Full Text CA-94-010

CLINICAL/METABOLIC STUDIES IN NUTRITION AND BREAST CANCER PREVENTION

NIH GUIDE, Volume 23, Number 10, March 11, 1994

RFA:  CA-94-010

P.T. 34

Keywords: 
  0715036 
  Disease Prevention+ 
  Nutrition/Dietetics 
  Metabolism 


National Cancer Institute

Letter of Intent Receipt Date:  April 12, 1994
Application Receipt Date:  June 9, 1994

PURPOSE

The Division of Cancer Prevention and Control, National Cancer
Institute (NCI), invites Interactive Research Project Grants (IRPGs)
(see NIH Guide, Vol. 22, No. 16, April 23, 1994), to encourage and
facilitate formal interdisciplinary collaborations through the
coordinated submission of related research project applications that
share a common research focus relevant to the development and conduct
of clinical/metabolic studies for nutrition and breast cancer
prevention research and do not require extensive shared physical
resources or core functions.

Complex questions in nutrition and breast cancer prevention research
often require investigative efforts that extend beyond the level
practicable in a single project or that require a variety of
technical approaches beyond the means of a single investigator.  The
perceived merit of individual research project applications sometimes
may be limited by the lack of a comprehensive, interdisciplinary,
approach or by limitations in resident technical expertise.  Many
areas of nutrition and breast cancer investigations are
under-represented in grant applications either because they cannot
effectively be exploited without a collaborative effort or local
opportunities for such interactions are not available.

The objectives of this RFA for Interactive Research Project Grants
(IRPGs) are to (1) increase the investigator-initiated pool of
quality applications employing clinical/metabolic studies in human
nutrition and breast cancer research and (2) stimulate an
intermediate level of interdisciplinary collaborative efforts to
build stronger research bridges between nutritional science and the
disciplines that relate closely to basic and clinical research for
the development, application and evaluation of new approaches to
nutrition and breast cancer prevention research utilizing
clinical/metabolic studies.

A minimum of two independent investigators with related research
objectives will be encouraged to submit concurrent, collaborative,
cross-referenced individual research project grant applications that
share a common research focus.

The overall goals are to encourage and stimulate the integration of
state-of-the-art approaches and skills to address the clinical
relevance of findings suggested by epidemiologic and laboratory
studies and provide more definitive data on the link between dietary
intake or nutritional status and cellular/molecular mechanisms in the
etiology, pathogenesis, and prevention of breast cancer.

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), Clinical/Metabolic Studies in Nutrition and
Breast Cancer Prevention, is related to the priority area of cancer
prevention.  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. 017-001-0043-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Domestic and foreign non-profit and for-profit organizations and
institutions, governments, and their agencies are eligible to apply.
Applications may be submitted from a single institution or may
include arrangements with multiple institutions if appropriate.
Applications from or involving minority institutions, individuals,
and women are encouraged.

MECHANISM OF SUPPORT

Support of this program will be by the research project grant (R01).
Applicants will be responsible for the planning, direction, and
execution of the proposed projects.  The total project period for
each application submitted in response to the present RFA must not
exceed four years.

This is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to
customary peer review procedures.

FUNDS AVAILABLE

Approximately $2.5 million in total costs per year for up to four
years will be committed to specifically fund applications that are
submitted in response to this RFA.  It is anticipated that six to
nine awards will be made.  This level of support is dependent on the
receipt of a sufficient number of applications of high scientific
merit.  Although this program is provided for in the financial plans
of the NCI, awards pursuant to this RFA are contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Historically, the NCI has relied on multi-component awards, such as
program projects (P01) and Cancer Center Support grants (P30), to
encourage interdisciplinary collaborations in areas requiring
integration and central direction of basic and clinical research
components.  A hallmark of such awards is the provision for extensive
core facilities/resources to support the common research efforts of
the program and appointment of a program director to manage the
overall effort.

For many investigations in nutrition and breast cancer research it
may be more appropriate to consider an intermediate level of
collaboration, less extensive than that described above, but beyond
that practical for single projects.  For such limited collaborative
efforts, the exchange of research materials and ideas, rather than
shared physical resources, is the primary requirement.  The proposed
concept of IRPGs aims to address and facilitate this class of
research activities.  Typically, the IRPG approach will be suited to
many basic research questions, as well as research to develop and
apply innovative technology or evaluate intervention strategies in
individuals and target subpopulations.  The IRPG mechanism is well
suited for clinical/metabolic studies to differentiate the biological
activities of dietary patterns and dietary constituents with respect
to their functions, actions, and associations and to quantitate the
responses at the cellular and molecular level in the intact human
host.

Use of the IRPG mechanism will benefit applicants by establishing a
larger framework of reference for the proposed work, facilitating
formal collaborations tailored to achieving research objectives,
providing a record of independently acquired awards credited to each
funded investigator, and allowing retention of research autonomy by
the named Principal Investigator on each of the interactive grants.
Each grantee will have the ability to submit, on his/her own behalf,
competing supplements as appropriate to incorporate promising new
directions of research as they evolve.  The freedom to establish
collaborations at separate sites and the improved transferability of
awards made to individual Principal Investigators also are
significant benefits.  In contrast, translational research programs
that span a variety of disciplines and programs that require
extensive ties to co-located core resources would continue to be
served best by traditional multi-component program award mechanisms.

The NCI encourages qualified investigators to develop and submit
concurrently coordinated research project applications that address
areas of relevance to nutrition and breast cancer where the
interactive research project concept may be applied.  Applications
submitted as a package must be tightly focused and the interactions
and benefits of the proposed linkages must be made explicit as
explained in the section on "Special Instructions for IRPG
Applications."

Research Areas of Interest

In U.S. women, breast cancer is the cancer with the highest incidence
and, behind lung cancer, the second highest mortality.  Approximately
one of every eight women will develop breast cancer during her life.
Epidemiological and animal studies provide evidence that dietary
patterns or dietary constituents are associated with breast cancer
incidence and mortality.  Animal studies have demonstrated that
mammary carcinogenesis can be influenced by dietary components.
Further studies may permit the isolation of the active dietary
constituents, define the underlying mechanisms for the effects of
dietary components, and identify an optimal dietary pattern or
dietary components that have potential for reducing breast cancer
risk.  Persistent interaction and research collaborations among the
various disciplines of biomedical research are needed to fill the
gaps and provide a more definitive understanding of how dietary,
environmental and genetic factors interact to influence the risk of
breast cancer.

Representative areas of particular interest for this RFA include many
basic issues of biological functions and modulating actions of
dietary patterns and nutrients that need to be investigated directly
in human studies.  Another area of interest is the application of
innovative research approaches to the development and evaluation of
specific methodologies for use in human studies to elucidate the
mechanisms of action and quantify the role of diet and dietary
components in breast cancer prevention and control.  Such human
studies should contribute to an improved and more precise
interpretation of the epidemiologic associations of diet with breast
cancer risk; to the identification and evaluation of improved markers
of dietary exposure and early indicators of breast cancer risk; and
to broadening of the understanding of the role of diet and nutrition
in women's health and breast cancer prevention.  Although laboratory
and animal studies provide valuable qualitative and mechanistic
knowledge, it remains unknown whether the results of animals studies
can be extrapolated to humans.

Clinical/metabolic studies are a logical step in advancing our
knowledge on the role of diet and nutrition in breast cancer cause
and prevention and will provide a stronger scientific base for
progression to randomized controlled clinical trials to determine the
efficacy of optimal dietary intervention strategies for prevention of
breast cancer.

Several typical (non-exhaustive) examples of research areas relevant
to the dietary intervention clinical/metabolic studies for nutrition
and breast cancer prevention in which the IRPG concept may be applied
are as follows:

o  Identification, evaluation, and validation of specific molecular,
cellular, metabolic, and endocrine biomarkers that are associated
with initiation and/or promotion of preneoplastic transformations
that may be responsive to foods and nutrients

o  Determine the relation between dietary intake and gene expression
in breast epithelial cells and breast cancer cells

o  Evaluate interactions such as nutrient-nutrient, nutrient-drug,
and genetic-environment interactions

o  Define dose-response relationships for macronutrients,
micronutrients, and non-nutrient dietary constituents on molecular
and cellular events and alterations in metabolic pathways

o  Characterize individual variability in the biological response to
specific dietary patterns or nutrients

o  Identification of biochemical markers as quantitative measures of
food intake, digestion, absorption, metabolic breakdown of specific
nutrients or nutritional status

o  Bioavailability of nutrients and non-nutrients at various intakes
and from different food sources

o  Determine the relation between dietary intake of environmental
carcinogens, i.e., pesticides and dioxins, and breast cancer,
including potential effects of contaminants in the food and water
supply

Prospective applicants are encouraged to explore other areas of
potential for the IRPG mechanism with the NCI Program Director.  The
overall goal is to provide more definitive data for developing
quantitative dietary guidance and translation into optimal and
desirable eating patterns and food choices that have the potential
for a substantial reduction in the risk of diet-related cancers in
the general population.

Special Instructions for IRPG Applications

One Principal Investigator from the IRPG group must be identified as
the "Program Coordinator," and should be cited in all applications on
Page 2 of form PHS 398 (rev. 9/91).  Individual investigators may
request funds for the time and effort contributed toward the
coordination of the overall research and for collaborative resource
activities.

To facilitate referral, all applications submitted under the IRPG
mechanism MUST be as a single package.  Each application must be
complete in itself, with all appropriate approvals, budgets and
signatures.  A cover letter must accompany the package identifying
all principal investigators and project titles that are a part of the
combined submission.  The letter should be firmly attached to the
face page of the top application.  Each application must be
identified by checking "YES" on line 2a of the PHS 398 face page and
citing this RFA, "Clinical/Metabolic Studies in Nutrition and Breast
Cancer Prevention."

The use of the IRPG mechanism must be mentioned briefly in form PHS
398 (rev. 9/91), Sections 1-4 of the Research Plan.  The goal of the
collaborative efforts MUST be identified in the specific aims of each
application, with the major rationale and explanation for the use of
the IRPG mechanism to be given in Section 7,
Consultants/Collaborators.  A complete list of applications in the
IRPG must be provided in Section 7, as well as an indication of the
specific collaborations to be established for the individual
application under consideration.

Requests for limited shared resources, if any, should be
proportionally budgeted in each application based on anticipated use,
with a full explanation given in the budget.  Personnel Time and
Effort requests for management of shared resources are allowable.
Where consortium arrangements between independent institutions are
proposed that would make transfer of funds for required new equipment
impractical, the entire equipment request may be budgeted by the
responsible laboratory.  This must be clearly justified.

All PHS and NIH grants policies will apply to applications received
in response to this RFA.

STUDY POPULATIONS

SPECIAL INSTRUCTION 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 will be 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.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information should be included in the form PHS 398
in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.

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 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 tissue from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application may be returned, or may be deferred until additional
information can be provided.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or 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 that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 12, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the
names of other key personnel, the 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, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.

The letter of intent is to be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard
Executive Plaza North, Room 636
Rockville, MD  20852
Telephone:  (301) 496-3428
FAX:  (301) 402-0275

APPLICATION PROCEDURES

The regular research grant application form PHS 398 (rev. 9/91) is to
be used in applying for these grants.  These forms are available at
most institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/435-0714; and from the NCI Program Director listed under
INQUIRIES.

The RFA label available in the application form PHS 398 must be
affixed to the bottom of the face page.  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 title of the application, "Clinical/Metabolic Studies in
Nutrition and Breast Cancer Prevention," and the RFA number,
CA-94-010, must be typed on line 2a of the face page of the
application form.

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

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

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

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard
Executive Plaza North, Room 636
Bethesda, MD  20852

Applications must be received by June 9, 1994.  If an application is
received after that date, it will be returned.  Also, the Division of
Research Grants (DRG) will not accept any application in response to
this RFA that is the same as one currently being considered by any
other NIH review group or awarding unit.

Each application will be considered on its own merit as an individual
research project.  Therefore, applicants for IRPGs may not
concurrently submit R01 applications that represent significant
duplication of the efforts described in the applicant's IRPG.  In
this regard, it should be noted that the NCI will consider funding
meritorious individual IRPG applications if it is not possible to
fund the IRPG package as a whole.  Concurrent submission of program
project (P01) applications that request support for essentially
similar work is prohibited.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator could be included
with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed (initially) by the DRG
for completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NCI program staff function.  Questions concerning the
responsiveness of proposed research to the RFA may be directed to the
Program Director listed under INQUIRIES.

Applications may receive a preliminary scientific peer review by an
NCI peer review group on the basis of relative competitiveness.  The
NCI will withdraw from further competition those applications judged
to be noncompetitive for award and notify the applicant Principal
Investigator and institutional business official.  Those applications
judged to be both competitive and responsive will be further
evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of National Cancer
Program.

The following factors will be considered in evaluating the scientific
merit of each response to this RFA:

o  Scientific, technical, or medical significance and originality of
the proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  Qualifications and research experience of the Principal
Investigator and staff particularly, but not exclusively, in the area
of the proposed studies;

o  Adequacy of plans for coordination of the overall research and for
collaborative resource activities;

o  Availability of resources necessary to perform the research;

o  Appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Qualifications and experience of Principal Investigator identified
as the "Program Coordinator" in the context of having an oversight
role in the IRPG research effort.

For each application that is given a priority score, the review group
will assign an adjectival descriptor that reflects the extent and
effectiveness of its collaboration(s) with other applications
included in the IRPG.  This assessment will be documented in a brief
administrative note in the summary statement to assist the NCI in
making final decisions on each application in the context of the
overall IRPG.

AWARD CRITERIA

The anticipated date of award is March 1, 1995.  Although this
program is provided for in the financial plans of the National Cancer
Institute (NCI), awards made pursuant to this RFA are contingent upon
the availability of funds for this purpose.  In addition to the
scientific merit; priority score, availability of funds, and
programmatic priorities will be considered in making awards.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope
of this RFA and inquiries about whether or not specific proposed
research would be responsive are encouraged.  The program staff
welcomes the opportunity to clarify any issues or questions from
potential applicants.

Direct inquiries regarding programmatic issues to:

Carolyn K. Clifford, Ph.D.
Division of Cancer Prevention and Control
National Cancer Institute
Executive Plaza North, Suite 212
Bethesda, MD  20892-6130
Telephone:  (301) 496-8573
FAX:  (301) 402-0553

Direct inquiries regarding fiscal matters to:

Kathleen Shino
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard
Executive Plaza South, Room 243
Rockville, MD  20852
Telephone:  (301) 496-7800 Ext. 48

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.399, Cancer Control.  Awards will be made under the
authority of the Public Health Services Act, Title IV, Section 301
(Public Law 78-410,;42 U.S.C. 241 and Section 412, as amended by
Public Law 99-518, 42 U.S.C 258a-1); and administered under PHS
grants policies and Federal regulations 42 CFR Part 52 and 45 CFR
Part 74 and 92.  This program is not subject to the intergovernmental
review requirements of Executive Order 12732 or Health Systems Agency
review.

.

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