Release Date:  April 6, 1999  

RFA:  CA-99-011


National Cancer Institute

Letter of Intent Receipt Date:  June 11,1999
Application Receipt Date:  July 16, 1999


The Division of Cancer Prevention (DCP), National Cancer Institute (NCI),
invites applications for cooperative agreements to establish a national
Network that will have responsibility for the development, evaluation, and
validation of biomarkers for earlier cancer detection and risk assessment.
Biomarkers are defined as cellular, biochemical, molecular, or genetic
alterations by which a normal or abnormal biologic process can be recognized
or monitored. Biomarkers are measurable in biological media, such as in
tissues, cells, or fluids. The purpose of the Network is to establish a
scientific consortium of investigators, academic as well as industrial, with
resources for basic, translational, and clinical research. The consortium will
have three main components -- Biomarkers Developmental Laboratories,
Biomarkers Validation Laboratories, and Clinical/Epidemiologic Centers. The
Biomarkers Developmental Laboratories will have responsibility for the
development and characterization of new or refinement of existing biomarkers;
the Biomarkers Validation Laboratories will serve as a Network resource for
clinical and laboratory validation of biomarkers, which include technological
development and refinement; and the Clinical/Epidemiology Centers will conduct
clinical and epidemiological research regarding the clinical application of
biomarkers. A Steering Committee composed of the Principal Investigators in
the Network and appropriate NCI staff will coordinate the work of the
consortium. Logistic support and informatics will be provided through an
auxiliary Data Management and Coordinating Center.

The purpose of this Request for Applications (RFA) is to establish the Data
Management and Coordinating Center.  RFAs were previously issued for:

Biomarkers Developmental Laboratories - CA-98-028

Biomarkers Clinical/Epidemiologic Centers - CA-99-007

Biomarkers Validation Laboratories - CA-99-008

Applicants are encouraged to seek funding to participate in more than one


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, Early Detection Research
Network: Data Management and Coordinating Center, is related to the priority
area of cancer prevention. Potential applicants may obtain a copy of "Healthy
People 2000" (Full Report: Stock No. 017-001-00474-0 or 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 


Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and Local governments, and eligible agencies of
the Federal Government.  Domestic institutions may propose collaborations/
consortia with foreign institutions. Applications will not be accepted from
foreign institutions.

An applicant may be an academic institution; a clinic; or a combination of
academic institutions, hospitals, clinics, clinical trial cooperative groups,
and/or health maintenance organizations that agree to work together with a
principal investigator and a single administrative focus.


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 this RFA
may not exceed five years. The anticipated award date is April 2000.

Awards and level of support depend on 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. 

At this time the NCI anticipates that there will be a renewed competition
after five years. If the NCI does not continue the program, awardees may
submit grant applications through the usual investigator-initiated grants
program. However, before submitting such an application, applicants are
advised to contact the program director listed under the INQUIRIES section.


An estimated $400,000 will be available per year for the first project period.
Only one award will be made. Funding beyond the initial budget period will be
contingent on the continued availability of funds for this purpose, and the
continued progress of the awardees and the Network as a whole. At the present
time, the NCI has not determined whether or how this solicitation will be
continued beyond the present RFA and related RFAs for the Network.



Although the primary tumor can usually be controlled by local therapy, most
cancer deaths are caused by metastatic disease. The goal of early detection
and screening is therefore the diagnosis and treatment of cancer before it
spreads beyond the organ of origin, perhaps even in its pre-invasive state.
Unfortunately, available early detection and screening techniques pick up many
tumors at a relatively late stage in their natural history. As a result,
decrements in mortality with the current available detection modalities are
likely to be modest. New technologies coming from the field of molecular and
cellular biology are able to identify genetic as well as antigenic changes
during the early stages of malignant progression. Some of these changes show
promise as biomarkers for preneoplastic development or for early malignant
transformation. The application of these emerging technologies in the field of
early detection and risk assessment is a high priority in the National Cancer
Institute's strategy for reducing mortality from cancer. Detection of early
cancer has been identified as an area of extraordinary opportunity for
investment in the NCI 2000 Bypass Budget. 

Data show that detection and prompt treatment of pre-malignant or small
lesions can reduce mortality, for instance, from mammography and Pap
screening. Therefore, it seems reasonable to explore the application of the
new molecular-based technologies for earlier and more specific detection and
even for risk assessment, that is, before the cancer physically develops in
order to institute chemoprevention. These are the overarching goals of the
research Network.

The continued acceleration of scientific progress is no doubt faster than it
has ever been; consequently, the need for clinical application is now greater
than ever. Research in molecular genetics, cell biology, protein chemistry and
immunology has found that cells undergo many changes during neoplastic
progression. Often occurring early in the malignant process, these changes
include, for example, production of novel proteins, growth factors, cytokines,
etc., in addition to multiple genetic alterations. Because these changes have
been associated with malignant transformation, they are now recognized as
biomarkers for cancer. Such biomarkers, whether present in tissue, serum,
urine, etc., could serve as indicators of early cancer or as markers of risk
for impending cancer.

Early detection technologies are also rapidly evolving while existing
technologies are undergoing progressive refinement in their sensitivity,
specificity, and throughput. Improved analytic tools have allowed a more
detailed examination of the molecular basis of carcinogenesis and provided the
ability to identify the molecular and cellular signatures of cancer and to
explore gene-environment interactions relevant to early detection. To explore
fully the application of molecular profiles for earlier detection and risk
assessment, it is essential to understand the molecular pathogenesis of
cancer, that is, the natural history of tumor progression at the molecular
level, so that the biological behavior of an evolving lesion (for example,
dysplasia or field change) can be predicted with greater accuracy. Current
observations indicate that cancers usually evolve through many complex
cellular processes, pathways, and networks. A better understanding of the
circuits in these pathways is critical if we are to successfully apply these
molecular-based technologies to earlier detection.

Progress in the field, however, is currently impeded by some practical
hurdles. The systematic application of biomarkers for earlier cancer detection
or even for risk assessment has been fragmented and not well coordinated.
While studies conducted by individual investigators have been useful in
advancing our understanding of carcinogenesis, there has been a lack of
research emphasis on the continuum from preclinical tumor development to early
evaluation of new techniques and their clinical application. In many of these
reported studies the investigators have not been able to explore fully the
biological implications or to test systematically the clinical application of
these molecular markers. This has resulted, in part, from the lack of a stable
connection between basic laboratory research and the opportunity for rapid
clinical evaluation. Other factors contributing to the lack of systematic
evaluation include the non-availability of high quality matched specimens from
normal, suspicious, preneoplastic and multistage neoplastic lesions along with
demographic and follow-up data. As a consequence, much work in this area has
been fragmented into numerous small and disconnected studies without complete
evaluation. Usually, the results of these studies cannot be generalized to the
population as a whole.

Objectives (applicable to Network as a Whole)

This initiative will support the creation of a national Network for early
cancer detection with resources for translational research that will include
the laboratory sciences, clinical sciences, public health, biostatistics,
informatics, and computer sciences. The goals of the Network will be to
discover and to coordinate the evaluation of biomarkers/reagents for the
earlier detection of cancer and for the assessment of risk. Specifically, the
objectives of the Network will include:

-- the development and testing of promising biomarkers or technologies in
institutions having the scientific and clinical expertise, in order to obtain
preliminary information that will guide further testing;

-- the timely and early phase evaluation of promising, analytically proven
biomarkers or technologies. Evaluation will include measures of diagnostic
predictive accuracy, sensitivity, specificity, and whenever possible, medical
benefits, such as predictors of clinical outcome or as surrogate endpoints for
early detection and for prevention intervention clinical trials;

-- the timely development of biomarkers and expression patterns, sometimes of
multiple markers simultaneously, which will serve as background information
for subsequent large definitive validation studies in the field of cancer
detection and screening;

--  collaboration among academic and industrial leaders in molecular biology,
molecular genetics, clinical oncology, computer science, public health, etc.,
for the development of high throughput, sensitive assay methods for biomarkers
from an early detection and risk assessment viewpoint;

-- conducting early phases of clinical/epidemiological studies, e.g. cross-
sectional, retrospective, to evaluate predictive value of biomarkers; and

--  encourage collaboration and rapid dissemination of information among
awardees to ensure progress and avoid fragmentation of effort.

The ultimate impact of the new technology on reducing mortality will not be
felt until highly predictive biomarkers are developed for earlier cancer
detection or for risk assessment. The success of this effort depends in large
measure on exploring the concordance between genetic or molecular markers and
the morphologic changes associated with premalignant and pre-invasive lesions
that have life-threatening potential. In other words, we need to identify
biomarkers that are predictive of clinical outcomes. 

Because early detection and treatment issues are often related, the Network
will need meaningful participation from various medical organizations. In some
of its activities, the Network may need to relate programmatically to the
research infrastructures supported by NCI (for example, the Specialized
Programs of Research Excellence, Cancer Genetics Network, Breast and Colon
Cancer Family Registries, Cooperative Human Tissue Network, Cancer Genome
Anatomy Project), with ongoing NCI clinical research programs/trials (for
example, the Clinical Community Oncology Program); or with other health
agencies, such as the Food and Drug Administration, Department of Defense, and
Veterans Administration. Certain types of trials in earlier detection,
especially those involving interventions, may best be conducted as intergroup
studies with treatment-oriented cooperative groups, such as the NCI Clinical
Cooperative Groups, NCI designated Cancer Centers, international
collaborators, and health maintenance organizations. The need for such
cooperation should be anticipated and provided by the Network leadership.

Scope (applies to this RFA)

The scope of this RFA is to establish the Data Management and Coordinating
Center to coordinate the activities of the Network and to provide logistic
support for the conduct of the Steering Committee meetings, provide
statistical and data management support for protocol development, conduct
analysis and develop relevant informatics. The Data Management and
Coordinating Center will also conduct studies in applied and theoretical
approaches that relate specific patterns of array analyses to risk assessment
and disease prediction. Specifically, the DMCC will be responsible for three
major Network activities: (1). Network Coordination, (2). Data Management, and
(3). Theoretical and Applied Research.  Before submission, it is recommended
that applicants consult companion RFAs:  CA-98-028 (The Early Detection
Research Network: Biomarker Developmental Laboratories, NIH Guide, January 20,
1999), CA-99-008 (The Early Detection Research Network: Biomarker Validation
Laboratories, NIH Guide, March 5, 1999).

1. Network Coordination: It is expected that the DMCC will:

-  provide logistical and administrative assistance in arranging meetings of
the Steering Committee and the Advisory Committee, arranging Workshops, and
providing other operational support for the Network (e.g., communications,
subcommittee meetings). The DMCC will prepare, distribute, and maintain
minutes of the meetings.
-  produce and maintain all documents, including Network Operating Policy and
Procedures manuals.
-  support the development, coordination, and implementation of collaborative
research protocols within the Network infrastructure.
-  assist in the collection of epidemiologic information, data analysis, study
designs quality assurance for a central database, statistical analyses of
pooled data, and distribution of specimens stored at sites participating in
the Network.
-  develop and maintain an interactive Web page to publicize EDRN, announce
the availability of EDRN-supported resources and receive input from
-  develop and maintain a "listserv" interactive email system for
communication within the Network.

2. Data Management: The DMCC under the direction of the Steering Committee

-  develop and maintain computerized data system for data management and
statistical analysis.This may not be very intensive in the initial two years.
-  develop worksheets and study data as needed for the collection of data in
multi-center biomarkers validation studies, verify all data, develop test, and
maintain software for within-form edit checks at data entry.
-  develop uniform investigative protocols for data and specimen collection.
-  ensure that data are collected to determine the benefits and risks that
follow from positive or negative test results.
-  provide support services for the production of data forms and reports,
graphics, and other materials as required.
-  provide a mechanism for rapid and routine (to be decided by the Steering
Committee) transmittal of materials (e.g. computer output, reports, etc.)
among the network participants and the NCI Program Director.
-  monitor Network protocol adherence, data collection and data submission,
and report violations to the Steering Committee.

3. Theoretical and Applied Research: It is expected that DMCC will assist the
Steering Committee and conduct research on the development of statistical and
computational tools, some examples of which, are provided below:

-  With the rapid development of array technology for DNA, RNA, and protein
based markers, it is possible to detect multiple genomic abnormalities
simultaneously. Due to the complex interactions among these markers, the DMCC
will explore statistical/computer methods that predict whether a specific
pattern will indicate that an individual is at higher risk than the population
for developing cancer. 
-  develop analytical tools for analyzing expression data (from DNA, RNA, or
protein array expression) with respect to clinical endpoints.
-  development of new analytical software to extract novel, relevant
information on potential biomarkers from the genomic databases, such as Cancer
Genome Anatomy Project (CGAP).

Capability and Characteristics of the Data Management and Coordinating Center:
The expertise of the Data Management and Coordinating Center should include
logistic support capability plus expertise in biostatistics and information
technology. As the Network gains experience and its responsibilities shift and
broaden, the number and identity of the personnel should change in response to
the scientific opportunities. Qualified investigators in the Data Management
and Coordinating Center should be invited to assume responsibility in a
flexible manner as the need arises.

Scientific Agenda: Applicants of the Data Management and Coordinating Center
should develop and articulate a plan that summarizes their views and their
anticipated lines of research for the issues discussed above on which they
choose to focus. 


Network Components

The Early Detection Research Network will consist of four components: 1) the
Consortium, 2) a Steering Committee (SC), 3) an Advisory Committee (AC), and
4) a Data Management and Coordinating Center.

Consortium: The Consortium will consist of three scientific components: i) the
Biomarkers Developmental Laboratories (BDL), ii) the Biomarkers Validation
Laboratories (BVL), and iii) the Clinical/Epidemiologic Centers (CEC). These
three components jointly will be known as the Consortium for Biomarkers in
Early Detection Research (CBEDR) and will be assembled by the NCI. Each
component will be funded through a separate Request-for-Application. An
applicant, however, may seek funding to participate in more than one
component. The awardee will conduct independent research using the U01 or U24
funds and collaborative research using the Core Funds from the Headquarters
(see definition of "Headquarters" below) and from the set-aside funds in the
U01 or U24 awards pending approval by the Steering Committee and release by
the NCI, respectively. 

Each laboratory/center, which will be managed by a Principal Investigator, may
include academic and industrial biotechnology investigators who are involved
in cancer detection and diagnostic research. In order to expedite the
translational research, the Consortium may be supplemented by the ad hoc
participation of additional investigators (academic, industrial or community-
based) who are able to complement or conduct studies within the Network.

It is anticipated that the CBEDR will consist of experts in molecular biology,
laboratory technology, clinical studies, biometry, and in epidemiology. The
expertise in laboratory science should include research in the biology of
incipient neoplasia as well as the development, characterization, and testing
of biomarkers of early cancer and risk, development of relevant technologies
for biomarker detection, and analytical tools for the evaluation of biomarkers
for detection and risk assessment. The expertise in laboratory validation
should include knowledge and practice of Standard Operating Procedures (SOPs),
and experience in the statistical evaluation of accuracy (both for clinical
and experimental tests), precision, reproducibility, and performance
characteristics of tests in multi-institutional settings. Expertise in patient
accrual and associated clinical issues for pilot studies will be needed to
apply basic science discoveries to clinical settings. Computational and
informatic needs of the Consortium will be provided by a Data Management and
Coordinating Center. Therefore, the Consortium, in concert with the Steering
Committee, the Advisory Committee, and the Data Management and Coordinating
Center will constitute the Network (see definition of "Network" above).   An
NIH intramural laboratory may be one of the research members in the Biomarkers
Developmental Laboratories within the Consortium.

Steering Committee: The Steering Committee will have major scientific
management oversight, including monitoring the activities of the Data
Management and Coordinating Center. For administrative structure, and
responsibilities of the Steering Committee, see "Collaborative

Advisory Committee: An independent Advisory Committee will be established by
the NCI to ensure that the overall Network is adequately responsive to
promising opportunities, exhibits the desired degree of flexibility in
composition and decision-making and makes prioritization decisions free from
conflicts of interest. For further details, see "Collaborative

Data Management and Coordinating Center: The Data Management and Coordinating
Center will provide logistic support for the conduct of the Steering and
Advisory Committee meetings, provide statistical and data management support
for Network collaborative studies, including protocol development, analysis of
clinical data, and informatics. It will study applied and theoretical
approaches to the simultaneous analysis of multiple markers. In addition, the
Data Management and Coordinating Center will develop common informatic and
analytical tools for the interpretation of data and instruments for checking
uniformity, consistency, accuracy, timing, reproducibility, and privacy of the

Headquarters: The institution of the Chair of the Steering Committee will
serve as the Headquarters of the Network. The Chair of the Steering Committee
can be any Principal Investigator involved in the Network. The Chair serves as
the Principal Investigator of the Headquarter's awards and implements the
scientific, operational and organizational policies of the Network. The
headquarters provides the executive leadership, scientific direction, and
management for the Network. It serves as a center for information
dissemination to investigators and institutions in the Network as well as to
others outside the Network.


Funds will reside with 1) the individual awardees in the Consortium For
Biomarkers in Early Detection Research, 2) the Data Management and
Coordinating Center, and 3) the Headquarters.

Consortium for Biomarkers in Early Detection Research: The Principal
Investigators will have funds available through their individual U01 or U24
awards to support the development of the scientific program and clinical
protocols. All investigators will be encouraged to seek supplemental funding
through the Small Business Innovation Research Award (SBIR, R43 and/or R44),
Small Business Technology Transfer (STTR, R41 and/or R42),
Exploratory/Developmental grants (R21/R33), and other research support

Data Management and Coordinating Center: The Data Management and Coordinating
Center will be funded through a separate RFA. 

Core Funds for the Headquarters: Core funds will be available to the Chair of
the Steering Committee. Applicants under this RFA need not apply for the Core
Funds in their U01 applications. Core funds are reserved for post-award
collaborative Network research and for a variety of other functions, for

1. Core funds would be used to expand participation within the Consortium
through supplemental funding to an investigator, not part of the Consortium.
However, receipt of these supplemental funds does not, in and of itself imply
membership on the Steering Committee. Core Funds that are provided for these
supplements will represent direct cost only. Facilities and administrative
costs will not be provided for research activities supported by the
supplemental core funds.

2. Funds will often be needed in moving a new marker test to the point at
which it can be validated at multiple centers and in larger populations. Test
reagents will require scale-up at this point, and the Steering Committee will
require sufficient funding to contract to laboratories or companies that can
scale up production and maintain quality of the reagents (e.g.- monoclonal
antibodies, labels, etc.) and to Clinical/Epidemiologic Centers for subject
accrual. Funds will also be required for data management, travel, meetings,
and other collaborative activities of the Network. 

The above activities will be supported by the funds that will be added to the
Chair's award (The Core Funds). The use of this fund will require NCI


The Steering Committee will be responsible for coordinating the research
effort across the Consortium, including the Data Management and Coordinating
Center, and will formulate policies and procedures for the operation and
management of the Network. 

The following example illustrates the functions of the Network and the support
it offers for moving basic research findings into clinical practice. 

An investigator within the Consortium identifies a putative biomarker through
original laboratory research. Based on the pilot research findings, the
putative marker seems to be useful for early cancer detection. The
investigator can then approach the Steering Committee for additional
evaluation of the marker and possible support for further testing. The
Steering Committee then has the responsibility to review the data on the
potential marker using its standing formal criteria as a guide. The Steering
Committee can consult the Advisory Committee to obtain information on the
requirements and need for additional research on the marker. It also can
consult the Biomarkers Validation Laboratories and the Clinical Centers
regarding requirements for laboratory tests, needs for quality assurance, and
the availability of patient groups for clinical validation. If necessary,
scientific resources from other Centers can be pooled to conduct studies.
Concurrently, the informatics team in the Data Management and Coordinating
Center can develop tools for the analysis of results.

There will also be flexibility so that investigators outside the Consortium
will be able to collaborate with an existing center or bring their discoveries
directly to the Steering Committee (for example, by Letter of Intent). To
support such efforts, the Steering Committee will be able to use core funds to
supplement the investigator's ongoing research. The investigator, in turn,
will agree to share his research findings and become an associate member of
the Consortium.



Awardee: The institution to which a cooperative agreement (U01) is awarded.

Principal Investigator (PI): The investigator who is designated by the
applicant organization to direct the project that is supported by the U01
grant in response to this RFA. The PI will assume the responsibility and
accountability to the applicant organization officials and to the NCI for the
performance and the proper conduct of the research supported by the U01
mechanism in accordance with the terms and conditions that are stated in this
RFA. The PI will be a voting member of the Steering Committee.

NCI Program Director: A scientist administrator from the NCI extramural staff,
the Program Director will not only provide normal stewardship for the U01
grants awarded under this RFA, but will also be substantially involved in the
service responsibility and scientific coordination within the Network, will
have responsibilities in broad scientific and programmatic issues, and serve
as a voting member of the Steering Committee, as defined under the "Terms and
Conditions of Award." 

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 Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements. [Part 92 applies when state and local governments are
eligible to apply as a "domestic organization." ].

In addition, the following terms and conditions will be incorporated into the
U01 award statement, and will be provided to the PI and the awardee
institutional official at the time of award. 

Under the cooperative agreement, the NCI 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.
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 Director.

A. Rights and Responsibilities of the Data Management and Coordinating Center:

--  The PI of the DMCC will have the primary authority and responsibility to
define objectives and approaches, including the logistic support for the
Steering Committee, organization of Workshops, and providing assistance for
other activities of the Network. The PI will also have responsibility for data
management, analysis, and statistical research.

--  The PI of the DMCC will be responsible for accepting and implementing the
goals, priorities, common protocols, procedures, and policies agreed upon by
the Steering Committee. 

--  The PI of the DMCC will assume responsibility for individual
protocols/research and collaborative Network projects approved by the Steering

--  The PI of the DMCC will assume responsibility and accountability to the
applicant organization officials and to the NCI for the performance and proper
conduct of the research supported by the U01 in accordance with the terms and
conditions of the award.

--  The PI of the DMCC will serve as a voting member of the steering
committee, will attend the Planning meeting and two Steering Committee
meetings in the first year and two Steering Committee meetings a year in
subsequent years.

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

--  The PI of the DMCC will be responsible for collaborating on common
research designs or protocols, including methods and requirements for joint
participation and collaboration as directed by the Steering Committee, and
handling of data, including appropriate sharing of methods and data among
collaborating organizations. 

B. NCI Extramural Staff Responsibilities 

There will be one primary NCI Program Director for the Network. However, the
Program Director may be assisted by other NCI staff on specific scientific or
programmatic issues as needed.

The NCI Program Director will have substantial scientific programmatic
involvement during conduct of this activity, through technical assistance,
advice and coordination above and beyond normal program stewardship for grants
as described below. 

Because of the Network's diverse scientific agenda and the number of tasks
that have to be accomplished to achieve its goals, a number of NCI staff
members may interact with the Network as needed. The NCI Program Director (a
staff member in the Division of Cancer Prevention) will assist the Network on
scientific and programmatic issues and advise the Network on the availability
of other resources. Staff members from the Chemopreventive Agent Development
Branch, NCI, will be available to report the status of intermediate endpoints
and on active chemoprevention trials relevant to the Network studies. Staff
members from the Biometry Branch, NCI, will also be available to assist the
Network on the issues of study design, sample size, and other statistical
computations. Other NCI staff may assist and advise the Network on relevant
programmatic and scientific issues through the NCI Program Director.

The NCI Program Director will convene the initial meeting of the Steering
Committee, have voting membership on the Steering Committee, and, as
determined by the Committee, its subcommittees.

Although the PI will have lead responsibilities in all collaborative tasks and
research activities, it is anticipated that the NCI Program Director will have
lead responsibilities in sharing the broad programmatic issues among awardees.

The NCI reserves the right to adjust funding, withhold support, suspend,
terminate, or curtail the study or an individual award in the event of a
failure to comply with the Terms and Conditions of Award, substantial
shortfall in participant recruitment, follow-up, data reporting, quality
control, or other major breach of the protocol, or human subject ethical
issues, whenever applicable.

C: Collaborative Responsibilities

Steering Committee: The Steering Committee will have major scientific
management oversight and responsibility for developing collaborative Network
research designs, protocols and manuals, facilitating the conduct and
monitoring of studies, and reporting study results. The Steering Committee
will be composed of the Principal Investigators from each member of the
Consortium, the Principal Investigator of the Data Management and Coordinating
Center, and the NCI Program Director. Each member will have one vote. The
Chair (non-NIH person) will be selected by the Steering Committee. The
institution of the Chair of the Steering Committee will serve as the
Headquarters (for definition, see "Network Organization"). Subcommittees will
be established by the Steering Committee, as it deems appropriate; the NCI
Program Director will serve on subcommittees as appropriate.

-  After all the Network components have been funded, the Steering Committee
will convene its first Planning Meeting. Initial responsibilities of the
Steering Committee will be to: 

1.  establish policies and procedures for the operation of the Network;

2.  establish policies and procedures for protocols, relations with industry,
and collaborative Network-defined projects;

3.  establish policies and procedures for reviewing changes in projects not
showing translational significance at the request of the laboratories/centers,
and making recommendations to the NCI for replacing the project with more
promising ones with revised scope and adjusted budget (increase in the budget
will not be permitted);

4.  set initial standards or "decision criteria" for prioritizing and for
validating biomarkers/reagents for further clinical studies;

5.  establish policies and procedures for accepting, reviewing, and
recommending proposals from investigators outside the Network for supplemental
funding and expanding the Network participation; 

-  The Steering Committee will establish and support a Data and Safety
Monitoring Committee for Network collaborative clinical studies to ensure
protection of human subjects. The Data and Safety Monitoring Committee should
be independent of study leadership and free from conflicts of interest. The
Committee will insure that the subjects in clinical studies are protected and
that their interests are not made secondary to the interests of the scientific

-  The Steering Committee will review patient accrual, follow-up, protocol
compliance, results of audits, and regulatory requirements at the
participating Centers and formally report the results of its reviews to the

-  The Steering Committee will promote and foster the inclusion of women and
ethnic minorities in clinical studies and assure the completeness of informed

-  The Committee will track the collaborative Network research progress and
assure that the results of laboratory research and clinical studies are
published in peer-reviewed journals in a timely manner and in accordance with
the publication policies of the Network.

-  At any time during the Network project, the Steering Committee may examine
the validation data for biomarkers/reagents developed by the Network, and
decide when a biomarker is sufficiently validated, or recommend when to stop
non-productive experiments relating to biomarkers validation.

-  The Steering Committee will discuss collaborative projects to be pursued
jointly with the funds available from Headquarters and from individual U01 or
U01 awardees or NIH intramural project budgets.

-  The collaborative Network studies/protocols will be approved by the
Steering Committee. Data will be submitted centrally to the Data Management
and Coordinating Center. The Steering Committee will define the rules
regarding access to data and publications. 

-  The Steering Committee will plan one of several Workshops during the
network project period to inform the scientific community and relevant
advocacy groups of the progress made toward development and clinical
application of biomarkers developed through the Network. The NCI Program
Director, the Network Advisory Committee, and other NCI staff will advise the
Steering Committee regarding participants for the workshops and symposia. The
Data Management and Coordinating Center will manage the logistics for these

Advisory Committee:

1.  The Advisory Committee will advise the Steering Committee through the NCI
on relevant scientific issues, including study design, prioritization of
biomarker development, development of collaborative study protocols, including
decision criteria for clinical applications, for example, early detection,
prognosis, intermediate end point, etc. 

2.  Membership on the Committee and duration of service will be decided by the
NCI in consultation with the Steering Committee. The membership will include
members or institutions not participating in the Network. The Advisory
Committee will include basic scientists, clinicians, public health scientists,
epidemiologists, ethicists, statisticians, and members from relevant advocacy
groups. Scientific experts will be drawn from various disciplines relevant to
multi-center detection research and experts in data management, biostatistics,
and clinical study design. 

3.  The Chair of the Advisory Committee will be elected by its members. The
Chair of the Steering Committee will also serve as a member of the Advisory
Committee. The NCI will be represented by program staff. The Chair of the
Advisory Committee will also serve as a member of the Steering Committee.

4.  The Advisory Committee will evaluate the progress and success of the
Network against the criteria developed by the Steering Committee.

5.  The Advisory Committee will assist the NCI on site visits to the
participating institutions, as necessary. 

6.  The Advisory Committee will collaborate with the Steering Committee to
suggest participants for and to assist in the implementation of workshops and
symposia and to provide liaison between the cancer research community and the

Data Safety and Monitoring Committee: 

The Data Safety and Monitoring Committee will be appointed by and report to
the Steering Committee in consultation with the NCI Program Director who will
also be the member of this committee. The Data Safety and Monitoring Committee
will be composed of external, non-participating scientists appointed by the
Steering Committee to monitor patient safety, conduct data audits, and
document progress to the NCI Program Director and the Advisory Committee.

D. Arbitration

A panel will be formed to review any scientific or programmatic disagreement
(within the scope of the U01 award) between U01 awardees and the NCI. The
panel will be composed of three members: one selected by the Steering
Committee (with the NCI Program Director not voting), or by an individual U01
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.
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

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 regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part


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 consult
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.

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.


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 consult
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


Prospective applicants are asked to submit, by June 11, 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 conflicts of
interest in the review.  The letter of intent is to be sent to the program
staff listed under INQUIRIES.


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 or may be obtained from the
Division of Extramural Outreach and Information Resources, National Institutes
of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, Email:  Application kits are also available

Special Instructions for Preparation of the Application

The responsibilities of the Data Management and Coordinating Center of the
Network are diverse. Each of the responsibilities described in the section
"Scope" under the Research Objectives is relevant to the overall performance
of the Network. Applications must address each responsibility and focus in
areas they may have specific expertise without having to address components
beyond their scope of experience or research interest.

Applicants must describe in detail the development, implementation, and
maintenance plans for each responsibility. These plans should include
description of design, personnel requirements, infrastructure (hardware,
software, other), and costs. Applicants are encouraged to describe in their
application the cost-efficient use of existing technologies. 


Reasonable consultant cost will be allowed, if the consultant is contributing
directly to the conduct or development of laboratory research. Clear and
quantifiable justification is required. 

Budget for personnel service directly involved in the activities of the Data
Management and Coordinating Center should be clearly identified.

Travel: Applicants must budget for travel and per diem expenses for Steering
Committee meetings. In the first year, applicants should plan for two
investigators, the principal investigator and additional staff to attend a
Planning Meeting and two Steering Committee meetings. In the second and
subsequent years, applicants should plan for the PI and another investigator
to attend two Steering Committee meetings per year.

Applicants must budget for travel and per diem expenses for participation in
Network workshops and symposia. Applicants should plan that at least two
investigators will attend a workshop or symposium every year in years 2-5.

Applicants must budget $30,000 (direct cost only) each year for reserving a
site for the Steering Committee and Advisory Committee meetings and other
related expenses. The place and dates for the meeting will be decided by the
Program Director in consultation with the Steering Committee. The use of this
set aside funds is restricted and must be reviewed and approved by the
Steering Committee and by the NCI. 


Applicants must include their specific plans for responding to the "Terms and
Conditions" of the RFA. Applicants should state their willingness to
collaborate and share data freely with the other Network components, to
participate in planning and attending workshops and symposia, to serve on the
Steering Committee and be bound by its decisions, particularly those that
relate to setting priorities for quality control and validation of new or
existing biomarkers, and willingness to interact with each other and the NCI
in an Internet environment. Applicants must describe computer, Internet, and
other communication resources for this type of interaction. Applicants should
also discuss the interaction with the NCI Program Director as to how they will
fulfill the responsibilities of the Network to work together cooperatively.

2. Interaction with Industry (only if applicable): It is anticipated that the
creation of the Network will serve as an attractive collaborator for industry,
since it will provide clinical opportunities for the evaluation of new
technologies. The Network will encourage collaboration with industry on a
substantial cost-sharing basis. NCI funds will be used to support the
underlying infrastructure and the cost of studies not having direct
implications for a company's product development or marketing strategy.
However, for new technologies that are part of a company's development or
product plans, the individual companies will be responsible for costs in such
areas as technology standardization and quality assurance as well as scale-up
of laboratory techniques, in collection and formatting of specialized data
required by regulatory agencies for device approvals, in the preparation of
registration documents, and in supporting a portion of the accrual to studies
pivotal for registration. It is anticipated that industry participating in the
Network will not charge investigators or NCI for technologies/reagents that
will be evaluated in collaborative studies. NCI views the partnership with
industry as an important component without resorting to the subsidization of
private companies. 

Since basic research and development of new biomarkers/reagents is an
objective of this effort and since active involvement by the industrial
laboratories is often facilitated by the existence of adequate patent
coverage, it is essential that applicants provide plans to assure such
coverage, as appropriate. Since multiple institutions may be involved, the
situation can become complex. Each applicant, therefore, must provide a
description of the approach to be used for obtaining patent coverage, and for
licensing in particular where the inventions may involve investigators from
more than one institution. Attention is drawn to Bayh-Dole Act (Public Law 96-
517). Pursuant to Bayh-Dole, inventions made by the extramural investigators
belong to their respective institutions. This may be of concern to
collaborators, especially those who are the source of proprietary
biomarkers/reagents. The Cancer Therapy Evaluation Program (CTEP), NCI, is
addressing this concern by obtaining voluntary agreement of participating
extramural parties as described below (the following language is provided to
applicants to aid in their own proposal):
-- Institution agrees to promptly notify industrial collaborators, hereafter
called "Collaborator" in writing of any inventions, discoveries or innovations
made by the Institution's principal investigator or any other employees or
agents of Institution, whether patentable or not, which are conceived and/or
first actually reduced to practice in the performance of this study using
Collaborator's Study Drug (hereinafter "Institution Inventions").

-- Institution agrees to grant to Collaborator: (i) a paid-up nonexclusive,
nontransferable, royalty-free, world-wide license to all Institution
Inventions for research purposes only; and (ii) a time-limited first option to
negotiate an exclusive, world-wide royalty-bearing license for all commercial
purposes, including the right to grant sub-licenses, to all Institution
Inventions on terms to be negotiated in good faith by Collaborator and
Institution. Collaborator shall notify Institution, in writing, of its
interest in obtaining an exclusive license to any Institution Invention within
six months of Collaborator's receipt of notice of such Institution
Invention(s). In the event that Collaborator fails to so notify Institution,
or elects not to obtain an exclusive license, then Collaborator's option shall
expire with respect to that Institution Invention, and Institution will be
free to dispose of its interests in such Institution Invention in accordance
with Institution's policies. If Institution and Collaborator fail to reach
agreement (within 90 days, or such additional period as Collaborator and
Institution may agree) on the terms for an exclusive license for a particular
Institution Invention, then for a period of six months thereafter Institution
shall not offer to license the Institution Invention to any third party on
materially better terms than those last offered to Collaborator without first
offering such terms to Collaborator, in which case Collaborator shall have a
period of 30 days in which to accept or reject the offer.

-- Institution agrees that notwithstanding anything herein to the contrary,
any inventions, discoveries or innovations, whether patentable or not, which
are not subject Inventions as defined in 35 USC 201(e)* arising out of any
unauthorized use of the Collaborator's Study drug and/or any modifications to
the Study Drug, shall be the property of the Collaborator (hereinafter
"Collaborator Inventions"). Institution will promptly notify the Collaborator
in writing of any such Collaborator Inventions and, at Collaborator's request
and expense, Institution will cause to be assigned to Collaborator all right,
title and interest in and to any such Collaborator Inventions and provide
Collaborator with reasonable assistance to obtain patents (including causing
the execution of any invention assignment or other documents).

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. In addition, the RFA title "Early
Detection Research Network: Data Management and Coordinating Center" and
number must be typed on line 2 of the face page of the application form and
the YES box must be marked.
Applicants should submit a typewritten, signed 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 express/courier service)

At the time of submission, two additional signed photocopies 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 16, 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


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

Review Method

Upon receipt applications will be reviewed for completeness by the CSR and
responsiveness by the NCI.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  Applications that
are complete and responsive to the RFA will be evaluated for scientific and
technical merit by an appropriate peer review group convened by the 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

The evaluation will be based on the demonstrated capabilities of the
prospective applicants in relation to the needs of the RFA.  The merit of each
application will be evaluated carefully, based on review criteria below. 
Applicants must submit information to permit evaluation of their applications. 
Failure to provide the information required to evaluate the application may
result in rejection of the proposal without further consideration.

1.  Understanding of Responsibilities: Does the principal investigator
understand the objectives, and methods, and responsibilities for accomplishing
the goals of the RFA? Has the applicant adequately addressed the
responsibility as indicated in the "Scope"? Has the applicant provided
evidence of understanding the relevant technical problems and their timely and
effective solutions?

2.  Personnel: Are the principal investigator and support personnel adequately
trained and qualified for participating and managing multi-institutional
collaboration?  Do the proposed staff have capabilities, qualifications, and
experience to perform tasks of the RFA? The key staff shall include PI and
other investigators directly contributing to the logistic support and the data

3.  Environment: Are facilities and equipment for data storage, data security
and data analysis appropriate to support the objectives of the RFA?  Has the
applicant demonstrated adequacy of proposed infrastructure; unique features
for collaborative research; commitment and documented evidence of
institutional support for proposed endeavor, and institutional support for
computer services including Internet access?

In addition to the above criteria, the reviewers will consider the proposed
research plans under the "Scope" section "Theoretical and Applied Research,"
using the following additional criteria:

1.  Significance. Does the proposed research address an important need for
statistical/analytical tools development for earlier cancer detection and risk
assessment. What is the immediacy of the research opportunity? Over the
project period, is there potential for the applicant to develop statistical
and analytical approaches other than those specified in the application?

2.  Approach. Are the conceptual framework, design, methods, and analyses
adequately developed and appropriate to the aims of the proposed research?
Does the applicant acknowledge potential problem areas and consider
alternative tactics? Can these approaches be generally applicable to all

3.  Innovation. Will the proposed Data Management and Coordinating Center
employ novel concepts, approaches or methods? Does the proposed
approach/methodology challenge existing paradigms or develop new
computational/statistical approaches? Will the approaches advance the field of
cancer detection and risk assessment? Has the applicant adequately addressed
his/her institutional patent policy, if applicable?

4.  Investigators. Are the principal investigator and his/her collaborators
appropriately trained and well suited to carry out this work, especially in
the area of statistical, mathematical and computation biology? To what extent
do these investigators have the necessary complementary skills? Have
collaborations been established or consultants identified to provide the
appropriate depth and breadth of scientific expertise required for the
project? Will this team of investigators contribute unique skills to the
overall Network?

Additional Considerations:

1. Interactions. Are there adequate plans for effective interaction and
coordination with the other components of the Consortium, the Steering
Committee, the Data Management and Coordinating Center, and the NCI? Do the
investigators state their willingness to collaborate and share information? Do
the investigators state their willingness to abide by the priorities and
policies agreed upon by the Steering Committee for Network collaborative

2. Budget. For U01 applications, does the apportionment of the budget reflect
that the applicants understand the requirements of managing the Data
Management and Coordinating Center in the Network enterprise? 


The intent of this RFA is to enable the NCI to assemble the Data Management
and Coordinating Center, composed of highly qualified investigators whose
complementary scientific skills and expertise will enable them to achieve the
goal of coordinating the activities of the Network successfully. The NCI will
choose the applicant who will collectively provide the Network the most
creative approaches to coordinate and data management activities with the
ultimate goal of successful development and validation of biomarkers, and the
range of statistical, mathematic and computation experience to ensure that the
biomarkers/reagents that are validated as appropriate for various aspects of
cancer research are derived efficiently. 

U01 applications recommended by the National Cancer Advisory Board will be
considered for an award based upon (a) scientific and technical merit; (b) the
importance of the proposed research; (c) the degree of originality and
innovation in research design; (d) the creativity of the approaches; (e) the
likelihood for substantial contribution by the applicants to a successful
collaborative Early Detection Research Network; (f) the evidence for
willingness to work cooperatively; (g) the quality and availability of
scientific expertise, infrastructure and resources; (h) consideration for the
geographical diversity; and (i) the availability of funds. 


Letter of Intent Receipt Date:    June 11, 1999
Application Receipt Date:         July 16, 1999
Review by NCAB Advisory Board:    February 14-16, 2000
Earliest Anticipated Start Date:  April 1, 2000

EVALUATION OF THE NETWORK (for information only)

The establishment of improved strategies for the identification of individuals
with small neoplastic or preneoplastic lesions with reasonable probability of
progression (and that are amenable to cure) is the primary goal of this
research program. It is anticipated that the research will develop and
evaluate an ensemble of biological markers that will indicate the presence of
early cancer or preneoplastic events. An ensemble of markers is likely to be
more useful and a better predictor of disease status than a single marker or a
narrow range of markers that might focus only on one or two pathways in
carcinogenesis. The development and application of an ensemble of markers will
require a multidisciplinary, multi-institutional approach, such as the Network
presented here. 

This RFA is not the only way to support a collaborative discovery and clinical
evaluation of biomarkers. Before deciding whether the Early Detection Research
Network should be reissued, the NCI wishes to have an assessment of the
effectiveness of this mechanism over the first few years of its operation. The
evaluation process will include members of the various advisory groups of the
NCI, such as the Board of Scientific Advisors and the National Cancer Advisory
Board, to help assess the program against the criteria established by the
Steering Committee. The NCI staff will present biennial reports to the NCI
Board of Scientific Advisors. 


Due to the complex application format and complexity of this RFA, the NCI
encourages potential applicants to take this opportunity to clarify any issues
or questions. Written and telephone inquiries concerning the RFA are welcome.

Direct inquiries regarding programmatic issues to:

Sudhir Srivastava, Ph.D., M.P.H. 
Early Detection Branch, Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, Room 330F
Bethesda, MD  20892
Telephone:  (301) 496-3983
FAX:  (301) 402-0816

Direct inquiries regarding review issues 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

Direct inquiries regarding fiscal matters to:

Mr. William Wells
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800 ext. 250
FAX:  (301) 496-8601


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 Sections 301 and 405 of the Public Health Service Act as
amended ( 42 USC 241 and 284) and administered under PHS grants policies and
Federal Regulations [42 CFR Parts 52 and 45 CFR Part 74 and Part 92 when
applicable for State and Local governments].  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.

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