. Complementary studies commonly use retrospective data sources, such as insurance claims and electronic health record databases, population-based national registers, or population-based case-control studies, to quantify the magnitude of an association between a pregnancy exposure and a specific outcome. Pharmacovigilance encompasses spontaneous reports to drug sponsors and FDA and case reports published in the medical literature. Given the limitations associated with retrospective data collection from complementary studies, including misclassification bias and controls recruited by convenience sampling that are prone to selection bias, and the limitations of pharmacovigilance reports that are often incomplete and represent one case without a known denominator, registries are critical to obtain prospective and detailed data about the exposed group and a control group. The data obtained from registries is necessary to derive and compare rates on safety outcomes of drugs and biological products used during pregnancy. Although registries are crucial to understanding the safety and potential toxicity of prescription products in the perinatal population, many registries fail to adequately enroll pregnant individuals. Among 242 postmarketing studies associated with FDA-approved products from 1991-May 2022, 38 have been terminated. Among the 38 studies that have been terminated, 24 (63%) were terminated due to low enrollment. This failure to meet enrollment goals involves expenditure of valuable resources to create the registry protocol, advertise the registry and staff the data collection without yielding results.

Enrollment into registries involves identifying potential patients, recruiting them, and obtaining consent. One published study found that direct recruitment by health care providers (HCPs) was a more efficient approach than online recruitment via social media. After enrollment, most registries rely upon voluntary reports from HCPs. Thus, HCPs are integral to the registry enrollment process. Low enrollment in registries may be due to HCPs’ lack of time to inform patients about registries or lack of awareness about registries. While there are speculations about the barriers that HCPs face, HCPs have not been surveyed to understand their challenges.

The goal of the Pregnancy Exposure Registry Enrollment Project is to determine HCPs’ perceived barriers to sufficient patient enrollment in pregnancy registries. Using an email survey, this research project will assess HCPs’ knowledge of registries, their attitudes towards them, the barriers they face to recruiting patients, and their ideas about improving registry enrollment. Results from this project will advance pregnancy safety data collection in registries and ultimately improve health communications through inclusion of human safety data in pregnancy labeling.

Pharmacogenomics Evaluation of Histone Deacetylase Inhibitors on the Treatment of Triple-Negative Breast Cancer Subtypes – George Hammons, PhD, NCTR

Triple-negative breast cancer is an aggressive breast cancer type with very few effective treatment options, prone to recurrence and metastasis, and has poor prognosis in affected patients.  This cancer is characterized by a lack of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors; therefore, it does not respond to targeted therapies or therapeutic treatments that target these receptors. Several of the cancer’s subtypes respond to different treatments. Recently, the US Food and Drug Administration approved Vorinostat for the treatment of cutaneous T cell lymphoma, a rare type of cancer that begins in white blood cells called T cells.  Since approval, Vorinostat has been studied for its ability to treat other cancer types in combination with other therapeutics with promising results.  We propose to build upon previous studies that have demonstrated diverse responses to treatment with Vorinostat in triple-negative breast cancer subtypes.  We will specifically evaluate the anti-cancer effect of Vorinostat and the mechanisms employed by the drug to execute its therapeutic responses by analyzing expression of genes known to cause the progression of the disease. This will lead to further insights into potential drug targets for this disease affecting approximately 13 in 100,000 women each year.  

A systematic evaluation of sex difference in drug exposure, pharmacodynamic response and treatment effects in therapies for neurodegenerative diseases - Sreedharan Sabarinath, PhD, CDER

Sex‐related differences in the prevalence, risk factors, symptoms, progression, mortality rates, and treatment of neurological diseases are well‐documented. Differences in these critical elements will have implications in drug development, and, more importantly, on therapeutic management of the disease, including safety and efficacy considerations. The objective of this proposal is to conduct a systematic evaluation of demographic features of patients enrolled in contemporary clinical trials in neurological diseases, including neurodegenerative conditions such as Alzheimer’s disease (AD) and Parkinson’s disease, and neurological autoimmune conditions such as multiple sclerosis (MS) and generalized myasthenia gravis. The relationships between demographic data and key clinical pharmacology and clinical attributes such as pharmacokinetics (PK), pharmacodynamic (PD) biomarkers, efficacy, and safety outcomes will be assessed. Furthermore, modeling and simulation approaches following MIDD (model informed drug development) principles will be implemented to guide and design future clinical trials and to identify optimal clinical trial populations by considering potential scenarios with various proportions of sexes and other demographic features. This proposal will address critical knowledge gaps in generalizing the findings from clinical trials to the general population and will provide supportive scientific rationale for optimizing clinical trial designs. This project will provide a deeper understanding of PK/PD, biomarker response, efficacy/safety differences, and design considerations related to sex in clinical trials. The planned MIDD strategy will provide a tool to quantitatively evaluate clinical trial designs. Ultimately, these findings will help optimize drug development for neurological diseases and enhance access to safe/effective therapeutics in both women and men.

A sub-chronic and chronic geriatric female mouse model of Parkinson’s disease: Evaluating the ITIS diet on reducing inflammation and improving L-DOPA drug metabolism and PD outcomes by targeting the gut microbiome - Sumit Sarkar, PhD, NCTR

Post-menopausal women who suffer from significant inflammatory diseases like Crohn’s disease and rheumatoid arthritis are at an at increased risk for Parkinson’s disease (PD).  Unfortunately, this population is underrepresented in PD therapeutic research studies. The progression of PD is likely initiated by inflammation of the gastrointestinal tract and the innervation of the Vagus X nerve, formally called the gut-brain axis. Reducing global inflammation may reduce symptomology and improve pharmacological interventions with L-DOPA.  Inflammatory microbiota mediated L-DOPA metabolism negatively impacts therapeutic effects. Some dietary interventions have been developed to try to reduce inflammation and improve patient outcomes, such as the supercharged Mediterranean diet known as ITIS.  We will evaluate how a post-menopausal, colitis female mouse model subjected to chemically induced sub-chronic or chronic PD is impacted by an anti-inflammatory diet.  The purpose of this study is to evaluate how post-menopausal women suffering from colitis differ in PD symptomology and microbiota-host physiology and how inflammation mediated changes alter L-DOPA metabolism and efficacy. 

Development of methodology for evaluating AI-based computer-aided rule-out devices for mammography screening - Elim Thompson, CDRH

Mammography screening has been shown to reduce breast cancer morbidity and mortality, but it also increases radiologists’ workloads. With the recent advancement in AI/ML, the FDA has received several pre-submissions for ‘rule-out’ devices intended to autonomously remove non-cancer cases from radiologists’ reading lists, so they are not read by a radiologist. While such devices are promising in improving the clinical workflow in mammography screening, evaluation metrics to assess their diagnostic performance do not yet exist. Therefore, our project goal is to develop performance metrics in the premarket setting that can appropriately characterize the overall diagnostic performance generalizable to clinical settings when a rule-out device is deployed in a clinical workflow.  
We will extend the conventional methods to analytically define the diagnostic performance metrics for a rule-out device. We will collaborate with clinical partners to collect retrospective data which will be used to simulate a with-device workflow by applying an AI algorithm to analyze the images. Then we will apply our assessment method to quantify the overall diagnostic performance of the with-device workflow using the performance of without-device workflow as a comparator. Our evaluation methods and tools will be made public for the assessment of rule-out devices by sponsors.

Systematic Evaluation of Reconstructed Human Skin Models to Predict the Percutaneous Absorption of Cosmetic Ingredients and Other FDA-regulated Products - Luísa Camacho, PhD/NCTR

The cosmetic industry in the United States is a multibillion-dollar industry, with most consumers using more than one cosmetic product daily and women using more than men.  Therefore, cosmetic products are a substantial source of chemical exposure, especially for women and girls given the number of products used and their frequency of use.  Skin is the organ most exposed to cosmetic products.  Understanding whether a cosmetic ingredient applied topically remains on the skin or can permeate the skin and reach the blood circulation is an important consideration when assessing the safety profile of such chemicals.  Permeation testing can provide useful information regarding the skin absorption of cosmetic ingredients.  Human-relevant, animal-free in vitro permeation methods have been developed utilizing excised human skin; however, human skin explants used for such experiments are often difficult and costly to obtain.  These limitations have motivated the development of alternative models that aim to replicate directly the structure and physiology of human skin.  These models have been validated for in vitro testing of skin irritation, corrosion, and phototoxicity; however, they have yet to be evaluated comprehensively for in vitro testing of skin permeation.  In this study, we propose to conduct a systematic evaluation of an array of commercially available alternative models for their potential to predict the absorption of cosmetic ingredients through human skin.  A range of chemicals will be tested for their ability to penetrate through these alternative models in a side-by-side comparison with excised human skin.  The permeation findings will be interpreted based upon skin barrier-relevant properties, including histology, electrical resistance, rate of water evaporation, and lipid composition.  Ultimately, this work will help determine whether any of these commercial alternative skin models can be adopted as a novel tool in support of the FDA regulatory mission, specifically, to inform the safety profile of cosmetic ingredients, as well as human drug products and veterinary drug products with potential for human exposure.  

Sex-comparative cancer modeling: Determining the sex differences in lorcaserin-induced non-genotoxic mechanisms associated with increased female lung cancer prevalence – Rose Willett, PhD/NCTR

Lung cancer is the number one cause of cancer related deaths in women, and women have a 1 in 17 lifetime risk of developing lung cancer, regardless of smoking status. Lung cancer incidence rates are currently rising in pre-menopausal women age 30-49 compared to age/smoking/location matched men, indicating the driving force of additional sex-specific factors which are currently unknown. Lorcaserin is a serotonin receptor subtype 2C (5HT2c) receptor agonist and was previously marketed as a weight-loss drug but was later revoked from FDA approval after increased rates of cancer were found in animal studies and human trials, including increases in respiratory cancers. The driving mechanism behind lorcaserin induced carcinogenicity, however, is still unknown. To date, very few studies have investigated the cellular changes resulting from Lorcaserin exposure, particularly in an in vitro system to tightly control the testing environment. In this study, we will perform a comprehensive sex-comparative in vitro analysis of lorcaserin induced lung cell neoplastic transformation. Using a multi-omic approach, we will determine the changes to DNA methylation, gene transcription, and canonical cancer signaling pathways in female- and male-derived normal lung cells after lorcaserin induced cell transformation. Additionally, we will test the effect of sex-hormone β2-Estradiol on the progression/severity of lorcaserin-induced cell transformation in female-derived cells. Finally, we will compare the pathways we identify to be differentially regulated in female-derived cells from our in vitro studies and determine if these changes are also detected in female and male human lung cancer patient tissue samples. The results of this study will provide an inclusive analysis of sex-specific drivers of lung cancer in women, as well as to provide a multi-omic model that can be used for in vitro testing of unknown lung cancer carcinogens.

Pregnancy Pharmacokinetic Database – Kiara Fairman, PhD/NCTR

Pregnant women are often excluded from clinical trials due to the unknown potential for harm to the fetus from drug exposure. Lack of controlled clinical trials has created a scarcity of data in this life-stage.  Drug pharmacokinetic data in pregnant women are instead often reported as case studies or observational studies. Although these types of studies have small numbers of patients, they are numerous in the published literature. This has led to a mountain of data that is scattered and almost impossible to sort through.  Analyzing these data to draw significant conclusions regarding PK changes in pregnancy can be difficult and time-consuming. Reducing time spent acquiring data would allow for more resources to be dedicated for model building, designing studies, and focusing on the patient at a clinical level. We propose to develop a free, searchable database that will allow clinicians, PK modelers, and regulatory personnel to assess PK information in pregnant women from published studies as an added tool during the safety and efficacy assessment of drugs or to make quantified, evidence-based decisions for medication use in pregnant patients. This database will be searchable and updatable to incorporate newly published reports. Furthermore, there will be features to submit data and an iterative process for reviewing the submitted pregnancy data for inclusion. In spite of the increased focus on including pregnant women in clinical trials and the revamped pregnancy and lactation labeling rule (PLRR), there still remains a scarcity of pregnancy PK data within drug labels, further emphasizing the need for a free, open access, centrally-located pregnancy pharmacokinetics database.

Identify sex disparities in opioid drug safety signals in FDA adverse events report system (FAERS) and social media Twitter to improve women's health‎ - Wenjing Guo, PhD/NCTR

Opioid drugs (opioids) are the most prescribed drugs for pain treatment in the United States. The widespread use of opioids has impacted all groups of people, especially women. Opioid use among women is increasing at an alarming rate. From 1999 to 2020, opioid-related overdose deaths increased around 10-fold in women, from 2,000 to 19,970, while the rate in men increased 8-fold.  Understanding how women respond to opioids, particularly with respect to adverse events, is crucial to improving women’s health by facilitating the development of opioids with a low potential for adverse events. There are a few reports that describe opioid-related adverse events in women, however, no systematic investigation on sex disparities in adverse events for opioids has been reported. This proposal aims to investigate sex differences in opioid-related adverse events from real-world data, including data in social media and the FDA Adverse Event Reporting System (FAERS). The opioid-related adverse events for men and women will be identified from FAERS and Twitter using big data analytics and artificial intelligence. The identified sex-specific adverse events will be used to measure sex disparities in the adverse events profile of opioids using different statistical methods. These quantitatively measured differences will provide information on adverse events of opioids for women and sex disparities, and are expected to improve women’s health in combatting the opioid crisis.

Investigation of sex difference in immunogenicity and efficacy of AAV mediated gene therapy – Ronit Mazor, PhD/CBER

Gene therapy is an emerging technology in which the expression of genes modifies the biological properties of cells or tissues for therapeutic purposes. Gene therapy offers solutions to rare genetic disorders including disorders that are unique to females or disproportionally associated with females. This technology takes advantage of the natural property of viruses to attach host cells, transfer their genetic material and highjack the protein expression machinery of the host to express their own proteins, resulting in expression of the therapeutic genes in the human body. Adeno-associated virus (AAV) is a small virus that is nonpathogenic when encountered naturally and one of the most commonly utilized gene delivery vectors. Despite the great promise of this technology and the dramatic increase in submissions of AAV-mediated gene therapies to the FDA in the past few years, the success of gene therapy has been hindered by the development of immune responses against AAV in treated patients as they cause accelerated clearance and/or neutralization of the gene delivery vector, as well as immune-mediated toxicities.

Studies show that females tend to mount stronger and more diverse immune responses against viral infections and vaccines with higher antibody levels than males, particularly during their reproductive life stage. This heightened immune protection in females can become a double-edged sword for viral-mediated gene therapy where the immune response may cause stronger and faster clearance, neutralization of the gene delivery vector, and may also increase T cell-mediated toxicity. Our goal is to investigate if there are sex differences in the immune response against AAV vectors and if these differences could compromise the safety or efficacy of this emerging technology. Importantly, subjects can have antibodies to AAV even before gene therapy due to environmental exposure (also known as pre-existing antibodies). Indeed, preliminary studies in our laboratory identified significantly higher titers of pre-existing anti-AAV antibodies in female human donors than males indicating that there are immunological differences that may impact efficacy. Therefore, there is a critical need to further investigate the sex difference in immunogenicity and consequent efficacy of AAV. Our studies will help the agency understand whether females will be at higher risk of reduced efficacy and increased toxicity in AAV-mediated gene therapy and provide necessary data to justify new guidance with regard to separate analysis of male and female efficacy and toxicity data in gene therapy clinical trials.

Informed prediction of anthracycline-induced cardiotoxicity (IMPACT): A multicenter biomarker qualification study - Li-Rong Yu, PhD/NCTR

Chemotherapy is a major treatment option for cancer patients, and anthracyclines (e.g., doxorubicin (DOX)) are commonly used for treating a wide range of cancers, including breast cancer. However, the use of anthracyclines has been associated with life-threatening heart damage (i.e., cardiotoxicity) in some patients. Currently, non-invasive medical imaging tests are the most practical cardiotoxicity monitoring tools; nonetheless, they have not been sufficiently validated for prediction of adverse heart effects. Our previous data from female breast cancer patients at a single medical center resulted in identification of several candidate protein biomarkers for predicting increased risk of chemotherapy-related heart injury, based on blood samples collected from patients before initiation of DOX-based treatment and correlation with adverse clinical outcomes of the heart. The goal of this study is to verify the predictive performance of these candidate biomarkers in blood samples collected from a cohort of 250 female cancer patients enrolled at multiple medical centers. Ultimately, these biomarkers may provide a novel tool for predicting individual patient’s risk of developing cardiotoxicity and, thus, early identification of the highest at-risk patients, which could  inform decisions related to cardiac monitoring, chemotherapeutic treatment regimens, proactive prevention, and/or early therapeutic intervention of cancer treatment-related cardiac injury. Thus, these newly discovered predictive biomarkers of drug-related cardiotoxicity could enable personalized cancer therapy in females tailored towards maximal efficacy and minimal cardiotoxicity, and may have the potential to assess cardiac safety of new anticancer therapies.

Potential Context of Use for a Human-Based Engineered Heart Tissue System to Detect Sex Disparities of Chemotherapy Drugs – Chengzhong Cai, PhD/NCTR (Special Funding)

Growing awareness of sex and gender disparities in drug-induced cardiovascular disease, especially during cancer treatment, affirms that careful investigation into understanding sex-dependent adverse cardiac effects could play an important role in optimizing treatment regimens in order to ensure patient safety, particularly for female cancer patients. For example, women can be exposed to higher amounts of chemotherapy drugs than men due to differences in the drug absorption, distribution, metabolism, and excretion between sexes, which can be responsible for sex differences in drug-induced cardiotoxicities observed in the clinic with chemotherapeutics. Nonclinical research heavily relies on the use of animal models; however, the safety and efficacy of chemotherapeutic agents cannot be accurately predicted from pre-clinical animal models alone due to the differences in physiology and variations in the homology of drug molecular targets. Accordingly, new approach methodologies (NAMs) that encompass human-based alternatives to animal-based research is continuing to gain greater appreciation, and various in vitro human cell-based assays are currently under evaluation for their context of use, but also have inherent limitations to assess function. This proposal will evaluate the potential of a human-based engineered heart tissue (EHT) testing system, which is an image-based tissue analysis platform that can measure cardiac contractile force, to model sex differences in susceptibility to adverse effects of chemotherapeutic drugs using human-induced pluripotent stem cell-derived cardiomyocytes. Cardiac contractility as a measurement of function will be assessed in response to drug treatment, along with clinically relevant toxicological endpoints to assess adverse cardiac effects. This model could play an important role in identifying drugs with increased risk for sex-dependent cardiac effects, which could improve patient safety.


Identify therapeutic biomarkers and develop and characterize novel bispecific antibodies (BsAbs) to treat ovarian cancer and aid quality reviews of FDA-regulated BsAbs - Wen Jin Wu, PhD/CDER

In 2020, there were approximately 21,750 new cases of ovarian cancer diagnosed and 13,940 ovarian cancer (OC) deaths in the US. Several targeted therapy approaches have been investigated to manage recurrent and advanced stage of OC, which led to the FDA-approval of bevacizumab and olaparib to treat ovarian cancers. Despite recent advances in therapy, advanced OC remains a disease of high unmet need. Bispecific antibody (BsAb) is an emerging new class of therapeutic molecules that have capacity to simultaneously target two epitopes on the same or distinct antigens. It provides a unique opportunity to combine two target functionalities using single antibody-based molecule. The diversity of BsAb structure is fast-growing, which creates a large amount of BsAbs in different molecular formats and provides great functional variety. However, it also poses significant challenges to FDA to understand BsAbs and to assess quality attributes of BsAbs physiochemically and biologically to ensure that BsAbs are consistently produced. We generated several BsAbs in the different molecular formats based on widely used BsAb manufacturing platforms. In this investigation, we will (1) characterize physiochemical and biological properties of BsAbs; (2) investigate the mechanisms of action and anti-tumor potency of BsAbs using ovarian cancer cell models; (3) and develop appropriate bioassays using ovarian cancer cellular models to evaluate the potency of BsAbs in different molecular formats. The outcome from this study will provide knowledge, regulatory tools, and technical skills to FDA assessors to evaluate BsAbs and inform optimal science-based regulatory decisions.     

Evaluation of the Impact of Dose Interruptions and Reductions on the Clinical Efficacy of Targeted Breast Cancer Drugs – Amal Ayyoub, PhD/CDER

Breast cancer is the second leading cause of cancer death among women in the U.S.  Existing drug therapies have significant toxicities that require dosage modifications (interruptions and reductions). Up to 25% of patients on any chronic cancer therapy require a dosage reduction within the first 60 days of treatment. Dosage interruptions/reductions have been shown to have an impact on efficacy of chemotherapy treatment in breast cancer. Although newer targeted therapies have improved the landscape for the treatment of breast cancer, they are commonly associated with significant toxicities requiring high rates of dosage interruptions/reductions in up to 75% of patients. Dosage reduction strategies are used empirically to mitigate toxicities and improve tolerability; nonetheless, the impact of dosage modifications on efficacy has not been characterized. The dosage reduction levels are commonly selected based on available formulation strengths without justification with regards to efficacy. There are currently no formal review guidelines to assess the appropriateness of dosage modification strategies. The Office of Clinical Pharmacology utilizes model-informed drug development (MIDD) methods to characterize the relationships between drug exposure and efficacy endpoints (E-R for efficacy). E-R analyses are critical in cancer drug development to inform selection of the dosing regimen that maximizes the risk-benefit ratio and can be utilized to optimize dosage modification strategies with minimal impact on efficacy. Relative dose intensity (RDI) is the ratio of the effectively delivered dose to the theoretically administered cumulative dose and represents a tolerability metric to demonstrate whether the planned dose was administered. With this project, we propose to assess the optimal method to estimate RDI as a marker of dosage reductions/interruptions to integrate into E-R analyses for efficacy to evaluate the impact of dosage reductions/interruptions on efficacy of breast cancer drugs and optimize dosage modification strategies.

Investigating Early Signs of Sex-Difference in Adverse Drug Events to Better Protect Women’s Health - Dongying Li, PhD/NCTR

Several reports indicate that women suffer from more adverse events (AEs) than men for many approved drugs. The proposed work investigates disproportional AEs in women and aims to identify early signs for sex-dependent AEs in clinical trials and animal studies using a bioinformatics approach. Early identification of disproportional AEs would improve drug review process, which may eventually result in better protecting women from preventable AEs. The female (F) physiology is different from the male (M) counterpart, not just in reproductive and/or hormonal variations, but also in many other factors that can impact internal drug concentrations and distribution, such as liver enzyme levels and fat content. These seemingly simple factors may play a significant role in drug metabolism, especially for drugs that have strong dose dependent AEs. By conducting a comparative analysis of toxicokinetic and drug exposure parameters, we aim to examine drug-induced disproportional AEs in F vs M (sex difference in AEs). We hypothesize that drugs that show disproportional AEs in post-market surveillance may have exhibited signals specific to sex difference during the early stages of drug development. Thus, we will first track the AE reports back to their corresponding clinical trials and animal studies, and look for such signs of disparity in M vs F populations (identification stage). Once these early signs are identified we will then test if/how they indeed manifest to post-market surveillance for a different set of drugs with similar mechanisms of action (verification and prediction stage). Through this endeavor, we may identify and predict the sex different AEs at early stages of drug development. We anticipate that our findings could facilitate review process improvements and inform clinical trials to help mitigate sex-dependent AEs earlier, thereby enhancing protection of women’s health. 

Tackling sex bias in AI for severity assessment of COVID-19 – Ravi Samala, PhD/CDRH

With the proliferation of artificial intelligence (AI)-enabled devices in the healthcare industry, the U.S. Food and Drug Administration is at a unique cross-roads. The agency aims to give patients in the U.S. first access to high-quality, safe, and effective AI-enabled devices in the world through its initiatives to empower stakeholders in this area to advance health care, and through a new proposed regulatory framework for addressing modifications to AI-enabled devices. With an influx of AI-enabled devices and a broad intended use population, it is even more important now to measure how imbalances in the data used to train AI-enabled devices introduces biases in the final AI prediction models and develop approaches to reduce or mitigate this effect. In this project, we propose developing novel methods that identify and measure the representation and diversity of the data, its influence on the complex learning processes of AI-enabled devices and to mitigate any possible disparities with particular emphasis on sex related disparities. We will develop an AI model to predict the severity of COVID-19 disease on chest x-ray images using deep neural network (DNN) while accounting for imbalances in the data to allow for more robust and fair AI models. This quantitative assessment when coupled with clinical measurements and physical symptoms may assist in patient treatment monitoring. Our approach will provide AI developers and review staff with tools to measure potential imbalances and improve the development process for DNN AI models. We will independently verify the project goals using data from an external institution. These goals are in alignment with the FDA’s vision through Digital Health Center for Excellence and the OWH research priority centered on developing novel computational methods and AI
designs to eliminate algorithmic bias and improve representation and diversity of data.

Identify genetic and nongenetic factors with increasing susceptibility to herbal dietary supplement (HDS)-induced liver injury in women - Minjun Chen, PhD/NCTR

Americans spend $10 billion on herbal dietary supplement (HDS) annually, and adult females, especially elderly women, use HDS more frequently than men. Herbal products are believed as to be natural and safe; however, scientific studies have found that some herbal products are not as safe as expected. According to hepatotoxicity registry data in US, the proportion of HDS related liver injury cases has increased three times from 7% in 2004 to 20% in 2013. Notably, many HDS induced liver injuries are predominantly found in middle-age women and may lead to severe outcomes (i.e., liver transplant and death) as compared to liver injury from prescribed medications. FDA recently announced new efforts to strengthen regulation of HDS and put safety of HDS use as a top priority. Increasing evidence suggests sex hormones can influence immune responses toward foreign antigens, and two-thirds of HDS induced liver injury have evidence of immune mediated damage; but the underlying mechanism is unknown. So, it is critical to identify risk factors, including genetic and nongenetic, to help reduce risk of liver injury associated with HDS use in women. Rich information exists in clinical and histopathological data of case reports in published literature and genetic variations in patients, but is stored as uncodified text, impeding further analysis. An approach called ontology can structurally organize and logically define concepts from different sources, thereby harmonizing aggregated data sources and enabling computational analysis. Here, the investigators will introduce a new ontology-based approach and use published case reports and genetic sequencing data to identify immune-related risk factors that could explain the sex differences in liver injury caused by HDS. By using advanced computer technologies and analytical methods, the investigators will develop a scoring model by using the identified key immune factors to assess risk of liver injury caused by HDS products for individual patients.

Application of in vitro and in silico models to predict the total estrogenicity of chemicals released from cardiovascular medical devices - Caroline Pinto, PhD/CDRH

Breast cancer is the second most prevalent cancer type in American women. Exposure to xenoestrogens, chemicals found in the environment that mimic the activity of the natural hormone 17β-estradiol, has been shown to promote breast cancer growth and inhibit the effect of drugs used for breast cancer treatment in cell culture and in animal models. Several studies have reported that xenoestrogens can be released from medical devices, including devices used in breast cancer patients, that directly contact blood (e.g., intravenous applications). The effect of exposure to mixtures of xenoestrogens released from medical devices on the pathogenesis and progression of the disease is not understood. In this research project, we will study the potential for mixtures of xenoestrogens released from medical devices to mimic 17β-estradiol activity and promote breast cancer cell proliferation. We will identify xenoestrogens in medical devices used for intravenous procedures and estimate the combined estrogenic activity of the mixture using the concentration addition model, which estimates the total estrogenic activity of a mixture of xenoestrogens. The concentration addition model will be used to select medical device materials for extraction and the total estrogenic activity of material extracts will be measured in cell culture. We will study the potential for these medical device materials to promote the growth of breast cancer cells in culture and reduce the efficacy of drugs used for breast cancer therapy. This research will enable FDA to evaluate the applicability of these tools for screening endocrine activity in the safety assessment of medical devices. In addition, this research will provide FDA a method to address xenoestrogen exposure from medical devices and make informed communications to patients and healthcare providers on the safety of medical devices with the aim to prevent or reduce exposure of breast cancer patients to xenoestrogens. Disclaimer: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Investigating the impact of SARS-CoV-2 infection on female fertility and assessing vaccination-induced immunity in protecting pregnant K18-hACE2 transgenic mice against emerging SARS-CoV-2 variantsHang Xie, PhD/CBER

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and causes coronavirus disease 2019 (COVID-19) in humans. Currently the cumulative number of global SARS-CoV-2 cases has exceeded 200 million, including > 4 million new infections and > 65,000 new deaths reported in the first week of August 2021 alone. SARS-CoV-2 enters human cells via a receptor called Angiotensin-converting enzyme 2 (ACE2) that is anchored on the cell membrane. Human ACE2 (hACE2) is widely expressed in skin, blood vessels, central nervous system, heart, lung, liver, intestines, kidney and reproductive system (testis, ovary, uterus, vagina, placenta, etc.). Although SARS-CoV-2 mainly causes respiratory pathology, the viral RNA and/or proteins have also been detected in reproductive organs of both sexes. It is currently unknown whether detected viral RNA and/or protein has any effect on male or female fertility. However, available epidemiological evidence suggests that pregnant women have a higher risk than nonpregnant women for severe COVID-19 including ICU admission, ventilator usage and death. Despite CDC recommendations for COVID-19 vaccination during pregnancy, some pregnant women may be hesitant to get vaccinated. The K18-hACE2 transgenic mouse strain bearing human-like ACE2 has been used as an animal model to address the pathogenesis of SARS-CoV-2. In this project, we will investigate how SARS-CoV-2 infection affects the fertility of female K18-hACE2 mice. We will also evaluate whether COVID-19 vaccination induced-immunity can protect pregnant K18-hACE2 mice against SARS-CoV-2 infection including infection due to emerging variants. The results should provide insight into further research to study the impact of SARS-CoV-2 on female fertility and inform the development of effective medical countermeasures to protect women’s health. 

Affordable generics for menopausal women: Mechanistic evaluation of formulation design and performance of estradiol intravaginal ring products - Nahid Kamal, PhD/CDER

Intravaginal Ring (IVR) is a drug device combination for self-administration. It delivers estradiol in the vagina for the treatment of post-menopausal symptoms. IVR is a polymeric ring that delivers the drug to the vaginal epithelium at a controlled rate to achieve a desired steady serum concentration for a definite period of wear time after which it is replaced with a fresh IVR. Two brands of IVR products of estradiol, namely Estring® (matrix type) and Femring® (reservoir type) are commercially available, but no generic yet. The IVRs are developed to have specific physicochemical, mechanical, and drug release characteristics to achieve its intended use. The manufacturing process of IVR involves molding, extrusion, and welding steps. Various geometric designs, formulation (e.g. API to polymer ratio, in put level of excipients etc.) and process (e.g. curing time, temperature, humidity) parameters may affect its physicochemical (e.g. polymorph, saturation solubility of API) and drug release characteristics. In this regard, there is a knowledge gap in understanding the root causes of product failures in terms of drug release and product quality, such as welding defects, missing cores, broken rings, bubbles, discoloration etc. and their relation to the formulation and process variables and eventually to the product performance. The currently used in vitro release methods are not discriminatory and are not suitable for evaluating the bioequivalence of IVRs. Therefore, this study aims at evaluating the effects of formulation, process, and geometric design on the quality and performance of estradiol IVR and developing a more time-efficient discriminatory in vitro drug release test method as a surrogate for bioequivalence evaluation. This study will facilitate the development of cost-effective generic IVR products for women. The knowledge gained will also help the review, policy, and development of product specific guidance.  

Dataset to validate digital-pathology algorithms that quantify tumor-infiltrating lymphocytes in breast cancer - Brandon Gallas, PhD/CDRH

We will create a validation dataset of pathologist annotations for artificial intelligence and machine learning (AI/ML) algorithms that process whole slide images (WSIs). Our focus will be on algorithm performance assessment in the context of estimating the density of immune cells in breast cancer called stromal tumor infiltrating lymphocytes (sTILs). The density of sTILs has been shown to predict outcomes without therapies and responses to immune therapies. sTILs can be evaluated simply at low cost with a microscope and standard specimen preparation. As such, sTIL evaluation can be incorporated in breast cancer management activities worldwide, even low-to-middle-income settings, and is expected to reduce the use of toxic chemotherapies.

We have engaged an international, multidisciplinary team working in the pre-competitive space. Collaborators and consultants include clinician-scientists from academic hospitals, international health systems, academics, professional societies, and medical device manufacturers. By engaging diverse stakeholders, we aim to address multiple perspectives and emphasize interoperability across platforms.

To collect the data, we will recruit and train pathologists to estimate sTILs. We will collect the data on microscope and digital platforms. In addition to live events where we can use the microscope system, the digital platforms allow us to crowdsource pathologists from anywhere in the world on web-based platforms (PathPresenter and caMicroscope). We have found these events are low-cost, efficient opportunities to recruit and train pathologists to collect high quality data.

We are pursuing qualification of the validation dataset as an FDA Medical Device Development Tool (MDDT). This offers an opportunity to receive feedback from an FDA review team while building the dataset fit for a regulatory purpose. The pursuit of MDDT qualification will inform regulatory frameworks and be instructive to others to develop their own validation datasets, and the dataset will be a high-value public resource that can be used in AI/ML algorithm submissions.

Next Generation Sex-Specific Ventilator Systems Enabled by Neural Activity - Ramin Bighamian, PhD/ CDRH

There are no sex differences in clinician recognition of Acute Respiratory Distress Syndrome (ARDS), a condition where a person’s lungs cannot provide enough oxygen to the body. Recent studies of the influence of sex on management of ARDS shows that, normalized by height of subjects and compared to males, females connected to ventilators receive significantly higher tidal volumes. However, the females with severe ARDS have a higher mortality risk. Furthermore, oxygen saturation (SpO2) levels that are still normal in males may be consistent with disease in females. Researchers have determined that women are less likely to receive the right diagnosis and treatment for ARDS, highlighting the need for a better ventilatory management in females.

This project will collect data from healthy subjects to identify sex-specific coupling between breathing biomarker used in the standard of practice respiratory rate (RR), SpO2, and end-tidal CO2 (EtCO2) and electroencephalogram (EEG) neural activity, boosting the FDA regulatory science in two main aspects: First, we characterize sex-specific features of spatiotemporal neural activity as well as breathing biomarkers to determine the influence of sex on spontaneous respiratory function under instructed patterns of breathing. The results from this thrust may motivate the ARDS Network for modifications to the existing guideline, by including sex-specific ARDS diagnosis criteria and therapy adjustments; thus, potentially leading to a better care for women with ARDS.  Second, we identify sex-specific coupling between the identified features of respiratory biomarkers and neural activity, the mechanism to which the spontaneous breathing is highly linked. It is projected that brain-controlled ventilators will be the next coming technology, as they enable adjusting patient specific settings for improved comfort and avoiding the disharmony between patient respiratory effort with ventilator breaths. The results from this thrust will improve our regulatory knowledge on next generation sex-specific neural enabled ventilator devices.

Prediction of response to therapy for advanced/metastatic breast cancer: Joint analysis of radiologic and genomic data using machine learning - Berkman Sahiner, PhD/CDRH

Although various treatment options are available for metastatic breast cancer (MBC), it is an incurable condition. The key goals in the treatment of patients with MBC are to prolong survival and symptom relief, with an emphasis on restricting treatment-related toxicities. Drug therapy is helpful for prolonging survival and maintaining quality of life for MBC patients. A range of data sources are available for personalizing a patient’s response to therapy, but the information incorporated into oncology drug development is typically limited to one or a few markers, and it is currently unclear how different information about a patient (e.g. imaging, genomic, histopathologic, clinical data) can be best integrated to individualize patient management.

Machine learning algorithms have recently been applied to a range of tasks in medicine. However, important gaps remain: Only a limited number of studies have applied machine learning to predict response to cancer therapy based on serial imaging. The potential of using machine learning to combine data from multiple disciplines (e.g., radiology, genetics, pathology and informatics) has not been fully tapped. The goal of this project is to develop machine learning models to combine different sources of data for the same patient to help predict the patient’s response to therapy while undergoing drug treatment for MBC. The models will be trained and validated on a large, multi-institutional data set provided by our pharmaceutical industry collaborator.

The developed models may significantly help MBC patients and the care team by enabling timely decisions about whether to continue treatment or seek alternative treatments. As importantly, the development of such models with collaboration from multiple Centers within the FDA is likely to provide important indications about potential pitfalls in model development and generalizability of the machine learning approaches for these purposes, thus preparing the Agency for likely future submissions in this area.

Developing quality standards for innovative personalized 3D ‎printed intravaginal rings for menopausal women‎ - Ahmed Zidan, PhD/CDER

Intravaginal rings (IVRs) are drug-device combination delivery systems ‎for controlled release of drugs in the vagina. IVRs can ‎produce local and/or systemic pharmacological effects. IVRs are well ‎tolerated by women, are efficacious for contraception and hormone ‎replacement therapy, and have high patient compliance. FDA approved ‎several hormonal IVR products including Estring (estradiol), Femring ‎‎(estradiol-acetate), NuvaRing (etonogestrel/ethinylestradiol), and ‎Milprosa (progesterone), for contraception, treatment of vaginal ‎atrophy, hot flashes associated with menopause, and infertility. These marketed ‎IVR products are manufactured with fixed shapes, sizes, and doses. The ‎use of fixed dose of estrogen in menopause is associated with an ‎increased risk of venous thromboembolism and stroke. Nonetheless, ‎these risks vary depending upon the woman's age, time since ‎menopause, presence of other comorbidities, the menopausal estrogen ‎therapy regimen used (including concomitant use of a progestogen) and ‎the formulation, dose, and route of administration. These risks may be ‎mitigated by the personalization of estrogen therapy; however, it is ‎challenging to develop a personalized IVR due to the complexity of ‎current manufacturing processes and difficulty to mandate drug-‎specific customized IVR design of specific drug release properties. ‎

As one of the emerging technologies identified by FDA, 3D printing ‎provides a unique opportunity to manufacture a personalized IVR with ‎complex geometries that cannot be achieved with the traditional ‎injection molding or extrusion processes. The complex geometries ‎within the hormonal IVR will allow precise fine-tuning of the diffusion ‎and release properties of drugs to mitigate health risks and meet specific ‎needs of menopausal women. More importantly, multipurpose IVR that ‎can integrate 2 or more drugs of different release profiles can be ‎produced by 3D printing in a rapid and cost effective single-step ‎process. The proposed study will then provide a comprehensive ‎evaluation of microextrusion 3D printing emerging technology to produce ‎personalized hormonal IVR for menopausal women. The research outcome from this project will have significant impact on the fundamental analytical science and ‎regulatory policy on IVR products. Disclaimer: This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Define a biomarker of decidual inflammation to predict recurrent pregnancy loss  - Mate Tolnay, PhD/CDER

Pregnancy complications are leading contributors to infant and maternal death and suffering.  No existing therapy can effectively control recurrent pregnancy loss, which takes an enormous and potentially avoidable physical and emotional toll on expecting couples. Inflammation of tissues that bridge the mother and fetus is thought to facilitate pregnancy loss in unclear ways.  We aim to investigate the significance of inflammation in causing recurrent pregnancy loss.  A novel activator of the inflammatory process, secretory IgA, will be examined as a possible trigger for immune-mediated pregnancy loss.  During pregnancy regulatory T cells protect the fetus from the mother’s immune system.  We have recently identified a novel mechanism whereby regulatory T cells lose their critical inhibitory function upon binding secretory IgA.  Secretory IgA is a type of antibody that helps control pathogens on surfaces of body cavities including the womb.  We reason that small undetected injuries to the womb’s protective cell layer could expose residing regulatory T cells to secretory IgA, promoting tissue inflammation that endangers the fetus.  This project is designed to study whether such mechanisms could increase the chance of miscarriage.  The larger question is the role of inflammation in recurrent pregnancy loss, whether secretory IgA driven or not.  We aim to ultimately define a biological indicator of tissue inflammation measured using a laboratory test, which can inform doctors about increased pregnancy risk and give time for possible intervention. By identifying probable causes of repeatedly losing a pregnancy, this research can also suggest novel therapies to reduce and prevent recurrent pregnancy loss.

Verification of Novel Predictive Biomarkers of Doxorubicin-induced Cardiotoxicity in Breast Cancer Patients - Li-Rong Yu, PhD/NCTR

Chemotherapy is a major treatment option for cancer patients and anthracyclines (e.g., doxorubicin (DOX)) are commonly used for treating a wide range of cancers. However, they can cause life-threatening heart damage (cardiotoxicity) for some patients. Currently, non-invasive medical imaging tests are the most practical cardiotoxicity monitoring tools; nonetheless they are not sensitive enough for early detection of heart damage.  In a preliminary analysis of blood samples from 70 female breast cancer patients taken before and after the first and second cycles of DOX treatments, we identified potential novel blood protein and metabolite biomarkers for predicting heart injury resulted from the treatment. The goal of this study is to verify the predictive performance of these biomarkers in a separate group of 120 new patients. Ultimately, these predictive biomarkers may provide an earlier and better individualized risk assessment in female breast cancer patients of chemotherapy-induced cardiotoxicity, thus providing opportunities for prevention or therapeutic intervention of cardiac injury.

These novel biomarkers could enable personalized female breast cancer therapy tailored toward maximal efficacy and minimal cardiotoxicity and have a potential to assess the safety of promising new therapies.

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Effect of Sex Differences on the Drug Absorption, Biological Responses and Adverse Events Elicited by Paclitaxel Containing Medical Devices - Vaishnavi Chandrasekar, PhD/CDRH

According to the American Heart Association, cardiovascular disease is the leading cause of death among women in the United States, accounting for approximately 1 in every 3 female deaths. Peripheral arterial disease (PAD) is associated with reduced blood flow to the extremities due to the buildup of atherosclerotic plaque in the femoropopliteal artery. Recent studies report a high prevalence of PAD in women, particularly at the extremes of ages (>80 years and <40 years).1 Paclitaxel coated stents and balloons are used to treat PAD.  Notably, recent reports of a link between these treatments with increased 2 to 5-year patient mortality rates prompted FDA to urge caution in using these devices. Unfortunately, mechanistic insights are currently lacking, and causes of death have not been determined. The goals of this project are (1) to characterize differences in the uptake, distribution, and accumulation of paclitaxel within atherosclerotic tissues between men and women due to sex-based differences in the plaque composition; and (2) reveal clues about why accumulation and release of paclitaxel from atherosclerotic tissues may increase mortality rates. Different paclitaxel levels in plaques of men and women can potentially affect its ability to inhibit restenosis. Additionally, reservoirs of paclitaxel gathering in the vessel tissue can lead to its slow release in the circulation and accumulation in tissues of downstream organs. We hypothesize that accumulation of paclitaxel in downstream tissues causes a loss of microvasculature in the organs over time contributing to the reported mortality rates in patients receiving paclitaxel-coated stents/balloons. Potential sex-based differences revealed from the proposed studies will be complemented by statistical evaluation of clinical data and adverse event reports to determine clinical significance of our observations. Outcomes from this research will enable FDA to make informed decisions regarding current and potential future use of paclitaxel.

Sex differences in Alzheimer’s disease associated with blood-brain barrier and immunological responses: Basis for emerging technologies for discovery of potential biomarkers and new therapies in women – Elvis-Yane Cuevas-Martinez, PhD/NCTR

Women have a 63% higher incidence of Alzheimer’s disease (AD) relative to men. Early detection and treatments remain a challenge for both sexes, but there is no evidence on how a person’s risk of AD is influenced by simply being male or female. This hinders regulatory agencies from providing authoritative guidance on the use of new treatments or biomarkers that could promote or protect women’s health. Transgenic mouse models of AD have the unique ability to mimic the neurological problems seen in human AD and are therefore important tools to study sex differences and to best guide regulatory decisions about AD in women. There is some evidence that the increased risk of AD in woman is because women have a diminished capability to regulate the removal of toxic proteins and the neuroinflammation that are characteristic of AD. However, that hypothesis has not been fully investigated. For personalized or precision medicine to fully be effective for AD, there must be targeted therapies and biomarkers to specific AD populations, such as women. This study is an initial step in that direction. We will evaluate sex differences in the elimination of specific toxic proteins and neuroinflammation in AD in two species: an established transgenic mouse model of AD and human post-mortem AD brain tissues. Similar tests will be done in both species so that a comprehensive comparison can be done. The results obtained from these comparisons will help to develop new technologies/methodologies and assist in the regulation of the safety and efficacy of new drugs that may treat or to slow AD progression in women.

Impact of sex-based differences in the expression of host non-coding RNA biomarkers that can diagnose early HIV-1 infection - Krishnakumar Devadas, PhD/CBER

The current pattern of human immune deficiency virus (HIV-1) transmission is changing, with heterosexual transmission now accounting for greater than 70% of the new cases identified worldwide, leading to a greater number of infections in females. There exists a huge knowledge gap in the identification of molecular mechanisms and pathways leading to sex-based differences in the outcome of HIV-1 infection. Early studies on HIV-1 transmission were focused mainly on males and majority of the outcomes and conclusions about pathogenesis, disease progression and therapeutic options were derived from studies conducted on male populations. Numerous epidemiological studies have documented differences between females and males in acquisition rates and manifestations of HIV-1 infection. Recent studies have shown that females are more susceptible to HIV-1 acquisition than males. Following HIV-1 infection, females have lower viral loads during acute infection and exhibit stronger antiviral responses than males, which may contribute to differences in the size of viral reservoirs. Furthermore, immune activation, a hallmark of HIV-1 infection, is generally higher in females than in males and could be a central mechanism in the differences observed in the speed of HIV-1 disease progression in females. 
Owing to the high abundance and stability in biofluids, non-coding RNAs are attractive candidates as non-invasive, blood-based biomarkers that can provide information on HIV-1 infection. Identifying individuals in the early stage of HIV-1 infection is critical to prevent further HIV-1 transmission. Results from our previous studies indicate that non-coding RNAs  could be used as a diagnostic biomarker for detecting early stage HIV-1 infection. Here we propose to build on these initial findings and assess the impact of sex-based differences in the expression of non-coding RNAs that could be used as surrogate biomarkers for the detection of early stage HIV-1 infection, when viral markers may or may not be detected. The detection of early stage HIV-1 infection will help to reduce the window period, facilitate early initiation of antiretroviral treatment (ART) and would greatly reduce HIV-1 transmission. 

Pregnancy and Lactation Labeling Rule (PLLR): Health Care Provider Testing to Improve Health Communications Related to Lactation - Miriam Dinatale, DO/CDER

The objective of the PLLR End-User Testing Project is to improve health communications between health care providers (HCPs) and lactating women by identifying gaps in HCP understanding of the content and format of new prescription product labeling under the PLLR. The PLLR aims to more clearly communicate to HCPs and patients the available data regarding the risks of prescription product use during pregnancy and lactation by providing clinically relevant information in product labeling. However, the data available are often limited and difficult to interpret. The lack of interpretable data along with potential risk misperceptions can impact appropriate benefit-risk decisions about prescription product use by lactating women. The communication of the uncertainty in the data presents a unique challenge and one that has not been studied previously in the context of the PLLR. An additional objective of this project is to develop improved approaches for the presentation of lactation information in prescription product labeling to enhance risk communication. The regulatory impact may include policy changes that improve prescription product labeling for lactating women, improve prescription product labeling overall, and ultimately improve health outcomes for all patients who take prescription products.  This project stems from the Risk Communication Advisory Committee (RCAC) Meeting for PLLR held in March 2018 at the FDA, “Communicating Information about Risks in Pregnancy in Product Labeling for Patients and Providers to Make Informed Decisions about the Use of Drugs during Pregnancy.” The objectives of the RCAC meeting included: discussing meaningful factors that influence the interpretation of risk messages by HCPs and pregnant women, evaluating the effectiveness of communications to inform about risks in product labeling under PLLR, identifying approaches to effectively communicate risk in a helpful manner for treatment decision making, and identifying strategies to minimize potential unintended adverse consequences of risk communication.

Development of an integrated database for sex-specific toxicological assessments - Rosalie Elespuru, PhD/CDRH

FDA reviews many products, such as medical devices, drugs, biologicals, tobacco, and radiation-emitting diagnostic and therapeutic instruments to assure that they are safe as well as performing as expected.  Standard safety tests are performed in experimental systems before marketing, and the FDA also pays attention to what happens in humans after the products are on the market.  However, it is clear, that males and females, whether animals or humans, do not always react in the same way.  There are many reasons for this, including hormones and body weight.  This project aims to assemble information on the different responses and reactions of males and females to different types of medical treatments and therapies, in order to better understand these differences and to eventually make products safer for everyone.

Predicting the response to hormonal treatment of women with atypical endometrial hyperplasia using artificial intelligence/machine learning (AI/ML) algorithms - Marios Gavrielides, PhD/CDRH

Endometrial cancer (EC) is the most common gynecologic malignancy, with incidence increasing largely due to increase in obesity and diabetes. Atypical endometrial hyperplasia (AH) is considered a high-risk precursor to EC and hysterectomy is typically recommended. Premenopausal women with AH often try to avoid hysterectomy by electing extended hormonal treatment, with about a quarter of these patients having AH persist after treatment or progress to EC. Improved prediction of response to treatment would allow for personalized and potentially improved recommendations for AH management. Women with AH predicted as non-responders to hormonal treatment could be triaged sooner to hysterectomy instead of attempting an extended trial of medical management, thus preventing such cases from progressing to overt endometrial cancer. Premenopausal women predicted as responding to treatment would have greater confidence in avoiding surgical intervention. Recently, AI/ML technologies have shown the ability to link complex image data to patient outcomes, including a predictive biomarker for immune checkpoint inhibitor response in metastatic non-small cell lung cancer. This project will take advantage of recent innovations in AI/ML and relevant expertise in our team to develop a novel predictive biomarker of treatment response across AH patients.  Through an existing collaboration with the Washington University School of Medicine, we have access to retrospective cases of AH, including tissue slides at time of diagnosis and multi-year follow-up after hormonal treatment. Tissue slides will be digitized using whole slide imaging (WSI) and the acquired images will be used to train and validate AI/ML algorithms for identifying responders and non-responders to treatment (progestin). The output of the study will enable personalized and better-informed choices for women with AH at the time of diagnosis and will inform regulators on factors that can affect the generalizability of AI/ML algorithm results in the clinical setting and that would need to be controlled. 

Mechanistic evaluation of genotoxic potential of black cohosh, a dietary supplement widely marketed for relief of gynecologic disorders and menopausal symptoms - Nan Mei, PhD/NCTR  

Black cohosh has been traditionally used by Native Americans for the treatment of a variety of disorders, including various conditions specific to elderly women. Contemporary uses of black cohosh include relieving menstrual and perimenopausal symptoms in women (primarily hot flashes, sleep disturbances, and depression) and inducing labor during pregnancy. Therefore, black cohosh is one of the most popular botanical dietary supplements in the U.S. and Europe. According to current estimates, black cohosh was the 6th top-selling herbal supplements in the mainstream U.S. market in 2017 with about $32.4 million in sales, and the 33rd in the U.S. natural channel with about $3.1 million in sales. Although positive effects of black cohosh have been well documented, the adverse events associated with its consumption have also raised significant concerns. From 2002 to 2009, there were more than 80 cases of hepatoxicity related to black cohosh-containing products, and the adverse effects ranged from mild reactions to acute liver damage and even death, suggesting a serious human risk. Recently, studies from the National Toxicology Program showed that black cohosh extract increased the frequency of micronuclei in erythrocytes of mice and rats, and in cultured human lymphoblastoid cells, indicating chromosomal damage. It is of great interest to investigate the potential mechanisms of toxicity and genotoxicity of black cohosh extract. In this proposal we plan to conduct three in vitro genotoxicity assays that are generally recommended in regulatory test batteries for short-term tests for genotoxicity and evaluate the toxicity and genotoxicity of black cohosh and six of its constituents including cimigenol and formononetin. The underlying mechanisms of black cohosh-associated genotoxicity will be explored by investigating DNA damage, oxidative stress, and related signaling pathways. With a comprehensive evaluation of the genotoxicity, we will try to identify the constituent(s) of black cohosh that are responsible for its genotoxicity.

CURE Pregnancy Treatment Repository - Heather Stone, MPH/CDER

Due to concerns for maternal and fetal safety, pregnant women have historically been absent from clinical trials, there by leaving very few drugs approved for this patient population. Since pregnant women are usually not included in clinical trials, there is either no or limited data to support the safety of a drug taken during pregnancy. Pregnant women, however, need to manage acute and chronic health conditions during pregnancy.  Drugs are prescribed to pregnant women, but their effects are not always known as that data is not systematically collected. It is important to collect the clinical data regarding drugs taken during pregnancy as it can aid in tracking drug outcomes and adverse events which in turn is used to help update safety information. The FDA encourages pregnant women to participate in pregnancy registries that track the outcomes from drugs taken while pregnant. FDA and NCATS/NIH have built a mobile application and website called CURE ID to capture the experiences of clinicians around the globe when they find novel ways of using FDA approved drugs to treat infectious diseases, emerging threats and multidrug resistant organisms. With the help of the Office of Women’s Health grant, we are proposing to expand our program to collect data on the use of drugs for infectious diseases and cancer among pregnant women. The CURE Pregnancy Treatment Repository application will gather data on drugs used during pregnancy to expand our knowledge about their effects in pregnant women. 

Identify unique antibody characteristics for prediction of effective influenza vaccination in pregnant and lactating women - Hang Xie, PhD/CBER

Following conception, the female body undergoes significant hormone changes that shift the maternal immunity to the tolerance stage to help embryo implantation and prevent fetal rejection. This pregnancy-induced immune tolerance also makes pregnant women highly susceptible for maternal infections including influenza. As pregnancy progresses, the risks for severe clinical complications such as miscarriage, preterm delivery, or even death are heightened. Moreover, newborns and infants obtain their immunity through breastfeeding. Insufficient immune defense in lactating women against influenza infections not only jeopardizes nursing mothers’ health but also endanger newborns and infants. Seasonal influenza vaccination can effectively reduce severe influenza-like illness and are routinely recommended during pregnancy regardless of trimester. However, the vaccination coverage in pregnant women remains low, partially due to misconceptions about the benefits and safety of seasonal influenza vaccines. Additionally, clinical studies that are designed to demonstrate seasonal influenza vaccine-induced protection also traditionally have pregnant and lactating women excluded. To fill the gap, we propose to systemically analyze antibodies produced by different subpopulations of women (pregnant, lactating and non-pregnant) as compared to men following seasonal influenza vaccination and identify characteristics (structures and functions) unique to women, especially those that can be used to predict protection efficiency in vaccinated pregnant and lactating women against severe influenza infections. The obtained results will provide insights into universal influenza vaccine development and help to optimize vaccination strategies to address specific needs of pregnant and lactating women.

An Innovative Approach to Promote Generic Intrauterine Systems: More Affordable Options for Women - Xiaoming Xu, PhD/CDER

Levonorgestrel (LNG) intrauterine systems (IUSs) is an effective and reversible long-term contraception option and its popularity has grown considerably in the past few decades. Currently, there are four FDA approved long-acting LNG IUSs on the U.S. market and several are about to come off patent. However, due to the lack of generic competition, the cost of the IUSs remain high. The high cost forces many women to consider less effective but more affordable options such as condoms and once-daily pills, despite preference for more long-term options like IUSs.  Therefore, there is a need to promote product development and regulatory approval of generic LNG IUSs to increase their affordability. Yet, the long duration of application and complex product design present unique challenges which could hinder the development of generics. For instance, even for a generic product that is qualitatively (Q1) and quantitively (Q2) the same as the reference product, the multi-year in vivo/in vitro studies to demonstrate bioequivalence can be difficult. In vitro drug release testing and physicochemical characterizations are important tools that not only ensure product quality and consistent performance, but also assist in the product development and regulatory review processes. However, details regarding the appropriate recommendations for the industry on the LNG IUSs are still not available, largely due to the complex formulation design and prolonged application duration ranging from 3 to 5 years. Therefore, in this project, we aim to obtain mechanistic understanding on formulation design and performance of LNG-IUSs through novel in vitro drug release testing (both accelerated and real time conditions) and advanced morphological characterization with micro-imaging. We envision that this study will shorten the time-exhaustive procedure required to support bioequivalence, reducing both scientific and regulatory burden on approving generic LNG-IUSs.

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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, PhD/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, PhD/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, PhD/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, PhD/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, MS/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.

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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, which can cause the heart to beat irregular (arrhythmia)and accidently to stop beating. Women are at a much higher risk than men for experiencing drug-induced arrhythmia. Due to the lack of appropriate tools, few studies have investigated whether genetic differences between men and women have any effects on drug-induced arrhythmia, and sex hormones are believed to play a predominant role. Recent progress in induced pluripotent stem cell (iPSC) technology (a technology that can produce stem cells directly from adult cells and make them capable of giving rise to several different types of cells) has made it possible to utilize a human heart muscle cell (hiPSC-CMs) model to investigate the influence of both genetics and sex hormones on heart muscle cell function. In this study, we are using hiPSC-CMs from normal male and female donors to investigate sex differences and hormonal effects on drug-induced arrhythmia. We found that female heart cells showed bigger responses to potassium channel blockers, which indicate that the female cells are more sensitive to these drugs and are more likely to develop arrhythmias. Sex hormones only had limited effects. The study will provide valuable information in understanding the mechanisms of sex differences in human heart muscle cell beating process and for assessing the risk 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. 

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Gender differences related to Alzheimer’s disease as revealed by Exome sequencing and RNA sequencing (Special Funding) – Sherry Ferguson, PhD/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

CDRH's efforts on strengthening medical device evaluation imply the need for more predictive assessment of real-world performance of implantable devices and materials. This project was aimed to explore novel evidentiary approaches to evaluating implant-related adverse outcomes in sex/race-stratified patient subgroups. Based on utilization of pre-existing data, the project started with a systematic literature review on implant-related biological responses and clinical outcomes. Using hip arthroplasty as an example of orthopedic implants that can benefit from novel biomarkers for diagnostic/prognostic management, our AHRQ-based epidemiologic analysis identified sexual dimorphism in the main arthroplasty-related adverse outcomes. Unlike dislocation and periprosthetic fracture which showed female predominance, periprosthetic osteolysis (PO) was more frequent among males. Next, an in silico framework for epidemiologic and genetic evidence synthesis was applied for discovery and functional plausibility analysis of biomarkers for PO as a main underlying cause of orthopedic implant failure. Using MCRI/PMRP genetic data and HIVE analytics, the GNAS rs7121 single nucleotide polymorphism (SNP) was found to be associated with the male sex related risk of PO. Thus, in addition to exploring sex-related outcome heterogeneity and identifying corresponding candidate SNPs, the project highlighted the guiding role of real-world epidemiologic evidence in biomarker discovery and illustrated transferable evidentiary and analytic approaches for healthcare applications aimed to inform optimal use of medical products and enhance treatment outcomes in patient subgroups.

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

Pregnant women are sensitive to thyroid disruption due to iodine insufficiency and exposure to thyroid-active chemicals.  Perchlorate, an environmental contaminant present in food and drinking water, is of regulatory interest to both the FDA and EPA.  Co-exposure to other thyroid-active chemicals in food, such as thiocyanate, could predispose pregnant women to additional thyroid dysfunction.  A population-based computational model was developed to describe the dose-response relationships of iodide, perchlorate, and thiocyanate on thyroid function in late-gestation pregnant women. Innovative methodologies were implemented in the development of this complex predictive tool to aid regulatory determinations in support of pregnant women’s health.  The findings of this research include an estimation, for the first time, that 21% to 43% of the late-gestation pregnant women in the U.S. have inadequate daily iodine dietary intake.  The model also indicates that the current levels of perchlorate in food alone do not result in a significant decrease in thyroid hormone levels in this population, but statistical significance was reached when an added contribution from drinking water was simulated. Moreover, our work challenges the current regulatory risk assessment paradigm of assuming only one mode of action for thiocyanate in a co-exposure scenario at environmentally relevant levels.

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 transcriptomics-based predictions of sex- and age-related susceptibilities to treatment-induced adverse effects in F344 rats (Special Funding) - James Fuscoe, PhD/NCTR

Safety assessments of new drug candidates are an important part of the drug development and approval process. Often, possible sex-associated susceptibilities are not adequately addressed, and better assessment tools are needed. We hypothesized that hepatic transcript profiles of drug metabolizing enzymes and transporters (DMETs) can be used to predict sex-associated differences in drug metabolism, and possible adverse events. Comprehensive hepatic transcript profiles were generated for F344 rats of both sexes at nine ages, from 2 weeks (pre-weaning) to 104 weeks (elderly). Large differences in the transcript profiles of 29 DMETs were found between adult males and females (8-52 weeks). Using the PharmaPendium database, 41 drugs were found to be metabolized by one or two cytochrome P450 (Cyp) enzymes encoded by sexually dimorphic mRNAs, and thus were candidates for evaluation of possible sexually dimorphic metabolism and/or toxicities. Suspension cultures of primary hepatocytes from three male and three female adult rats (10-13 weeks old) were used to evaluate the metabolism of 11 drugs predicted to have sexually dimorphic metabolism. The pharmacokinetics of the drug or its metabolite was analyzed by liquid chromatography/tandem mass spectrometry using multiple reaction monitoring. Of those drugs with adequate metabolism, the predicted significant sex-different metabolism was found for six of seven drugs, with half-lives 37%- 400% longer in female hepatocytes than in male hepatocytes. Thus, in this rat model, transcript profiles may allow identification of potential sex-related differences in drug metabolism.

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Evaluation of thromboembolic events following C1-inhibitor therapy - Paul Buehler, PharmD, PhD/CBER

FDA-approved C1-inhibitor (C1INH) products are indicated for replacement therapy in patients with hereditary angioedema. However, treatment of other conditions is proposed at C1INH supra-physiological doses. Currently the prescribing information for plasma-derived C1INH products contains a warning for risk of thromboembolic events. However, the mechanism(s) that could explain thrombosis due to C1INH remain unknown. This project focused first on the evaluation of C1INH interaction with coagulation. Our results suggest a mechanism of thrombosis development by C1INH suppression of protein C [1]. Further, we evaluated the concentration-dependent effect of C1INH on fibrinolysis using plasmin generation in parallel with thrombin generation [2]. Our observations suggest simultaneous induction of coagulation and inhibition of fibrinolysis by C1INH and define the critical role of thrombomodulin in coagulation assays. In this progression of studies, we focused the final set of experiments on understanding C1INH dose-dependent gender differences in coagulation and fibrinolysis and the impact of oral contraceptives. These findings are relevant to understanding the effects of C1INH plasma concentrations on coagulation and fibrinolysis in males and females, the impact of common concomitant drug therapies in females, and also provide useful assays for monitoring coagulation status during C1INH therapy across a range of disease conditions.

1. Tarandovskiy ID, Buehler PW, Ataullakhanov FI, Karnaukhova E. C1-esterase inhibitor enhances thrombin generation and spatial fibrin clot propagation in the presence of thrombomodulin. Thrombosis Res. 2019; 176: 54-60. 
2. Tarandovskiy ID, Rajabi AA, Karnaukhova E, Buehler PW. Contradictory to its effects on thrombin, C1-inhibitor reduces plasmin generation in the presence of thrombomodulin. 2019; J Thromb Thrombolysis. doi: 10.1007/s11239-019-01869-y. 

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. 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 using quantitative modeling to improve the drug development process. In this project, a database with prognostic factors and outcomes of tumor size and survivals for metastatic breast cancer patients was constructed, including eight phase III clinical trials from 3 NDAs and 2 BLAs submission. Treatment specific tumor dynamic model was separately built for each arm and patient-level tumor size metrics in different categories were derived. Mathematic models were then built to quantify the relationship between early tumor size after treatment and clinical outcome (PFS and OS) in the database. Parametric survival models for PFS and OS were established with either tumor size metrics or longitudinal tumor growth data. Good predictions of treatment effects (i.e., hazard ratio) for clinical trials in metastatic breast cancer patients were generated except for trials with high proportion of progressed patients only caused by new lesions and/or non-target lesions and clear difference in censored rate between active arm and control arm. The establish models can be utilized as a tool to simulate the clinical efficacy based on tumor sizer measured in early times to facilitate the drug development for the treatment of metastatic breast cancer.

Bacteria and virus migration through latex condoms in the presence of personal lubricants - Srilekha Das, PhD/CDRH

To address the critical public health concern related to the potential passage of pathogenic viruses through natural rubber latex condoms, studies were undertaken in CDRH in the 1990s using a non-pathogenic bacteriophage, ΦX 174, which is similar in size and shape to the pathogenic HIV viruses. Although 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), the method did not account for the presence of personal lubricants that are often used in conjunction with condoms. Over–the–counter personal lubricants, comprised of various biocompatible chemicals, 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, migration of pleomorphic Ureaplasma urealyticum and bacteriophage PhiX174 (a surrogate to HIV virus) through 22 latex condom materials was examined in the presence of six commercial and six individual ingredients. Results suggest that U. urealyticum does not pass through latex male condoms under current experimental conditions; whereas PhiX174 does pass through a limited number of test subjects under specific conditions. Results also suggest that appropriate selection of the collection fluid is very important in migration testing.

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

Characterizing properties of coronary artery plaques is critical for risk stratification for intermediate risk patients. Dual-energy CT have been studied for its potential to quantify coronary artery calcium and to characterize the composition of plaques. However, existing studies have not focused on measuring and optimizing performance of dual-energy CT for women; research is needed to investigate how quantitative coronary calcium scoring and plaque material characterization are affected by gender differences and CT acquisition techniques. Women have smaller vessels and higher heartbeat rate, which may make it more difficult for characterizing plaques with accuracy and precision.

In this work, we first designed and built vessel phantoms with sizes representative of those in average men and women and included plaques with various properties in terms of occlusion size and density. Then we scanned the vessel phantom in controlled cardiac motion with multiple acquisition protocols by varying important imaging parameters such as radiation dose and image reconstruction algorithms. We developed algorithms to quantify calcium scores and differentiate calcified occlusion from iodine and/or soft plaque. Statistical assessments of the measurements showed that the accuracy of the calcium quantification is highly dependent on the size and density of the plaques. Similarly, it was more difficult to differentiate calcified occlusion from iodine or soft plaque when the vessel/calcium occlusion was small, the calcium had low density, or there was more motion. This indicates that it is more challenging to characterizing materials in women’s arteries due to its smaller size on average and the higher heartbeat rate.

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

Approximately 33% of young women (ages 21-40) and 79% of older women (ages 61-70) have one or more degenerated spinal discs [1]. Degenerated discs can result in neck or low back pain. Surgical treatment options for this condition are interbody cages and total disc replacement medical devices. However, high rates of subsidence (the device migrates into the vertebral body) have been reported from clinical studies [2-6]. In fact, women have been shown to have higher rates of subsidence when compared to men [6]. The risk of subsidence is influenced by factors such as vertebral anatomy, bone mineral density, bone quality, spinal loading, and flexibility of the spine. Many of these factors are gender-specific and women with low bone density and/or quality may lead to poor outcomes as compared to men. Identifying a method that can predict the type of patient that is more susceptible to subsidence will help reduce the risk of this adverse event for future devices. Therefore, the goal of this study is to develop a validated computational and experimental framework to examine subsidence by accounting for anatomically different spines with varying bone density. The results of this study will improve upon existing methodologies and ultimately aid in understanding the risk of spinal implant subsidence. This study coincides precisely with the FDA’s mission of promoting public health, particularly for women.

Spectral photoacoustic tomography (PAT) for breast tumor oximetry: Test method development, in vivo validation, and computational modeling - Brian Garra, MD/CDRH

Photoacoustic imaging (PAI) is a rapidly emerging hybrid modality that combines optical excitation with acoustic detection to achieve deep tissue imaging of light-absorbing molecules such as hemoglobin in blood. The ability of multispectral PAI to detect vasculature and map tissue blood oxygen saturation (SO2) enables many potential clinical applications, especially breast cancer detection, tumor margining, and treatment monitoring. PAI systems are commercially available for research use and FDA has received several photoacoustics-based submissions. To facilitate PAI device development, reduce testing costs, and streamline regulatory evaluation, we developed several device performance evaluation tools, including 1) tissue phantom-based test methods, 2) image processing algorithms for improving SO2 measurement accuracy, and 3) computational models for simulating and predicting device performance. First, we developed a PAI oximetry test method based on our previously developed PVC plastisol phantom material, which has breast-mimicking optical and acoustic properties. Phantoms were connected to a blood flow circuit with adjustable blood SO2¬, which was measured using both FDA’s custom PAI system and gold-standard CO-oximetry. SO2 measurements were highly susceptible to spectral artifacts produced by spatially- and spectrally-dependent light distribution in turbid tissues. Image processing algorithms often used to correct these artifacts are a critical aspect of PAI device design and performance evaluation. To enable evaluation of such algorithms, we developed a novel correction algorithm based on diffusion theory of light transport and validated the algorithm through additional phantom test methods. This algorithm achieved accuracy similar to gold-standard Monte Carlo simulations, but with lower computational cost and ease of implementation. Computational modeling represents a potentially fast, low-cost alternative to more burdensome bench, animal, and clinical testing, but models require rigorous verification and validation to ensure confidence that model outputs represent reality and can support regulatory evaluation of a device. We built a model combining light and sound transport software, validated the model in phantoms, and demonstrated that model outputs could adequately predict image quality metrics produced in phantom bench tests. In summary, this set of tools may be used to support device development and optimization, generate high-quality performance data to support regulatory decision-making, and guide standardization of PAI device performance assessment methodology.  

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 cancer (TNBC) is a subtype of breast cancer that is highly aggressive and has poor prognosis. About 15-20 % of breast cancers fall into this category. This subtype of cancer lacks  FDA approved targeted therapies mainly due to the lack of receptors, such as the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor-2 (HER2). Therefore, the only treatment is chemotherapy and radiation. Vorinostat, a HDAC inhibitor (HDACi), and a dietary agent,  indole-3-carbinol, have shown significant anti-cancer effects in specific subtypes of TNBC by re-expressing ERα, thus making these cells sensitive to tamoxifen. In addition, this drug has exerted its anti-cancer effects by modulating the expression of critical miRNAs that regulate genes involved in proliferation, apoptosis, invasion, apoptosis and down-regulating cancer stem cells. New targets were identified with vorinostat treatment that need further validation for their importance in TNBC. One exciting finding in this study is that tamoxifen alone  inhibited growth in two cell lines representing  the most aggressive subtype, basal 2. Although these cells lack ERα, research suggests that they may exert this effect due to ERβ expression. This study also clearly demonstrated that vorinostat was able to down-regulate cancer stem cells by decreasing expression of CD44 cells. Vorinostat is currently in clinical trials for several cancers.

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 microbicidal drugs to women by application to the vaginal tract may be improved by use of chemical structures called nanoparticles. Previously, we found that certain dissolving drug-delivery nanoparticles are toxic to vaginal cells and cause inflammation, even though similar material is not toxic in larger medical devices. In this work, we observed mice with vaginal yeast infections to determine if body defenses limit cellular toxicity and inflammation caused by nanoparticles in the vaginal tract. We observed uptake of nanoparticles by several types of vaginal cells increased with yeast infections.  Although the mice did not show signs of stress, similar types of damage to vaginal cells and inflammation responses were observed as in previous cell culture experiments.  These mechanisms included damage to cellular DNA and to intracellular transportation systems.  Death of vaginal cells increased in mice with yeast infections treated with the nanoparticles and the amount and residence time of nanoparticles taken up by vaginal cells and dispersed systemically was increased.  The results suggest intravaginal nanoparticles could increase toxicity in women taking them during vaginal yeast infections.  The FDA recommends that microbicidal drugs and their delivery devices be tested for toxicity and inflammation, possibly using methods like those described in this study.

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 - Anil Patri, PhD/NCTR

Nanosilver is used in many commercial consumer products, including feminine hygiene products, for their antimicrobial activity. The potential risks of such exposure to vaginal tissue is unknown. This study evaluated whether vaginal exposure to nanosilver results in migration of silver to other parts of the body or causes toxicity in a rodent model. Fourteen out of thirty diverse feminine hygiene products screened (gels, towels, napkins, and pads) were found to contain silver. Custom tampons were fabricated to mimic a practical scenario in which consumer products containing silver may be administered. Single- and multi-dose administration of a commercial product along with standard nanosilver materials were tested for tissue biodistribution and toxicity evaluation. Tissue biodistribution was treatment specific but indicated a 2 - 18% total recovery of the administered dose with >90% of this silver primarily localized in the reproductive tract. In vivo studies showed that the silver test compounds were non-toxic at the concentrations tested. Additionally, histopathology and clinical chemistry following acute exposure to silver nanomaterials were unremarkable. Overall, acute exposure to silver nanomaterials resulted in limited persistence and no notable toxicity. However, long-term studies have not been performed.

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 (ZIKV) infections have been associated with an increased incidence of severe microcephaly and other neurodevelopmental disorders in newborn babies [1]. Treatment with human anti-ZIKV neutralizing antibodies may become a feasible option during pregnancy. However, it is unknown if ZIKV could be transferred vertically by anti-ZIKV antibodies to mediate fetal infection, as reported for other viruses [2, 3] or immunogens [4]. 

We used mammalian cell monolayers as a model to investigate the role of anti-ZIKV antibodies in facilitating mother-to-child transmission of ZIKV and ZIKV envelope glycoprotein protein E (GpE). We also characterized immune complexes (IC) between antibodies and GpE using Dynamic Light Scattering and other methods to assess stability and whether it may affect transcytosis. 

We found that 1) at high concentration, GpE can enter and pass through placental and other epithelial cells with or without the presence of antibodies. 2) When present at insufficient amounts, monoclonal antibodies do not block and may facilitate the transfer of the ZIKV through placental cells. 3) The stability of antibody preparations and presence of aggregates can affect in vitro measurements; adequate characterization of antibody and antigen preparations are essential to ensuring reliable data and sound conclusions from in vitro studies. 

Our studies confirm that Zika virus or its envelope protein have the potential to be transferred across placental and other epithelial cells, making these in vitro systems appropriate tools for screening potential prophylactic and therapeutic antibody treatments. 

1. Petersen E et al, Int J Infect Dis 2016, 44:11-15. 
2. Maidji E et al, Am J Pathol 2006, 168:1210-1226. 
3. Parry S et al, J Gen Virol 2006, 87:2269-2278. 
4. Bundhoo A et al, Clin Exp Allergy 2015, 45:1085-1098.

Optimization of an in silico cardiac cell model for predicting sex differences in drug-induced proarrhythmia risk (Special Funding) - Wendy Wu, PhD/CDER

Women are at elevated risk of drug-induced Torsade de Pointes (TdP), a potentially fatal ventricular tachyarrhythmia, relative to men. Furthermore, limited evidence suggests that TdP risk in women changes across the menstrual cycle: high when estradiol level is high and low when progesterone level is high. Given that drug-induced TdP is most often caused by drugs directly acting on cardiac ion channels, this research used single cell electrophysiology to examine the chronic effects of estradiol and progesterone on the electrical behavior of ventricular myocytes in females, using guinea pigs as an animal model. The results were compared with ongoing in silico effort to create male and female heart cell models for TdP risk prediction. The data show that estradiol prolongs, and progesterone shortens ventricular action potentials in female animals. These are long lasting changes and could be detected in in vitro assay without the addition of sex hormones. Action potentials from female cells are qualitatively longer than those from male cells, suggesting reduced activities of repolarizing K+ channels and/or increased activities of depolarizing ion channels in female cells relative to male cells. In in silico studies, activities of these ion channels were adjusted to create a “female” cell, which was then used to rank order drugs into different TdP risk categories. This multi-disciplinary research is consistent with the OWH’s mission to protect and advance the health of women through policy, science, and outreach.

Development of the US Women's Health Coordinated Registries Network (Special Funding) - Nilsa Loyo-Berrios, PhD/CDRH

Historically, scientific questions that uniquely affect women have been evaluated in stand‐alone studies. Although single-purpose registries were created, linkages to other data sources were not possible, missing the opportunity to create infrastructure to advance women’s health in routine clinical practice. Therefore, our goal was to help support CDRH work to establish a Women’s Health Technologies (WHT) “Coordinated Registries Network” (CRN) that could serve as the national infrastructure for evaluation of medical products in clinical areas unique to women, to efficiently extract, standardize and exchange data from electronic health records, and link data sources. 

We leveraged the Medical Device Epidemiology Network (MDEpiNet) as part of a broader WHT initiative funded by PCOR-TF.   One of our project goals was to identify key stakeholders  for the  PCOR-TF multi-stakeholder collaboration that included clinical,  informatics and interoperability work (e.g. structured data capture and harmonized definitions). Our collaboration with the PCOR-TF WHT project ensured a strategic approach for the CRN development. 

An Expert Core Working Group was established with leadership from the FDA/CDRH, NIH, ONC, and MDEpiNet partners: Cornell University, COMPARE-UF registry, American College of Obstetrician and Gynecologist (ACOG), and the American Urogynecologic Society (AUGS). We organized two public workshops held at the FDA on September 15, 2017 and September 7, 2018. The products of these two workshops have been incorporated into the development of the CRN governance framework. Work will continue under the CRN governance agreement.  White papers are being prepared for publication of the findings from the Delphi surveys (subject matter experts consensus approach).

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.

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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 (Special Funding) - Danica Marinac-Dabic, MD, PhD/CDRH 

Inclusion of Minority Racial/Ethnic Subjects in OB-GYN Device Applications and Device Labeling, 2005-2015 - Christopher Ronk, 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, PhD/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. 

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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

Trastuzumab (Herceptin®, from now on we only use trastuzumab) is a humanized monoclonal antibody directed against the extracellular domain IV of HER2 and approved for the treatment of HER2-positive breast cancer and gastric cancer or gastroesophageal junction adenocarcinoma. Even though trastuzumab is clinically highly efficacious, it has been shown to be associated with considerable cardiotoxicity and cardiomyopathy, the mechanism of which remains unclear. HER2 signaling plays a pivotal role in cardiomyocytes development and survival and is essential for the prevention of cardiomyopathy. However, a direct link has not been confirmed between trastuzumab-induced cardiomyopathy and impaired HER2 signaling. Using animal and cellular model systems, our lab revealed a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in upregulation of mTOR signaling pathway and subsequently inhibition of autophagy in primary cardiomyocytes and C57BL/6 mice. Trastuzumab-induced downregulation of autophagy is further supported by the fact that trastuzumab treatment reduces protein levels of autophagosome-associated signaling molecules such as Atg 5-12, Atg 7, Atg 14, and Beclin 1. We further demonstrated that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab (Perjeta®, from now on we only use pertuzumab for the rest of report.), another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to inhibit autophagy and to increase ROS production in cardiomyocytes. 

This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which can assist in formulating novel approaches for clinical management of women who suffer HER2-positive breast cancer with significant site effect from trastuzumab treatment. 

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 (Special Funding) - Anne Pariser, MD/CDER (Support for implementation of FDASIA Section 907 Action Plan)

The U.S. Food and Drug Administration (FDA) has made efforts to encourage adequate assessment of women, racial/ethnic minorities, and geriatric participants in clinical trials through regulations and guidance documents. 

This study surveyed the demographics of clinical trial participants and the presence of efficacy and safety analyses by sex for new drugs approved between 2013 and 2015 by the FDA Center for Drug Evaluation and Research. New drug marketing applications submitted to FDA were surveyed for demographic data (sex, race, ethnicity, and age) and the presence of sex-based analyses for efficacy and safety. The Ratio of the Proportion of women in clinical trials for the indicated disease population relative to the estimated Proportion of women in the disease population (PPR) was calculated for new drug indications. 

Of the 102 new drugs in this cohort (defined as new molecular entity drugs and original therapeutic biologics), sex was reported for >99.9% of trial participants, and women accounted for 40.4% of these participants. An estimated 77.2% of participants were White, 6.4% were Black/African American, and 29.1% were aged ≥65 years. Sex-based analyses for both efficacy and safety were conducted for 93.1% of applications. PPR was calculated for 82 new drugs for a total of 60 indications, of which 50 indications (83.3%) had a PPR ≥0.80. 

A trend toward higher participation of women and those ≥65 years in later phase trials than in phase 1 was seen and is not unexpected. In contrast, participation of pooled racial minorities was relatively consistent by phase and participation by Hispanic/Latino ethnicity (for those who reported this information) also did not show a trend toward higher participation in the later phases. The reasons for these trends are not clear; however, the results did show that although collection of race subgroup data by sponsors was high, collection of ethnicity data was more limited and was inconsistent across applications.
Compliance with Federal regulations for demographic reporting of sex in patient-level data submitted to FDA by drug sponsors was high. The increased reporting of participant age (<65 years, ≥65 years) over the years may be due to the 2012 amendment to the International Council for Harmonisation E-7 guidance, which emphasized the importance of including patients ≥65 years of age.

Sex data are now collected for almost all study participants, and this study shows appropriate sex participation for most new drugs when estimated disease prevalence by sex (PPR) is considered. Therapeutic area and disease indication are important considerations when assessing the sex of participants because variation occurs depending on the disease under study. Some racial minorities, especially Blacks/African Americans, are still not well represented in most drug development programs and remain an area where improvement is needed.

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Evaluation of HSV-2 co-infection and hormonal contraceptive use on HIV acquisition and pathogenesis using patient-derived clinical specimens - Indira Hewlett, PhD, CBER

Women account for one half of new HIV infections world-wide. To avoid unintended pregnancies, HIV infected women use either oral (progestin pills) or intravenous contraceptives. While these hormones avoid unintended pregnancies, they also enhance HIV acquisition. HSV-2 co-infection further increases HIV-1 multiplication. Population level studies showed conflicting findings with hormonal contraceptive use; some studies observed increased HIV acquisition while others did not observe any change. Hence, understanding the cellular mechanisms behind the observed augmentation of HIV acquisition and the use of progesterone as a contraceptive would be relevant and important for reproductive age HIV-1 positive women. The goal of our study is to test whether progesterone treatment enhances HIV viral load with or without HSV-2 co-infection and to understand the molecular mechanisms behind these effects. Clinical samples will be collected from four geographic locations from HIV positive women and plasma viral load measured for HIV and HSV-2. PBMC collected from these women will be analyzed for cytokine levels.  The expression levels of Bcl2, a major anti-apoptotic marker will be measured by qPCR and western blot. Novel biomarkers will be identified from mRNA screen and miRNA screen which will be further confirmed with western blot and qPCR. This study will provide scientific data on the impact of HIV and HSV-2 co-infection and progesterone treatment on HIV disease outcome in women.

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)

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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

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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

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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)

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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)

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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)

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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)

Extramural studies:

Drug Eluting Stent (DES)/Thrombosis - Bram Zukerman PhD, Norman Stockbridge, PhD, Duke Clinical Research Institute

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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)

Extramural studies:

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

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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)

Extramural studies:

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.

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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)

Extramural studies:

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

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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)

Extramural studies:

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

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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)

Extramural studies:

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

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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)

Extramural studies:

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

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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)

Extramural studies:

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

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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)

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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)

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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)

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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)

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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)

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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)


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