Science & Research

List of Research Science Program Awards - by Therapeutic Categories

Since 1994, the FDA Office of Women’s Health has funded approximately 300 studies in the following areas:

Autoimmune Diseases, Bioinformatics, Breast Implants, Breast Cancer/Mammography, Cancer, Cardiovascular Diseases, Cosmetic, Device Safety, Diet/Obesity, Dietary Supplement, Feminine Hygiene, HIV/STD, Hormone, Infant Feeding, Infectious Diseases, Osteoporosis, Pregnancy, Sex Differences, Women in Clinical Trials, Other

Autoimmune Diseases

Clinical and Biological Significance of Three Identified Targets in Systemic Lupus Erythematosus Patient PBMCs: IL-18, TNFSF13B, and FOXP3 - Beverly Lyn-Cook, PhD, NCTR (13)

Use of innate immune response modulators in women: The perfect storm to trigger autoimmune disease?
- Daniela Verthelyi, MD, PhD, CDER (13)

Sex Disparities in Autoimmune Treatment Response - Lanyan Fang, PhD, CDER (12)

A Mechanistic Study of the Capacity of Silicone to Present (Self) Antigens to the Immune System - Jack Ragheb, PhD, CDER (12)

Lupus Workshop – Shashi Amur, Special funding/CDER (11)

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 (11)

The Role of Vaccine Adjuvant Mediated TACI Upregulation in SLE - Mustafa Akkoyunlu, PhD, CBER (08)

Gender, Ethnicity and Pharmacogenomics in Systemic Lupus Erythematosus (SLE) - Shashi Amur, PhD, CDER (07)

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, PhD, NCTR (07)

Evaluation of the Tk knockout (TkKO) mouse as a model of systemic lupus erythematosus - Vasily Dobrovolsky, PhD, NCTR (00)

Postmarketing drug risk assessment using the ARAMIS database in RA patients – Mary Willy, PhD, CDER (99)

A novel approach to the treatment of lupus nephritis - Dennis Klinman, MD, PhD, CBER (96)

Cytokine induced activation of the Jak kinase/STAT transcription factor pathway in immune cells (monocytes and lymphocytes) of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) - David S. Finbloom, MD, CBER (95)

Hormonal regulation of cytokine producing cells in women with systemic lupus erythematosus - Dennis Klinman, MD, PhD, CBER (95)

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Bioinformatics / Data mining / Safety

Population-Based Computational Framework for Assessing Xenobiotic Disposition and Interaction Effects in Pregnant Women-Pilot Study - Annie Lumen, PhD, NCTR (13)

Continuation of a pilot study on performing sex analysis on a vaccine database – Jingyee Kou, PhD, Special funding/CBER (11)

A pilot study on performing sex analysis on a vaccine database – Jingyee Kou, PhD, Special funding/CBER (10)

Development of an FDA resource for sex difference-related pharmacogenomics data review-Phase II - Weida Tong, PhD, NCTR (09)

Detection and Confirmation of Gender Related Safety Signals Using the Electronic Healthcare Data from the Department of Defense - Ana Szarfman, MD PhD, CDER (08)

Development of a FDA Resource for Improved Efficiency of Sex Difference Related Pharmacogenomic Data Analysis and review - Weida Tong, PhD, NCTR (07)

Adverse Events Reporting System (AERS): Risk assessment, compliance, and management - Ralph Lillie, RPh, CDER, (98)

Data mining techniques for identifying potential serious drug interactions in women - Ana Szarfman, MD PhD, CDER (98)

Visualization tools for studying gender differences - Ana Szarfman, MD PhD, CDER (97)

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Breast Implants

MRI Safety Testing of Breast Tissue Expanders used in Mastectomy Patients - Sunder Rajan, PhD, CDRH (13)

MRI and Ultrasound imaging of silicone filled breast implants – Rajan Sunder, PhD, CDRH (11)

Abrasion testing of breast implants - Patricia Dubill, PhD, CDRH (98)

Protocol for a study of breast implant rupture - S. Lori Brown, MD, CDRH (97)

A study of safety of silicone breast implants - IOM study, Institute of Medicine/S. Lori Brown, MD, CDRH (97)

Development of a safe, economical assay for silicone containment in blood and tissue - Marwood N. Ediger, PhD, CDRH (96)

Mechanism of immunotoxicity and carcinogenicity associated with silicone breast implants - S. Jill James, PhD, NCTR (95)

Noninvasive assessment of silicone migration from gel-filled breast implants - Kyle Myers, PhD, CDRH (95)

Silicone Gel Alternatives Workshop - John Langone, PhD, CDRH (94)

Immunogenetic risk factors for silicone-associated multiple myeloma and monoclonal gammopathy of undetermined significance - Frederick Miller, MD, PhD, CBER (94,98)

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Breast Cancer / Mammography

Preservation of relevant clinical information in lossy compressed digital mammograms using objective image quality metrics - Aria Pezeshk, PhD/CDRH (16)

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.

Mammographic CAD device testing using computationally inserted microcalcification clusters and masses - Berkman Sahiner, PhD/CDRH (16)

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.

Spectral photoacoustic tomography (PAT) for breast tumor oximetry: Test method development, in vivo validation, and computational modeling - Brian Garra, MD/CDRH (16)

Breast cancer is the second leading cause of cancer–related death in American women. A new imaging modality called Photoacoustic Tomography (PAT) can potentially help with detection and classification of breast cancers. In PAT, a laser pulse stimulates tissue to generate and send back sound waves from which images are created by an ultrasound machine. PAT can not only image abnormal small blood vessels due to absorption of the laser pulse by hemoglobin, but can also measure the amount of oxygen in the hemoglobin (called oximetry). Both of these features can be used to distinguish cancers from benign tumors and can help identify aggressive cancers. Despite great scientific interest and development of new PAT products intended for commercial use, no standard methods for testing PAT oximetry systems exist. This lack of proper test methods has hampered FDA regulatory review of new systems. We propose using tissue simulating materials and phantoms we previously developed for PAT imaging testing, to construct new phantoms and tests for PAT oximetry performance testing. A custom research-grade PAT system will be tested for its ability to measure hemoglobin oxygenation using these new phantoms, and the test results will be validated against measurements obtained using the same PAT system on rats. These results will be used to devise a simple but scientifically rigorous phantom and test methods for testing of new commercial systems during design, production and regulatory review. The results will also be used to complete development of a computational model of PAT system performance that, in the future, could be used in place of the phantom tests. Together all of these methods will markedly reduce the time and expense of performance testing and regulatory evaluation of new PAT systems for breast cancer evaluation.

Tool development of modeling and simulations for metastatic breast cancer - Jingyu Yu, PhD/CDER (16)

Worldwide, breast cancer is the leading type of cancer in women, accounting for 25% of all cases. Although survival rate is high for women with breast cancer, the five-year survival rate after diagnosis for metastatic (stage 4) breast cancer patients is 40 percent based on MD Anderson researchers. The Critical Path Initiative of the US Food and Drug Administration calls for leveraging existing knowledge from clinical data through the use of quantitative modeling to improve the drug development process. We therefore propose to quantify the relationship between early tumor size after treatment and clinical outcome (e.g., patient survival, progression free survival) in women with metastatic breast cancer using the pooled clinical data submitted to the Food and Drug Administration by multiple pharmaceutical companies. Our proposal aims at demonstrating how data mining of drug registration trials for metastatic breast cancer agents enables us to develop a pharmacostatistical model that can capture the time course tumor size change and link time of death or disease progression to risk factors and the tumor size information after start of therapy. The disease model we propose here may reduce the failure rate of drugs by selecting the right dose for right candidate compounds that are highly efficacius on the basis of a predicted survival benefit for women with metastatic breast cancer.

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 (16)

Triple negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. About 15% of breast cancers falls into this category. TNBC often strikes premenopausal women. TNBC patients generally have a poorer prognosis and early relapse that often results in death. This subtype of cancer lacks targeted therapies receptors, such as the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor-2 (HER2). TNBC patients cannot, thereby, be treated with targeted therapies that blocks the action of these receptors, such as tamoxifen and Herceptin. Therefore, these patients are limited to cytotoxic chemotherapies with harsh side effects. Risk factors for TNBC include: being of African descent, BRCA1 mutation, a strong family history of breast cancer, lifestyle and environmental factors. Although mutations are involved in the initiation of TNBC, research has revealed that individuals are controlled by factors other than DNA sequences; these factors are termed epigenetics. Epigenetics refers to changes in gene expression that do not directly affect DNA sequences. In humans, these epigenetic mechanisms involve DNA methylation, histone modifications, and noncoding RNAs that control tissue-specific gene expression. This study will examine whether an epigenetic drug (vorinostat) and a dietary agent (indole-3-carbinol), which have been shown to exert their effects through epigenetic mechanisms, can re-express critical targeted receptors (ER, PR and HER2) in TNBC cells and render these resistant cells sensitive to approved FDA cancer drugs such as tamoxifen, raloxifene or Herceptin.

Oncomutation profile of triple negative breast cancer: Additional studies in African American women - Meagan Myers, PhD/NCTR (15)

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.

Phantom-based evaluation of photoacoustic imaging systems for breast tumor vasculature quantification - Brian Garra, MD, CDRH (14)

Calcium and material characterization in women using dual-energy computed tomography - Nicholas Petrick, PhD, CDRH (14)

Incremental Values of Sequential Procedures for Diagnosing Breast Cancer - Zhiwei Zhang, PhD, CDRH (13)

Safety and Efficacy of Iron Oxide Nanoparticles Used as MRI Contrast Agents for Breast Cancer Imaging - Peter Goering, PhD, CDRH (12)

Quantitative oncomutation profile of triple negative breast cancer - Meagan Myers, PhD, NCTR (12)

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 (12)

Development of a targeted microRNA-based epigenetic therapeutic approach for breast cancer treatment – Igor Pogribny, PhD, NCTR (11)

Integrated analysis of single nucleotide polymorphism and copy number variation in genome association of breast cancer - Ching-Wei Chang, PhD, NCTR(11)

Evaluating radiation risks and benefits of breast CT for diagnosing breast cancer – Robert Jennings, PhD, CDRH (11)

Reproducibility in the quantitative assessment of multiple tissue-based biomarkers for breast cancer using light and digital microscopy – Nicholas Petrick, PhD, CDRH (11)

Safety and efficacy of biomarkers using gene expression data for breast cancer patient treatment and care - Subok Park, PhD, CDRH (10)

Dose and image quality optimizations in various full-field digital mammography systems - Kish Chakrabarti, PhD, CDRH (10)

Development of standard color management methods for assessment of immunohistochemical HER2 expression in breast cancer using digital microscopy, Aldo Badano, PhD, CDRH (10)

Inactivation of UDP-Glucuronosyltransferases (UGTs) in human breast tissues: Accessing cancer risk, tamoxifen safety and toxicity - Athena Starlard-Davenport, PhD, NCTR (09)

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 (09)

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 (09)

Effects of Proposed Revisions to the Regulations Implementing the Mammography Quality Standards Act - Steven Tucker, OC (08)

Dose and Image Quality in Full Field mammography - Kish Chakrabarti, PhD, CDRH (08)

Qualifying Imaging Biomarkers to Monitor Neoadjuvant Chemotherapy in Breast Cancer Patients to Identify Responders Using Positron Emission Tomography (PET), Christy John, PhD, CDER (08)

Patient Safety and Imaging Performance of Three-Dimensional (3D) X-Rays Systems for Detection of Breast Cancer - Subok Park, PhD, CDRH (08)

Implications of Gender-based Differences in Cardiovascular Disease on Imaging for Treatment and Diagnosis - Iacovos Kyprianou, PhD, CDRH (05)

Discovery and evaluation of interspecies biomarkers to identify and characterize the cardiotoxic effects of Transtuzumab (Herceptin), a novel antibody used in the treatment of breast cancer - Eugene Herman, PhD, CDER (01)

Improve the efficacy of chemotherapeutic drugs for the treatment of breast cancer - Emily Shacter, PhD, CBER (98)

Mammography breast cancer screening rates among disadvantaged women within a prepaid health care system - Rosalie Bright, ScD, CDRH (97)

Optimization of mammography - Robert Jennings, PhD, CDRH (97)

IP-10: A potential new therapeutic for breast cancer - Giovanna Tosato, MD, CBER (96)

DNA adducts of tamoxifen - Frederick A. Beland, PhD, NCTR (96, 99)

Mammography quality standards act facilities workshop - Barbara Ward-Groves, MPH, ORA (95)

Development of Mammography Quality Standards Act (MQSA) Speaker Kits - Carol Sierka, CDRH (94)

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Non-clinical mechanistic studies in addressing ovarian cancer risk from talc use in cosmetics - Nakissa Sadrieh, PhD, Special Funding/CFSAN (16)

Talc is an important industrial chemical, that is widely used in plastic apparatus and plastic surfaces, including surgical gloves, and gynecologic procedures, and women are commonly known to use products containing talc for hygiene and cosmetic purpose. Although some epidemiologic and animal studies have examined the relation between talc and ovarian cancer, talc’s 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 in which talc (100 mg in 0.5 ml saline) was given intravaginally daily for 3 months had unfavorable effects on the female genital system. However, these effects seemed to be in the form of foreign body reactions or infections without specific . This suggests 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.

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 – Liu Juhong, PhD, CDER (11)

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, PhD, NCTR (08)

Sex differences in chemotherapeutic toxicity: profiling of transporter genes in human - Beverly Lyn-Cook, PhD, NCTR (06)

Quantitative Tumor Size- Survival relationship in Oncology clinical trials - Jogarao Gobburu, PhD, CDER (06)

Improving the evaluation of ovarian cancer treatment - Vance Berger, PhD, CBER (99)

In Vitro Prediction of Time to Neutropenic Nadir: Anti-neoplastic Alkylating Agents as Prototype Drugs, Donna A. Volpe, Ph.D., CDER (96)

Development of a Safe, Economical Assay for Silicone Containment in Blood and Tissue, Marwood N. Ediger, Ph.D., CDRH (96)

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 (96)

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Cardiovascular Diseases

Evaluation of thromboembolic events following C1-inhibitor therapy- Paul Buehler, PharmD, PhD/CBER (16)

Hereditary angioedema (HAE) is a rare potentially life threatening disorder associated with a deficiency of functional C1-esterase inhibitor (C1INH), and it is more severe and frequent in female population than in men. Until recently, there was no HAE-targeted therapy available in the United States, and only fresh-frozen plasma or attenuated androgens were used to provide some relief during acute attacks. Since 2008, DHRR/CBER approved three C1INH products for replacement therapy in patients with HAE for the treatment of acute attacks and for prophylaxis. According to the available database and recent publications, C1INH therapy in HAE patients is associated with a risk of thromboembolic events. Thrombosis also has been predominantly reported in women and appears to depend on hormonal status. This project will focus on the evaluation of a risk of thromboembolic events due to C1INH administration at supraphysiological levels and elucidation of possible underlying mechanisms. Secondly, to assure safety and effectiveness of C1INH treatment in case of recently proposed concomitant administration of C1INH and pharmaceutical heparins, this project will focus on the evaluation of the C1INH potentiation by heparin and the impact of various compositions and conditions on possible thrombotic events. The proposed studies, both in vitro and in animal models, are essential for the development of reliable biomarkers to evaluate and predict thromboembolic events in women during C1INH therapies, as well as for elucidating the mechanisms for possible enhancement of currently available C1INH therapies by pharmaceutical heparins and its impact on a risk of thrombosis.

Developing biomarkers for trastuzumab-induced cardiotoxicity- Wen Jin Wu, MD, PhD/CDER (16)

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.

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 (16)

Calcium and material characterization in women using dual-energy CT: Phase II - Nicholas Petrick, PhD/CDRH (16)

Cardiovascular disease is the leading cause of death for American women and women have higher cardiovascular mortality rates compared with men. Large numbers of cardiovascular events occur in asymptomatic people who do not belong to high risk groups. Risk-based markers, such as coronary artery calcium score, have been suggested as methods for identifying candidates for primary prevention of coronary artery disease (CAD) through risk-factor modification. The calcium score, related to the amount of calcium found in coronary vessels, is used as a summary measure of coronary health, with higher scores indicating higher risk of CAD. Women have smaller, faster beating hearts, smaller arteries, and different anatomy than men. While research in standardizing CT quantification of coronary calcium has been carried out, little has been done to 1) address gender differences, 2) develop methods for systematically quantifying measurement error or 3) validate the performance of calcium scoring and plaque material characterization in dual-energy CT. In Phase I (OWH funded 2014-15), we are evaluating the accuracy and precision of calcium scoring in single- and dual-energy CT scans through static phantom studies. Our initial results show that vessel size and gender-based anatomy are significant factors that strongly influence calcium scoring. In Phase II, we propose to investigate how quantitative coronary calcium scoring and plaque material characterization are affected by gender difference and CT acquisition techniques with a special focus on measuring and optimizing performance of dual-energy CT in women. We will build on our initial static phantom studies by developing a dynamic motion controller that allows the impact of heart motion to be accounted for. We are also proposing a substantial expansion to evaluate the potential of dual-energy CT for characterizing the material composition of coronary plaques and in particular to validate how well dual-energy CT can differentiate hard from soft plaques. While the phantoms developed are specific to coronary vessel measurements, the general approaches and validation methods developed will generalize to the assessment of technical performance for other quantitative imaging biomarkers.

Cardiovascular Risk of Testosterone Treatment in Women- LaiMing Lee, PhD, Special Funding/CDER (16)

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.

Optimization of an in silico cardiac cell model for predicting sex differences in drug-induced proarrhythmia risk- Wendy Wu, PhD, Special Funding/CDER (16)

The FDA is generating computer models of human heart cells to improve the prediction of drug safety, specifically the risk of a drug inducing a life-threatening ventricular arrhythmia called Torsade de Pointes (TdP). These models will be used by both drug developers and FDA reviewers to define the appropriate drug candidates for human use and to inform clinical trial design strategies. It is known that women are at higher risk of developing TdP than men, and so two computer models - a male and a female human heart cell - will be needed for drug-induced TdP risk prediction. The proposed project uses single-cell electrophysiology recording techniques and an animal model to generate the data needed to create a male and a female heart cell model in which drug effects can be simulated. This research will contribute to protecting and advancing women’s health by ensuring that future drug safety evaluations take into account biological differences between women and men.

Capturing Sex-Specific Data in Regulatory Submissions and National Vascular Quality Initiative Registry- Danica Marinac-Dabic, MD, PhD/CDRH (15)

Addressing the unmet medical needs for cardioprotection in women receiving chemotherapy (Supplementary funds)- Ashutosh Rao, PhD/CDER (15)

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.

Preclinical test methods for percutaneously implanted heart valves - effect of non-circular valve configuration after implantation on valve leaflet dynamics- Terry Woods, PhD/CDRH (15)

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 (Support for implementation of FDASIA Section 907 Action Plan)- Daniel Canos, PhD/CDRH (15)

A pilot study for evaluating genetic influences on sex differences of drug-induced proarrhythmia - Li Pang, MD/ NCTR (15)

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.

Ensuring accessible supply of safe and effective drugs: Quantifying women-specific pro-arrhythmia risk of drug therapies - David Strauss, MD/PhD/CDER (15)

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.

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 (14)

Blood pressure threshold for cardiovascular disease risk: an assessment of sex-based criterion - Ching Wei Chang, PhD, NCTR (14)

Novel therapeutic approaches to prevent drug-induced torsade de pointes - Norman Stockbridge, MD, PhD, CDER (14)

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 (14)

PK analysis of the samples for a study funded by CDER Critical Pathways titled, “A double-blind, randomized, placebo-controlled single-dose, five-period crossover study of the electrocardiographic effects of ranolazine, dofetilide, verapamil and quinidine in healthy subjects” – David Strauss, MD, PhD, Special Funding/CDRH (13)

Gender-Specific Predictors of Heart Failure Hospitalization and Death in Cardiac Resynchronization Therapy - David Strauss, MD, PhD, CDRH (12)

Novel Electrocardiographic Device Algorithms to Assess Cardiac Safety of Investigational Drugs - David Strauss, MD, PhD, CDRH (12)

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 (12)

Abdominal Aortic Aneurysms: analysis of patient Characteristics and Anatomy Related to EVAR treatment and outcomes- AAA CARE - Tina Morrison, PhD, CDRH (12)

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 (11)

Addressing the unmet medical needs for cardioproctection in women receiving chemotherapy – Rao, Ashutosh, CDER (11)

Preclinical Test Methods for Percutaneously Implanted Heart Valves: Effect of Non-Circular Valve Configuration After Implantation On Valve Leaflet Dynamics – Terry Woods, NCTR (11)

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 (11)

Atrial Fibrillation Ablation Registry Study  (SAFARI) - Ellen Pinnow, MPH, CDRH (10)

Assessment of outcomes and bleeding complications following implantation of drug eluting stents (DES) and dual anti-platelet therapy (DAPT) - Hesha Duggirala, Ph.D, CDRH (10)

The swan-ganz balloon flotation pulmonary artery catheter: possible racial and sex discrepancies - Daniel Canos, Ph.D,, CDRH (10)

Sex- and age- related differences in baseline QT, QT prolongation, and TdP risk - Christine Garnett, PharmD, CDER (10)

Risk of Adverse Events Following Cardiac Catheterization by Hemostasis Device Use – Phase III - Dale Tavris, MD, MPH, CDRH (10)

Analysis of sex-differences in cardiac resynchronization therapy devices: inclusion, adverse events, and outcomes - Kathryn O'Callaghan, CDRH (09)

Workshop: Guidance for the Study and Analysis of Sex Differences in the Clinical Evaluation of Cardiovascular Medical Devices - Kathryn O’Callaghan, CDRH (08)

Gender-Related Differences in QT Effects and Torsade de Pointes Potential of Drugs - Christine Garnett, PharmD/ Phillip Dinh, PhD, CDER (08)

Factors Accelerating the Progression of Heart Failure (HF) in Women: Implications for Drug Interactions with Medical Devices - Soma Kalb, PhD, CDRH (07)

Drug Eluting Stent (DES)/Thrombosis - Bram Zukerman;  Norman Stockbridge, Duke Clinical Research Institute (07)

Real-World Outcomes of Drug-Eluting Stents - Art Sedrakyan, MD, PhD, CDRH/AHRQ (07)

The Impact of Sex-Based Differences in Atherosclerotic Plaque on the Response to Drug Eluting Stent Implantation - Dinesh Patwardhan, PhD, CDRH (07)

ECG Warehouse - Mortara Instruments Inc., Justin Mortara, PhD, Mortara Instruments Inc., (06)

ECG Warehouse - Duke Clinical Research Institute and Duke University - Christopher Cabell, M.D., MHS, Duke Clinical Research Institute (DCRI) (06)

Assessment of the Accuracy of the Troponin Assay and the Diagnosis of Myocardial Infarction by Gender - Azadeh Shoaibi, PhD/ Dale Tavris, MD, MPh, CDRH (05)

Systems Biology Approach to Evaluate Sex Differences in Heart of a Rat Model - James C. Fuscoe, Ph.D., NCTR (05)

Use and Outcomes of Coronary Stents in Women: Use of a National Medicare Database - Karen Freund, MD, Boston Univ (05)

Transmission Attenuation Correction for Female Patients Undergoing Myocardial Perfusion Imaging: Correction for Confounding Breast Tissue Artifact - Michelle Dew, MD, Univ. of Arizona, (04)

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 Univ (04)

Are Women at Higher risk from Proarrhythmic Drugs? - Jogarao Gobburu, PhD, CDER (03)

Discovery and Evaluation of Interspecies Biomarkers to Monitor the Early Onset and the Progression of Cardiovascular Toxicity Associated with Thiazolidinedione Compounds Used in the Treatment of Type 2 Diabetes - Eugene Herman, PhD, CDER (03)

Cardiovascular Effects Of Ultrasound Contrast Agents in Intact and Ovariectomized Female Animals - Melvin Stratmeyer, PhD, CDRH (03)

Project Title: Electrophysiological Characterization of Several Torsadogenic Drugs in Isolated Rabbit Hearts - John Koerner, PhD, CDER (03)

Incidence and attributable risk of serious adverse events and death associated with the use of homeostasis devices by gender - Dale Tavris, MD, MPH, CDRH (02)

Women's participation in clinical drug trials for unstable angina and myocardial infarction - Ann Farrell, MD, CDER (00)

Flow studies and the use of a waveguide in cardiovascular devices - Harvey Rudolf, PhD, CDRH (98)

Ovarian steroids and cardiovascular disease: The role of gender in the effectiveness of interventional medical devices - James Karanian, PhD, CDRH (98)

Variations in the drug-induced QT interval prolongation during the menstrual cycle - Ana Szarfman, MD, PhD, Raymond L. Woosley, MD, PhD, CDER (co-funded by NIH ORWH, 98)

A comparison of gender specific utilization of implantable cardioverter defibrillator therapy and post-implantation survivability - Steven Lascher, DVM, MPH, CDRH (97)

Administration of thrombolytic therapy to women with acute myocardial infarction. Is it too late? - Emily B. Shacter, PhD, CBER (96)

Gender differences in early and long-term results of coronary angioplasty with the Palmaz/Schatz stent - Danica Marinac-Dabic, MD, CDRH (95, 96, 97)

Comparison of the beta-adrenergic antagonist actions of propranolol in men and women - David Flockhart, MD, PhD, CDER (94)

Comparison of the potassium channel blocking actions of quinidine in men and women - Raymond L. Woosley, MD, PhD, CDER (94)

Terfenadine/Oral contraceptive study - Lou Cantillina, MD, CDER (94)

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Cosmetics / Skin

Effect of Injection Techniques, Materials Chemistry and Physical Properties of Dermal Fillers on Potential for Bacterial Colonization and Infection - Kenneth Phillips. PhD, CDRH (13)

Risk Assessment of Human Skin Microflora Metabolism of Synthetic Azo Colorants used in Women’s Cosmetics - Huizhong Chen, PhD, NCTR (08)

Optimization of UV exposure patterns:  Maximizing perceived benefits while minimizing photocarcinogenic and photoaging effects, Sharon Miller, MS, CDRH (01)

Latex allergy genomics study: Developing a diagnostic gene expression microarray for Type 1 latex allergy using transcriptome profiling - Rosalie Elespuru, PhD, CDRH (01)

Birth defect potential of cosmetic products containing retinol (vitamin A) and retinyl palmitate - Jeffrey Yourick, PhD, CFSAN (00)

Evaluation of the Tg.Ac transgenic mouse as a model for predicting the photocarcinogenicity of pharmaceuticals and cosmeceuticals - Ronald Honchel, PhD, CDER (99)

Potential Exposure of Women to Estrogens, Phytoestrogens and Xenoestrogens through Cosmetic Products, Robert Bronaugh, PhD, CFSAN (99)

Cosmetics Initiatives Alpha Hydroxy Acids (AHAs), John E. Bailey, Ph.D., CFSAN (94)

AHA Literature Search, John E. Bailey, PhD, CFSAN (94)

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Device Safety

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 (16)

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.

Improving assessment of spinal device subsidence by incorporating female anatomy and density - Srinidhi Nagaraja, PhD/CDRH (16)

Patients with severe neck or low back pain are often treated with spinal medical implants such as interbody cages or total disc replacement devices. Although these are relatively successful procedures, it is possible for the device to push into the top or bottom of the vertebra. This is referred to as device subsidence. If severe, the patient may experience more pain or loss of back flexibility. This is an important issue for women’s health as many older women have neck and low back pain that may require implantation of spinal devices. It is unknown, however, if implant subsidence occurs more frequently in women because of osteoporotic changes leading to lower bone density and poorer bone quality than men. Therefore, the goal of this study is to better understand factors that put a patient at risk for implant subsidence. By using experiments and computer simulations, our goal is to develop a method that can better predict if this adverse event may occur when a spinal device is used to treat these patients.

Development of the US Women's Health Coordinated Registries Network- Nilsa Loyo-Berrios, PhD, Special Funding/CDRH (16)

Background: Historically, scientific questions that uniquely affect women (e.g. pelvic floor disorders, uterine fibroids, female sterilization) have been evaluated in stand‐alone studies. When targeted registries were created, linkage to other data sources was not possible, missing the opportunity to create infrastructure to advance women’s health in the continuum of routine clinical practice. Therefore, we propose to create a “Coordinated Registries Network” (CRN), which will serve as the national infrastructure for the evaluation of medical devices in clinical areas unique to women. Specific objectives: to, (1) establish a Public‐Private‐Partnership (PPP) with stakeholders; (2) identify/prioritize clinical conditions and devices unique to women; (3) convene an “Expert Core Working Group”; (4) establish convener group within MDEPINet; (5) hold stakeholders workshops at FDA Campus; (6) create a robust consortium of registries that can incorporate IDE and postmarket mandated studies into their infrastructure. Methods: Key stakeholders will be identified and invited to join the Expert Core Working Group, which will be charged with: (1) identification of clinical conditions and device areas to prioritize, (2) evaluation of existing efforts and models that can be applied in the realm of women specific devices/health issues, and (3) selection of the convener group within MDEpiNet. The convener group will coordinate CRNs work per identified priority areas, and will develop the business and sustainability model. CRNs will allow for data involving diagnostic and treatment modalities to be captured in a “Suite” of registries. The individual registries would operate under the auspices of health care professional societies (e.g. ACOG, AUGS, ASPS, etc.), ideally sharing a common platform, analytical and support infrastructure, while maintaining the flexibility necessary to address specific questions unique to the clinical conditions covered by the respective registries. The infrastructure will also incorporate premarket (IDE) and postmarket mandated studies, which will limit startup costs and implementation time of clinical trials as well as review time for FDA to evaluate premarket applications or postmarket submissions. FDA has preliminarily identified the following areas of concern: uterine fibroids, abnormal uterine bleeding (non‐fibroid related), contraception methods, stress and urge urinary incontinence, fecal incontinence, pelvic organ prolapse, urinary retention, outcomes for breast implants, cosmetic surgery, obesity, infertility, reproductive cancer detection and treatment, labor and delivery, pregnancy and postpartum, menstruation, sexual function, and TMJ disorders. Collaboration has already begun with the COMPARE‐UF Registry, and discussions have taken place to adapt the registry for collection of data on medical devices used during treatment of uterine fibroids.

Advancing Methods for Assessment and Prediction of Clinical Performance of High Intensity Therapeutic Ultrasound Systems- Keith Wear, PhD, Special Funding/CDRH (16)

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.

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 (15)

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.

The effects of gender differences in adverse events for integrated fixation spinal implants - Srinidhi Nagaraja, PhD/CDRH (15)

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.

Sex-specific modeling and analysis of ACL injury susceptibility- James Coburn/CDRH (15)

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.

Identifying and characterizing key mechanical characteristics of surgical meshes used for pelvic organ prolapse repair and treatment of stress urinary incontinence in women (Supplementary Funds) - Terry Woods, PhD/CDRH(15)

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.

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, PhD, CDRH (14)

Mechanical causes of higher hip implant failure rates in women - James Coburn, MS, CDRH (13)

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 (13)

TREAT Registry: Women's Health Safe PCI Study: Bleeding Risk and Transradial Catheterization - Bram Zuckerman, MD, Katie O’Callaghan, Special funding/CDRH (11)

Sex-based differences in the molecular mechanisms of polymer degradation in drug eluting stents (DES) - Rallabhandi, Prasad, PhD, CDRH (11)

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 (11)

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, CNM, PhD, CDRH (10)

Sex-based differences in the safety of drug-eluting stents containing bioresorbable materials - Dinesh Patwardhan, PhD, CDRH (09)

Quality of life and significant symptoms after LASIK - Malvina Eydelman, MD, CDRH (09)

The Safety and Effectiveness of Surgical Mesh Implant Use in Uro-Gynecologic Surgery for Soft Tissue Augmentation - Cara Krulewitch, CNM, PhD, CDRH (08)

Gender Differential in National Estimates for Medical Device-Associated Adverse Events (MDAEs) from Emergency Departments - Cunlin Wang, MD, PhD, CDRH (08)

Active postmarketing surveillance methods: hospital pilot - Roselie Bright, ScD, CDRH (99)

Epidemiology of medical devices in women - Danica Marinac-Dabic, MD, CDRH (97)

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Diet / Obesity

Review of herbal weight loss product experiences and adverse events - Sara Warber, MD, Univ. of Michigan (00)

Breast cancer in African-American women: Metabolic modification of dietary and hormonal risk factors - Christine Ambrosone, PhD, NCTR (97)

Obesity: Its effect on antioxicant and estrogen metabolism - Shirley Blakely, PhD, CFSAN (97)

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Dietary Supplement / Safety

Hepatotoxicity database for herbal/dietary supplements - Weida Tong, PhD/NCTR (16)

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.

Detection of synthetic drugs as adulterants in natural and herbal slimming products by UPLC-mass spectrometry - Phyllis Wilson, PhD, ORA (14)

Effects of phytoestrogens on gene expression responses of vaginal epithelial cells after contact with candida albicans - R. Doug Wagner, PhD, NCTR (10)

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, PhD, CDER (09)

Understanding Consumer Behavior Associated with Changing Messages on Listeria monocytogenes and Food Safety - Elizabeth Calvey, PhD/ Marjorie Davidson, PhD, CFSAN (07)

Phytoestrogens: Drug interaction potential in women - Gail Anderson, PhD, Univ. of Washington (00)

Use and interaction of dietary supplements in the SEA Trial - Mara Vitolins, DrPH, Wake Forest Univ. (00)

The effects of St Johns Wort on the efficacy of oral contraception - Stephen Hall, PhD, Indiana University (00)

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 Univ. (00)

Pattern of botanical dietary supplement usage in menopausal women - Gail Mahady, PhD, Univ. of Illinois at Chicago (00)

Contaminants in dietary supplements frequently used in women - Nancy Slifman, MD, MPH, CFSAN (98)

Vitamin K status of non-Hispanic balck 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 II - Mona Calvo, PhD, CFSAN (97)

Women’s Health Information Line, Ruth Welch, MS, CFSAN (96)

CFSAN’s Women’s Health Internet Initiative: Phase II, Kenneth T. Durham, CFSAN (96)

CFSAN’s Women’s Health Internet Initiative - Phase I, Kenneth T. Durham, CFSAN (95)

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Feminine Hygiene

Drug-delivery nanoparticle immunological effects on induction of pro-inflammatory responses to Candida albicans in mice - Doug Wagner, PhD/NCTR (16)

Delivery of drugs to women by direct application to the vaginal tract may be improved by use of very small chemical structures called nanoparticles. In previous research, we have found that certain dissolving drug-delivery nanoparticles are toxic to vaginal cells and cause the cells to recruit inflammation. When the same material is used in medical devices larger than 1 micrometer in size inserted into the body, it is not toxic. These drug-delivery nanoparticles may be used to provide medicines into a women’s vaginal tract when she has a yeast infection. Vaginal yeast infections often cause inflammation. We propose to conduct experiments in a mouse model of inflammatory vaginal yeast infections to determine whether the nanoparticles make the inflammation during yeast infections worse. This will provide important knowledge for FDA to make regulatory decisions regarding when it will be appropriate to use these kinds of drug-delivery nanoparticles. In the experiments, mice will be given vaginal yeast infections by an established method and given nanoparticles into their vaginal tracts at doses similar to those that would be used to treat women with drugs, such as those that prevent viral infections. We will measure the damage to DNA and cellular machinery of the vaginal tissue by the nanoparticles as well as the inflammation that occurs with or without yeast infections. We will also determine whether the nanoparticles cause the yeast infections to spread into the body. Vaginal drug delivery in nanoparticles is a promising new technology to improve women’s health, but the risks of their use during a common yeast infection have not been determined. This project will allow us a better understanding of those risks.

Evaluating the migration and toxic potential of silver nanoparticles in feminine hygiene products into vaginal tissue: In vivo rodent and human in vitro 3D mucosal models - Yongbin Zhang, DVM, PhD/NCTR (16)

There is increasing manufacturing and market interest in the development of more effective feminine hygiene products. These developments are usually based on improvements in manufacture or fiber/polymer technology, and lately, the ability to manufacture nanoscale materials that reportedly have bacteriostatic/bactericidal properties. Some feminine hygiene products (e.g. cleansers and pads) currently available on the market claim to include nanoscale silver. Nanomaterials in feminine hygiene products potentially could migrate into vaginal tissue and become a hazard to the consumer. A key challenge for biomedical research on nanomaterials is understanding the biological fate of nanomaterials (where do the materials go; do they have any effect) and the cumulative risk following daily use/exposure (does the effect accumulate/increase with continued use; does the material and effect go away when use stops). This study will use both in vitro cell culture and a rodent model to examine the penetration/permeation of different species of silver (nanoparticles, nanoparticle agglomerates, and silver ions) into vaginal mucosal tissue. In addition the toxic potential of the silver species will be examined on vaginal mucosal tissue and the microbiota found in the vaginal environment. This project takes advantage of the outstanding facilities available at the collaborating laboratories, and the NCTR-ORA Nanotechnology Core Facility at FDA’s Jefferson Laboratories campus.

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, PhD, NCTR (14)

Nanoparticle Effects on Induction of Pro-inflammatory Responses to Candida albicans by Cultured Vaginal Epithelial Cells - Robert Wagner, PhD, NCTR (13)

Detection of Nanoscale Materials in Products Targeted to Women: Feminine Hygiene Products and Dietary Supplements - Linder Sean, PhD, ORA (11)

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, PhD, NCTR (09)

Development of a Rapid Version of the Tampon Test Method Based on 21CFR801.430 - Lesley Kerr, ORA (07)

Protective effect of vaginal Lactobacillus species against Staphylococcus Aureus-mediated toxic shock syndrome - Christopher Elkins, PhD, NCTR (06)

Analysis of Dioxins/Furnas Levels in Tampons - Jeff Archer, PhD, ORA (00)

Vaginal volume: optimizing vaginal deployment of topical microbicides - Debra Birnkrant, MD, CDER (00)

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HIV / Sexually Transmitted Disease

Bacteria and virus migration through latex condoms in the presence of personal lubricants - Srilekha Das, PhD/CDRH (16)

In the 1990s, studies were undertaken in CDRH to address the critical public health concern related to the possibility of passage of pathogenic viruses, such as HIV, hepatitis virus, and human papilloma virus, through natural rubber latex condoms. To more easily conduct the experiments, a bacteriophage, ΦX 174, of similar size and shape to the pathogenic viruses was used as a non-pathogenic test surrogate. Results of this investigation confirmed the effectiveness of intact condoms in preventing the passage of small molecules and thus, protecting consumers from sexually transmitted infections (STI). As a result, a modified version of the method was introduced in FDA guidance and an ISO standard. This method, however, did not account for the presence of personal lubricants that are often used in conjunction with condoms. Over–the–counter personal lubricants are comprised of an assortment of various chemicals; major components are usually water, glycerol, sorbitol, polyethylene or poly propylene glycol, and silicone oils, and also include a number of minor chemical components for smell, taste, and color. The presence of a personal lubricant may promote the transmission rate of small biological molecules through the thin layer of a condom by either increasing the pore size in the condom material or increasing the chemical affinity of the molecule in the external environment. In this investigation, we plan to determine if the presence of personal lubricants that may swell the latex material and change its elasticity by relaxing the polymer network, change the permeability of the membrane to ΦX 174, as well as of two of the smallest known pleomorphic (capable of changing shape) bacteria, Ureaplasma urealyticum and Mycoplasma hominis, compromising the ability of the condom to prevent transmission of STI.

Evaluation of HSV-2 co-infection and hormonal contraceptive use on HIV acquisition and pathogenesis using patient-derived clinical specimens - Indira Hewlett, PhD, CBER (13)

Women in HIV trials: a comprehensive review and meta-analysis for safety - Guoxing Soon, PhD, CDER (10)

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, PhD, CBER (09)

Effects of B-Estradiol, on the Safety of Anti-HIV Drugs - Andrew Dayton, PhD, CBER (08)

Evaluation of gender differences in detection, replication and transmissibility of emerging HIV-1 Variants - Indira Hewlett, PhD, CBER (07)

Molecular mechanisms underlying gender-associated differences in the adverse reactions to the anti-retroviral agent, zidovudine (AZT): Role of mitochondrial toxicity - Varsha Desai, PhD, NCTR (06)

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. and Surender Khurana, Ph.D, CBER (06)

Sex difference dependent drug-drug interactions of anti-HIV therapeutics - Hyojong Kwon, PhD, CDER (05)

Gender Dimorphism in HIV Infection in Primary Macrophages and T-Lymphocytes: Kinetics of HIV Replication and Efficacy of Antiretroviral Agents - Andrew Dayton, PhD, CBER (04)

Thymic regeneration and immune reconstitution: Development of animal models to study the role of cytokines and hormonal contributions - Hana Golding, PhD, CBER (01)

Vaginal volume: optimizing vaginal deployment of topical microbicides-- Debra Birnkrant, MD, CDER (00)

Effect of reproductive hormones on the pathogenesis and host cell interactions of Neisseria gonorrhoeae - Carolyn Deal, PhD, CBER (99)

Antigenic characteristics and immunogenicity of synthetic peptide vaccines for the pathogenic Neisseria: Neisseria meningitides and Neisseria gonorrhea - Margaret Bash, MD, MPH, CBER (97, 98, 99)

The role of HIV-1 co-receptors in sexual and mother-to-infant transmission - Hana Golding, PhD, CBER (97, 98)

A computer model for simulating virus transport through barriers - Matthew R. Myers, PhD, CDRH (96)

Human cytotoxic T lymphocyte recognition of Papilloma virus - Penelope Robbins, PhD, CBER (96)

Induction of mucosal immunity to protect females from HIV-1 - Basil Golding, MD, CBER (95)

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, MD, CBER (95)

Conference on STD clinical trials workshop - NIH/OEA (94)

Prevention of sexual transmission of HIV- Michael Norcross, MD, CBER (94)

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Hormone / Endocrine Disruptors

Investigation of Drug-Drug Interactions with Hormonal Contraceptives - Chongwoo Yu, PhD, CDER (12)

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 (12)

An investigation of sexual dysfunction in depressive trials – Peiling Yang, PhD, CDER (11)

Effects of body mass index (BMI)/body weight (BW) on effectiveness of hormonal contraceptive products for women – Chongwoo Yu, PhD, CDER (11)

The Role of Estrogen in Controlling Hepatitis C Virus Replication – Deborah Taylor, CBER (11)

Quantum mechanical and NMR spectral approaches for the rapid prediction of estrogen activity of FDA regulated chemicals - Jon Wilkes, PhD, NCTR (10)

Genome wide methylation arrays for detecting markers of increased susceptibility to mammary cancer caused by in utero exposures to endocrine disruptors - Cecilia Aguila, DVM, CVM (09)

The role of estrogen in enhancing innate immunity during viral infection - Deborah Taylor, PhD, CBER (09)

Gene Expression Responses of Estrogen-Primed Vaginal Epithelial Cells After Contact With Candida albicans and Probiotic Lactobacilli - R. Doug Wagner, PhD, NCTR (08)

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, PhD, CFSAN (08)

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, PhD, CDER (08)

Development and Validation of an HPLC method for the Simultaneous Determination of Estradiol, Estriol, Estrone and Progesterone in Pharmaceutical Preparations - Phyllis Wilson, ORA (07)

The Role of Estrogen in Enhancing Innate Immunity During Viral Infection - Deborah Taylor, PhD, CBER (07)

Modulating effects of estrogen in food allergen induced lung inflammation in a highly sensitive rat model for postmenopausal women(Do Phytoestrogens Modify Asthmatic Response to Food Allergens in Newly Validated, highly sensitive, in-bred asthmatic rat mouse - Mona Calvo, PhD, Maria Lorenzo, DVM, CFSAN (04)

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, PhD, CBER (04)

Effect of Sex Hormones on the Immune response of CpG ODN - Daniela Verthelyi, PhD, CBER (02)

Evaluation of the effects of daidzein and genistein (hormone replacement agents) on the genotoxic and carcinogenic activity of the model mammary carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) in ovarectomized transgenic Big Blue rats - Anane Aidoo, PhD, NCTR (00)

Chemical characteristis of conjugated estrogens - Thomas Layloff, PhD, CDER (98)

In-vivo modeling of steroid-mediated gender effects in drug metabolism, Phase I and II - Patricia Thompson, PhD, NCTR (98)

Contribution of estrogen components to the efficacy of conjugated estrogens-preliminary analytical chemistry - John Strong, PhD, Mei-Ling Chen, PhD, CDER (97)

Development of in vitro human cell culture systems to screen compounds suspected to have estrogenic or anti-estrogen activity - William Tolleson, PhD, NCTR (97)

Experimental assessment of environmental estrogens - Dan Sheehan, PhD, NCTR (96)

Development of an estrogen knowledge base for research and regulation - Darnell Carlton Jackson, PhD, NCTR (96)

Hormone replacement therapy in women with a previous diagnosis of endometrial cancer - Bruce V. Stadel, MD, MPH, CDER (95)

Mechanism of tamoxifen development toxicity and neoplasia: Tamoxifen effects on the rat uterine insulin like growth factor system, Randal Streck, PhD/ Dan Sheehan, PhD, NCTR (95)

A novel molecular approach to risk assessment of hormonally active compounds, John Leighton, PhD, CVM (95)

Estimation of reproductive toxicity of pharmaceuticals using QSAR software programs, Edwin Matthews, PhD, CDER (95)

Effects of toremifene and ICI 182,780 on rat uterine growth and differentiation, Dan Sheehan, PhD, NCTR (94)

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Infant Feeding

Ciprofloxacin and Doxycycline in lactating women and in the elderly - Raymond Galinsky, PharmD, Indiana School of Medicine (02)

Development of a general approach for the investigation of drug transfer in breast milk: In vitro assessment of drug distribution into breast milk - Patrick McNamara PhD/ Gerald Fetterly, PhD, CDER (01)

Infant Feeding Practices Study - Sara Fein, PhD, CFSAN (94)

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Infectious Disease

Assessment of Placental Transmission of Zika Virus Glycoprotein E Immunogen - Evi Struble, PhD, Special Funding/CBER (16)

Zika virus infection has reached epidemic proportions in Latin America. Based on the geographical distribution of its mosquito carriers, it is likely that Zika virus will spread to the U.S. Zika infections during pregnancy have been associated with increased number of severe neurologic birth defects in newborn babies. Treatment with human antibodies against Zika virus may become a likely treatment option during pregnancy. Given the limited scientific data on Zika disease and treatment during pregnancy, it is very important to collect and analyze safety and efficacy data for this potential medical intervention. Toward this goal, we propose to use our expertise on placental transfer studies to investigate whether circulating non-neutralizing ZIKV antibody complexes contribute to fetal infection and the potential for interaction with pre-existing immunity to other flaviviruses. We will use monoclonal antibodies and antibodies from individuals that have recovered from the Zika infection in complex with the virus envelope protein E, the viral component that mediates both viral infection of human cells and the host immune response to the Zika virus. Experiments will be performed to evaluate whether Zika protein E/antibody complexes are required for the passage of E protein across a laboratory model of the placental barrier. In addition, we will determine if differences in antibodies produced by different recovered individuals or individuals with antibodies against other mosquito borne viruses can have an effect in the placental transfer of Zika. Our study should provide critical information on what constitutes an efficacious and safe immunoglobulin therapy during pregnancy to benefit the mother and her baby.

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Osteoporosis and Bone Health

Disease systems analysis: towards a generic framework for characterizing disease progression and treatment effects in osteoporosis - Li Li, PhD, CDER (14)

Exploring Potential Safety Issues of PPIs on Osteoporosis in Elderly Women Using the PPI Legacy Database - Zhongjun Luo, MD, PhD, CDER (12)

Assessment of Risk Factors Associated with Exposure to Proton Pump inhibitors and Fracture and CV outcomes in post-menopausal osteoporosis women - Antonio Paredes, PhD, CDER (10)

Do vertebroplasty procedures increase the risk of adjacent level vertebral fractures in osteoporotic women - Srinidhi Nagaraja, PhD, CDRH (09)

Development and Guidelines for Evaluating the Appropriateness of Vertebroplasty Surgery for Patients with Osteoporosis - Jove Graham, PhD, CDRH (04)

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, PhD, CDRH (00)

Development and validation of ultrasonic backscatter measurement for bone density assessment - Keith Wear, PhD, CDRH (98)

Application of ultrasonic tissue characterization to diagnosis of bone disease, Keith Wear, PhD, CDRH (95)

Osteoporosis Prevention in Adolescent Girls, Ruth Welch, MS, RD and Carole Schiffman, CFSAN (95)

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Pregnancy / Prevention / Exposure

Bayesian demographic subgroup analyses for pregnant women- Judy X. Li, PhD/CBER (15)

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.

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 (15)

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 pro-coagulant impurity on coagulation in plasma from pregnant women- Mikhail Ovanesov PhD/CBER (15)

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 (15)

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.

Population-based computational framework for assessing xenobiotic disposition and interaction effects in pregnant women (Supplementary Funds) - Annie Lumen, PhD/NCTR (15)

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.

Bayesian assessment of safety profiles for pregnant women-From animal study to human clinical trial - Judy X. Li, PhD, CBER (14)

Evaluation of pharmacokinetics of thrombogenic impurity following different routes of immune globulin administration during pregnancy - Mikhail Ovanesov, PhD, CBER (14)

Assessing Passive Prophylaxis of Infection at Different Stages during Gestation in a Pregnant Animal Model
- Evi Struble, PhD, CBER (13)

Applications of Clinical Pharmacology Principles in Pharcotherapy of Diseases in Pregnancy - Srikanth Nallani, Ph.D CDER (12)

Improving safety of blood products administered during pregnancy - Mikhail Ovanesov, PhD, CBER (12)

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 (12)

A Comparitive Analysis of Adverse Events Between Conventional Tube Ligation and Transcervical Occlusive Devices of the Fallopian Tube for Female Sterilization: A Cohort Study - Colin Anderson-Smits, MPH, CDRH (12)

MRI in pregnant patients: A systematic analysis of Radio-frequency heating with multi-transmit technology - Leonardo Angelone, PhD, CDRH (12)

Prophylaxis of HBV infection with HBIGIV in a pregnant animal model – Pei Zhang, MD, CBER (11)

Treatment of progressive vaccinia in a pregnant immunocompromised mouse model - Dorothy Scott, MD, CBER (10)

An analysis of safety signal detection methods for pregnancy exposure registries - Paul Schuette, PhD, CDER (10)

Applications of clinical pharmacology principles in pharmacotherapy of diseases in pregnancy - Shrikant Nallani, Ph.D, CDER (10)

Ethics roundtable: the ethics of studying drugs and biologics in pregnant women - Karen Feibus, MD, CDER (09)

The Asthma and Allergy Medications in Pregnancy Surveillance System (AAMPSS) Demonstration Project - Sandra Kweder, MD, CDER (08)

Pharmacokinetics and Pharmacodynamics of Selected Antibiotics during Pregnancy - Gloria Sarto, MD, PhD, Univ. of Wisconsin (06)

Research on the Effects of Drug Exposure in Pregnancy - Anne Trontell, MD, MPH, CDER/AHRQ (06)

Drug Use in Pregnancy - Mary Willy, PhD, CDER (06)

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, PhD, OC (06)

Drug Metabolism in Women - Stephen Hall, PhD, Indiana Univ. (04)

Pharmacokinetics of Atenolol in Lactating Women - Mary Hebert, PharmD, Univ. of Washington (04)

Developmental Toxicity of Androstenedione in Rats - Robert Sprando, PhD, CFSAN (04)

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 Univ. (03)

Characterization of the effect of androstenedione exposure on female reproductive health, fertility and the development of the F1 generation - Robert Sprando, PhD, CFSAN (02)

Pharmacokinetics and Pharmacodynamics (PK/PD) of Atenolol in Pregnancy - Mary Hebert, PharmD, Univ. of Washington (02)

Labetalol and Hypertension in Pregnancy: Pharmacokinetics and Pharmacodynamics - James Fischer, PharmD, Univ. of Illinios, Chicago (01)

The PK of Amoxicillin during Pregnancy and Postpartum - Mary Hebert, PharmD, Univ. of Washington (01)

The effects of Echinacea on cytochrome P450 enzymes and oral contraceptives - Stephan Hall, PhD/ Shiew-Mei Huang PhD, CDER (01)

Use of a Unique Animal Model to Study Placental and Milk Transfer of Enrofloxacin from the Dam to the Offspring During the Perinatal Period - Jurgen von Bredow, PhD, CVM (00)

Focus group testing of labing for tampons and barrier contraceptives - Robert Navario/S. Lori Brown, CDRH (99)

Determination of antigenic biomarkers of estrogen catechol metabolism for post-market surveillance of oral contraceptives and hormone replacement therapy - Dean W. Roberts, PhD, NCTR (99)

Teratogen Surveillance - Carolyn McCloskey, MD, CDER (98)

Accelerated aging studies of condoms/condom materials - Harvey Rudolf, PhD, CDRH (98)

Pregnancy Labeling Taskforce: Focus Group testing - Kathryn Aiken, PhD, CDER, (98, co-funded by NIH ORWH)

Development and validation of a universal water leak test method for barrier contraceptives - Leslie Kerr (Neunaber), ORA (98)

Molecular and metabolic determinants of maternal risk and progression of Down Syndrome: potential for nutritional intervention - S. Jill James, PhD, NCTR (97)

Optimization of mammography - Robert Jennings, PhD, CDRH, (97)

Screening for nervous system dysfunction in offspring of dams exposed to natural food contaminates during pregnancy - Thomas Sobotka, PhD, CFSAN (96)

Contraceptive efficacy table for uniform contraceptive label-a consumer focus group study-Part I and Part II- Paula G. Silberberg, MD, CDRH (95, 96)

The effect of Thalidomide on the pharmacokinetics of ethinyl estradiol and norethindrone - Carol B. Trapnell, MD, CBER (95)

Thalidomide: Are there gender disparities in treatment outcome and non-teratogenic adverse effects? Benda Vaughan, MD, CDER (95)

Rapid method for detection and enumeration of Listeria monocytogenes in foods - Mary L. Tortorello, PhD, CFSAN (95)

Profile of drug use in pregnancy - Sheila Weiss, PhD, CDER (95)

An open-label, randomized, crossover, feasibility study to quantify the retention of vaginally administered nonoxynol-9 (N-9) foam in premenopausal women - Carol Trapnell, MD, CDER (94)

FDA-Regulalted Products and Pregnant Women: Workshop, OWH (94)

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Sex Differences

The Effects of Gender Differences in Revision Rates for Spinal Total Disc Replacement Procedures - Srinidhi Nagaraja, PhD, CDRH (13)

Sex differences in biomarkers of kidney injury in patients with metal-on-metal hip implants - Ronald Brown, MS, CDRH (13)

Gender differences in neuronal reward circuit activation by nicotine and tobacco smoke using magnetic resonance spectroscopy - Serguei Liachenko, PhD, NCTR (12)

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 (12)

Gender effect on PK/PD of hypnotic drug: Driving impairment and dosing recommendations - Jagan Mohan Parepally, PhD, CDER (12)

Pharmacokinetics (PK) and biomarkers of the medications used to treat multiple sclerosis (MS) – any gender difference? - Wu Ta-Chen, PhD, CDER (11)

A pilot study on performing sex analysis on a vaccine database - Jingyee Kou, PhD, CBER (10)

“Sex Differences in FDA Regulated Products: Research for the Future” seminar series - Beverly Lyn-Cook, PhD, NCTR (09)

Mechanisms of Gender Differences in Aspirin Effects: Metabolizing Enzymes and Therapeutic Targets - Baitang Ning, PhD, NCTR (07)

CYP2B6 Genotype-Phenotype and the Influence of Sex and Ethnicity - Erin G. Schuetz, PhD, St. Jude’s Research Hospital (05)

Gender Differences in the Willingness to Read and Follow Patient Information - Ellen Tabak, PhD, CDER (04)

Gender effect on the assessment of bioavailability and bioequivalence in bioequalence trials - Mei Ling Chen, PhD, CDER (01)

Development and characterization of conditionally immortalized human primary hepatocyte cell lines from female and male donors- Phase I - Angela Harris, PhD, NCTR (02)

Mechanistic basis for gender-dependent differences in pharmacokinetics - Chandra Sahajwalla, PhD, CDER (99)

Gender differences in P450 activities and their implications - Shiew Mei Huang, PhD, Robert Branch, PhD, CDER (98)

Gender differences in perception of risks communicated by prescription and over-the-counter drug labels, Phase I and II - Ellen Tabak, PhD, CDER (95)

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Women in Clinical Trials

Individual patient-data meta-analysis and postmarket analysis as a method for improving data quality in demographic subgroups (Support for implementation of FDASIA Section 907 Action Plan- Daniel Canos, PhD/CDRH (15)

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.

Evaluation of gender-related clinical pharmacology information in the labelings on adverse events and outcomes - Lei Zhang, PhD, CDER (10)

Identification of Sex Differences in Adverse Outcomes for New Molecular Entities (NMEs) Approved from 2000-2002 - Yongsheng Yang, PhD, CDER (07)

Participation of Women in Clinical Trials and Gender Analysis in Original NDAs Approved 2000-2002 - Yongsheng Yang, PhD, CDER (06)

Women in HIV Trials: A comprehensive Review and Meta-analysis - Greg Soon, PhD, CDER (06)

Gender Differences and Impact of Pharmacogenomics in Rheumatoid Arthritis, Shashi Amur, PhD, CDER (06)

Impact of Gender Analysis and Pharmacogenomics on Clinical Efficacy, Safety, and Pharmacokinetics of Drugs Used for the Treatment of Alzheimer's Disease - Angela Men, PhD, CDER (06)

Statistical analysis of gender specific data from New Drug Application (NDA) submissions - Ohidul Siddiqui, PhD, CDER (06)

Evaluation of Availability and Quality of Information Available on Females Included in Mechanical device Implant Trials - Kathryn O'Callaghan, CDRH (06)

Women’s participation in clinical drug trials for unstable angina and myocardial infarction - Ann Farrell, MD, CDER (00)

FDA Scholarship in Women’s Health Program: Participation of Females in Clinical Trials and Gender Analysis of Data in Biologic Product Applications. Marion Gruber, PhD, CBER (2000)

Development and expansion of a pilot tracking system for monitoring the barriers to the enrollment of women in clinical trials, Toigo, Teresa, OC/OEA (95)

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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 (12)

The Molecular Assays and Targeted Therapies (MATT) Consortium - Ray Woosley, MD, PhD, Critical Path Institute (06)

Self-Monitoring of Blood Glucose with Finger-Tip versus AST: Effect on Long term Glycemic Control - Caroline Apovian, MD, Boston Univ (03)

Drug update in human mammary gland epithelia - Shinya Ito, MD/ Gerald Fetterly, PhD, CDER (01)

CFSAN’s Internet Initiative: Infra-structure support - Kenneth T. Durham, CFSAN (98)

Research involving human subject committee (RIHSC) - Peter Rheinstein, MD, JD, OC/OEA (95)



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