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Autoimmune diseases are a varied group of more than 80 serious, chronic illnesses that involve almost every human organ system. These diseases are characterized by dysregulation of the immune system resulting in tissue injury from immune mediated tissue destruction. For reasons not well understood, about 75 percent of autoimmune diseases occur in women, most frequently during the childbearing years.
COMPLETED PROJECTS
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)
Cytokines have been implicated as important mediators and regulators of the chronic inflammatory responses associated with SLE and RA. This project examined the possibility that cells from patients with RA or SLE respond abnormally to cytokines and that these responses could be involved in the immune dysregulation in these diseases. Peripheral blood mononuclear cells from SLE and RA patients and control individuals were assayed for activation of STAT proteins in response to a panel of cytokines. The data suggest that a majority of SLE and RA patients are unable to assemble complete STAT complexes in response to IFN-a, which may result in impaired IFN-a signaling. Defining this defect in the cytokine signaling pathway will lead to a better understanding of potential therapeutic options for the treatment of these diseases.
Hormonal regulation of cytokine producing cells in women with systemic lupus erythematosus - Dennis Klinman, MD, PhD, CBER(95)
Epidemiologic, clinical and laboratory data suggest that women generally have heightened humoral immune responsiveness, which may contribute to greater susceptibility to autoimmune diseases such as RA and SLE. Female sex hormones play an important role in this disease, yet their mechanism of action remains obscure. The effect of physiologic fluctuations in sex hormone levels on cytokine production is poorly understood. This work examined whether serum levels of estrogen, progesterone and/or dehydroepiandrosterediones (DHEAs) correlate with the activity of cells secreting pro-inflammatory, type 1 and type 2 cytokines. The results indicate that sex hormones may modulate cytokine production in vivo and contribute to gender-related differences in normal and pathologic immune response. Increasing our understanding of sex-related differences in disease mechanisms will improve science-based regulation of new treatments for autoimmune diseases.
A novel approach to the treatment of lupus nephritis - Dennis Klinman, MD, PhD, CBER(96)
SLE is characterized by the production of anti-DNA antibodies that form immune complexes that deposit in the kidneys and vascular epithelium, causing severe glomerulonephritis and vasculitis. DNAse is a recombinant biological product with potential to fragment DNA and dissolve DNA - anti-DNA immune complexes. This study examined the efficacy of DNAse therapy in a murine model of lupus. The study concluded that DNAse treatment did not improve clinical outcome. Examining the biological basis of therapies targeted toward women will aid the agency in making regulatory judgments that affect women's health.
FUTURE DIRECTIONS - FUNDING IN FY 2000
Evaluation of the Tk knockout (TkKO) mouse as a model of systemic lupus erythematosus - Vasily Dobrovolsky, PhD, NCTR (00)
SLE is an autoimmune disease with a poorly understood etiology. The hallmark of SLE is the presence of antibodies to nuclear antigens such as DNA, ribonucleoprotein, and nuclear chromatin. In the severe form, it can involve almost any tissue or organ, with the most common being skin, joints, kidney, heart, lung and the vascular system. Although no single gene has been linked clearly to the disease, there is evidence suggesting that genetic factors are involved in development of SLE. Mice deficient for the endogenous cytosolic thymidine kinase (Tk) gene were developed recently in the Division of Genetic and Reproductive Toxicology, NCTR and observed to die prematurely due to kidney failure. Microscopic abnormalities commonly observed in Tk knockout (Tk KO) mice resemble cases of advanced SLE, with kidneys and arteries affected. If Tk KO mice exhibit a lupus-like phenotype, the Tk deficiency could be linked to onset and/or progression of the disease. In the project funded by OWH, the Tk-deficient mouse phenotype will be studied in greater detail to determine if the Tk KO mouse could be used as an animal model for SLE, and if so, to assess the role of Tk in the disease etiology. The outcome of this project may result in a better understanding of the etiology of SLE, and suggest novel methods for the diagnosis and treatment of SLE.
Breast implants have been marketed since the early 1960's before medical device laws were enacted, charging FDA with their regulation. Every year, thousands of women have implant surgery for augmentation or reconstruction following mastectomy. Concerns over potential negative health effects of chronic exposure to silicone breast implants present an important post-market surveillance issue for the FDA.
COMPLETED PROJECTS
Mechanism of immunotoxicity and carcinogenicity associated with silicone breast implants - S. Jill James, PhD, NCTR(95)
Controversy over silicone breast implants has raised questions regarding the potential carcinogenicity of lifetime tissue exposure to silicone products. This study was designed to determine whether the inflammatory and fibrotic reactions associated with silicone implants are due to a nonspecific foreign-body reaction or whether these responses reflect the chemical composition of silicone. The data suggest that the surface morphology of the implant determines the nature of the cellular response that may predispose to tumor development. These results can assist the agency in regulatory decisions regarding the potential carcinogenic risk of chronic implant exposure.
Development of a safe, economical assay for silicone containment in blood and tissue - Marwood N. Ediger, PhD, CDRH(96)
Although the impact of silicone leakage is subject to debate, the integrity of implants is of great concern to the FDA. Inconsistency in the published rupture rates can be attributed to the lack of a reliable method for detection and quantification of silicone leakage. This project completed preliminary work on a quantification method for the detection of silicone in blood and tissues, which is economical, safe, and nondestructive. The results of this work has been recommended by the Office of Technology Transfer for submission to the patent process. In addition, collaborations with National Institutes of Health (NIH) have been initiated to expand the utility of this technology.
Silicone Gel Alternatives Workshop - John Langone, PhD, CDRH(94)
This scientific workshop sponsored by CDRH explored the alternatives to silicone gel for use in breast implants. It was designed to provide a forum for the FDA to gather information prior to drafting regulations on testing requirements for alternative breast prostheses. In addition, the workshop, which was held on October 21, 1994 in Washington, D.C., included discussion and information exchange by FDA-invited scientific authorities.
*Protocol for a study of breast implant rupture - S. Lori Brown, MD, CDRH (97)
It has been estimated that by 1993, 1.3 million women in the US had undergone mammoplasty, the majority with silicone gel-filled breast implants. Because of the large number of women exposed to silicone gel breast implants, the failure of the device by rupture is a major concern. This study included an interview questionnaire on the history of breast surgeries after implantation in women with silicone gel breast implants initially implanted prior to 1988. Available medical records detailing the surgeries were collected for women who consented to medical record retrieval. If there were no contraindications for Magnetic Resonance Imaging (MRI), women were invited to participate in the MRI portion of the study until all of the appointments for MRI were full. Of the 907 women who responded to the interview, 344 had MRI examination of their silicone gel breast implants. Radiologists reviewed the results of the MRI examination and rated the implants as having no evidence of rupture, being indeterminate for rupture, or ruptured. One third of the women responding to the interview (303/907) reported having at least one additional surgery after implantation to remove their original silicone gel breast implant. The most common reason given for surgery was because of local complications, especially suspected implant rupture, pain related to implant, and capsular contracture. A majority of women (69%) undergoing MRI examination had at least one implant rated as ruptured. Fifty-five percent of implants in this study were rated as ruptured and silicone gel was observed outside of the fibrous capsule in 21% of women. Factors influencing implant rupture were advancing implant age, implant location (submuscular vs. subglandular) with submuscular implants more likely to be ruptured, and implant manufacturer.*
*A study of safety of silicone breast implants - IOM study, CDRH(97)
The Institute of Medicine (IOM) conducted an exhaustive literature review, published in June of 1999, on the safety of silicone gel breast implants and concluded that Connective Tissue Disease is no more common in women with silicone gel breast implants than in women without implants. The IOM also found that there was no increase in the occurrence of primary or recurrent breast cancer in women with breast implants. The IOM concluded that resurgery and local complications, including implant rupture, capsular contracture, infection and pain, are frequent enough to be a cause for concern and to justify the conclusion that they are the primary safety issue with silicone gel breast implants.
ONGOING PROJECTS
Immunogenetic risk factors for silicone-associated multiple myeloma and monoclonal gammopathy of undetermined significance - Frederick Miller, MD, PhD, CBER(94,98)Based on animal models of silicone-induced plasmocytomas, this research study seeks to answer the question, "Is there a genetic predisposition to silicone-associated multiple myeloma (malignant tumors of the bone marrow)?" CBER scientists continue to examine the clinical and genetic differences among three sets of women: a control group of healthy women with silicone breast implants, women with silicone breast implants who later develop multiple myeloma, and women without implants with multiple myeloma.
Noninvasive assessment of silicone migration from gel-filled breast implants - Kyle Myers, PhD, CDRH(95)
For the last three decades, silicone gel has been widely used in breast implants. Because of the phagocytic function of the liver's Kupffer cell filtration system, one might expect that any migrating silicone that enters the blood stream from breast implants might be detectable in the liver. While many investigators have studied the question of the relationship between silicone implants and disease, none have had the opportunity to quantify the amount of silicone that has migrated to distant organs for use as a measure of overall exposure to silicone in their analysis. The primary purpose of this study was develop a new magnetic resonance spectroscopy method for detecting the presence of silicone compounds in the liver. A secondary objective was determine the mean levels of silicone in the livers of women with silicone gel-filled breast implants with and without rheumatic symptoms.
Abrasion testing of breast implants - Patricia Dubill, PhD, CDRH(98)
Abrasive degradation of breast implants is believed to be a contributing factor for many of the reports of ruptures, tissue reactions, and other problems received by FDA for these devices. Abrasive wear is believed to weaken the implant shell, making it more susceptible to rupture, and can also release small particles of silicone elastomers into the body, causing adverse tissue reactions. Given that many women undergoing mammoplasty have long life expectancies, breast implant durability, including abrasion resistance, is a significant concern. A relatively new agency guidance requires manufacturers of breast implants to submit abrasion resistance data to obtain premarket approval of their products. Evaluation and comparison of abrasion data from different manufacturers is difficult due to the current lack of finalized and acceptable standards. This project aims to develop new methods for evaluating the safety and effectiveness of breast implants as well facilitate the development of standards for abrasion resistance.
Breast cancer is the most frequently diagnosed non-skin cancer in women in the US, afflicting more than 180,000 individuals per year. More than 46,000 women die from breast cancer each year, making it second only to lung cancer in cancer-related deaths. The lifetime risk for developing breast cancer is now 1 in 8 women-significantly increased from the 1 in 20 risk just two decades ago. Early detection and availability of effective treatments are crucial for successfully combating this disease.
COMPLETED PROJECTS
DNA adducts of tamoxifen - Frederick A. Beland, PhD, NCTR(96,99)
The nonsteroidal antiestrogen tamoxifen, currently approved as a chemoprotective agent for women with breast cancer, has also been shown to induce cancer. To determine if tamoxifen is acting through a genotoxic mechanism, DNA adducts of suspected tamoxifen metabolites were analyzed. In rat liver, two major DNA adducts formed. One adduct appears to arise from alpha-hydroxy-tamoxifen, while the other is due to demethylated alpha-hydroxy-tamoxifen. These data suggest that tamoxifen can be metabolized to compounds that interact with DNA. The interaction with DNA may play a role in the carcinogenic action of tamoxifen.
IP-10: A potential new therapeutic for breast cancer - Giovanna Tosato, MD, CBER
The dependence of solid tumors on neovascularization for growth in vivo provides and opportunity for therapeutic intervention. This study examined the therapeutic potential of the a-chemokine IP-10 as a novel anti-cancer agent for the treatment of breast cancer. The results demonstrated that IP-10 failed to significantly affect breast tumor growth against human Burkitt lymphoma in a mouse model. Additional research will be conducted to elucidate why IP-10 did not display an antitumor effect against experimental breast adenocarcinoma. Understanding potential new treatments provides the agency with the scientific knowledge needed to effectively regulate new products.
Breast cancer in African-American women: Metabolic modification of dietary and hormonal risk factors - Christine B. Ambrosone, PhD, NCTR(97)
Despite a concentrated focus on determining the etiology of breast cancer, little progress has been made in identification of modifiable risk factors, especially for medically-underserved rural and urban African-American women. Racial disparities in incidence could be related to greater exposure to some carcinogenic factors, variability in response to agents, as well as differences in hormonal metabolism. Research regarding breast cancer in African-American women may be hampered by a growing difficulty in recruitment of participants into research studies. Using a novel approach for enrolling minority women into research studies, the effects of genetic variability in hormone metabolism and the role of dietary sources of heterocyclic amines on breast cancer risk in African American women will be evaluated in this study. With OWH funds, the investigator has developed the infrastructure needed to get this study into the field and enrollment has begun. Additional funds from the Department of Defense will allow the investigators to complete this project over the next 2.5 years.
Mechanism of tamoxifen development toxicity and neoplasia: Tamoxifen effects on the rat uterine insulin like growth factor system- Randal Streck, PhD, NCTR(95)
Estrogens are developmental toxicants and tumor promoters in animals and humans. Tamoxifen (TAM) has developmental toxicity in the uterus as a result of estrogen agonist activity and it is hypothesized that TAM agonist activity causes endometrial adenocarcinoma. The insulin-like growth factor (IGF) system is comprised of several IGFs, IGF binding proteins and IGF receptors. The IGF system is thought to mediate some uterine agonist actions of estrogens. TAM acts as an estrogen agonist for IGF system responses. The goal of this project is to examine the effects of developmental TAM treatment on 1GF responses in the rat uterus. This information can be utilized to assess the potential risk to the human fetus of exposure to tamoxifen and other antiestrogens.
Effects of Toremifene and ICI 182,780 on rat uterine growth - Dan Sheehan, PhD, NCTR(94)
Estrogens and antiestrogens cause uterine abnormalities when administered during development. To help define the mechanism by which antiestrogens cause developmental toxicity in the uterus, toremifene and ICI 182,780 were tested in a developing rat uterus model. Toremifene, an antiestrogen developed to treat breast cancer, displays both estrogen agonistic and antagonistic activity. ICI 182 876 is a pure estrogen antagonist. Toremifene was administered to neonatal rats are various time periods and the effect on uterine growth and differentiation was examined. Toremifene induce uterine weight gain in all time periods indicating that it is a partial estrogen agonist. Toremifene also caused the induction of luminal and glandular epithelium indicating full estrogen agonist activity. The effect of toremifene on uterine glandular genesis did not persist to postnatal day 26. These results show that toremifene can induce abnormal uterine development in the rat and could cause developmental abnormalities in humans if in utero exposure occur. When ICI 182,780 was administered to female neonatal rats, uterine weight was decreased in a dose-dependent manner and decreased the estrogen receptor content of uterine cells. These results show that ICI 182,780 blocks uterine growth stimulated by endogenous estrogens. There was no effect of ICI 182,780 on either uterine luminal epithelium hypertrophy or gland genesis. ICI 187,780 also and blocked tamoxifen-induced uterine developmental changes. This finding suggests that the induction of uterine growth by tamoxifen is due to tamoxifen's estrogenic activity.
Development of Mammography Quality Standards Act (MQSA) Speaker Kits - Carol Sierka, CDRH(94)
The MQSA is a law implemented by FDA which is intended to ensure all women receive uniform quality mammography services. A total of 125 speaker kits were produced for use by the Division of Mammography Quality and Radiation Programs, FDA field personnel, and State radiation control personnel to educate government and facility personnel, as well as other interested groups and organizations about MQSA. The text explains MQSA requirements, as well as FDA's programs and policies for mammography facility accreditation and inspection.
Mammography quality standards act facilities workshop - Barbara Ward-Groves, MPH, ORA(95)
This program involved five grassroots, workshops on FDA's requirements for compliance with the MQSA, which is designed to bring all mammography facilities nationwide up to standards for equipment, personnel, quality control, and record keeping. The workshops were held in locations throughout the country. These workshops included presentations by staff from the FDA division responsible for implementation of MQSA as well as by staff from FDA approved accreditation bodies and the attendees are mammography facility personnel and inspectors. The projected resulted in a better understanding of MQSA and its implementation with improved compliance. All of this should ultimately enhance the quality of the mammogram a woman receives. Recipient of a Hammer Award.
Mammography breast cancer screening rates among disadvantaged women within a prepaid health care system - Rosalie Bright, ScD, CDRH(97)
Under-utilization of breast cancer screening by women in low socioeconomic strata has been thought to contribute to the differing breast cancer rates for women across socioeconomic levels. By utilizing a database from a Medicare Managed Care Organization, this study evaluated whether rates of mammography utilization vary by factors other than direct expense to patients such as age, race, health status, socioeconomic status, and health service structure. The results indicated that age was the most powerful and consistent predictor of mammography utilization, and that race and health service structure also correlated with utilization. Obtaining information on mammography utilization rates in different demographic groups will allow FDA to efficiently target information to groups with the most need.
ONGOING PROJECTS
Improve the efficacy of chemotherapeutic drugs for the treatment of breast cancer - Emily Shacter, PhD, CBER(98)
Most chemotherapy drugs are thought to kill tumor cells by inducing a form of cell death called apoptosis. Agents which interfere with the ability of an antineoplastic agent to induce this type of cell death may limit drug efficacy and exacerbate the side effects of treatment. Preliminary studies on lymphoma cells indicate that the presence of the oxidant hydrogen peroxide interferes with apoptosis. The goal of this work is to test the hypothesis that oxidants can interfere with chemotherapy for breast cancer. If this is correct, then the possibility may exist that treatment could be improved and adverse side effects reduced by co-administration of antioxidant compounds such as vitamins C and E.
*Optimization of mammography - Robert Jennings, PhD, CDRH(97)
A mammographic system design with substantially reduce the amount of radiation delivered to the patient has been developed by the Department of Aerospace Engineering at the University of Southern California working in conjunction with FDA staff from the CDRH. The goals of this project are to make some improvements to the computerized system and perform a clinical evaluation of the design. Preliminary evaluation of the design in FDA X-ray laboratories has confirmed that the new design can reduce radiation dose to the patient by more than a factor of three. Recent work has shown that the system can also produce mammograms of improved quality at dose levels comparable to current clinical practice. The increase efficiency of the new design offers benefits for all women undergoing mammography, especially for women with dense, difficult-to-examine breasts.
For women age 25-74, the leading cause of death is cancer. Although breast cancer tends to be the most common cancer concern among women, other cancers substantially contribute to female mortality in the US. For example, since 1987, more women died from lung cancer than breast cancer. The risk of developing various other cancers significantly increases after menopause. Cases of endometrial cancer are rising among women older than 50, and one woman in 65 will develop ovarian cancer before the age of 85.
COMPLETED PROJECTS
In Vitro prediction of time to neutropenic nadir: anti-neoplastic alkylating agents as prototype drugs - Donna A. Volpe, PhD, CDER(96)
Drug-induced bone marrow suppression is a frequent occurrence in cancer chemotherapy that limits the effectiveness of available treatments due to dose reductions and increased periods between courses. This project aimed to develop a battery of hematopoietic clonal assays that could preclinically predict whether an antineoplastic agent would be myelosuppressive, including the severity and time of onset. This information could then be used to predict myelosuppression of a treatment and aid in determining an appropriate starting dose, escalation scheme, and time between cycles. The data demonstrated that the assay scheme was not predictive for all the drugs tested. Additional studies are needed.
The Transfer of Defense, Intelligence and Space Technologies for the Early Detection and Control of Cancers in Women - Melvyn Greberman, MD, MPH, CDRH (conference, 96)
PHS Office on Women's Health, FDA, and National Cancer Institute (NCI) planned a collaborative workshop that reviewed defense, intelligence and space technologies that were being evaluated for clinical utility in the early detection and control of cancers in women. This program initiative sponsored the technology transfer section of the workshop that addressed FDA/CDRH regulatory requirements related to the introduction of safe and effective medical devices. The program and follow-up actions facilitated the product review process and scientific knowledge base of FDA staff.
Hormone replacement therapy in women with a previous diagnosis of endometrial cancer - Bruce V. Stadel, MD, CDER(95)
Hormone replacement therapy (HRT) is a high priority issue in the area of women's health primarily because a large number of studies have found HRT to be associated with a substantially decreased risk of coronary heart disease (CHD), which is the leading cause of death for U.S. women. The primary goals of this project are to investigate the extent to which HRT is being used by women who have a previous diagnosis of endometrial cancer, and to determine the frequency and severity of menopausal vasomotor symptoms among these women. Project terminated due to contract difficulties.
ONGOING PROJECTS
Improving the evaluation of ovarian cancer treatment - Vance Berger, PhD - CBER (99)
Ovarian cancer is potentially one of the most treatable gynecological malignancies since most tumors are sensitive to anticancer therapy. However, due to difficulties in detecting the disease in the population most at risk, most women present with advanced or disseminated disease. This causes ovarian cancer to be the leading cause of death among women with gynecological malignancies. Consequently, there is an urgent need for effective treatments for ovarian cancer. One approach to accelerating the drug development process is to derive innovative analyses that permit smaller trials to have a reasonable chance for success. The goal of this project is to develop and evaluate new and underutilized biostatistical methods to evaluate the safety and efficacy of new medical interventions for ovarian cancer in smaller clinical studies.
COMPLETED PROJECTS
CFSAN: Cosmetics initiatives: Alpha hydroxy acids (AHAs) - John E. Bailey(94)
The FDA is interested in learning if there are public health issues that need to be addressed in the cosmetics area. Sustained by the quest for a youthful appearance, the use of AHAs in skin care products has dramatically grown throughout the last decade. These products claim to reduce wrinkles, spots, and other signs of aging. In spite of the claims made regarding substantial changes in skin, there is little information about their short- and long-term effects. The CFSAN conducted two double blind clinical trials to assess the effects of topically applied AHA on the skin's sensitivity to ultraviolet radiation. The data suggest that the use of AHAs in cosmetic formulations can lead to increased sensitivity to UV, but is reversible when application of the AHA is discontinued. This information will assist FDA in developing appropriate policies related to AHAs in cosmetics.
CFSAN: AHA literature search - John E. Bailey(94)
AHAs have become among the most popular ingredients in skin care products. However, the long-term safety of AHA products has not been thoroughly established. The lack of well-controlled, published studies of long-term safety has been recognized by both the technical and popular press. The purpose of this project is to review and analyze the scientific and patent literature obtained by a thorough search, as well as internal company reports provided to the FDA by the Cosmetic Ingredient Review (CIR) and the Cosmetic, Toiletries and Fragrance Association (CTFA). Results of all papers and unpublished reports that contained relevant data are presented along with the author's major conclusions.
The analysis addressed two questions:
Are the AHA products sold at retail to consumers for home use safe for both short-term and repeated or long-term use?
What are the effects of AHAs on the structure or physiology of the skin?
Overall, the review concluded that there was a paucity of data available, particularly regarding long-term effects.
ONGOING PROJECTS
Investigation of the potential enhanced exposures of women to estrogens, phytoestrogens, and xenoestrogens through cosmetic products - Robert Bronaugh, PhD, CFSAN (99)
Evidence is accumulating that people are being exposed to chemicals with estrogenic activity by use of consumer products and from contact with chemicals in the environment. This exposure has unique consequences for women since intake of chemicals with estrogenic activity (xenoestrogens) has been tentatively linked to increased incidences of breast cancer and endometriosis. The Office of Cosmetics and Colors has received adverse reaction reports concerning cosmetic products labeled to contain estrogenic hormone constituents or placental extract. Other products are known to contain phytoestrogens extracted from plants such as the wild yam. In vivo and in vitro studies are proposed to examine cosmetic products and raw ingredients for estrogenic activity.
Traditionally, dietary supplements referred to products made of one or more of the essential nutrients, such as vitamins and minerals. But the 1994 Dietary Supplement Health and Education Act, or DSHEA, broadens that definition to include, with some exceptions, any product intended for ingestion as a supplement to the diet. This includes such items as: vitamins, minerals, herbs, botanicals, and amino acids. Under DSHEA, FDA has regulatory authority over dietary supplements, although FDA's requirements for premarket review of dietary supplements is less than that over other products it regulates. Dietary supplements come in many forms, and a variety of products are marketed toward women for PMS, menopause, and osteoporosis, to name a few. According to one market research firm (Packaged Facts Inc.), in 1996 alone, consumers spent more than $6.5 billion on dietary supplements.
ONGOING PROJECTS
Contaminants in dietary supplements frequently used in women - Nancy Slifman, MD, MPH, CFSAN(98,99)
Based on the potential for botanical products to become contaminated with heavy metals, an evaluation of the lead and cadmium levels in botanical products marketed to women will be conducted. If measured levels are unacceptably high, specific regulatory activities may be initiated in an effort to limit future adverse events.
COMPLETED PROJECTS
Epidemiology of medical devices in women - Danica Marinac-Dabic, MD, CDRH (conference, 97)
As medical technologies advance, the use of medical devices and related procedures is expanding dramatically, and women in particular are increasingly exposed to medical devices. The purpose of the workshop was to foster communication between government agencies, manufacturers of medical devices, the medical community, epidemiologic community, and academia. Approximately 200 people attended the two-day event which featured oral and poster presentations related to topics on general device epidemiology related to women's health, unique methodological issues used in studying medical devices, and evaluation of gender influences on the performance of devices. The presentations were submitted as a Supplement to the journal Epidemiology and are currently being peer reviewed.
ESTROGENS/ANTI-ESTROGENS
COMPLETED PROJECTS
A novel molecular approach to risk assessment of hormonally active compounds - John K. Leighton, PhD, CVM(95)
The goal of this project was to develop a sensitive and rapid in vitro bioassay to assess the estrogenic activity of unknown compounds. Current methods used in regulatory science to measure hormonal activity of drugs and other xenobiotics rely upon gross physical changes such as the presence of tumors in endocrine organs, disruption of reproduction and alterations in endocrine biochemistry in rodents. A compound suspected of having hormonal activity is tested in non-human primates to determine a hormonal no-observed-effect level. However, hormonal activities of some exogenous compounds are not detected in this system due to insensitivity of the assay's biological endpoints. The goal of this proposal was to develop a novel assay that would be a valuable regulatory tool in assessing compounds with unknown estrogenic activity. A cell line expressing a reporter gene was developed which demonstrated dose-dependent response to certain estrogens and proved useful in assessing relative estrogenic potency of fungal mycotoxins.
Development of an estrogen knowledge base for research and regulation - Carlton D. Jackson, PhD, NCTR(96)
Computer models and a database developed with compounds displaying a biological response of interest can be used to quantitatively predict compounds that will display this response. The estrogen knowledge base was developed to identify the structural elements that are responsible for binding to the estrogen receptor, a requirement for estrogenic activity. The development of a knowledge base based to predict estrogenic activity is particularly challenging because of the wide range of compounds that display estrogenic activity. The knowledge base was constructed using a relatively large number of structurally diverse compounds that all bind to the estrogen receptor. The quantitative structure-activity relationship predictive model was developed from the regression correlation of biological activity with chemical structure. Using this predictive model, a compound's binding to the rat or calf uterine estrogen receptor could predict the compound's binding to the human estrogen receptor from breast tissue. Additional studies have demonstrated that the predictive model has sufficient rigor to be used as the first step in determining the estrogenic potential of a chemical.
Experimental assessment of environmental estrogens - Dan Sheehan, PhD, NCTR(96, 97)
Exposure to xenobiotics which possess the capability of interacting with the endocrine system (termed "endocrine disruptors") is of potential public health concern. This concern has prompted studies to assess a range of compounds with potential for human exposure. Two chemicals of interest are genistein (GEN) and methoxychlor (MET), which were selected for a multigeneration study. As part of this project, estrogenic activity using in vivo assays was determined, as was the binding of these chemicals to serum binding proteins and to the estrogen receptor. The data suggests that GEN is weakly estrogenic in the developing rat uterus and is capable of inducing uterine developmental abnormalities. It did not appear that sufficient quantities of GEN were passed to the pups via milk following feeding to induce uterine responses. High purity MET did not appear estrogenic under any of the parameters examined;lower purity MET is active in other assays, consistent with the presence of an estrogenic contaminant. The results of these studies were used in developing criteria for the tiered testing system for detection of estrogenic chemicals and for use in the NCTR Estrogen Knowledge Base.
Development of in vitro human cell culture systems to screen compounds suspected to have estrogenic or anti-estrogen activity - William H. Tolleson, PhD, NCTR(97)
Terminated due to lack of Center support.
DEVELOPMENTAL/REPRODUCTIVE TOXICOLOGY
COMPLETED PROJECTS
Estimation of reproductive toxicity of pharmaceuticals using QSAR software programs - Edwin J. Matthews, PhD, CDER(95)
This project is an experimental approach to determine whether quantitative structural activity relationship (QSAR) computer software programs can reliably estimate the reproductive toxicity of a pharmaceutical and its contaminants and metabolites. The long-range objective is to use validated QSAR programs to provide decision support information for pharmaceuticals being tested in women in Phase I Clinical Trials. QSAR programs will be validated by comparing predictions of toxicities with experimental results for 430 compounds. The study will evaluate CASEToxII and TOPKAT QSAR predictions and experimental results. Metabolites of the pharmaceutical will be predicted by the META software program. OWH funded a portion of this project. The development of the software programs is continuing.
Screening for nervous system dysfunction in offspring of dams exposed to natural food contaminates during pregnancy - Thomas J. Sobotka, PhD, CFSAN(96, 97)
There is increasing awareness that various types of neurotoxic chemicals may appear in the food supply as natural contaminants (e.g. bacterial toxins and mycotoxins) or natural constituents (e.g. plant toxins). The objective of this work is to assist CFSAN in assessing the spectrum of female reproductive hazards, including adverse effects to offspring, which may be associated with exposure to food chemicals. This project worked to identify new measures with which to screen food chemicals for developmental neurotoxicity by screening for brain dysfunction ion offspring of pregnant rats exposed to low doses of domoic acid, a natural seafood contaminant known to be neurotoxic to adult humans and animals.
FUTURE DIRECTIONS- FUNDING IN FY 2000
Use of a unique animal model to study placental & milk transfer of ciprofloxicin from the dam to the offspring during the perinatal period - Jurgen von Bredow, PhD, CVM (00)
Infections during pregnancy and lactation require treatment with effective antibiotics. Most often, the choice of treatment is dependent upon the potential transfer of drug to the nursing infant. Although transfer of drug into breast milk is easy to monitor, the amount of drug absorbed by the nursing infant is uncertain. In the proposed study, ciprofloxicin, a broad-spectrum antibiotic useful against penicillin resistant strains of bacteria and useful in patients allergic to beta-lactam antibiotics, will be studied using a cow-calf model. The pregnant cow will be dosed with ciprofloxacin shortly before parturition, during the birth of the calf, and for the 7 days following the onset of lactation. The drug will be monitored in the cow's plasma and milk and also in the plasma of the calf after each nursing. This study may predict whether ciprofloxicin may be administered to the lactating mother without causing significant plasma concentrations to accumulate in the nursing offspring.
OTHER
FUTURE DIRECTIONS- FUNDING IN FY 2000
Birth Defect Potential of Cosmetic Products Containing Retinol (Vitamin A) and Retinyl Palmitate - Jeffrey Yourick, PhD, CFSAN (00)
Many new cosmetic products containing retinol (Vitamin A) have recently appeared on the market because of technological advances in preserving retinol with antioxidants and liposomes. This is reflected in the 50 cosmetic products containing retinol and 639 products containing retinyl palmitate, registered in the 1999 FDA Cosmetic Voluntary Registration Program Database. Retinoic acid, a breakdown product of retinol, causes birth defects when given orally to several different animal species. Use of retinol-containing cosmetics by women of childbearing age has the potential of being a public health concern. The potential for birth defects from retinol applied to the skin when contained in a cosmetic product remains undefined. The effects of retinol on the fetus from a cosmetic product are determined by the quantity of retinol or its breakdown products that cross through the skin to enter the body circulation. This project will investigate the skin absorption of retinol from several relevant cosmetic
formulations. If there is absorption of retinol or its breakdown products, then the second phase of this study will involve a developmental toxicity study of retinol in pregnant rats testing skin applications of retinol-containing cosmetic formulations.
Evaluation of the Tg.Ac transgenic mouse as a model for predicting the photocarcinogenicity of pharmaceuticals and cosmeceuticals - Ronald Honchel, PhD, CDER (00)
Ultraviolet (UV) radiation is a natural component of solar light. UV light can produce damage to the DNA of skin cells and increased exposure to UV light increases the risk for developing skin cancer. Drug photocarcinogenicity is the ability of a drug to enhance the cancer-producing ability of UV. The widespread use of pharmaceuticals and the expanding cosmeceutical market make improved photocarcinogenicity testing a women's health concern. The main objective of this study is to evaluate the utility of the Tg.AC transgenic mouse model for predicting the photocarcinogenic potential of pharmaceuticals. The propensity of the Tg.AC mouse model to develop an easily identifiable, relatively quick response to carcinogens may make Tg.AC mice ideal models for testing the photocarcinogenic potential of pharmaceuticals. It is anticipated that the Tg.AC mouse model will provide a more robust, quicker, and less expensive option over current models for predicting photocarcinogenic potential.
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 ovariectomized transgenic Big Blue® rats - Anane Aidoo, Ph.D., NCTR (00)
Estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) are used to alleviate menopausal and/or postmenopausal symptoms. The treatment has both benefits and hazards, including decreased risk of osteoporosis and increased risk of breast cancer. Thus, the challenge is to identify and evaluate experimental agents that exhibit estrogenic properties in alleviating postmenopausal symptoms, while preventing breast cancer. A growing number of studies suggest that isoflavones found in soybeans have estrogenic activity and may be safe, effective ways to alleviate the adverse symptoms of menopause. Among the isoflavones derived from soy proteins are daidzein and genistein, which appear to exhibit anticancer effects in hormone-dependent malignancies such as breast cancer. Although the health benefits of these agents appear intriguing, limited information is available on their potential toxicity, including genotoxic effects. A recent preliminary study has indicated that genistein may enhance, rather than attenuate, the tumorigenicity of the model rodent mammary gland carcinogen DMBA. This study will assess whether daidzein and genistein, given singly or in combination, ameliorate or enhance the genotoxic and tumor-inducing effects of DMBA in female rats. The finding from this study will provide valuable information regarding the chemopreventive ability and safety of soy isoflavones as dietary supplements, especially for women.
Numerous factors interact to determine health and disease states however, today it is recognized that nutritional status plays a role in modifying disease processes in many serious and chronic women's health conditions. It is well accepted that the nutritional status of a pregnant woman affects the health of her child as seen with the correlation between maternal folate levels and the incidence of neural tube birth defects. Nutrition can also play a role in preventing chronic diseases which plague American women, such as osteoporosis and cardiovascular disease.
COMPLETED PROJECTS
Obesity: Its effect on antioxidant and estrogen metabolism - Shirley R. Blakely, PhD, RD, CFSAN(97)
Obesity is characterized by excess body adipose tissue and is a risk factor in a number of diseases including cardiovascular disease, diabetes, and breast cancer. Dietary antioxidants, protect against oxidative tissue damage and may help in preventing a variety of chronic illnesses. This project aimed to gain information regarding the relationship between obesity and availability and metabolism of antioxidants. The study investigated the effects of obesity on biomarkers of oxidative stress, and the bioavailability of antioxidants in rats. The results indicated that obesity enhances the biomarkers of oxidative stress, and that as the biomarkers increase, the utilization and metabolism of antioxidants also increased. The findings of this study will assist FDA with mission-related nutrient requirements by helping to determine the effects of antioxidant supplementation in obese populations.
ONGOING PROJECTS
Vitamin K status of non-Hispanic black and white girls and young adult women: Direct measure of serum phylloquinone levels and measurement of a new functional endpoint in serum samples from NHANES II - Mona S. Calvo, PhD, CFSAN(97)
A number of studies have demonstrated that vitamin K may be involved in the etiology of both osteoporosis and atherosclerosis, two chronic diseases of major public health significance to women. Effective absorption of vitamin K from the diet requires the presence and absorption of fat, and does not occur when vitamin K is consumed with no fat or very low fat foods. FDA's approval of the fat substitute olestra, the first in a growing category of novel food additives, highlighted the need to know the nations' vitamin K status. The objective of this project is to determine the vitamin K status of a segment of the US population considered at great risk of vitamin K deficiency and examine the influence of age and race on the nutritional status of vitamin K.
Molecular and metabolic determinants of maternal risk and progression of Down Syndrome: Potential for nutritional intervention - S. Jill James, PhD, NCTR(97,98,99)
The prevention of neural tube defects (NTD) with folate supplementation is an important precedent that warrants further investigation into the possibility that similar gene nutrient interactions may be involved in the etiology of other developmental defects. Evidence exists which supports the idea that abnormalities in maternal folate metabolism that are predisposed to NTD may also be expressed in mothers with children with Down Syndrome. This project proposes to develop and validate an assay to determine if maternal risk and progression of Down Syndrome is related to genetic and/or nutritionally induced abnormalities in folate metabolism. This information would lend scientific support to the controversial FDA decision to fortify the US food supply with folic acid.
Osteoporosis, which means "porous bone", is the most common type of metabolic bone disease in the US. Osteoporosis affects 25 million Americans, most of which are older women. According to the National Osteoporosis Foundation, osteoporosis leads to 1.5 million fractures per year and costs $10 billion annually. With the US population aging, it is anticipated that these numbers will rise in the near future.
COMPLETED PROJECTS
Application of ultrasonic tissue characterization to diagnosis of bone disease - Keith A. Wear, PhD, CDRH(95)
Osteoporosis is a major public health issue, and is a disease that affects women in greater numbers than men. Early diagnosis of low bone strength would be beneficial insofar as treatment could be prescribed that would reduce the risk of bone fracture. Many methods of bone densitometry exist and bone mineral density is thought to be related to bone strength. These methods, generally based on X-ray technology, give measurements that correlate fairly well with bone density but suffer from a number of problems, including: (1) ionizing radiation; (2) use of radioactive isotopes; (3) high cost; (4) long scan times; and (5) sensitivity to bone density but not bone architecture (the latter being important in determining bone strength and risk of fracture). This project investigated the feasibility of ultrasonic bone evaluation, based on backscattered ultrasound. This measurement is nonionizing, quick, easy, and inexpensive. In addition, ultrasonic backscatter is sensitive in a way that should provide information regarding bone architecture as well as density The results indicated that ultrasonic backscatter is a sensitive index of bone mineral density, and may provide information which is complementary to that provided by other X-ray or ultrasonic methods. Development of experience and expertise in this rapidly evolving field will enable FDA personnel to assess safety and efficacy of new devices.
ONGOING PROJECTS
Development and validation of ultrasonic backscatter measurement for bone density assessment - Keith A. Wear, PhD, CDRH(98)
A preliminary study funded in 1996 showed that ultrasonic backscatter is a sensitive index of bone mineral density. The goals of this project are to validate this new technology by testing the device in a larger population, which includes peri- and post-menopausal women, and to develop methods to minimize variability of measurements.
FUTURE DIRECTIONS-FUNDING IN FY 2000
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)
Ultrasound Bone Measurement (UBM), a rapidly emerging technology in the measurement of bone status in post-menopausal women, is being used to aid in the detection of osteoporotic women who are at higher risk of atraumatic fracture. UBM devices provide results in terms of T-scores, a scale developed by the World Health Organization (WHO) that is designed to help in determining if a woman is osteopenic or osteoporotic. It appears that the T-scores as measured by UBM devices are not consistent across ultrasound devices and could provide potentially misleading information to practitioners on a patient's risk of fracture. Thus, there is an acute need to develop a more informative, useful, and consistent method for presenting the results of these devices to practitioners. Furthermore, physicians need to monitor bone status of women over relatively short intervals (i.e., less than a few years). However, the inter-operator variability, as well as other sources of variability of these devices, may be too large for the devices to be used for this purpose. Neither of these issues has been addressed in the literature. Therefore, this study will evaluate the performance and utility of the T-scores obtained from ultrasound devices for measuring and monitoring bone status. In addition, the ability of these devices to discriminate between fractured and non-fractured subjects (in a retrospective study) will be compared with 2 X-ray devices (spine and hip). Also, using statistical modeling, the two commonly used ultrasound measurements (BUA and/or SOS) will be used to explore new measures of fracture risk as a potential alternative to the T-score.
Women's reproductive capacity and status plays and important role in shaping their lives and health throughout the life course. From issues in contraception, prevention of STDs, and pregnancy in the childbearing years, to the impact of hormone replacement therapy on quality of life and chronic disease issues, reproductive health is viewed by many as the cornerstone of women's health.
CONTRACEPTION
COMPLETED PROJECTS
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)
This study is the first step in determining the safety, duration of effectiveness and efficacy of different products containing N-9 for the prevention of the sexual transmission of HIV and other sexually transmitted diseases (STDs). This CDER pilot study quantified the retention of N-9 foam in the vagina and developed an N-9 analytic assay. Additional studies were proposed which could evaluate the pharmacokinetics of several additional N-9 containing products.
The effect of Thalidomide on the pharmacokinetics of ethinyl estradiol and norethindrone - Carol B. Trapnell, MD, CBER(95)
An investigation of a possible drug interaction between thalidomide and the hormones found in oral contraceptives was necessary due to 1) data suggesting that thalidomide might induce the metabolism of the drugs found in oral contraceptives, rendering them less effective in preventing conception; 2) the fact that thalidomide is a known human teratogen; and 3) the potential for the approval and marketing of thalidomide for at least one indication. This study was an open-label, crossover study designed to evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol and norethindrone. It was concluded that thalidomide does not appear to affect the pharmacokinetics of the hormones and, therefore, there is no drug interaction. This information allowed FDA to conclude that the practice of prescribing hormonal contraceptives as one form of birth control for women of childbearing potential who require thalidomide therapy is appropriate.
Contraceptive efficacy table for uniform contraceptive label-a consumer focus group study-Part I and Part II- Paula G. Silberberg, MD, CDRH(95, 96)
Women need to understand contraceptive efficacy in order to make intelligent selections of contraceptives. This project, a combined CDER and CDRH effort, involved obtaining consumer reaction to several model contraceptive efficacy tables (for example, tables showing contraceptive effectiveness rates or failure rates, displayed graphically or numerically), through focus group testing, a form of qualitative research. Armed with the useful information focus groups can provide, the FDA made informed decisions about the best way to uniformly present contraceptive labeling information. This project resulted in a contraceptive efficacy table designed to simplify consumer product comparison. This table is now used in the labeling of all drug and device contraceptives. In addition, as a result of focus groups, CDRH developed a guidance for industry on uniform labeling of contraceptive devices.
*Accelerated aging studies of condoms/condom materials - Harvey Rudolf, CDRH (98)
ONGOING PROJECTS
Development and validation of a universal water leak test method for barrier contraceptives - Leslie Kerr (Neunaber), ORA(98)
Barrier contraceptives are used for the prevention of pregnancy and are currently a some of the most popular methods used for protection against sexually transmitted diseases. Water leakage tests are effective methods for testing the barrier properties of condoms. Two different methods are currently in practice, which are validated for use in one type of condom; one used by FDA, and another used by industry. This project addresses the need for the development of a method to be used to test all currently marketed types of male condoms. This study will develop and validate a better, universal, water leak test method for condoms of all materials.
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)
Adverse reactions to hormonal therapies, such as oral contraceptives (OCs) and hormone replacement therapies (HRT), contribute significantly to many women's decision to discontinue the use of these therapeutically important products. The relative importance of competing pathways of estrogen metabolism to the risk of adverse side effects during the usage of exogenous hormonal compounds, such as OCs and HRT, has not been adequately studied. Metabolism of certain estrogens can take either of two pathways, which may account for individual variability in the adverse side effect profile associated with the use of hormonal therapies. This project aims to develop a new methodology to correlate estrogen metabolites with adverse side effects. This information could assist in the post market surveillance of hormonal therapies, and assist physicians in identifying and predicting individual susceptibility to specific side effects.
FUTURE DIRECTIONS- FUNDING IN FY 2000
Vaginal volume: optimizing vaginal deployment of topical microbicides-- Debra Birnkrant, MD, CDER (00)
Topical microbicides are products under development for the prevention of transmission of sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV). Formulations of these topical intravaginal products may include foams, creams, bioadhesive gels, films, etc. It is hypothesized that applied volume and formulation characteristics will influence deployment, i.e., the retention and distribution of the formulation over the vaginal space and other susceptible surfaces. Optimal volume of a product is also likely to be dependent on patient factors (e.g., size and parity). This project will assess ideal volume for a range of intravaginal formulations of topical microbicides in 10-12 non-parous women, using multiple formulations and volumes. Measurement of vaginal deployment will be assessed using an optical sensing device developed at the Duke University Departments of Biomedical Engineering and Obstetrics and Gynecology. Information generated from this and subsequent studies of vaginal deployment is urgently needed to be able to advise sponsors on product development and delivery systems for clinical trials. Ultimately, this information will be used in product labeling and patient education to promote public health.
HIV/STDs
COMPLETED PROJECTS
Conference on STD clinical trials workshop - NIH/OEA(94)
The workshop focused on design issues in clinical trials for contraceptive products and products to prevent STDs. This workshop, convened by the Office on Women's Health on April 6-8, 1994, was held in conjunction with the National Institute of Child Health and Human Development and the Centers for Disease Control and Prevention and involved participants from academia, industry, and government agencies.
Prevention of sexual transmission of HIV- Michael Norcross, MD, CBER(94)
The objective of this project was to explore the basic science of HIV transmission and to apply that knowledge to the identification and characterization of agents that could block the process. Work on the characterization of biological and immunologic properties of HIV-1 contributed to our understanding of how the monocytotropic phenotype of HIV-1 escapes from immunity. Initial work was also completed to develop virologic assays to provide a comprehensive assessment of the activity of microbicides against cell-associated and cell-free HIV. These accomplishments provide information that is useful for the development of virucides and virucide testing methods.
Induction of mucosal immunity to protect females from HIV-1 - Basil Golding, MD, CBER(95)
The primary mode of transmission of HIV to women in the US is heterosexual contact. This project will or proposes to determine if a conjugated peptide vaccine candidate could prevent heterosexual and vertical transmission by inducing mucosal immunity against HIV-1 in female mice and macaques. The data suggest that B. abortus as a carrier for HIV-1 peptides or proteins can induce anti-HIV-1 neutralizing antibodies and CTL even in mice lacking CD4+ T cells. Understanding potential new vaccines provides the agency with the scientific knowledge needed to effectively regulate new products.
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)
Genital herpes causes disproportionate disease and clinical consequences to women. The purpose of this project was to develop a test methodology to allow FDA and manufacturers to determine whether a product influences viral latency in animal infections caused by Herpes simplex virus type 2 (HSV-2), the leading cause of genital herpes. The strategy included the development of mutant HSV-2 viruses that expressed reporter genes that can be easily detected, even in the latent state. Mutant viruses that expressed the green fluorescent protein reporter gene were successfully engineered, but latent expression was suboptimal. Additional modifications have been completed and the results will be used to develop improved constructs that will be useful for testing antivirals and vaccines.
A computer model for simulating virus transport through barriers - Matthew R. Myers, PhD, CDRH(96)
Exposure to infectious viruses constitutes a significant women's health risk in the United States today. The risk is often reduced through the use of protective barriers, including elastic gloves and condoms. Existing methods for evaluating the effectiveness of barriers are limited in their ability to simulate realistic use conditions, particularly with regard to the transmitted virus. This project proposes to develop a new method for evaluating barrier performance, via computer implementation of a mathematical model based upon the physical mechanisms of virus transport and calibrated through transmission experiments using actual viruses and membranes.
Human cytotoxic T lymphocyte recognition of Papilloma virus - Penelope Robbins, PhD, CBER(96)
Human papilloma viruses (HPV) are the most common sexually transmitted viral pathogen and are associated with the development of cervical cancer. The objective of this study is to demonstrate cell mediated immunity to papilloma virus (HPV-16) in order to characterize a protective immune response. Preliminary data suggests that lymphocytes collected from cervical cancer patients demonstrate limited cytotoxicity to a specific peptide from the HPV-16 E7 protein. In addition, E7 protein peptide sequences which bind particular Human Leukocyte Antigen class I molecules (HLA I) were predicted. This project contributed to FDA understanding of the cellular immune response to HPV and will assist in the effective regulation of potential new prophylactic and therapeutic vaccines.
The role of HIV-1 co-receptors in sexual and mother-to-infant transmission - Hana Golding, PhD, CBER(97, 98)
Heterosexual transmission and vertical transmission of HIV-1 have been rising in many countries around the globe. In order to impact on this mode of transmission, it is necessary to understand the mechanism by which the HIV virus gains entry into cells in the female reproductive track and the developing fetus. It is now known that the entry of HIV-1 into target cells requires the participation of CD4, the primary HIV-1 receptor, and co-receptors, such as CXCR-4 and CCR-5. This project elucidated the expression and function of these co-receptors on a variety of cells found on cervicovaginal surfaces and fetal/neonatal organs known to be targets of HIV infection. The results of this study assist in the development and regulation of rational drug design for preventing HIV-1 infection by blocking the co-receptors.
ONGOING PROJECTS
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 pathogenic Neisseria species cause significant morbidity and mortality in women and children in the US and worldwide. There are currently no licensed vaccines to protect women from gonorrhea. The licensed vaccine for prevention of menigococcal septicemia and meningitis is not effective in children under two years of age and does not protect against serogroup B disease at any age. This project proposes to investigate the molecular epidemiology and immune response of epitopes of the closely related porin proteins of N. meningitides and N. gonorrhoeae. This work will increase our understanding of the potential for limiting antigens in vaccines to specific portions of proteins. Ultimately, this will facilitate the development of well-characterized vaccines, which supports FDA's mission to enhance the purity and safety of biological products.
Effect of reproductive hormones on the pathogenesis and host cell interactions of Neisseria gonorrhoeae - Carolyn Deal, PhD, CBER (99)
Infections due to Neisseria gonorrhoeae represent a significant cause of morbidity and mortality in women and children throughout the world. The pathogenesis of gonococcal infections is not well understood, particularly with respect to the effect of patient hormonal status on the infectious disease process. Currently, there are no licensed vaccines for prevention of gonorrhea. This project will investigate the effect of reproductive hormones, estradiol and progesterone, and oral contraceptives, on the expression of gonococcal outer membrane antigens in both the laboratory and clinical settings. We will also evaluate whether or not these hormones affect attachment and/or invasion to human cervical and endometrial tissue culture cells. The goal is to identify potential new antigens that may be particularly relevant in gonococcal infections in women and to determine if hormonal status may be a factor to be considered in the evaluation of models of infection.
HORMONE REPLACEMENT THERAPY
COMPLETED PROJECTS
*Contribution of estrogen components to the efficacy of conjugated estrogens - preliminary analytical chemistry - John Strong, PhD, CDER(97)
Within the US, postmenopausal women are one of the fastest growing populations utilizing medical treatment. Premarin", a conjugated estrogen product, has been widely used in the prevention and treatment of postmenopausal symptoms. This innovator's product is derived from the urine of pregnant mares and is recognized as a complex mixture. There is a paucity of information on the relative contribution of the estrogen components to the overall efficacy of Premarin". This clinical research project proposes to compare the therapeutic effects of the two major estrogen components on the postmenopausal vasomotor symptoms and to investigate the dose-response relationship in order to define changes in the clinical activity that might occur at lower doses. The resolution of these questions will facilitate availability of synthetic conjugated estrogen products and benefit the increasingly growing population of postmenopausal women.
*Chemical characteristics of conjugated estrogens - Thomas Layloff, CDER(98,99)
Within the US, postmenopausal women are one of the fastest growing populations utilizing medical treatment. PremarinW, a conjugated estrogen product, has been widely used in the prevention and treatment of postmenopausal symptoms. This innovator's product is derived from the urine of pregnant mares and is recognized as a complex mixture. There is a paucity of information on the relative contribution of the estrogen components to the overall efficacy of PremarinW. This project will develop and validate an high-pressure liquid chromatography (HPLC) method to identify the chemical components of PremarinW.
PREGNANCY
COMPLETED PROJECTS
*FDA-Regulated Products and Pregnant Women - Office of Women's Health(94)-
In July 1993, the FDA published new guidelines on the inclusion of women in clinical trials. These new guidelines removed a 16-year old restriction on the inclusion of women in the earliest phases of clinical trials. Left unresolved, however, were issues regarding the testing of FDA-regulated products in pregnant women. This Office of Women's Health conference provided background on the scope and need for medical interventions in pregnancy and on the extent to which physiologic changes of pregnancy alter the pharmacokinetics, and pharmacodynamics of drugs and biologics in pregnant women. It also identified methods and strategies to promote collection of data on use of drugs, biologics and devices in pregnant women, their effectiveness for the woman and their effects on the fetus. The conference, held on November 7 and 8, 1994 in Arlington, Virginia, featured speakers from FDA and other government agencies, the scientific community, health provider and consumer groups and private industry.
Infant Feeding Practices Study - Sara Fein, PhD, CFSAN(94)
This study is designed to create databases of detailed longitudinal information related to infant feeding and health promotion practices by examining areas such as breastfeeding, adverse experiences with infant formula, food handling, introduction of solid foods, use of prenatal and infant vitamins, prenatal and well-baby care, among others. It is anticipated that the study will be used by researchers from FDA, Center's for Disease Control and Prevention (CDC) and universities to evaluate various aspects of infant feeding practices and improve consumer information on infant feeding and breastfeeding education. For example, one FDA evaluation determined that breast feeding decreases the incidence of infant ear infections.
Rapid method for detection and enumeration of Listeria monocytogenes in foods - Mary L. Tortorello, PhD, CFSAN(95)
Listeria monocytogenes, a microorganism that causes foodborne illness of high mortality and of particular danger to pregnant women and newborn infants, is widespread in the environment and thus may contaminate many types of food. There is a lack of easy, reliable analytical methods for the microorganism, particularly quantitative methods. The project proposed to develop a rapid, quantitative method for assessing the presence of Listeria monocytogenes in foods by adapting a technique that was used to detect E. coli. The method results were ambiguous, therefore, not appropriate for regulatory use.
Profile of drug use in pregnancy - Sheila Weiss, PhD, CDER(95)
To address the lack of data on risk to pregnancy from use of prescription drugs, this study developed a profile of drugs used during pregnancy from an Health Maintenance Organization (HMO). This initial effort determined the most commonly used therapeutics according to pregnancy outcome and estimated the proportion of pregnancies that are potentially exposed to these drugs. This system has the potential for producing additional postmarketing information related to drug use in pregnant women.
*Pregnancy Labeling Taskforce: Focus Group testing - Kathryn Aiken, PhD, CDER, (98-co-funded by NIH ORWH)
The 1977 FDA guideline, "General Considerations for the Clinical Evaluation of Drugs" recommended excluding women with childbearing potential from participating in clinical studies which take place before reproductive toxicity testing has taken place. This policy was developed to reflect societal interests in protecting vulnerable populations-particular the fetus. As a result, women did not participate in clinical trials in large numbers, resulting in paucity of data about the effect of medical products in women. In later years, the recommendation raised important ethical and legal questions about the appropriateness of such a policy. In 1993, FDA reversed its recommendation, as outlined in the "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs." This new guideline also called for data to be analyzed to assess gender effects.
CARDIOVASCULAR DISEASE
COMPLETED PROJECTS
Women in Clinical Trials- CDER, (94)
The OWH in conjunction with the CDER sponsored research which consists of three studies in women or in mixed panels of men and women to identify pharmacokinetic/pharmacodynamic differences in prototypic drugs and to evaluate the effect of commonly used medications on oral contraceptives. The data resulting from these studies are important to regulatory decisions and ultimately, to the clinical use of the drugs in question. The first two studies use prototypic drugs (propranolol and quinidine) to examine the unique physiologic status of women with respect to the menstrual cycle and other hormonal influences. Propranolol is a drug of critical importance because of its widespread use; it is the prototypic drug in the beta-blocker class and is currently approved for use for nine clinical indications. Quinidine can sometimes lead to life-threatening cardiac arrhythmia (Torsade de pointes). An earlier study showed that women are more prone than men to the development of this toxicity. The third study involves the evaluation of terfenadine, a commonly used antihistamine product, when used in combination with oral contraceptives. It will also determine if terfenadine metabolism is altered during the menstrual cycle.
Comparison of the beta-adrenergic antagonist actions of propranolol in men and women - David Flockhart, MD, PhD, CDER(94)
Very little data exists for any drugs on differences in their actions between men and women. This is the case despite the fact that gender-related changes in pharmacokinetics have been shown with a number of drugs. Because differences in pharmacokinetics do not always predict pharmacodynamic changes, it is important to avoid reliance on pharmacokinetics alone to understand differences observed and to include measures of drug effect. This study was performed to assess the influence of gender and the menstrual cycle on the actions of propranolol and to delineate the mechanisms responsible for any changes observed. Preliminary results suggest that gender-related changes in propranolol pharmacokinetics do not seem to result in different chronotropic pharmacodynamics in men and women.
Comparison of the potassium channel blocking actions of quinidine in men and women - Raymond L. Woosley, MD, PhD, CDER(94)
Torsades de pointes (TdP) is a syndrome of marked prolongation of the electrocardiogram (ECG) QT interval associated with the development of a particular ventricular tachycardia. The syndrome is most often seen after recent administration of drugs, such as quinidine, that prolong the QT interval by blocking potassium channels. Previous human and animal data suggests the existence of a gender-specific response to quinidine. This study was designed to compare the response of normal males and female subjects to quinidine. The results indicate that women had a greater response to quinidine at any given concentration than did men and there were no major differences in pharmacokinetics or protein binding of quinidine in males and females. In addition, ECGs were analyzed to compare dispersion of repolarization in men and women. The study found that baseline QT dispersion was greater in men but after quinidine, the degree of dispersion increased only in women so that they became equal. These results indicate that men and women have a different sensitivity to the potassium channel blocking actions of quinidine and provide leads to possible mechanisms to prevent drug-induced torsades in women.
Terfenadine/Oral contraceptive study - Lou Cantillina, MD, CDER(94)
Administration of thrombolytic therapy to women with acute myocardial infarction. Is it too late? - Emily B. Shacter, PhD, CBER(96)
Women who enter the hospital with an acute myocardial infarction die at almost twice the rate of men. This study examined the data from major clinical trials to determine whether the increased mortality rate in women was due to ineffective administration of thrombolytic drugs. This information would assist the agency in capturing important gender-specific safety and efficacy data on the product label. The retrospective analysis of men and women after acute myocardial infarction suggests that a disproportionate number of men die before hospitalization, biasing clinical studies in hospitalized patients.
A comparison of gender specific utilization of implantable cardioverter defibrillator therapy and post-implantation survivability - Steven Lascher, DVM, MPH, CDRH(97)
Implantable cardioverter defibrillators (ICDs), because of their ability to detect and treat potentially lethal ventricular arrhythmias, have become one of the most important life saving cardiac devices. Studies have suggested that generally, the use of procedures to diagnose and treat cardiac disease is greater in men than women. This study examined gender specific utilization of ICDs and post implantation survival among the Medicare population. The results indicate that women are implanted with ICDs less frequently than men despite similar cardiac disease incidence, and older women (70-85 years) who are treated with ICD live significantly longer than men of similar age.
*Flow studies and the use of a waveguide in cardiovascular devices - Harvey Rudolf, CDRH (98)
ONGOING PROJECTS
Gender differences in early and long-term results of coronary angioplasty with the Palmaz/Schatz stent - Danica Marinac-Dabic, MD, CDRH(95, 96, 97)
Coronary heart disease is a predominant cause of mortality in women in the United States. However, the preponderance of scientific studies have focused on men. Among the studies that have included women, a number of gender differences have been reported: presenting clinical symptoms, results of diagnostic testing, success of treatment regimens, and prognosis. Since the approval of the Palmaz/Shatz (PSS) stent in August of 1994, it has become one of the most frequently used medical devices. Recent studies of short-and long-term outcomes of coronary stent had limited sample size of women treated with this device. This project utilized a combination of retrospectively and prospectively collected data from clinical sites that participated in the New Approaches to Coronary Intervention (NACI) Registry to investigate gender differences after coronary angioplasty with the PSS. The major conclusion of this study was that, although men and women are dissimilar in their baseline clinical and lesion characteristics, the women treated with PSS appear to do as well as the men treated with stents.
Ovarian steroids and cardiovascular disease: The role of gender in the effectiveness of interventional medical devices - James Karanian, PhD, CDRH(98)
Large-scale studies have documented higher risk of coronary artery disease with aging in both sexes and the relatively lower risk in females compared to males. The incidence among women rises markedly in the fifth and sixth decades of life, approaching but not reaching the incidence among men. The basis of the greater incidence of cardiovascular death in postmenopausal women compared to premenopausal women could involved factors that are modulated by the hormones. This study will attempt to clarify the role of the aging process and estrogens in modulating coronary function in women. Through the use of a swine model, the investigators hope to determine why menopause promotes cardiovascular disease, and will specifically address the lack of data concerning the effects of angioplasty on coronary vascular reactivity, mechanics, and pathology in females. This project supports FDA's regulatory mission by evaluating how devices and drugs differentially affect women.
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)
Women have slower cardiac repolarization that is expressed as longer QTc intervals on the ECG. An evaluation of the effect of the differing levels of sex hormones experienced during the menstrual cycle on the QT prolongation seen after the administration of an antiarrythmic drug will be conducted.
FUTURE DIRECTIONS-FUNDING IN FY 2000
Women's participation in clinical drug trials for unstable angina and myocardial infarction - Ann Farrell, MD, CDER (00)
Women have been underrepresented in clinical trials for cardiovascular heart disease. Differences between men and women exist for risk factors, disease manifestation, medication and procedure use. Recognizing the underrepresentation of women in clinical trials, the FDA and NIH now have gender-related policies in place to encourage greater participation. This project will review the participation of women in cardiovascular clinical trials in terms of numbers and the clinical characteristics of these women who were enrolled in clinical cardiovascular drug trials included in NDA submissions over the last ten years.
POST-MARKET AER ANALYSIS
COMPLETED PROJECTS
Visualization tools for studying gender differences - Ana Szarfman, MD, PhD, CDER(97)
Concern about the incidence of severe adverse drug reactions has led to an increased interest in improving the safety monitoring of new and existing drugs. Because many NDAs do not include data which can detect sex differences in serious rare adverse events, finding new and improved ways of utilizing the data collected from the post-market adverse event reporting systems could provide sex-specific safety data to generate a more comprehensive safety profile for women. This project developed and implemented software programs that apply exploratory statistics and visualization tools to the FDA Spontaneous Reporting System to aid reviewers in determining if gender specific effects exist. This information can be used target post-market surveillance activities.
*Adverse Events Reporting System (AERS): Risk assessment, compliance, and management - Ralph Lillie, RPh, CDER (98)
*Postmarketing drug risk assessment using the ARAMIS database in RA patients - Mary Willy, PhD, CDER (99)
ONGOING PROJECTS
Data mining techniques for identifying potential serious drug interactions in women - Ana Szarfman, MD, PhD, CDER(98)
Concern about the incidence of severe adverse drug reactions has led to an increased interest in improving the safety monitoring of new and existing drugs. Currently, there are limited tools available that systematically screen and analyze new drugs in the postmarketing period for adverse events associated with drug interactions. This project will adapt newly developed data mining techniques to screen for serious drug interactions in women in the FDA's Adverse Event Reporting System. This study will enhances the agency's mission of assuring that drugs are effective by addressing gaps in the current knowledge related to drug interactions in women.
Teratogen Surveillance - Carolyn McCloskey, MD, CDER (98)
Despite the incredible concern about the potential dangers posed by drugs taken during pregnancy, very little is known about the teratogenicity of the vast majority of agents to which pregnant women are commonly exposed. In order to gain information regarding the teratogenicity of newly released drugs as well as those in which adverse reactions have been identified, this project proposes to establish a centralized database, the Teratogen Surveillance System, using existing Teratogen Information Services. This system will allow FDA to evaluate postmarketing data on human use of drugs during pregnancy that may potentially be included in product labeling.
Active postmarketing surveillance methods: hospital pilot - Roselie Bright, ScD, CDRH (99)
Women, on average, use more drugs, have more health care encounters, and more hospitalizations than men, potentially putting them at greater risk for adverse events. Without good data on the extent of adverse events and medical product experience, it is impossible to verify this theory or effectively identify areas in need of improvement. Evidence from a number of sources suggests that only a small proportion of adverse device or drug related events are reported to the FDA surveillance systems. Several studies attempting to enhance the detection of adverse drug events in hospital settings have obtained more verifiable reports by active solicitations and searches through hospital records. In response to the high-priority need to improve FDA's methods of identifying problems women have with marketed regulated products, this project proposes to develop an active gender-based surveillance method, that exploits advancing computerization of medical logs and records, for discovering signals of adverse events related to medical devices and drugs.
FUTURE DIRECTIONS- FUNDING IN FY 2000
Surveillance of sex-specific utilization, morbidity, and mortality associated with transmyocardial revascularization (TMR) - Ronald Kaczmarek, M.D., MPH, CDRH (00)
Women may be the population segment most in need of alternative methods of coronary revascularization. Two laser systems for TMR have been recently introduced to the U.S. market and are indicated for the treatment of severe angina that is refractory to medical therapy in patients that are not candidates for coronary artery bypass graft surgery. However, women were underrepresented in the clinical studies that formed the basis for market approval of the two TMR laser systems, and the effect of gender on outcomes following TMR has not been investigated. This project will utilize the existing infrastructure of the Society of Thoracic Surgeons' (STS) National Adult Cardiac Surgery Database to ascertain detailed clinical information on all patients undergoing TMR at hospitals from across the nation performing this procedure in the U.S. These data, captured while TMR diffuses from selected institutions to the rest of the surgical community, will allow for the determination of whether gender differences exist in the utilization and outcomes associated with this new technology.
TOXICOLOGY
ONGOING PROJECTS
In-vivo modeling of steroid-mediated gender effects in drug metabolism, Phase I &II - Patricia Thompson, PhD, NCTR(98, 99)
Though gender-based studies on human drug metabolism are relatively limited, several examples of sex-related differences in drug pharmacokinetics and enzyme activity have been reported. Little is known about the cellular and molecular mechanisms that underlie these observed sex-related differences. This project seeks to advance our understanding of gender differences in the clinical outcome of FDA-regulated products by investigating the hormonally mediated changes in the levels of cytokines known to modulate the expression of an enzyme in the cytochrome P450 superfamily.
Gender Differences in P450 activities and their implications - Shiew Mei Huang, PhD, Robert Branch, PhD, CDER (CO-funded by NIH ORWH, 98)
Recently is has been recognized that, as women need and use drugs as much as men and may respond differently, there is a public need to know the safety and efficacy for new chemical entities in women. It is known that the whole-body activity of cytochrome P450 isozymes has important implications for the metabolism of diverse medications. This study attempts to determine gender-specific differences in drug metabolizing activity by evaluating whether men and women have similar isozyme activity levels. Once obtained, this information could provide a scientific base from which the Agency can develop a regulatory algorithm for requesting gender-specific pharmacokinetic information with New Drug Applications (NDAs).
Mechanistic Basis for Gender-dependent Differences in Pharmacokinetics- Chandra Sahajwalla, PhD, CDER (99)
The literature indicates varying degrees of gender-dependent clearance for several drugs. Some drugs are cleared differently in men and women, whereas many have no gender-dependent differences in their pharmacokinetics. In spite of these random observations, no systematic comparison has been made as to the mechanism for differences (or sameness) in the drug pharmacokinetics in each gender. The goal of this project is to obtain an understanding of the mechanistic basis of gender-dependent differences in pharmacokinetics. NDAs submitted to the FDA in the past 5 years will be surveyed and submissions having gender analysis will be identified. The NDAs will be reviewed for gender analysis, physicochemical properties, basic pharmacokinetics and gender specific pharmacokinetics. The compiled data will be assessed and attempts will be made to identify which metabolizing enzyme and or physicochemical properties are most likely to produce gender-dependent differences in the pharmacokinetics of the drugs.
TRACKING SYSTEMS
COMPLETED PROJECTS
Development and Expansion of a pilot tracking system for monitoring the barriers to the enrollment of women in clinical trials - Theresa A. Toigo, RPh, OEA(95,96)
Over the past several years, there has been a growing concern that women are inadequately represented in clinical trials during the drug development process. Attention to potential gender differences is part of a larger effort by the FDA to ensure that the safety and efficacy of drugs are adequately studied in the full range of patients who will receive them, allowing physicians to most effectively individualize therapy. On July 22, 1993, the FDA published the "Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drug". " The guideline emphasizes entry of women in early phases of clinical trials so that important information may be obtained beginning in phase 1 (safety) and phase 2 (safety and early efficacy) trials and used to develop relevant studies for phase 3 (efficacy) trials. Using data from NDA's in several divisions in CDER, this project established a pilot tracking system to review and evaluate protocols and that will observe trends over time and assess the relationship between eligibility criteria and the sponsor's success in enrolling women in clinical trials. The data demonstrated that while there was an overall increase in the number of protocols which permitted the participation of women and women with childbearing potential, a notable number of protocols continue to exclude these important subgroups.
RISK PERCEPTION
COMPLETED PROJECTS
Gender differences in perception of risks communicated by prescription and over-the-counter drug labels, Phase I and II - Ellen R. Tabak, PhD, CDER(95,97)
Crucial to the effectiveness of drug therapies is the aspect of consumers' making appropriate decisions about using medicines properly. There is some evidence that women's information processing preferences and styles regarding drug risk information differ from men's. The purpose of this study is to gain information about how women use and understand information about risks and benefits of prescriptions and over the counter medications. The goal of collecting such information at the FDA is to be able to design patient drug labeling that is meaningful and useful to women. Gender differences in processing of risk information were examined by showing consumers of both genders a simulated label for one prescription and one over the counter drug. This study was done in two phases. The first phase resulted in the development of a survey instrument to be used in the second phase. The second phase of the study utilized the survey instrument to address the question: How do variations in presentation of risk and benefit information influence the risk/benefit perceptions of pharmaceutical products by men and women? The results indicated that experimental variations of benefit and risk information dramatically affected respondent's' willingness to use information. However, there were no dramatic differences in men's and women's processing of risk/benefit information about drugs.
*Focus group testing of labeling for tampons and barrier contraceptives - Robert Navario, CDRH (99)
MISCELLANEOUS
COMPLETED PROJECTS
Thalidomide: Are there gender disparities in treatment outcome and non-teratogenic adverse effects? - Brenda Vaughan, MD, CDER(95)
Thalidomide use in pregnant women resulted in severe birth defects in their babies. However, since 1960, thalidomide has shown promising therapeutic effects in a number of disease states. With more reliable forms of birth control, women may be included in Phase 1 and 2 clinical trials. This group reviewed investigational new drug (IND) requests for thalidomide which were submitted to the FDA for rheumatoid arthritis, ophthalmologic, and dermatologic indications from 1984 to 1994 to determine if there is a gender disparity in participation, treatment outcome measures or non-teratogenic adverse effects. This information could provide gender-related recommendations regarding monitoring during clinical trials. Firm conclusions could not be reached regarding treatment outcomes and adverse effects due to incomplete data as a result of regulatory difficulties inherent in the monitoring of single-patient INDs. However, the study demonstrated that women have not been denied access to thalidomide in this group of INDs.
Research involving human subject committee (RIHSC) - Peter H. Rheinstein, MD, JD, MS, OEA(95)
The FDA has a human research subjects oversight committee which is called the Research Involving Human Subjects Committee (RIHSC). To provide information to FDA reviewers on human research subject protection and special populations in clinical research, the CDER Staff College has developed a training program. As part of a CDER Staff College course, there will be at least two sessions that address the use of women as human research subjects, including issues such as current policies, regulations and guidances regarding women in clinical trials, and pregnant women.
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* Projects funded through small grants or end of fiscal year funding. OWH does not track all of these projects, therefore, abstract and outcomes data may not be available.