Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
National Cancer Institute (NCI) (http://www.cancer.gov/)

Title: The Early Detection Research Network: Biomarker Reference Laboratories (U24)

Announcement Type
Reissuance of RFA-CA-05-009

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

• November 06, 2014 - This RFA has been reissued as RFA-CA-14-016.
• August 19, 2009 - See Notice NOT-CA-09-033 The NCI will hold a pre-application meeting.

Request For Applications (FOA) Number: RFA-CA-09-019

Catalog of Federal Domestic Assistance Number(s)
93.393, 93.394

Key Dates
Release Date: July 24, 2009
Letters of Intent Receipt Date: September 29, 2009
Application Receipt Date: October 29, 2009
Peer Review Date: February/March 2010
Council Review Date: May 2010
Earliest Anticipated Start Date: July 2010
Additional Information To Be Available Date (URL Activation Date): Not applicable
Expiration Date: October 30, 2009

Due Dates for E.O. 12372

Not Applicable.

PRE-APPLICATION MEETING

The NCI anticipates holding a pre-application meeting on September 29, 2009 at 9:00 AM- noon EDT to which all interested prospective applicants are invited. NCI program and review staff members will make presentations to explain the goals and objectives for the NCI Early Detection Research Network and its components, including Biomarker Reference Laboratories. The discussion will also cover the preparation of applications and the peer review process. An NCI Grants Management Specialist will be available to answer financial questions. The meeting will be videocast with an opportunity for internet viewers to submit questions by e-mail.

Additional Overview Content

Executive Summary

• Purpose. This funding opportunity announcement (FOA) solicits cooperative agreement applications for Biomarker Reference Laboratories (BRLs), one of the four components of the Early Detection Research Network (EDRN). EDRN is a national consortium funded to discover, develop, and validate biomarkers for early cancer detection, risk assessment and molecular diagnosis and prognosis of early cancer. The BRLs serve as a Network resource for clinical and laboratory validation of biomarkers, including technological developments and assay refinement. The other three main components of the EDRN are: the Biomarker Developmental Laboratories (BDLs), which have the responsibility for the development and characterization of new, or the refinement of existing, biomarkers and biomarker assays, the Clinical Validation Centers (CVCs), which conduct clinical research on the validation of biomarkers in early cancer detection and risk assessment and serve as resource centers for the EDRN by participating in collaborative biomarker validation studies and collaborating with EDRN BDLs and BRLs; and the Data Management and Coordinating Center (DMCC), which supports statistical and computational analyses, informatics infrastructure, and the coordination of network-wide meetings and conferences.
• Mechanism of Support. This FOA utilizes the NIH Cooperative Agreement (U24) award mechanism. Parallel FOAs for other EDRN components include RFA-CA-09-017 (U01) for BDLs, RFA-CA-09-018 (U01) for CVCs, and RFA-CA-09-020 (U24) for DMCC.
• Funds Available and Anticipated Number of Awards. The NCI expects to commit $3 million per year to fund up to 5 BRL awards.
• Budget and Project Period. An applicant may request a project period of up to 5 years at a budget of up to $300,000 per year (direct costs).
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization 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 support.
• Number of PDs/PIs. Only one PD/PI may be designated on the application.
• Number of Applications. Applicants may submit more than one application, provided each application is scientifically distinct. However, applicants must be aware that a given PD/PI may serve in this role on only one funded EDRN award.
• Resubmissions. Resubmission applications are not permitted in response to this FOA.
• Renewals. Renewal applications are permitted in response to this FOA.
• Special Date(s). This FOA uses non-standard receipt and other dates. See Receipt, Review and Anticipated Start Dates.
• Application Materials. See Section IV.1 for application materials.
• Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY 301-451-5936.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2. Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt, Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)
4. Intellectual Property Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

In this Funding Opportunity Announcement (FOA), the Division of Cancer Prevention (DCP), National Cancer Institute (NCI), solicits new and competing renewal applications for Biomarker Reference Laboratories (BRLs) awards. The BRLs serve as a Network resource for clinical and laboratory validation of biomarkers, including technological developments and assay refinement.

BRLs are one of the four components of the national Early Detection Research Network (EDRN or Network , http://edrn.nci.nih.gov/). The mission of EDRN is the development, evaluation, and validation of biomarkers for early cancer detection, risk assessment and the molecular diagnosis and prognosis of early cancer. Each of the four scientific components of EDRN is covered by a parallel FOA.

These main EDRN components include:

1. Biomarker Reference Laboratories (BRLs) (this RFA-CA-09-019);

2. Biomarker Developmental Laboratories (BDL) (RFA-CA-09-017), which will have responsibility for the development and characterization of new, or the refinement of existing, biomarkers and biomarker assays;

3. Clinical Validation Centers (CVCs; formerly known as Clinical Epidemiology and Validation Centers) (RFA-CA-09-018), which will: (a) conduct clinical research to validate biomarkers for early cancer detection, risk assessment, and the molecular diagnosis and prognosis of early cancer and (b) serve as resource centers for collaborative research within the EDRN by participating in collaborative biomarker validation studies and collaborating with EDRN BDLs and BRLs; and

4. Data Management and Coordinating Center (DMCC) (RFA-CA-09-020), which will (a) support statistical and computational analyses, data management, protocol development, informatics infrastructure, and (b) coordinate network-wide meetings and conferences.

All EDRN-related FOAs are open to all qualified applicants, NOT only to the current EDRN awardees.

Biomarkers-Definition. Biomarkers are defined as cellular, biochemical, and molecular (including genetic and epigenetic) characteristics by which normal and/or abnormal processes can be recognized and/or monitored. Biomarkers are measurable in biological materials, such as in tissues, cells, and/or bodily fluids.

Background

Overall Goals of the Early Detection Research Network. The EDRN program is established to: (a) promote translational research to identify biomarkers for cancer risk, early detection, and molecular diagnosis and prognosis of early cancer; and (b) coordinate biomarker research and therapeutic strategies in order to reduce cancer morbidity and mortality. These goals are to be achieved through a systematic, evidence-based discovery, development, and validation of biomarkers (for details, see the EDRN Objectives in the Guidelines document on the EDRN web site at http://edrn.nci.nih.gov/FOA-guidelines).

EDRN s goals include but are not limited to the following:

• Improve the screening processes for major epithelial cancers with national recommendations for cancer screening, such as for cancers of the colon, breast, cervix, and prostate;
• Develop biomarkers for the early detection of cancers that are major causes of cancer-related morbidity and mortality (e.g., those of the ovary, pancreas, liver, and stomach);
• Facilitate the co-development of diagnostics with prevention or therapeutic interventions (theranostics);
• Integrate the state-of-the-science knowledge of genetic, cell signaling, and biochemical pathways with biomarker discovery efforts to have a broader applicability across different tumor types;
• Determine the potential of novel, network- and pathway-based biomarkers to detect and diagnose cancer (noting that pathway biomarkers would allow a systems biology-based approach to diagnosis, prevention, and therapy);
• Develop new serum- and tissue-related methods for early detection and diagnosis.
• Identify clinically significant disease and predictions of clinical outcome, with or without conventional tissue examination, and identify currently available biomarker tests;
• Expand collaborative efforts and shared resources to improve the capacity to conduct biomarker development and validation trials;
• Establish a biomarker database to capture and share methods and pre-competitive data on the validation and qualification of biomarkers;
• Employ cost-effectiveness measuring tools to evaluate biomarker discovery, development, and validation, and collaborate with the NCI’s CISNET (Cancer Intervention and Surveillance Modeling Network) on integrating cost-benefit effect models in the biomarker discovery and development processes; and
• Create well-defined standards and guidelines for biomarker development, validation, and qualification using the NCI-led Translational Research Working Group (TRWG)-developed Device Pathway to reduce uncertainty in discovery and development of biomarkers.

Since its inception in 1999, the EDRN has followed a "vertical" approach to biomarker research that is, through the development, use, and support of an established, integrated, multidisciplinary research environment, which facilitates collaborations and hand-offs among technology developers, basic scientists, clinicians, epidemiologists, biostatisticians, and other health professionals, and, therefore, one that expedites efficacious clinical applications of the molecular knowledge that has burgeoned in recent years.

EDRN Phases of Biomarker Development. EDRN has produced a system for evaluating biomarkers as tools to clinically detect cancer before symptoms appear, and to identify people at risk (http://edrn.nci.nih.gov/). A five-phase approach has been established as a standard and a roadmap for successfully translating research on biomarker applications from the laboratory to the bedside:

Phase 1: the pre-clinical exploratory phase;

Phase 2: the validation phase;

Phase 3: the retrospective longitudinal phase;

Phase 4: the prospective screening study phase; and

Phase 5: the cancer control phase.

For more details, see Biomarker Development Plan in the FOA Guidelines, Section I: http://edrn.nci.nih.gov/FOA-guidelines.

In addition to the establishment of the five-phase approach for biomarker development, a coherent and comprehensive set of guidelines for study design for the discovery and evaluation of biomarkers for use in screening and early cancer detection, diagnosis, or prognosis has been delineated. A prospective-specimen collection, retrospective-blinded-evaluation (PRoBE) design for biomarker development is proposed. A set of rigorous study design standards and guidelines are described, which further address issues regarding the rate of false discovery due to the use of samples of convenience and introduction of bias and data over-fitting. The PRoBE study design includes four key components, which relate to: 1) the clinical context and outcomes; 2) criteria for measuring biomarker performance; 3) the biomarker itself; and 4) the sample size included in the study (see Biomarker Development Plan in the FOA Guidelines, Section I: http://edrn.nci.nih.gov/FOA-guidelines).

EDRN Administrative Structures

EDRN Organization: Structured around four main scientific components, EDRN currently includes 24 Biomarker Developmental Laboratories (BDLs), six Biomarker Reference Laboratories (BRLs), 10 Clinical Epidemiology and Validation Centers (CEVCs), and a Data Management and Coordinating Center (DMCC) (see The Early Detection Research Network: Investing in Translational Research on Biomarkers of Early Cancer and Cancer Risk, Fourth Report; NIH Publication No. 07-6135, January 2008 at http://edrn.nci.nih.gov/docs).

Steering Committee: The Steering Committee (SC) is the governing body of EDRN and is comprised of all EDRN Principal Investigators (PIs), including the PDs/PIs of Multi-PI awards, and the NCI-designated Program Coordinator. The SC has responsibility for the scientific management and oversight of all Network activities, including monitoring the activities of the DMCC. For the administrative structure and responsibilities of the Steering Committee, see "Collaborative Responsibilities."

The Network Consulting Team (NCT) is composed of a Chairperson and non-EDRN members appointed by NCI. The NCT reviews the progress of the EDRN, recommends new research initiatives, and ensures that the Network is responsive to promising opportunities in early detection research and risk assessment. The NCT can recommend new research projects to the SC or to NCI. Members of the NCT can serve on ad-hoc Committees of the EDRN, internal review groups, and as consultants to subcommittees.

The DMCC provides logistic support for the conduct of the SC and NCT meetings.

Headquarters: The institution of the Chair of the SC serves as the Headquarters of the EDRN. The Chairperson of the SC is a Principal Investigator (PI) of an EDRN cooperative agreement award and is elected by the SC. The Chairperson serves as the PI of the Headquarters and implements the scientific, operational, and organizational policies of the Network. The SC Chairperson provides executive leadership, scientific direction, and management for the Network. The Headquarters serve as a center for dissemination of information to investigators and institutions in EDRN, as well as to others outside the Network.

Funds: Funds will reside with: 1) the individually funded U01/U24 awardees in EDRN; and 2) the Headquarters.

The Principal Investigators (PIs) will have funds available through the individual EDRN U01/U24 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 awards (SBIR, R43 and/or R44), Small Business Technology Transfer awards (STTR, R41 and/or R42), Exploratory/Developmental grants (R21 and/or R33), and other research support mechanisms.

Core Funds will be available to the institution of the Chair of the SC. Applicants cannot apply for the Core Funds in their U01 applications submitted in response to this FOA. Core Funds are reserved for post-award collaborative research and for a variety of other functions. Release of these Core Funds will be based on the recommendations of the SC.

Core Funds are used to:

1. Support EDRN multisite biomarker validation trials (see Process of Biomarker Validation in Section I of the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines);

2. Expand participation in EDRN through supplemental funding to an investigator, who is not part of the Network (however, receipt of these supplemental funds does not, in and of itself, imply membership on the SC);

3. Provide support for the development of new biomarker tests to the point at which they can be validated at multiple centers and in larger populations. If test reagents are required to scale-up at this point, the SC may provide funding to contract commercial laboratories or companies that can scale up production and maintain the quality of the reagents (e.g., monoclonal antibodies, labels, etc.), and to CVCs for subject accrual; and

4. Support data management, travel, meetings, and other EDRN collaborative activities, including participation in the EDRN Associate Membership Program (see EDRN Administrative Structures in the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines).

Semi-annual financial reports from the Headquarters will be required to report Core Funds.

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 IV.6 of the corresponding EDRN FOA for Other Submission Requirements and Information. Awardees must advise Core Funds recipients and outside investigators of these requirements.

Specific Research Objectives and Requirements of this FOA:

Scope. The BRL provides resources and support for analytical and clinical validation of biomarkers, including testing of candidate biomarkers; development of assays and technologies or their refinement; and standardization of assay methods as requested by the EDRN SC. In this context, BRLs will have the following two main responsibilities (see details below):

1. The primary responsibility of a BRL is to participate in Network collaborative studies approved by the EDRN SC.

2. The secondary responsibility of a BRL is to conduct an individual developmental study that is relevant to the goals of EDRN and is primarily associated with diagnostic methods improvement. A Developmental Study must be proposed withthin BRL application for the first year or for multiple years up to the 5-year period of the award.

BRL’s Network Collaborative and Individual Developmental Studies:

1. Collaborative Studies

The BRLs will be responsible for standardizing laboratory assays and methodologies, instituting quality control for reagents and technologies for collaborative Network-directed studies, and collaborating in other studies as directed by the SC. Ultimately, BRLs should operate under the Good Laboratory Practice (GLP), a system of management controls governing the conduct of laboratories to ensure the consistency and reliability of the results.

The BRL applicants should have knowledge and practical experience with Standard Operating Procedures (SOPs) for the development of reagents, assays, and technology, and in the evaluation of the accuracy, precision, reproducibility, and performance characteristics (e.g., sensitivity, specificity, and positive and negative predictive values) of tests in multi-center settings. These characteristics are important when sampling body fluids or mixed cell types where only a very small percentage of cells may exhibit the specific genetic, epigenetic or other molecular changes. BRL awardees may be asked to conduct studies on a variety of assays in order to improve their performance characteristics.

To meet the expectations for BRLs, applicants must demonstrate their capabilities and expertise in research areas that include, but are not limited to:

Methodology/Assay Refinement and Technology Optimization:

For early detection screening tests, it is crucial to develop appropriate high-throughput assays/technologies that are accurate, reproducible, and cost-effective. The BRLs are expected to plan, design, and conduct analytic validation studies, as directed by the SC, for assay procedures, protocols, sample collection, etc. Some examples of validation issues are provided below to outline the anticipated lines of research that BRL applicants are expected to address to document their respective capabilities.

Methodologies:

• Determining measures of diagnostic discrimination: sensitivity, specificity, and predictive accuracy, as appropriate for clinical applications;
• Establishing basal levels and reproducibility for various tests, as appropriate; and
• Ensuring that data and specimens are collected under uniform protocols/SOPs.

Assay Design:

• Selection of optimal target sequences, primers, and/or probes;
• Handling single versus multiple targets;
• Selection of specimen types;
• Handling problematic specimens; and
• Designing internal controls, controls for contamination, reagent and instrument standards, and well characterized panels of reference reagents.

Assay Optimization:

• Extraction methods, sampling, internal controls, specimen storage, and processing conditions
• Length, sequence, efficiency, and specificity of primers/probes;
• Efficiency and specificity of enzymes/antibodies/immunoreagents;
• Configuration and performance of controls, calibrators, capture probes, detectors, etc.
• Optimization of parameters that may affect reproducibility;
• Assay conditions: time, temperature, storage, and transport stability
• Extended reproducibility testing: multiple sites, different days, operators and kit lots - proficiency testing: single operator, multiple days and kit lots.

Assay Validation and Application Development:

• Analytical validation of each assay developed within the Network;
• Development of a scale-up and automated methods for high volume throughput;
• Multi-center cross-checks for pooled specimens, and other inter- and intra-laboratory interfering factors;
• Development of appropriately rigorous, GLP-compliant formats and systems (paper or electronic) for reporting/archiving test results; and
• Development of kits for rapid, inexpensive testing.

Quality Control Program:

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

• Device and instrument calibration, precision, and reproducibility;
• Quality control of data. The BRL will follow the network procedures for data quality and laboratory quality control in accordance with the network guidelines and policies; and
• Interim evaluation and consideration of assays/reagents developed by the network scientific components for tests/reagent scale-up for multi-center studies per direction of the SC.

Reference Materials:

With the rapid advances in molecular, genomic, and proteomics-based diagnostic technologies, reference materials for controls in molecular assays/technologies, such as mass spectrometry-based multiple reaction monitoring (MRM) for quantitative proteomic analysis; or DNA-based Comparative Genomic Hybridization (CGH), or gene and oligonucleotide microarrays, are of great importance for proficiency testing. A BRL may be asked to develop and/or test such reference materials at the onset of analytical validation of specific biomarkers.

Study Organization:

Capability and Characteristics of the BRL: BRL applicants must meet several important requirements for the participation in EDRN. The expertise of the BRL applicant team must encompass broad subject areas within the clinical diagnostic field. One requirement is the flexible composition of BRL teams. As the areas of specific projects and responsibilities of the Network are expected to shift and expand, the number and expertise of the investigators should change in response to the scientific needs and opportunities. Qualified supporting personnel in laboratory technology should be identified for their availability to assume responsibility in a flexible manner as the need arises.

Scientific Plan:

BRL applicants must outline their vision on how they would provide the anticipated lines of laboratory support for the issues listed above and how their activities would fit into EDRN s overall scope and goals. Applicants goals for such support (both short-term and long-term) must be consistent with the practice of a typical reference laboratory. The plans must also be substantiated by applicants experience and expertise as well as current resources of their laboratory(-ies). All these factors will be considered in peer-review.

Partnering with BDLs and CVCs and other BRLs:

All awarded BRLs will be expected to partner with those EDRN BDLs, CVCs and other BRLs that may benefit from joint efforts (as those listed above under Scope ). NCI will work with the funded BRLs, CVCs and BDLs to establish such partnerships. The collaborations between BRLs with CVCs and BDLs may include (but will not be limited to) the following aspects:

• BRL consulting with BDLs and CVCs on study’s need for reference related work;
• BRL consulting with BDLs and CVCs on clinical matters such as selection of subjects and specimens and performance parameters that markers need to be analytically validated for;
• BRL working jointly with BDLs and CVCs to validate biomarkers developed in the latters laboratories.

2. Developmental Studies

BRLs may seek Developmental Study funds (see additional instructions in Section IV.6. Instructions for Application Preparation of this FOA) for conducting analytical validation of published, but not validated biomarkers; pilot studies on reagents and/or technology development and refinement that will have a broad impact on cancer detection and risk assessment. A one- or multi-year Developmental Study submitted with the BRL application will be considered.

Prior to proposing the developmental study, applicants are encouraged to contact the program officials listed in this FOA to discuss the needs of EDRN in the area of technology and assay refinement (see specific instructions in Section IV.6). In addition, applicants are encouraged to review research activities across the Network and develop collaborations by visiting the following website http://edrn.nci.nih.gov/, by reading the EDRN fourth progress report at http://edrn.nci.nih.gov/docs, or the EDRN strategic goals in the Appendix of EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines.

The following (non-inclusive) examples of developmental studies are provided to illustrate the types of developmental studies that are relevant to EDRN:

• Analytical validation of published candidate biomarkers, which were not previously validated. High throughput deep sequencing of the cancer transcriptomes revealed a large number of mutations, fusion transcripts and aberrant rearrangements in a variety of cancers (colon, pancreas, breast, lung, prostate and Glioblastoma multiforme). Some of these recurrent genetic alterations are potential cancer biomarkers. Similarly, recurrent epigenetic alterations were reported as highly associated with specific cancers. Applicants may propose to conduct an analytical validation of candidate biomarkers; develop high throughput assays and tools for their analysis. Applicants are encouraged to develop partnerships with investigators or private diagnostic/pharmaceutical companies who are engaged in the whole genome sequencing of various cancer types. The NCI-supported The Cancer Genome Atlas (http://tcga.cancer.gov/) may be informative in identifying researchers/partners in this area.
• Recent Genome Wide Association Studies (GWAS) revealed putative cancer risk markers. Applicants are encouraged to develop functional assays (e.g., enzymatic assays) to quantitatively measure activities associated with cancer risk marker. For such studies, applicants are encouraged to develop collaborations with the GWAS community, including CGEMS (http://cgems.cancer.gov/).
• Development and verification of affinity reagents (e.g., monoclonal antibodies, recombinant antibodies such as scFv, aptamers) for quantitative assays of human candidate biomarkers and proteins (including aberrantly modified proteins) associated with cancer. The developed quantitative assays should target biomarkers for risk assessment, early detection, diagnosis, and prognosis.
• Development of standardized technologies, assays and methods for validation of proteins and peptides, transcripts or metabolites, highly or specifically associated with cancer. The focus should be on candidate biomarkers for early detection, diagnosis, and early detection of aggressive cancers.
• Development of innovative assay(s) for detection of cancer stem cells from pre-malignant lesions (e.g., DCIS, HPIN); from exfoliated cells of early stage cancer patients (e.g., urine sediment of bladder cancer);

Activities Requiring Unique Resources: For activities requiring unique resources, such as innovative or specialized technologies, unique specimens, molecular probes, and specialized assays, methods, and protocols the BRL applicants are encouraged to develop collaborations with investigators participating in various NCI-sponsored programs such as Specialized Programs of Research Excellence (SPORE) (http://spores.nci.nih.gov/), Innovative Molecular Analysis Technology (IMAT) (http://otir.nci.nih.gov/tech/imat.html), Cancer Genetic Markers of Susceptibility (CGEM) (http://cgems.cancer.gov/), Cancer Genetics Network (CGN) (http://epi.grants.cancer.gov/CGN/), Clinical Proteomic Technologies for Cancer (CPTC) (http://proteomics.cancer.gov/), The Cancer Genome Atlas (http://TCGA.nci.nih.gov/), Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) (http://www3.cancer.gov/prevention/plco/index.html); or with other governmental agencies, such as the Department of Defense (DOD), and the Veteran’s administration (VA). Awardees must advise prospective collaborators, that with respect to these collaborations, their institutions will be subject to the resource sharing and intellectual property management requirements set forth in Section IV of the Supplemental Instructions of this FOA.

NON-RESPONSIVE. This FOA will not support research on fundamental biological mechanisms, such as studies on growth regulation, cell cycle control, or other basic studies, which are not explicitly focused on risk assessment, on early cancer detection, and on molecular diagnosis and prognosis of early cancer in humans.

Note: EDRN applicants are encouraged to seek actively additional funding/resources to push the biomarkers validation/implementation efforts beyond the EDRN-sponsored scope of research.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This funding opportunity uses the NIH U24 cooperative agreement award mechanism(s).The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity uses a cooperative agreement award mechanism. In the cooperative agreement mechanism, the PD/PI retain the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the PD/PI, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

2. Funds Available

The NCI intends to commit approximately $3 million in FY 2010 to fund up to five new and/or renewal cooperative agreements (U24) in response to this FOA. An applicant should request support for five years. Future year amounts will depend on annual appropriations.

An applicant may request a project period of up to 5 years at a budget of up to $300,000 per year (direct costs).

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 funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative (F&A) costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education;
• Private Institutions of Higher Education;
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education);
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education);
• Small Businesses;
• For-Profit Organizations (Other than Small Businesses);
• US Territories or Possessions
• Other(s):
  • Eligible Agencies of the Federal Government.

Non-Domestic (i.e., Foreign) organizations are NOT eligible for application submission but may participate (under subcontractual arrangements) in a BRL proposed by an eligible Domestic applicant institution.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her 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 support.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewal. Applicants may submit a renewal application. Renewal applications are permitted but only for U24 awards supported by previous EDRN funding (i.e., RFA-CA-05-009: Biomarker Reference Laboratories). Note that these renewal applications will be subject to evaluation using additional Review Criteria relative to new applications (see Section V of this FOA).

Number of Applications. Applicants may submit more than one application, provided each application is scientifically distinct. However, applicants must be aware that a given PD/PI may serve in this role on only one funded EDRN award. Still, investigators, who are PDs/PIs on one type of EDRN application, may be included as non-PD/PI key personnel and/or co-investigators on another EDRN award.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance, contact GrantsInfo -- Telephone: (301) 710-0267; Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

The exceptions from the PHS398 instructions and detailed information on the application structure and components are provided in Section IV.6. Other Submission Requirements. All applicants must follow the specific instructions in that section.

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review, and Anticipated Start Dates
Letters of Intent Receipt Date: September 29, 2009
Application Receipt Date: October 29, 2009
Peer Review Date: February/March 2010
Council Review Date: May 2010
Earliest Anticipated Start Date: July 2010

3.A.1. Letter of Intent

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

• Descriptive title of proposed research;
• Name, address, and telephone number(s) of the PD/PI(s);
• Names of other key personnel;
• Participating institutions; and
• Number and title of this funding opportunity.

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 in Section IV.3.A.

The letter of intent should be sent to:

Sudhir Srivastava, Ph.D., M.P.H.
Program Coordinator
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3142
Bethesda, MD 20892-7362
Telephone: (301) 435-1594
FAX: (301) 402-8990
Email: [email protected]

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. 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 (for U.S. Postal Service express or regular mail)
Bethesda, MD 20817 (for express/courier delivery; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).
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 Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: [email protected]

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute. Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity 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 a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity 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.

Information on the status of an application should be checked by the PI in the eRA Commons at https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project; and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm).

6. Other Submission Requirements

Special Instructions for the Preparation of EDRN BRL Applications

Budget (PHS 398 Form Pages 4 and 5): Follow the current PHS 398 instructions to provide a detailed budget (direct costs) for the entire application for the first 12-month period (Form page 4) and the entire proposed project period (Form page 5).

Use additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) for the Developmental Studies component.

For further details, see item Additional Budget-related Information below.

RESEARCH PLAN: The standard PHS398 Research Plan (Items 2-5 as per Revision 11/07 of the PHS 398 Table of Contents) is altered as follows:

• Standard Items 2-5 of the PHS 398 Research Plan are replaced by the following four sections: 1) Research Team and Organizational Structure; 2) Environment; 3) Collaborative and Developmental Studies; and 4) Compliance with terms and conditions of award for EDRN Cooperative Agreement.
• The PHS 398 standard page limit for Items 2-5 is replaced by a new limit of 30 pages for the new Sections 1-4. Note: Applicants are encouraged to use the minimum number of pages necessary to describe the research plan clearly and succinctly.
• Other items of the PHS398 Research Plan remain unmodified.

Specific Sections 1-4 to be included in Research Plan are described below. (Table of Contents should be modified accordingly.)

Section 1. Research Team and Organizational Structure (up to 8 pages suggested)

Describe the team’s general expertise relevant to the participation in EDRN collaborative validation studies with the emphasis on experience with laboratory test validation, scale-up and refinement. Outline the roles of all key personnel, collaborators, and consultants who are associated with the application. Applicants must list and summarize each of the agreements with individual collaborators that could provide flexibility in the available expertise of the BRL to meet any shift in Network collaborative study needs. This part should also include a description of the materials, technologies, and expertise to be provided by such collaborators.

Describe the laboratory's organizational structure (and provide a chart), including lines of authority, with particular attention to qualifications for validation studies (see "Scope"), service resources, and the Network's major objectives (see "EDRN’s Goals"). Describe any certification(s) from laboratory accrediting agencies/organizations, for example from CLIA, College of American Pathologists. Describe plans for interaction among laboratory staff and with the various Network components. Describe any ongoing grant-supported, institutional, or private sector resources that augment or complement resources for which funding from this FOA is sought.

Applicants are strongly encouraged to develop partnership(s) with industry, which can provide expertise and resources in the support and development of high throughput assays.

Summarize any experience in one or more of the research areas listed under "Scope". Briefly describe previous and current research experience and accomplishments in dealing with validation studies, quality control and excellence in assay development and refinement. Applicants must also describe the experience of their group in collaborative programs and activities with partners in academia and industry. Some examples of collaborations that may be provided in support of the application are, but not limited to, 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.

For Competing Renewal Applications: Applicants must list their previous EDRN assignments and achievements. In brief, they must provide documented evidence of the following:

• Participation in ongoing EDRN and non-EDRN collaborative projects and publications;
• Sharing of data and resources, e.g., specimens, technology, research protocols;
• Participation in pre-validation and validation of biomarkers; and/or
• Validation of or development of an assay and/or technology for biomarker detection and/or diagnosis.

Section 2. Environment (up to 2 pages suggested)

Briefly describe how the facilities and equipment for experimentation are appropriate to support the Network's endeavor and the scientific environment in which the work will be done. Describe how the proposed environment contributes to the research and encourages collaborative and service arrangements. Whenever applicable, provide Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP) plans.

Many biotechnology and diagnostic companies have already established GCP and GMP plans. Collaboration with these entities will be mutually beneficial to the applicant and the EDRN. BRL applicants should develop collaboration with these companies in which they can benefit from industrial know-how on technology development and industry can benefit from access to clinical samples and clinical expertise within EDRN in verifying their technology for suitability in clinical use.

Section 3. Collaborative and Developmental Studies (up to 15 pages suggested)

Collaborative Studies: For this FOA, collaborative studies refer to validation studies involving one or more of the EDRN components (BDL, CVC). The collaboration must include:

• Validation study approved by the EDRN SC
• Must be for a Phase 2 study and beyond
• Milestones must be clearly laid out and approved by the EDRN SC

Applicants need not submit Collaborative Study proposals with this application. However, incumbents must provide a budget for their ongoing Collaborative Studies (see Additional Budget Information below). BRLs may submit a proposal for Collaborative Studies after award subject to review by the EDRN SC.

Developmental Studies: All BRL applicants must describe their plans for a well justified developmental project. Project description must contain the following elements:

• Project Title Page containing Project Title, name of Project Leader, Project Summary (abstract), and a list of Key Personnel (listing months/effort of each individual);
• Research Plan to include the following items (the first four items being analogous to standard Items 2-5 in the PHS 398 instructions):

1) Specific Aims;

2) Background and Significance;

3) Preliminary Results (for incumbents Progress Report);

4) Research Design and Methods;

5) Project Management Plan - applicants must describe the management and communication plan among the investigators and between the PD/PI and the NCI. In no more than 1-2 pages the following two requirements must be covered:

a) A tentative timeline for conducting the proposed developmental project (with brief descriptions of how the goals of each of the proposed specific aims will be achieved on the basis of tentative, interim milestones, which in case of multi-year studies should be provided on a year-by-year basis).

b) Overall project milestones, which must be well described, quantitative, and scientifically justified. Discuss the milestones as a means of judging the success of the proposed developmental studies. Specific aims may not be regarded as milestones (unless they include quantitative end points). Quantitative milestones are a way of determining whether an applicant has successfully reached the specified goals. Examples of quantitative milestones are:

• numerical specifications of analytical sensitivity of developed assay relative to the current gold-standard
• projected maximum level of inter-assay reproducibility (CV)

Any application lacking acceptable milestones as determined by involved NCI program staff members will be considered non-responsive to this FOA.

Progress made toward achievement of the described milestones will be reviewed by the EDRN SC and recommendation will be made to NCI program for approval of subsequent years of funding.

Developmental studies may include, but are not limited to, analytical validation of published candidate biomarkers for early detection, diagnosis, early detection of aggressive cancer and for cancer risk assessment; biomarker assay refinement; automation and high throughput assays; analytical validation of reagents and assays; development of integrated technology platforms in support of ongoing studies within EDRN and other biomarker studies conducted elsewhere.

Some examples of developmental studies are provided in Section I. Research Objectives. It is expected that the proposed developmental projects will lead to:

• Development of quantitative measures to determine analytes or biomarkers of interest; and/or
• Development of multiplexed assays or tools; and/or
• Creation of a reference set of markers and reagents that may be used to assess predictive efficacy; and/or
• Development of Standard Operating Procedures (SOPs) for relevant diagnostic methods and/or biological specimens and diagnostic analyses.

Section 4. Compliance with terms and conditions of award for EDRN Cooperative Agreement (up to 5 pages suggested)

In section 4, applicants must include their specific plans for responding to the "Cooperative Agreement Terms and Conditions of Award" section. Applicants should state their willingness to participate in the required EDRN activities listed below:

a) Applicants must collaborate and share data freely with the other EDRN components, participate in planning and attending workshops and symposia, to serve on the SC and be bound by its decisions. Applicants are expected to participate in collaborative studies conducted by their respective EDRN collaborative group focusing on cancers of defined organ site(s).

b) Applicants must 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 (CDEs) and register their protocols with the Network’s DMCC.

c) Every Biomarker Reference Laboratory will be required to collaborate with at least one EDRN BDL and CVC. In addition, applicants must work with the Network statistical core in developing research designs for testing biomarkers and sharing the data generated in these pre-validation studies with the statistical core to assess biomarker performance. Although it is not a requirement, new applicants are encouraged to develop collaborations with the existing EDRN Clinical Validation Centers, which have collected specimens under the auspices of EDRN. Additional collection of specimens, if required, will be supported through the applicant’s set-aside funds or through the EDRN Core Fund.

d) Investigators are encouraged to team with industrial partners to facilitate bringing diagnostic clinical tests to market; however, each investigator must consult with NCI prior to doing so to ensure that the licensing agreement does not hinder collaboration and that the technology/ biomarkers are freely available for clinical validation or related studies by EDRN (see also http://edrn.nci.nih.gov/FOA-guidelines).

Additional Budget-related Information:

Applicants must adhere to the overall budget limits as defined in Section II. Funds Available. Applicants must budget for a) Administrative Costs; b) EDRN Collaborative Studies; and c) Individual Developmental Studies. They must provide the budget for each activity separately. However, set aside funds for Collaborative Studies can be identified in the budget for Administrative Costs.

a) Administrative Costs (up to $50,000)

Applicants must request funds to cover applicable administrative and travel costs (only for EDRN activities). Administrative costs may include partial salary support for the PI and administrative staff and other expenses required for the applicant to participate in EDRN activities. Applicants must budget for travel expenses and per diem expenses for participation in Network workshops and symposia. Applicants must plan for two investigators, the PI and an additional senior investigator, to attend the Planning meeting and two SC meetings in the first year and two SC meetings in each subsequent year. Additionally, they must budget for the attendance of the PI and an additional senior investigator in one Network-sponsored workshop or symposium every 18 months.

b) Collaborative Studies (Set-aside $150,000)

Collaborative studies must be submitted as a team of BRL and at least one other component of EDRN (BDL and/or CVC) and budgeted using this set-aside fund. Set-aside funds from others will not be utilized in budgeting. Funding for multiple years will be allowed subject to annual approval and the completion of the interim milestones provided for the project. This set-aside fund should be listed as Collaborative Study in the budget section of PHS398. The scope of collaborative studies is given in Section I. Specific Research Objectives and Requirements of this FOA.

The use of set-aside funds will be restricted to collaborative projects relevant to the Network’s objectives, and must be reviewed and approved on an as needed basis by the EDRN SC and the NCI. For renewal applications, incumbents must budget the actual amount that has been approved by NCI for the duration of the ongoing collaborative studies; otherwise, a budget must be proposed as indicated for new applicants.

c) Individual Developmental Studies (up to $100,000)

Applicants must submit a research proposal for a developmental study for one or multiple years, up to five years, as part of this application. In case that a one-year developmental project is submitted with this application, developmental studies proposed in future years will be reviewed and approved by the EDRN SC and NCI. In such case, for budgeting purposes, the applicant must budget $100,000 from second year onward as Developmental Study in the budget section of PHS398.

Appendix Materials

All paper PHS 398 applications must provide appendix material on CDs only, and include five identical CDs in the same package with the application (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html).

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information, see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088 and http://grants.nih.gov/grants/gwas/.

In addition to the standard NIH rules, the following EDRN-specific requirements apply:

(d) Unique Research Resources and Specimen Sharing: The success of EDRN is dependent on collaborative interactions of all its laboratories. Unique research resources and clinical specimen collections funded through EDRN cooperative agreements must become available to all investigators in the Network and must be made available for Network validation studies. Applicants seeking to use funding via this U24 mechanism to develop research resources, such as human biospecimens, novel cancer biomarkers, tools and software, must state their willingness to share these resources with others in the Network.

(e) Intellectual Property: 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.

Since it is the policy of the NIH to make available to the public the results and accomplishments of the activities which it funds, applicants who respond to an EDRN FOA are expected to submit an Intellectual Property Management Plan (IPMP), which addresses the strategy to be followed for both solely or jointly owned inventions (including patents and licensing issues) and how these resources will be made available to the broader scientific community, consistent with the EDRN initiative. This plan should be included in the program description of the application and any approved IPMP will become a condition of the grant award. Progress Reports must contain information on activities for the sharing of research resources and intellectual property. For more details on the preparation of an IPMP can be found at http://ttb.nci.nih.gov/ipplans.html. For further Licensing and IP issues related to Biomarker Discovery, Development, and Validation, see Section III of the FOA Guidelines document, at http://edrn.nci.nih.gov/FOA-guidelines.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

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

The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by peer review;
• Availability of funds;
• Relevance of the proposed project to program priorities; and
• Compliance with resource and data sharing policies.

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact. Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance. Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, and/or preventative interventions that drive this field?

In addition, specific to this FOA: Does the application document evidence that the applicants understand the objectives and the goals of this FOA? Does the applicant demonstrate understanding of the technical requirements and the technical challenges in biomarkers validation? Do the applicants describe new ideas about how best to meet the goals of the Network, and address issues identified under the "Specific Research Objectives and Requirements of this FOA? Is the knowledge base, practices of assay validation, and the availabilities of infrastructure, including equipment, to support them adequate for meeting the requirements of a BRL as defined by this FOA?

For the proposed Developmental Study, does the applicant address an important need for technology, reagent and other resource development, standardization, quality control, or protocols suitable for early cancer detection and risk assessment, molecular diagnosis and prognosis of early cancer? Has the applicant established the scientific rationale by prior discovery research, translational research and/or clinical research that provide the scientific basis for the proposed study? Are the milestones given in the project management plan appropriate for the success of the proposed Individual Developmental Study? What is the likelihood that the proposed study will lead to a routine clinical practice?

Investigator(s). Are the PDs/PIs, collaborators, and/or other researchers well suited to the project? If Early Stage Investigators or New Investigators are involved, do they have appropriate experience and training? If established investigators are involved, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise and are their leadership approach(es), governance plan(s), and organizational structure appropriate for the project?

In addition, specific to this FOA: (All applications): How extensive is the research experience and expertise of the research team in assay development (including high volume assays) and laboratory quality control (including adherence to established standards, such as GLP, when appropriate). How strong is the background of the team in the fields related to the expected collaborative EDRN projects and the proposed BRL developmental studies (e.g., in molecular genetics, genomics, proteomics, and pathology for early cancer detection, diagnosis and risk assessment). How well is the PI qualified to participate in multi-institutional collaborations?

(Renewal Applications): How successful were the incumbent applicants in performing EDRN validation and developmental studies? How meaningful (for the EDRN mission) were their contributions to collaborative efforts within and outside the Network?

Innovation. Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches, methodologies, instrumentation, and/or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches, methodologies, instrumentation, and/or interventions proposed?

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

In addition, specific to this FOA: Can the proposed approaches be used for clinical testing of biomarkers/reagents for a variety of incipient neoplastic lesions? Are parameters, such as sensitivity, specificity, and predictive value chosen to characterize the biomarkers/reagents to be developed sufficient and appropriate? Will the laboratory be able to carry out its planned studies in a reasonable period of time?

Environment. Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, and/or collaborative arrangements?

In addition, specific to this FOA: How suitable are the facilities and equipment for the BRL role? Are appropriate facilities and infrastructure (including equipment for high-throughput testing) available to the applicant’s team? If a collaboration with a private sector entity is proposed, will such collaboration be beneficial to the BRL goals and to the mission of EDRN?

In addition to the above review criteria, the following criteria will be applied to applications in the determination of scientific merit and the impact/priority score.

Collaborative Strengths: Are there adequate plans for effective interaction and coordination with the Network components, the SC, the DMCC, 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 SC for collaborative studies?

Additional Review Criteria. As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, but will not give separate scores for these items.

Protections for Human Subjects. For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects; 2) adequacy of protection against risks; 3) potential benefits to the subjects and others; 4) importance of the knowledge to be gained; and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption; 2) human subjects involvement and characteristics; and 3) sources of materials.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

Vertebrate Animals. The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the American Veterinary Medical Association (AVMA) Guidelines on Euthanasia.

Renewal Applications. When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

Biohazards. Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Additional Review Considerations. As applicable for the project proposed, reviewers will address each of the following items, but will not give scores for these items and should not consider them in providing an overall impact/priority score.

Budget and Period Support. Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Select Agent Research. Reviewers will assess the information provided in this section of the application, including: 1) the Select Agent(s) to be used in the proposed research; 2) the registration status of all entities where Select Agent(s) will be used; 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s); and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans. Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not applicable.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in Item

12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

2. A.1. Principal Investigator Rights and Responsibilities

The PD/PI will have the primary responsibility and accountability to the applicant organization officials and to the NCI for the performance and the proper conduct of the research supported by the U24 mechanism in accordance with the terms and conditions that are stated in this FOA. The PD/PI will be a voting member of the Steering Committee and together with an additional senior investigator will attend a Planning Meeting and two SC meetings in the first year, two SC meetings in each of the subsequent years of the award, and one EDRN-sponsored scientific workshop every 18 months (this usually coincides with one of the SC meetings). Attendance at these meetings is required as part of this cooperative agreement.

All funded applications will be discussed by the SC or its designee to help coordinate the project management plan, collaborations, and protocol design. Approval is required prior to project commencement.

PD/PI Responsibilities for BRL Network Collaborative Studies:

• The PD/PI will collaborate with BDLs, CVCs and with other EDRN components to advance promising biomarkers towards EDRN validation studies.
• The PD/PI will be responsible for accepting and implementing the goals, priorities, common protocols, procedures, and policies agreed upon by the SC for the individual and Network collaborative studies.
• The PD/PI will ensure Network and NCI review and approval of protocols, concepts, final protocol documents, informed consents, and study amendments, and advise NCI of changes in protocol status.
• The PD/PI will be responsible for collaborating on common research designs or protocols, including methods and requirements for joint participation and collaboration as recommended by the SC, and handling of data, including appropriate sharing of methods and data among collaborating organizations.

PD/PI Responsibilities for BRL Individual Developmental Study:

The PD/PI will have the primary responsibility to define the scientific objectives for the developmental project, including research design and protocol development (if applicable), quality control, safety monitoring, conduct data collection and analysis, and publication of results.

Under Collaborative Studies or under a separate activity funded through EDRN Core Funds, the BRL may be asked to provide services (e.g., assay optimization), and standards for reagents, assays and specific technology.

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

2. A.2. NIH Responsibilities

An NIH Project Scientist [and/or Project Coordinator, or Project Collaborator, or Intramural Scientist ] will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

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. 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 members on specific scientific issues as needed.

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 (who is and will be 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, DCP, 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, DCP, 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 NCI Program Coordinator will convene the initial meeting of the SC, have voting membership on the Steering Committee, and, as determined by that committee, its subcommittees.

Although the PD(s)/PI(s) 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.

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

The NCI Project Scientists/Coordinators/Collaborators and other substantially involved NIH staff members will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Additionally, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. A Program Official may also have substantial programmatic involvement (e.g., as a Project Scientist). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications, or will seek NCI waiver.

2.A.3. Collaborative Responsibilities

1. Steering Committee (SC):

The SC will be a governing body of the EDRN. It will provide overall scientific management oversight and will be responsible for developing collaborative research designs, protocols, and manuals, facilitating the conduct and monitoring of studies, and reporting study results. The SC will be composed of: (a) the PD(s)/PI(s) representing EDRN awardees (one representative per each EDRN award); and (b) the NCI Program Coordinator. Each voting member will have one vote.

The Chair (non-NIH person) will be selected by the SC. The awardee institution represented by the Chair of the SC will serve as the Headquarters (for definition, see Network Organization). Subcommittees, including the existing ones, will be established and maintained by the SC, as it deems appropriate; the NCI Program Coordinator will serve on subcommittees, as he/she deems appropriate.

After all the Network components have been funded, the SC will convene. Responsibilities of the SC include, but are not limited to (investigators are encouraged to review the EDRN Manual of Operations at http://edrn.nci.nih.gov/about-edrn/edrn-mo-v3-1-0.pdf/download), the following activities:

• Updating and refining established Network policies and procedures;
• Updating and refining established policies and procedures for collaborative projects, protocols, and Network-defined projects;
• Updating and refining established policies and procedures for reviewing changes in projects not showing translational significance at the request of the laboratories/centers, and making recommendations to the NCI for replacing the project with more promising ones with revised scope and adjusted budget (increase in the budget will not be permitted);
• Updating and refining established standards or decision criteria for validating biomarkers/reagents for further clinical studies, such as testing early detection strategies, or as risk factors; and
• Updating and refining established policies and procedures for accepting, reviewing, and recommending proposals from investigators outside the Network for supplemental funding and expanding the Network participation.

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

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

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

The SC 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 (i.e., collaborative research using Core Funds), the SC may ask a BDL or CVC to serve as a BRL on an as needed basis with appropriate compensation from Core Funds. The SC may also examine the validation data for biomarkers/reagents developed by the Network, and decide when a biomarker is sufficiently validated, or recommend when to stop non-productive experiments relating to biomarkers validation.

The SC will discuss collaborative projects to be pursued jointly with the funds set aside from the Headquarters and from individual U01/U24 awardees.

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

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

The SC in consultation with the NCI will determine the PI of the Network-wide validation study.

For additional information on PD(s)/PI(s) responsibilities for the SC, see the EDRN Manual of Operations posted at http://edrn.nci.nih.gov/about-edrn/

All EDRN PDs/PIs and their awardee institutions will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. A Dispute Resolution Panel will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's rights in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research; peer review; and financial or grants management issues.

1. Scientific/Research Contacts:

Sudhir Srivastava, Ph.D., M.P.H.
Program Coordinator
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN Room 3142
Bethesda, MD 20892-7362 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 435-1594
FAX: (301) 402-8990
Email: [email protected]

2. Peer Review Contacts:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: [email protected]

3. Financial or Grants Management Contacts:

Funmi Elesinmogun
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, Suite 243
Bethesda, MD 20892(for regular mail)
Rockville, MD 20852(for non-USPS delivery)
Telephone: 301-496-7245
FAX: 301-496-8601
EMAIL: [email protected]

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

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:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (Phase I); efficacy studies (Phase II); and efficacy, effectiveness, and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local institutional review board (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.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/

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 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 funding opportunity 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.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is 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 Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

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 (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 applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 (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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

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).

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. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for 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 FOA 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. 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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.