THE EARLY DETECTION RESEARCH NETWORK: BIOMARKERS DEVELOPMENTAL LABORATORIES

Release Date:  January 20, 1999 (see reissuance RFA-CA-04-006)

RFA:  CA-98-028

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  March 11, 1999
Application Receipt Date:  April 26, 1999

PURPOSE

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,
abnormal, or simply 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 wide 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 Biomarkers
Developmental Laboratories. Subsequent RFAs will be issued to establish the
Biomarkers Validation Laboratories, Clinical/Epidemiologic Centers, and the Data
Management and Coordinating Center.  Applicants are encouraged to seek funding
to participate in more than one component, because it is recognized that
collaboration already exists in individual institutions for clinical testing and
validation of biomarkers/reagents.

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, Early Detection Research Network:
Biomarkers Developmental Laboratories, 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
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, 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.

For this RFA, teams composed of NIH intramural investigators may submit project
applications to become components of the Network, but they may not request or
receive funds from this program.

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 this RFA may
not exceed five years. The anticipated award date is September 30, 1999.

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 INQUIRIES.

FUNDS AVAILABLE

An estimated $4.6 million will be available for the first year. It is anticipated
that 8 to 10 awards will be made.  Because the nature and scope of the research
proposed may vary, it is anticipated that the size of the awards will also vary.
Funding beyond the initial budget period will be contingent on the continued
availability of funds for this purpose, 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.

In addition, the NCI anticipates incorporating up to two NIH intramural projects
as components of the Consortium.  Although no funds from the amount set aside for
this RFA will be used to support intramural projects, NIH intramural project
applicants must verify that the amount of the resources allocated from intramural
sources does not exceed $500,000 direct costs. For further budget information
pertaining specifically to NIH intramural applications, see the "APPLICATION
PROCEDURES" "Additional Instructions for NIH Intramural Project Applicants." 
Funding for the NIH intramural projects will be derived from existing intramural
resources.

RESEARCH OBJECTIVES

Background

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 the gene-
environment interaction 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 of preclinical tumor development, 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 even 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:

o  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;

o  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;

o  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;

o  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;

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

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

The ultimate impact of new technology on prolonging survival and 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 the various medical organizations. In some of
its activities, the Network may need to relate programmatically to the research
infrastructures supported by NCI (e.g., Specialized Programs of Research
Excellence [SPOREs], Cancer Genetics Network, Breast and Colon Cancer Family
Registries, Cooperative Human Tissue Network, Cancer Genome Anatomy Project),
with ongoing NCI clinical research programs/trials (e.g., Clinical Community
Oncology Program, Prostate, Lung, Colon, and Ovarian Trial); or with other health
agencies, such as Food and Drug Affairs, Department of Defense, and Veteran
Administration.  Certain types of trials in earlier detection, especially those
involving treatment, 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, clinical epidemiologists,
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 Biomarkers Developmental Laboratories
(BDL) which will form one of the three scientific components within the
Consortium for the Network. The BDL will conduct translational research in the
biology of incipient neoplasia encompassing the development, characterization and
testing of biomarkers of early cancer or risk, development of relevant
technologies for biomarker detection, and analytical tools for the evaluation of
biomarkers. Translational research in this context is defined as the movement of
discoveries from the laboratories into patient or population research settings
or the movement of observations from patient settings back to the laboratory.
Biological, morphological, and clinical alterations occurring in premalignant and
malignant lesions offer the opportunity to delineate the early stages of tumor
progression, thereby providing a wider window of opportunity for intervention. 
The National Cancer Institute has identified several high priority research
opportunities in early detection and risk assessment:

o  Determine secreted proteins that correlate with the presence of pre-cancerous
and cancerous lesions

o  Develop highly sensitive and specific assays to detect cancer related proteins
in body fluids

o  Develop highly specific and sensitive assays to detect tumor cells in body
fluids

o  Develop highly specific and sensitive assays to detect molecular products of
tumor cells in body fluids with emphasis on the identification of molecular
determinants (risk factors) in accessible surrogate anatomic sites for the less
accessible major cancer sites

This initiative encourages the submission of applications in broad categories of
translational studies on complex cellular pathways, processes, and networks to
identify the molecular and cellular signatures of cells, which can be used for
earlier detection or for risk assessment. The scope of the BDL is limited to
translational research leading to identification and/or characterization of
biomarkers or to a panel of biomarkers. Special emphasis should be placed on
cancers of the prostate, breast, colon, lung, ovary, upper-respiratory tract and
other epithelial cancers, which are the major causes of cancer-related mortality
and have yet to be controlled with screening and prevention.  The search for new
markers should reflect new information about key points in cancer biology (i.e.
apoptosis, cell cycle control). However, this initiative will not support
research of a fundamental nature, such as studies on growth regulation, cell
cycle control, or other basic studies that are not explicitly focused on tumor
target systems. To expedite clinical application, the validation of the
biomarkers will be performed in collaboration with the other scientific
components of the Consortium.

NETWORK ORGANIZATION

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). 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
their U01 funds and the collaborative research using the Core Funds from the
Headquarters (see definition of "Headquarters" below) and from the set-aside
funds in their U01 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 will be supplemented by the ad hoc participation of
additional investigators (academic or community-based) who are able to validate
the results of laboratory studies through patient accrual.

It is anticipated that the CBEDR will consist of experts in basic molecular
science, laboratory technology, clinical studies, biometry, and in epidemiology.
The expertise in laboratory science should include conducting research in the
biology of incipient neoplasia encompassing 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, precision,
reproducibility and performance characteristics of tests in multi-center
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).

NIH intramural laboratory may be one of the research members in 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 Responsibilities."

Advisory Committee: A separate 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 Responsibilities."

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 protocol
development, conduct 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, timelessness,
reproducibility and privacy of the data.

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 Headquarters 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

Funds will reside with 1) 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 the individual U01 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 Award (SBIR, R43 and/or R44), Small Business Technology
Transfer (STTR, R41 and/or R42), Exploratory/Developmental grants (R21/R33), and
other research support mechanisms.

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 research and for a variety of other functions:

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 Core supplemental 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) and the use of this fund will be restricted
pending NCI approval.

Governance

The Steering Committee will be responsible for coordinating the research effort
across the Consortium, including the Data Management and Coordinating Center, and
will formulate policy and procedures for the operations 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 informatic 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 could
form a collaboration with one of the existing centers, or directly bring their
discoveries to the Steering Committee (e.g., 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 part of the Consortium .

SPECIAL REQUIREMENTS

Definitions

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 to be supported by the U01 grant or NIH
intramural project in response to the 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
or the NIH intramural project in accordance with the terms and conditions that
are stated in the 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 scientific
coordination and collaboration 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."].

Additionally, 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.

For NIH Intramural Projects, these terms and conditions will be provided to the
PI of the NIH Intramural Project and the NIH Institute Scientific Director at the
time of selection to be a Network component. 

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. Awardee Rights and Responsibilities: Extramural and NIH Intramural Projects 

The PI of a U01 or NIH Intramural project will have the primary authority and
responsibility to define objectives and approaches, including research design and
protocol development; participant recruitment and follow-up, if applicable, data
collection, quality control, interim data and safety monitoring, and to plan,
conduct, analyze, and publish results.
 
The PI of a U01 or NIH Intramural project will assume responsibility for managing
individual protocols/research and collaborative projects approved by the Steering
Committee.

The PI of a U01 or NIH Intramural project 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 or the NIH
intramural project in accordance with the terms and conditions of the award.

The PI of a U01 or NIH Intramural project 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 PI of a U01 or NIH Intramural project will be responsible for accepting and
implementing the goals, priorities, common protocols, procedures, and policies
agreed upon by the Steering Committee. 

The PI of a U01 or NIH Intramural project 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 a U01 or NIH Intramural project 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 only one NCI Program Director for the Network.  However, the
Program Director may be assisted by other NCI staff  on specific scientific
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 research 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.  A member from the Chemoprevention Branch, NCI, will be available to
assist the Network on intermediate endpoints and on any ongoing chemoprevention
trials relevant to the Network studies.  A member from the Biometry Branch, NCI,
will be available to assist the Network on the issues of study design, sample
size, and other statistical computations. The other NCI staff  may assist and
advise the Network on relevant programmatic and scientific issues through the NCI
Program Director.

The Program Director  will convene the initial meeting of the Steering Committee,
have voting membership on the Steering Committee, and, as determined by that
committee, its subcommittees.
 
Although the PI will have lead responsibilities in all collaborative tasks and
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:

o  The Steering Committee will have major scientific management oversight and
responsibility for developing collaborative 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 he/she deems appropriate.

o  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:
- establish Network policies and procedures;
- establish policies and procedures for collaborative projects, protocols, and
Network-defined projects;
- 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);

- set initial standards or "decision criteria" for validating biomarkers/reagents
for further clinical studies, such as testing early detection strategies, or as
risk factors;

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

o  The Steering Committee will establish a Data and Safety Monitoring Committee
for clinical trials as appropriate to ensure protection of human subjects.

o  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 NCI.

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

o  The Committee will track the 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.

o  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.

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

o  The collaborative 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.

o  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 provide the Steering Committee with advice
on participants for the workshops and symposia. The Data Management and
Coordinating Center will manage the logistics for these meetings.

Advisory Committee:

1.  An Advisory Committee will be established by the NCI.  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, e.g., early detection, prognosis, etc. 

o  The membership to the Committee and duration of service will be decided by the
NCI in consultation with the Steering Committee.  The membership will include
members/institutions not participating in the Network. The Advisory Committee
will include basic scientists, clinicians, prevention 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 the relevant program staff.

o  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 help the NCI in site visits to the participating
institutions, as necessary. 

o  The Advisory Committee will collaborate with the Steering Committee to suggest
participants for and to assist in the implementation the workshops and symposia
and to provide liaison between the cancer research community and the Network.
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 that is formed to review any scientific or programmatic disagreement
(within the scope of the U01 award or the NIH Intramural Project), between U01
awardees or NIH intramural projects 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 or NIH intramural project
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
arbitration. 

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 16.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
 
It is the policy of the NIH that women and members of minority groups and their
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.

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

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:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 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.

APPLICATION PROCEDURES

Applicants must use PHS 398 (rev. 4/98).  Applications kits are available at most
institutional offices of sponsored research and 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,
E-mail: [email protected]. For those applicants with Internet access, the 398
kit may be found at https://grants.nih.gov/grants/forms.htm.

Special Instructions for Preparation of the Application

The application must use the format described in PHS 398 (rev. 4/98).  "The
Research Plan" section must not exceed a total of 35 pages.  To promote the
development of a collaborative program among the award recipients, a number of
issues need to be addressed in their applications as discussed below.

Budget:

NOTE: NIH intramural project should supply the budget information and a composite
budget as described below in "Additional Instructions for NIH Intramural Project
Applicants"]

o  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 an additional senior investigator, 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.

2.  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.

o  Applicants must set aside 10% of their annual budget after the first year for
Network collaborative studies. The use of these set aside funds will be
restricted and must be reviewed and approved by the Steering Committee and then
recommended to, and approved by the NCI for release from the individual U01
awards. 
General:

1.  Applicants must include their specific plans for responding to the "Terms and
Conditions" section. 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 which relate to setting priorities for
quality assurance and validation phase of the biomarker development, and to be
able and willing to interact with each other and the NCI in an Internet
environment. Applicants must describe computer and Internet 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.

o  Interaction with Industry (Patent Rights):  Applicants are strongly encouraged
to forge a partnership with industry/biotechnology firms in developing
biomarkers/reagents. 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 (6) 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 ninety (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 (6) 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 thirty (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 for review.  In addition, the RFA title "Early
Detection Research Network: Biomarkers Developmental Laboratories" and number
must be typed on line 2 of the face page of the application form and the YES box
must be marked.

For U01 applicants only (NIH intramural project applicants must use the address
in section "Additional Instructions for NIH Intramural Project Applicants"
described below), 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:

Referral Officer
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 April 26, 1999. If a U01 application is received
after that date, it will be returned to the applicant without review. The Center
for Scientific Review (CSR), NIH, will not accept any U01 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.

Additional Instructions for NIH Intramural Project Applicants

NIH intramural project applicants must use the PHS 398 application form and the
modified format and content described above under "APPLICATION PROCEDURES" with
the following additional modifications.

On the Face Page, fill out only items 1., 2., 3. (leave 3c. blank), 4., and 5.
The remainder of the items should be left blank, and the application must not be
signed by either the PI or an NIH Institute official. The RFA label must be
affixed to the bottom of the Face Page, as described above in section 2.

Do not submit "Other Support", Checklist", "Personnel Report", or "Personal Data"
pages.

The PI must obtain the approval of his/her NIH Institute Scientific Director for
applying, for collaboration, for participating as a component of the Network
under the terms and conditions of the RFA, and for complying with the policies
of the Steering Committee. A copy of that letter of approval must be provided as
part of a cover letter, addressed to the NCI Referral Officer, for the
application. 

The composite budget page and the individual budget pages for each part should
supply the time and effort for each project participant, but no other budget
figures should be included. The resources available for the project and the
research environment should be carefully described, but no budget figures should
be included. The NIH Institute Scientific Director, as part of the letter of
approval for participation, must verify that no more than $500,000 direct costs
of intramural resources will be allocated to the project described in the
application, and provide assurance that the conduct of the project will comply
with the DHHS regulations for research involving human subjects (if applicable)
and with the PHS policy on vertebrate animal research. 

Submit an unsigned, typewritten original of the application, and five photocopies
to:

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

Do not send the application or any copies to the Center for Scientific Review.
NIH intramural project applications must be received by April 26, 1999. If an
application is received after that date, it will be returned to the applicant
without review.

REVIEW CONSIDERATIONS

All U01 and NIH intramural project 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. Other considerations, such as the multi-
disciplinary nature of the studies, will be part of the evaluation criteria. 

Factors considered to be important for review include: demonstrated expertise in
molecular genetics and pathology of early cancer as applied to the design and
derivation of the research plans; a multi-disciplinary team of collaborators;
substantial interactions among collaborating researchers; demonstration of
appropriate facilities and resources; willingness to share data and reagents
freely. 

Review Method

Upon receipt by the Center for Scientific Review, U01 applications will be
reviewed for completeness. Incomplete applications will be returned to the
applicant without further consideration.  Upon receipt by the NCI Referral
Office, NIH intramural project applications will be reviewed for completeness;
incomplete applications will be returned to the applicant without further
consideration. Complete U01 or NIH intramural project applications will be
reviewed for responsiveness by NCI staff.  If a U01 or NIH intramural project
application is not responsive to the RFA, NCI staff will contact the applicant
to inform him/her of that decision and will return the application.

Applications may receive a preliminary scientific peer review to determine their
relative competitiveness by a NCI-convened peer review group. The NCI will
withdraw from further competition those applications judged to be non-competitive
and notify the Principal Investigator and applicant institution official or NIH
Institute Scientific Director. For applications that are complete and responsive,
and judged to be competitive, the NCI will convene an appropriate peer review
panel to provide further scientific merit review in accordance with the criteria
stated below for scientific/technical merit. The second level of review for the
U01 and NIH intramural project applications will be provided by the National
Cancer Advisory Board at their September 23-24, 1999 meeting.

Review Criteria
 
Applicants for the Biomarkers Developmental Laboratories are encouraged to submit
and describe their own ideas about how best to meet the goals of the Network, and
are expected to address issues identified under "SPECIAL REQUIREMENTS FOR THE
RFA." The peer review group will assess the scientific merit of the applications
and related factors, including:

1.  Significance. Does the proposed research for biomarkers/reagents development
address an important need 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 biomarkers/reagents 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 project? Does the
applicant acknowledge potential problem areas and consider alternative tactics?
Can these approaches be used to derive biomarkers/reagents for a variety of
malignant tumors? Are the parameters chosen to characterize the
biomarkers/reagents sufficient and appropriate? Are these parameters generally
applicable to all biomarkers/reagents? Are the criteria chosen to characterize
biomarkers/reagents for early detection and/or risk assessment appropriate and
adequate? 

3.  Innovation. Does the project employ novel concepts, approaches or methods?
Is the project original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies? Will the approaches
advance the field of biomarkers/reagents development in the context of cancer
detection and risk assessment? Has the applicant adequately addressed his/her
institutional patent policy?

4.  Investigators. Are the principal investigator and his/her collaborators
appropriately trained and well suited to carry out this work? 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?

5.  Environment:  Are the facilities for experimentation appropriate to support
the endeavor? Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed experiments take
advantage of unique features of the scientific environment and incorporate the
best use of collaborative arrangements? Is there evidence of institutional
support? Is there institutional support for computer services, including Internet
access? 

6.  Access to Specimens: Does the applicant have access to required human
specimens, e.g. tissues, biological fluids, archived materials? Does the
applicant have access to pathology review and documentation of pathology report?
Does the applicant have the cooperation of surgeons? Does applicant have access
to normal tissues from the patients, or access to matched controlled specimens?

Additional Considerations

o  Interactions. Are there adequate plans for effective interaction and
coordination with the Consortium components, 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 collaborative studies? Have the applicants proposed sound
strategies for communication among themselves, with the other Network components,
and with the NCI?

2.  Budget. For U01 applications, does the apportionment of the budget for
biomarkers development, characterization, and technology innovation  indicate
that the applicants understand the requirements of managing a Biomarkers
Development Laboratory in the Network enterprise? For the NIH intramural project
applications, is the commitment of effort appropriate to the scope of the
project, and are the resources and environment adequate to support the project? 
 
The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific goals of the
research; the adequacy of plans for including children as appropriate for the
scientific goals of the research, or justification for exclusion; the provisions
for the protection of human and animal subjects (if applicable); and the safety
of the research environment.

AWARD CRITERIA

The intent of this RFA is to enable the NCI to assemble the Biomarkers
Developmental Laboratories, composed of highly qualified investigators whose
complementary scientific skills and expertise will enable them to achieve the
goal of deriving validated biomarkers that are predictive of risk or the presence
of human cancer. The NCI will choose the members who will collectively provide
for the Network the most creative approaches to the development and validation
of biomarkers, and the range of research experience, technology, and resources
to ensure that the biomarkers/reagents that are validated as appropriate for
various aspects of cancer research are derived rapidly.

U01 applications recommended by the National Cancer Advisory Board will be
considered for 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 and technologies for
development, characterization, and validation of biomarkers; (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. 

NIH intramural project applications recommended by the National Cancer Advisory
Board will be selected as components of the Network based upon (a) scientific and
technical merit; (b) the importance of the proposed research; (c) the degree of
originality and innovation; (d) the creativity of the approaches and
technologies; (e) the likelihood for substantial contribution by the applicants
to a successful collaborative Network; (f) the evidence for willingness to work
cooperatively; (g) the quality and availability of research infrastructure and
resources; and (h) how well the project augments or complements the scientific
and technologic expertise available in the U01 applications, or provides unique
expertise or technology.

SCHEDULE

Letter of Intent Receipt:         March 11, 1999
Application Receipt Date:         April 26, 1999
Review by NCAB Advisory Board:    September 23-24, 1999
Earliest Anticipated Start Date:  September 30, 1999

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. 

INQUIRIES

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.
Division of Cancer Prevention
National Cancer Institute
Executive Plaza North, Room 330F
Bethesda, MD  20892
Telephone:  (301) 496-3983
FAX:  (301) 402-0816
Email:  [email protected]

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
Email:  [email protected]

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
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.393 Cancer Cause and Prevention Research.  Awards are made under authorization
of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended
by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 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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