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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 Developmental Laboratories (U01)

Announcement Type
Reissuance of RFA-CA-05-023.

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

Request For Applications (FOA) Number: RFA-CA-09-017

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

Key Dates
Release Date: June 25, 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 Developmental 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

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 Developmental Laboratories (BDLs) awards. BDLs are responsible for the development and characterization of new or the refinement of existing biomarkers and biomarker assays.

BDLs 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 Developmental Laboratories (BDLs) (this RFA-CA-09-017);
  2. Biomarker Reference Laboratories (BRLs) (RFA-CA-09-019), which will serve as a Network resource for clinical and laboratory validation of biomarkers, including technological development and refinement;
  3. Clinical Validation Centers (CVCs; formerly known as Clinical Epidemiology and Validation Centers) (RFA-CA-09-018 class=regulartext>), 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 the 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 strategic and 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:

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. To establish and enhance the Biomarker Developmental Laboratories (BDLs), which form one of the four scientific components of the EDRN. The Primary Objectives of applications submitted in response to this FOA must be focused on at least one of the following:

Applicants may also propose the development of diagnostic and/or prognostic markers, provided that: (a) the selection is sufficiently justified and reflects urgent clinical needs; and (b) the effort proposed is part of the overall strategy to improve early detection and risk assessment.

In the context of this FOA, development will encompass correlative studies to further develop and validate biomarkers initially identified or characterized by applicants themselves or by other investigators in accordance with EDRN-defined Phase 1 and Phase 2 of the Biomarker Phase Development Approach.

The BDL will conduct translational research to:

This FOA encourages the submission of applications in broad categories of translational studies on complex cellular pathways, processes, and networks to identify the molecular and cellular signatures of cells, which can be used for early detection of cancer or for risk assessment. Use of systems biology approaches and/or signaling pathway analyses to identify biomarkers that not only predict onset of a certain cancer but also delineate the specific biochemical, cellular, and physiological characteristics associated with this neoplasia is encouraged.

Types of Cancer. Applications for research on cancers of common occurrence (e.g., those of the prostate, breast, colon, and lung) are encouraged. Proposed studies may also focus on other cancers that are major causes of cancer-related morbidity and mortality (e.g., those of the ovary, pancreas, liver, and stomach).

For further details see section on Organ-specific Strategic Goals in the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines.

Possible Topical Areas. Proposed research activities may include, but are not limited to, the following areas:

I. Development of comprehensive panels of biomarkers/methods to identify molecular alterations, e.g., gene aberrations, changes in gene or protein expression, post-translational modifications, epigenetic changes, and changes in metabolite profiles, associated with cancer in order to:

II. Identification and evaluation of molecular profiles for risk stratification by improving pathological classification of early lesions. Expansion of marker identification to predict onset of disease and risk of recurrence in order to:

III. Development of highly specific and sensitive assays to detect molecular alterations in circulating nucleic acids or exfoliated cells in body fluids, including serum/plasma, urine, stool, and/or saliva, in order to:

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

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

VI. Development of subcellular imaging modalities in tandem with molecular markers to interrogate the dynamic modulation of cancer progression correlated with results derived from clinical trials. Exploitation of these technologies could lead to biomarkers applicable to prognosis or targeted therapy.

Other approaches for the development of biomarkers for early detection, diagnosis, prognosis or assessment of cancer risk will be accepted as well.

Time-line and Phases of Biomarker Development. The application should clearly delineate the time-line for biomarker development from Phase 1, to Phase 2, and to Phase 3. In addition, decision criteria at specific stages of the project should be planned to either continue to develop promising biomarkers or triage biomarkers unlikely to yield fruitful prospects for clinical use.

The search for new markers should reflect new information about key points in cancer biology (i.e., molecular pathogenesis, apoptosis, cell cycle control, etc).

To avoid bias and make best use of resources, discovery studies should follow EDRN-established Phase 1 and Phase 2 guidelines and use key elements of the PRoBE design (see Biomarker Development Plan in the FOA Guidelines, Section I: http://edrn.nci.nih.gov/FOA-guidelines). Among others, these criteria also include the randomized selection of case patients and control subjects from a well-defined prospective cohort that is relevant to the intended clinical application, rigorous protocols that precisely define data items and procedures to measure them, and mechanisms to ensure that biomarker and outcome assessments cannot influence each other. Nested case control studies can improve the quality of discovery research and increase the chances that truly valuable biomarkers will undergo definitive evaluation. A PRoBE evaluation study should be conducted for biomarkers that show promise in discovery studies that use the same clinical context and population. Simultaneous discovery and evaluation of the performance of a marker or marker combination can be undertaken by using a PRoBE design and randomly splitting the dataset into a training set for discovery and a test set for evaluation.

The importance of defining the intended clinical context in which a biomarker will be used during the initial phases of its development also entails the modeling and analysis of the cost-benefit effect of its implementation in the clinic. Such modeling and analysis is intended to aid the optimized combination of the developed biomarker with other existing modalities to increase their combined impact on the targeted population. EDRN expects that applicants will develop active collaborations with investigators funded by the NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET; http://cisnet.cancer.gov/index.html), which will facilitate the efficient incorporation of cost-benefit effect modeling and analysis in the study design and the development of biomarkers.

Collaborative Interactions. To expedite clinical application, the validation of the biomarkers will be performed in collaboration with the other EDRN scientific components (i.e., CVCs, BRLs, and DMCC). For more details, see the Process of Biomarker Validation in FOA Guidelines, Section I: http://edrn.nci.nih.gov/FOA-guidelines).

In addition, for discovery technology and molecular tools, applicants are encouraged to develop collaborations with investigators participating in various NCI-sponsored programs, such as Specialized Programs of Research Excellence (SPOREs) (http://spores.nci.nih.gov), the Innovative Molecular Analysis Technology (IMAT) (http://innovation.cancer.gov), Clinical Proteomics Technology Assessment Program (http://proteomics.cancer.gov), NCI Alliance for Nanotechnology in Cancer (http://nano.cancer.gov), The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov), the Cancer Genetics Network (CGN) (http://epi.grants.cancer.gov/CGN/), the Mouse Models of Human Cancers Consortium (MMHCC) (http://emice.nci.nih.gov), and the Tumor Microenvironment Network (TMEN) (http://tmen.nci.nih.gov). With respect to these collaborations, applicants must advise any collaborating investigators from these programs that their institutions will be subject to the resource sharing and intellectual property requirements set forth in Section IV.2 of this FOA under Collaborations and in Section IV.6 under Other Submission Requirements and Information.

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.

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.

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 U01 cooperative agreement award mechanism(s).The Project Directors/Principal Investigators (PDs/PIs) 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 or PDs/PIs retain(s) 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(s)/PI(s), as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award."

2. Funds Available

The estimated amount of funds available for support of 20-25 projects awarded as a result of this announcement is $10-11 million for fiscal year 2010. 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 $600,000 per year (direct costs). The upper budget limit may be appropriate for larger projects involving multiple laboratories (and possibly multiple PIs). Smaller projects (e.g., involving one PI and a single laboratory) are also encouraged but they are expected not to exceed $400,000 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:

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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a team science approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills, and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

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. The application should indicate success in previous years of EDRN funding in terms of biomarker development and progression to clinical validation. See Scope of Research in Section IV.2.

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.

Foreign Organizations (Non-Domestic [non-U.S.] Entity)

NIH policies concerning grants to Foreign (non-U.S.) organizations can be found in the NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260.

Applications from Foreign organizations must:

In addition, for applications from Foreign organizations:

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide Items 3a 3h for all PD/PIs. NIH requires one PD/PI be designated as the contact PD/PI for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the Contact PD/PI, et. al. The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled Multiple PD/PI Leadership Plan must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

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:

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 Preparation of the BDL Application

Instructions for the Preparation of EDRN BDL Applications 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:

Specific Sections 1-5 to be included in Research Plan are described below. (Table of Contents should be modified accordingly.)

Section 1 Biomarker Development Team

Applicants must identify the Team Leader (or Project Director) and may include members from the Team Leader’s own laboratory or members from other institutions complementing the applicant’s proposed research projects. Applications proposing multiple PD/PI Teams, as described in Applications with Multiple PDs/PIs section below, will also be considered. Specifically, each PI should employ a different technology platform for biomarker discovery and development focused on the same or different types of related cancers. For applications where only one PI is specified, the Team Leader will be the PI. The term applicant used subsequently in this FOA also refers to the prospective Team Leader.

In this section, the applicant should provide full details of the proposed team structure and describe what expertise each member of the Team encompasses, including their specialized or unique facilities, core resources, and services that relate to achieving the major objectives of the project. Applicants should describe any ongoing grant-supported, institutional, and/or private sector resources that augment or complement resources for which funding from this FOA is sought. The roles of all key personnel, collaborators, and/or consultants who are associated with the application may be briefly described; however, the full extent of activities for each participant should be covered in Section 2 below. Letters from collaborators and consultants should be included in the Appendix. Following funding decisions, the Team Leader must partner with an awarded EDRN Clinical Validation Center (CVC) and must specify which specimens are to be used in the Team’s coordinated discovery efforts. A searchable database revealing many specimens available from EDRN resources is available at the EDRN Resource Network Exchange web site (https://ginger.fhcrc.org/edrn/imp/GateServlet?pwd=).

The PI must demonstrate training and expertise in the technologies proposed to be applied to biomarker discovery and development. It is not sufficient for the PI to simply have expertise complementary to the team and manage this team as a coordinator. For example, the PI should not rely on core facilities of their institute as the primary resource to enable biomarker discovery these resources must be within the laboratory under direct oversight of the PI.

Every Team should have access to a pathologist to provide expertise in specifying characteristics of the disease encountered in the clinical specimens being tested by this group, as well as a clinical epidemiologist with expertise in defining inclusion/exclusion criteria of cohort populations to include in biomarker prevalidation and validation studies.

Every Team should designate a Project Manager with whom NCI Program staff or other Network participants can communicate regarding various details and activities of the study. Usually, the Project Manager will be the Team Leader; however, another person can be specified to fulfill this role.

Section 2 Scope of Research

For all applicants, depending on the composition and structure of the group, this section may be organized as distinct projects or as one integrated plan. In either case, the page limitation remains the same. There is no requirement for applicants to use the format of an R01 application. Instead, applicants should define the major research questions and opportunities related to objectives of EDRN that their group effort proposes to undertake. Applicants should describe the approaches to be taken by the group in the aggregate or as inter-dependent projects, and should describe the rationale for approaches to be used or planned for development. Applicants are encouraged to use this section of the application to highlight how the diverse expertise of the group members contributes to the innovation of which the group is capable, the flexibility they possess to redirect research when scientific progress warrants it, and their ability to anticipate new directions, based on their individual experience and ability to contribute to a collective effort. The roles and expertise of all key personnel, collaborators, and consultants who are associated with the application should be documented. Applicants should list and summarize each of the agreements with industry collaborators, including a description of the materials, technologies and/or expertise to be provided by such collaborators. Detailed documentation of license agreement(s), intellectual property arrangements, and data sharing concerning the proposed or existing collaboration with industrial partner(s) will be requested as appropriate if an applicant is selected for consideration for funding (for more details, see Section III of the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines). These documents must be submitted by the Institutional Technology Transfer Office.

Competing renewal applicants must include additional information in this section as a progress report summarizing the current 5-year funding period. In the progress report, the applicant should include the following (a-e) items.

a) List the Specific Aims from your previously funded proposal. Describe the progress made relevant to these specific aims. Note that other projects funded through set-aside funds and/or core funds should not be included in this discussion.

b) Detail research developments made from other EDRN funding sources such as projects funded through set-aside or EDRN core funds. Applicants should describe their participation in EDRN activities, and their contributions in terms of collaborations within, and outside the Network in meeting the EDRN mission. They are also required to list all Programmatically approved collaborative studies.

c) Provide a table listing all biomarkers that have been investigated through the previous U01 and indicate the extent to which these biomarkers have progressed in terms of the EDRN-defined phases for validation. What steps have been taken to advance biomarkers beyond the discovery and development stage to pre-validation or to Phase 2/Phase 3 clinical validation? In addition, indicate all biomarkers that have been eliminated from further investigation and briefly explain the reasons for that decision. For any unsuccessful discovery efforts, describe the alternative approaches that can be taken in the present proposal to be more effective.

d) Provide a brief synopsis of the reviews from the latest site visit by NCI Program staff and external consultants.

e) If the applicant has participated in any Network-wide validation studies, elaborate on the role(s) played and the contribution(s) made to the outcome of the study.

Section 3 Project Management Plan

Applicants must include in the Research Plan a specific section of no more than three pages labeled Project Management Plan. The page number of the Project Management Plan should be indicated in the Table of Contents. The Project Management Plan should cover the following three major requirements.

a) A tentative timeline for conducting the proposed studies (with brief descriptions of how the goals of each of the proposed specific aims will be achieved on a year-by-year basis by providing tentative, interim milestones).

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 studies during the initial 3 years of support by the U01 award. Specific aims may not be regarded as milestones (unless they include quantitative end points). The specific aims describe the goals and intended path of the proposed research. Quantitative milestones are a way of determining whether an applicant has successfully reached the specified goals. In most cases, applicants should provide a milestone for each specific aim. Milestones should be clearly stated and presented in a quantitative manner, such as numerical specifications of sensitivity and specificity or a count of some newly discovered molecules or molecular pattern(s) that can be used as biomarkers for early cancer detection, risk assessment, diagnosis or prognosis of cancer.

Several examples of quantitative milestones are listed below:

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

c) Applicants should also elaborate on a decision-tree scheme to be used during biomarker developmental studies to determine the stages at which specific biomarkers should continue to be pursued or whether to triage any biomarkers. The criteria that will be used to make these decisions should be specified, as appropriate, as well as the alternative steps that will be taken should certain biomarkers be dropped at any stage (i.e., will only the best performing biomarkers from a large set be retained [ go or no go decision] or will a new approach to biomarker discovery be taken to identify new markers?). Examples of a go or no go paradigm are provided in the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines.

Shortly before the 3 years are completed, the progress made towards these milestones will be reviewed by a site visit of the laboratory by Program staff and external expert consultants. A decision by NCI will be made at this time based on the comments from the site visit review team whether funding for this BDL should continue for the remaining period of the 5-year term.

Section 4 Collaborations

The collaborative requirements are integral to EDRN activities and applications will be judged for their scientific merit of the collaborative study, not just the individual study. Applicants must highlight, whenever possible, the collaborative component in the study with justifications as to why collaboration is needed and how this would add value to their proposed study as opposed to individual study. Applicants should describe their plans for any future collaboration for the proposed EDRN biomarker studies, both within and outside the Network.

For new applications, applicants should describe the experience of their group in collaborative programs and activities with academic and industry partners. Examples of collaborations that may be provided in support of the application include demonstrated evidence of:

a) collaborative projects and publications;

b) collaborative funding; and

c) sharing of data and resources, e.g., specimens, technologies, and research protocols.

Industry-EDRN collaboration: EDRN encourages Pharma and Biotech to participate in Network-sponsored studies for moving biomarkers through qualification for an FDA-approved clinical use. NCI will serve as a concierge to facilitate partnership with relevant laboratories and centers within EDRN.

If an Industry Partner is involved in the proposed research, acquiring a letter of commitment for resources and/or technology to be made available is required.

Section 5 - Compliance with terms and conditions of award for EDRN Cooperative Agreement

In Section 5, 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 Developmental Laboratory will be required to collaborate with at least one EDRN CVC for obtaining clinical or preclinical specimens for biomarker discovery or testing. In addition, the Applicant must work with the Network statistical core in developing research designs for testing biomarkers and sharing the data generated in these prevalidation studies with the statistical core to assess biomarker performance. Although it is not a requirement, applicants are encouraged to develop collaborations with the existing EDRN Clinical Epidemiology and Validation Centers (now called Clinical Validation Centers or CVCs; see also the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines), 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 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 the 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 Licensing and IP issues in Section III of the EDRN FOA Guidelines document at http://edrn.nci.nih.gov/FOA-guidelines).

Additional Budget-related Information

a) Applicants must adhere to the overall budget limits as defined in Section II. Funds Available.

b) The lead PD/PI must include a minimum of 1.8 person months of his/her time per year to the U01 application and award. This commitment cannot be reduced in later years of the award. For multiple PD/PI applications, the other PDs/PIs must devote a minimum of 1.2 person months effort per year to their respective projects.

c) Applicants must budget for travel and per diem expenses for SC meetings. In the first year, applicants should plan for two investigators, the Team Leader, and an additional senior investigator to attend a Planning Meeting and two SC meetings. In the second and subsequent years, applicants should plan for the PI and another investigator to attend two SC meetings per year. For multiple PD/PI teams, no more than two PDs/PIs should be budgeted for travel to these meetings.

d) Applicants must budget for travel and per diem expenses for participation in Network workshops and symposia. Applicants should plan that at least two investigators will attend a Network workshop or symposium every 18 months.

e) Applicants must set aside 30 percent of their annual budgets as follows:

During years one and two, the set aside funds may be used to foster collaborations for the discovery of new biomarkers and development of new assays. However, for years three through five, set aside funds are for but not limited to:

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

f) Applicants must budget for data collection on relevant common data elements (CDEs) for specimens during the course of study. For CDEs, please visit the EDRN web site at http://edrn.nci.nih.gov/FOA-guidelines.

Appendix Materials

All paper PHS 398 applications must provide appendix material on CD 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) Specimen Sharing: The success of EDRN is dependent on collaborative interactions of all its laboratories. 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 U01 mechanism to collect clinical specimens must state their willingness to share these samples 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.

Foreign Applications (Non-Domestic [non-U.S.] Entities)

Indicate how the proposed project has specific relevance to the mission and objectives of the NIH/IC and has the potential for significantly advancing the health sciences in the United States.

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:

The following will be considered in making funding decisions:

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: How significant would be the proposed research in terms of complementing or augmenting existing biomarker detection systems or methodologies? What is the likelihood that this research during the next five years will succeed in moving biomarkers to Phase 2 or Phase 3 in light of the EDRN-established phases of biomarker development for early detection of cancer? Has the applicant provided adequate scientific evidence from epidemiologic, model systems (cell culture, animal models) or clinical studies warranting the proposed study? What is the likelihood that the proposed study will lead to a potentially routine use of a new biomarker in 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) Does this team of investigators show a significant measure of success in experimental approaches to biomarker discovery and development? Will this team of investigators contribute unique skills to the overall Network? Is the commitment of the PD(s)/PI(s) and other key investigators in line with the scope of the proposed project? Is there evidence that different PDs/PIs and co-investigators have effectively worked together in the past?

(Renewal Applications): Have the applicants developed any biomarkers that have been tested or are currently being tested in validation or prevalidation studies? What is the likelihood that viable clinical biomarker candidates will be forthcoming from this current EDRN applicant? Are reviews from site visits conducted by NCI program and external consultants positive about the progress made by the laboratory?

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 to derive biomarkers/reagents for a variety of malignant tumors? Has the applicant provided documentation to show acquisition of high quality clinically-annotated preclinical and clinical specimens for discovery research? Are parameters, such as sensitivity, specificity, and predictive value chosen to characterize the biomarkers/reagents sufficient and appropriate? Are the study designs supported by adequate sample size and statistical reasoning? Are considerations given to minimize bias, chance, over-fitting and reproducibility issues in the proposed study design? Does the study design incorporate principles suggested by the PRoBE study design as described in Section I of the FOA Guidelines document, at http://edrn.nci.nih.gov/FOA-guidelines here)?

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 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 Steering Committee (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?

Project Management Plan: Are the milestones given in the Project Management Plan appropriate for a successful biomarker development project? Are the decision criteria well defined to select for biomarkers that are likely to succeed in clinical testing? Has the applicant justified the estimates of years required to advance the proposed biomarker developmental study toward an EDRN Phase 2 validation study?

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).

Applications from Foreign Organizations. Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, and/or environmental conditions that exist in other countries and either are not readily available in the United States (U.S.) or augment existing U.S. resources.

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 or PDs/PIs 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 U01 mechanism in accordance with the terms and conditions that are stated in the FOA. The PI [or one of the PDs/PIs] will be a voting member of the Steering Committee (SC) 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.

The PD(s)/PI(s) will have the primary responsibility to define the scientific objectives and approaches for the individual BDL, including research design and protocol development, if applicable, participant recruitment and follow-up, data collection, quality control, and interim data and safety monitoring, and to plan, conduct, analyze, and publish results.

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 Network Collaborative Studies:

The PD(s)/PI(s) will collaborate with CVCs and with other EDRN components to advance promising biomarkers towards EDRN validation studies.

The PD(s)/PI(s) 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(s)/PI(s) 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(s)/PI(s) 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.

The PD(s)/PI(s) will be responsible for accruing subjects on collaborative studies approved by the Steering Committee.

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:

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 awardees.

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

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.

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