METHODS

1. FDA Office of Women’s Health Funded Biological Studies: 1994-2010, a summary report: M. Yu, E. Fadiran, R. Poon, V. Copeland, A. Parekh FDA, 10903 New Hampshire Avenue, Silver Spring, MD INTRODUCTION RESULTS RESULTS (CONT’D) • Sex-based biology is a growing area of research that shows clinical benefits for both men and women. The exclusion of women from some past clinical studies has resulted in knowledge gaps about the effects of medical treatments in women. The FDA Office of Women’s Health (OWH) was established • in 1994 with the mission to: • protect and advance the health of women through policy, science, and outreach, and • advocate for the inclusion of women in clinical trials and analysis of sex/gender effects. • As an office within FDA, OWH advances women’s health through its alignment with FDA’s public health mission. FDA’s mission is to protect public health by assuring the safety and efficacy of human and veterinary drugs, biological products, medical devices, cosmetics, products that emit radiation and the safety of the nation’s food supply. The FDA is also responsible for advancing public health by helping to accelerate innovations that make medications and foods safer, more effective and affordable; and by providing the public with accurate, science-based information they need when using medications and foods to improve health. (http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm227527.htm). FDA accomplishes this mission through its various Centers and Offices that have specific regulatory and administrative roles. Figure 1 is an overview of FDA’s Organizational Structure. • Intranasal immunization elicits neutralizing antibodies and interferon gamma-secreting T- • cells at mucosal surfaces that may protect individuals from HIV-1 infection. • A test methodology and reagents were successfully developed to determine whether a • product influences the establishment of Herpes simplex virus type 2 (HSV-2) viral latency in • animal infection. However, the results did not produce acceptable signals to detect the latent • virus burden in infected animals. This project will continue to assess the quantifiability of • fluorescing signals, leading to the development of improved models that will be useful for • testing antivirals and vaccines. • Sex hormones effects (4 studies): • • During Hepatitis C infection the combination of interferon alpha (IFNα) and estradiol • caused a synergistic effect resulting in a 50% decrease in viral titer over IFNα alone. • • Female sex hormone can further enhance the effect of anthrax lethal toxin on chemokine • release from human lung microvascular endothelial cells and may alter adhesion molecule • expression. • • β-estradiol and progesterone inhibit the efficacy of stavudine (anti-retroviral drug), in • peripheral blood mononuclear cell cultures. β-estradiol may inhibit the efficacy of • saquinavir (anti-retroviral drug). To optimize antiretroviral drug therapy, it may be necessary • to monitor patient hormonal status as well as plasma drug levels. • • CpG ODN (oligodeoxynucleotides) will likely have similar safety and efficacy profiles in • male and female subjects. However, under conditions where estrogen or progesterone levels • are altered, the immune response to TLR (toll like receptors) agonists may differ. • Autoimmune Diseases (3 studies): • • Increased 17 β-estradiol and reduced dehydroepiandrosterone-sulphate (DHEAS) levels in • lupus patients may induce cytokine abnormalities early in the disease. However, subsequent • cytokine imbalance does not correlate with sex hormone levels. • • DNAse treatment does not improve the survival of lupus prone mice. • • Most systemic lupus erythematosus and rheumatoid arthritis patients are unable to assemble • complete transcription complexes in response to INFα, resulting in impaired INFα • signaling. • Breast Cancer (1 study): • • Interferon-inducible protein-10 (IP-10) did not display antitumor activity in the mice tumor • model. The finding also indicates that the tumor suppressor gene p53 appears to play no role • in the regulation of IP-10 gene expression. • Cardiovascular disease (1 study): • • The study examined data from the GUSTO-1 and INJECT clinical trials to determine whether • the increased mortality rate in women entering the hospital with an acute myocardial infarction • was due to ineffective administration of thrombolytic drugs. The results showed that: a) there • were no differences in the thrombolytic drugs tested; b) more high-risk men would be excluded • from these studies than women due to death before hospitalization; hence gender comparisons • of in-hospital mortality rates may be artificially inflated for women. A totalof 234 intramural studies were funded by OWH during 1994-2010. Of these, a majority of the studies were in the areas of drugs, biologics, devices, foods and toxicology. Figure 2 shows a distribution of the numbers of studies funded in the various Centers. • Figure 2: OWH-Funded studies distribution • Of all the studies funded, CBER conducted a total of 29 biologics studies. Among the 29 biologics-related studies, 17 are completed, 5 are on-going, 5 were unsatisfactorily terminated and 2 have not yet submitted final reports. Figure 3 illustrates the numbers of studies in the 5 therapeutic areas: • Figure 3: Therapeutic areas of biologics studies • A summary of the study findings and impact is summarized : • HIV/sexually transmitted diseases (STDs) (8 studies): • • Viral subtype and sex hormones may play a role in the transmission of HIV. • • A novel HIV diagnostic test (HIV SELECTEST) has been developed to differentiate between • antibody responses due to vaccination versus actual HIV infection. The sensitivity of the test • showed no significant difference in men and women. • • The ability of the thymus to provide T-cells is critical in fighting HIV infection. Following T-cell • depletion in the thymus, Intrathymic IL-7 may play an important role in thymic regeneration with • naïve CD8+ T-cells. The results may contribute to the development of immune reconstitution • therapies. • • Human macrophages are infected more efficiently by M-tropic than by T-tropic HIV-1 strains. • • Gonorrhea is a major cause of pelvic inflammatory disease in women. Neisseria gonorrhoeae • porin protein regions (Por) are the leading targets for gonococcal vaccine development. The result • of the Por variable region typing suggests that vaccines targeting a limited number of Por protein • epitopes could protect against a majority of strains. The finding also suggests that genetic • mosaicism, not mutational events, is responsible for the majority of Por diversity. • A CD4 cytotoxic T lymphocytes (CD4 CTLs) cell line can either protect itself against • macrophage M-tropic HIV-1 infection or allow replication of M-tropic and T-tropic HIV-1 • strains in vitro depending on antigen presentation. The results suggested that CD4 CTLs in vivo • might similarly participate in regulating HIV-1 virus replication. Figure 1: FDA Organizational Chart Between 1994 to 2010 OWH Research and Development Program funded various scientific studies within the FDA Centers to develop a better understanding of sex differences in the safety and efficacy of FDA-regulated products. The Center for Biologics Evaluation and Research (CBER) is one of the main Centers in FDA. CBER is responsible for assuring the safety, purity, potency, and effectiveness of biological and related products such as blood, vaccines, and tissues. This paper is a review of all OWH-funded studies conducted on biologics products within CBER. CONCLUSION METHODS OWH has supported biological studies that have had significant regulatory impact and have helped advance the understanding of sex differences in disease diagnosis and treatment. An important impact of the funded studies led to the development of HIV SELECTEST, the test to differentiate between antibody responses due to vaccination versus actual HIV infection. The sensitivity of the test for infection detection in men and women showed no significant difference. Currently, National Heart, Lung and Blood Institute of NIH has awarded funds to two companies to develop HIV SELECTEST, bring it to licensure and to produce enough test kits for the next large HIV vaccine trials. The results of these studies serve as an important stepping stone for the continuation of sex-based biologics research. In addition, these studies yielded 28 publications in peer-review journals, further advancing the science of sex difference. • All OWH-funded intramural biologics studies conducted in CBER from 1994 to 2010 were retrieved from the OWH database and from paper records. Review of the final reports or publications related to the funded studies was conducted. The completed biologics studies were classified into the following 5 therapeutic areas: • • HIV/sexually transmitted diseases (STDs) • Breast cancer • • Sex hormones effects • Cardiovascular disease • • Autoimmune diseases • The completed studies were summarized and assessed for their public health or regulatory impact.