THE EARLY DETECTION RESEARCH NETWORK: CLINICAL AND EPIDEMIOLOGIC CENTERS

Release Date:  March 16, 1999

RFA:  CA-99-007 (see reissuance RFA-CA-05-005)

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  June 11, 1999
Application Receipt Date:  July 16, 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 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 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. 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
Clinical and Epidemiologic Centers.  An RFA (CA-98-028) for the Biomarkers
Developmental Laboratories was previously issued in the NIH Guide, January 20,
1999. This RFA is available at:
https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-028.html).  An RFA for the
Biomarkers Validation Laboratories is concurrently being issued (CA-99-008). 
This RFA is available at:  https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-008.html).
An RFA for the Data Management and Coordinating Center will be issued at a
later date.  Applicants are encouraged to seek funding to participate in more
than one component.

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, The Early Detection Research
Network: Clinical and Epidemiologic Centers, 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.

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.

MECHANISM OF SUPPORT

The administrative and funding instrument 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 stimulate the recipient's activity by involvement in and otherwise working
jointly with the award recipient in the role of a partner, 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 has been included
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 program director listed under the INQUIRIES section listed
below.

FUNDS AVAILABLE

An estimated $4.0 million will be available for the first year. It is
anticipated that 5-6 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.

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 acceleration of scientific progress is 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 the pathogenesis of cancer, 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
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 the predictive accuracy of biomarkers;
and

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

The ultimate impact of 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.

Scope (applies to this RFA)

The scope of this RFA is to establish the Clinical and Epidemiologic Centers
(CEC), one of the three scientific components of the Consortium within The
Early Detection Research Network. The responsibilities of the CEC will be to:
1) develop a scientific agenda to conduct clinical research regarding the
application of biomarkers in early cancer detection and risk assessment, and
2) serve as a resource for collaborative research within the Network under the
coordination of the Steering Committee, as appropriate. The scientific agenda
applies to research carried out within the individual Centers and to the
Network, as appropriate.

This initiative encourages the submission of applications in broad categories
of clinical, epidemiological, and translational research in earlier cancer
detection and risk assessment. Translational research in this context is
defined as the movement of laboratory discoveries into patient or population
research settings or the movement of observations from these settings back
into the laboratory. While the major thrust of the Network will be on cancers
of the prostate, breast, colon, lung, ovary, and upper-respiratory tract,
which are the major causes of cancer-related mortality, applications on other
organ sites will also be accepted for review. The applicants should develop,
articulate, and follow a research plan that conforms with the individual
Center's and with the Network's overall objectives (see above). Before
submission, it is recommended that applicants consult the 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).

1) Scientific Agenda:

Applicants should propose a scientific agenda that includes a mix of short and
long term clinical studies. The plan may include a balanced and inter-related
program of small developmental studies, feasibility studies, larger pilot
studies, and large-scale efforts. Studies can be intra- or inter-
institutional. It is essential, however, that the Centers identify and
concentrate their resources on the most promising scientific opportunities,
that studies be completed as planned, and that the methodologies employed are
sound and, where appropriate, innovative.

Applicants may propose studies that can be conducted within the individual
Centers or through inter-institutional collaboration with other investigators.
These studies could include, but are not limited to:

-- Preliminary studies to establish and compare the sensitivity, specificity
and predictive accuracy of biomarkers in a clinical context, including inter-
and intra-laboratory reproducibility. A number of putative biomarkers exist
that could be tested in clinical settings. These include, for example, loss of
heterozygosity, microsatellite alterations, cancer specific methylation
abnormalities, mutated genes, and products of the mutated genes.

-- Relating biomarker expression to clinical outcome. Sequential molecular
genetic changes are known to occur in many types of cancer. Correlating these
sequences with the natural history and clinical outcome may prove valuable for
therapeutic and follow-up strategies.

-- Evaluating markers of risk for second primary cancers in patients with a
previously diagnosed cancer. Biomarkers that detect recurrence of treated
primary tumors may serve as an additional model for early detection.

--  Evaluating the accuracy of biomarkers in predicting extent or severity of
disease.

--  Evaluating computational methods for combining multiple biomarkers for
earlier detection and risk assessment in clinical settings.

--  Identifying high-risk populations and performing comprehensive studies in
targeted high-risk populations for validation and potential integration of
novel detection strategies.

--  Evaluating gene-environmental interactions for understanding risk and
variations (polymorphisms) in susceptibility in high-risk cohorts. There are
several high-risk tumor registries and networks that are available to
investigators, such as the Cooperative Family Registries for Breast Cancer
Studies, Cooperative Familial Registries for Colorectal Cancer Studies, Cancer
Genetics Network, and screening trials, that are supported by the NCI.

2) Resource for Network Clinical Collaborative Research:

As a collaborative resource for the Network, the Centers will expedite the
clinical validation and application of biomarkers through participation in
multi-institutional studies. These Centers will provide the clinical expertise
including patient accrual, design of clinical trials, estimation of sample
sizes, pathological assessment, etc.

It is expected that the Centers will be able to recruit appropriate subjects
to insure the success of the collaborative Network research projects. As part
of collaborative studies, the Centers will provide clinical specimens for the
other scientific components of the Consortium, as appropriate. Reimbursement
for subject accrual will be on a per case basis (see "Instructions for
Application Preparation"). For collaborative Network research, guidelines for
the collection and distribution of specimens will be developed by the Steering
Committee.

Organization of the Center:

Each Center will be assembled by a Principal Investigator (PI) who will form a
multidisciplinary and, if appropriate, inter-institutional arrangement for
both the individual Center's research and for Network collaborative research
projects. The Center should be constructed in a flexible manner to permit the
ad hoc affiliation with qualified groups to participate in high-priority
research across the entire range of clinical studies relevant to earlier
cancer detection and risk assessment.

Study Sites:

Investigators participating in a Center may come from academic, community, and
industrial settings. For participation in a particular study, the Center
leadership can solicit any site that has the necessary technical
qualifications and accrual potential to contribute meaningfully to the study's
timely completion and to the Center's accrual responsibility.

Because early detection and treatment issues are often related, the Centers
may need meaningful participation from various medical organizations. For some
activities, the Centers may need to relate programmatically to other research
infrastructures supported by the NCI (for example, the Specialized Programs of
Research Excellence, Cancer Genetics Network, Breast and Colon Cancer Family
Registries, the Cooperative Human Tissue Network, the Cancer Genome Anatomy
Project); with ongoing NCI clinical research programs/trials (for example, the
Clinical Community Oncology Program); and with other agencies, such as the
Food and Drug Administration, Department of Defense, and the 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, clinical
epidemiologists, and health maintenance organizations. The need for such
cooperation should be anticipated and provided by the Center leadership.

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
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-Applications. An applicant,
however, may seek funding to participate in more than one component. The
awardees will conduct independent research using the U01 funds and Network
collaborative research using Core Funds from Headquarters (see definition of
"Headquarters" below) and from the set-aside funds in the U01 awards pending
approval by the Steering Committee and release by the NCI, respectively.

Each laboratory/center, which will be managed by a Principal Investigator,
will 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 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 molecular biology,
laboratory technology, clinical studies, biometry, and epidemiology. The
expertise in laboratory science is expected to include 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 will also 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). 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
Responsibilities."

Advisory Committee: An independent Advisory Committee will be established by
the NCI to insure 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 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 informatics and
analytical tools for the interpretation of data and instruments for checking
uniformity, consistency, accuracy, timing, 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 additional 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 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 should not apply for the
Core Funds in their U01 applications. Core funds are reserved for post-award
Network collaborative research and for a variety of other functions, for
example:

1. Core funds will be used to expand participation within the Consortium
through additional funding to investigators who are not part of the
Consortium. However, receipt of these additional funds does not, in and of
itself, imply membership on the Steering Committee. Core Funds that are
provided for these supplements will represent direct costs only. Facilities
and administrative costs will not be provided by the 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
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 policies 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 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
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 an associate member 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 award
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
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 to the institutional
official at the time of award.

Under the cooperative agreement, the purpose of NCI is to support and
stimulate the recipient's activity by involvement in and otherwise working
jointly with the award recipient in the role of a partner, 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 Clinical and Epidemiologic Center Awardees

Individual Center Studies:

The PI of a Clinical and Epidemiologic Center will have the primary authority
and responsibility to define the scientific objectives and approaches for the
individual Centers, 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 Center will develop procedures for study monitoring to assure
compliance with protocol designs and protection of patients from research
risk.

The PI of a Center will provide guidance to the investigators regarding
clinical studies, including ethical issues involved in clinical research and
conflict-of-interest considerations.

The PI of a Center will assume responsibility for managing individual
protocols/research and collaborative projects approved by the Steering
Committee.

The PI of a Center will verify that participating sites have all relevant
human risk assurance documents, as required, on file with the Office for
Protection from Risk (OPRR), NIH. Physicians in private practice must have an
approved Non-institutional Investigator Agreement (NIA) on file with the
Center.

The PI of a Center will monitor and maintain appropriate records for
protocols, informed consent, assurances, and annual certification of
Institutional Review Board (IRB) review and approval (HHS Optional Form 310)
for all participating sites.

The PI of a Center 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 a Center 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 Center 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.

Network Collaborative Studies:

The PI of a Center will be responsible for accepting and implementing the
goals, priorities, common protocols, procedures, and policies agreed upon by
the Steering Committee for the Network collaborative studies.

The PI of a Center will ensure Network and NCI review and approval of
protocol, concepts, final protocol documents, informed consents, and study
amendments, and advise NCI of changes in protocol status.

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

The PI of a Center will be responsible for accruing subjects on collaborative
studies approved by the Steering Committee.

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 assist the Network on the status of
intermediate endpoints and on any ongoing 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 that committee, its subcommittees.

Although the PI of each Center 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:

1.  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 include 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 will be selected by the Steering
Committee from among the non-NIH members. 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.

2.  After the Network components have been funded, the Steering Committee will
convene its first Planning Meeting. Initial responsibilities of the Committee
will include:

-- establish policies and procedures for the operation of the Network;

--  establish policies and procedures for protocols, relations with industry,
and collaborative 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 prioritizing and for
validating biomarkers/reagents for further clinical studies;

--  establish policies and procedures for accepting, reviewing, and
recommending proposals from investigators outside the Network for 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
investigation.

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

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

5.  The Steering 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.

6.  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 termination of
non-productive experiments relating to biomarkers validation.

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

8.  The Network 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.

9.  The Steering Committee will plan 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 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 workshops.

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, e.g., 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/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
NCI will be represented by program staff.

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 in 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
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 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
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 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.

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

LETTER OF INTENT

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 that it
contains 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]. Application kits are also available
at: https://grants.nih.gov/grants/forms.htm

Special Instructions for Preparation of the Application

Format:

The application must use the format described in PHS 398 (4/98). "The Research
Plan" section is not subject to the page limitations stated in the PHS 398.
However, the suggested format and page recommendations should be noted.
Indicate the sections in the Table of Contents using the following titles:

Research Objectives and Approaches (25 pages): This section should concisely
describe the Center's proposed research objectives. Applicants must document
their ability to recruit patients and procure specimens.

Organizational Structure (10 pages): This section should clearly describe the
formal organizational structure of the Center, including lines of authority
and responsibility, with particular attention to the relationship of the
organizational structure to the Center's major objectives.

Development Fund (5 pages): Applicants should also describe and justify the
use of Developmental Funds, (up to $50,000, direct costs) if requested in the
application, including the procedures the Center will use for allocating these
funds to areas of special opportunity during the period of support. Applicants
should describe previous experience they have had, if any, with developmental
funds.

Quality Assurance (5 pages): Applicants should describe procedures for quality
assurance and laboratory quality control. This includes confirmation of
pathology and radiology reports and inter-laboratory comparisons of test
results and procedures. The need for formal mechanisms of medical review,
audits, and quality control is clear. The applicants must discuss quality
control issues and other considerations that may arise in multi-institutional
studies.

Budget:

1.  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 for a minimum of two
investigators to attend an annual workshop or symposium in years 2-5.

3.  Applicants must set aside 15% of their annual budget for subject accrual
after the first year for Network collaborative studies. The reimbursement will
be based on the complexity and amount of clinical data, specimen types,
duration of follow-up, and other factors within collaborative studies as
decided by the Steering Committee. Reimbursement will be provided through this
set-aside U01 funding and from the Core Funds. The use of these set-aside
funds will be restricted and must be reviewed and approved by the Steering
Committee and 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 patient safety and protocol development, and 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.

2.  Applicants must include plans for innovative community programs to order
to recruit women and minorities into clinical studies.

3.  Collaboration with Industry (Patent Rights, if applicable): 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 "The Early Detection Research Network: Clinical and Epidemiologic
Centers" and number must be typed on line 2 of the face page of the
application form and the YES box must be marked.

Submit a 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 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), NIH, will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of a substantial
revision of an application already reviewed, but such an application must
follow the guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

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 application s 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.

All applications will be judged on the basis of the scientific merit of the
proposed project and the documented ability of the investigators to meet the
"RESEARCH OBJECTIVES" of the RFA.  Although the technical merit of the
proposed protocol is important, it will not be the sole criterion for
evaluation of a study. 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 clinical studies on early cancer as applied to the design and derivation of
the research plans; a multi-disciplinary team of collaborators; substantial
interactions among collaborating investigators; demonstration of appropriate
facilities and resources; ability to accrue subjects, access to specimens, and
willingness to share results freely.

Review Criteria

Applicants for the Clinical/Epidemiologic Centers are encouraged to 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 clinical/epidemiologic research address
an important need for earlier cancer detection and risk assessment? Over the
project period, is there potential for the applicant to test
biomarkers/reagents other than those specified in the application?

2.  Approach.  Is 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 test in clinical settings
biomarkers/reagents for a variety of incipient neoplastic lesions? Are the
criteria chosen to characterize the biomarkers/reagents sufficient and
appropriate? Have all aspects of data collection and management for the Center
been considered, with appropriate attention to the quality and timeliness of
data submission? Will the Center be able to carry out its planned studies in a
reasonable period of time? Will the Network collaboration be utilized when
necessary to satisfy the requirements for timely completion? Has the applicant
adequately addressed his/her institutional patent policy?

Do appropriate quality assurance and quality control programs exist, including
on-site audits that assure high-quality research and patient safety? Are
institutional data management and statistical analyses, procedures, and
policies adequate, appropriate, and consistent with accepted standards?

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 clinical parameters? Will the approaches advance the
field of biomarkers/reagents development in the context of early cancer
detection and risk assessment?

4.  Investigators.  Are the principal investigator and collaborators
appropriately trained and well suited to carry out this work? Are the numbers
and roles of staff for each study defined and justified? Does the research
experience and qualifications demonstrate understanding of the biomarkers
research, of the design, administration, and analysis of multi-institutional
clinical research, and of laboratory studies? Have collaborations been
established or consultants identified who will provide the appropriate depth
and breadth of scientific expertise required for the project? Will these
investigators contribute unique skills to the overall Center and to the
Network? Will they provide guidance to other collaborators regarding clinical
studies, including ethical issues involved in clinical research and conflicts
of interest?

5.  Environment:  Does the principal investigator and collaborators have
access to the appropriate patient populations? Are mechanisms in place to
track patient accrual? Does the applicant have access to human specimens,
e.g., fresh tissues, biological fluids, archival materials? Are the principal
investigator and collaborators willing to share specimens and clinical data
with other investigators in the Network? Does the applicant have access to
pathology review and documentation of the pathology report? Does the applicant
have the cooperation of surgeons and other medical specialties as needed? Does
the applicant have access to treatment information and other necessary patient
data, such as medical history? Have appropriate endpoints been defined? Does
the applicant have access to normal tissues from patients or access to matched
control specimens? Have arrangements been made for appropriate informed
consent? Has protection of patients from research risks been assured? Are
mechanisms for IRB approval in place? Have ethical and counseling issues been
considered? Has the confidentially of patient records been assured?

Will the Center be well administered by the PI? Does its organization and
infrastructure allow it to meet the Network's major objectives? Are the
Center's organizational and administrative plans likely to lead to a well
functioning, cohesive research group? Will there be adequate interdisciplinary
participation in proposed studies? Are there plans for collaboration and
interaction with other clinical trials organizations, health maintenance
organizations, and with industrial sources of scientific and technological
expertise? Do plans include for recruitment of special populations including
both gender and minorities and relevant subgroups as appropriate for the
scientific goals of the research? Are federal guidelines for the inclusion of
women and minorities as research subjects being followed?

Are the facilities appropriate to support the endeavor? Does the scientific
environment in which the research will be done contribute to the likelihood of
success? Do the proposed experiments take advantage of unique features of the
scientific environment and incorporate the appropriate collaborative
arrangements? Is there evidence of institutional support? Is there
institutional support for computer services including Internet access? Are the
participant members of the Center able to accrue sufficient patients for the
proposed studies and for the Network's collaborative studies? Is the principal
investigator and collaborators willing to use common (paper or electronic)
forms required for the collection of collaborative Network study data? Are the
plans for the use of any developmental funds appropriate and consistent with
the Center's overall goals and priorities? Will the fund be managed with
appropriate oversight?

Additional Considerations

1.  Interactions: Are there plans for effective interaction and coordination
within 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? Are investigators willing to comply with
protocol designs developed for collaborative Network studies by the Steering
Committee? Do the investigators state their willingness to abide by the
priorities and policies agreed upon by the Steering Committee for Network
collaborative studies?

2.  Budget: Does the apportionment of the budget for clinical/epidemiologic
research indicate that the applicants understand the requirements of managing
the Centers within the Network enterprise? 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 the
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 Clinical and
Epidemiology Centers, a component of the scientific consortium within The
Early Detection Research Network. The Centers should include highly qualified
investigators whose complementary scientific skills and expertise will enable
them to achieve the goal of clinically validating biomarkers that are
predictive of risk or the presence of incipient human cancer. The NCI will
make awards that will collectively provide 1) the most creative approaches for
the validation and clinical application of biomarkers, and 2) the range of
research experience, technology, and resources to ensure that the
biomarkers/reagents are validated 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 ability to recruit participants in
clinical studies; (e) the likelihood for substantial contribution by the
applicants to a successful collaborative Early Detection Research Network; (f)
willingness to work cooperatively within the Network; (g) the quality and
availability of scientific expertise, infrastructure and resources; (h)
consideration for the geographical diversity; and (i) the availability of
funds.

SCHEDULE

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 plans to assess 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
Rockville, MD 20850 (express courier)
Bethesda, MD  20892-7399
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 . 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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