RELEASE DATE:  April 9, 2004
RFA Number:  RFA-CA-05-009

Update: The following update relating to this announcement has been issued:

(Reissued as RFA-CA-09-019)

EXPIRATION DATE:  August 17, 2004

Department of Health and Human Services (DHHS)
National Institutes of Health (NIH) 

National Cancer Institute (NCI) 


This RFA is a reissue of RFA CA-99-008, which was published in the NIH Guide on 
March 16, 1999.


o Purpose of this RFA 
o Research Objectives 
o Mechanism of Support 
o Funds Available  
o Eligible Institutions  
o Individuals Eligible to Become Principal Investigators 
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations


The Division of Cancer Prevention (DCP), National Cancer Institute (NCI), 
invites new and competing renewal cooperative agreement applications to 
continue the national Network that has the responsibility for the development, 
evaluation, and validation of biomarkers for earlier cancer detection and risk 
assessment. Biomarkers are defined as cellular, biochemical, and molecular 
(genetic and epigenetic) 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 Network has four main 
components: Biomarker Developmental Laboratories (BDLs), Biomarker Reference 
Laboratories (BRLs) (formerly known as Biomarker Validation Laboratories), 
Clinical Epidemiology and Validation Centers (CECs)(formerly known as Clinical 
and Epidemiologic Centers), and a Data Management and Coordinating Center 
(DMCC). The BDLs have responsibility for the development and characterization 
of new or the refinement of existing biomarkers and assays. The BRLs serve as a 
Network resource for clinical and laboratory validation of biomarkers, which 
include technological development and refinement. The CECs collaboratively 
conduct clinical and epidemiological research on the Network-wide clinical 
validation of biomarkers. The DMCC supports statistical and computational 
analysis and informatics infrastructure and coordinates network-wide meetings 
and conferences. For further details, see

The Early Detection Research Network (EDRN) Steering Committee (SC) is composed 
of the Principal Investigators (PIs) in the Network and appropriate NCI staff 
to coordinate the work of the Network. 

The purpose of this Request for Applications (RFA) (CA-05-009) is to invite new 
and competing renewal applications for the BRLs. An RFA (CA-04-006) for the 
BDLs was previously published in the NIH guide, September 26, 2003.  This RFA 
is available at  
The RFA for the CEC (CA-05-005) was published in the NIH Guide on 
January 14, 2004, and is available at  
The RFA for the DMCC is being issued at a later date. Applicants are encouraged 
to seek funding to participate in more than one component, because it is 
recognized that collaborations already exist in individual institutions for 
clinical testing and validation of biomarkers and reagents.  


A. Background

The Network has a straightforward mission, which is to translate newly emerging 
molecular knowledge into practical clinical tests to detect cancer and cancer 
risk.  For most cancers, successful treatment depends on early detection, and 
successful prevention depends on the accurate evaluation of risk.  The EDRN 
seeks to give treatments a greater opportunity to work and to make prevention 
more possible.

The Network is using cutting-edge technologies to identify the changes that 
occur in the earliest stages of a cell’s transformation onto the road of 
cancer.  Scientific expertise from leading national and international 
institutions has been harnessed to identify and validate crucial molecular 
markers to detect cancer and to assess cancer risk.  The Network is an 
investigator-initiated Network for collaborative research to link the discovery 
of biologic markers directly to the next steps in the process of developing 
early detection tests. The power of bioinformatics and computer-assisted 
programs are being put to full use to analyze Network data and to facilitate 
faster answers to key questions.  New technologies, such as genomics, 
epigenomics, and proteomics, 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 use of these emerging technologies in the field of early 
detection and risk assessment is a high priority in the NCI’s strategy for 
reducing mortality from cancer. Detection of early cancer has been identified 
as an area of extraordinary opportunity for research investment in the NCI 2004 
Bypass Budget ( 

The Network is an opportunity and a challenge for the scientific community; an 
opportunity to make science work for people and a challenge to make this new-
found model of collaboration a productive scientific construct.  Collaborations 
and partnerships that are necessary for the ultimate success of this project 
have been put into place.  The acceleration of scientific progress through the 
Network is faster than it has ever been; consequently, the need to translate 
the results to the clinical setting is now greater than ever. New detection 
technologies are under development and are rapidly evolving while existing 
technologies are undergoing progressive refinements in their sensitivity, 
specificity, and levels of throughput. Improved analytic tools have allowed 
more detailed examinations of the molecular bases of carcinogenesis, the 
molecular and cellular signatures of cancer, and the gene-environment 
interactions that are 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.

Since its inception in 1999, the EDRN has followed a “vertical” approach to 
biomarker research that is an established, integrated, multidisciplinary 
environment that would facilitate collaboration among technology developers, 
basic scientists, clinicians, epidemiologists, biostatisticians, and other 
health professionals. Such an environment would expedite efficacious clinical 
applications of the molecular knowledge that has burgeoned in recent years 
(Srivastava, 1999). The Network has produced a system for evaluating biomarkers 
as tools to clinically detect cancer before symptoms appear and to identify 
people at risk ( A five-phase approach has been 
established as a standard and guidelines for successfully translating research 
on biomarker applications from the laboratory to the bedside (Pepe, M.S., 
Etzioni, R., Feng, Z., Potter, J., et al.;. Phases of biomarker development for 
early detection of cancer; J Natl Cancer Inst 2001; 93: 1054-1061). The phases 
are as follows:

Phase I: exploratory studies to identify potentially useful biomarkers, i.e., 
the “discovery” phase; 
Phase II: studies to determine the capacity of biomarkers for distinguishing 
between people with cancer and those without, i.e., the validation phase; 
Phase III: studies to assess the capacity of a biomarker to detect preclinical 
disease by testing the marker against tissues collected longitudinally from 
research cohorts; 
Phase IV: prospective screening studies; and
Phase V: definitive large-scale population studies to the overall impact of 
screening on health outcomes in the target population.

Significant progress has been made by the EDRN investigators from discovery to 
development, to validation, and application. The pace of identification of 
molecular signatures (e.g., those that are identified by proteomics and/or 
genomics technologies) that are associated with causal pathways and processes 
is accelerating. However, the major challenges remain in integrating these 
discoveries and developments into clinical practice. The Network stimulates 
collaborative research to meet this challenge by supporting translational 
research. For further research activities across the Network, see Applicants are encouraged to see the EDRN’s second 
progress report at

Applicants are strongly encouraged to forge partnerships with industry 
(including biotechnology firms), and to develop biomarkers, reagents, 
technologies, and assays. The Network continues to serve as an attractive 
source of collaborations for industry, since it will provide clinical 
opportunities for the evaluation of new technologies. The Network will 
encourage collaborations with industry in order to leverage funds awarded under 
this RFA. 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. NCI views partnerships with industry as an 
important component of the EDRN mission. However, with respect to new 
technologies and/or reagents provided by such participants that are part of 
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, collection and formatting of specialized 
data required by regulatory agencies for device approvals, preparation of 
registration documents, and supporting a portion of the accrual to studies 
pivotal for registration. 

B. Network Administrative Structures

Network Organization: The Network is structured around four main components, 
and currently includes eighteen BDLs, three BVLs, nine CECs, and a DMCC. See 
the Early Detection Research Network: Translational Research to Identify Early 
Cancer Risk; NCI Publication No. 01-4852, August 2001). 

o The BDLs develop and characterize new biomarkers, or refine existing 
biomarkers (Phase I and Phase II).  Current RFA for BDL can be found at  

o The BRLs (which replace the Biomarker Validation Laboratories in this 
reissuance) serve as a resource for the clinical and analytical validation of 
biomarkers, including development of technology, standardization of assay 
methods, and refinement of existing methods. (See previous RFA BVL:

o The CECS conduct or participate in early phases (Phase II and Phase III) of 
clinical validation and epidemiological research into the application of 
biomarkers. (See the current CEC RFA: CA-05-005.)

o The DMCC provides statistical, logistic, and informatics support and develops 
the theoretical and statistical approaches to the simultaneous pattern analysis 
of multiple markers (see the previous RFA for the DMCC at

Four federal agencies participate in the EDRN through interagency agreements: 
the National Institute of Standards and Technology (NIST), which serves as a 
validation laboratory; the Centers for Disease Control and Prevention (CDC), 
which serves as a Clinical and Epidemiologic Center; the Food and Drug 
Administration (FDA), which serves on the Network Consulting Committee; and the 
Jet Propulsion Laboratory (JPL), NASA, which provides informatics support. 

Each component is funded through a separate RFA.  An applicant, however, may 
seek funding to participate in more than one component. Each awardee will 
conduct independent and/or collaborative research using their U01 or U24 funds, 
respectively, collaborative research using the Core Funds from the Headquarters 
(see definition of the Headquarters below), and from the set-aside funds in 
their U01, pending approval by the EDRN Steering Committee and release by the 
NCI, respectively. 

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

Currently, the Network consists of experts in basic molecular science, 
laboratory technology, clinical studies, biometry, and epidemiology. The 
expertise in laboratory science includes conducting research on 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 
includes 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 
studies will be needed to apply basic science discoveries to clinical settings. 
Computational and informatics needs of the Network are provided by a Data 
Management and Coordinating Center and the JPL. 
Steering Committee (SC): The SC has responsibility for scientific management 
and oversight, including monitoring the activities of the DMCC. For 
administrative structure and responsibilities of the SC see “Collaborative 

Network Consulting Committee (NCC): A separate advisory committee has been 
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 (DMCC):  The DMCC provides logistic 
support for the conduct of the SC and NCC meetings, provides statistical and 
data management support for protocol development, and conducts analyses of 
clinical data and informatics. It studies applied and theoretical approaches to 
the simultaneous analysis of multiple markers.  In addition, the DMCC, in 
collaboration with JPL and EDRN investigators, has developed common 
informatics, Common Data Elements (CDEs), and analytical tools for the 
interpretation of data, as well as instruments for checking uniformity, 
consistency, accuracy, timeliness, reproducibility, and privacy of the data.

Headquarters: The institution of the Chair of the SC serves as the Headquarters 
of the Network. The Chair of the SC can be any PI involved in the Network. The 
Chair serves as the PI of the Headquarters and 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 individually funded U01/U24 awardees in 
the Network and 2) the Headquarters.

The PIs with U24 awards will have funds available to cover applicable 
administrative costs, and conduct developmental studies. The BRL will be 
provided support for the collaborative validation studies from the Core Fund 
(see below) on an as needed basis. 

Core Funds for the Headquarters:  Core Funds will be available to the Chair of 
the SC. Applicants under this RFA should not apply for the Core Funds in their 
U24 applications.  Core Funds are reserved for post-award collaborative 
research and for a variety of other functions: 

1. Core Funds are used to expand participation within the Network through 
supplemental funding to an investigator who is not part of the Network.  
However, receipt of these supplemental funds does not, in and of itself, imply 
membership on the SC.

2. Core Funds can also be used to move 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 SC will require 
sufficient funding to contract with commercial laboratories or companies that 
can scale up production and maintain quality of the reagents (e.g., monoclonal 
antibodies, labels, etc.) and to fund CEC for subject accrual.  Funds will also 
be required for data management, travel, meetings, and other collaborative 
activities of the Network. However, Core funds should not be used to pay for 
activities that have direct implication for a company’s product development or 
marketing strategy.

Supplements from the Core Funds may provide direct costs and appropriate 
facilities and administrative costs. 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 Network 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 SC for additional evaluation of the marker and possible 
support for further testing. The SC then has the responsibility to review the 
data on the potential marker using its standing formal criteria as a guide. The 
SC consults the Advisory Committee to obtain information on the requirements 
and need for additional research on the marker. It also can consult the BRLs 
and the CECs 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 DMCC can develop tools for 
the analysis of results.

There is also flexibility so that investigators outside the Network could form 
collaboration(s) with one of the existing centers, or directly bring their 
discoveries to the SC (e.g., Letter-of-Intent). To support such efforts, the SC 
is able to use core funds to supplement the investigator’s ongoing research. 
The investigator, in turn, must agree to share his research findings and become 
part of the Network as an associate member.

Recipients of core funds, such as commercial laboratories or manufacturing 
companies and institutions of outside investigators, participating for example 
in validation studies, will be subject to the plans applicant submits and are 
accepted that address the sharing of research resources and intellectual 
property as noted in Section 6 of the Supplementary Instructions of this RFA. 
Awardees must advise core funds recipients and outside investigators of these 
terms and conditions of the award.

C. Objectives (applicable to Network as a Whole)

The goals of the Network are to discover, develop, evaluate, and validate 
biomarkers/reagents (Phase I-III) for the earlier detection of cancer and for 
the assessment of risk for developing cancer. The intent of this RFA is to 
continue to foster research investigations, technological innovations, and 
collaborations to accelerate the development and validation of biomarkers and 
tools that have the potential of rapidly moving to Phase II and Phase III. 
Specifically, the objectives of the Network include:

o	the development and testing of promising biomarkers or technologies at 
institutions with the necessary scientific and clinical expertise, with the 
goal being to obtain preliminary information to guide further testing; 

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

o	the timely development of biomarker expression patterns, sometimes of 
multiple markers simultaneously, that can serve as background information for 
subsequent large definitive validation studies in the field of cancer detection 
and screening; 

o	collaboration among academic and industrial leaders in molecular biology, 
molecular genetics, proteomics, clinical oncology, computer science, public 
health, and other areas to facilitate the development of high-throughput, 
sensitive assay methods to identify biomarkers that are useful in detecting 
cancer in its early stages and in assessing cancer risk; 

o	conducting early phases of clinical/epidemiological studies (e.g., cross-
sectional, retrospective, Phase I-III studies as described above), to evaluate 
predictive value of biomarkers; and 

o	encouragement of collaboration and rapid dissemination of information among 
awardees to ensure progress and avoid fragmentation of effort; management of 
intellectual property rights in ways that do not restrict the ability to share 
research materials or impede products being brought to market to benefit the 

Because early detection and treatment issues are often related, the Network 
seeks meaningful participation from various medical organizations. In some of 
its activities, the Network may need to relate programmatically to research 
infrastructures supported by NCI. The NCI anticipates that augmenting the EDRN 
expertise with a broad base of clinical and public health perspectives will 
enable the Network to apply existing methods and newly discovered technologies 
toward clinical application.

For some activities, the Centers may need to relate programmatically to other 
research infrastructures supported by the NCI (for example, Specialized 
Programs of Research Excellence [SPOREs](, Cancer 
Genetics Network [CGN] (, Breast and Colon 
Cancer Family Registries (;, Cooperative Human Tissue Network 
(, Cancer Genome Anatomy Project 
(, with ongoing NCI clinical research programs/trials 
(e.g., Clinical Community Oncology Program 
[CCOP](, Prostate, Lung, Colon, and 
Ovarian Trial PLCO)(; or with 
other health agencies, such as the Food and Drug Administration (FDA), the 
Department of Defense (DOD), and the Veteran’s administration (VA). Certain 
types of trials in earlier detection, especially those involving treatment, may 
best be conducted as inter-group 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. Awardees must advise prospective 
collaborators, that with respect to these collaborations, their institutions 
will be subject to the plans applicant submits and are accepted that address 
the sharing of research resources and intellectual property as noted in Section 
6 of the Supplemental Instructions of this RFA.

D: Scope (applies to this RFA)

A BRL provides resources for analytical and clinical validation of biomarkers, 
including development of technology, standardization of assay methods, and 
refinement of existing methods. The primary responsibility of the BRL is to 
participate in and perform Network collaborative studies approved by the EDRN 
SC. The secondary responsibility of the BRL is to develop an individual 
developmental study that is directly relevant to the goals of the EDRN. The 
funded BRLs will work in close collaboration with EDRN investigators under the 
direction of the EDRN SC. 

BRL’s Network Collaborative and Individual Developmental Studies: 

1.	BRL’s Network collaborative Studies: 

The BRLs are responsible 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 
SC. 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, and 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 BRL may be asked to conduct studies 
on a variety of assays in order to improve their performance characteristics. 
Studies may include, but are not limited to: 

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 BRL are expected to plan, design, and conduct analytic 
validation studies, as directed by the SC, 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.


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

Assay Design: 

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

Assay Optimization: 

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

Assay Validation: 

o	conducting analytical validation of each assay developed within the Network;
o	developing scaled-up, automated methods for high volume throughputs;
o	conducting multi-center cross-checks for pooled specimens, and other inter- 
and intra-laboratory interfering factors;
o	developing additional formats and systems (paper or electronic) for 
reporting test results; and
o	developing kits for rapid, inexpensive testing.

Quality Control Program: Although each of the BDLs and CECs will take primary 
responsibility for its on-site quality control and quality assurance 
activities, the BRL may be asked to advise the SC on quality control issues and 
to implement them in the collaborative Network-directed studies. Quality 
control at a minimum should consist of:

o	device and instrument calibration, precision, and reproducibility;
o	quality control of data. The BRL will follow the Network procedures for data 
quality and laboratory quality control in accordance with the Network 
guidelines and policies; and
o	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 SC. 

Reference Materials: With the rapid advances in molecular, genomic, and 
proteomics-based diagnostic technologies, reference materials for controls in 
molecular assays/technologies, such as Polymerase Chain Reaction (PCR), 
Comparative Genomic Hybridization (CGH), gene and nucleotide microarrays, etc., 
and for proficiency testing are needed. The BRL will work with the SC to:

o	refine and develop guidelines for using references, establish criteria for 
the storage, preservation, and transportation of specimens; and
o	assist the DMCC continuous effort in developing computer-based catalogues of 
published data on biomarkers for Network investigators with the format and 
design of the database to be determined by the SC.

Study Organization: 

Capability and Characteristics of the BRL: This is an important requirement of 
the BRL and is critical in support of their participation as a BRL. The 
expertise of the BRL must 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:

In support of their applications, applicants for the BRL must develop and 
articulate a plan that summarizes their views and their anticipated lines of 
laboratory support for each issue discussed above on which they choose to 
focus. The applicants must describe both short-term and long-term goals in the 
plan demonstrating their knowledge and practice of a typical reference 
laboratory. The applicants must also describe the experience, expertise, and 
resources of the laboratory, all of which will be a consideration in peer-

2.	BRL’s Individual (Developmental) Studies: 

The BRL may seek developmental funds (see section on Instructions for 
Application Preparation) for conducting pilot studies on reagents and/or 
technology development and refinement that will have a 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 the scientific 
review committee. Support for subsequent years will be reviewed by the EDRN SC, 
which will make recommendations to the NCI. Prior to proposing the 
developmental study, applicants are encouraged to contact the program officials 
listed on this RFA to discuss the needs of EDRN in the area of technology and 
assay refinement.

All funded BRLs will be encouraged to develop validation studies with other 
EDRN investigators and seek funding from the Core Fund. Applicants are 
encouraged to review research activities across the Network and develop 
collaborations by visiting the following website and 
by reading the EDRN second progress report at


This RFA will use the NIH Cooperative Agreement (U24) award mechanism. As an 
applicant, you will be primarily responsible for planning, directing, and 
executing the proposed project. The anticipated award date is July 2005.  The 
RFA may be reissued in the future, contingent upon the availability of funds.  

This RFA uses just-in-time concepts. It also uses the non-modular budgeting 
formats (see  Follow 
the instructions for non-modular budget research grant applications.  This 
program does not require cost sharing as defined in the current NIH Grants 
Policy Statement at

The NIH (U24) is a cooperative agreement award mechanism. In the cooperative 
agreement mechanism, the PI retains the primary responsibility and dominant 
role for planning, directing, and executing the proposed project, with NIH 
Program Coordinator being substantially involved as a partner with the PI, as 
described under the section "Cooperative Agreement Terms and Conditions of 
Award.” At this time, the NCI anticipates that there will be a renewed 
competition after 5 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 Coordinator listed under the INQUIRIES section 
listed below. 

The NCI intends to commit approximately $2 million in FY 2005 to fund up to 
four new and/or competitive continuation grants in response to this RFA. An 
applicant should request support for 5 years. Because the nature and scope of 
the proposed research will vary from application to application, it is 
anticipated that the size of each award will also vary. Although the financial 
plans of the NCI provide support for this program, awards pursuant to this RFA 
are contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. 

You may submit (an) application(s) if your institution has any of the following 

o For-profit or non-profit organizations 
	o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic institutions 
o Foreign institutions are not eligible to apply 
o Faith-based or community-based organizations. 


Any individual with the skills, knowledge, and resources necessary to carry out 
the proposed research is invited to work with their institution to develop an 
application for support.  Individuals from underrepresented racial and ethnic 
groups as well as individuals with disabilities are always encouraged to apply 
for NIH programs.



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 SC and will attend two SC meetings 
in the first year and two SC meetings and a workshop a year in subsequent 
years. Attendance at these meetings are required as part of this cooperative 

NCI Program Coordinator:  A scientist administrator from the NCI extramural 
staff, the Program Coordinator will be substantially involved in the scientific 
coordination and collaboration within the Network, will have responsibilities 
in broad scientific and programmatic issues, and will serve as a voting member 
of the SC, as defined under the “Cooperative Agreement Terms and Conditions of 

NCI Program Director: A Health Scientific Administrator from the NCI extramural 
staff will provide normal stewardship for U24 grant awardees.

Cooperative Agreement 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.")

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 Coordinator. 

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.

A. Rights and Responsibilities of BRL Awardees 
BRL Individual (Developmental) Study:

The PI of a BRL will have the primary authority and responsibility to plan, 
design, and execute the research objective of the developmental project. The PI 
will also be responsible for laboratory service, standards for reagents, 
quality control, safety monitoring, conduct, data collection and analysis, and 
publication of results. 

The PI of a BRL 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. 

BRL Network Collaborative Studies:

The PI of a BRL will be responsible for collaborating on common research 
designs and protocols, including methods, handling of data, appropriate sharing 
of methods and data among Network investigators and collaborating organizations 
as directed by the EDRN SC. 

The PI of a BRL will assume responsibilities for laboratory support of 
individual protocols/research and collaborative projects that were approved by 
the EDRN SC. 

The PI of a BRL will attend two SC meetings and any other meeting required for 
the conduct of the collaborative study.

The PI of a BRL will be responsible for accepting and implementing the goals, 
priorities, common protocols, procedures, and policies agreed upon by the SC.

B. NCI Extramural Staff Responsibilities

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

The NCI Program Coordinator 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 Coordinator (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. 

The NCI Program Coordinator will convene the initial meeting of the SC, have 
voting membership on the SC, and, as determined by the Committee, its 

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

An NCI Program Director designated in the Notice of Grant Award will be 
responsible for normal programmatic stewardship and monitoring of the awards.  
The NCI Program Coordinator will identify other participating NCI staff. The 
NCI Program Coordinator may also serve as the NCI Program Director.

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, data reporting, 
quality control, or other major breach of the protocol, or human subject 
ethical issues, whenever applicable.

C. Collaborative Responsibilities

1. Steering Committee (SC):  The SC will have major scientific management 
oversight and responsibility for developing collaborative research designs, 
protocols and manuals, facilitating the conduct and monitoring of studies, and 
reporting study results. The SC will be composed of the PIs from each member 
organization in the Network, the PI of the Data Management and Coordinating 
Center, and the NCI Program Coordinator. Each member will have one vote. The 
Chair (non-NIH person) will be selected by the SC.  The institution of the 
Chair of the SC will serve as the Headquarters (for definition see Network 
Organization). Subcommittees, including the existing ones, will be 
established/maintained by the SC, as it deems appropriate; the NCI Program 
Coordinator will serve on subcommittees as he/she deems appropriate.   

After all the Network components have been funded, the SC will convene.  
Responsibilities of the SC include, but are not limited to, the following 
activities (investigators are encouraged to review the EDRN Manual of 

o updating and refining established Network policies and procedures;

o updating and refining established policies and procedures for collaborative 
projects, protocols, and Network-defined projects;

o updating and refining established 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);

o updating and refining established standards or “decision criteria” for 
validating biomarkers/reagents for further clinical studies, such as testing 
early detection strategies, or as risk factors; and

o updating and refining established policies and procedures for accepting, 
reviewing, and recommending proposals from investigators outside the Network 
for supplemental funding and expanding the Network participation. 

2. The SC will establish Data and Safety Monitoring Committee (DSMC) for 
clinical trials as appropriate to ensure protection of human subjects.

3. The SC 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 SC will promote and foster the inclusion of women and ethnic minorities 
in clinical studies and assure the completeness of informed consent. 

5. The Committee will track the Network research progress and assure that the 
results of laboratory research and clinical studies are published in peer-
reviewed journals in a timely manner and in accordance with the publication 
policies of the Network.  At any time during a Network project, the SC may ask 
BDL or CEC to serve as a Biomarker Reference Laboratory on an as needed basis. 
The SC may also 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 

6. The SC will discuss collaborative projects to be pursued jointly with the 
funds set aside from the Headquarters and from individual U01 awardees.

7. Collaborative studies/protocols will be approved by the SC. Data will be 
submitted centrally to the DMCC. The SC will define the rules regarding access 
to data and publications consistent with NCI policies. 

8. The SC will plan one of several Workshops during the network project period 
to inform the scientific community and relevant advocacy groups of the progress 
made toward development and clinical application of biomarkers developed 
through the Network. The NCI Program Coordinator, the NCC, and other NCI staff 
will provide the SC with advice on participants for the workshops and symposia. 
The DMCC will manage the logistics for these meetings. 

9. The SC or its Executive Committee (EC) in consultation with the NCI will 
determine the PI of the Network-wide validation study. 

Network Consulting Committee (NCC):

1. A Network Consulting Committee (NCC) was established by the NCI. The NCC 
advises the SC through the NCI on relevant scientific issues, including study 
design, prioritization of biomarker development, development of collaborative 
study protocols, including decision criteria for clinical applications, e.g., 
early detection, prognosis, etc. 

2. The membership to the Committee and duration of service was established by 
the NCI in consultation with the SC.  The membership includes 
members/institutions not participating in the Network.  The NCC includes basic 
scientists, clinicians, prevention scientists, epidemiologists, ethicists, 
statisticians, and members from relevant advocacy groups.  Scientific experts 
were 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 NCC is elected by its members.  The Chair of the SC also 
serves as a member of the advisory committee.  The NCI is represented by 
relevant program staff.

4. The NCC evaluates the progress and success of the Network against the 
criteria developed by the SC.

5. The NCC helps the NCI in site visits to the participating institutions, as 

6. The NCC collaborates with the SC to suggest participants for and to assist 
in the implementation of the workshops and symposia and to provide liaison 
between the cancer research community and the Network.

Data Safety and Monitoring Committee (DSMC): 

The DSMC will be appointed by and report to the SC in consultation with the NCI 
Program Coordinator who will also be the member of this committee.  The DSMC 
will be composed of external, non-participating scientists appointed by the SC 
to monitor patient safety, conduct data audits, and document progress to the 
NCI Program Director and the NCC.

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 SC (with the NCI 
Program Coordinator not voting), or by an individual U24 or 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 appeal able in accordance with the 
PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into four 
areas:  scientific/programmatic, intellectual property and technology 
licensing, peer review, and financial or grants management issues:

o Direct your scientific/programmatic questions for this RFA to:

Sudhir Srivastava, Ph.D., M.P.H.
Program Coordinator
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3142
Bethesda, MD  20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 435-1594
FAX:  (301)402-8990

Jacob Kagan, M.Sc., Ph.D.
Program Director
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3140
Bethesda, MD  20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-8397
FAX:  (301) 402-8990

o Direct questions about intellectual property, technology licensing, data 
sharing, and research tools issues for this RFA to:

Wendy E. Patterson, Esq.
National Cancer Institute
Technology Transfer Branch
6120 Executive Blvd., EPS Suite 450
Bethesda, MD 20892-7182
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 435-3110
FAX:  (301) 402-2117

o Direct questions about peer review issues for this RFA to:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041
Bethesda, MD 20892-8329
Telephone: (301) 496-3428
FAX: (301) 402-0275 

o Direct questions about financial or grants management matters for this RFA 

Karen Chuang
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd., EPS Room 243
Bethesda, MD  20892
Telephone:  (301) 496-2784
FAX:  (301) 496-8601


Prospective applicants are asked to submit by July 16, 2004, a letter-of-intent 
that includes the following information:

o Descriptive title of the proposed services and research;
o Name, address, and telephone number of the PI;
o Names of other key personnel; 
o Participating institutions; and 
o Number and title of this RFA. 

Although a letter-of-intent is not required, is not binding, and does not enter 
into the review of a subsequent application, the information that it contains 
allows NCI staff to estimate the potential review workload and plan the review. 

The letter-of-intent is to be sent by the date listed at the beginning of this 
document. The letter-of-intent should be sent to:

Sudhir Srivastava, Ph.D., MPH
Program Coordinator
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3142
Bethesda, MD  20892-8329
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 435-1594
FAX:  (301)402-8990


It is also the intent of the program to hold a pre-submission meeting on about 
May 27, 2004 in Bethesda, MD, with the potential applicants prior to deadline 
for submission of Letters-of-Intent. Updated information on the pre-submission 
meeting will be posted on the website, http://www.cancer/gov.edrn.


Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering 
System (DUNS) number as the Universal Identifier when applying for Federal 
grants or cooperative agreements. The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at The 
DUNS number should be entered on line 11 of the face page of the PHS 398 form. 
The PHS 398 document is available at in an interactive 
format.  For further assistance, contact GrantsInfo; Telephone: (301) 710-0267; 
and/or E-mail:


Special Instructions for Preparation of the Application

For this RFA, the format for the "Research Plan" of the PHS 398 grant 
application is changed.  "The Research Plan" section is not subject to the page 
limitations stated in the PHS 398.  Sections a. through d. of the “Research 
Plan” should be replaced with the following sections: 1) Organizational 
Structure; 2) Personnel; 3) Experience with Laboratory Test Validation, Scale-
up, and Refinement; 4) Environment; 5) Developmental Studies; and 6) Compliance 
with terms of EDRN Cooperative Agreement. The remainder of the “Research Plan,” 
sections e. through i., remains the same. 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 (maximum 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. Describe any ongoing 
grant-supported, institutional, or private sector resources that augment or 
complement resources for which funding from this RFA is sought

2.  Personnel (maximum 10 pages): Applicants should concisely describe what 
expertise the group encompasses, that are available to support their 
participation in EDRN collaborative validation studies. The roles of all key 
personnel, collaborators, and consultants who are associated with the 
application may be described, including those with no requested salary support. 
Applicants should list and summarize each of the agreements with individual 
collaborators, including a description of the materials, technologies, and 
expertise to be provided by such collaborators.

3.  Experience with Laboratory Test Validation, Scale-up, and Refinement 
(maximum 10 pages): Summarize experience in each of chosen areas (see "Scope"). 
Briefly describe previous and current research experience and accomplishments 
in dealing with validation studies, quality control and excellence in assay 
development and refinement. 
Applicants should also describe the experience of their group in collaborative 
programs and activities with partners in academia and industry. Some examples 
of collaborations that may be provided in support of the application are listed 
below, but are not limited to:

o	Demonstrated evidence of collaborative projects and publications;
o	demonstrated evidence of collaborative funding; and
o	sharing of data and resources, e.g., specimens, technology, research 

For competing renewal applications, applicants should use the Metrics for 
Programmatic Evaluation that can be found in the EDRN Second Report, In brief, they 
should provide:

Documented evidence of: 
o	participation on ongoing collaborative projects and publications; and
o	sharing of data and resources, e.g., specimens, technology, research 
4. Environment (maximum 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.

5.	Developmental Studies (maximum 15 pages): Justification and plans for the 
use of developmental funds (see Budget section below) should be carefully 
described, including specific aims to address the research questions, 
background and significance, preliminary results/progress report, study design 
and methods, anticipated outcome, and the overall impact on furthering the 
Network's objectives. The studies may include, but are not limited to, 
refinement, automation, analytical validation of reagents, biomarker assays, 
development of integrated technology platforms in support of ongoing studies 
within EDRN and other studies conducted elsewhere for the identification of 
risk and early cancer. The applicant may submit a research proposal for a 
developmental study for year one; this proposal will be peer reviewed by the 
scientific review committee. The budget for this one year developmental study 
may not exceed $200,000 in direct costs. For each of the subsequent years, the 
PI should submit an application for the set aside funds ($200,000 in direct 
costs, see Budget section below) for developmental projects/collaborative 
studies, even if the applicant did not request this fund for developmental 
study in year 1. The use of the set-aside fund will be reviewed by the EDRN 
Executive Committee and approved by the NCI. 

6. Compliance with terms of EDRN Cooperative Agreement (maximum 10 pages):  
Specific issues related to cooperative agreements must be addressed in this 

Applicants must include their specific plans for responding to the "Cooperative 
Agreement Terms and Conditions of Award" section. Applicants should state their 
willingness to collaborate and share data freely with the other EDRN 
components, to participate in planning and attending workshops and symposia, to 
serve on the SC and be bound by its decisions, and to be able and willing to 
share data and research resources with each other and the NCI. Successful 
applicants will be expected to adapt information on specimen collections to the 
Network’s Common Data Elements (CDEs) and register their protocols with the 
Network’s DMCC.  

At the end of this section, applicants must append a letter from the applicant 
institution describing how that institution intends to address the NIH policies 
for sharing of data or why data sharing is not possible.  In this regard, 
attention is drawn to the NIH Final Statement on Sharing Research Data 
( and, which was 
published in the NIH Guide on February 26, 2003. This is an extension of NIH 
policy on sharing research resources, and reaffirms NIH support for the concept 
of data sharing. 

To address the interest in assuring that research resources are accessible, NIH 
also requires applicants who respond to this RFA to submit plans (1) for 
sharing the unique research resources, e.g., human biospecimens and novel 
cancer biomarkers, generated through the grant; and (2) for addressing how they 
will exercise intellectual property rights, should any be generated through 
this grant, while making such research resources available to the broader 
scientific community.  Dissemination of research resources and management of 
intellectual property in accordance with these plans are consistent with NCI’s 
programmatic objectives for the EDRN.  


The EDRN is premised on the belief that an established integrated, multi-
disciplinary environment will expedite clinical applications of biomarker 
research.  From the outset, the NCI anticipated that EDRN members would 
collaborate with industry both to develop biomarkers and/or reagents and to 
provide a clinical environment for the evaluation of new technologies.  Early 
interactions with industry are expected to permit research collaborations 
likely to benefit both EDRN grantees and industry partners.  It is hoped that 
validated biomarkers may ultimately be commercialized into diagnostic products 
for early detection of cancer and cancer risk.  Many of the EDRN investigators 
have had active collaborations with industry.  While the one-university/one-
company collaborations have worked well, there is general agreement that 
successful multi-institution/multi-company collaborations have been harder to 

Restricted availability of unique research resources, upon which further 
studies are dependent, can impede the advancement of research. The NIH is 
interested in ensuring that the research resources developed through this grant 
also become readily available to the broader research community in a timely 
manner for further research, development, and application, in the expectation 
that this will lead to products and knowledge of benefit to the public health.

Investigators conducting biomedical research frequently develop unique research 
resources. The policy of the NIH is to make available to the public the results 
and accomplishments of the activities that it funds.  To address this interest 
in assuring that research resources are accessible, NIH requires applicants who 
respond to this RFA to submit a plan for sharing the research resources 
generated through the grant (e.g., human biospecimens and novel cancer 
biomarkers) and for addressing how they will exercise intellectual property 
rights, should any be generated through this grant, while making such research 
resources available to the broader scientific community consistent with this 
initiative. Therefore, the research resources tools sharing plan and 
intellectual property management plan must make unique research resources 
readily available for research purposes to qualified individuals within the 
scientific community in accordance with the NIH Grants Policy Statement 
( and the Principles and Guidelines 
for Recipients of NIH Research Grants and Contracts on Obtaining and 
Disseminating Biomedical Research Resources: Final Notice, December 1999 
( and“NIH Research Tools Policy”).   
These documents define terms, parties, and responsibilities prescribe the order 
of disposition of rights, and a chronology of reporting requirements; and 
delineate the basis for and extent of government actions to retain rights.  
Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible 
from the Interagency Edison web page, 
(; see also, 35 USC § 210(c); Executive Order 12591, 52 
FR 13414 (Apr. 10, 1987); and Memorandum on Government Patent Policy (Feb. 18, 
1983). If applicant investigators plan to collaborate with third parties, the 
sharing plan must address how such collaborations will not restrict their 
ability to share research materials produced with NIH funding.

Reviewers will comment, as appropriate, on the adequacy and feasibility of the 
sharing of research resources plan and the intellectual property plan.  
Comments on the plans and any concerns will be presented in an administrative 
note in the Summary Statement.  These comments will not affect the priority 
score of the proposal.  NIH program staff will consider the adequacy of the 
plans in determining whether to recommend an application for award.  The 
approved plans will become a condition of the grant award and Progress Reports 
must contain information on activities for the sharing of research resources 
and intellectual property.

It is essential that applicants provide plans to address further development of 
technologies consistent with the goals of this RFA in a manner that does not 
restrict research use by the scientific community, both nonprofit and for 
profit.  NCI has not requested a Determination of Exceptional Circumstances 
(DEC) in accordance with 35 USC § 202(a) (ii) to effectuate the collaborative 
mission of the EDRN as set forth in this RFA.  However, the success of the 
entire enterprise will depend on the successful collective management of 
intellectual property arising out of Network activities. 

Where it is anticipated that there will be an exchange of collections of human 
tissues, consideration should also be given to obtaining the appropriate 
assurances from the DHHS Office of Human Subject Protections 
( and necessary IRB approvals and/or 
exemptions.  In addition, issues pertaining to the protection of patient 
identifiable information under the Privacy Rule of the Health Insurance 
Portability and Accountability Act of 1976 (HIPAA) should be addressed.  For 
more information concerning the HIPAA Privacy Rule, see

In the development of the research resource sharing and intellectual property 
management plans, applicants should confer with their institutions’ office(s) 
responsible for handling technology transfer-related matters and/or sponsored 
research.  If applicants or their representatives require additional guidance 
in preparing these plans, they are encouraged to make further inquiries to the 
appropriate contacts listed above for such matters.  Furthermore, applicants 
may wish to independently research and review examples of approaches considered 
by other institutions such as those described on the NCI Technology Transfer 
Branch website (  


Applicants should budget for the following three activities:
o	Administrative Cost;
o	Individual Developmental Study; and 
o  Collaborative Studies.

Provide the budget for each activity separately.
Administrative Costs: The applicants should request funds to cover applicable 
administrative and travel costs (only for EDRN activities). Applicants must 
budget for travel expenses for SC meetings and workshops. Applicants should 
plan for two investigators, the PI and an additional senior investigator, to 
attend two SC meetings and an annual Workshop each year. Administrative costs 
may include salary support for the PI and administrative staff and other 
expenses required for the applicant to participate in EDRN activities. 

Individual Developmental Study: 

The budget may include salary for the PI (Laboratory Director) and support 
staff for the time and effort involved in managing the developmental project. 
Provide justification for each key personnel. The direct cost must not exceed 
$200,000 a year. The proposed developmental studies for the first year will be 
evaluated as part of the peer review of the overall U24 application.

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.

Collaborative Studies:

New applicants should budget $200,000 (direct cost) in set-aside funds from the 
second year onward. The use of these set-aside funds will be restricted to 
collaborative projects relevant to Network’s objectives, and must be reviewed 
and approved by the EDRN SC and the NCI. For competing renewals, the applicant 
should budget the actual amount that has been approved by NCI for the duration 
of the ongoing collaborative studies, otherwise budget as indicated for the new 

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number, CA-05-009, on the label. 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, 
typed on line 2 of the face page of the application form and the YES box must 
be marked.  The RFA label is also available at

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the Checklist, and three signed photocopies, in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:

Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8041, MSC-8329
Bethesda MD 20892-8329
Rockville, MD 20852 (express courier)

Appendices should be comprised of single-sided, unbound materials, with 
separators between documents.

WILL NO LONGER BE ACCEPTED.  This policy does not apply to courier deliveries 
(i.e., FEDEX, UPS, DHL, etc.)
( ).  
This policy is similar to and consistent with the 
policy for applications addressed to Centers for Scientific Review as published 
in the NIH Guide Notice at

APPLICATION PROCESSING:  Applications must be received on or before the 
application receipt date, June 25, 2004, listed in the heading of this RFA.  If 
an application is received after that date, it will not be reviewed.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within eight weeks.
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the previous 
unfunded version of the application. 


Upon receipt, U24 applications will be reviewed for completeness by the CSR and 
for responsiveness by NCI program staff.  Incomplete and/or nonresponsive 
applications will not be reviewed.

U24 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 Division of Extramural Activities at the NCI in accordance with the 
review criteria stated below. As part of the initial merit review, all 
applications will:

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


Overall Review

In view of the roles and responsibilities of a BRL, the applications will 
primarily be reviewed for their presentations of the knowledge and practices of 
assay validation and the availabilities of infrastructure, including equipment, 
to support them. Secondarily, the proposed developmental study will be reviewed 
in light of its relevance in enhancing the current or future validation study 
(see below). The scientific review group will consider the following criteria 
in assigning the application overall score, weighting them as appropriate.

1. Understanding the Scientific Issues: Does the application document evidence 
that the applicants understand the objectives and the goals of the RFA? Is the 
study design appropriate? Do the methods and approaches proposed demonstrate 
understanding of the technical requirements and the technical challenges in 
biomarkers validation? Are the proposed solutions timely and effective? 
Applicants for the BRL 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 the "SPECIAL REQUIREMENTS” section of the RFA."

2. Personnel: Research experience and qualifications of the PI in managing 
relevant laboratory studies and multi-institutional collaboration; 
capabilities, qualifications, and experience of staff to perform tasks of the 
RFA. Factors considered to be important for review include: demonstrated 
expertise in laboratory diagnostic research including, but not limited to 
validation studies of biomarkers; quality control; and adequate experience in 
molecular genetics, genomics, proteomics, and pathology for early cancer 
detection to execute the proposed research plans. 

3. Equipment and Environment: Adequacy and suitability of facilities and 
equipment for experimentation to support validation of biomarkers; adequacy of 
the scientific environment in which the work will be done; commitment and 
documented evidence of institutional support for BRL; appropriate facilities 
and infrastructure including equipment for high-throughput testing, computer 
services including Internet access; unique features for collaborative research; 
multi-disciplinary team of collaborators; substantial interactions among 

For competing renewal applications, applicants will be also evaluated on their 
performance of EDRN validation and developmental studies, and their overall 
contribution to collaborations within, and outside the Network in meeting the 
EDRN missions (see EDRN Second Report,, Metrics for 
Programmatic Evaluation).

Review of Developmental Studies: 

For the developmental study, the scientific review group will address and 
consider each of the following criteria and rate them as “acceptable” or 
“unacceptable.” The reviewer may recommend removing the proposed developmental 
study without affecting the overall score.

1. Significance. Does the proposed developmental research address an important 
need for technology and/or reagents development, standardization, quality 
control, or 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 address the objectives of the RFA?  
Does the applicant acknowledge potential problem areas and consider alternative 
strategies? Can the test results be confirmed by an independent method? Can 
these approaches be used for clinical testing of biomarkers/reagents for a 
variety of incipient neoplastic lesions? Are the criteria chosen to 
characterize the biomarkers/reagents sufficient and appropriate? Will the 
laboratory be able to carry out its planned studies in a reasonable period of 

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

4. Investigators. Are the PI 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? 


In addition to the above criteria, the following item will be considered in the 
determination of scientific merit and the priority score:

1. Interactions: Are there adequate plans for effective interaction and 
coordination with the Network components such as the CEC, the BDL, the DMCC, 
the SC, and the NCI? Do the investigators state their willingness to abide by 
the priorities and policies agreed upon by the SC for collaborative studies?  
Have the applicants proposed sound strategies for communication among 
themselves, with the other Network components, and with the NCI? 

subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section 
on Federal Citations, below.)

to include subjects from both genders, all racial and ethnic groups (and 
subgroups), and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be 
used in the project, the five items described under Section f of the PHS 398 
research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS The following items may be also be considered 
by reviewers but will not be included in the determination of scientific merit.

Sharing Research Data

Applicants requesting more than $500,000 in direct costs in any year of the 
proposed research must include a data sharing plan in their application. The 
reasonableness of the data sharing plan or the rationale for not sharing 
research data will be assessed by the reviewers. However, reviewers will not 
factor the proposed data sharing plan into the determination of scientific 
merit or priority score.  (See URL in Federal Citations, below.)

Budget: Does the apportionment of the budget reflect that the applicants 
understand the requirements of managing a BRL in 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?


Letter of Intent Receipt Date: July 16, 2004
Application Receipt Date: August 16, 2004
Peer Review Date: February/March 2005 
Council Review: June 7, 2005
Earliest Anticipated Start Date: July 1, 2005 


Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and others, 
and the importance of the knowledge gained or to be gained. See

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all 
types of clinical trials, including physiologic, toxicity, and dose-finding 
studies (phase I); efficacy studies (phase II); and efficacy, effectiveness, 
and comparative trials (phase III).  The establishment of data and safety 
monitoring boards (DSMBs) is required for multi-site clinical trials involving 
interventions that entail potential risk to the participants. (NIH Policy for 
Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:  

Clinical trials supported or performed by NCI require special considerations.  
The method and degree of monitoring should be commensurate with the degree of 
risk involved in participation and the size and complexity of the clinical 
trial.  Monitoring exists on a continuum from monitoring by the PI/project 
manager or NCI program staff or a Data and Safety Monitoring Board (DSMB).  
These monitoring activities are distinct from the requirement for study review 
and approval by an Institutional review Board (IRB).  For details about the 
Policy for the NCI for Data and Safety Monitoring of Clinical trials, see  For Phase I and II 
clinical trials, investigators must submit a general description of the data 
and safety-monitoring plan as part of the research application.  See NIH Guide 
Notice on “Further Guidance on a Data and Safety Monitoring for Phase I and II 
Trials” for additional information:  
Information concerning essential elements of data 
safety monitoring plans for clinical trials funded by the NCI is available at

SHARING RESEARCH DATA:  Starting with the October 1, 2003, receipt date, 
investigators submitting an NIH application seeking $500,000 or more in direct 
costs in any single year are expected to include a plan for data sharing or 
state why this is not possible (see  Investigators should seek 
guidance from their institutions, on issues related to institutional policies, 
local IRB rules, as well as local, State, and Federal laws and regulations, 
including the Privacy Rule. Reviewers will consider the data-sharing plan but 
will not factor the plan into the determination of the scientific merit or the 
priority score.

NIH that women and members of minority groups and their sub-populations must be 
included in all NIH-supported clinical research projects unless a clear and 
compelling justification is provided indicating 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 (Section 492B of 
Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
a complete copy of the updated Guidelines are available at   
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials, that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; and 
b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

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

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at

requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  
You will find this policy announcement in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at A 
continuing education program in the protection of human participants in 
research is available online at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see  
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s) for the hESC line(s) to be used in the proposed research.  
Applications that do not provide this information will be returned without 

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a project 
that is supported in whole or in part with Federal funds and (2) cited publicly 
and officially by a Federal agency in support of an action that has the force 
and effect of law (i.e., a regulation) may be accessed through FOIA.  It is 
important for applicants to understand the basic scope of this amendment.  NIH 
has provided guidance at

Applicants may wish to place data collected under this RFA in a public archive, 
which can provide protections for the data and manage the distribution for an 
indefinite period of time.  If so, the application should include a description 
of the archiving plan in the study design and include information about this in 
the budget justification section of the application. In addition, applicants 
should think about how to structure informed consent statements and other human 
subjects procedures given the potential for wider use of data collected under 
this award. 

Department of Health and Human Services (DHHS) issued final modification to the 
“Standards for Privacy of Individually Identifiable Health Information”, the 
“Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal regulation 
under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 
that governs the protection of individually identifiable health information, 
and is administered and enforced by the DHHS Office for Civil Rights (OCR). 
Those who must comply with the Privacy Rule (classified under the Rule as 
“covered entities”) must do so by April 14, 2003 (with the exception of small 
health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, including a 
complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the internet sites.  Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 
2010," a PHS-led national activity for setting priority areas.  This RFA is 
related to one or more of the priority areas. Potential applicants may obtain a 
copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 301 
and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and 
under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are 
subject to the terms and conditions, cost principles, and other considerations 
described in the NIH Grants Policy Statement.  The NIH Grants Policy Statement 
can be found at

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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 


Early Detection Research Network. Disease Markers. Volume 15, No. 4, December 
1999, pages 213-219.

Pepe, M.S., Etzioni, R., Feng, Z., Potter, J., Thompson, M. L., Thornquist, M., 
Yasui, Y. (2001). Phases of biomarker development for early detection of 
cancer. J Natl Cancer Inst. 93, 1054-1061.

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