It is critical that applicants follow the Research (R) 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.

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

The purpose of this FOA is to solicit applications for Clinical Validation Centers (CVCs); one of the three scientific units of the Early Detection Research Network (EDRN). EDRN (http://edrn.nci.nih.gov/) is an integrated infrastructure to develop and validate biomarkers and imaging methods for the detection of early stage cancers and risk assessment. Clinical Validation Centers (CVCs) will conduct research to validate biomarkers and/or imaging methods for risk assessment and detection of early stage cancers. CVCs will also serve as resource centers for collaborative research within the EDRN by partnering with BCCs to provide high-quality specimens for Phase 1 and 2 biomarker refinement studies, as well as collaborating with other CVCs, BCCs and the DMCC for conducting Network collaborative biomarker validation studies. The CVCs must also have the expertise and ability to conduct Phase 4 clinical utility trials of validated early detection biomarkers and/or imaging methods. The other two scientific units of the EDRN are Biomarker Characterization Centers (BCCs) and a Data Management and Coordinating Center (DMCC).

Each BCC (RFA-CA-21-035 U2C) will have two functional components: (1) a Biomarker Developmental Laboratory, which will discover, develop, characterize and test new biomarkers or refine existing biomarkers and (2) a Biomarker Reference Laboratory, which will (i) develop, refine and/or standardize biomarker assays and (ii) provide resources and support for the validation of biomarkers developed by the EDRN.

Data Management and Coordinating Center (DMCC) (RFA-CA-21-034 U24), which will support the coordination and management of EDRN-sponsored biomarker and/or imaging validation studies, provides statistical and computational analyses, supports an informatics infrastructure and repository, assists with study design of collaborative projects, manages Core Funds, and coordinates Network-wide meetings and workshops.

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.

The mission of the EDRN is to discover, develop, and validate biomarkers and imaging methods to detect early stage cancers and precancers that are likely to progress and to translate these into clinical tests. EDRN is a highly collaborative program that helps coordinate biomarker research within the extramural community and with other NCI programs in cancer prevention, screening, and treatment to reduce cancer incidence, morbidity and mortality (see EDRN Strategic Plan, https://edrn.nci.nih.gov/about/bookshelf). Since its inception in 2000, the EDRN has followed a "vertical" approach to develop and validate early detection biomarkers that relies on collaborations and hand-offs among technology developers, basic scientists, clinicians, radiologists, epidemiologists, biostatisticians, and other health professionals.

The NCI expects 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 fruitful collaborations with the industry in the past. It is hoped that validated molecular biomarkers and/or imaging methods will ultimately be commercialized into diagnostic products for early detection of cancer and cancer risk assessment, and subsequently be tested in clinical utility trials.

The EDRN provides an infrastructure to expedite the clinical application of molecular and imaging data through its knowledge environment, which was developed in collaboration with NASA's Jet Propulsion Laboratory (JPL). The architecture of the knowledge environment is based on supporting and linking diverse molecular data (genomics, proteomics etc.) to clinical phenotypes and imaging. The EDRN Informatics Center (IC) at JPL leverages cloud-based capabilities to support the increasing data and computational demands of the program. The infrastructure also supports capabilities to run repeat analyses of complex genomics and proteomics data, image analysis including radiomics, and other complex data types. Over the years, EDRN has built several data repositories on biomarkers, imaging, and analytical tools. These resources will be employed to help build specific, interoperable data platforms that will allow investigators to mine and analyze data using artificial intelligence (AI) and other machine learning languages (MLL). Data science is poised to play a major role for new or improved risk stratification, early detection, and precision prevention strategies, particularly in patients with ambiguous symptoms or at high risk for the disease. In recent years, EDRN has amassed large amounts of imaging data and combined it with clinical information to diagnose patients, recognize tumor types, and/or make any follow-up care and treatment decisions. These imaging and data analytics will provide unprecedented opportunities for in silico biomarker discovery, accurately identify early-stage aggressive neoplasms from indolent or benign lesions for many cancers and make more accurate predictions about their aggressiveness.

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 diagnosis and prognosis of early stage cancers and pre-neoplastic lesions.
• Develop and validate biomarkers to improve the detection of cancer progression for patients on active surveillance.
• Develop and implement diagnostic assays/tests for accelerating biomarker discovery and translation into the clinic. This would include measures of diagnostic or predictive accuracy, sensitivity, specificity.
• Facilitate the development of high-throughput, sensitive assay methods to identify, verify and validate biomarkers that are useful in assessment of risk, detection, diagnosis and prognosis of early stage cancers or their lethal precursors.
• Integrate molecular biomarkers with imaging approaches to improve performance of tests, reduce false positive rates, and improve detection of clinically significant cancers.
• Implement, expand and/or modify new or existing imaging modalities, protocols, and associated informatics to improve performance of tests.
• Develop and implement AI and MLL algorithms to facilitate the discovery and translation of multiplex biomarkers.
• Support collaboration among academic and industrial leaders, whose areas of interest are in molecular biology/molecular genetics, imaging, data science, clinical oncology, public health and/or other related areas, leading to the development of early cancer diagnostics.
• Conduct clinical/epidemiological studies (e.g., cross-sectional, prospective, retrospective) in order to evaluate the predictive value of biomarkers.
• Improve the informatics infrastructure to facilitate precompetitive data and/or image 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, clinical utility trials, and cancer prevention and 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, as well as Network scientific, operational, and organizational policies and procedures as described in the EDRN Manual of Operations (https://edrn.nci.nih.gov/about/bookshelf). The EDRN has established a five-phase biomarker development framework 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 clinical assay validation phase (case/control);
• Phase 3: The retrospective longitudinal validation phase;
• Phase 4: The prospective screening 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 (see link below). 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 study 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 study 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 and other molecules may be increased by inflammatory and other conditions present near the time of symptomatic diagnosis.

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

EDRN will be structured around the three main scientific units BCCs, CVCs and DMCC. Although individual teams of EDRN awardees (BCCs, 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 current 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 PD/PI or MPI from BCCs who are involved in assay development, the NCI Project Coordinator, and the Chairs of the EDRN Collaborative Groups. (EDRN Collaborative Groups are based on organ sites and EDRN PDs/PIs can be members of one or more Collaborative Groups.)

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

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 EDRN Executive Committee. Following these recommendations and the NCI approval of funds release, the DMCC will distribute the approved funds under appropriate subaward agreements.

Network Consulting Team: The Network Consulting Team (NCT) provides independent oversight of research directions and progress of EDRN and is composed of experts in oncology who are not EDRN members and who do not receive funding from EDRN. They are drawn from the extramural community, the FDA, and the private sector. The NCT evaluates EDRN to ensure that the Network is responsive to promising scientific, technological, and collaborative opportunities, by exhibiting flexibility in its structure, composition and decision-making process, and prioritizing decisions free from conflicts of interest. The NCT meets biannually.

Scope. This FOA encourages the submission of applications to establish and enhance EDRN CVCs. Prior affiliation with the EDRN is not required and all qualified investigators are invited to apply.

The responsibilities of CVCs include:

• Conduct research on the validation of biomarkers and/or imaging methods for cancer risk assessment, early cancer detection and early cancer diagnosis and prognosis (i.e., EDRN-defined Phase 2, Phase 3 and Phase 4 validation studies), as well as short-term (less than 5-year duration) prospective, biomarker screening studies.
• Develop and validate biomarkers for early detection of cancers to reduce gaps in early detection among different racial/ethnic groups. Partner with patient advocates and with clinical centers that provide the ability to accrue patients from underserved and hard to reach communities and minorities who are at greatest risk of late stage diagnosis, and laboratories that are conducting research on differences in biomarker performance in different ethnic/racial groups.
• Participate in EDRN-sponsored clinical utility trials. The EDRN intends to conduct one or two biomarker utility trials. The objective of such utility trials is to demonstrate the ability of validated diagnostic tests to prevent adverse health outcomes, such as morbidity and mortality, and to improve clinical management and adoption in clinical practice. Examples of clinical utility endpoints include, but are not limited to, stage shift of detected cancers, reduction in the number of unnecessary diagnostic workups, improved benefit vs. harm test outcome, and cost effectiveness. Such clinical utility trials will be designed post-award under the guidance and approval of the EDRN Steering Committee and will be supported by EDRN Core funds and set-aside funds of individual awards. For the purpose of this FOA, applicants should express their interest in participating in such trials and list resources available to support these trials. Prioritization and selection will be made by the EDRN Steering Committee based on clinical significance, expertise of the funded CVCs and BCCs, readily available catchment areas, and other available resources.
• 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, and where applicable PRoBE-compliant, biological specimens to other EDRN investigators, and by contributing biospecimens for the formation of EDRN standard reference sets (note that the types and quantities of specimens will be agreed upon between the individual CVCs, BCCs, and NCI after the U01s/U2Cs are awarded).
• Partner with EDRN BCCs by providing expertise in the design of their post-award biomarker developmental projects, defining unmet clinical needs, and providing high-quality biological specimens for use in biomarker refinement and characterization.
• Develop a plan to support early-stage/junior investigators who wish to enhance or refocus their careers on biomarker research, including investigators from underrepresented minorities.

Partnerships with National Health Research Programs and Organizations: It is recognized that CVCs may accelerate translational research by establishing partnerships with other translational research infrastructures and resources supported by the NCI, including cancer centers and cooperative groups, the Specialized Programs of Research Excellence (SPOREs), established cohorts and other relevant community and hospital-based programs, including NCI's National Clinical Trials Network (NCTN; https://www.cancer.gov/research/infrastructure/clinical-trials/nctn), the National Clinical Oncology Research Program (NCORP; https://ncorp.cancer.gov/), the Clinical and Translational Science Awards Program (CTSA; https://ncats.nih.gov/ctsa), the Prostate, Lung, Colon, and Ovary (PLCO) Screening Trial, the Cohort Consortium (https://epi.grants.cancer.gov/cohort-consortium/), the Breast and Colon Cancer Family Registries (https://epi.grants.cancer.gov/cancer-registries/; https://epi.grants.cancer.gov/survivor-cohort-resources/ccfr.html), Cooperative Human Tissue Network (CHTN, https://www.chtn.org/), as well as other Federal agencies and Health Maintenance Organizations (HMOs). These partnerships will provide access to samples from existing resources while also contributing to the accrual of 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 and 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.

Types of Cancer: Applications on cancers of major public health concern (e.g., those of the prostate, breast, colon, and lung) or on cancers that are major causes of cancer-related morbidity and mortality (e.g., those of the ovary, pancreas, liver,esophagus, and stomach) are encouraged. Focus on individual tests for more than one cancer type or on one test for simultaneous detection of multiple cancers is acceptable.

Non-responsive Applications: This FOA will not support research on new genome-wide association studies (GWAS), 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. Applications using convenience samples (i.e., samples to be used were not collected based on SOPs and/or the intended clinical use of the biomarkers to be developed and, for phase 3 studies, not in compliance with the PRoBE or a similar study design for minimizing bias) will also be considered non-responsive. Non-responsive applications will not proceed to review.

Note: NCI will hold a pre-application informational webinar for this FOA. When published, the related Notice will be linked with the FOA and webinar details will also be posted at http://edrn.nci.nih.gov/.

See Section VIII. Other Information for award authorities and regulations.

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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

• Eligible Agencies of the Federal Government
• 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.

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) 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.
• o 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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.

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.

An investigator designated as a Contact PD/PI of an application under this FOA must not be the designated Contact PD/PI of another application under this initiative or under any of the companion FOAs.

The Contact PD/PI can be a Multi-Principal Investigator (MPI) or Co-I on another application, whether for this FOA or its companion FOAs. An MPI on a CVC application may be an MPI or a Co-I on another application, whether in response to this FOA or any of the companion FOAs.

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

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).

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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.

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.
National Cancer Institute
Telephone: 240-276-7028
Email: [email protected]

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 section is limited to 30 pages.

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.

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

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

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 file names as indicated in the examples provided below (these file names will become bookmarks in the application).

• Filename: "Biomarker Tables": Provide a table(s) with comprehensive lists of biomarkers investigated in current EDRN project period (for competing renewals) and preliminary studies (both renewal and new applicants).
• Filename: "Certifications": List any 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 PD/PI or other participating investigators. For all unpublished patents and patent applications include their abstracts. For publicly accessible patents, list the corresponding patent numbers.

All instructions in the SF424 (R&R) Application Guide must be followed. The PD/PI must also designate a member of the CVC to serve as Project Manager who will liaise with his/her counterpart at the NCI and will communicate with other EDRN centers 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 designated to fulfill this role.

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

The following additional instructions apply:

a) Leadership Effort Commitment: The contact-PD/PI must include a minimum of 1.2 person months of his/her time per year to the U01 award. This commitment cannot be reduced in later years of the award. For multiple PD/PI applications, each of the other PD(s)/PI(s) must devote a minimum of 1.2 person months effort per year to their respective projects.

b) Set-Aside Funds: Applicants must set aside 30 percent of their annual budget from the second year onward for Network collaborative studies. Network collaborative studies, including utility trials (Phase 4), will be discussed and developed post-award. Release of the set-aside funds will be given preference in support of utility trials.

The use of the set-aside funds will be restricted for Network collaborative studies and must be reviewed by the Steering Committee and approved by the NCI for release from the individual U01 awards.

The set-aside amount should be presented in the "Other Expenses" category under the heading Network Collaborative Funds.

c) Single Institutional Review Board (sIRB): Applicants should budget for sIRB expenses, if applicable to the proposed study.

d) Support of early-stage/junior career investigators: The budget should include funds to support the professional development and training activities for early-stage/junior investigators who wish to enhance or refocus their careers on biomarker research, including investigators from underrepresented minorities.

e) Travel Funds: Applicants must budget for travel and per diem expenses to attend Steering Committee and other Network-sponsored meetings. Applicants should plan for the PDs/PIs and other CVC members (including early-stage/junior investigators), to attend the 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 Scientific Workshop every 18 months (this usually coincides with one of the Steering Committee meetings).

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

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

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 and/or imaging methods for early cancer detection and/or risk assessment that conform to EDRN-defined Phase 2, Phase 3 or Phase 4 studies (https://edrn.nci.nih.gov/about/bookshelf). 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 BCC (its BRL component), may also be proposed (partnering with a BRL will be negotiated and decided upon post-award). Projects on validation studies and their likelihood of leading to a Phase 4 utility trial will be considered as the most important part in determining the suitability of the application.

Define the intended clinical context in which a biomarker will be used and the likelihood of its use in routine clinical practice. This will include the modeling and analysis of the cost-benefit effect of its implementation in the clinic. Such modeling and analysis are intended to aid the development of an optimized combination of the biomarker with other existing modalities to increase their combined impact on the targeted population. For further support with the incorporation of cost-benefit effect modeling and analysis in the study design and the development of biomarkers, applicants may consider developing active collaborations with investigators funded by the NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET; http://cisnet.cancer.gov/index.html).

Sub-section B: Previous Accomplishments

Relevant Recent Accomplishments (all applications): Applicants must provide a brief description of previous research accomplishments relevant to the development of biomarkers and/or imaging methods.

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

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 (https://edrn.nci.nih.gov/about/bookshelf).

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 the 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 (as described in Strategic Plan at https://edrn.nci.nih.gov/about/bookshelf).

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 and technological expertise in industry, and resources from disease-oriented networks (e.g., NCI's NCTN, NCORP, CTSA, and Cohort Consortium, NCI-designated Cancer Centers and Cooperative Groups, 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, as well as to ensure the ability to accrue patients from underserved and hard to reach communities and minorities and/or collaborate with laboratories that are conducting research on differences in biomarker performance in different ethnic/racial groups.

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 assembled in a flexible manner to allow for other investigators and qualified groups to join for conducting high-priority clinical studies on 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, while ensuring equity and inclusion among different racial/ethnic groups.

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, including some examples of demonstrated evidence of productive partnerships and collaborations (e.g., Collaborative projects and publications; Collaborative funding; Sharing of data and resources such as specimens, technology, study protocols; Past participation in multi-center trials, etc.).

Applicants should describe experience in collaborating with investigators involved in biomarker discovery and development or with investigators involved in assay development and describe plans to establish post-award partnerships with EDRN BCCs (BDLs and BRLs) that will be supported by the corresponding companion FOA (RFA-CA-21-035).

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

Applicants must describe and submit the distribution policy and procedures for their existing biospecimen resources, as well as 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.

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 https://biospecimens.cancer.gov/bestpractices/overview.asp.

Applicants are expected to participate in the development of validation study protocols, Standard Operating Procedures (SOPs), common data elements (CDEs), etc., in collaboration with other CVCs, BCCs and the DMCC. CVCs are also expected to coordinate with the EDRN DMCC for biospecimen blinding, biospecimen data deposition in a Laboratory Information Management System (LIMS) supported by the DMCC, to contribute to data analysis and data sharing, as well as for populating all biomarker relevant information into the Biomarker Data Commons.

Applicants are encouraged to form formal collaborations with other programs, networks and/or community-based organizations to broaden the coverage of different organ sites and for accrual from ethnically and racially diverse populations. 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 translational research infrastructures and resources supported by the NCI - e.g., Specialized Programs of Research Excellence (SPOREs), Breast and Colon Cancer Family Registries (https://epi.grants.cancer.gov/cancer-registries/; https://epi.grants.cancer.gov/survivor-cohort-resources/ccfr.html), Cooperative Human Tissue Network (CHTN, https://www.chtn.org/), with ongoing NCI clinical research programs/trials such as the NCI Community Oncology Research Program (NCORP; https://ncorp.cancer.gov/), the Clinical and Translational Science Awards Program (CTSA; https://ncats.nih.gov/ctsa), the Cohort Consortium (https://epi.grants.cancer.gov/cohort-consortium/), the Prostate, Lung, Colon, and Ovary (PLCO) Screening Trial, 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 National Clinical Trials Network (NCTN ; https://www.cancer.gov/research/infrastructure/clinical-trials/nctn), NCI-designated Cancer Centers, international collaborators, clinical epidemiologists, and Health Maintenance Organizations (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, such as the use of imaging and radiomics methods as well as machine learning language algorithms and AI approaches.

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 approaches and strategies

Applicants should concisely describe their proposed biomarker validation research projects by following the EDRN-established Phase 2, Phase 3 and Phase 4 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 must be described for minimizing bias, chance, overfitting and reproducibility issues. A description of the target population must be included in which the validated biomarkers will be used. It is preferred that the biospecimens included in a validation study are representative of the diversity in the US population.

Applicants must provide preliminary data from EDRN-defined Phase 1, Phase 2 and/or Phase 3 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. Applicants should focus on validation studies that are likely to yield significant results within 3 years, which will allow the applicants to make a go or no-go decision for further study. The success of the project(s) 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 must be provided on how statistical power is defined in multiple tests and what sample size is required to achieve this power. 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 EDRN Steering Committee, approved by the NCI, and registered with the EDRN DMCC. All statistical analyses will be conducted by the DMCC in collaboration with the funded investigators. In case of a Phase 2, Phase 3 or Phase 4 multi-center validation trial requiring new specimen collection, the use of EDRN’s LIMS supported by the DMCC is mandatory. The single Institutional Review Board (sIRB) policy must be adhered to, with the designation of the DMCC as the sIRB-site of record. 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 must document their ability to recruit patients, procure specimens prospectively, collect epidemiological and clinical data using EDRN-developed CDEs (https://edrn.nci.nih.gov/data-and-resources/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 data/metadata that are positioned to best inform the performance of the biomarker test in the target population, types of high-quality specimens to be collected and other relevant information on specimen collection, processing and storage. The clinical and epidemiological variables include, but are not limited to, age, gender, race/ethnicity, exposure to risk factors, family disease history, method of diagnosis (screen detected, symptom-detected, incidental, etc.), histopathology, etc.

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 where necessary in collaboration with 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.

Applicants may consider developing active collaborations with investigators funded by the NCI’s CISNET program (http://cisnet.cancer.gov/index.html) for obtaining support with the use of mathematical/statistical data modeling approaches to predict the translational efficacy of the proposed biomarkers. The employment of such models in study design will ensure a greater chance of success of the proposed validation studies and for the validated biomarkers reaching the clinic. Late-phase biomarker studies are generally limited in the early detection strategies they can evaluate due to the need for very large sample sizes and long-term follow-up. This is particularly problematic as options for precision screening expand and novel early detection technologies proliferate. There are three key components of disease models: natural history of disease (including disease- and stage-specific survival/mortality), performance of proposed screening test, and outcomes with and without screening. Models integrate information about these components to translate performance to outcomes of benefit and harm. A fourth component involves gathering model projections and computing evaluation metrics such as cost effectiveness, with specific metrics tied to the model objective. The goal of disease modeling in the early detection setting is to project key clinical and policy-relevant outcomes, and to determine the ratio of benefits (e.g. cancer deaths prevented, years of life saved) versus harms (e.g. unnecessary biopsies, overdiagnosis). Projecting the benefit of an early detection/screening test requires an estimate of baseline survival in the absence of the test as well as an estimate of how this changes under screening. Active collaborations with CISNET investigators will be of particular importance for the validation of multi-cancer biomarker tests and for the design and conduct of Phase 4 biomarker utility trials.

Sub-section E: Collaborative Resource of the Network

As a collaborative resource of the Network, CVCs will facilitate the biomarker refinement and characterization of biomarkers, as well as their clinical validation and clinical application through participation in multi-institutional studies. CVCs will provide archived specimens (regardless of the funding source) for refinement, characterization, and clinical validation studies.

Propose active prospective collections only for:

• Validation studies proposed in this application;
• EDRN-sponsored Reference Set collections (in conjunction with proposed validation studies requiring prospective sample collection);
• Studies proposed post-award by other EDRN investigators that have been recommended by the Steering Committee and approved by NCI; and
• Collaborative studies with 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, participate in validation study data quality control, analysis, and interpretation. The EDRN Steering Committee has developed guidelines for the collection and distribution of specimen reference sets for collaborative Network research (https://edrn.nci.nih.gov/data-and-resources/sample-reference-sets), and CVCs are expected to help develop additional guidelines for new reference sets.

EDRN Biomarker curation in biomarker database. Describe the proposed CVC's expertise in clinical epidemiology, which will be crucial in leading the expert review of the captured biological, clinical, and epidemiological data on biomarkers to be included in the EDRN Biomarker Database. 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 BCCs (BDLs and BRLs). To facilitate the development and validation of clinically useful biomarkers, all awarded CVCs must partner with awarded EDRN BCCs that focus on cancers in the same organ sites. Partnership with a BRL will provide necessary expertise to help develop and analytically validate the biomarker clinical assays being employed by the partnering CVC and BDLs. After the awards are made, NCI will work with the funded CVCs and BCCs to establish these partnerships.

The partnering between CVCs and BCCs 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 meet to be clinically useful;
• CVC will provide the BDLs with adequate, high-quality, and where applicable PRoBE-compliant specimens for biomarker refinement, characterization and development;
• BCCs will work with appropriate CVCs to validate biomarkers developed in their laboratories.

Participation in EDRN-sponsored biomarker validation and clinical utility trials. Applicants must describe their expertise in designing and conducting clinical utility trials (Phase 4), and their ability to establish a network of catchment areas of ethnically, racially, and socioeconomically diverse populations. These post-award trials will be designed by the EDRN Steering Committee and funded with CORE and set-aside funds. Applicants with demonstrated expertise and access to catchment areas with specific patient populations may consider proposing to participate in ongoing EDRN-sponsored validation studies or proposing a potential Phase 4 trial on any of the EDRN FDA- or CLIA-approved test(s). A list of ongoing EDRN validation studies and FDA- and CLIA-approved biomarker tests is provided in EDRN Scientific Advances available at https://edrn.nci.nih.gov/about/bookshelf.

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 in conjunction with a validation study, the timeline could include:

• Assembling the team, including other collection sites;
• Study protocol development and approval by the Steering Committee and NCI;
• IRB and MTA approvals;
• Where appropriate, registration of study on NIH Clinical Trials website (https://clinicaltrials.gov/);
• Initiation of patient enrollment and accrual;
• Completion of patient enrollment and 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). While Specific aims describe the goals and intended path of the proposed research, quantitative milestones are a way of determining whether an applicant has successfully accomplished the specified goals. In most cases, applicants should provide a milestone for each specific aim or project.

Shortly before completion of the third year of award, the progress made towards these milestones and achieving the proposed timelines will be reviewed by a virtual or in-person 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 the overall goals of the CVC should be adjusted and/or modified for remaining period of the 5-year term.

Any application lacking acceptable milestones will be considered

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 CVCs and BCCs (BDLs and/or BRLs) (Sub-section E: Collaborative Resource of the Network: Partnering with EDRN BCCs). The following is an example of a quantitative milestone:

Establish collaborative projects with two EDRN BCCs and provide specimens to these BCC-BDLs for biomarker refinement and for EDRN-defined Phase 2 studies; establish a collaborative project with an EDRN BCC (BRL) to develop and analytically validate a clinical-grade assay for a specific biomarker or a multiplexed biomarker panel.

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 as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a 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 centers. 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, academic and 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 (https://edrn.nci.nih.gov/about/bookshelf). 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:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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.

This initiative is not subject to intergovernmental review.

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.

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 How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 and compliance with application instructions by the Center for Scientific Review and responsiveness by NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials: A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation

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).

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.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Specific to this FOA: What is the likelihood that the proposed biomarkers and/or imaging methods will be adopted into routine clinical practice if shown to be efficacious?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

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, including screening trial (Phase 4) study design and/or conduct?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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 Phase 2 and/or Phase 3 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 (https://edrn.nci.nih.gov/about/bookshelf). Are parameters chosen to characterize the biomarkers/imaging methods/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 BCCs (BDL and/or BRL functional components) 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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

Specific to this FOA: Do the applicants have access to appropriate patient populations that include a racial and ethnic diversity that is representative of the US population that can support the design and conduct of Phase 3 and Phase 4 biomarker studies? 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?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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? Are the roles of collaborating units clearly defined? Are there adequate plans for effective interaction and coordination with the other Network units, the Steering Committee, the DMCC, and the NCI? Has the applicant developed collaborations with an industry partner(s), if applicable, who is 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 CVC on the proposed biomarker validation projects, specimen collections, and partnering with BCCs (BDLs and/or BRLs)? Are the decision criteria well defined for the selection of those biomarkers that are likely to succeed in clinical testing?

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

For research that involves human subjects but does not involve one of the 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 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.

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 individuals of all ages (including children and older adults) 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.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

For Renewals, the committee will consider the progress made in the last funding period. 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

Not Applicable.

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.

Not Applicable.

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).

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) Genomic Data Sharing Plan (GDS).

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.

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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 recipient’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.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE

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, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75.

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 PDs/PIs will have the primary responsibility for:

• Defining the scientific objectives and approaches and overseeing the scientific research in the CVC, including research design and study protocol development, participant recruitment and follow-up (if applicable), data collection, quality control, interim data and safety monitoring, analyzing and interpreting research data, reporting results to the scientific community and publishing results.
• Being accountable 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.
• Committing and maintaining throughout the life of the CVC a minimum of 1.2 person-months of effort per year for any investigator designated as a PD/PI (contact PD/PI or MPI) of the CVC.
• Agreeing to be an active participant in the EDRN, including collaborative activities and attending and organizing meetings/scientific workshops. In accordance with this cooperative agreement, the contact PD/PI together with at least one MPI and/or an early-career/junior investigator, will attend the 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).
• Serving on the EDRN Steering Committee and participating as a voting member of the Steering Committee.
• Organizing scientific working groups to facilitate collaborative projects and cross-testing of experimental, analytical and validation concepts.
• 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 efforts within EDRN and cooperating with the other scientific units of the Network and with NCI staff members.
• Overseeing the implementation of the approved resource and data sharing plan; the PDs/PIs and their awardee institutions will be accountable for implementing the approved plan.
• Sharing of knowledge, data, research materials, and any other resources necessary and relevant to the EDRN CVC award among all institutions/organizations participating in each CVC, as well as with other EDRN awardees.
• Disseminating research resources (e.g., approaches, methods, models, software, tools, biospecimens) to the scientific community and posting these resources on the EDRN website, when appropriate.
• Ensuring that data are deposited in a timely manner to the EDRN DMCC for collaborative projects.
• Ensuring that experimental data and their format, analytical algorithms, computational modeling and data 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 & Information Technology (CBIIT; http://cbiit.nci.nih.gov/), as well as with the EDRN-developed informatics platforms.
• Abiding by the governance of the EDRN and all program policies agreed upon by the EDRN Steering Committee and approved by NCI Program Officials to the extent consistent with the applicable rules and regulations.
• Reporting progress to the NCI Program Officials on all CVC research and outreach activities annually. The PDs/PIs may be expected to provide additional information, outside the scope of the standard reporting requirement, as needed and requested by program staff members.
• Being prepared for the site visits of NCI Program staff members and participating in the NCI-coordinated evaluation of the CVC and the overall EDRN program, including site visits and the timely submission of required progress reports.
• 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.

PDs/PIs Responsibilities for Network Collaborative Studies:

• Accepting and implementing the goals, priorities, common study protocols, procedures, and policies agreed upon by the Steering Committee for the individual and Network collaborative studies to the extent consistent with grant regulations.
• Ensuring Network and NCI review and approval of study protocols, concepts, final protocol documents, informed consents, and study amendments, and advising/informing NCI of changes in study protocol status.
• Collaborating on common study 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.
• Accruing subjects on collaborative studies approved by the Steering Committee. Awardees will be expected to submit information on specimen collections per EDRN-developed CDEs and register their study protocols with the DMCC.
• Advising 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.

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 Official serving as the 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. 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. Additional Program Officials who are not responsible for the normal scientific and programmatic stewardship of the award may be designated as Project Scientists and assist in Network activities.

The specific roles of the substantially involved NCI staff members include the following activities:

• Coordinating and facilitating various activities of the EDRN program.
• Participating in the activities of the EDRN Steering Committee as voting and/or non-voting members.
• Serving as a liaison between the Steering Committee, the EDRN awardees, and the NIH;
• Ensuring that there is effective communication among the Network units, and between the EDRN and the NCI.
• Assisting the Steering Committee in developing and drafting Network operating policies and policies for dealing with recurring situations that require coordinated action.
• Facilitating collaborative research efforts that involve multiple EDRN awardees.
• Assisting the Steering Committee, the EDRN DMCC, and individual EDRN awardees in avoiding unwarranted duplication of efforts across the EDRN.
• Assisting the awardees as a resource in facilitating their broader interactions with other NCI and NIH programs to disseminate results, tools, and models from the EDRN and take advantage of existing NIH/NCI resources and infrastructures.
• Co-organizing and participating in the EDRN-sponsored meetings.
• Monitoring the scientific progress of individual U01/U2C/U24 awards and the entire EDRN program.
• Reviewing the compliance of EDRN awardees with the recommendations developed by the Steering Committee.
• 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.

Areas of Joint Responsibility include:

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

• All PDs/PIs representing each EDRN U01/U2C/U24 award.
• The NCI-designated Project Coordinator.

Each voting member will have one vote.

Additional NIH staff 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 an NIH staff) will be selected by the Steering Committee.

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 subcommittees for specific purposes. The NCI Project Coordinator/Scientists and Program Officials will serve on such subcommittees, as appropriate.

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

• Identifying scientific and policy issues that need to be, or can benefit by being, addressed at the Network level and develop recommendations to NIH/NCI Program Officials for addressing such issues.
• Updating and refining established policies and procedures, including those for collaborative projects, protocols, and Network-defined projects.
• Updating and refining established policies and procedures at the request of specific EDRN centers for reviewing changes in projects not showing translational significance, 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 Board 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 EDRN centers and formally report the results of its reviews to the NCI.
• Promoting and fostering the inclusion of women and racial/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 scientific workshop every 18 months during the Network project period to inform the scientific community and relevant patient advocacy groups of the progress made toward qualification 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 BCC or a CVC to serve the Network for developing clinical-grade assays 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 BCCs, CVCs, or the private sector.
• Reviewing (with assistance of external reviewers, as needed) and discussing collaborative projects/study protocols to be pursued with support of the EDRN Core Fund and individual set-aside funds. 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.
• Advising NCI on activating funds for the recommended collaborative projects.
• Determining the lead investigators for 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 U2C/U01/U24 awards.
• Reviewing progress of the EDRN toward meeting the overall Network goals.
• Ensuring that all EDRN members utilize the resources developed by the EDRN DMCC and JPL IC, as well as existing NCI and NIH resources and programs.
• 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).

Network scientific, operational, and organizational policies and procedures, are also described in the EDRN Manual of Operations (https://edrn.nci.nih.gov/about/bookshelf).

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.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

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

Christos Patriotis, Ph.D.,
National Cancer Institute (NCI)
Telephone: 240-276-7134
Email: [email protected]

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

Amy R. Bartosch
National Cancer Institute (NCI)
Telephone: 240-276-6375
Email: [email protected]

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.

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 Part 75.