BASIC SCIENCE RESEARCH ON FEMALE PELVIC FLOOR DISORDERS

Release Date: February 11, 1999

RFA:  HD-99-003

P.T.

National Institute of Child Health and Human Development
Office of Research on Women's Health

Letter of Intent Receipt Date:  March 10, 1999
Application Receipt Date:  May 12, 1999

PURPOSE

The Center for Population Research (CPR) of the National Institute of Child
Health and Human Development (NICHD) and the Office of Research on Women's
Health (ORWH) seek applications that address basic biomedical research on
female pelvic floor structure and function with the purpose of stimulating
research that can contribute to improving the understanding of pelvic floor
disorders and their sequelae.  In response to recommendations made at the
recent NIH-sponsored Workshop on Pelvic Floor Disorders, emphasis will be
placed on research to examine normal pelvic floor function and established
pelvic floor dysfunction, injury during vaginal delivery, development and
validation of research tools necessary to assess pelvic floor function,
development of animal models as surrogates to study normal human pelvic floor
function and established dysfunction, and studies on hormonal factors involved
in pelvic floor development and function.  It is anticipated that studies in
these under researched areas will provide much-needed information on the
normal anatomy and physiology of pelvic floor connective tissues, muscles and
nerves that will form a baseline to assess deviations from this norm that may
underlie dysfunctional states such as pelvic floor prolapse, urinary
incontinence and anal incontinence.

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 Request for Applications (RFA),
Basic Science Research on Female Pelvic Floor Disorders, is related to the
priority area of Maternal and Infant Health.  Potential applicants may obtain
a copy of "Healthy People 2000" at
hhttp://www.crisny.org/health/us/health7.html

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project
grant (R01) award mechanism. Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.  The
total project period for an application submitted in response to this RFA may
not exceed five years.  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.  The earliest anticipated award date is September 30,
1999.

FUNDS AVAILABLE

The NICHD and the ORWH intend to commit approximately $2 million (total costs)
in FY 1999 to fund six to eight new grants in response to this RFA.  Because
the nature and scope of the research proposed may vary, it is anticipated that
the size of each award will also vary.  Although the financial plans of the
NICHD and ORWH provide support for this program, awards pursuant to this RFA
are contingent upon the availability of funds and the receipt of a sufficient
number of applications of outstanding scientific and technical merit.

RESEARCH OBJECTIVES

Background

The term pelvic floor dysfunction refers to a group of clinical conditions
that includes urinary incontinence, anal incontinence, pelvic organ prolapse,
sensory and emptying abnormalities of the lower urinary tract, defecatory
dysfunction, sexual dysfunction and several chronic pain syndromes, including
vulvodynia.  The three most common and definable conditions encountered
clinically are urinary incontinence, anal incontinence and pelvic organ
prolapse.  It is estimated that at least one-third of adult women are affected
by at least one of these conditions.  Furthermore, statistics show that 30 to
40 percent of women suffer from some degree of incontinence in their lifetime,
and that almost 10 percent of women will undergo surgery for urinary
incontinence or pelvic organ prolapse.  Interestingly, 30 percent of those
undergoing surgery will have at least two surgeries in trying to correct the
problem.  With the steady increase in the population of older women, the
national cost burden related to pelvic floor disorders (PFDs) is enormous in
terms of lost productivity, decreased quality of life and direct health care
costs.

Little epidemiologic information on pelvic organ prolapse exists despite the
fact that this disorder is one of the most common indications for gynecologic
surgery.  Prolapse has been reported to be the most common reason for
hysterectomy in women older than 50 years, and in one report accounted for 13
percent of hysterectomies in all age groups.  Indeed, it is estimated that
one-half million surgical procedures for prolapse are performed annually in
the United States, almost twice as many as procedures performed for urinary
incontinence.  This is likely the consequence of the fact that pelvic organ
prolapse frequently is not recognized until end-stage disease exists, and
surgery is the only recourse.

Estimates of the prevalence of urinary incontinence in adult women vary
anywhere from 14 to 41 percent, depending on the case definition used and the
study population.  Although it is generally assumed that the prevalence of
urinary incontinence increases with age, some studies have demonstrated either
minimal increases in prevalence with age or even a higher prevalence in
younger age groups.  Over the lifespan, statistics show that women are
approximately twice as likely as men to have urinary incontinence, however,
the prevalence in the female population versus the male population may be as
much as seven times higher in younger adults.  Finally, there are data to
indicate that the incidence of urinary incontinence may be higher in Caucasian
women than in African-American women, thereby providing a basis to insure the
adequate representation of minority populations and their subgroups in study
designs.

Similar to urinary incontinence, inconsistent nonstandardized definitions are
also problematic in  epidemiologic studies of anal incontinence.  Anal
incontinence can include the involuntary and unwanted passage of gas, liquid
or solid stool.  Even though incontinence of gas (flatus incontinence) may be
as bothersome as infrequent incontinence of stool (fecal incontinence), it is
often discounted, a fact which may account for a significant underestimation
of the prevalence of anal incontinence.  For example, the overall prevalence
of fecal incontinence has been reported to approach 20 percent, while the
prevalence of fecal or flatal incontinence in a study population of women
following delivery was between 12 and 39 percent, depending on the type of
delivery.

Although factors such as radical pelvic surgery and radiation may provoke
pelvic floor dysfunction, the major inciting factor for the development of
pelvic floor dysfunction in women is vaginal delivery.  However, the magnitude
and duration of the effects of vaginal delivery, and the specific aspects of
the labor and delivery processes that affect the pelvic floor are not well-
understood.  Moreover, the role of specific events during the labor and
delivery processes in the development of pelvic floor dysfunction may differ
depending on the specific type of dysfunction.  For example, some studies show
increased risks for urinary incontinence related to parity, while others have
concluded that parity is not a risk factor for urinary incontinence.  In
contrast, childbirth is clearly an important inciting factor in the
development of pelvic organ prolapse and anal incontinence.

Chronic pain is often an insidious byproduct of many dysfunctional states of
the pelvic floor including vulvodynia and vulvar vestibulitis.  Such pain may
be localized as with vulvodynia or it may be diffuse.  In telephone interviews
with 5000 women of reproductive age, approximately 15 percent reported chronic
pelvic pain defined as pain longer than three months.  Fifteen percent
reported time lost from work as a result of the pelvic pain, and 45 percent
reported reduced work productivity.  Consequently, improvements in pelvic pain
management, as well as new approaches to the treatment and prevention of PFDs
will require research on the innervation of muscles and connective tissues of
the pelvic floor, an area which heretofore has been under-researched.

Research Scope

On September 28-29, 1998, the NICHD, in collaboration with the ORWH, the
National Institute on Aging, the National Institute of Diabetes and Digestive
and Kidney Diseases and the Office of Rare Diseases, held a workshop to
examine the state of basic, clinical and epidemiologic research addressing
PFDs.  A consensus emerged that underscored the lack of a substantive
knowledge base that defines normal structure and function of tissues
comprising the pelvic floor.  Such information was deemed critical to
developing standardized criteria for accurate and early diagnosis of PFDs,
elucidating the multiple etiologies of PFDs, and developing new treatment and
prevention strategies for PFDs.  Examples of research areas deemed important
for developing this knowledge base and beyond include the following:

Research into Normal Pelvic Floor Function - normal structure and function of
connective tissues, muscles and nerves comprising the pelvic floor; the role
of connective tissue strength in relation to development of PFDs;
rehabilitation of damaged connective tissues and muscles including
reinervation of these tissues; effects of aging on the various tissues
comprising the pelvic floor.

Research into Established Pelvic Floor Dysfunction - natural history of PFDs;
muscular, fascial and neurological injuries associated with established pelvic
floor dysfunction; the promoting, intervening and decompensating factors
involved in transition between latent injury and symptomatic condition;
relationship between injury type, physiological abnormalities, symptoms and
life impact.

Hormonal Factors - effects of sex steroid hormones on structure and function
of pelvic floor tissues; efficacy of treatment with estrogens and progestins
alone or in combination on PFDs; effects of selective estrogen receptor
modulators (SERMs) on pelvic floor dysfunction.

Research into Injury During Vaginal Delivery - mechanisms of injury during
vaginal delivery involving pelvic floor tissues, the cellular mechanisms
underlying repair from these injuries, and the mechanisms that influence
pelvic floor recovery from childbirth; prospective analysis of the
relationship between precise obstetrical events and pelvic floor injury;
effect of postpartum interventions or therapeutic agents on pelvic floor
recovery following normal and abnormal childbirth; protective effect and
timing of Cesarean section at different stages of labor; effect of episiotomy
related to different phases of the second stage of labor and fetal head
descent.

Develop and Validate Research Tools to Assess Pelvic Floor Function - validate
existing or develop and validate new techniques for assessing normal pelvic
floor function or dysfunction, and changes to pelvic floor structure and
function during pregnancy; develop and validate intermediate endpoints to act
as surrogates for long-term follow-up studies.

Develop Animal Models for Study of Human Pelvic Floor Function and
Dysfunction.

Since this list is not meant to be all-inclusive, prospective applicants are
encouraged to discuss their ideas for applications with the program staff
listed under INQUIRIES.

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 are provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research," which was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:
https://grants.nih.gov/grants/guide/notice-files/not94-100.html.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects' that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning policy.

LETTER OF INTENT

Prospective applicants are asked to submit 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 this RFA. 
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows NICHD staff to estimate the potential review workload and
avoid conflict of interest in the review.

The letter of intent is to be sent to the program staff listed under INQUIRIES
by March 10, 1999.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301-710-0267, Email: 
[email protected].

The RFA label available in the PHS 398 (rev. 4/98) 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, 'Basic Science Research on Female Pelvic Floor Disorders,'
HD-99-003, must be typed on line 2 of the face page of the application form
and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must be
sent to:

Scott Andres, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)

Applications must be received by May 12, 1999.  If an application is received
after that date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR 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 for completeness by the CSR and
responsiveness to the RFA by NICHD and ORWH staff.  Incomplete and/or non-
responsive applications will be returned to the applicant without further
consideration.  Applications that are complete and responsive to the RFA will
be evaluated for scientific and technical merit by an appropriate peer review
group convened by the NICHD in accordance with the review criteria stated
below.  As part of the initial merit review, a process will be used by the
initial review group in which applications receive a written critique and
undergo a process in which only those applications deemed to have the highest
scientific merit, generally the top half of the applications under review,
will be discussed, assigned a priority score, and receive a second level
review by the National Advisory Child Health and Human Development Council (NACHHD).

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments, reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.  Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score.  For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will also be
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the
proposed research.

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.

The initial review group will also examine the provisions for the protection
of human subjects and the safety of the research environment.

Schedule

Letter of Intent Receipt Date:    March 10, 1999
Application Receipt Date:         May 12, 1999
Peer Review Date:                 July 1999
Council Review:                   September 1999
Earliest Anticipated Start Date:  September 30, 1999

AWARD CRITERIA

Award criteria that will be used to make award decisions include scientific
merit (as determined by peer review); availability of funds; and programmatic
priorities.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Louis V. DePaolo, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
Building 61E, Room 8B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6970
FAX:  (301) 496-0962
Email:  [email protected]

Loretta Finnegan, M.D.
Office of Research on Women's Health
National Institutes of Health
Building 1, Room 201, MSC 0161
Bethesda, MD  20892-0161
Telephone:  (301) 402-1770
FAX:  (301) 402-1798
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Melinda Nelson
Grants Management Branch
National Institute of Child Health and Human Development
Building 61E, Room 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5482
FAX:  (301) 496-0915
Email:  [email protected]

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 CFR 52 and 45 CFR Part 74.  This program
is not subject to the intergovernmental review requirements of Executive Order
12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children.  This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.

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