Department of Health and Human Services

Part 1. Overview Information

Key Dates

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

This Funding Opportunity Announcement (FOA) is part of the Early Detection Research Network (EDRN) initiative. EDRN (https://edrn.nci.nih.gov/) is a national, integrated infrastructure for the development of biomarkers and the assembly of necessary resources. The goal of EDRN is the development, evaluation, and validation of biomarkers for risk assessment, detection, and the molecular diagnosis and prognosis of early cancer.

The purpose of this FOA is to solicit applications for EDRN Clinical Validation Centers (CVCs). The proposed CVCs will be responsible for conducting clinical research to validate biomarkers for early cancer detection and risk assessment and also serve as clinical resource centers for collaborative research within the EDRN by participating in collaborative biomarker validation studies and collaborating with other EDRN units. Prior affiliation with the EDRN is not required and all qualified investigators are invited to apply.

In addition to CVCs (this FOA), EDRN includes the following three scientific units, each supported by an independent FOA:

• Biomarker Developmental Laboratories (BDLs) (RFA-CA-14-014 U01), which will discover, develop, and characterize new, or refine existing, biomarkers and assays for risk assessment, detection, and the molecular diagnosis and prognosis of early cancer;

• Biomarker Reference Laboratories (BRLs) (RFA-CA-14-016 U24), which will serve as a Network resource for clinical and laboratory validation of biomarkers, including assay development and refinement;

• Data Management and Coordinating Center (DMCC) (RFA-CA-14-017 U24), which will conduct statistical and computational analyses and data management, study protocol development, study design, and coordination of EDRN-sponsored biomarker validation studies, participate in the development and maintenance of informatics infrastructure, and will coordinate Network-wide meetings and conferences.

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

Background

EDRN Scientific Premise

Since its inception in 2000, the EDRN has followed a "vertical" approach to biomarker research that facilitates collaborations and hand-offs among technology developers, basic scientists, clinicians, epidemiologists, biostatisticians, and other health professionals. It also expedites efficacious clinical applications of the molecular knowledge that has burgeoned in recent years. The NCI anticipates that EDRN investigators will collaborate with industry both to develop biomarkers and/or reagents and to provide a clinical environment for the evaluation of new technologies. Early interactions with industry leading to research collaborations are likely to benefit both EDRN grantees and industry partners. Many EDRN investigators have or have had active collaborations with the industry. It is hoped that validated biomarkers may ultimately be commercialized into diagnostic products for early detection of cancer and cancer risk assessment. Structured around four main scientific units, the EDRN currently includes 20 BDLs, three BRLs, eight CVCs, and one DMCC.

EDRN Goals

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 within the extramural community and with other NCI programs in cancer prevention, screening, and treatment to reduce cancer morbidity and mortality (see EDRN Strategic Plan, http://edrn.nci.nih.gov/docs). In the future, candidate biomarkers are likely to be discovered by integromic approaches where genomics data will increasingly be integrated with other 'omic' data, such as proteomic, epigenomic, metabolomic, etc., to take advantage of the exponentially growing genomic knowledge of the cancer landscape.

EDRN's specific interests include but are not limited to the following:

• Discover, develop, evaluate and validate promising 'omic' biomarkers (e.g., genomic, proteomic epigenomic, metabolomic) for effective cancer risk assessment, early detection, and early diagnosis and prognosis of cancer.

• Integrate biomarkers with imaging to reduce the false positive rate of imaging and to improve the detection of clinically significant cancers.

• Develop and validate biomarkers to improve the detection of cancer progression for patients on active surveillance.

• Develop assays for accelerating biomarker discovery and translation into the clinical area. This would include measures of diagnostic or predictive accuracy, sensitivity, specificity, and, whenever possible, clinical impact/benefits.

• Develop and implement diagnostic assays in support of the EDRN objectives by using multiple biomarkers, gene expression patterns, post-translational changes, epigenetic changes, and changes in metabolic profiles.

• Facilitate the development of high-throughput, sensitive assay methods to identify and implement biomarkers that are useful in assessing cancer risk, detecting early stage cancers, cancer diagnosis and prognosis.

• Support collaboration among academic and industrial leaders, whose areas of interest are in molecular biology/molecular genetics, clinical oncology, computer science, public health and/or other related areas, leading to the development of cancer diagnostics.

• Conduct clinical/epidemiological studies (e.g., cross-sectional, prospective, retrospective, etc.) in order to evaluate the predictive value of biomarkers.

• Continue to expand the informatics infrastructure to facilitate pre-competitive data sharing on biomarker discovery, development, and validation.
• Serve as a core resource so that NCI and the cancer community at large can leverage the well-developed EDRN infrastructure and expertise in order to facilitate translational cancer research and cancer therapeutic trials.

These goals are achieved through a systematic, evidence-based discovery, development, and validation of biomarkers, based upon Standard Operating Procedures (SOPs) and Common Data Elements (CDEs) developed by the EDRN investigators and described in the EDRN Manual of Operations (http://edrn.nci.nih.gov/docs). The EDRN has established a five-phase approach as a standard and a roadmap for successfully translating research on biomarker applications from the laboratory to the bedside. The five phases for biomarker discovery and validation are:

• Phase 1: The pre-clinical exploratory phase;
• Phase 2: The validation phase (case/control);
• Phase 3: The retrospective longitudinal phase;
• Phase 4: The prospective screening study phase; and
• Phase 5: The cancer control phase.

The EDRN has also proposed a coherent and comprehensive set of guidelines for biomarker discovery and validation studies for early cancer detection, diagnosis and prognosis, known as the prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) study design. The PRoBE study design includes four key units, 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. The PRoBE design involves prospectively collected biological specimens from a cohort that represents the target population envisioned for clinical application of the biomarker. Nested case-control studies, as described in the PRoBE design, can improve the quality of discovery research and increase the chances of truly valuable markers to undergo definitive evaluation. The biomarker is assayed in a blinded fashion on the specimens collected prior to and near the time of diagnosis among the case subjects and at similar times in the control subjects in the cohort. Studies using such banked specimens and data collected prior to symptoms or diagnosis are increasingly recognized as precious resources for making comparisons that have strong internal validity. Clinical studies seldom have prediagnostic specimens on most subjects because obtaining them requires following large cohorts of asymptomatic people, ideally at periodic intervals, to ascertain if they develop cancer. One biological explanation as to why prediagnostic and clinical early stage specimens may differ is that acute phase plasma proteins may be increased by inflammatory and other conditions present near the time of symptomatic diagnosis.

The articles on five-phase approach and PRoBE design are provided on the EDRN website (http://edrn.nci.nih.gov/docs).

EDRN Administrative Structure (For Information Only)

EDRN will be structured around the four main scientific units, funded through separate FOAs, to include approximately 12-16 BDLs, 4-5 BRLs, 8-9 CVCs, and one DMCC. Although individual teams of EDRN awardees (BDLs, BRLs, CVCs, and DMCC) will operate independently, they will be required to interact closely with other EDRN awardees and engage in collaborative activities with them.

The EDRN administrative structure is composed of the following:

Steering Committee: The Steering Committee, which includes representatives of the EDRN awardees and the NCI, is the governing body of EDRN that integrates the efforts of all EDRN awardees and provides oversight of collaborative activities. The Chair and co-Chair of the Steering Committee are PDs/PIs of EDRN cooperative agreement awards and are elected by the Steering Committee. Any member of the Steering Committee can offer nominations for the Chair and co-Chair. The co-Chair serves as the Chair of a small subgroup of the Steering Committee, the Executive Committee. Other members of the Executive Committee include the leading PD/PI of the DMCC, a representative PD/PI of BRLs, the NCI Project Coordinator, and the Chairs of the EDRN Collaborative Groups. The latter are based on organ site and EDRN PDs/PIs can be members of one or more Collaborative Groups.

Assisted by the Executive Committee and NCI Program staff, duties of the Chair of the Steering Committee include:

• Preside at all meetings of the Steering Committee;
• Appoint and re-appoint members of Subcommittees, Review Groups, and designate special assignments;
• Appoint ad hoc committees as needed;
• Invite consultants as needed to Subcommittees, etc.;
• Appoint EDRN liaison members to other organizations;
• Serve as an ex-officio member of all Subcommittees, ad hoc Committees, and Task Forces;
• Submit annual EDRN Progress Reports to NCI and the Network Consulting Team.

Further details of Steering Committee composition and responsibilities are provided in Section VI.2. Administrative and National Policy Requirements: Cooperative Agreement Terms and Conditions.

Headquarters: The institution of the Chair of the Steering Committee serves as the Headquarters of the EDRN. The Headquarters serve as a center for dissemination of information to investigators and institutions in EDRN, as well as to those outside the Network. The Chair serves as the PD/PI of the Headquarters and oversees the implementation of the scientific, operational, and organizational policies of the Network.

Core Fund:

The EDRN will have a restricted Core Fund that will be made available to support post-award collaborative research projects, validation of new biomarkers, expansion of the EDRN portfolio, and making the Network inclusive by supporting non-EDRN investigators. Since the Core Fund is restricted and reserved for post-award activities, no requests for Core Fund support can be made in the application in response to this FOA.

The management of the EDRN Core Fund will be a responsibility of the DMCC and will be restricted via a term of award pending review of proposed projects by the EDRN Steering Committee and NCI approval of the projects. The solicitation of requests for use of Core Fund and the organization of their review will be the responsibility of the Steering Committee. The procedure for selecting activities and releasing the funds will involve the following steps: EDRN-affiliated investigators as well as non-EDRN investigators will be able to request Core Fund support for specific collaborative activities relevant to the EDRN goals. The Steering Committee will assign these requests for review to PDs/PIs from appropriate EDRN Collaborative Groups with the assistance of external reviewers as needed. Final review and selection of requests to be recommended for funding will be conducted by the Executive Committee. Following these recommendations and the NCI approval of funds release, the DMCC will distribute the approved funds under appropriate sub-award agreements.

In the past, $2-5 million was allotted to the Core Fund and was contingent upon the availability of funds. In the new EDRN funding cycle, it is anticipated that a similar amount will be set aside for the Core Fund.

Network Consulting Team: The Network Consulting Team is composed of a Chair and non-EDRN members appointed by NCI. The Network Consulting Team 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 Network Consulting Team can recommend new research projects to the Steering Committee or to NCI. Members of the Network Consulting Team can serve on ad hoc Committees of the EDRN, internal Review Groups, and as consultants to subcommittees.

Specific Research Objectives and Requirements

Scope. This FOA encourages the submission of applications to establish and enhance EDRN CVCs. The responsibilities of CVCs will be to:

• Conduct research on the validation of biomarkers for early cancer detection and risk assessment (i.e., EDRN-defined Phase 2 and Phase 3 studies) and short-term (less than 5-year duration) prospective, comparative biomarker screening studies;

• Partner with NCI's National Clinical Trials Network (NCTN) and Cohort Consortium, and Health Maintenance Organizations (HMOs). It is recognized that partnerships with cooperative groups, cohorts and other relevant community and hospital-based programs will accelerate translational research by providing samples from their existing resources and for accruing subjects without the need of setting up an infrastructure for the collection of samples. This FOA will support forming alliances with academia and non-profit institutions, industry, and government entities for the validation and clinical implementation of biomarkers. The validation projects should take advantage of recently discovered and developed biomarkers both from within or outside of the EDRN, as well as the availability of biospecimens through the proposed partnerships. The impetus behind such partnerships is to accelerate the validation studies with existing samples and without the immediate need of prospective collections. The FOA seeks innovative strategies addressing the important issues of bringing together the necessary multi-disciplinary expertise and resources to validate biomarkers and for shortening the required time for bringing validated biomarkers to clinical use.

• Serve as a resource center for collaborative research within the Network by participating in collaborative biomarker validation studies under the coordination of the EDRN Steering Committee, by providing high quality biological specimens to other EDRN investigators for use in biomarker discovery, and by contributing biospecimens for the formation of EDRN reference sets (note that the types and quantities of specimens will be agreed upon between the individual CVC and BDL and NCI after the U01s are awarded);

• Partner with EDRN BDLs and BRLs.

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, esophagus, and stomach).

Non-responsive Applications: This FOA will not support biomarker discovery projects or other mechanistic studies, 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. Studies that did not consider ways to minimize bias between the compared groups and did not adopt principles explained in the PRoBE study design (http://edrn.nci.nih.gov/docs) (or a similar design) will not be supported. Non-responsive applications will not proceed to review.

Note: NCI will hold a pre-application informational webinar for this FOA. Date, time, and other details will be posted at (http://edrn.nci.nih.gov/).

Section II. Award Information

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

Eligible Organizations

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• Eligible Agencies of the Federal Governments
• U.S. Territory or Possession

Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

A proposed PD/PI may not serve as a contact PD/PI on more than one application submitted in response to this FOA..

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

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 IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Sudhir Srivastava, Ph.D., M.P.H.
Chief, Cancer Biomarkers Research Group
Division of Cancer Prevention
National Cancer Institute
9609 Medical Center Drive, Room 5E136, MSC 9790
Bethesda, MD 20892-9790 (for USPS Regular or Express delivery)
Rockville, MD 20850 (for non-USPS delivery)
Telephone: 240-276-7028
Fax: 240-276-7845
Email: [email protected]

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• For this specific FOA, the Research Strategy must not exceed 30 pages.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed. Additional instructions are defined below.

Facilities & Other Resources: In addition, applicants must describe the following:

• The specialized or unique facilities, core resources, and services each team member will provide to support their participation in EDRN validation studies.
• Any relevant ongoing institutional, and/or private sector support and resources that augment or complement resources for which funding from this FOA is sought.

Other Attachments: Applicants should provide additional supporting materials relevant to the proposed CVC in the categories defined below. Upload these materials as individual pdf files using the indicated file names (these file names will become bookmarks in the application).

• Filename: "Biomarker Tables": Table(s) with comprehensive lists of biomarkers investigated in current EDRN project period (for competing renewals)/preliminary studies (new applicants).

• Filename: "Certifications": Provide documentations for the relevant certifications such as: Clinical Laboratory Improvement Amendments (CLIA), College of American Pathologists (CAP), Good Laboratory Practice (GLP) etc. .

• Filename: "Patents": List patents that are relevant to the proposed study and are owned or licensed by the institutions of the PD(s)/PI(s) or other participating investigators. For all unpublished patents and patent applications, include their abstracts. For publically accessible patents, list the corresponding patent numbers/identifiers.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed. All Key Personnel must provide a detailed description of their expertise that is relevant to the proposed studies.

The PD/PI must designate a member of the CVC to serve as Project Manager who will interact with the NCI Program staff members and will communicate with other EDRN units about various details and activities of the validation study. The Project Manager will also monitor the CVC’s progress towards meeting its research goals. Although the PD/PI is expected to be the Project Manager, another person can be specified to fulfill this role.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

The following additional instructions apply:

a) The PD/PI must include a minimum of 1.8 person months of his/her time per year to the U01 award. This commitment cannot be reduced in later years of the award.

b) Applicants must set aside 30 percent of their annual budget for Network collaborative studies as follows:

• The competing renewal applicant should set aside funds from the first year onward; and
• The new applicant should set aside funds from the second year onward.

The use of the set-aside funds will be restricted for collaborative studies proposed post-award and must be reviewed by the Steering Committee. The release of these funds from individual U01 awards will be contingent upon the advice of the EDRN Executive Committee and authorization by the NCI. The amount should be presented in the Other Expenses category under the heading Network Collaborative Funds.

c) Applicants must budget for travel and per diem expenses for Steering Committee meetings. In the first year, applicants should plan for at least two senior investigators (all PDs/PIs, if desirable, or the PD/PI and a senior investigator if multi-PDs/PIs option is not used), to attend a Planning Meeting and two Steering Committee meetings. In the second and subsequent years, applicants should plan for at least two senior investigators (all PDs/PIs, if desirable, or the PD/PI and a senior investigator if multi-PDs/PIs option is not used) to attend two Steering Committee meetings per year and an EDRN Scientific Workshop every 18 months (this usually coincides with one of the Steering Committee meetings).

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: In addition to a brief description of the specific aims and approach(es) to be employed, applicants must outline the scope of the proposed research and its relevance to a specific unmet clinical need in the management of human malignancies.

Research Strategy:

Sub-section A: Overview

Outline the overall research theme of the proposed CVC, as well as the Significance and Innovation of the proposed study in the context of a specific unmet clinical need. Propose research projects on validation of biomarkers for early cancer detection and/or risk assessment that conform to EDRN-defined Phase 2 or Phase 3 studies (http://edrn.nci.nih.gov/docs). Analytical studies to establish and compare the sensitivity and specificity as well as the predictive accuracy of biomarkers in a clinical context, including inter- and intra-laboratory reproducibility to be conducted in collaboration with an EDRN BRL, may also be proposed. Projects on validation studies will be considered as the most important unit in determining the suitability of the application.

Define during the initial phases of development the intended clinical context in which a biomarker will be used and the likelihood of its use in routine clinical practice, if shown to be efficacious. This will also entail the modeling and analysis of the cost-benefit effect of its implementation in the clinic. Such modeling and analysis are 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.

Sub-section B: Previous Accomplishments

Relevant Recent Accomplishments (all applications): Applicants must provide a brief description of previous research accomplishments/preliminary studies upon which the team builds the proposed biomarker development and validation activities. .

Progress Report (renewal applications only). Include additional information in this section summarizing the current 5-year funding period and include the following items (a-e):

a) List the specific aims from your previously funded application. Describe the progress made relevant to these specific aims, and indicate the status of developed markers according to the EDRN-defined biomarker phases. Applicants should highlight their progress using the EDRN-developed Evaluation Metrics as described in the EDRN Manual of Operations (http://edrn.nci.nih.gov/docs).

b) Describe the progress made on biomarker research supported by other EDRN funding sources such as projects funded through the restricted set-aside funds or the EDRN Core Fund. If the applicant has participated in any Network-wide validation studies or other projects supported by the EDRN Core Fund, elaborate on the role(s) played and the contribution(s) made to the outcome of the studies.

c) State patient accrual and specimen collections proposed in the previous application and report the number of patients actually accrued during the current funding period, including the type of clinical information available on them. Applicants should specify features of specimen collection (e.g., study design and conduct) used to avoid bias between compared groups of cancer vs. non-cancer and to assure validity of study results, for example using principles in the PRoBE study design. Applicants should also describe the number and types of specimen aliquots collected, and numbers of these aliquots that are available for EDRN studies. They should also list the numbers and types of aliquots supplied to other EDRN investigators and to non-EDRN investigators. The same information must be provided on any specimens collected using their restricted set-aside funds.

d) Describe participation in EDRN activities and contributions in terms of collaborations within and outside the Network in meeting the goals of the EDRN (http://edrn.nci.nih.gov/docs).

e) Provide a synopsis of the review from the latest site visit by external reviewers and describe steps taken to address any concerns in these reviews.

Note: Supplementary data for this sub-section are requested under "Other Attachments" in Section IV.2. Content and Form of Application Submission.

Sub-section C: Organization of the CVC

Applicants must provide a description of the CVC organization based on the following instructions:

Applications submitted in response to this FOA are expected to bring translational research skills inherent in academic institutions, scientific expertise in industry, resources of disease-oriented networks (e.g., NCI's NCTN and Cohort Consortium, and HMOs). Custodians of such resources should be key investigators on the proposed studies. The CVC will be assembled by a PD/PI who will form a multidisciplinary team and, if appropriate, inter-institutional arrangements both for conducting the individual CVC’s research and for support of Network collaborative research projects.

Provide full details of the proposed team structure. Describe clearly the formal organizational structure of the CVC, including lines of authority and responsibility, with particular attention to the relationship of the organizational structure to the CVC's major objectives. 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 CVC should be constructed in a flexible manner to permit ad hoc affiliations with qualified groups to participate in high-priority research across the entire range of clinical studies relevant to early cancer detection and risk assessment. Investigators participating in a CVC may come from academic, community, and industrial settings. For participation in a particular study, the CVC leadership can solicit any site that has the necessary technical qualifications and accrual potential to contribute to the study's timely completion and to the CVC's accrual responsibility.

Applicants must mention if they have access to a large number of high quality, well-characterized biospecimen repositories and their willingness to share these biospecimens within EDRN.

Describe procedures for quality assurance and laboratory quality control. The procedures and the documentation should include confirmation of pathology and radiology reports and inter-laboratory comparisons of procedures and test results. Discuss experience with quality control issues and other considerations that may arise in multi-institutional studies. All new specimen collections and storage should follow the guidelines provided in the NCI Biospecimen Biorepositories and Biospecimen Research Branch's Best Practices, which are available at http://biospecimens.cancer.gov/practices/default.asp.

Describe experience in collaborating with investigators involved in biomarker discovery and development or with investigators involved in assay development, and describe plans to establish partnerships with EDRN BDLs and BRLs that will be supported by the corresponding companion FOAs.

State willingness to participate in the EDRN Research Network Exchange (ERNE; http://edrn.nci.nih.gov/), which allows investigators to locate appropriate specimens at the EDRN-supported CVCs and BDLs. Applicants must also describe and submit the distribution policy and procedures for their existing resources. The applicants must describe their plan to work with the EDRN Steering Committee and how their specimen distribution will be coordinated through their committee. The applicants should state which committee will have the veto power in case of a disagreement. The distribution of specimens collected through EDRN will be governed through the EDRN-established procedures, and the EDRN Steering Committee will be the final decision body.

Investigators participating in a CVC may come from academic, community, and industry settings. For participation in a particular study, the CVC leadership can solicit any site that has the necessary technical qualifications and accrual potential to contribute to the study's timely completion and to the CVC's accrual responsibility. Partners, such as biotechnology or diagnostic companies, who are willing to contribute to the study materially and financially agree to take the successful biomarker test to the FDA for approval, are welcome to participate in these studies. Applicants should describe the experience of their group in collaborative programs and activities with academic and industry partners.

Some examples of collaborations that may be provided in support of the application include demonstrated evidence of:

• Collaborative projects and publications;
• Collaborative funding;
• Sharing of data and resources, e.g., specimens, technology, study protocols; and
• Past participation in multi-center trials.

Applicants are encouraged to form formal collaborations with other networks, NCI's NCTN, and/or community-based organizations to broaden the coverage of different organ sites and accrual. Because early detection and treatment issues are often related, the CVC may need participation from various medical organizations. For some activities, the CVC may need to relate programmatically to other research infrastructures supported by the NCI (e.g., Specialized Programs of Research Excellence (SPOREs), Breast and Colon Cancer Family Registries (http://epi.grants.cancer.gov/CFR/about_breast.html;

http://epi.grants.cancer.gov/CFR/about_colon.html), Cooperative Human Tissue Network), with ongoing NCI clinical research programs/trials (e.g., NCI Community Oncology Research Program (NCORP), Prostate, Lung, Colon, and Ovarian Trial (PLCO), NCTN), or with other Federal agencies. Certain types of trials in earlier detection, especially those involving treatment, may best be conducted as inter-group studies with treatment-oriented groups such as NCI's NCTN, NCI-designated Cancer Centers, international collaborators, clinical epidemiologists, and HMOs. The need for such cooperation should be anticipated and provided by the CVC leadership.

Sub-section D: Research Project

Applicants may propose studies that can be conducted within the individual CVC or through inter-institutional collaboration. It is essential, however, that the CVCs identify and concentrate their resources on the most promising scientific opportunities, that studies be completed as planned, and that the methodologies employed are sound and, where appropriate, innovative.

Research projects may include, but are not limited to:

• Cross-section or case-control studies to determine the sensitivity and specificity of a defined biomarker or biomarker panel in clinically appropriate populations (EDRN-defined Phase 2 study);
• Determine the specificity of a defined biomarker or biomarker panel to detect preclinical disease (EDRN-defined Phase 3 study);
• Determine the accuracy of a biomarker or panel of biomarkers to predict progression from a precancerous lesion to cancer;
• Determine the accuracy of biomarkers to predict the extent or severity of disease;
• Evaluate methodological approaches for combining multiple biomarkers for early detection or risk assessment in clinical settings;
• Perform comprehensive studies in targeted, high-risk populations for validation and potential integration of novel detection strategies; and
• Evaluate gene-environmental interactions for understanding risk and variations (polymorphisms) in susceptibility in high-risk cohorts.

Applicants should concisely describe their proposed biomarker validation research projects by following the EDRN-established Phase 2 and Phase 3 guidelines and using key elements of PRoBE study design (or a similar design) to avoid bias and make best use of resources. The study design must be supported by adequate sample size and statistical reasoning, and considerations for minimizing bias, chance, overfitting and reproducibility issues must be provided. Provide preliminary data from EDRN-defined Phase 1 and/or Phase 2 biomarker studies, including biomarker performance criteria, in support of the proposed validation study(s). Applicants must describe the significance, background, rationale, preliminary data, study design, and approaches for the proposed studies. Applicant should focus on validation studies that are likely to yield significant results within 3 years, which will allow the applicant to make a go or no go decision for further study. The success of the project will be measured by the criteria conforming to the FDA’s Biomarker Qualification Program guidelines (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284076.htm).

A clear statement on how statistical power is defined in multiple tests and what sample size is required to achieve this power is required. Examples of power definition: (a) the probability to detect at least one of possible true non-zero effects; (b) the probability to detect all non-zero effects; and (c) true discovery rate, etc. Also, in case-control designs, clear descriptions of whether matching is involved and what cofounders are adjusted for and why, are required.

Applicants must note that a multi-center validation study will not commence until the study protocol is reviewed by the Steering Committee and approved by the NCI and registered with the EDRN DMCC. All statistical analyses will be conducted by DMCC in collaboration with the funded investigators. In case of a Phase 2 or Phase 3 multi-center validation trial requiring new specimen collection, the use of EDRN’s Validation Study Information System (VSIMS) is mandatory. Partners, such as biotechnology or diagnostic companies, who are willing to contribute to the study materially and financially agree to take the successful biomarker test to the FDA for approval, are welcome to participate in these studies.

Patient Accrual. Applicants must document their ability to recruit patients, procure specimens prospectively, collect epidemiological and clinical data using EDRN-developed CDEs (http://edrn.nci.nih.gov/docs/cde, and process, track, and store specimens. Applicants should describe in detail any proposed prospective specimen collections, either new or ongoing, that will be used for EDRN activities. The description should include information on the types of patients and controls to be accrued, retention and follow-up plans, clinical and epidemiological information to be collected, types of high-quality specimens to be collected and other relevant information on specimen collection, processing and storage. Describe any relevant quality assurance and quality control programs, including on-site audits that assure high-quality research and patient safety. Applicants should specify features of specimen collection (e.g., study design and conduct) used to avoid bias between compared groups of cancer vs. non-cancer and to assure validity of study results (e.g., using principles in the PRoBE study design). Active prospective collections can be proposed only for validation studies proposed in this application and in collaboration with NCTN or any ongoing trials that provide a unique opportunity for prospective longitudinal collection for major epithelial cancers to ensure the success of the collaborative Network research projects. If the applicants already have specimen repositories that they are willing to make available to ERDN-collaborative studies, they should describe the purpose of the study(s) from which samples are being made available and the extent of the clinical information collected. Sites with adequate existing case-control repositories that will be available to EDRN investigators should furnish a list of types and number of specimens by organ site and provide information on histopathological stage and clinical grade and the availability of follow-up data.

Sub-section E: Collaborative Resource of the Network

Explain how the proposed CVC can serve as a collaborative resource of the Network. In general, CVCs will be expected to facilitate the discovery, clinical validation, and clinical application of biomarkers through participation in multi-institutional studies.

CVCs will provide archived specimens (regardless of the funding source) for discovery and validation studies. Propose active prospective collections only for:

• Validation studies proposed in this application;
• EDRN-sponsored Reference Set collections;
• Studies proposed by other EDRN investigators that have been recommended by the Steering Committee and approved by NCI; and
• Collaborative studies with NCTN or any ongoing trials outside the EDRN that provide a unique opportunity for prospective longitudinal collection of specimens for major epithelial cancers to ensure the success of collaborative Network research projects.

Describe how the proposed CVC will provide expertise on population studies, study protocol development, pathological assessment, and participate in data quality control, analysis, and interpretation of validation studies. Specific areas to address are listed below.

• Specimen Collection Guidelines. The EDRN Steering Committee has developed guidelines for the collection and distribution of specimen reference sets for collaborative Network research (http://edrn.nci.nih.gov/). It is anticipated that CVCs will help develop additional guidelines for new reference sets.

• Biomarker Database. EDRN is in the process of developing a biomarker database. Explain the potential of the proposed CVC to share clinical epidemiology expertise and leading the expert review of the captured biological, clinical, and epidemiological data on biomarkers to be included in the database. For planning your role, note that the final biomarker lists and supporting data for all organ sites will be presented to an NCI-appointed Biomarker Expert Group for final recommendation for inclusion in the biomarker database.

• Partnering with EDRN BDLs and BRLs. To facilitate the development and validation of clinically useful biomarkers, all awarded CVCs must partner with awarded EDRN BDLs that focus on cancers in the same organ sites. After the awards are made, NCI will work with the funded CVCs and BDLs to establish these partnerships. Where appropriate, the CVC will also partner with an EDRN BRL that has the expertise to help develop the biomarker assays being employed by the CVC and BDLs.

The partnering between CVCs and BDLs will include but will not be limited to:

• CVC will consult with BDLs on study design;
• CVC will consult with BDLs on clinical matters such as selection of subjects and specimens and performance parameters that markers need to be clinically useful;
• CVC will provide the BDLs with adequate specimens for biomarker discovery and development;
• BDLs will work with CVC to validate biomarkers developed in their laboratories.

Sub-section F: Project Management Plan

Applicants should provide a Project Management Plan that covers the following:

1) Tentative timelines for conducting the proposed validation studies and specimen collections that briefly describe how and when the goals of the projects will be achieved. For a validation study, the timeline could include:

• Defining the patient population;
• Procuring the biospecimens;
• Analytical validation of the assay and creation of needed standard reagents;
• Assay completion and data analysis.

For a proposed biospecimen collection, the timeline could include:

• Assembling the team, including other collections sites;
• Study protocol approval by the Steering Committee and NCI;
• IRB and MTA approvals;
• Initiation of accrual;
• Completion of accrual.

2) Overall Project Milestones, which must be 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 for the U01 award. Specific aims may not be regarded as milestones (unless they include quantitative end points). 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 or project.

Any application lacking acceptable milestones will be considered incomplete.

Shortly before completion of the third year of award, the progress made towards these milestones and achieving the proposed timelines will be reviewed by site visit of the CVC by Program staff and expert external consultants. A decision by NCI will be made at this time based on the comments from the site visit review team as to whether funding for this CVC should continue for the remaining period of the 5-year term.

Applicants must list quantitative milestones related to their proposed biomarker projects and validation studies (Sub-section D: Research Project). The following are examples of quantitative milestones:

• Complete biomarker assay(s) on sera for 200 colorectal cancer cases and 200 matched controls, analyze data, and deposit results on EDRN secure website.
• Complete biomarker assay(s) using prediagnostic sera from 200 patients who develop colorectal cancer and from 200 matched controls, analyze data and deposit results on EDRN secure website.

Applicants must list quantitative milestones related to any proposed patient and specimen accrual and to specimen distribution to other EDRN and non-EDRN investigators (Sub-section E: Collaborative Resource of the Network). The following is an example of a quantitative milestone.

• Accrual of 500 new colorectal cancer cases and 500 matched controls and associated CDEs as described in the application; collect, process and store twelve 500-microliter aliquots of sera and twelve 500-microliter aliquots of plasma for each subject.

Applicants must list quantitative milestones related to establishing collaborative projects with EDRN BDLs (Sub-section E: Collaborative Resource of the Network: Partnering with EDRN BDLs and BRLs). The following is an example of a quantitative milestone:

• Establish collaborative projects with two EDRN BDLs and provide specimens to these BDLs for both discovery and EDRN-defined Phase 2 studies.

Letters of Support: In addition to standard items, provide:

• Letters of commitment for resources and/or technology made available by industry partners involved in the proposed research.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide with the following modifications.

All applications, regardless of the amount of direct costs requested for any one year, should address a Resource and Data Sharing Plan.

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

(a) 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.

(b) Intellectual Property: Collaboration among EDRN investigators, as well as between Network investigators and third-party industry partners is a core mission of the EDRN, which entails the sharing of intellectual property arising out of research resources developed in Network-related activities.

Applicants are expected to submit an Intellectual Property Management Plan (IPMP) in line with the accepted IP Rights and Responsibilities (http://edrn.nci.nih.gov/docs). The proposed plan should address 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. Any approved IPMP will become a condition of the award.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

4. Intergovernmental Review (E.O. 12372)

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.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NCI, NIH. Applications that are incomplete and/or non-responsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of 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 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 review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific 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, or preventative interventions that drive this field?

In addition, specific to this FOA: What is the likelihood that proposed biomarkers will be adopted into routine clinical practice if shown to be efficacious?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, 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; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, specific to this FOA: Do the research experience and qualifications of the PDs/PIs and co-investigators demonstrate an understanding of the design, administration, and analysis of multi-institutional clinical research? Has the applicant adequately addressed his/her institutional patent policy?

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 or methodologies, instrumentation, 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 or methodologies, instrumentation, 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?

In addition, specific to this FOA: Do the proposed biomarker validation studies incorporate principles suggested by the PRoBE (or a similar) study design? Has the applicant provided adequate data from EDRN-defined Phase 1 and/or Phase 2 biomarker studies to warrant the proposed validation trial? The articles on the phases of biomarker development and the PRoBE study design are provided on the EDRN website (http://edrn.nci.nih.gov/docs). Are parameters chosen to characterize the biomarkers/reagents, including biomarker performance criteria and the proposed study design, sufficient and appropriate?

Do the applicants present a sound plan for patient recruitment, retention, and follow up, for high quality specimen collection, processing, and storage, and for obtaining high quality clinical and epidemiological information linked to specimens? Do appropriate quality assurance and quality control programs exist? Are institutional data management and statistical analyses, procedures, and policies adequate, appropriate, and consistent with accepted standards? Will the Network collaboration be utilized when necessary to satisfy the requirements for timely completion of proposed studies?

Are the plans for partnering with EDRN BDLs and BRLs sound and adequately described?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

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, or collaborative arrangements?

In addition, specific to this FOA: Do the applicants have access to appropriate patient populations? Do they have access to a well-annotated biorepository with an appropriate collection of samples and, in particular, preclinical samples? Does the applicant have access to pathology reviews and documentation of the pathology reports? Does the applicant have access to treatment information and other necessary patient data, such as medical history?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Collaborative Strengths

Are the proposed collaborations justified? Is there partnership with NCTN, Cohort Consortium, and/or HMOs? Are the roles of collaborating units clearly defined? Are there adequate plans for effective interaction and coordination with the Network units, the Steering Committee, the DMCC, and the NCI? Has the applicant developed collaborations with an industrial partner(s), if applicable, who are committed to submit the validated assays for FDA approval?

Project Management Plan

Are the milestones provided in the Project Management Plan quantitative and appropriate to allow for an evaluation of the progress made by the CVCs on the proposed biomarker validation projects, specimen collections, and partnering with BDLs? Are the decision criteria well defined for the selection of those biomarkers that are likely to succeed in clinical testing?

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. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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 AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the current funding period. The following aspects will be evaluated:

Did the applicants undertake and complete the biomarker validation projects proposed in the previous application or supported with set-aside/Core funds? Were any other biomarkers from within and outside the EDRN moved forward towards clinical validation? Did the applicants accrue the numbers of patients and types of specimens proposed in their original application or supported with set-aside/Core funds? Was a reasonable fraction of these specimens provided to other investigators or used in EDRN validation studies or in the assembly of reference sets? Did the PD/PI participate in EDRN Steering Committee meetings, workshops and other collaborative activities? Is the review from the site visit conducted by NCI Program staff and external consultants positive and has the PD/PI addressed any concerns identified by the reviewers?

Revisions

Not Applicable

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS)

Intellectual Property Management Plan: Reviewers will comment, as appropriate, on the adequacy and feasibility of the sharing of research resources plan and the Intellectual Property Management Plan (IPMP). Comments on the plans and any concerns will be presented in an administrative note in the Summary Statement. NCI Program staff will consider the adequacy of the plans in determining whether to recommend an application for award.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Cancer Advisory Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities. This aspect will include the adequacy of the Intellectual Property Management Plan.

3. Anticipated Announcement and Award Dates

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.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

The award will also include a restricted Network Collaborative Fund that will be used to support research collaboration between the awardee and other EDRN units as recommended by the EDRN Steering Committee and approved by the NCI.

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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (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.

The PD/PI will have the primary responsibility for:

• Defining the scientific objectives and approaches for the individual CVC, including research design and study protocol development, participant recruitment and follow-up, data collection, quality control, and interim data and safety monitoring, and to plan, conduct, analyze, and publish results;

• 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 this FOA;

• Participating in and being a voting member of the Steering Committee. In accordance with this cooperative agreement, the PD/PI together with a senior investigator, will attend a Planning Meeting and two Steering Committee meetings in the first year, two Steering Committee 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 Steering Committee meetings);

• Accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee to the extent consistent with applicable grant regulations;

• Coordinating the CVC's efforts within EDRN and cooperating with the other units of the Network and with NCI staff members;
• Overseeing the implementation of the approved data sharing plan as appropriate; and

• Ensuring that experimental data and their format, analytical algorithms, computational modeling and visualizations, and other bioinformatics tools resulting from this FOA are compatible with the NIH-approved bioinformatics platforms, such as those designed and implemented by the NCI Center for Biomedical Informatics and Information Technology (CBIIT; http://cbiit.nci.nih.gov/).

In addition, the following responsibilities and obligations apply:

• The PD/PI and his/her awardee institution will be accountable for implementing the approved research resource sharing plan as appropriate;

• All institutions/organizations participating in a given CVC will be expected to share with each other knowledge, data, research materials, and any other resources necessary and relevant to the EDRN CVC award;

• Each CVC and the entire EDRN program will be subject to external evaluation (coordinated by the NIH). EDRN PD(s)/PI(s) will be expected to participate in such evaluations;

• 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; and

• The PD(s)/PI(s) will be required to partner with at least one BDL for providing clinical or preclinical specimens for biomarker discovery or testing.

PD/PI Responsibilities for Network Collaborative Studies:

• Develop validation studies with other EDRN investigators and seek funding in support of those activities from the EDRN Core Fund as needed;
• Accept and implement the goals, priorities, common study protocols, procedures, and policies agreed upon by the Steering Committee for the individual and Network collaborative studies;
• Ensure Network and NCI review and approval of study protocols, concepts, final protocol documents, informed consents, and study amendments, and advise NCI of changes in protocol status;
• Collaborate on common research designs or protocols, including methods and requirements for joint participation and collaboration as recommended by the Steering Committee, and handling of data, including appropriate sharing of methods and data among collaborating organizations;

• Advise any collaborating investigators outside of EDRN that their institutions will also need to agree to be subject to the EDRN resource sharing and intellectual property requirements.
• Accrue subjects on collaborative studies approved by the Steering Committee. Awardees will be expected to submit information on specimen collections per the Network’s CDEs and register their protocols with the DMCC.

If requested by NCI, the PD/PI must ship specimens from newly accrued patients to NCI toward the formation of reference sets. All specimen collection and storage should follow the guidelines provided in the NCI Biospecimen Biorepositories and Biospecimen Research Branch's Best Practices (http://biospecimens.cancer.gov/practices/default.asp).

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

A designated NCI Program staff member serving as Project Coordinator will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members may also become substantially involved as needed.

Main NCI responsibilities include the following:

• Coordinating and facilitating various activities of the EDRN program;
• Participating in the activities of the EDRN Steering Committee;
• Serving as a liaison between the Steering Committee, the EDRN awardees, and the NIH;
• Ensuring that there are effective mechanisms to enable electronic communication among the Network units, and between the EDRN and the NCI. The NCI Project Coordinator will oversee this in coordination with the NCI CBIIT;
• Assisting the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action;
• Assisting the investigators in avoiding unwarranted duplications of effort across the Network;
• Co-organizing and participating in the EDRN-sponsored meetings;
• Monitoring the scientific progress of individual U01/U24 awards and the entire EDRN program;
• Reviewing the compliance of EDRN awardees with the recommendations developed by the Steering Committee; and coordinating external evaluation of the Network.
• Authorizing the use of funds from the EDRN Core Fund and individual set-aside funds for activities reviewed and recommended by the Steering Committee.
• The NCI reserves the right to adjust funding, withhold, suspend, or terminate the support to those Network awardee institutions that are unable to meet the performance requirements set forth in these Terms and Conditions of Award, or significantly change the level of performance.
• Additionally, an NCI Program Director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Program Officials may also have substantial programmatic involvement (as Project Scientists).

Areas of Joint Responsibility Include:

Steering Committee: The EDRN Steering Committee will convene after all the Network units have been funded and will be composed of the following voting members:

• All PD(s)/PI(s) representing each EDRN U01/U24 award; and

• The NCI-designated Project Coordinator.

Each voting member will have one vote.

Additional NIH staff members may participate in Steering Committee meetings as non-voting members as needed (for example to provide additional expertise). The non-voting members may include representatives from NCI extramural divisions and a representative from the NCI CBIIT.

Additional non-voting members may participate on the Steering Committee in an advisory capacity on an as needed basis and decided by the existing voting committee members.

The Chair of the Steering Committee (who cannot be NIH staff member) will be selected by the Steering Committee. The awardee institution represented by the Chair of the Steering Committee will serve as the Headquarters (for definition, see Section I. Funding Opportunity Description. EDRN Administrative Structure).

The Steering Committee will meet twice every year, at locations selected by the Steering Committee in consultation with the NCI.

The Steering Committee may establish sub-committees for specific purposes. The NCI Project Coordinator/Scientists will serve on such sub-committees, as they deem appropriate.

Primary responsibilities of the Steering Committee include, but are not limited to, the following activities:

• Updating and refining established Network policies and procedures;
• Updating and refining established policies and procedures for collaborative projects, study protocols, and Network-defined projects;
• Updating and refining established policies and procedures for reviewing changes in projects not showing translational significance at the request of the laboratories/centers, and making recommendations to the NCI for replacing the project with more promising ones with revised scope and adjusted budget (increase in the budget will not be permitted);
• Updating and refining established standards or decision criteria for validating biomarkers/reagents for further clinical studies, such as testing early detection strategies, or as risk factors;
• Updating and refining established policies and procedures for accepting, reviewing, and recommending proposals from investigators outside the Network for supplemental funding and expanding the Network participation;
• Establishing a Data and Safety Monitoring Committee for clinical trials as appropriate to ensure protection of human subjects;
• Reviewing patient accrual, follow-up, study protocol compliance, results of audits, and regulatory requirements at the participating Centers and formally report the results of its reviews to the NCI;
• Promoting and fostering the inclusion of women and ethnic minorities in clinical studies and assure the completeness of informed consent;
• Tracking the Network research progress and assuring 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;
• Planning one Workshop every 18 months 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 Project Coordinator, members of the Network Consulting Team, and other NCI staff will provide the Steering Committee with advice on participants for the workshops. The DMCC will manage the logistics for these meetings.
• At any time during the course of a Network project (e.g., collaborative research supported by the Core Fund), the Steering Committee may ask a BDL or CVC to serve as a BRL on an as needed basis with appropriate compensation from the Core Fund. The Steering Committee may also examine the validation data for biomarkers/reagents developed by the Network, and decide when a biomarker is sufficiently validated, or recommend when to stop non-productive experiments relating to biomarkers validation.
• Discussing and authorizing the development of reagents or assay refinement through BRLs, CVCs, or the private sector.
• Approving collaborative studies/study protocols. Data will be submitted centrally to the DMCC. The Steering Committee will define the rules regarding access to data and publications consistent with NCI policies.
• Determining the lead investigators of Network-wide validation studies in consultation with the NCI.
• Discussing and authorizing collaborative projects to be pursued with support of the set-aside funds from individual U01/U24 awards.
• Reviewing (with assistance of external reviewers, as needed) and discussing collaborative projects to be pursued with support of the EDRN Core Fund and individual set-aside funds.

• Advising NCI on activating funds for the recommended collaborative projects.

• Implementing the policy that the resource sharing and intellectual property requirements set forth for EDRN awardees are also adhered to by collaborating non-EDRN investigators and their institutions, including those involved in Core Fund supported activities (e.g., investigators/institutions participating in validation studies).

Dispute Resolution Process

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 Dispute Resolution. A Dispute Resolution Panel composed of three members 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 right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

Approved Resource Sharing and Intellectual Property plans will become a condition of the grant award and Progress Reports must contain information on activities for the sharing of research resources and intellectual property.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Scientific/Research Contact(s)

Sudhir Srivastava, Ph.D., MPH
National Cancer Institute (NCI)
Telephone: 240-276-7028
Email: [email protected]

Peer Review Contact(s)

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Financial/Grants Management Contact(s)

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

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 Part 52 and 45 CFR Parts 74 and 92.