Full Text AG-94-002

MENOPAUSE AND HEALTH IN AGING WOMEN

NIH GUIDE, Volume 22, Number 32, September 3, 1993

RFA:  AG-94-002

P.T. 34, II

Keywords: 
  Aging/Gerontology 
  Human Reproduction/Fertility 
  Physiology, Human 


National Institute on Aging
National Institute of Nursing Research
Office of Research on Women's Health

Letter of Intent Receipt Date:  October 15, 1993
Application Receipt Date:  November 29, 1993

PURPOSE

The National Institute on Aging (NIA), the National Institute of
Nursing Research (NINR), and the Office of Research on Women's Health
(ORWH) invite cooperative agreement applications for Clinical Sites to
conduct prospective longitudinal studies of the natural history of
menopause and the decline in ovarian function in women.  The primary
objective of this initiative is to characterize the chronology of the
biological and psychosocial antecedents and sequelae of the menopausal
transition and the effect of this transition on subsequent health and
risk factors for age-related disease.  To promote essential
collaborative aspects of this initiative, applications are also
requested for a Central Laboratory to conduct standardized assays of
markers of ovarian aging or aging of the ovarian-hypothalamo-pituitary
axis and for a Coordinating Center to coordinate the collection,
management, and analysis of a common data set.  (The Clinical Sites,
the Central Laboratory, and the Coordinating Center are referred to
hereinafter as "Organizational Components or Components.")

Because the menopausal experience in minority women has been
particularly neglected, special emphasis in minority populations on the
unique biological and socio-cultural factors that may differentially
influence the menopausal transition and its consequences is an integral
part of this initiative.  Applications that propose studies in
populations that are predominantly or totally of minority composition
are strongly encouraged.

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), Menopause and Health in Aging Women, is related
to the priority area 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 "Healthy People 2000" (Summary
Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic 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.  Due to the need for close
coordination and monitoring, no foreign or international components
will be considered in this RFA.  Applications from minorities and women
are encouraged.

MECHANISM OF SUPPORT

The administrative and funding instrument to be used for this program
will be a cooperative agreement (U01), an assistance mechanism (rather
than an acquisition mechanism), in which substantial NIH scientific
and/or programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient's activity by
involvement in, and otherwise working jointly with, the award recipient
in a partner role, but it is not to assume direction, prime
responsibility, or a dominant role in the activity.  Details of the
responsibilities, relationships, and governance of the study to be
funded under cooperative agreement(s) are discussed under the section
Terms and Conditions of Award.  Applicants will be responsible for the
planning, direction, and execution of their individual proposed project
and for planning and participating in collaborative activities with
other award recipients under this RFA.  All parties agree to accept the
participatory and cooperative nature of the group process.

Awards will be administered under PHS grants policy as stated in the
PHS Grants Policy Statement, DHHS Publication NO. (OASH) 90-50,000,
revised October 1, 1990.

The total project period for applications submitted in response to this
RFA may not exceed five years in duration.  Proposed research should
pose hypotheses or questions that can be successfully addressed in this
period.  The anticipated award date is July 1, 1994.

It is anticipated that there will be a renewed competition after five
years because extended longitudinal follow-up beyond the initial
project period is strongly desired.  If the program of cooperative
agreements are not continued, the awardees may submit grant
applications through the usual investigator-initiated grants program.

FUNDS AVAILABLE

It is expected that up to $2.3 million (total cost) for first year
expenses will be available in Fiscal Year 1994 to fund five Clinical
Sites plus a Coordinating Center and a Central Laboratory from
applications submitted in response to this RFA.  If an institution
seeks to be selected for more than one type of Organizational
Component, separate applications must be filed for each Component, with
distinct budgets that are independent of each other and do not overlap
in either objectives or budget items.  The requested total funding
(direct plus indirect costs) for the first year may not exceed $350,000
for Clinical Site applications, $250,000 for Coordinating Center
applications and $300,000 for Central Laboratory applications.  For the
entire five-year project period, total (direct plus indirect) costs
requested per application may not exceed $1.75 million for each
Clinical Site, $1.25 million for the Coordinating Center and $1.5
million for the Central Laboratory.  Within these limits, escalations
after the first year for recurring costs are limited to 4 percent per
year.  Applications failing to meet these requirements will not be
reviewed.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program will be provided for in the financial plans of the NIA and
co-sponsors of this RFA, the award of grants pursuant to this RFA are
contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Menopause is a universal phenomenon in female aging.  Although the
decline in ovarian function is increasingly believed to play a
significant role in the etiology of short- and long-term disorders and
diseases, relatively little research has focussed on menopause and
scientific information is limited on the physiological and behavioral
changes preceding and following the cessation of menses.  Striking
hormonal aberrations have been observed in the perimenopause and
profound metabolic alterations are known to occur in very different
biological systems, such as the musculoskeletal system (accelerated
loss of bone and muscle), the urogenital system (atrophy) and the
central nervous system (hot flashes, mood and memory alterations and
sleep disturbances).  Reduced ovarian hormone levels may play a key
role in osteoporosis, and are associated with an increase risk of
cardiovascular disease (CVD) and other disorders, such as urinary
incontinence.

There is considerable individual variation among women in the
manifestation of perimenopausal signs and symptoms.  The peri- and
postmenopausal experience encompasses a complex interaction of
socio-cultural, psychological, and environmental factors as well as
biological changes relating strictly to altered ovarian hormone status
or deficiency.  In the U.S., the perimenopausal experience is usually
perceived largely in negative terms -- as a transitional phase
dominated by disturbing physical and mental symptoms.  It has been
suggested that highly negative characterizations of menopause may be
due to an over-sampling of clinical populations of perimenopausal
women, who, seeking treatment for symptoms, were more readily available
for study and whose experiences represented the extremes of a difficult
transition.  Importantly, our knowledge base on menopause is extremely
narrow in that it applies almost exclusively to white women (of
Northwest European ancestry) -- very little is known about the range of
perimenopausal experiences in women of other racial/ethnic (i.e.,
African, Asian, Native American, Hispanic) background(s).  The
socio-cultural and behavioral antecedents and consequences of menopause
have also not been well addressed and major gaps exist in our
understanding of factors that may profoundly influence the perception
of, and response to, perimenopausal symptoms and sequelae.

Because of a general lack of accurate information, there has also been
considerable confusion with respect to the potential risks and benefits
to be realized by long-term postmenopausal hormone therapy.  The NIH
Women's Health Initiative (WHI) will explore a variety of important
issues and interventions relevant to postmenopausal health, such as the
effects of dietary fat, specific dietary factors, and hormone
replacement therapy on endpoints that include cardiovascular disease,
osteoporosis; and breast, colon, and endometrial cancer.  However, an
assessment of pre- and perimenopausal women, and hence an understanding
of the natural history of menopause, is not among its objectives.  This
RFA will complement the WHI by providing information on the period
preceding the cessation of menstruation, which may be crucial in
clarifying why certain segments of postmenopausal women may benefit
more from hormone therapy than others.

Objectives and Scope

The goal of this RFA is to stimulate comprehensive multidisciplinary
research into the natural history of the menopause and the effect of
the perimenopausal transition on woman's aging and subsequent
susceptibility to disease.  Thus this RFA is relevant to the
implementation of Public Law 103-43, National Institutes of Health
Revitalization Act of 1993, Title VIII, Section 801, which directs the
NIA, in cooperation with other Institutes, Centers and Divisions
(ICDs), to support research on the aging processes of women, with
special emphasis on the changes associated with the transition from
pre- to postmenopause, and the effect of this transition on disorders
and complications related to aging and reduced ovarian hormone levels.

Because this initiative aims to generate epidemiologic studies in
premenopausal women of the chronology and characteristics of the
perimenopausal transition per se, and not to launch clinical
intervention trials of hormone or other therapies, applications focused
on testing treatment strategies will be considered not responsive to
this RFA.  However, it is recognized that as premenopausal women
approach and traverse the menopause, there will be subgroups who have
symptoms and/or other indications that are of sufficient concern to
warrant consideration of treatment with estrogen or other agents.
Hence, proposed research should address potential symptoms and problems
that may arise and require management and formulate approaches with
respect to providing information and/or referral.  Proposed studies
should also include methods for statistical handling of women who start
and stop estrogen therapy and of women whose menopausal experience may
be confounded by medications and procedures such as
hysterectomy/oophorectomy, radiation therapy which may induce an
apparent or artificial menopause, etc.

A number of research areas have been identified in a background paper
titled "The Menopause, Hormone Therapy, and Women's Health" [U.S.
Congress, Office of Technology Assessment, OTA-BP-BA-88, Washington
DC:U.S. Government Printing Office, May 1992] and in "Report of the
National Institutes of Health: Opportunities for Research on Women's
Health [S/N 017-040-00522-9 obtainable from the Superintendent of
Documents, Government Printing Office, P.O. Box 371954, Pittsburgh, PA
15230-7954; FAX 202-512-2250].  Additional research opportunities were
identified at the March 1993 NIH Workshop on Menopause: Current
Knowledge and Recommendations for Research.  The research objectives or
aims of this initiative reflect a consolidation of major recurring
themes from these sources.  Because of the multidisciplinary nature of
this RFA, applicants, either individually or in collaboration with
others, should demonstrate interdisciplinary skills and expertise in a
variety of areas such as gynecology, reproductive endocrinology,
internal medicine, geriatrics, nursing, cardiology, neurology, bone
metabolism, muscle and renal physiology, nutrition, psychology,
sociology, epidemiology, and biostatistics.

Awardees at Clinical Sites are expected to recruit a cohort of
premenopausal women to characterize the chronology and physiological
concomitants and consequences of the pre- to postmenopausal transition.
Planned research by all Clinical Sites and, where appropriate, by the
Coordinating Center and the Central Laboratory, should:

o  identify and utilize appropriate markers of ovarian aging or aging
of the ovarian-hypothalamo-pituitary axis (e.g., FSH, LH, or,
preferably, other state-of-the art measures) and relate these markers
to alterations in menstrual cycle characteristics as women approach and
traverse menopause

o  elucidate factors that differentiate (1) symptomatic from
asymptomatic women and (2) women most susceptible to long-term
pathophysiological consequences of ovarian hormone deficiency from
those who are protected;

o  insure adequate statistical power to evaluate the transition from
pre- to postmenopause in women undergoing natural menopause

o  collect and analyze data on demographics, health and social
characteristics, race/ethnicity, reproductive history, pre-existing
illness, physical activity, health practices

After addressing these general requirements, studies proposed by
Clinical Sites should focus on a specific system or function(s)
affected by, or of relevance to, menopause.  Examples of topic areas of
interest include, but are not limited to:

o  determinants of the age of menopause; age and menopause-related
changes in the female genitourinary tract; changes in circadian and
ultradian biorhythms

o  effects of menopause on alterations in body composition and
biological function (i.e., changes in muscle mass, adiposity and fat
patterning, skeletal mass, gastrointestinal function, cardiovascular
and renal function, immune function, cognitive function, etc);

o  the effect of the pre- to postmenopausal transition on bone mass,
bone quality, the recruitment and activity of bone cells (or their
precursors), markers of bone metabolism, the response of bone and bone
cells to mechanical stress

o  transmenopausal changes in cardiovascular risk factors and
characteristics such as cardiac or arterial responsiveness,
calcification or atherosclerosis progression

o  menopause-related changes in nutrition and metabolism

o  psychosocial interactions of menopausal symptoms and sequelae with
women's health-related behaviors, sexuality, social functioning and use
of health care

o  psychosocial, cultural and behavioral determinants of perceptions
of, and responses to, menopausal symptoms; factors affecting treatment
choices and management strategies for menopausal symptoms

SPECIAL REQUIREMENTS

The broad outline of areas of interest presented above is offered only
as a point of departure.  Studies proposed for Clinical Sites should
include discussion of design (including parameters and outcomes),
eligibility criteria, protocol issues, content of baseline and
follow-up examinations and related statistical and data management
issues.  Research planned for Clinical Sites and for the Central
Laboratory should indicate which measurements should be made in common
and include the rationale for selecting those measurements and their
proposed frequency.  All prospective awardees should describe
strategies for the establishment of collaborative arrangements with
other awardees.

The initial meetings of awardees of all Components (Clinical Sites,
Coordinating Center and Central Laboratory) and NIH program staff will
serve to coordinate the individual research projects by developing
operational definitions for the perimenopause, determining the
feasibility of adopting common age-ranges and eligibility criteria and
establishing a common data set for baseline and follow-up examinations.
It is anticipated that approximately six months will be required for
the development of a protocol and the drafting of a manual of
procedures for the generation of the common data set.

A Steering Committee will have overall responsibility for the
development and finalization of the collaborative protocol.  The
principal investigators of the Clinical Sites, the Coordinating Center,
the Central Laboratory and the NIA program administrator will comprise
the voting members of the Steering Committee.  The protocol will be
subject to review by an outside expert group.  The study will proceed
into its second (or implementation) phase only with the concurrence of
both the awardees and the NIH.

Designated NIH staff will meet in Bethesda with Principal Investigators
and key staff up to four times in the first year and at least every six
months thereafter to discuss new developments, review research progress
and difficulties, coordinate ongoing research and plan future research
activities.  Applicants should include a statement about their
willingness to participate in such activities.  Travel funds for key
staff (two to three people) to attend these meetings should be included
as a budget line item in each application.

Organizational Components

1.  Clinical Sites

A Clinical Site is the institution that receives an award for
recruiting a cohort of premenopausal women and for conducting the
investigation(s) under this RFA.  The Principal Investigator (PI) is
encouraged (as appropriate) to form a multidisciplinary team to focus
on biomedical and psychosocial aspects of the menopausal transition.
Applications for individual sites should provide evidence of ability to
recruit an adequate number of subjects in order to yield statistically
sound results in the proposed area of concentration.  There should be
evidence of strong institutional support for the site and a stated
willingness to follow shared aspects of design, measures and analysis
as approved by the Steering Committee. An organizational structure for
the site should be set forth in the application, designating lines of
authority and responsibility.

2.  Coordinating Center

The Coordinating Center (CC) will interface with the Clinical Sites,
the Central Laboratory, an Advisory Panel, and the NIA program
administrator on a variety of topics ranging from seeking and compiling
information to providing technical assistance.  The CC will have the
primary responsibility of standardizing data collection and management
and analysis of the common data set.  It will work with projects to
maximize the potential for cross-site comparability of data; and,
ensure that protocols and definitions are consistent across projects
through training sessions.  It will provide key assistance in designing
the data collection system for the shared data and will also be
responsible for developing and monitoring quality control.  Its staff
will collect, edit, store, and analyze shared data generated by the
Clinical Sites and participate with other awardees as co-authors in
preparing manuscripts that report results from the common data set.  In
addition, the CC will perform a variety of functions, such as,
developing a cross-project Manual of Procedures; maintaining a
directory of investigators and co-investigators; arranging all
meetings, e.g., for the Steering Committee and ad-hoc meetings of
project directors; and facilitating information exchange among the
Clinical Sites and NIH.  The latter role will include compiling
specific reports and developing and implementing common formats across
Clinical Sites for all reports, protocols and descriptions (e.g.,
progress reports, instrument protocols, manuals of operation).  The CC
will also devise plans for the dissemination of information from new
research developments to women, their health care providers, the
research community, and policy makers.

3.  Central Laboratory

The Central Laboratory will have primary responsibility for conducting
laboratory determinations in biological samples collected from study
subjects for the purposes of establishing the common data set.
Prospective awardees should identify the measurements to be made in
common and include the rationale for selecting those measurements and
the proposed frequency.  The final selection of assays will be
determined by the Steering Committee during the development of the
protocol for establishing the common data set.

4.  Steering Committee

The Steering Committee will serve as the main decision-making body for
the shared aspects of the study.  The Steering Committee will have
overall responsibility for the study and will develop modifications in
the site-specific protocols to facilitate establishment of a common
data set using the information provided in this RFA as a guide.  The
Committee will consist of the Principal Investigator from each Clinical
Site, the Coordinating Center, the Central Laboratory, and the NIA
Program Administrator.  At its first two meetings, the Steering
Committee will be convened by the NIA Program Administrator.  A
chairperson (not from NIH) will be elected subsequently.  The Steering
Committee will meet every three to six months as needed.

5.  Advisory Panel

An Advisory Panel (AP) will be selected by the Steering Committee to
serve in an advisory capacity to the study and to all of its
Organizational Components.  The functions of the AP include reviewing
project-specific and common core protocols and making suggestions to
the awardee(s) and the NIA Program Administrator; monitoring individual
project performance, using materials provided by the Coordinating
Center; monitoring protocols and information supplied through the
Coordinating Center for possible adverse effects associated with the
studies; reviewing and advising the awardee(s) and the NIA Program
Administrator regarding design and/or protocol changes requested by
individual investigators; and reviewing and advising the awardee(s) and
the NIA Program Administrator regarding analyses and publications
involving multi-project use of common core data.

The Panel will consist of experts in relevant medical, behavioral,
statistical, and bioethical fields and will convene once per year.
Candidates should not be recruited to serve on the Panel or be named
prior to the review of the applications by NIA.  However, applicants
are encouraged to enumerate areas of expertise appropriate for
representation on the Panel.  The experts must be independent of all
Components participating in the cooperative agreement (i.e., not
scientifically or fiscally involved).  A chair will be elected by
members of the Advisory Panel with input from the NIA Program
Administrator.  The chairperson of the Steering Committee, the
Principal Investigator from the Coordinating Center, and the NIA
Program Administrator will all participate as non-voting members during
each Panel meeting.  Per NIH regulations, Panel members will be
reimbursed for necessary travel, but will not receive consultant fees
for input to individual projects.  Travel funds for members of the AP
are to be included as a line item in the budget of Coordinating Center
applications.

Terms and Conditions of Award

The following special terms of award are in addition to, and not in
lieu of, otherwise applicable OMB administrative guidelines, HHS Grant
Administration Regulations at 45 CFR Parts 74 and 92 and other HHS,
PHS, and NIH Grant Administration policy statements.

The administrative and funding instrument used for this program is a
cooperative agreement (U01), an assistance mechanism (rather than an
acquisition mechanism) in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during
performance of the activity.  Under the cooperative agreement, the NIH
purpose is to support and/or stimulate the recipient's activity by
working jointly with the award recipient in a partner role, but it is
not to assume direction, prime responsibility or a dominant role in
this activity.  Consistent with this concept, the dominant role and
prime responsibility for the activity resides with the awardee(s) for
the project as a whole, although specific tasks and activities in
carrying out the collaborative aspects will be shared among the
awardees and the NIA Program Administrator.

1.  Awardee Responsibilities

Awardees will have primary authorities and responsibilities to define
objectives and approaches, and for participant recruitment and
follow-up, quality control, data analysis and interpretation, and for
preparation of publications from their site-specific protocols.
Awardees at the Clinical Sites shall retain custody of, and primary
rights to the site-specific data developed under their award, subject
to Government rights of access consistent with current HHS, PHS, and
NIH policies.  In addition, awardees of all Organizational Components
(Clinical Sites, Coordinating Center and Central Laboratory) will
engage in collaborative activities through participation in Steering
Committee meetings and conference calls in the development and
implementation of a common protocol establishing a shared data set.
Data for the shared data set will be submitted to the Coordinating
Center where it will be archived.  Protocols developed by the Steering
Committee will define rules regarding access to data and publication of
findings from analysis of the shared data set.

2.  Staff Responsibilities

The NIA Program Administrator will have substantial
scientific/programmatic involvement during conduct of this activity,
through technical assistance, advice and coordination above and beyond
normal program stewardship for grants.  The awardee agrees to accept
assistance from the NIA Program Administrator, as described below:

o  Participation in the development of the protocol for common measures

o  Monitoring of performance issues relating to steering committee
assignments necessary for the development of the common protocol,
recruitment, follow-up, quality control, adherence to protocol and
attainment of study objectives.

o  Providing technical assistance in the formulation or consideration
of refinements and adjustments of study objectives, designs and
protocols.

o  Assistance in analysis and reporting of intervention study results

The NIA Program Administrator may provide advice on staffing,
statistical requirements, and will cooperate with awardees in
considering protocol adjustments.  In instances where there has been
significant involvement in study design and analysis by the NIA Program
Administrator, and in accordance with Publication Guidelines developed
by the Steering Committee and with NIH policies regarding staff
co-authorship of publications resulting from extramural awards, he/she
may cooperate with awardees as co-authors in preparing manuscripts that
report results from these studies.

3.  Collaborative Responsibilities

A Steering Committee, composed of the Principal Investigators of each
Clinical Site, the Principal Investigator of the Coordinating Center,
the Principal Investigator of the Central Laboratory, and the NIA
Program Administrator will be the main governing board of the study and
will have primary responsibility for developing a protocol for the
shared aspects of the study.  The Steering Committee will develop
modifications in the site-specific protocols to facilitate
establishment of a common data set using the information provided in
this RFA as a guide.  The Steering Committee will also establish
subcommittees to oversee major operational components of the study.
One vote will be given to each Principal Investigator and to the NIH.
The Steering Committee will meet every three to six months as needed.

4.  Arbitration

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award), between award recipients and the NIH
may be brought to arbitration.  An arbitration panel will be composed
of three members -- one selected by the Steering Committee (with the
NIH member not voting) or by the individual awardee in the event of an
individual disagreement, a second member selected by the NIH, and the
third member selected by the two prior selected members.  This special
arbitration procedure in no way affects the awardee's right to appeal
an adverse action that is other wise appealable in accordance with the
PHS regulations at 42 CFR part 50, subpart D and HHS Regulation at 45
CFR part 16.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  For the purpose of this RFA,
investigations are limited to studies of menopause, an event which
occurs only in women.  If minorities are excluded or inadequately
represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of race/ethnic group.  In addition, racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information must be included in the form PHS 398 (rev. 9/91), Parts 1-4
of the Research Plan and summarized in Part 5, Human Subjects under the
heading "Study Populations."  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans (including American Indians or Alaskan
Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale
for studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from racial/ethnic
minorities when it is important to apply the results of the study
broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
minorities in a study design is inadequate to answer the scientific
question(s) addressed AND the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and will be reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are strongly encouraged to submit, by October
15, 1993, a letter of intent that includes a descriptive title of the
proposed research, the name, address, and telephone number of the PI,
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
allows NIA 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 Dr. Sherry Sherman at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the PHS 398 (rev. 9/91) application
form.  This form is available at most institutional offices of
sponsored research; from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone (301) 710-0267; and from the
NIH program administrators listed under INQUIRIES.

Essential information on budgets and direct and indirect cost limits is
discussed under FUNDS AVAILABLE, budget information on travel for
steering committee meetings is discussed under SPECIAL REQUIREMENTS,
and budget information about travel to advisory committee meetings is
under the description of the advisory committee.

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 must be included with the
application.

The RFA label available in the application kit must be affixed at the
bottom of the face page of the application.  Failure to use this label
could delay processing of the application such that it may not reach
the review committee in time for review.  In addition, the RFA title,
number, and type of application: "Clinical Site," "Coordinating
Center," or "Central Laboratory" must be typed on line 2a of the face
page of the application form and the YES box must be checked.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Two copies of the application with appendices must also be sent to:

Chief, Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C212
Bethesda, MD  20892

The deadline for receipt of applications is November 29, 1993.
Materials will not be accepted after this date.  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.  Nor will the DRG 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.

Applicants must obtain Institutional Review Board (IRB), and if
applicable, Institutional Animal Care and Use Committee approval of
their application prior to submission.  Applications not having these
approvals will be returned without review.  If approval is not obtained
prior to submitting the application, appropriate certifications must be
received by the Scientific Review Administrator (SRA) responsible for
the review within 60 days after the receipt date, unless requested
earlier by the SRA.  It is the applicant's responsibility to respond to
this requirement.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete and nonresponsive
applications will be returned to the applicant without further
consideration.  Those applications that are complete and responsive
will be evaluated in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group convened
by the NIA.  Applications may be subjected to triage by an NIA peer
review group to determine their scientific merit relative to other
applications received in response to this RFA.  The review criteria to
be used are identified below.  The NIH will withdraw from further
competition those applications judged by triage to be noncompetitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review.  The second level of
review will be provided by the National Advisory Council on Aging and
other relevant Advisory Councils.

The major review criteria to be used in the evaluation of applications
for all Organizational Components (Clinical Sites, Coordinating Center
and Central Laboratory) of this RFA include:  significance of the
proposed activities to the goals of the RFA; qualifications, experience
and commitment of the investigators and their ability to devote the
required time and effort to the project; appropriateness and adequacy
of the experimental approach and methodology proposed to carry out the
research; an understanding of the scientific objectives of the program,
as evidenced by discussion of issues relating to the design and
implementation of the collaborative aspects of the program; the
willingness to work collaboratively with other awardees and with the
NIA program administrator in the manner summarized in the RFA;
institutional commitment to the requirements of the project and
appropriateness of the total budget and budgetary requests.  Preference
will be given to those applicants who have experience in and commitment
to women's health research.

Additional review criteria for the Clinical Sites include: scientific
merit of the research proposed, justification for proposed sample
sizes, assurance that projected sample sizes can be obtained, estimates
of subject attrition, adequacy of inclusion of minorities, and
appropriateness of suggested measures to be performed in the
collaborative protocol.

Additional review criteria for the Coordinating Center include: prior
experience in functioning as a Coordinating Center in a multi-site
study; experience of the Principal Investigator and other key personnel
in statistical, data management, quality control, study coordination
and administrative aspects of multi-center clinical studies; and
proposed data collection and monitoring system.

Additional review criteria for the Central Laboratory include:
expertise and experience in serving as a Central Laboratory;
appropriateness of suggested measures to be performed in the
collaborative protocol; laboratory expertise with the procedures, assay
methods to be used; adequacy of plans for ensuring maintenance and
coordination of quality control standards; adequacy of facilities and
supportive environment, including space and equipment for the work
proposed; ability to accommodate samples for all sites; and suggested
protocol for shipping, handling, and storage of samples as well as for
management and transmission of data resulting from the laboratory
determinations.

AWARD CRITERIA

Applications recommended by the National Advisory Council on Aging and
other relevant council(s) will be considered for award based upon (a)
scientific and technical merit; (b) program balance, including in this
instance, sufficient compatibility of features to make a successful
collaborative program a reasonable likelihood; and (c) availability of
funds.

Letter of Intent Receipt Date:                 October 15, 1993
Application Receipt Date:                      November 29, 1993
Review by National Advisory Council on Aging:  June 1994
Anticipated Award Date:                        July 1994

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 related to physiologic
research on menopause and address the letter of intent to:

Dr. Sherry Sherman
Geriatrics Program
National Institute on Aging
Gateway Building, Room 3E327
Bethesda, MD  20892
Telephone:  (301) 496-1033

For programmatic issues related to social and behavioral research on
menopause, inquiries may be directed to:

Dr. Marcia Ory
Behavioral and Social Research Program
National Institute on Aging
Gateway Building, Room 2C234
Bethesda, MD  20892
Telephone:  (301) 496-3136

For programmatic issues of relevance to the National Institute of
Nursing Research, inquiries may be directed to:

Dr. Sharlene Weiss, Ph.D., R.N.
National Institute of Nursing Research
Westwood Building, Room 757
Bethesda, MD  20894
Telephone:  (301) 594-7496

Direct inquiries regarding fiscal matters to:

Ms. Joanne Colbert
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.866 (Aging 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 Part 52 and
45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372, or to
the Health Systems Agency review.

.

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