Full Text CA-95-003

COOPERATIVE FAMILY REGISTRY FOR EPIDEMIOLOGIC STUDIES OF BREAST
CANCER

NIH GUIDE, Volume 23, Number 39, November 4, 1994

RFA:  CA-95-003

P.T. 34

Keywords: 
  0715036 
  Epidemiology 
  Registries+ 


National Cancer Institute

Letter of Intent Receipt Date:  November 30,1995
Application Receipt Date:  February 17, 1995

PURPOSE

The Extramural Programs Branch, Epidemiology and Biostatistics
Program, Division of Cancer Etiology, National Cancer Institute (NCI)
invites cooperative agreement applications from investigators to
participate, with the assistance of the NCI, in a network of
organizations constituting a Cooperative Family Registry for Breast
Cancer (CFRBC).

The purpose of the proposed awards is to stimulate a cooperative
effort to:

1.  Collect pedigree information, epidemiological data and related
biological specimens from patients with a family history of breast
cancer in order to provide a registry resource for interdisciplinary
studies on the etiology of breast cancer, and to encourage
translational research in this area.

2.  Identify a population at high risk for breast cancer that could
benefit from new preventive and therapeutic strategies.

This Request for Applications (RFA) responds to Congressional
language instructing the Director of the National Cancer Institute to
conduct and support research to expand the understanding of the cause
of, and find a cure for, 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 RFA,
Cooperative Family Registry for Epidemiologic Studies of Breast
Cancer Studies, relates to the priority area of cancer.  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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign non-profit and
for-profit institutions, public and private, such as colleges,
universities, hospitals, research laboratories, units of State and
local governments, and eligible agencies of the Federal government.
Applications from minority and women investigators are encouraged.

MECHANISM OF SUPPORT

Support of this program will be through the cooperative agreement
(U01), an assistance mechanism in which substantial NCI scientific
and programmatic involvement with the recipients during performance
of the planned activity is anticipated.  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 awardee in a partner role, but is not to assume direction,
prime responsibility, or a dominant role in the activity.  Details of
the responsibilities, relationship, and governance of the study to be
funded under cooperative agreements are discussed later in this
document under the section "Terms and Conditions of Award."

The total project period for applications submitted in response to
the present RFA may not exceed four years.  The anticipated award
date is December 1995.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will
vary also.  Awards and level of support depend 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.

This RFA is a one-time solicitation.  At this time, the NCI has not
determined whether or how this solicitation will be continued beyond
the present RFA.

FUNDS AVAILABLE

Approximately $2 million in total costs per year for four years will
be committed to specifically fund applications that are submitted in
response to this RFA.  It is anticipated that two to five awards will
be made.  This funding level is dependent on the receipt of a
sufficient number of applications of high scientific merit.

RESEARCH OBJECTIVES

Background

According to 1993 Surveillance, Epidemiology and End Results (SEER)
Registry data, breast cancer is the second leading cause of cancer
death among women in the United States, second only to lung cancer,
and its incidence is increasing at a rate of approximately two
percent per year.  Breast cancer is a highly complex disease, and the
natural history of primary breast cancer varies considerably from
patient to patient.  The genetic heterogeneity and etiologic
complexity of breast cancer limit identification of high-risk
populations.  Family studies of breast cancer indicate that the
genetic contribution to breast cancer risk is an important component
of the heterogeneity of this disorder.  The compelling need for
validated screening procedures (especially among young women) and for
the identification of risk factors and predictors contributing to the
rising incidence of this disease have prompted Congress and the
scientific community to place high priority on research in breast
cancer etiology and on the development of preventive and therapeutic
strategies.

Recommendations from a conference on "Genetic Epidemiology of Cancer:
an Interdisciplinary Approach," sponsored by NCI in 1992, indicate
that extended families with high incidence of cancer or cancer
syndromes provide a unique research resource for epidemiologic,
molecular genetics, and prevention studies.  Epidemiologic and
interdisciplinary studies of major cancer genes are based on the
ascertainment of families with high incidence of cancer.  Large,
informative families are useful for identifying and characterizing
susceptibility genes involved in the etiology of cancer, and
elucidating gene-environment interactions.  Moreover, members of
cancer-prone families represent a population at high risk that could
benefit from novel preventive and therapeutic efforts.  Early
ascertainment of cancer-affected families is needed particularly for
tumors with high mortality rates, such as early-onset breast cancer
and breast/ovarian cancer.  In addition, the selection of rare
families with multiple cases of male breast cancer, or affected by
familial cancer syndromes that include breast cancer could offer a
substantial contribution to the study of this disease.  The meeting
report specifically recommends a concerted effort to identify such
families and avoid their loss to follow-up.

The meeting participants indicated that it is impractical, expensive
and scientifically unproductive to collect only a few families at a
time and that it is timely to develop larger registries of families
at high risk for cancer.  Such registries should include the
collection of epidemiologic and clinical data and of blood and
biological specimens, which would be used in future epidemiologic and
biologic studies.  This research has the potential to be translated
into clinical applications and public health measures to address the
pressing needs of at-risk populations.

Many different approaches to breast cancer research will be able to
take advantage of family registry resources, as new knowledge and
molecular tools become available.  The existence of an established
cooperative breast cancer family registry would enhance the cost-
effectiveness of:  (1) the identification and follow-up of high-risk
individuals for the purpose of preventive intervention; (2) the
evaluation of the effectiveness of optional treatment strategies as
they become available; (3) molecular epidemiology studies generating
and testing etiologic hypotheses; and (4) the integration of
laboratory studies into the biological mechanisms underlying breast
cancer with epidemiologic and genetic data.

Current epidemiologic studies of familial breast cancer are limited
by the feasibility and expense of collecting a sufficient number of
high-risk families to define the genetic heterogeneity of the
familial disorder.  Moreover, as new statistical approaches become
available to explore the interaction between genetic and
environmental factors in the etiology of familial breast cancer, the
collection of appropriate epidemiologic data on exposure to potential
risk factors in these same families becomes extremely important.
Other limitations are the lack of archival or fresh-frozen tissue
specimens and blood samples, and the difficulty in collecting and
validating clinical and epidemiologic data.

Efforts made to identify breast cancer-prone families have focused on
the localization and mapping of a putative gene for early onset-
breast cancer and breast/ovarian cancer, or BRCA1, using molecular
markers for a defined area on chromosome 17q.  Although an uncertain
fraction of familial breast cancer is attributable to BRCA1, the risk
for breast cancer of women inheriting this gene is extremely high (up
to 85 percent lifetime risk), while the risk for ovarian cancer is
also elevated.  Testing for the BRCA1 gene is currently limited to
very rare families being analyzed for research purposes.  However,
since the BRCA1 gene has been recently identified, and the mapping
and cloning of other possible breast cancer genes are being pursued,
it will be extremely important to identify and appropriately counsel
the individuals at high risk and their families on preventive and
therapeutic options.  A family registry for breast cancer would
greatly facilitate this process.

Research Goals and Scope

The purpose of this RFA is to stimulate cooperative efforts for the
establishment of a comprehensive family registry for epidemiologic
and interdisciplinary studies of individuals at high risk for breast
cancer.  The establishment of a population-based selection process
that could utilize already existing resources, such as SEER or other
cancer registries, is strongly encouraged.

The CFRBC will enable participant organizations to: identify
individuals with a family history of breast cancer, breast-ovarian
cancer syndrome, male breast cancer, and various familial syndromes
that include breast cancer; collect and define the related pedigrees;
and collect clinical (tumor type, stage at diagnosis, hormonal
evaluation, etc.), epidemiologic (age at diagnosis, sociodemographic
status, etc.), and other relevant data (such as dietary history) to
correlate with the pedigree information.  Support for the collection
of related biological specimens, such as blood samples, paraffin
blocks and fresh-frozen tissue, will be included.  This registry is
not intended to directly support research on the mapping and cloning
of the gene(s) for breast or breast/ovarian cancer, but to assist
investigators funded through other sources by providing the data and
biological specimens that can be used for a variety of purposes,
including etiologic studies and prevention and treatment-oriented
translational research.

The applicants should demonstrate the capability for developing
common protocols including, but not limited to:

o  ascertainment of breast cancer families;
o  epidemiologic and clinical data collection, validation and
management (statistical support);
o  collection and banking of biological specimens (blood and
tissues); o  limited follow-up for outcome, recurrence and mortality;
and o  counseling of family members on risk and possible preventive
or therapeutic interventions.

Each application must have an Operation Core for statistical and
logistic support, capable of providing the necessary coordination for
specimen and data collection, and functioning as a central facility
at the applicant's institution for data and specimens management and
storage.  Applicants must address coordination of quality control
among awardees with regard to collection and storage of data and
specimens.

The establishment of the CFRBC resource will promote the availability
of epidemiological and clinical data and the related specimens
necessary for multidisciplinary and translational studies on the
etiology of breast cancer.  The awardees will provide to the research
community at large pedigree information, epidemiological data, and
biological specimens for high priority research studies.  It is
anticipated that prioritization of the research study proposals
requesting access to the CFRBC's resources will be made by an
Advisory Committee (AC), and will be based on scientific validity
criteria established by the Steering Committee (SC) (for composition
and duties of AC and SC see below under special requirement).  The
NCI will help to coordinate and promote this process through the
Program Coordinator's membership in the AC and SC.

Of the funds provided by this RFA, at least 90 percent of the total
cost proposed in each application must be directed to the basic CFRBC
activities (accrual of families, data and specimen collection,
management, and retrieval). Up to 10 percent of the total cost, or
$50,000 per year (whichever is smaller, starting from the second year
of the cooperative agreement), can be requested for pilot or
feasibility studies utilizing the family registry resources.

Pilot/feasibility studies should be designed to obtain sufficient
data to form the foundation for future R01 research grant
applications, to help identify new areas where additional
investigations are warranted, and to promote interdisciplinary and
translational breast cancer research.

SPECIAL REQUIREMENTS

Definitions

AWARDEE  The organization to which a cooperative agreement is awarded
and that is responsible and accountable to NCI for the use of funds
provided and for performance of the project supported by the
cooperative agreement.

PRINCIPAL INVESTIGATOR (PI)  The single individual at the Awardee's
Institution designated by the Awardee in the cooperative agreement
application, who is responsible for the scientific and technical
direction of the project.

OPERATION CORE (OP)  The central site at the Applicant/Awardee
Institution that handles the epidemiological and pedigrees data and
the biological specimens.  All the data and specimens from each
Applicant/Awardee Institution will be coordinated and located at one
central location within the awardee's own Institution.  The PI serves
as the head of the Coordination Site.

NCI PROGRAM COORDINATOR  The Extramural Programs Branch (EPB) Program
Director who will be interacting scientifically and administratively
with the Applicant/Awardee Institutions and providing guidance for
the overall program for NCI.

STEERING COMMITTEE (SC) A committee whose membership includes the NCI
Coordinator, the PI and one other investigator from each awarded
cooperative agreement, and one research scientist with expertise in
translational breast cancer research who is not affiliated with any
of the Awardee Institutions.  This research scientist on the SC will
be appointed by mutual agreement of the NCI Program Coordinator and
the PIs.  The SC will serve as the governing board of the CFRBC (for
its functions, see under "Terms and Conditions of Award).

ADVISORY COMMITTEE (AC) A committee composed of six to eight senior
scientists with experience in multidisciplinary and translational
breast cancer research.  The members of the panel will evaluate all
research proposals (those of the awardees as well as proposals from
the research community at-large) proposing to utilize the CFRBC's
resources according to the evaluation and the review criteria
provided by the SC.  The AC will provide a recommendation to the SC
regarding the priority of the proposed research.  The membership of
the AC may vary, depending on the specific areas of the proposed
breast cancer research to be reviewed.  All AC members will be
selected by the SC (see under "Terms and Conditions of Award" for
function of the AC).  The NCI Program Coordinator will function as a
non-voting liaison member between the AC and the SC, and attend the
AC meetings.

Study Organization and Function

The overall structure of the CFRBC will consist of two to five funded
Institutions (awardees) that are governed and coordinated through the
SC.  Each awardee unit will be composed of one funded site, an
Operation Core at the funded site, and a PI providing the scientific
and administrative leadership for the unit and serving as the Head of
the Operation Core.

The overall function of the CFRBC is to promote multidisciplinary and
translational research in the framework of studies in the genetic
epidemiology of breast cancer, by serving as a national resource to
the research community at large.  Requests for specimen and data from
the awardees and their collaborators will be reviewed, prioritized by
the AC, and approved by the SC along with all other requests from
investigators in the research community at-large.

The Terms and Conditions of Award, below, will be included in all
awards issued as a result of this RFA.  It is critical that each
applicant include specific plans for responding to these terms.

Terms and Conditions of Award

These 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 part 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 involvement in and otherwise working jointly with the award
recipient in a partner role, but is not to assume direction, prime
responsibility, or a dominant role in the 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 studies
will be shared among the awardees and the NCI Program Coordinator.

1.  Awardee Rights and Responsibilities

Awardees will have primary rights and responsibilities to define
projects and approaches and to plan and conduct the project,
including:

o  The Awardee's PI will participate as a permanent member in the SC
and designate a second investigator from his/her institution to be a
permanent member of such committee.

o  The Awardee will work together with the other Awardees through the
SC to establish the registry operating policies, uniform collection
procedures, and quality control procedures for specimens and data.
The Awardee will be required to accept and implement the common
policies and procedures approved by the SC.

o  The Awardee must agree to provide access to both specimens and
data to investigators both within and outside the awardee's
institutions, based on the prioritization of the research proposals
set by the AC and final approval by the SC.  The Awardee will abide
by the decisions of the SC based on recommendations from the AC.

o  The Awardee will retain custody of, and have primary rights to,
the data developed under this awards, subject to the Government
rights of access consistent with current HHS, PHS, and NIH policies.

o  Each awardee will need to implement and comply with the common
study protocols as established by the SC, but additional elements
could be appended by individual institutions to address issues of
unique interest or capabilities in each center.

o  The Awardee must provide an annual progress report to the EPB,
DCE, NCI, and a copy to the chairperson of the SC, in a format that
is compatible with the annual progress report of the other awardees.
Information on the operation of the registry as well as performance
and progress on pilot studies are to be included.

o  Collaboration among awardees in the reporting of findings
originated from this initiative is encouraged.  Collaborative
publications among awardees and NCI are anticipated.

Immediately after the notification of award, the successful applicant
should also provide the name of one scientist not affiliated with
his/her Institution as a potential member of the SC.  In addition,
each applicant should provide the names and qualifications of two
scientists not affiliated with his/her Institution as potential
members of the AC.  Letters of commitment from the potential members
of the AC and SC should be attached.

2.  National Cancer Institute Staff Responsibilities

The NCI Program Coordinator will be designated by the Chief,
Extramural Programs Branch, EBP, DCE, NCI.  He/she will have
substantial scientific-programmatic involvement during conduct of
this activity through participation in the SC and AC activities.  The
Program Coordinator will provide technical assistance, advice and
coordination, assure that the SC and the AC follow the NIH guidelines
on conflict of interest issues, and play a critical role in promoting
the availability and use of the registry. The role of the Program
Coordinator is to assist and facilitate, but not to direct, the
activities supported by the CFRBC.

The NCI Program Coordinator will:

o  Lend his/her expertise and overall knowledge of the NCI- and NIH-
sponsored breast cancer research to facilitate the selection of
scientists non-affiliated with the awardees institutions who are to
serve in the AC and SC.

o  Serve as liaison, helping to coordinate activities among the
awardees; act as a liaison to the NCI, and as an information resource
about extramural multidisciplinary cancer research activities in the
area of genetics and molecular epidemiology.

o  Attend the SC meetings as a voting member, assist in developing
operating guidelines, quality control procedures, and consistent
policies for dealing with recurrent situations that require
coordinated action.

o  Serve as liaison between the SC and the AC, attending AC meetings
in a non-voting liaison member role, lending a degree of continuity
between AC and SC, as the ad hoc AC composition may change depending
on the expertise required to review the submitted research
applications.

o  Serve on subcommittee of the SC and the AC as required.

o  Assist in the monitoring of field data collection, helping to
ensure standardization in methods across study centers; and assist in
the interpretation and reporting of the collected information.  This
will be necessary because of the complexity of this multi-site
structure, requiring a high degree of coordination and program
involvement to achieve adequate standardization of procedures.

o  Assist by providing advice in the management and technical
performance of the investigation. The Program Coordinator will serve
as scientific liaison between the awardees and other program staff at
NCI who have previous experience in the establishment of cancer
registries and tumor bank.

o  Assist in promoting the availability of the CFRBC resources to the
scientific community at large, for use in translational and
prevention-oriented breast cancer research, as stated in this RFA
goals.

The National Cancer Institute reserves the right to reduce the
budget, to withhold support, and to suspend, terminate or curtail a
study or an award in the event of substantial shortfall in specimen
accrual, data reporting, inadequate quality control in specimens or
clinical data collection, other major breach of the protocol, or
substantial failure to comply with the terms of the award.

3.  Collaborative Responsibilities

a.  Steering Committee

The SC will serve as the main governing board of the CFRBC (see
"Terms and Conditions of Award").  The SC membership includes the NCI
Coordinator, the PI, one other investigator from each awarded
cooperative agreement, and one research scientist with expertise in
the field of multidisciplinary and translational breast cancer
research that is not affiliated with any of the awardees
institutions.  This last member will be appointed by mutual agreement
of the NCI Coordinator and the PI's.  Additional members can be added
by action of the SC.  Other appropriate NCI staff may need to attend
the SC meetings if their expertise is required, to participate in
specific discussions.

The SC will be responsible for reviewing the plans for development of
the CFRBC proposed in the individual applications of the awardees.
This Committee will develop uniform procedures for data collection
and management, tissue collection, processing and distribution, and
quality control.  The SC will develop the criteria for review and
prioritization of research proposals requiring the use of the CFRBC's
resources.  The NCI Program Coordinator will assist the other members
of the SC in all these tasks.  Furthermore, the NCI Program
Coordinator will serve as the scientific liaison between the awardees
and the other program staff of NCI who have previous experience in
the establishment of family cancer registries.  Awardees will be
required to accept and implement the common guidelines and procedures
approved by the SC.

The first meeting of the SC will be called by the NCI Program
Coordinator shortly after award of the cooperative agreements.  At
this initial meeting, the Committee will elect a Chairperson (someone
other than the Program Coordinator).  The Chair of the SC is
responsible for coordinating the Committee's activities, for
preparing meeting agendas, and for scheduling and chairing meetings.
The Program Coordinator attends and participates in all meetings of
the SC, and should be informed of any major interactions.  Subsequent
meetings will be planned and scheduled at this meeting.  Two
additional meetings will be held during the first year of operation,
and there will be two meetings a year thereafter, one of which with
the AC.  The meetings will be held in Bethesda or at another
convenient location.  Accordingly, respondents must request
sufficient funds within the submitted budgets to accommodate travel
expenses for the PI and his designee.  Subcommittees will be
established by the SC as it deems appropriate.

The SC is responsible for providing documentation as to the
availability and accessibility of specimens and data for the use of
investigators with approved research proposals requesting the use of
the registry resources.  In no circumstance will the SC overturn the
recommendation of the AC, except when specimens and/or data are not
available.

The SC will select members for the AC.  The SC in the conduct of all
business matters will pay particular attention to conflict of
interest issues, especially in actions regarding recommended
prioritization of the AC.

b.  Advisory Committee

The AC is responsible for reviewing, evaluating and approving
research proposals submitted by investigators from the research
community at large, as well as from the awardees, for the use of the
registry resources.  A recommendation in terms of priority of the
proposed research should be provided to the SC.  The only occurrence
in which the SC can overturn the recommendation of the AC is the
unavailability of the requested specimens and/or clinical data.  The
AC will meet with the SC at least once yearly, at one of the two
scheduled SC meetings.

The AC will be composed of six to eight senior scientists with
expertise in multidisciplinary and translational research in the
field of breast cancer, which may include epidemiologists, laboratory
researchers, clinicians, or other expertise that the SC deems needed.
The membership of the AC may vary, depending on the scientific areas
of the proposed research to be reviewed and evaluated.  All members
will be selected by the SC.  The Program Coordinator will function as
a non-voting liaison member between the AC and the SC, and attend the
AC meetings.

The members of the AC will evaluate all research proposals (those of
the awardees as well as from the research community at large)
proposing to utilize the CFRBC resources, according to the evaluation
and review criteria provided by the SC.  The review of proposals can
be conducted either in person, by conference call or by mail at least
twice a year.  All reviews will be conducted according to rules
pertaining to the conduct of reviews for NIH grants, contracts, and
cooperative agreements, paying special attention to issues of
conflict of interest, whether real or apparent.  The AC will provide
a recommendation to the SC as of the priority of the proposed
research.  The Chair of the AC will forward the final recommendation
to the SC.

4.  Arbitration Procedures

Any disagreement that may arise on scientific/programmatic matters
(within the scope of the award) between the award recipients and the
NCI may be brought to arbitration.  An arbitration panel will be
composed of three members, one selected by the SC (without the vote
of the Program Coordinator) or by the individual awardee in the event
of an individual disagreement, a second member selected by the NCI,
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 otherwise appealable in
accordance with the PHS regulation at 42 CFR part 50, subpart D and
HHS regulation at 45 CFR part 16.

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 subpopulation must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects and the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research," which was printed in the Federal
Register of March 28, 1994  (59 FR 14508-14513) and reprinted in the
NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23,
Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are requested to submit, by November 30, 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 institution(s), 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 is helpful in planning for the review of
applications.  It allows NCI staff to estimate the potential review
workload and avoid conflict of interest in the review.  The letter of
intent is to be sent to Daniela Seminara, Ph.D., M.P.H., at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on form PHS 398 (rev. 9/91),
available at most institutional offices of sponsored research and
from the Office of Grants Information, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301/710-0267, and from the NIH program
administrator listed under INQUIRIES.  The format and instructions
applicable to research grant applications must be followed.

It is critical that applicants clearly describe plans to accommodate
stated criteria and staff involvement as listed in the Terms and
Conditions of Award, and in the Review Criteria Section.

Applicants must propose detailed plans for how to organize the CFRBC
in the most cost-effective and scientifically sound manner.
Applicants are encouraged to submit and describe their own ideas on
how to best meet the goals of this RFA.  Advantages and disadvantages
of the proposed approaches should be discussed, and the plans for
establishing collaborations should be described.

Plans should describe resources, including information on number of
probands available and reasonable estimate of the expected number and
quality of pedigree information and related epidemiological data and
biological specimen available.

The Operation Core should be adequately described, including the
facilities for data collection and storage and specimen storage, as
well as the investigators' experience in this area.  The applicants
must provide details on appropriate facilities and biohazard
precautions and comply with the applicable Federal, State, and Local
regulations, laws and finances in the operation of the Registry.

Information on the nature of the data collected at baseline and
follow-up should be provided.

Examples of data forms, epidemiologic questionnaire, medical records
and abstracting procedures, and software that may be appropriate for
the use of the registry should be included in the appendix

Methods should be proposed to retrieve and establish an inventory of
biological specimens, such as blood, fresh-frozen tissue, tissue
blocks and slides.

Appropriate data retrieval and data management procedures and quality
control methods for the epidemiological and clinical data should be
detailed.  The applicants must state a willingness to cooperate with
other awardees in developing policies for quality control and to
share data with other awardees.

The applicants must state a willingness and should discuss their
approach to cooperate with the SC and the AC in evaluating research
proposals utilizing the CFRBC resources, and to abide by the
decisions of the AC in prioritizing such proposals, after final
approval by the SC based on data and specimen availability.

The applicant should provide the name and qualifications for the
second investigator from his/her Institution to be designed as member
of the SC.

As the principal investigators of the funded applications and one
designee will be members of a SC that will meet three times in the
first year and twice in each subsequent year, travel funds for these
meetings should be set aside as a budget item.  As the AC will meet
with the SC once a year, funds should also be included to support
travel by one member of the AC to one SC meeting once a year, plus
any additional travel anticipated for AC members.

Applicants seeking up to 10 percent of the total cost, or up to
$50,000 per year for three years (whichever is smaller, starting from
the second year of the cooperative agreement), for pilot studies
utilizing the CFRBC resources, should document their ability to
conduct breast cancer research and document any of their ongoing work
in this area.  The research hypothesis, background and rationale and
design of the pilot study should be described as part of the research
plan, keeping within the allowed page limits.  The SC and the AC will
review the pilot studies proposed in the application in response to
this RFA even if the studies received approval under peer review.
Moneys for pilot studies will be restricted until the AC gives these
pilot studies high priority ratings, and the requested specimens
and/or data are available and have been released by the SC.  The
review of these pilot studies will occur along with the review and
prioritization of other requests submitted by investigators in the
research community at large.  The pilot studies will begin no sooner
than year two of the cooperative agreement.  However, if the AC does
not rank the pilot project as a high priority, a new pilot study that
is rated as high priority by the AC can be substituted.

The RFA label available in the application form PHS 398 (rev. 9/91)
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 number and title of the RFA must be typed on line 2a of
the face page of the application and YES must be checked.

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

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Rockville, MD  20852 (if hand delivered or delivery service)
Bethesda, MD 20892 (if using U.S. Postal Service)

It is important to send these copies at the same time that the
original and three copies are sent to DRG;  otherwise, the NCI cannot
guarantee that the application will be reviewed in competition with
other applications received by the designated receipt date.

Applications must be received by February 17, 1995.  If an
application is received after that date, it will be returned to the
applicant without review.  If the application submitted in response
to this RFA is substantially similar to a research grant application
already submitted to the NIH for review, but has not yet been
reviewed, the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.  Therefore,
an application cannot be submitted in response to this RFA that is
essentially identical to one that has already been 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

General Considerations

All applications will be judged on the basis of the scientific merit
of the proposed project and the documented ability of the
investigators to meet the RESEARCH OBJECTIVES of the RFA.  Although
the technical merit of the proposed protocol is important, it will
not be the sole criterion of evaluation of a study.  Other
considerations, such as the importance and timeliness of the proposed
study, access to patients, and multidisciplinary and translational
nature of the studies, will be part of the evaluation criteria.

Review Method

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  Also, if
NCI staff find that the application is not responsive to the RFA, it
will be returned 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 NCI in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator/program director
and the official signing for the applicant organization will be
promptly notified.

Review Criteria

Applicants are encouraged to submit and describe their own ideas
about how to best meet the goals of the cooperative study and their
specific protocols, and are expected to address issues identified
under SPECIAL REQUIREMENTS of the RFA.

The review group will assess the scientific merit of the protocols
and related factors, including:

o  extent to which the application addresses the goals and objectives
of the RFA

o  adequacy of the applicant's plans for addressing the special
scientific and technical program requirements presented in the RFA;

o  merit of the proposed activities and organizational plans for
implementing the CFRBC;

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

o  time availability of the PI and staff

o  availability of, and access to, a suitable patient population;

o  adequacy of existing physical facilities and resources of the
applicants' Institutions.

o  demonstrated ability to carry out common protocol;

o  adequacy of plans for effective cooperation and coordination among
participating awardees and the NCI Program Coordinator, as per
Special Requirements of the RFA;

o  adequacy of proposed number of study subjects to be recruited

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

o  adequacy of proposed data to be collected and procedures for data
handling, managing, and preparing for analyses;

o  evidence that appropriate steps have been taken to insure the
rights of human subjects.

o  the scientific and technical significance or originality of the
proposed pilot studies in the field of translational breast cancer
research.  It is to be noted that the review of this part of the
grant application will be given much less weight relative to the
review of the registry facilities, procedures and epidemiological
data base, as no more than 10 percent of the total cost, or up to $
50,000 per year for three years (whichever number is smaller,
starting the second year of the Cooperative Agreement) may be
requested for these studies.

The review group will also examine the proposed budget and will
recommend an appropriate budget and period of support for each
application that is recommended for further consideration.

The second level of review by the National Cancer Advisory Board
considers the special needs of the NCI and the priorities of the
National Cancer Program.

AWARD CRITERIA

The earliest anticipated date of award is December 1, 1995.  The
following will be considered for making funding decisions:

o  scientific and technical merit of the proposed project as
determined by peer review;

o  availability of funds;

o  program balance among research areas.

INQUIRIES

Inquiries concerning the RFA and the opportunity to clarify any
issues or questions from potential applicants are welcome.

Direct inquiries regarding programmatic issues to:

Dr. Daniela Seminara
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Suite 535
6130 Executive Boulevard MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
FAX:  (301) 402-4279
EMAIL:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Kelli Newball
Grants Management Specialist
National Cancer Institute
6120 Executive Boulevard
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 61

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.393, Cancer Cause and Prevention 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 Part 74 and 92.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems Agency review.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.

.

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