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) 435-0714.

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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