PATHOPHYSIOLOGY, EPIDEMIOLOGY AND TREATMENT OF VULVODYNIA
Release Date: February 7, 2000
RFA: HD-00-008
National Institute of Child Health and Human Development
Office of Research on Women’s Health
Letter of Intent Receipt Date: March 15, 2000
Application Receipt Date: May 5, 2000
THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
PURPOSE
The Center for Population Research (CPR) of the National Institute of Child
Health and Human Development (NICHD) and the NIH Office of Research on
Women’s Health (ORWH) invite new and experienced basic scientists,
epidemiologists, and clinical investigators to submit research grant
applications to further our understanding of the etiology, prevalence,
criteria for accurate diagnosis, underlying pathophysiology and pain
mechanisms, and treatment strategies for vulvodynia. Research grant
applications are encouraged that address preclinical or clinical, biomedical
and/or behavioral research that concentrates on studies of relevance to
vulvodynia. This solicitation is intended to stimulate and strengthen a
multidisciplinary approach to this complex, underresearched area of women’s
health and form a framework for assessing future research needs. The goal is
to build a substantive scientific knowledge base related to this debilitating
condition. This initiative continues and expands the scientific objectives
represented in PA-98-112, Vulvodynia Systematic Epidemiologic, Etiologic
or Therapeutic Studies, and is responsive to the FY 2000 House and Senate
Appropriations Report Language directives recommending that NICHD expand and
intensify vulvodynia research.
HEALTHY PEOPLE 2010
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), Pathophysiology, Epidemiology and Treatment of
Vulvodynia, is related to one or more of the priority areas. Potential
applicants may obtain "Healthy People 2010" at
http://odphp.osophs.dhhs.gov/pubs/hp2000.
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. 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 anticipated
award date is September 29, 2000.
Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm
For this RFA, funds must be requested in $25,000 direct cost modules, up to a
total direct cost of $200,000 per year.
FUNDS AVAILABLE
The NICHD and ORWH intend to commit approximately $1 million in total costs
(direct plus Facilities and Administrative [F & A] costs) in FY 2000 to fund
four to six new grants in response to this RFA. An applicant may request a
project period of up to five years and a budget for direct costs of up to
$200,000 per year, including F & A costs on consortium arrangements. Because
the nature and scope of the research proposed may vary, it is anticipated
that the size of awards also will 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 meritorious applications.
RESEARCH OBJECTIVES
Background
Vulvodynia is one of the poorly understood complex focal pain syndromes,
representing a complex, multifactorial clinical syndrome of unexplained
vulvar pain, sexual dysfunction, and psychological disturbance. On April 2-
3, 1997, the NICHD, in collaboration with the Office of Research on Women’s
Health, Office of Rare Diseases, and the National Institute of Arthritis,
Musculoskeletal and Skin Diseases, convened the Vulvodynia Workshop:
Current Knowledge and Future Directions to explore the state-of-the-science
by reviewing current definitions, etiology, epidemiology, and treatment
modalities. In response to recommendations made at the conclusion of this
workshop, emphasis was placed on stimulating clinically relevant research on
promising biomedical, clinical or behavioral studies that would expand our
knowledge of vulvodynia. The Program Announcement (PA-98-112), Vulvodynia
Systematic Epidemiologic, Etiologic or Therapeutic Studies, was published on
September 29, 1998. It was anticipated that studies in this underresearched
area would form a foundation for assessing future research needs and
complement our overall commitment to support research important to women’s
health. As a result of the workshop and subsequent PA, the research
community was made aware of our interest in this area. Notwithstanding this
programmatic emphasis, additional efforts are now needed to strengthen the
science base. This RFA represents an expansion of ongoing research efforts
to reduce the burden of this disease and ultimately improve the quality of
life for women affected with this disorder. Moreover, this initiative
reflects the NICHD and ORWH research agendas for identifying and
characterizing the pathophysiologic factors, and potential avenues for
treatment related to benign gynecologic disorders.
Vulvodynia is a clinical condition with several different and poorly defined
antecedents. There is a need to increase knowledge and understanding about
vulvodynia and the biological processes that lead to its development and
long-term sequelae. The factors influencing a patient’s decision to seek
care and the criteria by which the clinician selects therapy are not uniform.
Patients frequently experience dyspareunia, persistent vulvar irritation,
burning and pain. Symptoms also may be associated with the urinary and
gastrointestinal tracts. In addition, diagnostic criteria that define the
categories and subtypes of vulvodynia are neither well defined nor utilized
consistently by many clinicians. While the true prevalence of vulvodynia
remains unknown, there are several common diagnostic subtypes that are
recognized, including (1) vulvar vestibulitis, (2) dysesthetic vulvodynia,
and (3) vulvar dermatosis and dermatitis. Vulvar vestibulitis, thought to be
the most common subtype, has been found in 15 percent of patients in a
general clinical practice in some studies. While histologic studies suggest
a chronic inflammatory reaction, the causes of the inflammation as well as
its significance remain unclear. The role of pelvic floor dysfunction as a
catalyst for the development of vulvar pain syndromes, particularly
dysesthethic vulvodynia, has been proposed in several published studies, but
its true impact is uncertain. Published studies also comment on the
influence of neurophysiological parameters as a potential association that
should be taken into account.
Surgery has been reported to be a successful intervention for selected cases
of vulvar vestibulitis, and is reserved for women with severe and long-
standing symptoms. However, optimum surgical management is still
undetermined and very few well-designed, long-term studies document the
outcome of surgical procedures. In addition, pharmacological and behavioral
therapies would benefit from treatment standardization and prospective
clinical studies.
Despite the use of surgery, pharmaceutical regimens, psychological support,
physical therapy, and pain management techniques, such as biofeedback and
behavior modification, there is no consensus on which procedure(s) offers the
most improvement and patient satisfaction. A combination of therapies is
frequently utilized and, while there are several options available for the
treatment of vulvodynia, most of the literature supports the conclusion that
cures for vulvodynia are uncommon and a specific inciting cause can be
diagnosed in a relatively small percentage of patients. Consideration of
these factors must be an integral part of the management of patients with
vulvodynia and this underscores the need to examine this condition in a
multidisciplinary context.
This elusive pain syndrome has many unexplored questions. Therefore, an
overall strategy of augmenting and strengthening a multidisciplinary approach
to this distressing condition, leading to improved diagnosis and therapy, is
warranted. Improvements in pain management, as well as approaches to the
treatment and prevention of vulvodynia will require insight and increased
knowledge of the underlying etiology and pathophysiological mechanisms.
Research Scope
Several research strategies are deemed important for the potential
development of new leads or approaches. Examples of the scope of research
areas considered responsive to this RFA include, but are not limited to, the
following:
o Elucidation of pathogenic antecedents involved in stimulating the
biological processes that lead to the development and long-term sequelae of
vulvodynia. Evaluation of the role of pathologic vaginal microbial and viral
agents or altered vagina flora in this process.
o Development of novel experimental preclinical or clinical studies in
animal models and/or humans to evaluate normal and dysfunctional
neurophysiological parameters and mechanisms. Determination of the role of
neurogenic irritability and/or regional autonomic dysfunction and its
influence on symptoms, muscle instability, tissue injury, and repair in
vulvodynia.
o Documentation of the use and evaluation of the effects of adjunctive
therapy in clinical trials, including behavioral, surgical, and medical
treatment, in women with vulvodynia. Investigation and translation of
promising, innovative, preclinical findings into clinical research
applications, including designing small clinical trials of novel therapeutic
interventions.
o Assessment of the natural history of vulvodynia. Creation and validation
of small population-based epidemiological studies that assist in defining the
prevalence and resolution of vulvodynia and its subtypes. Feasibility and
effectiveness of risk factor modification for prevention of vulvodynia.
o Assessment of normal tissue structure, muscle integrity, cellular
mechanisms, structural defects, and the factors involved in the transition
between latent injury, symptoms, and tissue rehabilitation in vulvodynia.
Detection of the role of nerve damage, muscular damage, and/or direct tissue
disruption.
o Determination of the influence of risk factors such as race, ethnicity,
and co-morbid medical conditions or previous surgery associated with the
occurrence of vulvodynia, treatment outcomes, and complications.
Prospective applicants are encouraged to consider relevant topics other than
those listed here and to discuss their ideas 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, 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, and available at:
http://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 subject 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, published in the NIH Guide for Grants and
Contracts, March 6, 1998, and available at:
http://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 the 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 Dr. Estella Parrott, by March 15, 2000,
at the address listed under INQUIRIES.
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, on the Internet at
http://grants.nih.gov/grants/funding/phs398/phs398.html, 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, E-mail: Grantsinfo@nih.gov.
Application Instructions
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The
just-in-time concept allows applicants to submit certain information only
when there is a possibility for an award. It is anticipated that these
changes will reduce the administrative burden for the applicants, reviewers
and Institute staff. The research grant application form PHS 398 (rev. 4/98)
is to be used in applying for these grants, with the modifications noted
below.
Modular Grant applications in response to this RFA will request direct costs
in $25,000 modules, up to a total direct cost request of $200,000 per year.
The total direct costs must be requested in accordance with the program
guidelines and the modifications made to the standard PHS 398 application
instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $200,000) and Total Costs [Modular
Total Direct plus Facilities and Administrative (F&A) costs] for the initial
budget period. Items 8a and 8b should be completed indicating the Direct and
Total Costs for the entire proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for
sample pages.) At the top of the page, enter the total direct costs requested
for each year. This is not a Form Page.
Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the
nearest $1,000. List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project. Indicate whether the collaborating institution
is foreign or domestic. The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.
Include the Letter of Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a
specific role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three
pages may be used for each person. A sample biographical sketch may be
viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm.
- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.
o CHECKLIST: This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied
in the calculation of the F&A costs for the initial budget period and all
future budget years.
o The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.
Submission Instructions
The RFA label available in the PHS 398 (rev. 4/98) application form must be
stapled to the bottom of the face page of the application and must display
the RFA number HD-00-008. A sample RFA label is available at
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this
is in the pdf format. 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 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 should be
sent to:
Director
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 5, 2000. 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
for responsiveness to the RFA by NICHD and ORWH. 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 NICHD in accordance with the review criteria stated below.
As part of the initial merit review, all applications will receive a written
critique and may undergo a process in which only those applications deemed to
have the highest scientific merit will be discussed, assigned a priority
score, and receive a second level review by the National Advisory Child
Health and Human Development Council.
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
methods? 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 also will 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 also will 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.
SCHEDULE
Letter of Intent Receipt Date: March 15, 2000
Application Receipt Date: May 5, 2000
Peer Review Date: June 2000
Council Review: September 2000
Earliest Anticipated Start Date: September 29, 2000
AWARD CRITERIA
Criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o 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:
Estella Parrott, M.D., M.P.H.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 496-6515
FAX: (301) 496-0962
E-mail: ep61h@nih.gov
Direct inquiries regarding fiscal matters to:
Michael J. Loewe
Lead Grants Management Specialist
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17J, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 435-7008
FAX: (301) 402-0915
E-mail: ml70m@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.864. 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 NIH grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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