Full Text HD-94-018 VAGINAL PHYSIOLOGY: INTERACTION WITH INTRAVAGINAL PRODUCTS NIH GUIDE, Volume 23, Number 12, March 25, 1994 RFA: HD-94-018 P.T. Keywords: National Institute of Child Health and Human Development Letter of Intent Receipt Date: May 31, 1994 Application Receipt Date: July 27, 1994 PURPOSE The National Institute of Child Health and Human Development (NICHD) invites research grant applications for the support of basic and applied research to evaluate the affect of intravaginal products, treatments and spermicides on vaginal physiology. An important part of the mission of NICHD is to gain new knowledge about human reproduction, especially those that may lead to new approaches to contraception. This Request for Applications (RFA) is intended to address that charge. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Vaginal Physiology: Interaction with Intravaginal Products, is related to the priority area of primary prevention of sexual spread of HIV infection with the use of topical microbicides and contraceptives. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9352 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic non-profit and for-profit organizations, public and private. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Minority individuals, persons with disabilities, and women are encouraged to apply. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) and FIRST (R29) award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed five years. FIRST awards must be for five years. The earliest expected award date is March 1, 1995. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will also vary. FUNDS AVAILABLE It is expected that up to five new applications will be funded, within the total cost limit of $1,000,000 available for the first year. This level of support is dependent on the receipt of sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NICHD, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background The vagina and cervix are a complex ecosystem that includes the vaginal and cervical epithelium, microbial flora, vaginal fluid, and cervical mucus. The vaginal environment is influenced by several biologic factors including individual characteristics, normal physiologic states, changes caused by systemic disease or treatment and other health practices, such as sexual and hygiene measures. The ecosystem is hormonally dependent and thus varies throughout the menstrual cycle. Longitudinal studies of the vaginal flora of women indicate that the prevalence of certain bacteria is increased during menstruation. The oxidation-reduction potential and pH also affect vaginal flora. When the oxidation reduction potential is low, anaerobic bacteria are favored. The pH may affect the viability of many organisms (for example, HIV does not survive in an acid pH), it may affect certain enzyme systems (for example, some strains of lactobacilli can break down glycogen at a low pH but not at a higher one) and it may also affect the solubility of nutrients. The relationship between genital tract infection risk and use of intravaginal products such as vaginal barrier contraceptives, treatments of vaginitis, and products for vaginal hygiene is not a simple one. The products may have direct effects on microbial pathogens, alter endogenous microbial flora, cause alterations in the vaginal environment, or have a direct effect on vaginal epithelium. For example, nonoxynol-9 (N-9) is toxic to Lactobacillus acidophilus, but has little or no direct effect on e. coli and may result in an increase in vaginal (and urethral) colonization by this pathogen. Of particular concern is the effect of vaginal chemical barrier contraceptives on risk of infection with HIV. A decreased risk for HIV transmission would be expected on the basis of protection against sexually transmitted diseases that cause genital ulcers and cervicitis, and on the basis of in vitro evidence that nonoxynol-9 is an effective virucide against HIV. Increased risk, however, is also biologically plausible. Spermicidal detergents can disrupt cell membrane integrity, including integrity of the vaginal or cervical epithelium and can cause inflammation severe enough to be visible or symptomatic in a significant number of users. This direct effect on vaginal epithelium has lead to concerns that the dose and frequency or duration of exposure to spermicides may determine the impact on HIV risk. It is also possible that using spermicides or other vaginal products may indirectly affect HIV risk, apart from or in addition to, the direct effect of spermicide on vaginal epithelial cells. For example, an alteration in vaginal pH or vaginal flora caused by barrier use might, in turn, alter HIV infectivity or might alter a woman's susceptibility. Our knowledge of the interaction between intravaginal products and vaginal physiology is very limited. Little is known about the effect of intermittent or chronic use of these intravaginal products on the vaginal ecosystem including the vaginal epithelium, cervical mucosa, secretions, cervical mucus, normal flora, and vaginal pH. In order to interpret the results of clinical studies (i.e., to identify and adjust for confounding variables) and in order to optimize existing products or develop new ones with favorable characteristics, a more thorough understanding of the vaginal environment is needed. Basic and applied research on the effects of intravaginal therapy on vaginal physiology is essential. Objectives For the purpose of this RFA, research subject areas would, include but not be limited to the following: o Identify the physical and chemical interactions throughout the menstrual cycle that occur between vaginal bacteria and the underlying epithelium. One approach is to consider the nutrients microorganisms need and to evaluate how the vaginal microenvironment supplies these requirements. These include nutritional substrates, need for appropriate physical environment (temperature, pH, hydration and oxygen tension) and the ability to survive in the presence of antibacterial factors produced by the host or other microbial species. o Delineate characteristics of normal vaginal physiology such as the amount of vaginal fluid released in the vagina during sexual excitement or how fast the vaginal epithelium is exfoliated and replaced. o Assess the value of artificial colonization with bacteria such as lactobacilli as a mechanism to resist disease. o Delineate endocrinologic or biological factors that may affect host susceptibility or infectiousness to HIV in vaginal and cervical mucosal tissues: e.g., time of the menstrual cycle, pregnancy, menopause, or exogenous hormones. Define the role of antiviral defense mechanisms in HIV transmission, e.g., low pH, lysozyme, hydrogen peroxide, and lactoferrin in vaginal fluids. o Determine how spermicides, douches, and topical or systemic agents (antibiotics, antifungals, etc.) affect the vaginal environment. Does use of any topical spermicides or microbicides reduce the infectiousness of seropositive women? o Determine how different formulations affect a product's activity in the vagina in terms of time required for activation, effect of pH on activity, or interaction with cervical mucus. o Determine what characteristics are desirable in a formulation of a topical drug including interaction with the vaginal environment, time to onset of activity, and limits on frequency of application. Note: The use of sexually transmitted diseases or human immunodeficiency virus infection as a model is not within the scope of this RFA. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 9, 1994 (FR 59 11146-11151) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. (NOTE: When the proposed study or studies in the RFA or PA involves a gender specific study or a single or limited number of minority population groups, this should also be stated to inform potential applicants and reviewers.) LETTER OF INTENT Prospective applicants are strongly encouraged, but not required, to submit, by May 31, 1994 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NICHD staff to estimate the potential review workload and to avoid conflict of interest circumstances in the review process. The letter of intent is to be sent to Dr. Pamela Stratton at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2a of the face page of the application form and the YES box must be marked. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must be sent to: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development Building 6100, Room 5E03 6100 Executive Boulevard Bethesda, MD 20892 Applications must be received by July 27, 1994. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by NIH staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, it will be returned to the applicant, who may then submit it for review in competition with unsolicited applications at the next available review cycle. Responsive applications may be triaged by a peer review group to determine their relative competitiveness. The NIH will withdraw from further competition those applications judged to be non-competitive for award and notify the applicant Principal Investigator and institutional official. Those applications judged to be competitive will undergo further evaluation for scientific merit. in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the National Advisory Child Health and Human Development (NACHHD) Council. Review criteria for RFAs are generally the same as those for unsolicited research grant applications, including: o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, and of collaborators, if applicable; o adequacy of time and effort dedicated to the project; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o for studies in HIV-infected women, documented collaboration with ongoing epidemiologic studies of HIV-infected women, including but not limited to the Women and Infants Transmission Study (WITS), the Women's Interagency HIV Study, and the HIV Epidemiologic Research Study (HERS). o for studies of any other cohort of women, documented collaboration with gynecologists or other clinicians who have access to the number and type of women who are proposed to be studied. AWARD CRITERIA The anticipated date of award is March 1, 1995. Funding decisions will be based on peer review and NACHHD Council recommendation, program relevance, and availability of funds. In some cases, if the proposed research has relevance to any other Institute of the National Institutes of Health (such as the National Institute of Allergy and Infectious Diseases), the application may be dually assigned to, and considered for funding by, that institute. Any such assignment will be made independently of peer review procedures. INQUIRIES Written and telephone inquires concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific issues and address the letter of intent to: Pamela Stratton, M.D. Contraceptive Development Branch National Institute of Child Health and Human Development Building 6100, Room 8B13 Bethesda, MD 20892 Telephone: (301) 496-1661 FAX: (301) 496-0962 Direct inquiries regarding fiscal matters to: Melinda Nelson Office of Grants and Contracts National Institute of Child Health and Human Development Building 6100, Room 8A17 Bethesda, MD 20892 Telephone: (301) 496-5481 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.864, Population Research. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CRF 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12374 or health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the american people. .
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