THE EARLY DETECTION RESEARCH NETWORK: BIOMARKERS VALIDATION LABORATORIES

Release Date:  March 16, 1999

RFA:  CA-99-008 (see reissuance RFA-CA-05-009)

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 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. 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
Biomarkers Validation Laboratories.  An RFA for the Biomarkers Developmental
Laboratories (CA-98-028) was previously issued (NIH Guide, January 20, 1999).
RFA CA-98-028 is available at:
https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-98-028.html.
An RFA for the Biomarkers Clinical/Epidemiologic Centers is concurrently being
issued (CA-99-007).  This RFA is available at:  
https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-007.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, Early Detection Research
Network: Biomarkers Validation 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.

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 to be used for this program will be
a cooperative agreement (U24), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during performance of
the activity. Under the cooperative agreement, the NIH purpose is to support
and/or stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the activity.
Details of the responsibilities, relationships and governance of the study to
be funded under cooperative agreement(s) are discussed later in this document
under the section "Terms and Conditions of Award."

The total project period for applications submitted in response to this RFA
may not exceed five years. The anticipated award date is April 2000.

Awards and level of support depend on receipt of a sufficient number of
applications of high scientific merit. Although this program is provided for
in the financial plans of the NCI, awards pursuant to this RFA are contingent
upon the availability of funds for this purpose.

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

FUNDS AVAILABLE

An estimated $1 million will be available for the first year. It is
anticipated that two 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 gene-environment interactions relevant to early detection. To explore
fully the application of molecular profiles for earlier detection and risk
assessment, it is essential to understand the molecular pathogenesis of
cancer, that is, the natural history of tumor progression at the molecular
level, so that the biological behavior of an evolving lesion (for example,
dysplasia or field change) can be predicted with greater accuracy. Current
observations indicate that cancers usually evolve through many complex
cellular processes, pathways, and networks. A better understanding of the
circuits in these pathways is critical if we are to successfully apply these
molecular-based technologies to earlier detection.

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

Objectives (applicable to Network as a Whole)

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

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

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

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

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

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

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

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

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

Scope (applies to this RFA)

The scope of this RFA is to establish the Biomarkers Validation Laboratories
(BVL) which will form one of the three scientific components within the
Consortium for the Network. The BVL will: 1) serve primarily as service
laboratories for validation studies for the Network, 2) have the ability to
scale-up assays to allow testing at multiple sites in modest size studies, and
3) participate in collaborative studies with the other components of the
Network.  Before submission, it is recommended that applicants consult
companion RFA CA-98-028 (The Early Detection Research Network: Biomarker
Developmental Laboratories, NIH Guide, January 20, 1999) and CA-99-007 (The
Early Detection Research Network: Clinical/Epidemiological Centers).

The BVL will have responsibility for standardizing laboratory assays and
methodologies, instituting quality control for reagents and technologies for
Collaborative Network-directed studies, and collaborating in other studies as
directed by the Steering Committee.  The Laboratory should have knowledge and
practical experience with Standard Operating Procedures (SOPs) and in the
evaluation of the accuracy, precision, reproducibility, and performance
characteristics, for example, sensitivity, specificity, positive and negative
predictive values, of tests in multi-center settings. These characteristics
are important when sampling body fluids or mixed cell types where only a very
small percentage of cells may exhibit the specific genetic or molecular
changes. The BVL may be asked to conduct studies on a variety of assays in
order to improve their performance characteristics.

Methodology/Assay Refinement and Technology Optimization:

In order to develop accurate early detection screening tests, it is crucial to
develop high-throughput assays/technologies that are reproducible and cost-
effective. The Biomarkers Validation Laboratories are expected to plan,
design, and conduct analytic validation studies, as directed by the Steering
Committee, for assay procedures, protocols, sample collection, etc. Some
sample validation issues are provided below to describe the anticipated lines
of research that the Laboratories will be expected to address.

Methodologies: conduct validation studies to ensure:

-  measures of diagnostic discrimination, that is, sensitivity, specificity,
and predictive accuracy, as appropriate for clinical application
-  determining range of normal values and reproducibility for various tests,
as appropriate
-  that data and specimens are collected under uniform investigative protocols
-  that data are collected to determine the benefits and risks that follow
from positive or negative test results

Assay Design: The Biomarkers Validation Laboratories may be asked to assist
Network investigators in:

-  optimizing the selection of target sequence, primer, and probe sequences
-  single versus multiple targets
-  selection of specimen types
-  handling problematic specimens
-  design of internal controls, controls for contamination, reagent and
instrument standards, and well characterized panels of reference reagents

Assay Optimization: The Biomarkers Validation Laboratories may be asked to
assist Network investigators in:

-  extraction methods, sampling, internal controls, specimen storage, and
processing conditions
-  length, sequence, efficiency, and specificity of primers, probes, enzymes
-  configuration and performance of controls, calibrators, capture probes,
detectors, etc.
-  independent reproducibility. Do multiple independent repetitions of the
test under the same conditions produce nearly identical results?
-  technical reproducibility. Are there technical factors in the performance
of the test that lead to inconsistent results?
-  assay conditions, for example, time, temperature, storage, and transport
stability
-  precision testing: multiple sites, different days, operators, kit lots
-  proficiency testing: single operator, multiple days, kit lots

Assay Validation: The Biomarkers Validation Laboratories may be asked to:

-  analytically validate each assay developed within the Network
-  develop scale-up, automated methods for high volume throughput
-  perform multi-center cross-checks for pooled specimens, and other inter-
and intra-laboratory interfering factors
-  develop formats and systems (paper or electronic) for reporting test
results
-  develop kits for rapid, inexpensive testing

Quality Control Program: Although each of the Biomarker Developmental
Laboratories and Clinical/Epidemiologic Centers will take primary
responsibility for its onsite quality control and quality assurance
activities, the Validation Laboratories may be asked to advise the Steering
Committee on quality control issues and to implement them in the Collaborative
Network-directed studies. Quality control at a minimum should consist of:

-  device and instrument calibration, precision, and reproducibility
-  quality control of data. The Biomarkers Validation Laboratories will follow
the Network procedures for data quality and laboratory quality control in
accordance with the Network guidelines and policies
-  interim evaluation and consideration of assays/reagents developed by the
Network scientific components for tests/reagent scale-up for multi-center
studies per direction of the Steering Committee

Reference Materials: With the rapid advances in molecular, genomic, and
proteomics-based diagnostic technologies, reference materials for controls in
molecular assays/technologies, such as PCR, Comparative Genomic Hybridization
(CGH), etc., and for proficiency testing are needed. The Biomarkers Validation
Laboratories will work with the Steering Committee:

-  to develop guidelines for using references, establish criteria for the
storage, preservation, and transportation of specimens
-  to assist the Data Management and Coordinating Center to develop computer
based catalogues of published data on biomarkers that will be available to
Network investigators.  The format and design of the database will be
determined by the Steering Committee.

Study Organization:

Capability and Characteristics of the Biomarkers Validation Laboratories: The
expertise of the Biomarkers Validation Laboratories should encompass broad
subject areas within the clinical diagnostic field. As the Network gains
experience and its responsibilities shift and expand, the number and expertise
of the investigators should change in response to the scientific
opportunities. Qualified investigators in laboratory technology should be
invited to assume responsibility in a flexible manner as the need arises.

Scientific Agenda: Applicants for the Validation Laboratories should develop
and articulate a plan that summarizes their views and their anticipated lines
of research for each issue discussed above on which they choose to focus. The
applicants should describe both short-term and long-term goals in the plan.
The applicants should also describe the experience, expertise, and resources
of the laboratory, all of which will be a consideration in peer-review.

Developmental Studies: The Biomarkers Validation Laboratories may seek
developmental funds (see section on Instructions for Application Preparation)
for conducting pilot studies on reagents/technology development and refinement
that will enable an assessment of the broad impact in cancer detection and
risk assessment. Applicants should clearly define the research objective for
the first year, which will be peer-reviewed by NCI. Support for subsequent
years will be reviewed by the Steering Committee who will recommend approval
to the NCI.

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) 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 or U24
funds and collaborative research using the Core Funds from Headquarters (see
definition of "Headquarters" below) and from the set-aside funds in the U01 or
U24 awards pending approval by the Steering Committee and release by the NCI,
respectively.

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

It is anticipated that the CBEDR will consist of experts in molecular biology,
laboratory technology, clinical studies, biometry, and epidemiology. The
expertise in laboratory science is expected to include research in the biology
of incipient neoplasia as well as the development, characterization, and
testing of biomarkers of early cancer and risk, development of relevant
technologies for biomarker detection, and analytical tools for the evaluation
of biomarkers for detection and risk assessment. The expertise in laboratory
validation will also include knowledge and practice of Standard Operating
Procedures (SOPs), and experience in the statistical evaluation of accuracy
(both for clinical and experimental tests), precision, reproducibility, and
performance characteristics of tests in multi-institutional settings.
Expertise in patient accrual and associated clinical issues for pilot studies
will be needed to apply basic science discoveries to clinical settings.
Computational and informatic needs of the Consortium will be provided by a
Data Management and Coordinating Center. Therefore, the Consortium, in concert
with the Steering Committee, the Advisory Committee, and the Data Management
and Coordinating Center will constitute the Network (see definition of
"Network" above). NIH intramural laboratory may be one of the research members
of 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 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 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 Headquarter's awards and implements the
scientific, operational, and organizational policies of the Network. The
headquarters provides the executive leadership, scientific direction, and
management for the Network. It serves as a center for information
dissemination to investigators and institutions in the Network as well as to
others outside the Network.

Funds

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 their individual U01 or U24
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 need not apply for the Core
Funds in their U24 applications. Core funds are reserved for post-award
collaborative Network 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 operation and
management of the Network.

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

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

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

SPECIAL REQUIREMENTS

Definitions

Awardee: The institution to which a cooperative agreement (U24) is awarded.

Principal Investigator (PI): The investigator who is designated by the
applicant organization to direct the project that is supported by the U24
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 U24
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 U24
grants awarded under this RFA, but will also be substantially involved in the
service responsibility and scientific coordination within the Network, will
have responsibilities in broad scientific and programmatic issues, and serve
as a voting member of the Steering Committee, as defined under the "Terms and
Conditions of Award."

Terms and Conditions of Award

These special Terms of Award are in addition to and not in lieu of otherwise
applicable OMB administrative guidelines, HHS Grant Administration Regulations
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration
policy statements. [Part 92 applies when state and local governments are
eligible to apply as a "domestic organization."].

In addition, the following terms and conditions will be incorporated into the
U24 award statement, and will be provided to the PI and to the institutional
official at the time of award.

Under the cooperative agreement, the NCI purpose is to support and/or
stimulate the recipient's activity by involvement in and otherwise working
jointly with the award recipient in a partner role, but it is not to assume
direction, prime responsibility, or a dominant role in the activity.
Consistent with this concept, the dominant role and prime responsibility for
the activity resides with the awardee(s) for the project as a whole, although
specific tasks and activities in carrying out the studies will be shared among
the awardees and the NCI Program Director.

A. Rights and Responsibilities of the Biomarkers Validation Laboratories:

The PI of a BVL will have the primary authority and responsibility to define
objectives and approaches, including laboratory service, standards for
reagents, research design, quality control, and protocol development for
specimen collection; if applicable, data collection, interim data and safety
monitoring, and to plan, conduct, analyze, and publish results.

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

The PI of a BVL 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 U24 in accordance with the terms and
conditions of the award.

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

B. NCI Extramural Staff Responsibilities

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

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

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

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

Although the PI 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 broad programmatic
issues among awardees.

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

C: Collaborative Responsibilities

Steering Committee: The Steering Committee will have major scientific
management oversight and responsibility for developing collaborative Network
research designs, protocols and manuals, facilitating the conduct and
monitoring of studies, and reporting study results. The Steering Committee
will 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.

1. 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 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.

2. 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 ensure 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 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 when to stop
non-productive experiments relating to biomarkers validation.

7. The Steering Committee will discuss collaborative projects to be pursued
jointly with the funds available from Headquarters and from individual U01 or
U24 awardees or NIH intramural project budgets.

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

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 Network Advisory
Committee, and other NCI staff will advise the Steering Committee regarding
participants for the workshops and symposia. The Data Management and
Coordinating Center will manage the logistics for these meetings.

Advisory Committee:

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

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

3. The Chair of the Advisory Committee will be elected by its members. The 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 on site visits to the
participating institutions, as necessary.

6. The Advisory Committee will collaborate with the Steering Committee to
suggest participants for and to assist in the implementation of workshops and
symposia and to provide liaison between the cancer research community and the
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 U24 award) between U24 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 U24
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 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 (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
on the web 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 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:

1.  Organizational Structure (10 pages, including organizational chart): This
should include a description of the laboratory's organizational structure,
including lines of authority, with particular attention to its qualifications
for validation studies (see "Scope"), service resources, and the Network's
major objectives (see "Objectives"). Describe any certification(s), from
laboratory accrediting agencies/organizations, for example from CLIA, College
of American Pathologists. Describe plans for interaction among laboratory
staff and with the various Network components.

2.  Personnel (10 pages): Describe the availability of professional staff,
including those with no requested salary support. Applicants should list all
individuals, including consultants, and their relevant expertise and
affiliations in the scientific execution of the project.

3.  Experience with Laboratory Test Validation, Scale-up, and Refinement (10
pages): Describe plans that summarize experience in each of chosen areas (see
"Scope"). Briefly describe previous and current research experience and
accomplishments in dealing with validation studies and quality control. List
available equipment.

4. Environment (5 pages): Briefly describe how the facilities and equipment
for experimentation are appropriate to support the Network's endeavor and the
scientific environment in which the work will be done. Describe the
institutional support for computer services, including Internet access, and
conference calls. Describe how the proposed environment contributes to the
research and encourages collaborative and service arrangements. Provide health
and safety plans.

Instruction for Developmental Studies

Developmental Studies (15 pages): Justification and plans for the use of
developmental funds (see Budget section below) should be carefully described,
including research questions, study designs, anticipated outcome, and its
overall impact on furthering the Network's objectives. The duration of and the
budget for the study should not exceed more than a year and $50,000 (direct
costs), respectively.

Budget:

Personnel: It is reminded that the other components of the Network will just
be getting started in year 1 and that NCI recommends that the applicants for
the validation labs recognize the initial "downtime" and budget for personnel
in the first year accordingly.

In the first year the budget may include salary for the PI (Laboratory
Director) and support staff for the time and effort involved in managing the
project and attending the Network meetings. For year 2 and beyond identify one
or two additional FTEs (full time equivalents) salary support for technical
staff in reserve. Since it is uncertain what the work load will be in
subsequent years, the actual recruitment of these staff will require review
and approval by the Steering Committee and by the NCI.

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

Budget for personnel service involved in the developmental studies should be
clearly identified. The total cost must not exceed $50,000 direct costs a
year. The proposed developmental studies for the first year will be peer-
reviewed by an ad hoc committee along with the U24 applications. The use of
set aside funds in subsequent years (up to $50,000, direct costs) per year
will be restricted and must be reviewed and approved by the Steering Committee
and by the NCI.

Travel: Applicants must budget for travel and per diem expenses for Steering
Committee meetings. In the first year, applicants should plan for two
investigators, the principal investigator and 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.

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.

General:

1. Applicants must include their specific plans for responding to the "Terms
and Conditions" of the RFA. Applicants should state their willingness to
collaborate and share data freely with the other Network components, to
participate in planning and attending workshops and symposia, to serve on the
Steering Committee and be bound by its decisions, particularly those that
relate to setting priorities for quality control and validation of new or
existing biomarkers, and willingness to interact with each other and the NCI
in an Internet environment. Applicants must describe computer 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. 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.  In addition, the RFA title "Early
Detection Research Network: Biomarkers Validation Laboratories" 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 applications 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 laboratory diagnostic research including, but not limited to, quality
control; molecular genetics and pathology for early cancer detection as
applied to the design of the research plans; a multi-disciplinary team of
collaborators; substantial interactions among collaborators; demonstration of
appropriate facilities and resources; and willingness to share data and
reagents.

Review Criteria

Criteria for Evaluating the Laboratory: Applicants for the Biomarkers
Validation Laboratories 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 evaluation will be based on the demonstrated capabilities of the
prospective applicants in relation to the needs of the RFA. The merit of each
application will be evaluated carefully, based on responsiveness to the RFA as
well as the thoroughness and feasibility of the technical approach taken.
Applicants must submit information sufficient to evaluate their proposals
based on the RFA research objectives and criteria listed below. Failure to
provide the information required to evaluate the application may result in
rejection without further consideration.

1. Understanding the Scientific Issues: Demonstrate evidence of understanding
the objectives and methods for accomplishing the goals of the RFA. Show
evidence of understanding the technical requirements of the objectives and
scope of the responsibility. Show evidence of understanding the relevant
technical problems and their timely and effective solutions. An understanding
of diagnostic research and method for accomplishing the proposed research plan
including study design must be specifically addressed.

2. Personnel: Research experience and qualification of the PI in managing
relevant laboratory studies and multi-institutional collaboration;
capabilities, qualifications, and experience of staff to perform tasks of the
RFA. The key staff shall include the PI and other investigators directly
contributing to the laboratory studies.

3. Equipment and Environment: Adequacy and suitability of facilities and
equipment for experimentation appropriate to support the endeavor; adequacy of
the scientific environment in which the work will be done contributing to the
probability of success, adequacy of proposed infrastructure, unique features
for collaborative research, commitment and documented evidence of
institutional support for proposed endeavor, and institutional support for
computer services including Internet access.

Review of Developmental Studies: In addition to the above criteria, the
reviewers will consider the proposed developmental studies for year 1, using
the following criteria:

1. Significance. Does the proposed developmental research address an important
need for technology/reagents development, standardization, quality control,
and protocols suitable 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 technology/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 criteria chosen to characterize
technology/reagents for early detection and/or risk assessment appropriate and
adequate? Are these criteria generally applicable to all biomarkers or
reagents or both?

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. Is the principal investigator and collaborators
appropriately trained and well suited to carry out this work, especially in
the area of laboratory quality control and high volume assays? To what extent
do these investigators have the necessary complementary skills? Have
collaborations been established or consultants identified to provide the
appropriate depth and breadth of scientific expertise required for the
project? Will this team of investigators contribute unique skills to the
overall Network?

Additional Considerations (applies to overall laboratory evaluation)

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

2. Budget. For U24 applications, does the apportionment of the budget reflect
that the applicants understand the requirements of managing a Biomarkers
Validation Laboratory in the Network enterprise?

AWARD CRITERIA

The intent of this RFA is to enable the NCI to assemble the Biomarkers
Validation Laboratories, that should include 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 early stages of human cancer. The NCI will make awards that
collectively will provide the Network with the most creative approaches to the
development and validation of biomarkers and with 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 efficiently.

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.

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 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:

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 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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