BASIC AND CLINICAL RESEARCH ON FIBROMYALGIA

Release Date:  March 26, 1998

RFA:  AR-98-006

P.T.

National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Dental Research
National Institute of Neurological Disorders and Stroke
Office of Alternative Medicine
Office of Behavioral and Social Sciences Research
Office of Research on Women's Health

Letter of Intent Receipt Date:  May 15, 1998
Application Receipt Date:  July 15, 1998

PURPOSE

The Rheumatic Diseases Program of the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS), Chronic Disabling Diseases Program,
National Institute of Dental Research (NIDR), Division of Convulsive, Infectious
and Immune Disorders, National Institute of Neurological Disorders and Stroke
(NINDS), Office of Alternative Medicine (OAM), Office of Behavioral and Social
Sciences Research (OBSSR), and the Office of Research on Women's Health (ORWH)
invite research grant applications (R01) and exploratory/developmental grants
(R21) from interested investigators for tightly focused innovative research
studies related to all aspects of pathogenesis and clinical manifestations of
fibromyalgia syndrome (FMS) and to relationships between FMS and
temporomandibular disorders (TMDs).  Improved understanding of the origins and
the biological, neurological and psychosocial mechanisms underlying the clinical
manifestations of fibromyalgia syndrome will have an impact on the development
of more effective diagnostic tests and new therapies for both FMS and related
disorders.

This Request for Applications (RFA) involves the use of the traditional research
project grant (R01) and the exploratory/developmental grant (R21).  The objective
of the exploratory/developmental mechanism (R21) is to encourage applications
from individuals who are interested in testing innovative or conceptually
creative ideas that are scientifically sound and may advance our understanding
of FMS and TMDs.  Another objective is to encourage necessary initial development
to provide a basis for future research project applications.

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, Basic and Clinical Research on
Fibromyalgia, is related to the priority areas of chronic disabling conditions
and of older adults and preventive services.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary
Report:  Stock No.017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).

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

Support of the program will be through the National Institutes of Health (NIH)
individual research project grant (R01) and the exploratory/developmental grant
(R21) mechanism.  This RFA is a one time solicitation.  The anticipated award
date is March 1, 1999.  All PHS and NIH grants policies will apply to
applications received and awards made in response to this request for
applications.  Applicants will be responsible for the planning, direction, and
execution of the proposed project.

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 should
be included within the application.

R01 Applications.  R01 awards will vary in size and duration reflecting the
nature and scope of the research proposed. Future unsolicited competing
continuation applications will compete with all investigator initiated
applications and be reviewed according to customary peer review.

R21 Applications.  Use of this novel mechanism by investigators experienced in
fibromyalgia research who wish to adapt new methods or techniques established in
other fields to develop scientific approaches and models to study the
pathogenesis, epidemiology and clinical aspects of FMS are encouraged to apply. 
Also encouraged to apply are investigators with expertise in fields other than
FMS who wish to establish new research programs on FMS or related disorders, such
as the TMDs.

Exploratory/developmental studies are not intended for large scale undertakings,
nor to support or supplement ongoing research. Instead, investigators are
encouraged to explore the feasibility of an innovative research question or
approach which may not be justifiable through existing research to compete as a
standard research project grant (e.g., R01), and to develop a research basis for
a subsequent application through other mechanisms, i.e., R01, P01.

Exploratory/developmental (R21) grants, may not exceed $75,000 per year in direct
costs, not including indirect costs for collaborating institutions, if any.  The
total project period for an R21 application submitted in response to this RFA may
not exceed three years.  These grants are non-renewable and continuation of
projects developed under the R21 program will be through the traditional
unsolicited (R01 or P01) grant programs.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the first year of
support for this RFA will be $1.825 million ($750,000 from the NIAMS, $400,000
from NIDR, $300,000 from NINDS, $250,000 from ORWH and $125,000 from OAM).  In
fiscal year 1999, approximately 5 to 10 awards related to this RFA are planned.
Actual funding is contingent upon receipt of a sufficient number of
scientifically meritorious applications.  Funding beyond the first and subsequent
years of the grant will be contingent upon satisfactory progress during the
preceding years and the availability of funds.

RESEARCH OBJECTIVES

Background

Patients with FMS have chronic widespread pain, fatigue, sleep disturbances and
tender points.  Paresthesias, anxiety, headache, and  irritable bowel syndrome
are also frequently seen in patients with FMS.  Current estimates of the
prevalence of FMS as diagnosed according to American College of Rheumatology
classification criteria, suggest that it may occur in up to 2 percent of the
population, but the prevalence is higher among women with estimates indicating
that it may affect up to 7 percent of women age 70 and older.  FMS may co-exist
with other conditions, for example TMDs, myofascial pain syndrome, rheumatoid
arthritis, lupus and hypothyroidism.  Many investigators believe that FMS
encompasses a spectrum of diseases with common pathogenic pathways.

There is a need to better understand the etiology and natural history of this
condition and to define the patho-physiologic and psycho-social mechanisms
leading to its clinical manifestations and responses to therapy.

Scope

The purpose of this RFA is to promote investigator-initiated research projects
and exploratory/developmental projects that will advance our understanding of FMS
and related disorders and provide critical knowledge needed for the treatment and
prevention of the syndrome.  Investigations in all areas related to FMS are
included with the exception of Phase II and III clinical trials.  Small pilot
clinical trials are acceptable under this RFA.  (Investigators who wish to
develop applications for Phase II-III clinical trials in FMS should contact the
program official listed under INQUIRIES.)

This initiative is intended to encourage applications in all areas relevant to
FMS, including basic, clinical, epidemiologic and behavioral research projects. 
Molecular, cellular and physiologic studies of neuroendocrine dysregulation,
sleep disturbances and pain control mechanisms are of interest. The development
of new in vivo and in vitro experimental systems to dissect and study the
components of the syndrome are emphasized. Epidemiological studies on the natural
history of the syndrome as well as observational studies on disease progression
and responses to interventions are included as are studies of behavioral
components and interventions. In addition epidemiological, basic, or clinical
research characterizing relationships between FMS and temporomandibular disorders
are specifically encouraged.  TMDs typically involve pain and/or tenderness in
cervical or craniofacial tissues, principally in the muscles of mastication or
the region surrounding the temporomandibular joint.

Areas of interest include, but are not limited to, the following:

Studies of pain, including: pain thresholds, exogenous and endogenous modulation
of pain perception; neurobiological and/or genetic identification of chemical and
structural bases of chronic pain; studies of interaction between peripheral sites
and the CNS structures involved in pain perception; and development of
experimental models of pain perception that recapitulate the features of FMS.

Development and validation of new methodologies to measure pain and pain
perception in patients with FMS or TMDs.

Research on the role of trauma in the onset of FMS or TMDs.

Molecular and physiologic studies of endocrine and neuroendocrine changes in FMS,
neuroendocrine mechanisms triggered as part of stress responses and how they
might relate to the onset and chronic course of FMS or TMDs.

Studies of mechanisms underlying FMS-related sleep disturbance and their
relationships to cognitive skill performance and memory; dissection of the
cellular and molecular factors that mediate the relation of sleep disturbance to
fatigue and chronic pain.

Studies aimed at identifying the hormonal and genetic factors that can explain
the higher frequency of FMS and TMDs among female patients.

Natural history of FMS; studies to establish the cause and nature of the co-
existence and/or overlap of FMS and TMDs with myofacial pain syndrome, rheumatoid
arthritis or other diseases, syndromes and conditions; development of clinical,
epidemiological or laboratory parameters useful to identify patient subsets;
studies of outcomes and responses to treatment.

Identification and analysis of biopsychosocial factors that contribute to
predisposition and onset of FMS symptoms; behavioral research on all aspects of
FMS, including the relation between disturbed sleep, inactivity, pain and
depression that are often observed in some patients with FMS; studies on stress
factors, and development of innovative behavioral approaches for treatment of FMS
or TMDs.

Pilot research on the effectiveness of alternative medicine approaches or
techniques for treatment and/or physical rehabilitation in FMS or TMDs

This list is intended to be illustrative and not exclusive or restrictive.
Applications combining interdisciplinary approaches that include collaborations
between FMS researchers and experts in other scientific fields are strongly
encouraged.

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 so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition under study. 
If women or minorities are excluded or inadequately represented, a clear
compelling rationale must be provided.  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 28, 1994 (FR 59 14508-14513) and in the NIH Guide
for Grants and Contracts, Volume 23, Number 11, March 18, 1994.  This information
is available on the Internet at
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.
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.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 15, 1998, 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 Institute staff to estimate
the potential review workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

Susana A. Serrate-Sztein, MD
Rheumatic Diseases Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25E, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email: szteins@exchange.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) 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 301/435-0714, email:  asknih@od.nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) 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 2 of the face page of the application form and the
YES box must be marked.

Specific Instructions for Exploratory/Developmental Grant Applications (R21)

Items a-d of the Research Plan may not exceed a total of ten pages.  Tables and
figures are included in the ten page limitation.  Applications that exceed this
page limitation or NIH requirements for type size and margins (refer to PHS 398
application for details) will be returned to the applicant without further
consideration. The ten page limitation does not include items (e)-(i) (Human
Subjects, Vertebrate Animals,Literature Cited,Consortia, Consultants/
Collaborators).

Submit a signed original of the application, including the Checklist, and three
signed copies 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 also be
sent to:

Tommy L. Broadwater, Ph.D.
Scientific Review Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25U, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-4952
FAX:  (301) 480-4543
Email:  broadwater@exchange.nih.gov

Applications must be received by July 15, 1998.  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 CSR and
responsiveness by the NIAMS 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 NIAMS in
accordance with the standard NIH peer review procedures.  As part of the initial
merit review, all applications will 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 applications under review, will be discussed,
assigned a priority score, and receive a second level review by the National
Arthritis and Musculoskeletal and Skin Diseases Advisory Council, The National
Dental Research Advisory Council and the National Neurological Disorders and
Stroke Advisory 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 review, comments on the following aspects of the application will be made
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 the assignment of the overall score.

(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?

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

The initial review group will also examine the provisions for the protection of
human and animal subjects, the safety of the research environment, and
conformance with the NIH Guidelines for the Inclusion of Women and Minorities as
Subjects in Clinical Research.

Because the exploratory grant mechanism (R21) is designed to support innovative
ideas, preliminary data as evidence of feasibility of the project are not
required.  However, the applicant does have the responsibility for developing a
sound research plan approach.  Innovation of the project and potential
significance of the proposed research will be major considerations in the
evaluation of this mechanism.

AWARD CRITERIA

The anticipated date of award is March 1, 1999.  Awards will be based upon the
following criteria:

o  scientific merit
o  availability of funds
o  programmatic priorities of the funding ICD
o  responsiveness to the RFA

Schedule

Letter of Intent Receipt Date:  May 15, 1998
Application Receipt Date:       July 15, 1998
Initial Review:                 November 1998
Second Level Review:            January 1999
Anticipated Award Date:         March 1, 1999

INQUIRIES

Written and telephone 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:

Dr. Susana A. Serrate-Sztein
Rheumatic Diseases Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-25E, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email: szteins@exchange.nih.gov

Dr. Patricia S. Bryant
Division of Extramural Research
National Institute of Dental Research
45 Center Drive, Room 4AN24K, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-2095
FAX:  (301) 480-8318
Email:  bryantp@exchange.nih.gov

Dr. Cheryl A. Kitt
Division of Convulsive, Infectious and Immune Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 504
Bethesda, MD  20892
Telephone:  (301) 496-1431
FAX: (301) 402-2060
Email:  ck82j@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Carol Fitzpatrick
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-43B, MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3503
FAX:  (301) 480-4543
Email:  fitzpatc@exchange.nih.gov

Martin R. Rubinstein
Grants Management Branch
National Institute of Dental Research
45 Center Drive, Room 4AN44A, MSC 6500
Bethesda, MD 20892-6500
Telephone:  (301) 594-4800
FAX:  (301) 480-8301
Email:  mr49c@nih.gov

Karen D. Shields
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
Email:  ShieldsK@ninds.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.846 and 93.121.  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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