THE EARLY DETECTION RESEARCH NETWORK: BIOMARKER DEVELOPMENTAL LABORATORIES
 
RELEASE DATE:  September 22, 2003
 
RFA Number:  RFA-CA-04-006 (see reissue RFA-CA-05-023)

Department of Health and Human Services (DHHS)
 
PARTICIPATING ORGANIZATIONS:

National Institutes of Health (NIH) 
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:

National Cancer Institute (NCI) 
 (http://www.nci.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.394
 
LETTER OF INTENT RECEIPT DATE: December 23, 2003
APPLICATION RECEIPT DATE:  January 23, 2004

This RFA is a reissue of RFA CA-98-028, which was published in the NIH Guide on 
January 20, 1999.

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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 and NIH intramural 
applications to continue the national Network that has the responsibility for 
the development, evaluation, and validation of biomarkers for earlier cancer 
detection and risk assessment. Biomarkers are defined as cellular, biochemical, 
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 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, and 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, 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 is to invite new and competing 
renewal applications for the Biomarker Developmental Laboratories. A subsequent 
Request for Applications will be issued to establish the Biomarker Reference 
Laboratories, Clinical Epidemiology and Validation Centers, and the Data 
Management and Coordinating Center.  Applicants are encouraged to seek funding 
to participate in more than one component, because it is recognized that 
collaboration already exists in individual institutions for clinical testing 
and validation of biomarkers/reagents.

RESEARCH OBJECTIVES
 
A. Background

The Network has a straightforward mission: 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 Early 
Detection Research Network (EDRN) seeks to give treatments the opportunity to 
work and to make prevention 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 first identify, and then validate, crucial 
molecular markers to detect cancer and to assess cancer risk.  The Network is 
an investigator-initiated Network for collaborative research to link the 
discovery of biologic markers directly to the next steps in the process of 
developing early detection tests. The power of bioinformatics and computer-
assisted programs are being put to full use to analyze Network data and to 
facilitate faster answers to key questions.  New technologies, such as 
genomics, epigenomics, and proteomics are able to identify genetic as well as 
antigenic changes during the early stages of malignant progression. Some of 
these changes show promise as biomarkers for preneoplastic development or for 
early malignant transformation. The application 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 our 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 for clinical 
application is now greater than ever. Early detection technologies are also 
rapidly evolving while existing technologies are undergoing progressive 
refinement in their sensitivity, specificity, and high-throughput. Improved 
analytic tools have allowed a more detailed examination of the molecular basis 
of carcinogenesis and provided the ability to identify the molecular and 
cellular signatures of cancer and to explore the gene-environment interaction 
relevant to early detection. To explore fully the application of molecular 
profiles for earlier detection and risk assessment, it is essential to 
understand the molecular pathogenesis of cancer, that is, the natural history 
of tumor progression at the molecular level, so that the biological behavior of 
an evolving lesion (for example, dysplasia or field change) can be predicted 
with greater accuracy. Current observations indicate that cancers usually 
evolve through many complex cellular processes, pathways, and networks. A 
better understanding of the circuits in these pathways is critical if we are to 
successfully apply these molecular-based technologies to earlier detection.

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, and therefore 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.,(2001). Phases of biomarker 
development for early detection of cancer. J Natl Cancer Inst. 93, 1054-1061). 
These phases are:

Phase I: exploratory studies to identify potentially useful biomarkers– the 
"discovery" phase. 
Phase II: biomarkers are studied to determine their capacity 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 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, to application. The pace at which molecular 
signatures, e.g., proteomics, genomics, associated with causal pathways and 
processes are identified 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 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, technology 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: Structured around four main components, the Network 
currently includes 18 Biomarker Developmental Laboratories (BDLs), three 
Biomarker Validation Laboratories (BVLs), nine Clinical and Epidemiologic 
Centers (CDEs), 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).  (See 
previous RFA BDL: 
http://grants.nih.gov/grants/guide/rfa-files/rfa-ca-98-028.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 BVL: 
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-99-008.html)

o	The Clinical/Epidemiologic Centers (to be replaced by Clinical Epidemiology 
and Validation Centers in reissuance) conduct early phases (Phase II and Phase 
III) of clinical validation and epidemiological research into the application 
of biomarkers. (See previous RFA 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 
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 serve 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); and the Jet Propulsion Laboratory (JPL), NASA, which 
provides informatics support. 

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

Each laboratory/center, which will be managed by a Principal Investigator, may 
include academic and industrial biotechnology investigators who are involved in 
cancer detection and diagnostic research. In order to expedite the 
translational research, the 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, conducts analysis 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, and 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, 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 will have funds available through the individual 
U01 awards to support the development of the scientific program and clinical 
protocols. All investigators will be encouraged to seek supplemental funding 
through the Small Business Innovation Award (SBIR, R43 and/or R44), Small 
Business Technology Transfer (STTR, R41 and/or R42), Exploratory/Developmental 
grants (R21/R33), and other research support mechanisms.

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. Funds are needed in moving a new marker test to the point at which it can be 
validated at multiple centers and in larger populations. Test reagents will 
require scale-up at this point, and the Steering Committee will require 
sufficient funding to contract to commercial laboratories or companies that can 
scale up production and maintain quality of the reagents (e.g., monoclonal 
antibodies, labels, etc.) and to Clinical Epidemiology and Validation Centers 
for subject accrual.  Funds will also be required for data management, travel, 
meetings, and other collaborative activities of the Network. 

Supplements from the Core Funds will 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., By 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 Supplemental 
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-98-028.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 innovation, and collaboration to 
accelerate the development 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, 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, which will serve as background information for 
subsequent large definitive validation studies in the field of cancer detection 
and screening; 

o	collaboration among academic and industrial leaders in molecular biology, 
molecular genetics, 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 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 (e.g., 
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 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 Biomarker Developmental 
Laboratories (BDL) which form one of the four scientific components within the 
Network. In the context of this RFA, development will encompass correlative 
study to further develop and validate biomarkers initially identified or 
characterized by applicants themselves or by other investigators in accordance 
with the Phase I and Phase II of the Biomarker Development Guidelines (Pepe et. 
al., 2001). The BDL will conduct translational research in the biology of 
incipient neoplasia encompassing the development, characterization and testing 
of biomarkers of early cancer or risk, development of relevant technologies for 
biomarker detection, and analytical tools for the evaluation of biomarkers. 
Translational research in this context is defined as the movement of 
discoveries from the laboratories into patient or population research settings 
or the movement of observations from patient settings back to the laboratory. 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 detail see section 
ADVANCING DISCOVERY AND ITS APPLICATION in the Plans and Priorities for Cancer 
Research (http://plan.cancer.gov/):

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

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

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

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

This RFA encourages the submission of applications in broad categories of 
translational studies on complex cellular pathways, processes, and networks to 
identify the molecular and cellular signatures of cells which can be used for 
earlier detection or for risk assessment. The scope of the BDL is focused on 
translational research leading to identification and/or characterization of 
biomarkers or to a panel of biomarkers (Phase I and Phase II). Special emphasis 
should be placed on cancers of common occurrence, such as prostate, breast, 
colon, lung, ovary, upper-respiratory tract, pancreatic, bladder; and other 
less prevalent epithelial cancers, which are the major causes of cancer-related 
mortality and have yet to be controlled with screening and prevention.  
These activities may include, but are not limited to:

I.  Development of comprehensive panels of biomarkers/methods to identify 
molecular changes, e.g., gene mutations, changes in gene and protein 
expressions, and epigenetic changes associated with early stages of cancer.

o	Identify and evaluate molecular fingerprints/expression profiles of genomic, 
proteomic and epigenetic alterations in tissue and body fluids, i.e., sputum, 
urine, pancreatic juices, serum and plasma.

o	Develop panels of biomarkers that can effectively identify early disease 
phenotypes or pre-cancerous lesions involving abnormalities in many biological 
processes.

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

o	Identify and evaluate molecular, genetic and cytologic markers of risk of 
impending cancer, and risk of progression to cancer.

o	Determine membrane and membrane-associated proteins and profiles, and other 
macromolecules that correlate with the presence of pre-cancerous and cancerous 
lesions.

II. Identification and evaluation of molecular profiles for risk stratification 
by improving pathological classification of early lesions. Expand marker 
identification to predict early stages of disease and risk of recurrence.

o	Develop molecular markers that can augment or replace tissue-based assays.

o	Develop markers/methods to improve current methods or modalities of 
detection.

III. Development of highly specific and sensitive assays/biomarkers to detect 
molecular alterations in circulating nucleic acids and cells in body fluids, 
including serum and plasma.

o	Develop reagents/biomarkers to detect cancer-specific signatures that may 
signal the presence of small numbers of premalignant cells. 

IV. Development of highly specific and sensitive markers to detect molecular 
products of tumor cells in body fluids with emphasis on the identification of 
molecular determinants in accessible surrogate anatomic sites for the less 
accessible major cancer sites.

V. Study of molecular signatures to identify risk and early stage disease due 
to infectious agents, pathogens and other environmental agents.

Other approaches for the development of biomarkers for early detection of 
cancer and identification of cancer risk will be accepted as well. However, the 
application should clearly delineate the time-line for biomarkers development 
from Phase I, to Phase II to Phase III. Decision criteria should be developed 
to triage biomarkers that are not relevant to identification of risk and 
detection of cancer at earlier stages. The search for new markers should 
reflect new information about key points in cancer biology (i.e. molecular 
pathogenesis, apoptosis, cell cycle control). However, this RFA will not 
support research of a fundamental nature, such as studies on growth regulation, 
cell cycle control, or other basic studies that are not explicitly focused on 
early detection and risk identification in humans. To expedite clinical 
application, the validation of the biomarkers will be performed in 
collaboration with the other scientific components of the Network.

For discovery of technology and molecular tools, applicants are encouraged to 
develop collaboration with investigators participating in various NCI-sponsored 
programs, such as the Innovative Molecular Analysis Technology (IMAT) 
(http://otir.nci.nih.gov/tech/imat.html), and Unconventional Innovative Program 
(UIP) (http://otir.nci.nih.gov/tech/uip.html). Some of the emerging 
technologies, such as nanotechnology, could offer important new tools for 
detection where existing and more conventional technologies may be reaching 
their limits. Applications employing nanotechnology to provide direct readout 
of genomic, proteomic, and epigenomic information both at the single cell and 
single molecule level are encouraged. Applicants must advise any collaborating 
SPOREs, IMAT, or UIP investigators that, with respect to these collaborations, 
their institutions will be subject to the resource sharing and intellectual 
property requirements set forth in Section 3 of the Supplemental Instructions 
of this RFA.

MECHANISM OF SUPPORT
 
This RFA will use the NIH Cooperative Agreement (U01) award mechanism.  As an 
applicant, you will be primarily responsible for planning, directing, and 
executing the proposed project. The anticipated award date is September 30, 
2004.  The RFA may be reissued in the future, contingent upon the availability 
of funds.  

This RFA uses just-in-time concepts.  It also uses the non-modular budgeting 
formats (see http://grants.nih.gov/grants/funding/modular/modular.htm ).  
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) is a cooperative agreement award mechanism.  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 five years. If the 
NCI does not continue the program, awardees may submit grant applications 
through the usual investigator-initiated grants program.  However, before 
submitting such an application, applicants are advised to contact Program 
Coordinator listed under the INQUIRIES section listed below. 

FUNDS AVAILABLE
 
The NCI intends to commit approximately $7 million in FY 2004 to fund 16-18 new 
and/or competitive continuation grants in response to this RFA. An applicant 
may request a project period of up to five 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. 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. At this time, the 
NCI has not determined whether or how this solicitation will be continued 
beyond the present RFA and related RFAs for the Network.
 
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 or foreign institutions/organizations
o Faith-based or community-based organizations 

Domestic institutions may propose collaborations/consortia with foreign 
institutions and vice versa. 

For this RFA, teams composed of NIH intramural investigators may submit project 
applications to become components of the Network, but they may not request or 
receive funds from this program. The intramural applicant will not compete for 
extramural funds in keeping with NIH policy. 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.   

The NCI encourages applications from extramural and NIH intramural scientists 
with broad expertise in the biology of cancer detection and risk assessment. 
Researchers in NIH intramural laboratories may submit applications. However, 
they may not receive salary, equipment, supplies, or other remuneration from 
the extramural RFA set-aside funds for this program.  An NIH intramural PI must 
obtain the approval of her/his NIH Scientific Director, or a designated 
official to allocate resources to the project, and must follow both the general 
application format instructions and the additional guidelines for NIH 
intramural project applications under    "ADDITIONAL INSTRUCTIONS".  NIH 
intramural project applications will be reviewed and scored with the U01 
applications. The NIH intramural projects selected by the NCI to be components 
of the EDRN will participate in a manner that is analogous to the U01 awardees.

SPECIAL REQUIREMENTS 

Definitions

Awardee: The institution to which a cooperative agreement (U01) is awarded.
 
Principal Investigator (PI): The investigator who is designated by the 
applicant organization to direct the project to be supported by the U01 grant 
or NIH intramural project in response to the RFA. The PI will assume the 
responsibility and accountability to the applicant organization officials and 
to the NCI for the performance and the proper conduct of the research supported 
by the U01 mechanism or the NIH intramural project in accordance with the terms 
and conditions that are stated in the RFA. The PI will be a voting member of 
the Steering Committee.

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

NCI Program Coordinator:  A scientist administrator from the NCI extramural 
staff, the Program Coordinator will be substantially involved in the scientific 
coordination and collaboration within the Network, will have responsibilities 
in broad scientific and programmatic issues, and will serve as a voting member 
of the 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."].

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

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

A. Awardee Rights and Responsibilities: Extramural and NIH Intramural Projects 

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

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

The PI of a U01 or NIH Intramural project will serve as a voting member of the 
steering committee will attend the Planning meeting and two Steering Committee 
meetings in the first year and two Steering Committee meetings per year and the 
EDRN-Sponsored Gordon Conference every 18 months in subsequent years. The 
attendance of PI at these meetings is considered an essential part of the 
grant.

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

The PI of a U01 or NIH Intramural project will retain custody of and have 
primary rights to the data developed under these awards, subject to Government 
rights of access consistent with current HHS, PHS, and NIH policies. 
 
The PI of a U01 or NIH Intramural project will be responsible for collaborating 
on common research designs or protocols, including methods and requirements for 
joint participation and collaboration as directed by the Steering Committee, 
and handling of data, including appropriate sharing of methods and data among 
collaborating organizations and submission of protocols to DMCC. 

Network Collaborative Studies:

The PI of a U01 or NIH Intramural project will be responsible for accepting 
and implementing the goals, priorities, common protocols, procedures, and 
policies agreed upon by the Steering Committee for the Network collaborative 
studies. In some cases, the PI may be asked to serve as a lead investigator 
for the Network collaborative studies. 
The PI of a U01 or NIH Intramural project will ensure Network and NCI review 
and approval of protocol, concepts, final protocol documents, informed 
consents, and study amendments, and advise NCI of changes in protocol status.

The PI of a U01 or NIH Intramural project will be responsible for 
collaborating on common research designs or protocols, including methods and 
requirements for joint participation and collaboration as recommended by the 
Steering Committee, and handling of data, including appropriate sharing of 
methods and data among collaborating organizations. 

The PI of a U01 or NIH Intramural project will be responsible for accruing 
subjects on collaborative studies approved by the Steering Committee.

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, 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.   

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

o update and refine established Network policies and procedures;

o update and refine established policies and procedures for collaborative 
projects, protocols, and Network-defined projects;

o update and refine 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 update and refine established standards or "decision criteria" for validating 
biomarkers/reagents for further clinical studies, such as testing early 
detection strategies, or as risk factors;

o update and refine 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. 

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.

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

Any disagreement that may arise based on scientific/programmatic matters 
(within the scope of the award), between award recipients and NCI may be 
brought to arbitration. An arbitration panel will  be formed to review any 
scientific or programmatic disagreement (within the scope of the U01 award or 
the NIH Intramural Project), between U01 awardees or NIH intramural projects 
and the NCI.  The arbitration 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 or NIH intramural project in the event 
of an individual disagreement; a second member selected by the NCI; and, the 
third member selected by the two prior selected members.   

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, 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
Building 6130 Executive Boulevard Room 3142
Bethesda, MD  20892
Telephone:  (301) 435-1594
FAX:  301-402-8990
Email: srivasts@mail.nih.gov

Mukesh Verma, Ph.D.
Division of Cancer Prevention
National Cancer Institute
Building 6130 Executive Boulevard Room 3144
Bethesda, MD  20892
Telephone:  (301) 496-3893
FAX:  301-402-8990
Email: vermam@mail.nih.gov

Jacob Kagan, Ph.D.
Division of Cancer Prevention
National Cancer Institute
Building 6130 Executive Boulevard Room 3146
Bethesda, MD  20892
Telephone:  (301) 496-9541
FAX:  301-402-8990
Email: kaganj@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
Executive Plaza South, 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, MSC 8329
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
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-2784
FAX:  (301) 496-8601
Email: chuangk@mail.nih.gov

LETTER OF INTENT
 
PRE-SUBMISSION MEETING

It is also the intent of the program to hold a pre-submission meeting on 
November 3, 2003 in Bethesda, MD with the potential applicants prior to the 
letter of intent deadline.

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 Division of Cancer Prevention
Institute or Center National Cancer Institute
Building 6130 Executive Boulevard 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

To promote the development of a collaborative program among the award 
recipients, a number of issues need to be addressed in the application as 
discussed below.

For U01 and NIH intramural applicants to this RFA, only the "Research Plan" 
section of the PHS 398 grant application is changed.  The remainder of the PHS 
398 application form remains the same.

The "Research Plan", sections a. to d. (the subsequent sections e. to i. remain 
the same), is altered as follows:

o The number of pages is increased from 25 to 35 pages; the 35-page limitation 
applies to the replacement for sections a. to d. only, and does not include the 
pages for sections e. to i.
o The 35 pages should be apportioned as desired by the applicant to cover new 
sections 1. to 3. that replace sections a. to d.  The three sections are: 1.  
Applicant ; 2. Scope of Research; and, 3. Collaborations.    

Section 1 – Applicant.  Applicants should briefly state the major 
objectives of the project and describe what expertise the group encompasses, as 
well as specialized or unique facilities, core resources, and services that are 
available to support these objectives.  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; however, the full 
extent of activities for each participant should be covered in Section 2.

Section 2 – Scope of Research.  For competing renewal applicants, Section 2 
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).  For all applicants, 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.  There is no 
requirement for applicants to use the format of an R01 application.  Instead, 
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 or planned for development.  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 1 of the research 
plan format 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.

Section 3 – Collaborations.  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).  

For new applications, 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:

- demonstrated evidence of collaborative projects and publications
- demonstrated evidence of collaborative funding
- sharing of data and resources, e.g., specimens, technology, research  
protocols

Specific issues related to cooperative agreements must also be addressed in the 
application as follows.

o In Section 3, 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 be able and willing to share data and research resources with each other and 
the NCI. Successful applicants will be expected to submit (on-line) information 
on specimen collections per the Network's Common Data Elements and register 
their protocols with the Network's Data Management and Coordinating Center.  

o At the end of Section 3, 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. Investigators submitting an 
NIH application will be required to include a plan for data sharing or to state 
why data sharing is not possible.

o Applicants to this RFA must also include a research tools and resources 
sharing plan in the letter to be appended to Section 3.  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 a plan (1) for sharing the unique research resources, e.g., human 
biospecimens and novel cancer biomarkers, generated through the grant; and (2) 
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 also define terms, parties, responsibilities, 
prescribe the order of disposition of rights, prescribe 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 (31) principal members, the EDRN is 
organized in four components: 18 Biomarker Developmental Laboratories, 3 
Biomarker Validation Laboratories, 9 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.

o 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 in Section 2 of the "Research Plan" can be 
accomplished.  A statement from the applicant institution to that effect is 
required in the letter to be appended to Section 3.

Budget:

NOTE: NIH intramural project should supply the budget information and a 
composite budget as described below in "ADDITIONAL INSTRUCTIONS FOR NIH 
INTRAMURAL PROJECT APPLICANTS" for NIH Intramural Project Applicants.

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 must set aside 20% of their annual budget or the actual amount of 
funds that was approved by the program staff for validation or any 
collaborative studies (applies to competing renewal applicant who is 
participating on ongoing validation studies) as follows: 

o	The competing renewal applicant should set aside funds from the first year 
onward;
o	The new applicant should set aside funds after the first 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 ). 

ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS:  NIH intramural 
project applicants must use the PHS 398 application form and the modified 
format and content described above with the following additional modifications.

o On the Face Page, fill out only items 1., 2., 3. (leave item 3c. blank), 4., 
and 5.  The remainder of the items should be left blank, AND THE APPLICATION 
MUST NOT BE SIGNED BY EITHER THE PI OR AN NIH INSTITUTE OFFICIAL. 

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

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

o The budget pages should supply the time and effort for each project 
participant, but no other budget figures should be included.  The resources 
available for the project and the research environment should be carefully 
described, but no budget figures should be included.  The NIH Institute 
Scientific Director, as part of the letter of approval for participation, must 
verify that appropriate intramural resources will be allocated to the project 
described in the application if it merits funding, and provide assurance that 
the conduct of the project will comply with the PHS regulations for research 
involving human subjects (if applicable), with the PHS policy on vertebrate 
animal research, and with the PHS policies for data sharing and access to 
research tools.

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-04-006 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: BIOMARKER DEVELOPMENTAL LABORATORIES, and 
number, RFA CA-04-006, 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:  For U01 applicants only (NIH intramural 
applicants must use the address in the Section below entitled "FOR NIH 
INTRAMURAL APPLICANTS"), 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

For NIH intramural Applicants:

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

DO NOT send the application or any copies to the Center for Scientific Review. 
NIH intramural project applications must also be received by January 23, 2004. 
If an application is received after that date, it will be returned to the 
applicant without review.

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 listed in the heading of this RFA.  If an application 
is received after that date, it will be returned to the applicant without 
review.

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, U01 applications will be reviewed for completeness by the CSR and 
for responsiveness by NCI program staff.  NIH intramural project applications 
will be reviewed for completeness by the NCI Division of Extramural Activities, 
and for responsiveness by NCI program staff. If the application is not 
responsive to the RFA, NIH staff may contact the applicant to determine whether 
to return the application to the applicant.  Incomplete applications will not 
be reviewed.  

U01 and NIH intramural project applications that are complete and responsive to 
the RFA will be evaluated for scientific and technical merit by an appropriate 
peer review group convened by the Division of Extramural Activities at the NCI 
in accordance with the review criteria stated below.  As part of the initial 
merit review, all applications will:

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

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.

1. Significance: Does the proposed research for biomarkers/reagents development 
address an important need for earlier cancer detection and risk assessment? 
What is the immediacy of the research opportunity in light of the EDRN-
established phases of biomarker development for early detection of cancer(see 
"Research Objective: Background" Over the project period, is there potential 
for the applicant to develop biomarkers/reagents other than those specified in 
the application?

2. Approach: Are the conceptual framework, design, methods, and analyses 
adequately developed and appropriate to the aims of the project? Does the 
applicant acknowledge potential problem areas and consider alternative tactics? 
Can these approaches be used to derive biomarkers/reagents for a variety of 
malignant tumors? Are the parameters chosen to characterize the 
biomarkers/reagents sufficient and appropriate? Are these parameters generally 
applicable to all biomarkers/reagents? Are the criteria chosen to characterize 
biomarkers/reagents for early detection and/or risk assessment appropriate and 
adequate in light of the EDRN-established phases of biomarker development for 
early detection of cancer (see "Research Objective: Background")? 

3. Innovation: Does the project employ novel concepts, approaches or methods? 
Is the project original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies? Will the approaches 
advance the field of biomarkers/reagents development in the context of cancer 
detection and risk assessment? 

4. Investigators: Are the principal investigator and his/her collaborators 
appropriately trained and well suited to carry out this work? To what extent do 
these investigators have the necessary complementary skills? Have 
collaborations been established or consultants identified to provide the 
appropriate depth and breadth of scientific expertise required for the project? 
Will this team of investigators contribute unique skills to the overall 
Network? Has the applicant adequately addressed his/her institutional patent 
policy?5. Environment: Does the applicant have access to required human 
specimens, e.g. tissues, biological fluids, archived materials?  Does the 
applicant have access to pathology review and documentation of pathology 
report? Does the applicant have the cooperation of surgeons?  Does applicant 
have access to normal tissues from the patients, or access to matched 
controlled specimens?  Are the facilities for experimentation appropriate to 
support the endeavor? Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment and incorporate 
the best use of collaborative arrangements?  Is there evidence of institutional 
support? Is there institutional support for computer services, including 
Internet access? 

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:

1. Interactions. 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 abide by the priorities and policies agreed upon by 
the Steering Committee for collaborative studies?  Have the applicants proposed 
sound strategies for communication among themselves, with the other Network 
components, and with the NCI? 

2. Budget. For U01 applications, does the apportionment of the budget for 
biomarkers development, characterization, and/or technology innovation indicate 
that the applicants understand the requirements of managing a Biomarker 
Developmental Laboratory in the Network enterprise? For the NIH intramural 
project applications, is the commitment of effort appropriate to the scope of 
the project, and are the resources and environment adequate to support the 
project? 
 
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:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date: December 23, 2003
Application Receipt Date: January 23, 2004
Peer Review Date: May/June 2004
Council Review: September 2004
Earliest Anticipated Start Date: September 2004

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

DATA AND SAFETY MONITORING PLAN: (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 more than $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

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

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


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