BREAST CANCER SURVEILLANCE CONSORTIUM EXPANSION

Release Date:  January 22, 1999

RFA:  CA-98-025

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  June 15, 1999
Application Receipt Date:  July 15, 1999

PURPOSE

The Division of Cancer Control and Population Sciences (DCCPS), National
Cancer Institute (NCI), invites applications from domestic institutions for
cooperative agreements to support collaborative research within the Breast
Cancer Surveillance Consortium (BCSC), established by the Cancer Surveillance
Research Program (CSRP) in 1994.  This is a follow up to RFAs (cooperative
agreements) awarded in 1994 and 1995 and coming to an end in 1999 and 2000. 
This RFA is intended to include recompetitions from existing centers and
applications from new centers.  Strengthening surveillance activities has been
identified as an NCI priority, particularly in order to allow more definitive
statements to be made regarding factors influencing cancer incidence,
mortality, and survival at the national level.  The Breast Cancer Surveillance
Consortium has led to the development of data linkages between radiologic
practices, pathology laboratories, and cancer registries to obtain data on
screening mammography, recommended and subsequent work up, diagnosis,
treatment, and mortality.  Some limited risk factor data thought to be most
relevant to screening and diagnosis are being collected and data on benign
breast disease pathology for biopsied non-cancer cases are being collected at
some sites.  This initiative will broaden the current Breast Cancer
Surveillance Consortium research effort in several key aspects, while
continuing to support the central goals and objectives.  In addition to
funding sites to collect data relevant to mammography performance, this RFA
will also support a Statistical Coordinating Center (SCC) to develop data
comparability processes, to serve as the central repository for pooled data
and to provide the research expertise on complex statistical issues for
analysis of these pooled data.

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, BCSC Expansion, is related to
the Priority area of cancer surveillance and data systems.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-512-1800), or at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, cancer
centers, hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Applications from minority and
women investigators are encouraged.  Since this RFA concerns breast cancer
surveillance research in the United States, a domestic application may not
include an international component.  New applicants and those with currently
funded programs are eligible as described below.  A BCSC applicant may be, but
is not limited to, a hospital, a clinic, a group of practicing physicians, a
health maintenance organization (HMO), or a consortium of hospitals and/or
clinics and/or physicians and/or HMOs that agree to work together with a
Principal Investigator and a single administrative focus.  If the expertise
required does not reside within one institution, an applicant may put together
a group with the necessary expertise, which may involve the use of several
institutions and/or organizations.  Each primary data collection and research
center applicant must have access to a resource unit that supports research
data management and statistical analyses locally.

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 later in this document
under the section "Terms and Conditions of Award".  The total project period
for applications submitted in response to the RFA may not exceed five years. 
Because the nature and scope of the research proposed in response to this RFA
may vary, it is anticipated that the sizes of awards will vary also.  Awards
will be administered under PHS grants policy as stated in the NIH Grants
Policy Statement, dated October 1998.

This RFA is a one-time solicitation.  If the NCI determines that there is a
sufficient continuing program need, a request for new and competitive
continuation applications will be announced.

FUNDS AVAILABLE

In fiscal year 2000, the NCI plans to make 9-11 awards for primary data
collection and research centers and one award for a SCC. Approximately
$5,000,000 total cost (total cost = direct plus facilities and administrative
costs) is expected to be available for the first year of support under this
RFA and the research effort will be renewable for up to 5 years.  It is
anticipated that the award for each primary data collection and research
center will be between $400,000 - $550,000 total cost for the first year and
the award for the SCC will be about $550,000 total cost for the first year. 
While it is possible that one institution may apply for a primary data
collection and research center and the SCC, separate applications must be
submitted.  It is anticipated that the relevant expertise necessary to lead
these two efforts would result in different PIs for the two applications
efforts should a single institution apply for both.

The number of awards to be made is dependent on the receipt of a sufficient
number of applications of high scientific merit and availability of funds. 
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.  The anticipated date of award is March 2000.

First year costs may include development of computer systems dedicated to this
research, if needed.  For purposes of budgeting, funds should be requested for
up to five persons to attend semi-annual BCSC meetings at alternating BCSC
sites or the NCI during each of the five years of award.  Funds should also be
requested for up to 2 persons to attend up to 2 smaller working group meetings
at alternating BCSC sites or the NCI during each of the five years of award. 
The SCC applicant should budget for up to 11 site visits (one to each
potential primary data collection and research center awardee) per year for
the purposes of improving data collection, formatting and transfer procedures
for pooled data analyses.

RESEARCH OBJECTIVES

Background

A more complete summary of the existing BCSC (16) can be obtained from the
American Journal of Roentgenology, October 1997; 169:1001-1008.  Excerpts from
that summary are included in this background.

Mammography is the primary method of detecting early stage breast cancer and
has been shown in randomized clinical trials to reduce breast cancer
mortality, especially among women 50 years old and older [1-5].  Authorities
in cancer screening have long recognized that the level of efficacy of
screening demonstrated in randomized clinical trials may not pertain to
community practice for several reasons [6].  These include possible
differences in the population groups receiving screening, lower accuracy of
screening mammography in the community, or lower compliance with diagnostic
follow-up and treatment in community practice, which may not lead to optimal
outcomes.  On the other hand, screening effectiveness in community practice
today could exceed that estimated in trials because the technical and
interpretative quality of mammography has improved since the trials were
performed.  Furthermore, clinical trial efficacy has been estimated based on
assignment to receive screening; to the extent that  women assigned to
screening were not screened or that women in the control groups were screened,
efficacy in trials may have been underestimated.

To optimally evaluate the performance of mammography in a community setting,
the screening prevalence and patterns, and the associated sensitivity,
specificity and predictive value of mammography in community screening
programs should be determined by linkage with cancer outcomes [7,8].  A
program of monitoring should also provide data on specific populations, such
as rural and minority subgroups, that are traditionally underserved by
screening programs and may have different breast cancer mortality rates [9]. 
Before the Mammography Quality Standards Act (MQSA) of 1992, most mammography
facilities in the United States did not maintain record systems that could
provide reliable and comprehensive data to evaluate the performance of
screening mammography [10].  The concept of a medical audit of outcomes data
had been proposed [11] but has not been routinely practiced in the community. 
The interim regulations of the MQSA mandated the maintenance of mammography
data and the performance of a medical outcomes audit [12].  In practical terms
the medical audit requirement of the MQSA was limited to an analysis of
patients with tests interpreted as "suspicious abnormality" or "highly
suggestive for malignancy, " which permits evaluation of the positive
predictive value of such interpretations.  However, the MQSA does not require
linkage to population-based cancer registry data or other source of pathology
data, without which it is impossible to accurately assess the outcomes of
patients with mammographic examinations interpreted as normal.  To understand
the full effect of breast cancer screening on cancer outcomes, data on breast
cancer screening practices should be linked to data from population-based
cancer registries.  Moreover, data on pathologic or biologic characteristics
of tumors, together with patient demographic and risk factor information, can
be linked to population-based registries in order to better understand staging
and survival of mammographically-detected compared to non-mammographically-
detected breast cancers.

Development and Purpose of the NCI Breast Cancer Surveillance Consortium

A section of the MQSA authorized the Secretary of the Department of Health and
Human Services to fund research establishing a breast cancer screening
surveillance system.  In response to this legislative mandate, the NCI
established the BCSC in 1994.  The three major objectives of the BCSC are: 1)
to enhance our understanding of breast cancer screening practices in the
United States through an assessment of the accuracy, cost, and quality of
screening programs and the relation of these practices to changes in breast
cancer mortality or other shorter term outcomes, such as stage at diagnosis or
survival; 2) to foster collaborative research among BCSC participants to
examine issues such as regional and health care system differences in the
provision of screening services and subsequent diagnostic evaluation; and 3)
to provide a foundation for the conduct of clinical and basic science
research, especially basic research on biological mechanisms, that can improve
understanding of the natural history of breast cancer.  The intent of the
third objective is to ensure that a core set of pathologic data on established
prognostic indicators is collected and to provide the capability to examine
the prognostic potential of other more investigational indicators.  The NCI
developed a Consortium of research sites in order to address issues that can
be adequately examined only in a very large sample drawn from diverse
geographic and practice settings.  The first major effort of the Consortium
was to create a standard set of carefully defined variables in order to
facilitate pooling of data with sample sizes sufficient to examine issues in
subgroups for which the number of cancers is relatively low, such as among
younger women, women with a family history of breast cancer, or some ethnic or
racial groups.  This latter, critical objective of national pooled data
analyses necessitated the development of a SCC and is the rationale for the
involvement of NCI surveillance research staff in this project through a
cooperative agreement mechanism.

In order to address these research objectives, the BCSC has developed
standardized data collection and linkage mechanisms for mammography practice
data and population-based cancer registry data.  This linkage can provide
cancer characteristics and follow-up of patients for vital status and cause of
death and will allow an assessment of the performance of screening mammography
in diverse community settings.  Furthermore, the linkage of these data will
provide a unique opportunity, in the short term, to determine whether
differences in the practice of screening mammography and subsequent diagnostic
evaluation influence breast cancer detection rates and stage at diagnosis.  In
the long term, such linked data may have the potential to provide information
on whether differences in practice patterns influence breast cancer mortality. 
The original 5 years duration of funding does not allow for evaluating this
long term objective.  By the year 2000 the database will contain information
on nearly 3.2 million mammographic examinations and over 24,000 cases of
breast cancer.  The estimated racial and ethnic distribution of women
receiving mammography reflects that of the geographic catchment areas for the
nine sites.  The age distribution of women currently receiving mammography
within the database is 8%, 31%, 26%, 19%, and 16% for ages less than 40, 40-
49, 50-59, 60-69, and 70 and older, respectively.

In addition to its intended purpose of evaluating population-based screening
mammography in the United States, the database will be a valuable resource for
future research.  For example, with continued collection of data in these
populations and follow up for outcomes, BCSC data will allow assessment of the
effect of community mammography screening on stage distribution of breast
cancer.  Current BCSC pilot studies are examining the hypothesis that the
performance of screening mammographic examinations varies by biologic
characteristics, stage, and rate of growth of breast tumors.  Furthermore, the
BCSC database will provide information on demographic, risk factor, clinical
characteristics, and treatment for women who subsequently develop breast
cancer.  It will also provide data on a large population-based sample of women
at high risk for breast cancer, including those with a family history of
breast cancer or benign breast disease.  Therefore, this resource may be
particularly useful for identifying patients relevant for research into the
population prevalence of genetic and other biological markers for breast
cancer risk and prognosis and potential associations of these markers with
other known breast cancer risk factors.  Data from the BCSC will provide
estimates of the prevalence of subsequent diagnostic follow-up and information
relevant to improving the communication of risks and benefits related to
screening.  The mammography registry may also serve as a resource for
intervention trials to study ways to improve screening compliance.

A second use of the database will be to permit the comparison of regional data
across the United States.  The process of identifying a uniform set of data at
the BCSC sites has improved consistency in data collection and provides a
model for the development of linkages between mammography and cancer
registries.  Other entities, such as states that are establishing mammography
registries, have sought information from the BCSC on how to set up comparable
systems.  Dissemination of such information should foster uniformity in data
collection among emerging software packages and at other facilities trying to
create linkages between mammography data and cancer registries, thereby
further improving the ability to compare the performance of mammography across
regions.  These efforts should also improve quality of data and, through
publication and feedback of the data to radiologists in the community, improve
mammography screening quality.

Accomplishments

In addition to the above background, some of the accomplishments of the BCSC
merit further discussion because they are distinctive to the needs and future
directions of national surveillance research.  These are chronologically
described and relate to the development of standardized, high quality methods
for data collection, ensuring confidentiality of data and research subjects,
novel approaches to data collection within the context of routine clinical
care, and, finally, the research productivity of the BCSC database.

Development of standardized, high quality data:

A data dictionary has been developed which details the standardized format
created to allow analysis of data pooled from multiple sites.  Unlike multi-
center clinical trials that use a common protocol and common data collection
instruments, the research projects within the BCSC rely on data collected
within the context of routine medical care.  Variability  in practices at
diverse sites presents a challenge to the collaborative research effort in
which all sites must collect the same core variables.  Core variables are
being collected to build three databases which can be linked: patient
demographic and health history, radiologic history, and follow-up.  Research
using the database will demonstrate the specific variables and level of detail
that are most valuable in assessing the performance of screening mammography
in community practice.  The results of this research effort  (and details of
level of specificity required) are likely to be central to future FDA revision
of the MQSA.  The data dictionary  has been a valuable resource to researchers
considering the development of similar systems in their own regions.

Ensuring confidentiality of data and research subjects:

Data confidentiality and protection of research subjects has become an
increasingly important issue with the development of large, linked
computerized databases with potential access by a variety of individuals.  The
absence of adequate legislative protection of the data during interstate
electronic transit and while at the SCC was a major issue influencing the
ability of the BCSC to perform pooled data analyses.  The concern was raised
because data contributed to the SCC are exceedingly sensitive in nature.  Data
from health care providers reflect their practice and their accuracy in
performing mammography, while data from patients pertain to their cancer
status.  Third party payers might have an interest in obtaining both types of
data.  Although state legislative statutes, institutional quality assurance
(QA) statutes, or both may (depending on state laws or institutional policies)
protect research databases and QA data from either litigation or access, once
the data cross state lines or institutional borders they may not be protected. 
The BCSC addressed this concern by applying for and receiving federal
Certificates of Confidentiality for each member site, including the NCI and
the SCC, in accordance with the provisions of Section 301(d) of the Public
Health Service Act (42 U.S.C.  241 (d)).  The Certificate is issued to protect
the privacy of research subjects by withholding their identities from all
persons not connected with the research.  This federal level of protection of
BCSC and SCC databases is the highest level of protection available in the
United States and represents the first Public Health Service Certificate of
Confidentiality that has included health care providers as research subjects. 
The Certificates provide protection to research data irrespective of location,
whether at the originating site, in transit to the SCC, or at the SCC.  Such
protection may become increasingly important to the conduct of research
involving community practice and patients.  To further protect data
confidentiality, common confidentiality procedures were detailed in a manual
and are followed at each site [17].

Novel approaches to data collection within the context of routine clinical
care:

The sources of data for this national mammography surveillance research effort
are diverse and range from solo practitioners in rural settings to multi-
speciality groups within large, structured managed care organizations in urban
settings.  The complexity of integrating data from these multiple sources and
the increasing use of computerized medical record systems for clinical care
necessitated the development of novel data collection and editing systems
within the BCSC.  Two examples of  very different systems developed by BCSC
investigators to accommodate their study populations are illustrative of the
innovation required.  The Carolina Mammography Data System collects data from
over 70 sites providing mammography to women in 24 largely rural counties in
the state of North Carolina.  Data collection methods initially included a
high proportion of paper data collection and transfer but now are primarily
accomplished via electronic systems.  Conversely, in the San Francisco
Mammography Registry data collection and transfer were developed as electronic
clinical practice systems and implemented in the largely urban, large multi-
speciality practices included in that registry.

Research productivity:

A major mandate within the MQSA called for the Secretary of DHHS to establish
research projects testing the feasibility of establishing population-based
linked databases for evaluating the performance of screening mammography in
community practice.  The mandate for this research effort was assigned to the
Cancer Surveillance Research Program within NCI.  A number of sites and the
BCSC have published baseline manuscripts describing the development of these
systems [13-16].  Ensuring confidentiality of data and research subjects is a
critical component of feasibility and has been described in a BCSC manuscript
[17].  Research at individual sites has addressed the performance of screening
mammography in diverse settings [18-20], the effect of patient
characteristics, such as family history for breast cancer, use of hormone
replacement, and breast density on screening performance [21-23], and the
accuracy and reliability of breast pathologic diagnosis in community practice
[24].  Data from one site have been used to estimate the cost and benefit of
screening mammography [25], and pooled data will allow these issues to be
examined in greater detail for population subgroups.  Results from one
research project within a large managed care organization, which has complete
ascertainment of mammography utilization in its population, have provided the
first community-based data demonstrating a decline in late stage breast cancer
associated with increasing screening mammography [20].  A facility survey on
technical quality assurance practices in Colorado has demonstrated continued
improvement in quality assurance practices (26); the effect of these improved
practices on mammography performance is being examined.  Initial collaborative
research within the BCSC includes methodologic analyses to examine which
parameters have the greatest influence on performance measures, and analyses
of whether the actual use of the recommended American College of Radiology
lexicon for classifying screening mammography interpretations are consistent
with follow-up recommendations for diagnostic evaluation.  The later has
important implications for assumptions currently used to estimate cost-
effectiveness and benefit of mammography screening.

Current Research Objectives and Scope

The original and continued objectives of the BCSC are: 1) to enhance
understanding of breast cancer screening practices in the United States
through an assessment of the accuracy, cost, and quality of screening programs
and the relation of these practices to changes in breast cancer mortality or
other shorter term outcomes, such as stage at diagnosis or survival; 2) to
foster collaborative research among BCSC participants to examine issues such
as regional and health care system differences in the provision of screening
services and subsequent diagnostic evaluation; and 3) to provide a foundation
for the conduct of clinical and basic science research, especially basic
research on biological mechanisms, that can improve understanding of the
natural history of breast cancer.

These objectives remain as priorities, although additional research priorities
detailed below have been identified since the first issuance of this RFA in
1993.  The BCSC has demonstrated that creating mammography registries with
data linked to pathology and cancer registry data is feasible.  Now longer
term research objectives can be accomplished.  Furthermore, significant
progress has been achieved in establishing a core set of data, and efforts to
move towards more standardized sets of questions for data collection have
begun.  Building future research capacity and continued collection of core
data remain priorities.

In addition to core data collection, each site will propose special projects. 
These special research projects may address a diversity of issues, including
but not limited to the following:

- innovative approaches for collecting more detailed risk factor data in
mammography registry areas, - utilization of state-of-the-art and emerging new
technologies in breast cancer screening and diagnosis, or
- the examination of differences in clinical management, biology, or outcome
of screen detected versus interval (non-screened detected) cancer.
The complex statistical issues, development of methods, and coordination of
data comparability for pooled analyses will be supported by a single SCC.

One purpose of this RFA is to stimulate multidisciplinary collaborative
research to enhance understanding of mammography screening in community
practice. The backgrounds of current members of the BCSC reflects the
diversity of research expertise that is needed: epidemiology, health services
and economics, clinical practice related to screening mammography and
subsequent diagnostic evaluation (nurses, internists, family physicians,
radiologists, pathologists), behavior (psychology, sociology, and health
education), statistics and computer modeling, and data management.

Continued collection of core data remains a priority

o  Longer term data are needed to evaluate whether the community practice of
mammography affects outcomes, such as breast cancer mortality.

o  Large sample sizes in diverse population subgroups are needed to track the
performance of mammography in diverse populations, and to track the diffusion
of new technologies into clinical practice.

o  Similarly, large sample sizes over time are needed to track changes in the
accuracy of mammography because of introduction of new technology or increased
adherence to quality assurance standards, and to assess whether these changes
influence cancer mortality.

Continued efforts to increase data comparability and standardization

o  Substantial progress has been made and efforts should be continued to
ensure comparability of data across sites.  This includes the development of a
standardized set of questions for collection of core data elements.  All
responses to this RFA must indicate familiarity with the core data elements
identified by the BCSC [16].  The NCI Program Director can be contacted for
documents which describe these data elements in detail.  The purpose of this
research effort is to evaluate the translation of mammography screening into
community practice within existing health care systems.

o  One objective in the next stage of this effort will be to clarify the most
critical data elements for evaluating the performance of mammography screening
in populations and improve standardization and to collect those elements
within routine clinical practice.

o  A second objective will be to identify innovative approaches to the
collection of data elements which may not be easily obtained within the
context of the routine clinical practice of mammography screening, such as
more detailed risk factor data.  There is a particular interest to collect
established risk factor data among both screened and nonscreened populations
in regions covered with both mammography and cancer registries.  Innovative
approaches could be developed and tested within the context of special
research projects carried out at individual primary data collection and
research sites. The innovative approaches proposed may vary by site.

o  These objectives require that all sites 1) provide core data elements to
the SCC for the purpose of conducting collaborative pooled data analyses, and
2) participate fully in the cooperative organization unit, referred to as the
BCSC, including collaborative biannual research meetings and working groups
identified to address specific research issues.  The BCSC has been formed for
the purpose of planning, developing, and conducting collaborative research
projects which share common protocols, study designs, research objectives, and
comparable data collection procedures.

Building future research capacity

Some research objectives, such as tracking the diffusion of new technology,
are likely to be best accomplished by adding items, such as use of MRI and
Nuclear Medicine to core data.  The BCSC has revised the core data elements to
anticipate the need for collecting these new data elements.  Information on
standardized questions and data format for core data elements are available
from the NCI Program Director.

Other research objectives are best accomplished by special research projects,
which will be proposed by each site.  Data collection and research center
applicants are encouraged to consider special research projects that might
include but are not limited to the following areas: (Because this RFA is
intended to build surveillance research capacity, these research projects
cannot address interventions to change patient or provider behavior.)

- innovative approaches for collecting more detailed risk factor data in
mammography registry areas.  While some limited risk factor data are collected
through core data collection at all sites, it is anticipated that much of the
expanded data collection effort on risk factors may be accomplished through
innovative special research projects at different sites.  Core data collection
provides information on the screened populations, while special research
projects may address both screened and nonscreened populations.  Special
research projects that address collecting more detailed risk factor data
through general population surveys, targeted samples of the population, or
other methods are encouraged.  Efforts to partner with existing risk factor
surveillance efforts in the defined region of the mammography registry and the
use of geographic information systems are encouraged but not required.

- utilization of state-of-the-art and emerging new technologies in breast
cancer screening and diagnosis.  Research is needed to improve the ability to
track the diffusion of new technology and emerging technology not yet included
in routine clinical practice.  Relevant radiologic procedures currently under
study for their utility in screening include but are not limited to the
following: digital mammography, computer aided diagnosis, transmission of
radiologic images with information technology for remote interpretation,
central review and other purposes, MRI for women with dense breasts,
stereotactic or ultrasound guided final needle aspiration and biopsy. 
Tracking potential biologic or pathologic modalities, such as pathologic
diagnostic testing of breast biopsy specimens or nipple aspirates for
evaluation of risk and prognosis, is also of interest.  Some aspects of these
objectives may require the addition of data elements to core data collection,
while special research projects may be needed to explore hypotheses that
cannot be examined with core data.

- examination of the reliability and validity of specific terms used in the
clinical practice of screening mammography.  Terms, such as breast density and
ACR BiRADs Lexicon codes, are based in part on subjective interpretation and
may be used differently across radiologists.  Studies to examine the
reliability and validity of these terms are encouraged.

- the examination of differences in clinical management, biology, or outcome
of screen detected versus interval (non-screened detected) cancer or basic
clinical studies of prognostic markers for screen detected vs interval cancer. 
Because this research effort is examining issues at the community level, basic
clinical studies of well-established prognostic markers are encouraged. 
Studies of less established markers are also of interest.

- development of statistical modeling.  There are a limited number of data
sets available that have information on entire mammography screening histories
for women. This type of data could be used to develop models for patterns of
mammography utilization in the community and among sub-populations. These
models could specifically address characteristics such as age of first
mammography exam and repeat screening behavior. There would be a number of
uses for comprehensive models of lifetime screening behavior, including
looking at issues of compliance to recommended guidelines, identifying how
actual utilization differs from guidelines, and prediction of how targeted
interventions may influence long term mammography use.  These issues are
clearly of interest to both the primary data collection and research centers
as well as the SCC.

- surveys of psychological and social consequences of screening mammography. 
While the core data of the BCSC will provide invaluable data on the extent and
outcomes of medical evaluation following screening mammography, data are also
needed on the psychological and social consequences of this increasing common
practice.

- better understanding of the mammographic characteristics of ductal carcinoma
in situ (DCIS).  The detection of DCIS has increased markedly with the advent
of ever more sensitive screening mammography.  The uncertainty of the clinical
consequences of this diagnosis drives the need to better understand whether
distinctive subcategories of DCIS in terms of clinical outcomes can be
identified in terms of unique mammographic characteristics, biological markers
or other parameters.  Special studies in this area are encouraged.

Research objectives and scope of the Statistical Coordinating Center (SCC)

It is essential that a SCC applicant show evidence of the ability

- to establish and evaluate data collection and formatting procedures to
create comparable data files for the type of pooled data analyzed within the
BCSC.  The SCC applicant should demonstrate good understanding about the
elements of the data dictionary which has been developed within the BCSC for
the purposes of pooled data analysis.  The NCI Program Director can be
contacted for documents which describe these data elements in detail. Unlike
controlled clinical trials, data used by the BCSC is collected within the
context of routine clinical practice and is therefore not completely
standardized across all sites.  The SCC applicant should demonstrate good
understanding of how to create comparable data files from these diverse
sources and how to link the various subcategories of data being collected for
this research effort.

- to develop a standardized set of questions for data collection at primary
data collection and research centers.  The SCC applicant should demonstrate
good understanding of the data elements and questions which the BCSC have
determined should be included as core items within all primary data collection
and research centers.  The NCI Program Director can be contacted for documents
which describe these data elements in detail.  Some evidence to support the
standardized set of questions proposed should be provided.

- to work with primary data collection and research centers to develop quality
control procedures for data collection, storage and transmission of data to
the SCC.  While primary data collection and research centers are responsible
for developing site specific quality control procedures for data collection
and storage at their sites, the SCC should present a process for working
across all centers to ensure that a minimum level of data quality is practiced
at all sites.

- to develop a process for transferring all data to a central repository using
file transfer protocols.  The SCC applicant should provide evidence of
understanding and experience in creating a central data repository, developing
procedures for primary data collection and research centers to transfer data.

- The SCC applicant should develop and describe a process that ensures data
security, privacy and confidentiality in the transfer process and while the
data resides at the SCC.

The above criteria for the SCC are essential to ensuring data quality and
comparability in order to accomplish pooled data analysis.  In addition to its
central role in moving the BCSC towards comparable data collection, the SCC is
intended to accomplish several other research objectives with this initiative.

Advancing statistical methodology for breast cancer surveillance research

-  Increased focus on the development of novel statistical methods and models
for the analysis of these complex population data.  Statistical methods to
address multiple measures over time, variability across populations,
facilities and providers are needed.  Incorporation of statistical experts
developing new methodologies is encouraged.  Processes for facilitating
understanding and further development of these methods among statisticians at
individual sites should be addressed.

- Statistical methods for creating standardized parameters, such as those that
adjust for underlying population characteristics in assessing the impact of
mammography on outcomes, such as late stage disease and mortality, are needed
and should be addressed by the SCC.

Data management for pooled data analysis

- In addition to its research role the SCC has a central responsibility for:
o  Data management, including data comparability, formatting, and
standardization of data elements;
o  Reporting out status of data submitted for pooled data analysis in terms of
completeness and utility for pooled analysis;
o  Creating an electronic system for disseminating information regarding
submitting core data elements and facilitating pooled data analysis; and
o  Review and assistance with prioritizing pooled data analysis based on data
available for proposed analysis and statistical methods available to address
proposed hypothesis.

Definitions of population-based mammography registries

Finally, clarification is needed on the definition of population-based
mammography registries for the purposes of this RFA.  Two distinct categories
of population-based mammography registries are included in the current Breast
Cancer Surveillance Research Consortium.  One category captures data on the
population receiving mammography in community practice within a defined
geographic region and links these mammography data with complete ascertainment
of all cancer outcomes (and in some cases of all pathologic evaluations,
including those for benign disease).  The second category captures screening
and risk data on a defined population, which may not be geographically
defined, such as members of health plans or managed care organizations, and
links these mammography data with complete ascertainment of all pathologic
evaluations, both benign and malignant.  This latter category provides the
opportunity to collect data on women who participate in screening and those
who do not.  This latter category allows tracking the diffusion of screening
mammography and directly evaluating the impact of diffusion on early and late
outcomes, such as declines in late stage disease and death, respectively. 
Both categories are critical for future research needs, but may not always be
available in a single site.

SPECIAL REQUIREMENTS

The NCI will convene the first of the semi-annual meetings for award
recipients to join the NCI's BCSC.  This BCSC consists of all investigators
and research staff participating in this research effort.  The BCSC Steering
Committee consists of one voting member from each award recipient (the
Principal Investigator or designee) from the primary data collection and
research centers and the SCC and one voting member from the NCI (the Program
Director or designee).  The awardees to this Consortium will review the
established group procedures and goals, and work with other investigators to
plan and set priorities for cooperative group studies.  The NCI Program
Director will coordinate and facilitate the interactions of the BCSC
institutions and will review their activities for relevance to the objectives
of the RFA and programmatic considerations.

The BCSC will convene as needed to discuss collaborative study progress and
address scientific and technical aspects of implementation.  At BCSC meetings,
members will strive to develop collaborative protocols and comparable
standards for data collection and management, examine the areas of
commonality, and discuss progress toward the agreed upon goals in all of the
RFA scope of activities.  These range from development of data collection
instruments to more complex procedures such as the study protocol required to
answer research questions in the collaborative studies proposed by the BCSC. 
Time lines will be established, revised and refined; BCSC members will
collectively address and solve problems within the project; outstanding
research questions will be defined and existing ones will be prioritized; data
will be analyzed and prepared for "pooled" statistical analyses to answer
agreed upon research questions requiring pooled analyses.

At these meetings, information relevant to collaborative studies will be
reviewed and discussed, including such issues as overall BCSC performance and
the science of current or proposed collaborative studies.  Data will be
analyzed and the outstanding research questions established and prioritized
into national research goals by the BCSC investigators and the NCI Program
Director.  The Principal Investigators will have the primary responsibility
for analyzing and prioritizing the research questions to be developed into
collaborative studies.  The NCI Program Director will provide assistance and
guidance as needed, for example, in developing shared study protocols,
selecting data elements, obtaining cooperation from the three types of
facilities, linking databases, and analyzing pooled data on the operational
aspects of screening.  Communication among PIs at the various stages of
protocol development is encouraged and communication systems have been 
developed by NCI to facilitate this communication.

Terms and Conditions of Award

Under the cooperative agreement, a partnership will exist between the
recipient of the award and the NCI, with assistance from the NCI in carrying
out the planned activity.  The following terms and conditions pertaining to
the scope and nature of the interaction between the NCI and the investigators
will be incorporated in the Notice of Grant Award.  These terms 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 inability of an awardee to meet the performance requirements set forth in
the Terms and Conditions of Award in this RFA, or significant changes in the
level of performance, may result in an adjustment of funding, withholding of
support, suspension or termination of award.

1.  Awardee Rights and Responsibilities

a.  Nature of Involvement with BCSC

The award recipients must join the NCI BCSC for the purpose of planning,
developing, and conducting collaborative projects which share a common
protocol, study design and research objectives, and comparable data collection
procedures.  Within this framework, the awardees will have primary and lead
responsibility for the project as a whole, including research design and
protocol development, and the planning, conduct, analysis, publication and
interpretation of their studies.  Data from these collaborative projects will
be pooled for joint analysis, interpretation and publication of results in
accord with policies and procedures established by the BCSC.  The BCSC will
convene as needed to discuss collaborative study progress and address
scientific and technical aspects of implementation.  In addition, when
relevant, the award recipients will provide reports on progress of other
funded projects external to the collaborative activities.

Awardees will be required to accept and implement the common processes and
procedures approved by the Steering Committee and the processes and procedures
established by the Statistical Coordinating Center.

Each primary data collection and research awardee must access three different
kinds of facilities for the purpose of data collection and analysis regarding
breast cancer screening practices.  Access to existing records and collection
of new information is required for:  mammography facilities, pathology
laboratories, and a quality-controlled, population-based cancer registry. 
Since this project includes substantial involvement in the use of the
facilities' records and practices, the awardee must ensure collaboration among
the three facilities throughout the award for purposes of this research
project.  Each awardee is required to submit core data elements for pooled
data analysis as approved by the Steering Committee.

In addition to responsibilities of the SCC noted under data collection and
management, the SCC awardee must participate actively on all meetings of the
NCI BCSC and provide scientific, statistical, and technical input into
discussions of pooled and collaborative research projects where relevant.

b.  Strategy Sessions and Meeting Attendance

The award recipients (Principal Investigator or designee) must attend semi-
annual BCSC strategy session meetings and cooperate fully as active
participants in the development and implementation of collaborative projects. 
Up to four additional staff will be required to attend as necessary to address
the wide range of substantive and methodological discussions conducted during
these strategy sessions.  In addition, award recipients must attend up to two
additional small working group meetings of PI subgroups working to facilitate
progress on specific analyses.

c.  Data Collection and Management

Award recipients:
- Must cooperate in the establishment of comparable data collection techniques
for collaborative studies;
- Ensure that the tripartite multi-institutional group is able to implement
the data collection procedures to be developed by the BCSC members;
- Ensure that the population-based registry data are compatible with SEER
Program standards;
- Make all data required by any collaborative BCSC study available for pooled
analyses within the time frame established by the Steering Committee;
and
- Ensure that core data elements are collected to allow pooled data analysis.

Awardees are required to collect prospective detailed data directly from
breast cancer screening facilities and from pathology records, and to link
these data to population-based cancer registry data.  These unique linkages
are required in order to conduct research on breast cancer screening programs
and to facilitate investigator initiated research on the immunobiology, cell
biology, molecular genetics and endocrinology of breast cancer.

The awardee for the SCC is required to:
- Maintain existing data comparability processes developed by the BCSC and
improve these processes where needed;
- Serve as the central repository for pooled data by maintaining confidential
and secure mechanisms for transmitting electronic files for core data elements
to the SCC;
- Examine and report on the quality of submitted data for the purpose of
pooled data analysis; and
- Provide the research expertise on complex statistical issues for analysis of
these pooled data.

Each awardee will retain custody of and primary rights to their data and is
responsible for statistical analysis of local data, computer processing and
statistical interpretations.  However, for any collaborative studies among the
BCSC members, the SCC will provide data analysis and statistical evaluation
for pooled analyses.  For these collaborative studies, the BCSC members will
be responsible for the study design, planning and interpretation of the data. 
The NCI Program Director or designee will have access to all data generated
under collaborative studies conducted under this award consistent with current
HHS, PHS, and NIH policies.  The NCI Program Director or designee will review
periodically data management and analysis procedures approved by the BCSC.

Data must also be available for external monitoring if required by NCI's
agreement with other Federal agencies, such as the FDA.

2.  NCI Staff Responsibilities

The NCI program director will be responsible for normal stewardship of this
award, and will also have substantial scientific/programmatic involvement as
described below:

a.  Establishment of Consortium
The NCI Program Director will convene the first of the semi-annual meetings
for award recipients to join the NCI's BCSC.  Principal Investigators from
each of the award recipients will meet with the NCI Program Director to build
a cooperative organizational unit, referred to as the BCSC Steering Committee. 
The Program Director may designate a staff person in the Surveillance Program
to assume some duties of this role as needed.

b.  Strategy Sessions
The NCI Program Director or designee, in cooperation with the Chair of the
Steering Committee, will sponsor semi-annual strategy sessions attended by the
Principal Investigators of the primary data collection and research centers
and the SCC, other appropriate BCSC staff, and appropriate NCI staff.

c.  Data Management
The NCI Program Director will have access to all data generated under this
award consistent with current HHS, PHS, and NIH policies.  The NCI program
director or designee will review periodically data management and analysis
procedures approved by the BCSC.

d.  Monitoring and Program Review
In addition to normally prescribed duties of program and grants staff, an
on-site program review will occur as early as 10 months but no later than 18
months after award.  The program review will be conducted to evaluate progress
of the BCSC, particularly the collaborative projects.  The inability of a BCSC
member to meet the performance requirements set forth in the Terms and
Conditions of Award in the RFA, or significant changes in the level of
performance, may result in an adjustment of funding, withholding of support,
suspension or termination of the award.

3.  Collaborative Responsibilities

This BCSC consists of all investigators and research staff participating in
this research effort.  The BCSC Steering Committee consists of one voting
member from each award recipient (the Principal Investigator or designee) from
the primary data collection and research centers and the SCC and one voting
member from the NCI (the Program Director or designee).  The Steering
Committee may form subcommittees or working groups to address specific issues. 
Members will be identified within the BCSC membership or from other NCI staff
suggested by the NCI Program Director and will be approved by the Steering
Committee.  The Steering Committee will meet separately during the course of
the semi-annual BCSC meetings.  It will also meet by conference call at least
twice between the semi-annual meetings.

Awardees (primary data collection and research center and SCC) to this request
must agree to join the BCSC.  The BCSC Principal Investigators from the
primary data collection and research centers and the SCC will establish a
leader (Steering Committee Chair, chosen from awardees) who, with the NCI
program director, will administratively preside at all BCSC meetings. The
Steering Committee Chair, other members of the BCSC, and the NCI Program
Director (Chief, Applied Research Branch, CSRP, DCCPS) have established
administrative procedures (i.e., meeting dates, guidelines for reporting,
etc.) and methods by which all scientific/analytic requirements of the RFA
will be met.  The collaborative protocols will be developed by the Steering
Committee.  Core data elements will be submitted centrally to the SCC. 
Information on standardized questions and data format for core data elements
are available from the NCI program director. The Steering Committee will
define rules regarding access to data and publications.  The new awardees will
review these procedures and work with the BCSC to determine the need for any
changes.  Awardees will be required to accept and implement the common
protocol and procedures approved by the BCSC Steering Committee.  Special
research projects occurring only at one site are not required to be approved
by the Steering Committee.  Collaborative research projects which utilize data
from more than one site will be required to be approved by the Steering
Committee.

Because the existing BCSC was a feasibility effort and was developed over
several years, some members of the BCSC were funded by sources other than the
BCSC RFAs, such as NCI funded R01 or grants funded by other agencies.  NCI
anticipates that this RFA will be the primary source of funding for nearly all
centers participating in the BCSC, but other centers with comparable research
objectives funded under other sources may be considered for membership into
the BCSC.  If the NCI and the BCSC Steering Committee determine and approve by
vote that such a center can accomplish the BCSC research objectives, including
sending required core data elements for pooled data analysis to the SCC, it
will participate in the BCSC as a full voting member.

4.  Arbitration Process

The Terms and Conditions of Award require that the NCI Program Director make
post-award decisions related to program performance and programmatic decisions
on scientific-technical matters.  Any disagreement that may arise on
scientific/programmatic matters (within the scope of the award) between award
recipients and the NCI may be brought to arbitration.  NCI will establish an
arbitration process when a mutually acceptable agreement cannot be obtained
between the awardee and the NCI Program Director.  An arbitration panel (with
appropriate expertise) composed of one member selected by the recipient group,
one NCI nominee, and a third member chosen by the other two will be formed to
review the NCI decision and recommend a course of action to the Director, NCI. 
These special arbitration procedures in no way affect the awardee's right to
appeal an adverse action in accordance with PHS regulations 42 CFR Part 50,
Subpart D, and DHHS regulations 45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

Because screening mammography for breast cancer is only recommended for women,
the research issues under study in this RFA are only relevant to women. 
Therefore, applicants to this RFA are not required to address the inclusion of
women in this RFA.  However, applicants are required to address the inclusion
of members of minority groups.

It is the policy of the NIH that women and members of minority groups and
their sub populations 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 or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993.

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994, available on the web at the following URL address:
http://www.nih.gov.grants/guide/1994/94.03.18/notice-nih-guideline008.html.

Investigators may also obtain copies of the policy from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

Because screening mammography for breast cancer is not recommended nor
practiced for children, the research issues under study in this RFA are not
relevant to children.  Therefore, applicants to this RFA may use Justification
1, the research topic to be studied is irrelevant to children, from the policy
announcement.  The following information is provided to ensure that all NIH
applicants become aware of this policy.

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are clear and compelling scientific and ethical reasons not
to include them.  This policy applies to all initial (Type 1) applications
submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by June 15, 1999, a letter of
intent that includes a descriptive title of the proposed research, name,
address, and telephone number of the Principal Investigator, identities of
other key personnel and participating institutions, and 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 NCI
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 the program staff listed under
INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  Applications kits are available at most
institutional offices of sponsored research; from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, E-
mail: grantsinfo@nih.gov; and on the web at:
http://grants.nih.gov/grants/forms.htm

Additional Materials to Include in the Application

Because the Terms and Conditions of Award 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.  Plans must describe how the
applicant will comply with NCI staff involvement as well as how all the
responsibilities of awardees will be fulfilled.

Criteria for the primary data collection and research centers

1.  In addition to providing a complete research plan based on the kind of
resources immediately available to the applicant, each applicant must
delineate its catchment area for each of the three facilities (mammography,
pathology, and tumor registry).

2.  A designated Principal Investigator is required.  An associate Principal
Investigator should be named to assure continuity in the event of resignation
of the Principal Investigator.  The qualifications and experience of both must
be described.

3.  Each applicant must describe the proposed duties and attendant necessary
qualifications required for all other proposed personnel, such as project
managers, pathology coordinators, statisticians, data managers, computer
programmers, and data entry clerks.

4.  Multiple research affiliations and related funded research are permitted
provided they are not conflicting.  The affiliation agreements must state
specifically how the problem of competing projects will be resolved.

5.  Quality control and assurance procedures for all phases of the research
proposed from data collection, storage, transfer and analysis must be
described in detail.  In addition, it is essential that the level of data
quality and quality control of the cancer registry be described.  Recent
descriptions of data quality within cancer registries in North America have
been developed by the North American Association of Central Cancer Registries
(NAACCR) and can be obtained from the NCI Program Director.

6.  The availability of facilities, including mammography facilities,
pathology laboratories, and quality controlled population-based cancer
registries, must be described for the primary data collection and research
centers.  A statement of commitment from each participating institution or
organization and/or documentation of collaborative arrangements must be
provided.  Each applicant must have a defined space for administrative
activities and administrative personnel which will serve as a focus for data
management, quality control, and communication.

7.  Each applicant's capability and expertise to manage the data must be
described.  Data management includes development of data collection forms,
procedures for data transmittal, procedures for data entry, data editing,
compilation, and analysis, as well as procedures for quality control and
verification of submitted data.  Statistical data collection comparability
must exist among the tripartite local facilities and the collaborative
research project.  Each applicant must provide evidence of their willingness
to pool statistical data for analysis as required for collaborative studies. 
Each applicant's ability to manage data from local facilities and to
participate in multi-institutional collaborative studies must be described.

8.  The applicant must describe how the issue of confidentiality will be
addressed, describing how the records of all research subjects will be
protected.  The applicant must include evidence and knowledge of legal issues
pertaining to the collection and analysis of data.  When relevant, specific
state and/or federal laws and their impact on the project must be fully
explained.

9.  Applicants need to demonstrate that they can successfully develop a
tripartite organization of local facilities (i.e., mammography, pathology
and/or registry) and show evidence that they will successfully participate in
a BCSC and conduct collaborative studies.  This will be the primary mechanism
by which the NCI Program Director will relate to all principal award
recipients over the duration of the period of the RFA.

10.  Each applicant for the primary data collection and research centers must
submit at least one and not more than five research plan(s) for special
research project(s), separate from the construction of the research database
in the application, with an additional five page limit being allowed to
describe each additional special research project.  In the event several
projects or components are proposed, the format of the program project grant
should be used in which separate budgets are used.

Criteria for the Statistical Coordinating Center

1.  A designated Principal Investigator is required.  An associate Principal
Investigator should be named to assure continuity in the event of resignation
of the Principal Investigator.  The qualifications and experience of both must
be described.

2.  Each applicant must describe the proposed duties and attendant necessary
qualifications required for all other proposed personnel, such as
statisticians, project coordinators, data managers, computer
programmers/analysts, program assistants, and data entry clerks.

3.  Multiple research affiliations and related funded research are permitted
provided they are not conflicting.  The affiliation agreements must state
specifically how the problem of competing projects will be resolved.

4.  Quality control and assurance procedures for all phases of the research
activities carried out by the SCC related to pooled data including data
transfer, and storage for pooled data files must be described in detail. The
procedures for minimum data quality assurance and control practices at primary
data collection and research centers must be described briefly.

5. The applicant must have a defined space for administrative activities and
administrative personnel which will serve as a focus for data management,
quality control, and communication.

6.  Each applicant must submit at least one and not more than 5 research
plan(s) for special research projects entailing advances in statistical
methodolgy for this research effort or for specific major analyses of pooled
data addressing key questions in mammography surveillance, separate from the
description of the data management, coordinating and analysis for pooled data,
with an additional five page limit being allowed to describe the research
plans for each of these special projects.  In the event several projects or
components are proposed, the format of the program project grant should be
used in which separate budgets are used.

7.  The applicant must describe how the issue of confidentiality will be
addressed, describing how the records of all research subjects will be
protected.  The applicant must include evidence and knowledge of legal issues
pertaining to the collection and analysis of data.  When relevant, specific
state and/or federal laws and their impact on the project must be fully
explained.

8. Documentation of prior experience in similar studies, in creating a system
for the transmission of data to a central facility, and in monitoring the
quality and timeliness of such data, should be demonstrated.

9. Knowledge of the potential problems associated with conduct of pooled data
analysis for this study, which is collecting data from routine clinical
practice and not controlled clinical trials and possible solutions must be
demonstrated.

10. The applicant must describe suitability of proposed data management and
analysis plans, and demonstrate the ability to design, implement and maintain
a data entry system for pooled data analysis for the primary data collection
and research centers.

11. The applicant must demonstrate knowledge and understanding of how to
create a standardized set of questions to mammography surveillance within this
research effort for data collection at primary data collection and research
centers.

12.  The applicant must describe the approach to and likelihood of soliciting
cooperation from the participating primary data collection and research
centers and exercising appropriate leadership in matters of study design and
protocol revisions, and data acquisition, management, and analysis.  Specific
plans for ensuring quality control of data collection for core data elements
are required.

The RFA label available in the PHS 398 (rev.4/98) application form must be
affixed to the bottom of the face page of the application.  Failure to use
this label could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition, the RFA
title and number must be typed on line 2 of the face page of the application
form and the YES box must be marked.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/express service)

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

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892
Rockville, MD  20850 (for express/courier service)

Applications must be received by July 15, 1999.  If an application is received
after that date, it will be returned to the applicant without review.  The
Center for Scientific Review  (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of a substantial
revision of an application already reviewed, but such an application must
follow the guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Review Method

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NCI.  Incomplete and/or non-respoonsive applications
will be returned to the applicant without further consideration.  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 for evaluation of a
study.

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 will be used by the initial review group in
which applications receive a written critique and undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of the applications under review, will be discussed assigned a
priority score, and receive a second level review by the National Cancer
Advisory Board.

Review Criteria

Applicants from existing BCSC sites and the SCC must include a comprehensive
progress report.  The BCSC sites must demonstrate successful collaborative
activities supported through their site.  Applicants who have not had a BCSC
site should explain how they will establish successful collaborative efforts.

Primary Data Collection and Research Centers

The following factors will be considered in evaluating the scientific merit of
each response of the primary data collection and research centers to the RFA:

1.  Scientific, technical, or medical significance and originality of each
research project within the application that includes analytic research on
breast cancer screening plus one or more of the following:  utilization of
state-of-the-art and emerging new technologies in breast cancer screening and
diagnosis, basic biology and immunobiology of screened detected versus
non-screened detected breast cancer, genetic alterations among women with
screened detected versus non-screened detected breast cancer, economics of
breast cancer screening techniques, development of innovative approaches to
collecting risk factor data on screened and non screened populations of women
within the geographic area or among defined populations covered by mammography
registry, and other investigator proposed studies.

2.  Appropriateness of plans to develop or modify current data collection,
formatting and transfer practices to conform to standards set by BCSC members
which should include:

o  evidence of obtaining cooperation of radiologists, pathologists, surgeons,
tumor registrars, etc., necessary for data collection efforts;

o  description of how data systems in the area will be linked to cancer
registry and plans to solve anticipated problems with data linkage.

The development of a database linking breast cancer screening facilities to
registries and pathology laboratories will be considered as a basic
requirement of the application.  The establishment of this database  is
necessary for the research priorities for this RFA to be completed. 
Establishment of this database  must be described succinctly so that reviewers
can determine its viability.  However, the mere establishment of the database 
is not equivalent to responsiveness to the RFA.

o  description of how systems for data collection, formatting and transfer
will be developed to incorporate standardized sets of questions approved by
the BCSC members.

The BCSC has already established sets of standardized data elements and a set
of standardized questions for self-report of a limited set of core data
elements for patient history.  The NCI program director can be contacted for
documents which describe these data elements and the standardized set of
questions for self report information in detail.

o  description of confidentiality and quality assurance and control practices
will be established to ensure the records and data of all research subjects
will be protected.

3.  Appropriateness and adequacy of the experimental approach and methodology
proposed to carry out the research.

4.  Qualifications and research experience of the Principal Investigator and
staff, particularly, but not exclusively, in the area of the proposed research
should include:

o  demonstration of a track record of interdisciplinary activity;

o  experience in the management of large data sets;

o  personnel with credentials and experience in cancer registration, breast
cancer pathology, mammography and other breast cancer screening technology,
breast cancer biology, biostatistics, data management and computer
programming.

5.  Adequacy of time (effort) that the Principal Investigator and staff would
devote to establishing the database and conducting the proposed studies.

6.  Availability of resources necessary to perform the research.

7.  Commitment to conduct pooled analyses of combined data across cooperative
agreements in the BCSC for research objectives that require pooled analyses of
data.

8.  Availability of a population for surveillance coverage and research which
complements the proposed research.  Surveillance of men and children is not
relevant to this research effort.  Adequacy of plans to include 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.

In addition, applications from existing BCSC awardees must include a
comprehensive progress report and demonstrate successful collaborative
activities supported through their CRC.  Applicants who have not had an BCSC
award should explain how they will establish successful collaborative efforts.

Statistical Coordinating Center

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

1.  Scientific and technical merit of each research plan within the
application that includes advances in statistical methodology and analytic
research on the evaluation of breast cancer screening within analysis of the
pooled BCSC data.

2.  Appropriateness of plans to develop or modify current data collection,
formatting and transfer practices to conform to standards set by BCSC members
for pooled data analysis which should include:

o  description of how data formatting and transfer systems will be set up to
ensure conformation to standards set by the BCSC and to facilitate pooled data
analysis.

o  description of procedures used at the SCC to protect data and research
subject confidentiality.

o  description of elements of a standardized set of questions for self-
reported data on patient history, and core data elements and sources of such
data for mammography, follow-up and pathologic diagnosis following mammography
screening and the potential problems with key core data elements.

3. Appropriateness of plans to solicit cooperation from the participating
primary data collection and research centers, including a description of plans
for site visits to primary data collection and research centers to facilitate
the conduct of pooled analytic research.

4. Scientific and technical significance and originality of the proposed
statistical methodologic research to advance methods in breast cancer
surveillance.

5.  Qualifications and research experience of the Principal Investigator and
staff, particularly, but not exclusively, in the area of the proposed research
should include:

o  demonstration of a track record of interdisciplinary activity, particularly
in terms of conducting pooled data analysis;

o  experience in the management of large data sets;

o  personnel with credentials and experience in supporting the activities of
the SCC, including biostatistics, computer systems programmer/analyst, and
project coordinating and data entry.

6.  Adequacy of time (effort) that the Principal Investigator and staff would
devote to establishing the database and conducting the proposed studies.

7.  Availability of resources necessary to perform the research.

In addition, applications from existing BCSC awardees must include a
comprehensive progress report and demonstrate successful collaborative
activities supported through their CRC.  Applicants who have not had an BCSC
award should explain how they will establish successful collaborative efforts.

AWARD CRITERIA

The anticipated date of award is March 2000.  In the final funding selection
process of peer-reviewed and scored applications, NCI program staff will make
funding decisions on the basis of scientific and technical merit as determined
by peer review, appropriateness and duration of the proposed budget in
relation to the proposed research, appropriate minority representation in the
BCSC as a whole, and rural/urban and geographic balance among primary data
collection and research centers.

Applications recommended by the National Cancer Advisory Board 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.

SCHEDULE

Letter of Intent Receipt Date:  June 15, 1999
Application Receipt Date:       July 15, 1999
Review by NCAB Advisory Board:  February 2000
Anticipated Award Date:         March 2000

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is
welcome.  Information on standardized questions and data format for core data
elements are available from the NCI program director.

Direct inquiries regarding programmatic issues to:

Rachel Ballard-Barbash, M.D., M.P.H.
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, Room 313, MSC 7344
Bethesda, MD  20892-7344
Telephone:  (301) 402-4366
FAX:  (301) 435-3710
Email:  rb59b@nih.gov

Direct inquiries regarding fiscal matters to:

Bill Wells
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext.250
FAX:  (301) 496-8601
Email:  ww14J@nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC 7399
Bethesda MD  20892-7399
Rockville, MD  20850 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
Email:  tf12w@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.399.  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 Parts 52 and 45 CFR Part 74 and Part 92.

This program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review. The PHS strongly
encourages all grant and contract recipients to provide a smoke-free workplace
and promote the non-use of all tobacco products.  In addition, Public Law 103-
227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or
in some cases, any portion of a facility) in which regular or routine
education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.

REFERENCES

1.  Shapiro S, Venet W, Strax P, Venet L.  Periodic screening for breast
cancer: the Health Insurance Plan Project and its sequelae, 1963-1986.
Baltimore:  Johns Hopkins University Press, 1988.

2.  Tabar L, Fagerberg G, Duffy SW, Day NE. The Swedish two county trial of
mammographic screening for breast cancer: recent results and calculation of
benefit. J Epidemiol Community Health 1989; 43:107-114.

3.  Eddy DM. Screening for breast cancer. Ann Int Med 1989; 111:389-399.

4.  Kerlikowske K, Grady D, Rubin SM, et al. Efficacy of screening
mammography: a meta-analysis. JAMA 1995; 273:149-154.

5.  Smart AR, Hendrick E, Rutledge III JH, Smith RA. Benefit of mammography
screening in women ages 40-49 years: current evidence from randomized
controlled trials.  Cancer 1995; 75:1619-1626.

6.  Chamberlain J. Planning of screening programmes for evaluation and non-
randomized approaches to evaluation. In: Prorok PC, Miller AB, eds. Screening
for Cancer. Geneva: International Union Against Cancer, 1984; 78:5-17.

7.  Clark RA, King PS, Worden JK. Mammography registry: considerations and
options. Radiology 1989; 171:91-93.

8.  Day NE, Williams DRR, Khaw KT. Breast cancer screening programmes: the
development of a monitoring and evaluation system.  Br J Cancer 1989; 59:954-
958.

9.  Miller BA, Kolonel LN, Berstein L, et al., eds.  Racial/ethnic patterns of
cancer in the United States 1988-1992, National Cancer Institute. Bethesda,
MD: National Institutes of Health Pubulication 96-4104, 1996.

10.  Brown ML, Houn F. Quality assurance audits of community screening
mammography practices: importance of active follow-up for data collection and
outcome assessment.  AJR 1994;163:825-829.

11.  Monticciolo DL, Sickles EA. Computerized follow-up of abnormalities
detected at mammography screening. AJR 1990; 155:751-753.

12.  21 CFR Part 900: Mammography facilities requirement for accrediting
bodies, and quality standards and certifying requirements; interim rules.
Federal Register Dec 21, 1993 58(243):57558-57572.

13.  CarneyPA, PoplackSP, WellsWA, LittenbergB.  The New Hampshire Mammography
Network:  Development and design of a population-based registry.  AJR 1996;
167:367-372.

14.  YankaskasBC, JonesMB, AldrichTE.  The Carolina Mammography Registry.  A
population-based mammography and cancer surveillance project.  J Registry
Management 1996; 23:175-178.

15.  GellerBM, WordenJK, AshleyJA, OppenheimerRG, WeaverDL.  Multipurpose
Statewide Breast Cancer Surveillance System: The Vermont Experience.  J
Registry Management 1996; 23:168-174.

16.  Ballard-Barbash R, Taplin SH, Yankaskas B, Ernster VL, Rosenberg RD,
Carney PA, Barlow WE, Geller BM, Kerlikowske K, Edwards BE, Lynch CG, Urban N,
Chrvala CA, Key CR, Poplack SP, Worden JK, and Kessler LG. Breast Cancer
Surveillance Consortium: A national mammography screening and outcomes
database. AJR 1997;169:1001-1008.

17.  Carney PA, Geller BM, Moffett J, Ganger M, Sewell M, Barlow WE, Burgess
K, Stalnaker N, Taplin SH, Sisk C, Ernster VL, Wilkie HA, Yankaskas B, Poplack
SP, Urban N, West MM, Rosenberg RD, Michael S, Ballard-Barbash R.  Medico-
legal issues and protective policies and procedures for data integrity and
confidentiality in a large multi-center research program: The National Cancer
Institute's Breast Cancer Surveillance Consortium.  submitted 1998.

18.  Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V.  Likelihood
ratios for modern screening mammography.  JAMA 1996; 276: 39-43.

19.  Rosenberg RD, Lando JL, Hunt WC, Darling RR, et al.  The New Mexico
mammography project: screening mammography performance in Albuquerque, NM,
1991 to 1993. Cancer 1996; 78:1731-1739.

20.  Taplin SH, Mandelson MT, Anderman C, White E, Thompson RS, Timlin D,
Wagner EH.  mammography diffusion and trends in late stage breast cancer:
evaluating outcomes in a population.  CA Epi Biom Prev 1997; 6:625-631.

21.  Laya MB, Larson EB, Taplin SH, White E.  The effect of estrogen
replacement therapy on the performance characteristics of screening
mammography.  J Natl Cancer Inst 1996; 88: 643-649.

22.  Kerlikowske K, Grady D, Barclay J, Sickles EA, Ernster V.  Effect of age,
breast density and family history on the sensitivity of first screening
mammography.  JAMA 1996; 276: 33-38.

23.  Rosenberg RD, Hunt WC, Kelsey CA, Williamson MR, Wiest PW, Linver MN. The
effect of age, breast density, ethnicity, and estrogen replacement therapy on
the sensitivity and cancer stage of screening mammography: A population based
review of 182,233 screening mammograms from the Albuquerque metropolitan area. 
Radiology 1997;205(P):141(ab).

24.  Wells WA, Carney PA, Eliassen MS, Tosteson A, Greenberg ER. A statewide
study of diagnostic agreement in breast pathology. J Natl Cancer Inst 1998;
90:142-145.

25.  Salzmann P, Kerlikowske K,  Phillips K. Cost-effectiveness of extending
screening mammography programs to include women 40-49. J Gen Intern Med 1997;
127:955-965.

26.  Hendrick RE, Chrvala CA, Plott C, Cutter G, Jessop NW, Wilcox-Buchalla P.
Improvement in mammography quality control. Radiology 1998; 207:663-668..


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.


ODY>