THE EARLY DETECTION RESEARCH NETWORK: CLINICAL EPIDEMIOLOGY AND VALIDATION 
CENTERS
 
RELEASE DATE:  January 13, 2004
 
RFA Number:  RFA-CA-05-005 

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

(Reissued as RFA-CA-09-018)

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATION: 
National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Cancer Institute (NCI) 
 (http://www.nci.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.393, 93.394
 
LETTER OF INTENT RECEIPT DATE: May 14,2004
APPLICATION RECEIPT DATE:  June 14, 2004

This RFA is a reissue of RFA CA-99-007, which was published in the NIH Guide on 
March 16, 1999.

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA 
o Research Objectives 
o Mechanisms 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

PURPOSE OF THIS RFA

The Division of Cancer Prevention (DCP), National Cancer Institute (NCI), 
invites new and competing renewal cooperative agreement applications to 
continue the national Early Detection Research Network (EDRN) 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, abnormal, or simply 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 (BDL), Biomarker Reference Laboratories (formerly 
known as Biomarker Validation Laboratories), Clinical Epidemiology and 
Validation Centers (formerly known as Clinical and Epidemiologic Centers), and 
a Data Management and Coordinating Center (DMCC). The Biomarker Developmental 
Laboratories have responsibility for the development and characterization of 
new, or the refinement of existing, biomarkers and assays. The Biomarker 
Reference Laboratories serve as a Network resource for clinical and laboratory 
validation of biomarkers, which include technological development and 
refinement. The Clinical Epidemiology and Validation Centers collaboratively 
conduct clinical and epidemiological research on the Network-wide clinical 
validation of biomarkers. The Data Management and Coordinating Center supports 
statistical and computational analysis and informatics infrastructure and 
coordinates network-wide meetings and conferences. For further details, see 
http://www.cancer.gov/edrn.  The 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)is to invite new and 
competing renewal applications for the Clinical Epidemiology and Validation 
Centers.  This RFA will allow the submission of applications involving U01 and 
U24 Cooperative Agreement award mechanisms.  An RFA (CA-04-006) for the 
Biomarker Developmental Laboratories was previously published in the NIH guide 
on September 26, 2003.  This RFA is available at 
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-04-006.html.  RFAs for the 
Biomarker Reference Laboratories (CA-05-009) and for the Data Management and 
Coordinating Center will be issued in the near future.  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.  

RESEARCH OBJECTIVES

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 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 
(http://plan.cancer.gov/). 

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 (http://www.cancer.gov/edrn). A five-phase approach has been 
established as a standard and a road map 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). These 
phases are:

Phase I: exploratory studies to identify potentially useful biomarkers– the 
“discovery” phase. 
Phase II: studies to determine the capacity of biomarkers for distinguishing 
between people with cancer and those without–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.
Phase V: definitive large-scale population studies to determine 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, 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 
http://www.cancer.gov/edrn. Applicants are encouraged to see the EDRN’s second 
progress report at 
http://www3.cancer.gov/prevention/cbrg/edrn/edrn_report2002.pdf.

Applicants are strongly encouraged to forge partnerships with industry, 
including biotechnology firms, 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 Biomarker Developmental Laboratories (BDLs), 
three Biomarker Validation Laboratories (BVLs), nine Clinical and Epidemiologic 
Centers (CECs), and a Data Management and Coordinating Center (DMCC) (The Early 
Detection Research Network: Translational Research to Identify Early Cancer 
Risk; NCI Publication No. 01-4852, August 2001). 

o	The Biomarker Developmental Laboratories develop and characterize new 
biomarkers, or refine existing biomarkers (Phase I and Phase II).  Current RFA 
for BDL can be found at 
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-04-006.html.  

o	The Biomarker Validation Laboratories (to be replaced by Biomarker Reference 
Laboratories in the reissuance of the RFA) 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 for BVL: 
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-008.html.)

o	The Clinical Epidemiology and Validation Centers (which replace the 
Clinical/Epidemiologic Centers in this reissuance) conduct or participate in 
early phases (Phase II and Phase III) of clinical validation and 
epidemiological research into the application of biomarkers. (see previous RFA 
for CEC: http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-007.html.)

o	The Data Management and Coordinating Center provides statistical, logistics, 
and informatics support and develops the theoretical and statistical approaches 
to the simultaneous pattern analysis of multiple markers. (see previous RFA for 
DMCC: http://grants.nih.gov/grants/guide/rfa-files/rfa-ca-99-011.html.)

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 (BDLs, BRLs, CECs and the DMCC) is funded through a separate 
Request-for-Applications.  An applicant, however, may seek funding to 
participate in more than one type of component. Each awardee will conduct 
independent and/or collaborative research using their U01 or U24 funds and will 
conduct collaborative research using either Core Funds from the Headquarters 
(see definition of a Headquarters below) and/or the set-aside funds in their 
U01 award. The use of Core Funds and individual set-aside funds must be 
approved by the Steering Committee and released by the NCI. 

Each laboratory/center will be managed by a Principal Investigator 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 investigators (academic or community-based) who are 
able to validate the results of laboratory studies through patient accrual.

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 informatic needs of the Network are provided by a Data 
Management and Coordinating Center and the JPL.  

Steering Committee: The Steering Committee (SC) has responsibility for 
scientific management and oversight, including monitoring the activities of the 
DMCC. For administrative structure, and responsibilities of the Steering 
Committee, see “Collaborative Responsibilities.”

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 Data Management and 
Coordinating Center 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 Steering Committee serves as 
the Headquarters of the Network. The Chair of the Steering Committee can be any 
Principal Investigator involved in the Network. The Chair serves as the 
Principal Investigator of the Headquarters 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 Principal Investigators with U01 awards will have funds available to 
support the development of their scientific programs and clinical protocols. 
The Principal Investigators with U24 awards will have funds available to cover 
applicable administrative costs and travel to EDRN steering committee meetings 
and workshops. All investigators will be encouraged to seek supplemental 
funding through the Small Business Innovation Award (SBIR, R43, and/or R44), 
Small Business Technology Transfer (STTR, R41, and/or R42), 
Exploratory/Developmental grants (R21/R33), and other research support 
mechanisms.

Core Funds for the Headquarters:  Core funds will be available to the Chair of 
the Steering Committee. Applicants under this RFA should not apply for the Core 
Funds in their U01 applications.  Core funds are reserved for post-award 
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 Steering Committee.

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 Steering Committee 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 subject accrual at 
Clinical Epidemiology and Validation Centers.  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 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 Biomarker 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 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 Steering Committee (e.g., Letter of Intent). To support such 
efforts, the Steering Committee 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 subjected to the resource sharing and 
intellectual property requirements set forth in Section 3 of the Supplementary 
Instructions of this RFA. Awardees must advise core funds recipients and 
outside investigators of these requirements.

C. Objectives (applicable to Network as a whole)

As described in the original RFA 
(http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-007.html), the goals of 
the Network are to discover, develop, and evaluate 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. 

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.

D: Scope (applies to this RFA)

The scope of this RFA is to establish and enhance the Clinical Epidemiology and 
Validation Centers (CEC), which form one of the four scientific components 
within the Early Detection Research Network. The responsibilities of a CEC are 
either: 1) to serve as a Resource Center for specimens for use in collaborative 
research within the Network and participate in collaborative biomarker 
validation studies under the coordination of the Steering Committee (these 
centers will be supported using the U24 cooperative agreement mechanism); or 2) 
to both serve as a Resource Center and develop a specific scientific agenda to 
conduct clinical research on the validation of biomarkers in early cancer 
detection and risk assessment (i.e., Phase II/Phase III studies as described in 
J. Natl. Cancer Inst., 2001; 93:1054-1061) and limited short-term (less than 5-
year duration) prospective, comparative biomarker screening studies using an 
established medical procedures as “gold standards” (these centers will be 
supported using the U01 cooperative agreement mechanism). The scientific agenda 
applies to research carried out within the individual Centers and to the 
Network, as appropriate. It is anticipated that biomarkers or tools validated 
through Phase III will later be validated for population use through long-
duration randomized screening trials, supported through other NCI-supported 
programs, including cooperative groups. Applicants interested in proposing a 
Phase IV randomized prospective cancer biomarker screening trial should contact 
NCI program officials prior to submitting their application for referral to the 
appropriate program. 

All funded Clinical Epidemiology and Validation Centers will be encouraged to 
develop epidemiologic and validation studies with other EDRN investigators and 
seek funding from the Core Fund.

1) Resource for Network Clinical Collaborative Research (both U01 and U24 
applicants):

As a collaborative resource for the Network, the Centers will facilitate the 
clinical validation and application of biomarkers through participation in 
multi-institutional studies. These Centers will provide clinical expertise on 
population studies, protocol development, and pathological assessment.  It is 
expected that the Centers will provide specimens for validation studies or 
active patient recruitment, depending on sample availability to insure the 
success of the collaborative Network research projects. The Centers will also 
participate in data quality control, analysis, and interpretation of validation 
studies. Reimbursement for subject accrual will be on a per case basis (see 
"Special Instructions for Preparation of the Application"). For collaborative 
Network research, guidelines for the collection and distribution of specimens 
will be developed by the Steering Committee.  Validation assays will be 
performed at the EDRN Biomarker Reference Laboratories or other facilities as 
determined by the EDRN Steering Committee.

2) Investigator-Initiated Biomarker Validation Studies (this section is 
applicable to those institutions that are proposing to both serve as a Resource 
Center for collaborative research and develop a specific scientific agenda to 
conduct clinical research on the validation of biomarkers in early cancer 
detection and risk assessment; U01 applicants):

A number of putative biomarkers exist that could be tested in clinical 
settings. These include, for example, loss of heterozygosity, microsatellite 
alterations, cancer-specific methylation abnormalities, mutated genes, gene 
expression analysis and protein profiling (proteomics) for classification of 
early disease, and products of the mutated genes. Studies conforming to the 
Phase II and/or Phase III of the EDRN-developed Five-Phase Guidelines will be 
considered. In addition, analytical studies to establish and compare the 
sensitivity, specificity, and predictive accuracy of biomarkers in a clinical 
context, including inter- and intra-laboratory reproducibility in collaboration 
with an EDRN Biomarker Reference Laboratory or the EDRN-designated Reference 
Laboratories will be entertained. 

Applicants should propose a scientific agenda that includes a mix of short- and 
long-term clinical studies. Applicants may propose studies that can be 
conducted within the individual Centers or through inter-institutional 
collaboration with other investigators. It is essential, however, that the 
Centers identify and concentrate their resources on the most promising 
scientific opportunities, that studies be completed as planned, and that the 
methodologies employed are sound and, where appropriate, innovative. These 
studies could include, but are not limited to:

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

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

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

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

o	Evaluating gene-environmental interactions for understanding risk and 
variations (polymorphisms) in susceptibility in high-risk cohorts. 

Investigators are encouraged to develop collaboration with several high-risk 
tumor registries and networks that are available to investigators, such as the 
Cooperative Family Registries for Breast Cancer Studies, Cooperative Familial 
Registries for Colorectal Cancer Studies, Cancer Genetics Network, and 
screening trials that are supported by the NCI.

This initiative encourages the submission of applications for clinical, 
epidemiological, and translational research in earlier cancer detection and 
risk assessment. Translational research in this context is defined as the 
movement of discoveries from the laboratories into patient or population 
research settings or the movement of observations from patient settings back to 
the laboratory. A major component of this process is to standardize assays and 
develop methods of analytic quality control. The NCI has identified several 
high priority research opportunities in early detection and risk assessment 
(for details see section ADVANCING DISCOVERY AND ITS APPLICATION in the Plans 
and Priorities for Cancer Research (http://plan.cancer.gov/). While the major 
thrust of the Network is on cancers of the prostate, breast, colon, lung, 
ovary, upper-respiratory tract, pancreas, and bladder, which are the major 
causes of cancer-related mortality, applications on other organ sites will also 
be accepted for review. The applicants should develop, articulate, and follow a 
research plan that conforms with the individual Center's and with the Network's 
overall objectives (see above). Before submission, it is recommended that 
applicants consult the companion RFAs, CA-04-006 (The Early Detection Research 
Network: Biomarker Developmental Laboratories, NIH Guide, September 26, 2003) 
and The Early Detection Research Network: Biomarker Reference Laboratories 
(CA-05-009 to be published in the near future.)

Organization of the Center:

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

Study Sites:

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

Institutions proposing to serve as Resource Center are encouraged to form a 
formal collaboration with existing Networks, Cooperative Groups, or Community-
based organizations to broaden the coverage of different organ sites and 
accrual. Because early detection and treatment issues are often related, the 
Centers may need meaningful participation from various medical organizations. 
For some activities, the Centers may need to relate programmatically to other 
research infrastructures supported by the NCI (for example, Specialized 
Programs of Research Excellence [SPOREs](http://spores.nci.nih.gov/), Cancer 
Genetics Network [CGN] (http://epi.grants.cancer.gov/CGN/), Breast and Colon 
Cancer Family Registries (http://epi.grants.cancer.gov/CCFR/index.html; 
http://epi.grants.cancer.gov/BCFR/index.html),
Cooperative Human Tissue Network (http://www-chtn.ims.nci.nih.gov/),
Cancer Genome Anatomy Project (http://cgap.nci.nih.gov/),
with ongoing NCI clinical research programs/trials (e.g., Clinical Community 
Oncology Program [CCOP](http://www3.cancer.gov/prevention/ccop/), Prostate, 
Lung, Colon, and Ovarian Trial [PLCO]) 
(http://www3.cancer.gov/prevention/plco/index.html); 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. 

MECHANISM OF SUPPORT

This RFA will use the NIH Cooperative Agreement (U01 and U24) award mechanisms.  
As an applicant, you will be primarily responsible for planning, directing, and 
executing the proposed project and/or conducting EDRN-initiated collaborative 
studies. The anticipated award date is March 1, 2005.    

This RFA uses just-in-time concepts. It also uses the non-modular budgeting 
formats. 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 
http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.

The NIH U01 and U24 are cooperative agreement award mechanisms.  In the 
cooperative agreement mechanism, the Principal Investigator 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 Principal Investigator, 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. 

FUNDS AVAILABLE

The NCI intends to commit approximately $7 million in FY 2005 to fund 8-15 new 
and/or competitive continuation grants in response to this RFA. An applicant 
may request a project period of up to 5 years. Because the nature and scope of 
the proposed research will vary from application to application, it is 
anticipated that the size and duration of each award will also vary. Applicants 
requesting more than $800,000 in direct costs for any year are encouraged to 
contact program staff prior to submitting the application.  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. 

ELIGIBLE INSTITUTIONS

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

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, but Domestic institutions may 
propose collaborations/consortia with foreign institutions
o Faith-based or community-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

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.

SPECIAL REQUIREMENTS 

Definitions

Awardee: The institution to which a cooperative agreement (U01 or U24) is 
awarded.
 
Principal Investigator (PI): The investigator who is designated by the 
applicant organization to direct the project to be supported by the U01 or U24 
grant. The PI will assume the responsibility and accountability to the 
applicant organization officials and to the NCI for the performance and the 
proper conduct of the research supported by the U01 or U24 mechanism in 
accordance with the terms and conditions that are stated in the RFA. The PI 
will be a voting member of the Steering Committee and will attend two Steering 
Committee meetings in the first year and two Steering Committee meetings and a 
workshop a year in subsequent years. Attendance at these meetings are required 
as part of this cooperative agreement.

NCI Program Director: A scientific administrator from the NCI extramural staff 
will provide normal stewardship for the U01 and U24 grants awardees.

NCI Program Coordinator:  A scientific 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 Steering Committee, as defined under the “Cooperative Agreement Terms 
and Conditions of Award.”  

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.

A. Rights and Responsibilities of Clinical Epidemiology and Validation Center 
Awardees 

Network Collaborative Studies:

The Centers will collaborate with other EDRN components to push promising 
biomarkers towards EDRN validation studies and provide EDRN investigators 
appropriate specimens for quick evaluation.

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

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

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

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

Individual Center Studies:

The PI of a Clinical Epidemiology and Validation Center will have the primary 
authority and responsibility to define the scientific objectives and approaches 
for the individual Center, including research design and protocol development, 
if applicable, participant recruitment and follow-up, data collection, quality 
control, and interim data and safety monitoring, and to plan, conduct, analyze, 
and publish results. The cohort or specimen repositories the Center establishes 
will provide specimens to address the scientific hypotheses of these studies, 
but the main portion of these specimens should be reserved for EDRN validation 
studies.  The PI will submit data on these resources to the EDRN-developed 
biorepository database on a monthly basis.

The PI of a Center will develop procedures for study monitoring to assure 
compliance with protocol designs and protection of patients from research risk.  
The PI of a Center will provide guidance to the investigators regarding 
clinical studies, including ethical issues involved in clinical research and 
conflict-of-interest considerations. 

The PI of a Center will assume responsibility for managing individual 
protocols/research and collaborative projects approved by the Steering 
Committee.  The PI of a Center will verify that participating sites have all 
relevant human risk assurance documents, as required, on file with the Office 
for Human Research Protections (OHRP), DHHS. 

The PI of a Center will submit the final protocol to the NCI for approval 
before the commencement of the study. Protocol must conform to the EDRN-
developed Common Data Elements (CDEs) for data collection. In case the CDEs are 
not available, the PI will work with the EDRN DMCC and NCI Program Coordinator 
to develop the CDEs.

The PI of a Center will monitor and maintain appropriate records for protocols, 
informed consents, assurances, and annual certifications of Institutional 
Review Board (IRB) review and approval (OMB No. 0990-0263, "Protection of Human 
Subjects, Assurance Identification/IRB Certification/Declaration of Exemption, 
(Common Rule) "http://www.hhs.gov/ohrp/humansubjects/assurance/OF310.rtf”) 
for all participating sites. 

The PI of a Center will assume responsibility and accountability to the 
applicant organization officials and to the NCI for the performance and proper 
conduct of the research supported by the U01 or U24 in accordance with the 
terms and conditions of the award. 

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

B.  NCI Extramural Staff Responsibilities 

There will be only one NCI Program Coordinator for the Network.  However, the 
Program Coordinator may be assisted by other NCI Program Directors and Staff on 
specific scientific issues as needed.

The NCI Program Coordinator will have substantial scientific programmatic 
involvement during conduct of this activity, through technical assistance, 
initiation of Network collaborative projects, data sharing and analysis, 
composition of reports, advice and coordination above and beyond normal program 
stewardship for grants as described below.  

Because of the Network’s diverse research agenda and the number of tasks that 
have to be accomplished to achieve its goals, a number of NCI staff members may 
interact with the Network as needed. The NCI Program 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.  A member from the Chemoprevention Branch, NCI, will be 
available to assist the Network on intermediate endpoints and on any ongoing 
chemoprevention trials relevant to the Network studies.  A member from the 
Biometry Branch, Division of Cancer Prevention, NCI will be available to assist 
the Network on the issues of study design, sample size, and other statistical 
computations. The other NCI staff may assist and advise the Network on relevant 
programmatic and scientific issues through the NCI Program Coordinator.

The Program Coordinator will convene the initial meeting of the Steering 
Committee, have voting membership on the Steering Committee, and, as determined 
by that committee, its subcommittees.
 
Although the PI will have lead responsibilities in all collaborative tasks and 
activities, it is anticipated that the NCI Program Coordinator will have lead 
responsibilities in managing and sharing the 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, 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

1. Steering Committee:  

The Steering Committee will have major scientific management oversight and 
responsibility for developing collaborative research designs, protocols and 
manuals, facilitating the conduct and monitoring of studies, and reporting 
study results. The Steering Committee will be composed of the Principal 
Investigators from each member of the Network, the Principal Investigator 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 Steering Committee.  The institution of the Chair of the Steering Committee 
will serve as the Headquarters (for definition see Network Organization).  
Subcommittees, including the existing ones, will be established/maintained by 
the Steering Committee, as it deems appropriate; the NCI Program Coordinator 
will serve on subcommittees as he/she deems appropriate.   

1. After all the Network components have been funded, the Steering Committee 
will convene.  Responsibilities of the Steering Committee include but are not 
limited to (investigators are encouraged to review the EDRN Manual of 
Operation)
(http://www3.cancer.gov/prevention/cbrg/edrn/organization.html#manual): 

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

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 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 Steering Committee may ask Biomarker 
Developmental Laboratories, or Clinical Epidemiology and Validation Centers to 
serve as a Biomarker Reference Laboratory on an as needed basis. The Steering 
Committee 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 validation. 

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

7. Collaborative studies/protocols will be approved by the Steering Committee. 
Data will be submitted centrally to the Data Management and Coordinating 
Center. The Steering Committee will define the rules regarding access to data 
and publications consistent with NCI policies. 

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

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

2. Network Consulting Committee:

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

2. The membership to the Committee and duration of service was established by 
the NCI in consultation with the Steering Committee.  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 Steering 
Committee 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 Steering Committee.

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

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

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

D. Arbitration
 
A panel will be formed to review any scientific or programmatic disagreement 
(within the scope of the U01 or U24 award) between the award recipients and the 
NCI.  The panel will be composed of three members: one selected by the Steering 
Committee (with the NCI Program Coordinator not voting), or by an individual 
U01 awardee in the event of an individual disagreement; a second member 
selected by the NCI; and, the third member selected by the two prior selected 
members.  Any disagreement that may arise on scientific/programmatic matters 
(within the scope of the award), between award recipients and the NCI may be 
brought to arbitration. 

This special arbitration procedure in no way affects the awardee's right to 
appeal an adverse action that is otherwise appealable in accordance with the 
PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 
16.
  
WHERE TO SEND INQUIRIES

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, peer 
review, and financial or grants management issues:

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

Sudhir Srivastava, Ph.D., MPH
Program Coordinator
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3142
Bethesda, MD  20892
Telephone:  (301) 435-1594
FAX:  (301)402-8990
Email: srivasts@mail.nih.gov

Paul Wagner, Ph.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3140
Bethesda, MD  20892
Telephone:  (301) 496-9424
FAX:  (301)402-8990
Email: wagnerp@mail.nih.gov

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
Telephone:  (301) 435-3110
FAX:  (301) 402-2117
Email: wp23x@nih.gov 

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 
Email: ncirefof@dea.nci.nih.gov 

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

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
Email: chuangk@mail.nih.gov

PRE-SUBMISSION MEETING

It is the intent of the program to hold a pre-submission meeting on about March 
15, 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.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes the 
following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
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
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3142
Bethesda, MD  20892
Telephone:  (301) 435-1594
FAX:  (301) 402-8990
Email: srivasts@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  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 
http://www.dunandbradstreet.com/. 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 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

SUPPLEMENTARY INSTRUCTIONS: 

Special Instructions for Preparation of the Application

For to this RFA, the format for the "Research Plan" of the PHS 398 grant 
application is changed.  Sections A. to D. of the Research Plan should be 
replaced with the following three sections; 1) Collaborative Clinical 
Validation Studies, 2) Research Plan for Clinical Biomarkers Validations 
Studies (Section 2 is only applicable to those applications proposing a 
specific scientific agenda to conduct clinical research on biomarker 
validation.), and 3) Compliance with terms of EDRN Cooperative Agreement. The 
remainder of the Research Plan, sections E. to I., remains the same.

Research Plan
Section 1 - Collaborative Clinical Validation Studies (maximum 10 pages)
a) Applicant:  Applicants should concisely describe what expertise the group 
encompasses, specialized or unique facilities, core resources, and services 
that are available to support their participation in EDRN collaborative 
validation studies. In this section, applicants should describe any ongoing 
grant-supported, institutional, or private sector resources that augment or 
complement resources for which funding from this RFA is sought.  The roles of 
all key personnel, collaborators, and consultants who are associated with the 
application may be briefly described.  This section should also clearly 
describe the formal organizational structure of the Center, including lines of 
authority and responsibility, with particular attention to the relationship of 
the organizational structure to the Center's major objectives. 

b) Patient accrual:  All applicants must document their ability to recruit 
patients, procure specimens prospectively, collect epidemiological and clinical 
data using EDRN-developed Common Data Elements 
(http://www3.cancer.gov/prevention/cbrg/edrn/press.html) and process, track, 
and store specimens.  The distribution of specimens collected through EDRN will 
be governed through the EDRN-established procedures, and the EDRN Executive 
Committee will be the final decision body. If the applicants already have 
specimen repositories which they are willing to make available to ERDN-
collaborative studies, they should describe the purpose of the study(s) from 
which samples are being made available and the extent of the clinical 
information collected. Applicants must also describe and submit the 
distribution policy and procedures for their existing resources. The applicants 
must describe their plan to work with the EDRN Steering Committee and how their 
specimen distribution will be coordinated through their committee. The 
applicants should answer questions concerning which committee will have the 
veto power in case of a disagreement. 

Applicants should describe the experience of their group in collaborative 
programs and activities with academic and industry partners. Some examples of 
collaborations that may be provided in support of the application are listed 
below:

o  demonstrated evidence of specimens collection and patient accrual
history
o  demonstrated evidence of collaborative projects and publications
o  demonstrated evidence of collaborative funding
o  sharing of data and resources, e.g., specimens, technology, research 
protocols
o  past participation in multi-center trials

For competing renewal applications, applicants should describe their 
participation in the EDRN activities, and the contributions in terms of 
collaborations within and outside the Network in meeting the EDRN missions (see 
EDRN Second Report, 
http://www3.cancer.gov/prevention/cbrg/edrn/edrn_report2002.pdf, Metrics for 
Programmatic Evaluation).

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

Section 2 - Research Plan for Clinical Biomarkers Validations Studies (maximum 
25 pages): This section is only applicable to those applications proposing to 
develop a scientific agenda to develop EDRN-defined Phase II and Phase III 
studies. 

Applicants should concisely describe the Center's proposed research objectives.  
Depending on the composition and structure of the group, this section may be 
organized as distinct projects or as one integrated plan; in either case, the 
page limitation is the same. 

Applicants must describe the significance, background, rationale, and 
approaches for the proposed studies.  For competing renewal applicants, this 
section should have a description of the goals of the previous grant and 
include the scientific progress from the previous project period.  Indicate the 
status of developed markers according to the biomarker developmental phases 
(Pepe et. al., 2001).  Applicants should highlight their progress using the 
EDRN-developed Evaluation Metrics 
(http://www3.cancer.gov/prevention/cbrg/edrn/edrn_report2002.pdf).

Applicants should define the major research questions and opportunities related 
to objectives of EDRN that their group effort proposes to undertake.  
Applicants should describe the approaches to be taken by the group in the 
aggregate or as inter-dependent projects, and should describe the rationale for 
approaches to be used.  Applicants are encouraged to use this section of the 
application to highlight how the diverse expertise of the group members 
contributes to the innovation of which the group is capable, the flexibility 
they possess to redirect research when scientific progress warrants it, and 
their ability to anticipate new directions, based on their individual 
experience and ability to contribute to a collective effort.  The roles and 
expertise of all key personnel, collaborators, and consultants who are 
associated with the application should be documented; letters from 
collaborators and consultants should be included in Section I of the research 
plan as specified in the instructions for the Form PHS398 application.  

Applicants should list and summarize each of the agreements with industry 
collaborators, including a description of the materials, technologies and/or 
expertise to be provided by such collaborators. Detailed documentation of 
license agreement(s), intellectual property arrangements, and data sharing 
concerning the proposed or existing collaboration with industrial partner(s) 
will be requested as appropriate if an applicant is selected for consideration 
for funding. These documents must be submitted by the Institutional Technology 
Transfer Office.

Awardees under the auspices of this RFA should obtain appropriate licenses for 
technologies that are necessary for the conduct of the proposed research so 
that the goals that are proposed can be accomplished.  A statement from the 
applicant institution to that effect is required in the letter to be appended 
to Section 3.

Section 3 – Compliance with terms of EDRN Cooperative Agreement (maximum 10 
pages):  Specific issues related to cooperative agreements must be addressed in 
this section. 

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 Steering Committee and be bound by its decisions, and to share 
data and research resources with each other and the NCI. Successful applicants 
will be expected to submit (via the internet) information on specimen 
collections per the Network’s Common Data Elements and register their protocols 
with the Network’s Data Management and Coordinating Center. Applicants should 
state their willingness to adapt their data management system so that it is 
compatible with EDRN data infrastructures. 

At the end of this section, applicants must append a letter from the applicant 
institution describing how that institution intends to meet 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 
(http://grants.nih.gov/grants/policy/data_sharing/index.htm and 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html), 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. The new policy becomes effective with the October 1, 2003 
receipt date for applications or proposals to NIH.  

Applicants to this RFA must also include a research tools and resources sharing 
plan in the letter to be appended to this section.  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. NIH recognizes that certain research 
activities may result in inventions and that grantees are entitled to protect 
such inventions through patenting and licensing activities in accordance with 
the Bayh-Dole Act, 35 USC § 200 et seq. and the implementing regulations, 37 
CFR Part 401 (“Bayh-Dole Act”). However, the EDRN’s core mission of 
collaboration both between Network members and between Network members and 
third party industry partners necessarily anticipates the sharing of 
intellectual property arising out of research resources developed in Network-
related activities.  To address the interest in assuring that research 
resources are accessible, NIH 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 (described 
below), should any be generated through this grant, while making such research 
resources available to the broader scientific community.

The sharing of research resources and intellectual property plans 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 (http://grants.nih.gov/grants/policy/nihgps/) and the 
Principles and Guidelines for Recipients of NIH Research Grants and Contracts 
on Obtaining and Disseminating Biomedical Research Resources: Final Notice, 
December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html and 
http://ott.od.nih.gov/NewPages/64FR72090.pdf)(“NIH Research Tools Guidelines”).  
These documents define terms, parties, and responsibilities.  The documents 
also 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,
(http://www.iedison.gov); 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 
research tools sharing plan must explain how such collaborations will not 
restrict their ability to share research materials produced with NIH funding. 
NCI believes that applicants can satisfy the requirement to submit the research 
resources plan and intellectual property plan in a number of ways. 

GUIDANCE FOR PREPARATION OF RESEARCH RESOURCES PLAN AND INTELLECTUAL PROPERTY 
PLAN

The EDRN is premised on the belief that an established integrated, multi-
disciplinary environment will expedite clinical applications of biomarker 
research.  Comprised of thirty-one principal members, the EDRN is organized in 
four components: eighteen Biomarker Developmental Laboratories, three Biomarker 
Validation Laboratories, nine Clinical and Epidemiology Centers, and one Data 
Management and Coordination Center.  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/company collaborations have been 
harder to implement. 

The NCI recognizes the rights of applicants under the Bayh-Dole Act to elect 
title to inventions made with federal funds by their investigators, which 
rights must be exercised in accordance with the NIH grants policy, including 
the NIH Research Tools Guidelines.  These guidelines in turn require 
investigators to make unique research resources readily available for research 
purposes to qualified individuals within the scientific community. NIH 
encourages the filing of patent applications on unique research resources if 
doing so will aid in the prompt commercialization of diagnostic, prognostic or 
therapeutic products.  Institutional ownership of such inventions may be of 
concern to collaborators, especially those who are the source of proprietary 
biomarkers, reagents, and/or technologies.  Since active involvement by the 
industrial laboratories is critical to the EDRN’s objective of basic research 
and development of new biomarkers/reagents, it is essential that applicants 
provide plans to assure both adequate patent coverage and opportunities to 
license such patent rights, as appropriate, 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.  The following guidance is intended 
to assist applicants in their preparation of the required intellectual property 
plan.

Each applicant, therefore, must provide a description of the approach to be 
used for licensing patented inventions developed through EDRN activities.  This 
requirement may be easily satisfied when the applicant’s plans involve 
collaboration with a single industry partner.  Attention is drawn to the 
approach utilized by the NCI’s Cancer Therapy Evaluation Program (CTEP), which 
obtains the voluntary agreement of participating extramural grantees to grant 
exclusive options to negotiate exclusive, world-wide, royalty-bearing licenses 
for all commercial purposes, including the right to grant sub-licenses, to all 
inventions resulting from the use of compounds supplied by collaborators.  For 
more information, including the specific terms of the intellectual property 
option (”IP Option”) granted voluntarily by NCI CTEP grantees, please see the 
CTEP website (http://ctep.cancer.gov/industry/ipo.html).  However, since 
multiple institutions and industry collaborators may be involved in a plan to 
develop diagnostic assays based on novel biomarkers, developed in part with 
proprietary biomarkers/reagents/technologies supplied by their collaborators, 
the situation can become quite complex. Under these circumstances, applicant’s 
institution might want to use the IP Option to license inventions within narrow 
fields of use so as not to preclude additional individual collaborations with 
other companies to develop these inventions.  Alternatively, applicant’s 
institution could enter into a multi-party agreement that appropriately 
incentivizes the companies for moving the products forward.  Possible 
approaches include: (i) granting an IP Option to each individual company for an 
exclusive commercialization license relating solely to such company’s product; 
or (ii) an IP Option for a co-exclusive license of intellectual property 
relating to a combination of products.  In situations where multiple patents 
are involved but exclusive (or co-exclusive) access is not required, applicants 
and their collaborators may wish to explore the creation of patent pools, which 
would enable all necessary patents relating to a technology to be licensed 
nonexclusively at reasonable royalty rates.  For more information on the use of 
patent pools for biotechnology patents, see  
(http://www.uspto.gov/web/offices/pac/dapp/opla/patpoolcover.html; 
http://www.uspto.gov/web/offices/pac/dapp/opla/patentpool.pdf); see also, 
“Antitrust Guidelines for the Licensing of Intellectual Property”, issued by 
the US Department of Justice and the Federal Trade Commission (April, 1995) 
(http://www.usdoj.gov/atr/public/guidelines/ipguide.pdf); “Antitrust Guidelines 
for Collaborations Among Competitors”, issued by the Federal Trade Commission 
and the U.S. Department of Justice (April, 2000) 
(http://www.ftc.gov/os/2000/04/ftcdojguidelines.pdf).  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 (http://www.hhs.gov/ohrp/assurances/assurances_index.html) 
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 
(http://www.hhs.gov/ocr/hipaa).

Regardless of the structure of the arrangement, the scope of the 
commercialization license should be commensurate with the research plan and 
relate to the proprietary product (drug, test, device, etc.) of the 
collaborator(s).  In addition, institutions should reserve a research use 
license for any resulting inventions in the final negotiated commercialization 
license, which ideally should include the right to share such inventions with 
others for noncommercial purposes.   In the event that institutions desire to 
use intellectual property resulting from such collaborations for the benefit of 
third parties for commercial purposes, they will want to obtain the consent of 
the relevant industry collaborators before doing so.

The foregoing guidance is provided by way of example to assist applicants in 
preparing the required research resources sharing and intellectual property 
management plans in a manner that encourages partnerships with industry. While 
these approaches will likely suit most situations, these approaches are not 
exclusive and applicants should feel free to submit alternative versions for 
consideration.

Budget:

Those applications that propose to function solely as a Resource Center and do 
not propose a specific scientific research agenda in biomarker validation 
should budget only for applicable administrative costs and travel expenses.  
When they join an EDRN collaborative study, funds will be allocated from EDRN 
core funds to cover costs of specimen collection, clinical testing, data 
management, etc.

1. Applicants must budget for travel and per diem expenses for Steering 
Committee meetings. In the first year, applicants should plan for two 
investigators, the Principal Investigator and an additional senior 
investigator, to attend a Planning Meeting and two Steering Committee meetings. 
In the second and subsequent years, applicants should plan for the PI and 
another investigator to attend two Steering Committee meetings per year.

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

3. Applicants (except those resource centers requesting only administrative 
costs and travel expenses) must set aside funds for Network Collaborative 
studies as follows:

o Competing renewal applicants, who are participating in ongoing validation or 
collaborative studies, should set aside funds that were approved by the NCI 
program staff for the years of these ongoing studies, otherwise they should set 
aside 20% of their annual budgets for Network collaborative studies.

o New applicants should set aside 20% of their annual budgets from the second 
year onward for Network collaborative studies. 

The use of these set aside funds will be restricted and must be reviewed and 
approved by the Steering Committee and then recommended to, and approved by the 
NCI for release from the individual U01 awards. Indicate this amount in the 
Other Expenses category under the heading ‘Network Collaborative Funds.’

4. Applicants must budget for data collection on relevant common data elements 
(CDEs) for specimens during the course of study. For CDEs, please visit the 
EDRN web site (http://www.cancer.gov/edrn). 

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-05-005 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, 
THE EARLY DETECTION RESEARCH NETWORK: CLINICAL EPIDEMIOLOGY AND VALIDATION 
CENTERS, and number, RFA CA-05-005, must be 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:  http://grants.nih.gov/grants/funding/phs398/labels.pdf.

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
Rockville, MD 20852 (express courier)
Bethesda MD 20892-8329

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

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE 
WILL NO LONGER BE ACCEPTED.  This policy does not apply to courier deliveries 
(i.e., FEDEX, UPS, DHL, etc.)
(http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html)  
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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.

APPLICATION PROCESSING:  Applications must be received on or before the 
application receipt date, June 14, 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. 

PEER REVIEW PROCESS  

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

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; and
o Receive a second level review by the National Cancer Advisory Board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In the 
written comments, reviewers will be asked to evaluate the application in order 
to judge the likelihood that the proposed research will have a substantial 
impact on the pursuit of these goals.  The scientific review group will address 
and consider each of these criteria in assigning the application’s overall 
score, weighting them as appropriate for each application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority score.  
For example, an investigator may propose to carry out important work that by 
its nature is not innovative but is essential to move a field forward.

All applications will be evaluated on issues related to patient accrual, 
collection of clinical data using EDRN-developed Common Data Elements 
(http://www.cancer.gov/edrn) and collaboration within the network. Applications 
proposing to develop a specific scientific agenda to conduct clinical research 
on biomarker validation, EDRN-defined Phase II and/or Phase III studies, will 
also be evaluated on the proposed research.

Although the applications will be peer-reviewed, all validation protocols, 
patient accruals, and data collection will also be reviewed by the EDRN 
Steering Committee, the DMCC, and NCI Staff in order to meet the Network-
established guidelines prior to initiation of the study.

1.  Significance:  
All applications: Are the types and numbers of patients or longitudinal samples 
to which the applicants have access relevant to EDRN validation studies?  Are 
they unique or difficult to obtain?

Applications proposing a scientific agenda in biomarker validation: Does the 
proposed clinical epidemiologic research address an important need for earlier 
cancer detection and risk assessment? What is the immediacy of the research 
opportunity in light of the EDRN-established phases of biomarker development 
for early detection of cancer? Over the project period, is there potential for 
the applicant to develop biomarkers/reagents other than those specified in the 
application?

2.  Approach:  
All applications: Are issues related to specimen collection, clinical testing, 
and data management adequately addressed? Are the plans for recruitment of 
special populations including both genders and minorities and relevant 
subgroups adequate and appropriate for the scientific goals of the research? Do 
the applicants present a sound plan for patient recruitment, retention, and 
follow up, for high quality specimen collection, processing, and storage, and 
for obtaining high quality clinical and epidemiological information linked to 
specimens? Do appropriate quality assurance and quality control programs exist, 
including on-site audits that assure high-quality research and patient safety? 
Are institutional data management and statistical analyses, procedures, and 
policies adequate, appropriate, and consistent with accepted standards? Will 
the Network collaboration be utilized when necessary to satisfy the 
requirements for timely completion of proposed studies? Has the applicant 
adequately addressed his/her institutional patent policy? 

Are the plans for administering and organizing the Center adequate and 
appropriate? Will these plans allow it to meet the Network's major objectives? 
Are the Center's organizational and administrative plans likely to lead to a 
well functioning, cohesive research group? 

Are there adequate plans for effective interaction and coordination with the 
Network components, the Steering Committee, the Data Management and 
Coordinating Center and the NCI?  Do the investigators state their willingness 
to collaborate and share information? Do the investigators state their 
willingness to share specimens and data in collaborative EDRN-validation 
studies? Do the investigators state their willingness to abide by the 
priorities and policies agreed upon by the Steering Committee for collaborative 
studies?  Have the applicants proposed sound strategies for communication among 
themselves, with the other Network components, and with the NCI? Have they 
agreed to adapt their data management system to be compatible with EDRN data 
infrastructure?

Applications proposing a scientific agenda in biomarker validation: 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? Are the criteria 
chosen to characterize the biomarker(s)/reagent(s) sufficient and appropriate? 
Can the proposed method(s) be used to measure the biomarker(s) in a clinical 
setting? Do the biomarker(s)/reagent(s) have the potential to detect incipient 
neoplastic lesions or to be useful for cancer risk assessment?  Will the Center 
be able to carry out its planned studies in a reasonable period of time? 

3.  Innovation: 
All applications: Do the applicants propose innovative or novel approaches to 
patient accrual and/or specimen collection?

Applications proposing a scientific agenda in biomarker validation: Does the 
project employ novel concepts, approaches or methods? Is the project original 
and innovative? Does the project challenge existing paradigms or develop new 
clinical parameters? Will the approaches advance the field of biomarkers in the 
context of early cancer detection and risk assessment? 

4.  Investigators:  
All applications:  Are the principal investigator and collaborators 
appropriately trained and well suited to carry out this work? Have 
collaborations been established or consultants identified who will provide the 
appropriate depth and breadth of scientific expertise required for the project? 
Will these investigators contribute unique skills to the overall Center and to 
the Network? Will they provide guidance to other collaborators regarding 
clinical studies, including ethical issues involved in clinical research and 
conflicts of interest?

Applications proposing a scientific agenda in biomarker validation:  Are the 
numbers and roles of staff for each study defined and justified? Do their 
research experience and qualifications demonstrate understanding of biomarkers 
research, of the design, administration, and analysis of multi-institutional 
clinical research, and of laboratory studies? 

5.  Environment:  
All applications: Are the facilities appropriate to support the endeavor? Does 
the scientific environment in which the research will be done contribute to the 
likelihood of success? Do the principal investigator and collaborators have 
access to the appropriate patient populations? Does the applicant have access 
to pathology review and documentation of the pathology report? Does the 
applicant have access to treatment information and other necessary patient 
data, such as medical history? Do they have a good biorepository, in 
particular, of preclinical samples?

Do the proposed experiments take advantage of unique features of the scientific 
environment and incorporate the appropriate collaborative arrangements? Is 
there evidence of institutional support? Is there institutional support for 
computer services including Internet access? Are the PI and collaborators 
willing to use common (paper or electronic) forms required for the collection 
of collaborative Network study data? 

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

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
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.)
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans 
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, 
below.)

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 

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 Federal Citations, below.)

Budget. Does the apportionment of the budget for clinical epidemiologic and 
validation research indicate that the applicants understand the requirements of 
managing the Centers within the Network enterprise? Is the commitment of effort 
appropriate to the scope of the project? 

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: May 14, 2004
Application Receipt Date: June 14, 2004
Peer Review Date: October/November 2004 
Council Review: February 16, 2005
Earliest Anticipated Start Date: March 1, 2005 

AWARD CRITERIA

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

o Scientific merit (as determined by peer review);
o Availability of funds; and
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

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 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.

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); 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: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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 principal 
investigator/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: 
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm.  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: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.  
Information concerning essential elements of data safety monitoring plans for 
clinical trials funded by the NCI is available:  
http://www.cancer.gov/clinical_trials/.

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. 
http://grants.nih.gov/grants/policy/data_sharing  
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.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.   
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 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
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 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH policy 
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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A 
continuing education program in the protection of human participants in 
research is available online at: http://cme.nci.nih.gov/ .

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).  
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 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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. 

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
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 
(http://www.hhs.gov/ocr/) 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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

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 http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at http://www.cfda.gov/ 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 http://grants.nih.gov/grants/policy/policy.htm .

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 
people.

References

Srivastava, S. 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. 

The Early Detection Research Network: Translational Research to Identify Early 
Cancer Risk; NCI Publication No. 01-4852, August 2001.


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