Part 1. Overview Information

Key Dates

It is critical that applicants follow the Multi-Project (M) 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this FOA is to solicit applications for Biomarker Characterization Centers (BCCs); a scientific unit 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. The other two scientific units of the EDRN are Clinical Validation Centers (CVCs) and a Data Management and Coordinating Center (DMCC).

Each BCC will have two main functional components (1) a Biomarker Developmental Laboratory (BDL), which will discover, develop, characterize and test new biomarkers or refine existing biomarkers, and (2) a Biomarker Reference Laboratory (BRL), 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. Both components will participate in collaborative projects with other laboratories and centers.

CVCs (RFA-CA-22-039; U01) will conduct research to validate biomarkers and 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 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 clinical utility trials of validated early detection biomarkers and/or imaging methods.

DMCC (RFA-CA-21-034; U24) will support the coordination and management of EDRN-sponsored biomarker and/or imaging validation studies, provide statistical and computational analyses, support data science with an informatics infrastructure and repository, assist with study design of collaborative projects, manage Core Funds, and coordinate 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.

Background

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 available at 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 rely 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 investigators and industry partners. Many EDRN investigators have had fruitful collaborations with the industry in the past. It is hoped that validated 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 at JPL (JPL IC) 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 in 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 preneoplastic 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, and specificity.
• Facilitate the development of high-throughput, sensitive assay methods to identify, verify and validate biomarkers that are useful in the assessment of risk, detection, diagnosis, and prognosis of early-stage cancers or their lethal precursors.
• Integrate molecular biomarkers with imaging approaches to improve the performance of tests, reduce false-positive rates, and improve the detection of clinically significant cancers.
• Implement, expand and/or modify new or existing imaging modalities, protocols, and associated informatics to improve the 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 pre-competitive data and/or image sharing for 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 (MOP) (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 biomarkers from the laboratory to the bedside. The five phases for biomarker discovery and validation are:

• Phase 1: The preclinical 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 the five-phase approach and PRoBE study design are available on the EDRN website (https://edrn.nci.nih.gov/about/bookshelf).

EDRN Administrative and Governance Structure (For Information Only)

EDRN will be structured around the three main scientific units - BCCs, CVCs, and DMCC. Although individual teams of EDRN awardees for the 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 make 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 the responsibility of the DMCC and will be restricted via a term of the award pending evaluation 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. The 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 disburse 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.

Specific Research Objectives and Requirements

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

The functions of the BCCs include:

• Discover, develop, characterize and test new biomarkers and/or refine existing biomarkers and/or develop imaging methods for detection, risk assessment, and molecular diagnosis and prognosis of early-stage cancers.
• Develop new approaches, methodologies, and technologies to detect candidate biomarkers.
• Access to Clinical Laboratory Improvement Amendments (CLIA) or College of American Pathologists (CAP) laboratories that are compliant with Good Laboratory Practice (GLP) or Good Manufacturing Practice (GMP) guidelines to standardize and scaleup assays and validate the analytical performance of biomarkers.
• Collaborate with other EDRN BCCs and CVCs to conduct collaborative research projects, including combining biomarkers to improve their performance, the design of post-award biomarker developmental projects, and/or blinded verification of developed assays.
• Participate in and help organize EDRN Steering Committee Meetings and scientific workshops.
• Develop a plan for the professional development of early-stage/junior investigators.
• In addition to the above functions, a BCC may also develop a robust data science-based biomarker discovery/developmental (in silico) research project.

Examples of specific research areas include but are not limited to:

• Discover, develop and validate biomarkers (e.g., genomic, proteomic, epigenomic, metabolomic, glycomic) for identification of cancer risk, early detection, and early diagnosis and prognosis of cancers.
• Use genomic and proteomic approaches to identify secreted proteins, membrane-associated proteins, and/or protein profiles that correlate with the presence of precancerous and cancerous lesions.
• Develop and validate new blood- or other bodily fluid- and tissue-related biomarker tests for early detection and diagnosis in order to identify clinically significant cancers and predictions of clinical outcomes, with or without conventional tissue examination.
• Develop and validate tests for simultaneous detection of multiple cancers (pan cancers); validation of such approaches will be decided by the EDRN Steering Committee post-award.
• Integrate genetic information, cell signaling, and biochemical pathways into biomarker discovery strategies to have a broader applicability across different tumor types. Determine the potential of novel network- and pathway-based markers to detect and diagnose cancers early.
• Integrate biomarkers and imaging methods to improve early detection and prediction of progression.
• Profiling of genes, proteins, cellular and/or subcellular features, and other molecules or molecular signatures that correlate with the presence of precancerous and cancerous lesions or for risk assessment.
• Develop AI/MLL algorithms to analyze big data (existing or generated by current studies) to aid in the development and characterization of biomarkers.
• Develop validation studies, verification and optimization of assays, and improvement of diagnostic methods.

Required Capabilities of the BCC

Each BCC will consist of a multidisciplinary, collaborative team with the expertise required to discover and develop biomarkers as well as capabilities to develop clinical-grade biomarker assays. It is desirable that expertise should include, but is not limited to:

• Cancer biomarker expertise in 'omics' technologies (e.g., genomics and/or proteomics and/or epigenomics and/or metabolomics, etc.) using biofluids, bulk tissues, and/or single cells.
• Clinical expertise such as pathology, molecular pathology, clinical oncology, cancer screening, surgery, radiology, and epidemiology;
• Include imaging expertise, such as imaging physics, radiomics and other approaches for quantitative description of large volumes of radiological images, if applicable;
• Knowledge of data science in relation to in silico biomarker discovery, if applicable;
• Expertise in bioengineering and synthetic biomarker development, if applicable;
• Expertise in determining measures of diagnostic discrimination: sensitivity, specificity, and predictive accuracy of tests; development of appropriate and rigorous CLIA/CAP/GMP/GLP-compliant formats and systems.

Structure of the BCC

Each BCC will consist of an Administrative Core and two highly integrated functional components, a BDL, and a BRL. A brief description of each is provided below, and more application-related details are provided in Section IV. Application and Submission Information of this FOA.

Administrative Core

The Administrative Core will be led by the contact PD/PI of the BCC. Multi-PD/PI and multi-institution applications are encouraged because of the distinct yet integrated nature of the BDL and BRL projects. The primary role is to ensure integrated operations of the BDL and BRL components. The Admin Core will also work with the EDRN DMCC to provide logistical and organizational support. It will ensure that the overall BCC conforms with the agreed practices and principles of the EDRN SOPs, CDEs, and data sharing plan as approved by the EDRN Steering Committee post-award and/or outlined in the EDRN MOP. The Administrative Core will also ensure bidirectional exchange of findings and insights with other BCCs and CVCs, provide resources and support for the validation of biomarkers developed by the EDRN, and ensure participation in collaborative projects with other laboratories and centers.

Biomarker Developmental Laboratory (BDL)

The primary responsibility is to discover, develop, characterize and test new biomarkers or refine existing biomarker-based diagnostic or early detection tests. The approach may include one or more broad discovery platforms or data mining or in silico approaches to support and/or complement discovery efforts. Within EDRN, BDLs will be the primary source of new biomarkers or panels of biomarkers on which validation studies will be conducted. BDLs may also develop new technologies to detect candidate biomarkers, integrate them with imaging methods, and work collaboratively with other laboratories to combine biomarkers to improve the test performance. Integration of multiple discovery platforms, use of modern tools and technologies, as well as data science and MLL algorithms are encouraged. The platforms need to be amenable to clinical use and supported through CLIA regulations.

Biomarker Reference Laboratory (BRL)

The primary responsibility is to develop, refine and/or standardize biomarker assays, either for the BCC it is part of or for other EDRN BCCs and/or CVCs. For early detection screening tests, it is crucial to develop appropriate high-throughput assays/technologies that are accurate, reproducible, and cost-effective. The BRL will provide resources and support for analytical and clinical validation of biomarker assays, including testing of candidate biomarkers, development of assays and/or their refinement, and standardization of assay methods as requested by the EDRN Steering Committee. When appropriate, BRLs must follow the principles described in the PRoBE (or a similar) study design. In addition to general sound laboratory practices, BRLs must adhere to the theory and principles of CLIA or CAP laboratories that are compliant with GLP or GMP practices. The main functions of a BRL component are: (1) methodology/protocol development; (2) assay design; (3) assay optimization; (4) assay validation and clinical application development; and (5) quality control program.

Types of Cancer: Applications on cancers of the breast, and other lethal cancers, e.g., sarcoma, stomach, melanoma, bladder, endometrial, etc. are encouraged. Currently, EDRN has a representation of BCCs for cancers of the prostate, lung, colon, and ovary based on response to the previous BCC FOA (RFA-CA-21-035). In addition, discovery of biomarkers for pancreatic cancer and liver cancer is conducted separately through the Pancreatic Cancer Detection Consortium (https://prevention.cancer.gov/major-programs/pancreatic-cancer-detection-consortium) and the Translational Liver Cancer Consortium (https://prevention.cancer.gov/major-programs/translational-liver-cancer-consortium), respectively. Applications focused on these cancer types will be considered of a lower priority to this FOA. 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 cancers 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 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 on the EDRN website (http://edrn.nci.nih.gov/).

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

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

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.

• 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.
  • 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; 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 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 diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

Given the multi-component nature of the EDRN BCC and the multidisciplinary expertise required for an exemplary response to the BCC objectives, this FOA encourages the use of the multi-PD/PI option.

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 the companion FOA (RFA-CA-22-039). The Contact PD/PI can be an MPI or Co-I on another application, whether for this FOA or its companion FOA. An MPI on a BCC application may be an MPI or a Co-I on another application, whether in response to this FOA or the companion FOA.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. 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 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

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

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

The letter of intent should be sent to:

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

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: Required
• Administrative Core: Required, maximum of 1
• Biomarker Developmental Laboratory (BDL): Required, maximum of 1
• Biomarker Reference Laboratory (BRL): Required, maximum of 1

Overall Component

When preparing your application, use Component Type Overall .

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project Summary /Abstract: Succinctly describe the types of biomarkers proposed and the tumor type(s) selected for the study to be conducted by the BCC. State briefly how the research will address a clinically unmet need and enhance public health.

Project Narrative: Describe the biomarker characterization project that must encompass a strong focus on discovery followed by clinical-grade assay development.

Facilities & Other Resources: In addition to the information required in the standard instructions, highlight available facilities and/or services that can be leveraged for the biomarker discovery and development (e.g., well-annotated existing cohorts, experimental and/or computational platforms etc.).

In addition, applicants must describe the following:

• The specialized or unique facilities, core resources, and services each team member will provide towards achieving the objectives of the proposed studies.
• The PDs/PIs should not rely on core facilities of their institute as the primary resource to enable biomarker discovery these resources must be within the laboratory under direct oversight of the PDs/PIs.
• 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 research for which funding from this FOA is sought in the categories defined below. Upload these materials as individual pdf files using the indicated file names (these file names will become bookmarks in the application).

• Filename: "Biomarker Tables": Provide in a tabular form the comprehensive lists of biomarkers investigated in research by the PD(s)/PI(s).
• Filename "Developed Assays": Provide Tables listing previously developed biomarker assays.
• Filename "Certifications": Provide documentation for the relevant certifications such as: CLIA, CAP, GLP, GMP etc.
• Filename "Patents": List patents that are relevant to the proposed study and are owned or licensed by the institutions of the PD(s)/PI(s) or other participating investigators. For all unpublished patents and patent applications, include their abstracts. For publicly accessible patents, list the corresponding patent numbers/identifiers.

Project/Performance Site Locations (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

In addition, the following specific requirements must be addressed:

• BCC team must have access to a pathologist to provide expertise in specifying characteristics of the disease encountered in the clinical specimens being tested.
• BCC team must have involvement of a clinical epidemiologist (or a biostatistician with appropriate clinical epidemiology expertise in research design) to understand and apply the five-phase biomarker development approach and principles of the PRoBE study design for discovery and pre-validation of biomarkers to assure strength of results between the compared groups.
• BCC team must include early-stage/junior investigators.
• Please also review "Required Capabilities of the BCC" described earlier for additional BCC-specific expertise.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

Introduction to Application:For Resubmission applications, an Introduction to Application is required in the Overall component.

Specific Aims: Outline the scope, overall vision, and goals for the proposed EDRN BCC for the funding period. Include a statement on the intended use/indication of the proposed product (e.g. diagnostic assay) and the public health gap the product is intended to fill. The goals must be overarching, a high-level view, and be distinct from the aims of the individual components, i.e., the BDL and BRL components.

Research Strategy: In lieu of the standard Research Strategy sub-sections (e.g., Significance, Innovation, Approach), applicants must use the sub-sections defined below to present a concise overall vision and plan for the proposed BCC.

Sub-section A: Scientific Rationale and BCC Product Development

• Outline the rationale and significance as they relate to the objectives of the EDRN and based on existing scientific evidence derived from epidemiologic, model systems or clinical studies, and/or preliminary data.
• Describe the novelty and overall translational potential and relevance of the proposed product to the early detection of cancer.
• A clear description of the final product, including one or more intermediate products, or stage(s) of product development to be completed during the award period. A specific final product profile that is intended for licensing indication is not requested
• Performance specifications of the product must demonstrate that it is equivalent or superior to the current gold standard/standard of care for identifying the disease being studied under this U2C; this encompasses analytical sensitivity (limit of detection), specificity, and analytical reproducibility of tests (test replicates at different agent concentrations, at different sites, etc.), as well as clinical sensitivity and specificity in appropriate human samples.
• Explain how the final product of the proposed research will enhance existing biomarker detection systems or methodologies, and describe the significance of the final product, including a brief description of key technology, objectives, innovation, and advantages compared to competing products, technologies, or services
• If no FDA-cleared test is available for the agent(s), the specifications should be equivalent to or exceed the performance specifications of FDA-cleared tests for similar types of agent(s);
• Discussions with FDA, if any, which are relevant to development activities for the candidate product should be included.

Sub-section B: BCC Organization and Team Integration

To facilitate biomarker translation into ultimate clinical application, BCC applicants are encouraged to actively seek additional funding/resources to push the biomarkers validation/implementation efforts beyond the EDRN-sponsored scope of research.

Address the following aspects:

• Applicants should provide a concise description of the BCC team structure and explain how the skills of individual team members will translate into a collective capability of the BCC to accomplish the stated biomarker research for early detection of cancers, i.e., how the team brings complementary scientific expertise needed to meet the BCC objectives.
• Applicants should explain how the multiple PD(s)/PI(s) will divide their scientific responsibilities in terms of focus on different platforms for biomarker discovery and development, and assay development and standardization across the different functional components. In this context, it is expected that each PD/PI will be responsible for a different platform (although overlap in types of tumors of focus across PDs/PIs is acceptable).
• Applicants should describe their plans for the organization of research teams within the BDL and BRL components.
• The BCC team must include early-stage/junior investigators and briefly describe a plan for their professional development and/or training.
• Applicants are encouraged to highlight 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.
• Applicants should highlight, whenever applicable, the collaborative aspects of the study with justifications as to why collaboration is needed and how this collaboration would add value to the proposed study. Provide evidence of previous successful collaborations among the team members.
• Applicants are encouraged to develop collaboration with the for-profit sector, industry, or diagnostic companies (e.g., such partnerships could be for biospecimens, reagents, protocols, assay development and/or refinement, technology, or any other resources) and to share pre-competitive data on their proposed research to avoid competition and foster complementarity.
• Applicants are also encouraged to bring a biotech or an industrial partner as the BRL component. The partner should have access to a CLIA-accredited laboratory and be willing to take the test(s) forward for FDA approval.
• Applicants are also encouraged to collaborate with experts in statistical modeling (e.g., NCI -supported Cancer Intervention and Surveillance Modeling Network [CISNET; http://cisnet.cancer.gov/index.html]).
• Applicants should describe their experience in collaborative programs and activities with academic and industry partners. Examples of collaborations that may be provided in support of the application include demonstrated evidence of collaborative projects and publications, collaborative funding, and sharing of data and resources (e.g., specimens, technologies, study protocols).
• Describe plans for any future collaboration for the proposed EDRN biomarker studies, both within and outside the Network, as well as any outreach activities.

Sub-section C: Workflow for the Functional Components

• Provide a succinct outline of the structure of each functional component, the BDL and the BRL, based on the requirements described earlier under "Required Capabilities of the BCC" and "Structure of the BCC".
• Explain how the BDL will integrate with the BRL to ensure the success of the final product development.
• Describe the workflow using a flowchart starting with subject accrual (if any), sample identification and acquisition for biomarker discovery and development, acquisition of experimental data based on bulk tissues and/or single-cell analysis, image analysis (if any), assay development, go/no-go decision-making process, standardization and validation in CLIA-accredited or CAP laboratory following GLP or GMP practices, data analysis and modeling, and anything else that is necessary to carry out the project successfully.
• Describe how flexibility is built into the workflow so that the BDL and BRL components can accommodate working with BDLs and BRLs of other BCCs for incorporation of new biomarkers and/or assay development.

Sub-section D: Previous Accomplishments

• Applicants must provide a brief description of previous research accomplishments/preliminary studies on which the team builds the proposed biomarker development and assay validation activities. Demonstrate prior success in biomarker research, with a specific focus on biomarker discovery and assay validation for early detection of cancers, as well as access to early cancer biospecimens and necessary controls based on the five-phase biomarker development and PRoBE guidelines.
• Provide highlights illustrating the BCC team's ability to serve as a resource to the Network, including, as appropriate, a history of accrual of subjects, sharing of research resources, dissemination of procedures and expertise, collaborative efforts resulting in new intellectual property, etc.

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

Applicant must demonstrate expertise in, although it is not limited to, the following:

Methodologies:

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

Assay Design:

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

Assay Optimization:

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

Assay Validation and Clinical Application Development:

• Development of appropriate high-throughput assays/technologies for early detection screening tests that are accurate, reproducible, and cost-effective;
• Planning, design, and conduct of analytical validation studies, including the development of assay procedures, protocols, sample collection, etc.;
• Development of scale-up and automated methods for high volume throughput;
• Multi-center cross-checks for pooled specimens, and other inter-and intra-laboratory interfering factors;
• Development of appropriately rigorous, GLP-compliant formats and systems (paper or electronic) for reporting/archiving test results; and
• Development of kits for rapid, inexpensive testing.

Quality Control Program:

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

• Device and instrument calibration, precision, and reproducibility;
• Quality control of data.

Sub-section E: Health Disparity

Demonstrate access to biospecimens from racial and ethnic minority populations that are representative of the race/ethnic diversity in the United States and/or from other NIH-designated populations that experience health disparities. Address any opportunities that exist and, if implemented, can narrow the gaps in minority health and NIH-designated populations that experience health disparities who continue to suffer disproportionately from certain cancers and have higher cancer incidence. NIH defines health disparity populations as racial and ethnic minority populations, less privileged socioeconomic status (SES) populations, underserved rural populations, sexual and gender minorities (SGM), andany subpopulations that can be characterized by two or more of these descriptions (https://www.nimhd.nih.gov/about/strategic-plan/nih-strategic-plan-definitions-and-parameters.html#:~:text=NIH%20defines%20health%20disparity%20populations,or%20more%20of%20these%20descriptions).

Sub-section F: Project Management Plan

Overall milestones: Describe the timeline for the overall BCC project with brief descriptions of how the goals of each of the proposed specific aims will be achieved annually. Specific aims themselves may not be regarded as milestones (unless they include quantitative endpoints). The overall milestones must be well-described, quantitative, and scientifically justified. Discuss the milestones as a means of judging the success of the proposed project during the 5-year support. In addition, the applicants should clearly delineate the timeline for the transition of biomarkers from Phase 1 to Phase 2, and to Phase 3 validation.

Shortly before the completion of the third year of the award, the progress made towards these milestones will be reviewed by a virtual or in-person site visit of the laboratory by Program staff members and external expert consultants. A decision by NCI will be made at that time based on the comments from the site visit review team as to whether the overall goals of the BCC should be adjusted and/or modified for the remaining period of the 5-year term.

Letters of Support: In addition to standard items, applicants must provide letters from the respective leadership official(s) in the institution(s) of the proposed center documenting specific institutional commitments to the proposed center. Letters should also be included that reflect any additional resources and partnerships (e.g., for-profit sector, industry) that will be employed to achieve the goals of the BCC.

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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Resource and Data Sharing Plan. The Resource and Data Sharing Plan should be provided only under the Overall component but it should cover all the activities of the BCC.

(a) Specimen and Data Sharing: The success of EDRN is dependent on the collaborative interactions of all its laboratories. Clinical specimen collections funded through EDRN cooperative agreements must become available to all investigators in the Network and must be made available for Network validation studies. Applicants seeking to use funding via this U2C mechanism to collect clinical specimens must state their willingness to share these samples with others in the Network.

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

Applicants are expected to submit an Intellectual Property Management Plan (IPMP) in line with the accepted IP Rights and Responsibilities (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 (https://edrn.nci.nih.gov/about/bookshelf).

Note: For EDRN-related public-private partnerships, please visit the EDRN website (http://edrn.nci.nih.gov). Industry scientists or collaborators can provide valuable expertise, reagents, and technology for biomarker discovery. EDRN encourages pharmaceutical and biotechnology companies to participate in Network-sponsored studies for moving biomarkers through qualification for an FDA-approved clinical use. In structuring such partnerships or collaborations, applicants need to consider pre-existing intellectual property rights associated with the use of existing models/reagents and make appropriate licensing arrangements. List and summarize each of the agreements with industry collaborators, including a description of the materials, technologies, and/or expertise to be provided by such collaborators. NCI will serve as a concierge to facilitate partnerships with relevant laboratories and centers within EDRN. If proprietary tools/devices are used in the BCC activities, applicants should clearly state the licensing agreement and are advised to contact NCI and seek assistance as needed from the NCI Technology Transfer Center (https://ttc.nci.nih.gov/) in determining whether such arrangements are appropriate and/or adequate. Detailed documentation of license agreement(s), intellectual property arrangements, and data sharing concerning the proposed or existing collaboration with an industrial partner(s) will be expected as appropriate if an applicant is selected for consideration for funding. The applicant's technology transfer office should be involved in reviewing such documents for the applicant institution prior to submission.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

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.

PHS Assignment Request Form (Overall)

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

Administrative Core

When preparing your application, use Component Type Admin Core.

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

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachments for additional entries.

Research & Related Senior/Key Person Profile (Administrative Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The BCC Contact PD/PI must serve as the Administrative Core Lead. Usually the Administrative Core Lead PD/PI is responsible for communicating with the NCI Program staff or other Network participants regarding various details and activities of the study; however, another person can be designated to fulfill this role.
• The Administrative Core is expected to have a qualified BCC Administrator to manage the day-to-day operations with responsibility for the administrative, budgetary, and operational aspects of the BCC. For the BCC Administrator, in the additional Senior/Key Profiles section, use Project Role of 'Other (Specify)' and provide the role under 'Other Project Role Category' as 'BCC Administrator'.

Budget (Administrative Core)

• Budget forms appropriate for the specific component will be included in the application package.
• Leadership Effort Commitment: The BCC Contact PD/PI must commit and maintain throughout the life of the award a minimum of 1.2 person-months of effort. For applications with multiple PDs/PIs, which is strongly encouraged for this FOA, 1.2 person-months of effort per additional PD/PI is required. The required levels of effort may reflect an aggregate of the effort for the entire BCC (listed here under Administrative Core) and the efforts for other BCC components, as applicable.
• Center Administrator: Applicants are expected to propose and budget for a Center Administrator to manage day-to-day operations and help coordinate activities with the larger Network.
• Set-Aside Funds for Trans-Network Projects: For Years 2-5, 30% of the BCC funds must be allocated to a restricted fund for the support of post-award collaborative projects, either with other EDRN centers or with external collaborators (in cases where necessary resources reside outside the EDRN). Examples of post-award collaborative projects include, but are not limited to, head-to-head comparison of biomarkers, prevalidation and validation studies, assay development, accrual of subjects/collection of biospecimens, etc. These funds should be presented in the Other Direct Costs category under the heading "EDRN BCC Collaborative Project Fund". Funds will be released pending approval by NCI following discussion of proposed projects by the EDRN Steering Committee.
• Single Institutional Review Board (sIRB): Applicants should account for sIRB expenses, if applicable to the proposed study.
• Support Early-stage/Junior Investigators: The budget should include funds to support professional development and training activities for early-stage/junior investigators.
• Travel Funds: The contact PD/PI together with at least one MPI or a senior investigator and an early-stage/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). The budget should also include funds to support the investigators travel for site visits; site visits will be conducted twice in the 5-year funding period.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Administrative Core)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Outline specific aims for the Administrative Core.

Research Strategy: In lieu of the standard Research Strategy subsections (e.g., Significance, Innovation, Approach), use the sub-sections defined below to explain how the effective administrative and organizational capabilities of the Administrative Core will:

• Support all aspects of the proposed research spanning from tissue identification, acquisition, and assay development and standardization;
• Foster synergy and integration of the BCC functional components (i.e., BDL and BRL);
• Provide efficiency in the management of large-scale collaborative research efforts involving multiple institutions and multiple PDs/PIs, including logistical services and organizational support;
• Provide coordination among EDRN BCCs, CVCs, and DMCC (agreed-upon practices and principles, SOPs, CDEs, etc.), including management of set-aside funds;
• Provide coordination of EDRN meetings and teleconferences;
• Support planning and evaluation activities for the Network;
• Coordinate with EDRN DMCC for protocol development, biospecimen sharing, biospecimen blinding, data analysis, data sharing, data deposition, populating Biomarker Data Commons, and any other relevant functions deemed necessary for BCC operations as well as for the larger network.

Applicants must also review Section I. Funding Opportunity Description for expectations from the Administrative Core.

Sub-section A. BCC Leadership and Admin Core Organization

Address the major responsibilities of the Administrative Core that are listed above. Outline the organization of the leadership structure and overall BCC structure (provide respective organizational diagrams). Describe the lines of responsibilities, including, as applicable, the effort distribution across the participating institutions (i.e., institution submitting application and participating institutions on a sub-contractual basis).

Sub-section B. Center Logistics and Communication

Describe the strategies for communication between:

• BCC leadership (multiple PDs/PIs) and key BCC investigators within the proposed BCC functional components (BDL and BRL) and between the functional units and the Admin Core;
• BCC and the larger EDRN;
• BCC and the DMCC (blinding of biospecimens to be tested by the BRL, data deposition to EDRN Biomarker Data Commons, study design of collaborative projects, data analysis etc.);
• BCC and the NCI.

State who will be the lead for each level of communication.

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.

Resource Sharing Plans should only be included in the Overall component, as instructed before.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Administrative Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

Biomarker Developmental Laboratory (BDL)

When preparing your application, use Component Type Core - Biomarker Developmental Laboratory (BDL)

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

SF424 (R&R) Cover (BDL)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (BDL)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (BDL)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations?

Vertebrate Animals: Answer only the Are Vertebrate Animals Used?

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachments for additional entries.

Project /Performance Site Location(s) (BDL)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachments for additional entries.

Research & Related Senior/Key Person Profile (BDL)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• BDL team must have a pathologist involved as a Senior/Key Person in specifying characteristics of the clinical specimens included in the study.
• The Senior/Key personnel must also include experts for the main technological platforms included in the study (e.g., genomics and/or proteomics and/or metabolomics).
• Biostatisticians are expected to be involved in determining sample numbers, biomarker test performance, etc.
• Please also review the "Required Capabilities of the BCC" described earlier for additional BDL-specific expertise.

Budget (BDL)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (BDL)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Outline specific aims for the BDL and provide a rationale and description of how each aim addresses a specific aspect of the overall development of new biomarkers to address an unmet clinical need or refinement of existing diagnostic or early detection tests.

Research Strategy: In lieu of the standard Research Strategy subsections (e.g., Significance, Innovation, Approach), use the sub-sections defined below to describe the activities of this functional component.

Applicants must also review Section I. Funding Opportunity Description for expectations from the BDL component.

Sub-section A. Study Rationale

The focus of the proposed translational studies is expected to be on the discovery, development and testing of biomarkers of cancer risk and/or early cancer. The development of diagnostic and/or prognostic markers for early cancers may also be proposed, provided that the selection is sufficiently justified and reflects urgent clinical needs. If proposing biomarker development for more than one organ site within the application, provide specific information for the organ sites in a distinct manner. If proposing simultaneous detection of multiple cancer types, provide justification for the different cancer types included as well as the types of biomarkers to be studied.

Sub-section B: Biospecimen Source and Identification

The applicant is required, if applicable to their proposed research, to address the following in the proposed study:

• Include a description of the target population in which the biomarkers will be used. Justify that the acquisition and identification of biospecimens for biomarker development are in accordance with the intended clinical use. It is also preferred that the biospecimens are representative of the diversity in the US population.
• Describe whether the applicant has resources or access to resources for sample acquisition, including accrual plans (if any). Samples must be collected under rigorous SOPs in compliance with PRoBE study design criteria.
• Specify features of specimen collection (e.g., study design and conduct) used to minimize bias between compared groups of cancer vs. non-cancer and to assure the validity of study results (e.g., using principles defined by the PRoBE study design). By taking into account the clinical question to be addressed, the investigator may anticipate which details of the study design and protocol are important to be considered.
• Describe the involvement of pathologists and the use of conventional and/or digital pathology in support of identifying and defining the required specimens.
• Studies encompassing preclinical samples and early-stage disease are encouraged to rule out inflammatory or other acute reactant markers that may be present near the time of clinical sample collection.
• If proposing sample acquisitions from cohort consortia, NCI's National Clinical Trials Network (NCTN), Health Maintenance Organizations (HMOs), etc., it is expected that the custodian or authorized PD/PI of the cohort will be an active participant on the proposed studies. A letter of support alone will not suffice.
• Applications should include plans to collect appropriate epidemiological and clinical data/metadata that are positioned to best inform the performance of the biomarker test in the target population. 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.

Sub-section C: Biomarker Development Plan

In the context of this FOA, the development will encompass further studies to evaluate and validate promising candidate biomarkers identified by applicants themselves or by other investigators in accordance with EDRN-defined Phase 2 and Phase 3 biomarker development approaches (described earlier). Integration of multiple discovery platforms, use of modern tools, technologies, digital approaches, in silico approaches, as well as a strong emphasis on data science, AI, and MLL algorithms are encouraged. Other modern technological approaches for the development of biomarkers for early detection, diagnosis, prognosis, or assessment of cancer risk will be accepted as well.

(A) Biomarker Development Approach:

Applicants must describe the study design and approaches to be followed for the proposed BDL studies. Broadly, the approach may include one or more of broad discovery platforms such as genomics, epigenomics, proteomics, metabolomics, etc.; data mining of existing data (e.g., based on DNA, cell-free DNA, gene fusion, RNA, circular RNA, microRNA [miRNA], small and long RNAs, non-coding RNA [ncRNA], mRNA, miRNA, isoforms) or in silico approaches to support/complement discovery efforts; and tissue and/or bodily fluids and exosomes as sources for discovery. BDLs may also develop new technologies to detect candidate biomarkers, integrate them with imaging methods, and work collaboratively with other EDRN laboratories to combine biomarkers for improving the test performance. Applicants may also consider using bioengineered tools and technologies to develop synthetic biomarker-based diagnostic tests.

The objectives include, but are not limited to, the following:

• Identify lethal precancers and early cancers;
• Identify molecular determinants in accessible surrogate anatomic sites for the less accessible major cancer types;
• Assess the risk of cancer development and/or progression;
• Discern which screen-detected lesions are aggressive and likely to cause significant morbidity and death from the ones that are indolent or slow-growing to reduce the burden of overdiagnosis and overtreatment;
• Assess risk and detect early-stage disease due to infectious agents, pathogens, and other environmental agents;
• Identify and evaluate molecular and genomic profiles for risk stratification and improve pathological classification of early lesions;
• Expand marker identification to predict the onset of disease and risk of cancer in order to develop molecular markers that can augment or replace tissue-based assays and/or improve current methods or modalities of detection;
• Identify populations that will benefit from a tiered approach to screening (biomarker tests to identify those high-risk smokers who need to go through lung cancer screening, age groups that fall outside of some available screening programs and may benefit from screening, those who can safely be followed via surveillance etc.).

As mentioned earlier, the key to discovery is to ensure that these platforms are amenable to clinical use and supported through CLIA regulations. Describe the development of rigorous study design and study protocols applicable to the proposed BDL, including robust data collection and quality control procedures. Some examples that illustrate the specific types of translational biomarker studies that could be conducted while taking advantage of technological advances to accelerate quantitative biomarker discovery to clinical translation include, but are not limited to, the following.

• Development of molecularly-informed highly sensitive and specific biomarkers or molecular signatures or biomarker panels (e.g., novel genetic aberrations, 'omic' profiles, post-translational modifications of proteins, etc.) in tissues and bodily fluids (e.g., serum, plasma, urine, stool, sputum, saliva, proximal fluids) in order to develop new serum or tissue-based tests.
• Next-generation sequencing (NGS) approach (whole genome sequencing, whole-exome sequencing or targeted sequencing) to discover and develop sequencing patterns as biomarker to illustrate the difference in progressor vs. non-progressor lesions.
• Study to improve cancer detection by proposing to integrate image-based diagnosis with innovations in molecular biology, genomics, proteomics and immunology.
• Develop subcellular imaging biomarkers in conjunction with molecular markers to interrogate the dynamic modulation of cancer progression.
• Extract radiomic features for small nodules/lesions with unknown clinical significance and predicting malignant lesions from imaging scans.
• Application of semantic and phenotypic features to decipher distinct features of screen-detected and interval cancers.
• Deep learning approaches to classify lesions into low- or high-risk groups based on imaging and molecular biomarker data.
• Integrated proteomic, genomic, and imaging approaches to develop predictive biomarkers for aggressive cancer.
• Development of digital biomarkers by digitizing histopathology, histochemistry along with imaging and molecular approaches to elucidate dynamic molecular changes occurring during progressive disease.
• Computational approaches (AI, MLL) to support multi-analyte diagnostic assay for pancancer detection.
• Use of AI and MLL on multiplex data on biomarkers to deep dive into biochemical, molecular, and imaging for analysis, interpretation, and visualization.

(B) Biostatistics, Bioinformatics and Data Modeling:

Applicants should propose their discovery studies based on the EDRN-established Phase 1 and Phase 2 biomarker development guidelines and PRoBE (http://edrn.nci.nih.gov/docs) or a similar rigorous study design to avoid bias and make best use of available resources. This will strengthen discovery research and increase the likelihood of reproducibility of results. In addition, a clear statement is required on how statistical power is defined in multiple tests and what sample size is required to achieve this power. Examples of power definition include: (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 are required of whether matching is involved and what cofounders are adjusted for, and why.

Applicants are encouraged to apply a "precision discovery" approach using bioinformatics and AI tools (MLL, deep learning) for data mining/analysis of large datasets (GWAS, The Cancer Genome Atlas [TCGA], Pre-Cancer Atlas [PCA], if available, etc.) and extract the molecular know-how/key biomarkers associated with a clinical phenotype of interest to the BCC and integrate into their discovery platform(s). This approach may strengthen the study. In addition, leverage, where feasible, technology from related NCI-sponsored informatics initiatives, for example, the NCI Informatics Technology for Cancer Research (ITCR; https://itcr.nci.nih.gov/) program, which supports the development of informatics algorithms, tools, and resources across the continuum of cancer research.

Applicants are also urged to use computational/mathematical data modeling approaches to predict the translational efficacy of the proposed biomarkers as this will ensure a greater chance of success in downstream validation phases and reaching the clinic. EDRN expects that applicants will develop active collaborations with investigators supported by the NCI CISNET program (http://cisnet.cancer.gov/index.html); such collaborations may enhance the discovery efforts by identifying opportunities for precision screening/early detection, provide a better understanding of real-world clinical settings and needs, and also support the development of statistical modeling and simulation models to evaluate the impact of the proposed biomarker tests.

Sub-section D: Preliminary Data

Use this sub-section to present preliminary data addressing, minimally, the following aspects of the BDL:

• Demonstrate the current capability within the BDL for biomarker discovery/development using the proposed technology platforms.
• Demonstrate adequate scientific evidence from epidemiologic, model systems (cell culture, animal models) or clinical studies warranting success of the proposed study.
• For projects proposing a novel combination/integration of several technology platforms, provide appropriate preliminary data for each individual platform as well as the entire combined approach.
• If technology platforms are located across institutions, provide a demonstration of the proposed workflow.

Sub-section E: Informed Consent

In this sub-section, provide details about the breadth of informed consent obtained from patients. Careful attention must be paid to the design of patient consent forms at the time of specimen collection. Consent forms must allow for data sharing as required by the NIH and the EDRN. Include an approved consent form in the Appendix materials or provide evidence that approval is expected.

Sub-section F: Annual Milestones

The following major benchmarks of progress must be addressed. Any application lacking acceptable milestones will be considered incomplete.

a) Applicants should provide a clear set of annual, quantitative benchmarks for each specific aim of BDL associated with timelines.

b) These milestones must be well described, quantitative, and scientifically justified. Discuss the milestones as a means of judging the success of the proposed studies in the first 3 years of the U2C award period. Specific aims may not be regarded as milestones (unless they include quantitative end points). The specific aims describe the goals and intended path of the proposed research. Quantitative milestones are a way of determining whether an applicant has successfully reached the specified goals. Generally, applicants are expected to provide milestones for each specific aim. Milestones should be clearly stated and presented in a quantitative manner, such as numerical specifications of sensitivity and specificity or a count of some newly discovered molecules or molecular pattern(s) that can be used as biomarkers for early cancer detection, risk assessment, diagnosis or prognosis of cancer.

Examples of quantitative milestones are listed below:

• Detection of one cancer cell in 10⁶ normal blood cells;
• Conduct three consecutive screening cycles to refine the search for identifying the top 10 most specific proteins [(DNAs, mRNAs, ncRNAs, metabolites, etc.) associated with early-stage pancreatic cancer;
• Identification of 10 new lung cancer-associated mRNAs;
• Phase 2 prevalidation of proteins x, y, and z as promising biomarkers to detect cancer in blood (plasma or serum), e.g., building and testing of a classifier model from a marker set with observed specificity of at least 95% among 100 cases and 300 controls.

c) Applicants should also elaborate on a decision-tree scheme to be used during biomarker developmental studies for triaging biomarker candidates, as well as the criteria based on which specific biomarkers should continue to be pursued ( go or no go decision). Should certain promising biomarkers be dropped at any stage during development, alternative steps or strategies to be followed must also be described.

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.

Resource Sharing Plans should only be included in the Overall component, as instructed before.

Appendix:

Only limited items are allowed in the Appendix.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Applicants should not use the Appendix to circumvent page limits.

PHS Human Subjects and Clinical Trials Information (BDL)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

Biomarker Reference Laboratory (BRL)

When preparing your application, use Component Type Core - Biomarker Reference Laboratory

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

SF424 (R&R) Cover (BRL)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project: Use 'Biomarker Developmental Unit' as the title for this Unit.
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (BRL)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (BRL)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations?

Vertebrate Animals: Answer only the Are Vertebrate Animals Used?

Project Narrative: Do not complete.

Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (BRL)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachments for additional entries.

Research & Related Senior/Key Person Profile (BRL)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The BRL must include investigators with significant experience leading multidisciplinary teams with hands-on experience in the development of reagents, assays, and technology, and in the evaluation of the accuracy, precision, reproducibility, and performance characteristics (e.g., sensitivity, specificity, and positive and negative predictive values) of tests in multi-center settings. These characteristics are important when sampling bodily fluids or mixed cell types where only a very small percentage of cells may exhibit specific genetic, epigenetic, or other molecular changes.
• The BRL should include personnel with experience in the development of appropriate and rigorous CLIA/CAP/GLP/GMP-compliant formats and systems etc.
• Please also review the "Required Capabilities of the BCC" described earlier for additional BRL-specific expertise.

Budget (BRL)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (BRL)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Outline specific aims for the BRL and provide a rationale and description of how each aim addresses a specific aspect of the overall development of new biomarker assays or refinement of existing assays for a clinically unmet need that the BCC is addressing. The aims should be consistent with the practice of a typical reference laboratory but should also ensure sufficient flexibility needed for changing and expanding needs of EDRN.

Research Strategy: In lieu of the standard Research Strategy sub-sections (e.g., Significance, Innovation, Approach), use the sub-sections defined below to describe the activities of this functional component.

Applicants must also review Section I. Funding Opportunity Description for expectations from the BRL component.

Sub-section A. Overview

Outline how the proposed BRL component will provide the anticipated lines of laboratory support for the core responsibilities that include:

• Development of diagnostic assays to address the BCC goals; and
• Participation in larger Network collaborative validation studies, verification and optimization of assays, and improvement of diagnostic methods.

Describe that the BRL is able to follow CLIA/CAP/GLP/GMP-compliant guidelines to ensure consistency and reliability of results. Applicants should document, when appropriate, compliance with guidelines that govern GLP, as defined by 21 CRF (58), and Current GMP, as defined by 21 CRF (211), manufacturing and/or investigational new drug (IND)/investigational device exemption (IDE) enabling studies that will be performed under the award as they would be applicable to eventual product licensure in the U.S. Applications for projects involving cGMP manufacture should ensure inclusion of appropriate personnel to provide regulatory guidance before, during and after manufacture.

Applicants should address, but not be limited to, the following specific aspects:

• Protocol development, assay development, standardization, verification, validation, etc.
• Ability to contribute to diverse projects and responsibilities of the Network that may require expertise in broad subject areas within the clinical diagnostic field, for example:
• Development of functional assays (e.g., enzymatic assays) to quantitatively measure activities associated with putative cancer risk markers identified in published studies (e.g. GWAS; for GWAS data, applicants are encouraged to develop collaborations with the GWAS community);
• Development and verification of affinity reagents (e.g., aptamers, monoclonal antibodies, recombinant antibodies such as scFv) for quantitative assays of human candidate biomarkers and proteins (including aberrantly modified proteins) associated with cancer.
• Development of standardized technologies, assays, and methods for validation of extracellular vesicles or exosomes, proteins and peptides, transcripts, metabolites, or imaging methods highly or specifically associated with cancer.
• Development of innovative assay(s) for detection of cancer stem cells from premalignant lesions (e.g., ductal carcinoma in situ, high-grade prostatic intraepithelial neoplasia, or from exfoliated cells of early-stage cancer patients (e.g., urine sediment of bladder cancer).
• Plans for the organization of research activities in the proposed BRL. A flexible organization that would allow them to adjust the number of investigators and/or the scope of their expertise in response to specific scientific needs and opportunities; and
• Availability of qualified supporting personnel (e.g., in specialized laboratory technologies) who could assume diverse responsibilities in a flexible, need-driven manner.

Sub-section B: Specific Plans for the Main Areas of Responsibility

BCC Specific Functions:

The proposed diagnostic assays must be designed to detect the target analytes in tissue, blood (serum, plasma), and other bodily fluids. The proposed diagnostic platforms and/or technologies must be supported by proof-of-concept data demonstrating the feasibility and meeting Phase 1 and Phase 2 criteria of the five-phase biomarker development approach and PRoBE (or similar) principles. Such biomarkers or analytes may also come from existing ongoing EDRN discoveries.

Briefly explain the rationale of the proposed development(s) of previously identified candidate diagnostic technology(s), including proof-of-concept data demonstrating feasibility. Describe the development of rigorous study design and study protocols applicable to the proposed BRL (including robust data collection and quality control procedures). Include the following:

• A clear description of the capabilities of the platform, method, technology, or assay;
• A clear description of how the diagnostic/technology will be used;
• Plans for determining the sensitivity, specificity, and validation of the technology, assay, or diagnostic test;
• A description of a specimen type (e.g., blood, serum, plasma, or other bodily fluids) in which biomarkers will be detected;
• Applications must include plans to detect one or more of the major epithelial tumors or tumors associated with high morbidity and mortality (e.g., breast and other lethal cancers ).

Network Collaborative Studies:

Explain the strategy to ensure that the BRL can meaningfully contribute to collaborative studies and assist Network partners in such activities as:

• Assay verification/optimization;
• Standardizing laboratory assays and methodologies;
• Instituting quality control for reagents and technologies for Network collaborative studies; and
• Collaborating in other studies as directed by the Steering Committee.

The BRL component may be asked by the Steering Committee to conduct studies on a variety of assays in order to improve their performance characteristics. Based on the capabilities of the proposed BRL and the knowledge and experience of its investigators, describe:

• Optimal strategies and standard procedures, if applicable, for the development of reagents, assays, technologies, etc., and
• Approaches and procedures for the evaluation of the accuracy, precision, reproducibility, and performance characteristics (e.g., sensitivity, specificity, and positive and negative predictive values) of tests in multi-center settings.

Explain to what degree these strategies and approaches will be applicable to:

• Multi-center settings; and
• Sampling bodily fluids or mixed cell types, where only a very small percentage of cells may exhibit specific genetic, epigenetic or other molecular changes.

As a collaborative resource of the Network, BRLs will be expected to facilitate the discovery, clinical validation, and clinical application of biomarkers through participation in collaborative Network studies with other BCCs and/or CVCs. Outline your anticipated role(s) in this context. Examples of collaborative projects include but will not be limited to the following:

• BRL consulting with BDL and/or BDL components of other BCCs and/or CVCs on addressing reference-related needs of biomarker development studies;
• BRL consulting with BDL and/or BDL components of other BCCs and/or CVCs on quality control and selection of specimens, as well as performance parameters for the analytical validation of marker assays;
• BRL working jointly with BDL and/or BDL components of other BCCs and/or CVCs to validate biomarkers.

Sub-section C: Development of Reference Materials, If Applicable

Applicants must provide details for developing reference materials for controls in molecular assays/technologies, such as NGS and/or quantitative proteomic analysis and/or extracellular vesicle (exosome)-based isolation and characterization, and/or other technologies that are of great importance for proficiency testing. A BRL may be asked to develop and/or test such reference materials at the onset of analytical validation of specific biomarkers.

Sub-section D: Industry Participation

The BRL can be in part or completely run by a qualified industrial lab. The BRL from academic institutions is required to demonstrate substantive participation in the project by at least one industry participant. For the purpose of this FOA, "industry" is defined as domestic, large or small, pharmaceutical, biotechnology, bioengineering, and/or chemical companies, or non-profit agencies with demonstrated experience in product development. Substantive participation" is defined as a commitment of one or more resources including, but not limited to: product/prototype development support/guidance; personnel; in-kind contributions of materials and/or reagents (i.e., diagnostic analytes, innovative biotechnology platforms, material/reagent scale-up, etc.); or regulatory support.

Sub-section E: Preliminary Data

Use this sub-section to present preliminary data addressing, minimally, the following aspects of the BRL:

• Demonstrate the current capability within the BRL using the proposed technology platforms.
• For projects proposing a novel combination/integration of several technology platforms, provide appropriate preliminary data for each individual component as well as the entire combined approach.
• If technology platforms are located across institutions, provide a demonstration of the proposed workflow.

Sub-section F: Annual Milestones

The following major benchmarks of progress must be addressed. Any application lacking milestones will be considered incomplete.

a) Applicants should provide a clear set of annual, quantitative benchmarks for each specific aim of BRL associated with timelines.

b) These milestones must be well described, quantitative, and scientifically justified. Discuss the milestones as a means of judging the success of the proposed studies in the first 3 years of the U2C award period. Specific aims may not be regarded as milestones (unless they include quantitative end points). The specific aims describe the goals and intended path of the proposed research. Quantitative milestones are a way of determining whether an applicant has successfully reached the specified goals. Generally, applicants are expected to provide milestones for each specific aim. Milestones should be clearly stated and presented in a quantitative manner, such as numerical specifications of sensitivity and specificity or a count of some newly discovered molecules or molecular pattern(s) that can be used as biomarkers for early cancer detection, risk assessment, diagnosis or prognosis of cancer.

Examples of quantitative milestones are:

• Numerical specifications of analytical sensitivity of developed assay relative to the current gold-standard, both for BCC and the larger Network; and
• Projected maximum level of inter-assay reproducibility (e.g., coefficient of variation).

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.

Resource Sharing Plans should only be included in the Overall component, as instructed before.

Appendix:

Only limited items are allowed in the Appendix.

Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. Applicants should not use the Appendix to circumvent page limits.

PHS Human Subjects and Clinical Trials Information (BRL)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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) using ASSIST or other electronic submission systems. 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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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.

Post Submission Materials

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.

Section V. Application Review Information

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.

For this FOA, note the following:

• Overall Component: Reviewers will provide an overall impact score for the entire BCC. In addition, assigned reviewers will provide individual "criterion scores" for the Overall component but not for the other components, as described below.
• Administrative Core: The Administrative Core component will be evaluated by each reviewer but will receive only one overall adjectival rating.
• Functional Component BDL: The BDL component will be evaluated by each reviewer but will receive only one overall numerical score.

• Functional Component BRL: The BRL component will be evaluated by each reviewer but will receive only one overall numerical score.

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.

Significance

Does the proposed Center address the needs of the research network that it will serve? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research network

Specific to this FOA:

What is the likelihood that the proposed research will succeed in moving biomarkers to EDRN-established Phase 2 and/or Phase 3 validation during the next five years?

For the proposed product development, does the applicant address an important need for technology, reagent, and other resource development, standardization, quality control, or protocols suitable for risk assessment, detection, molecular diagnosis and prognosis of early cancer?

How likely will the proposed biomarkers be useful to population of the United States, including minority health and NIH-designated populations that experience health disparities ?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing biomarker research? Do the investigators demonstrate significant experience with coordinating collaborative biomarker translational research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?

Specific to this FOA: To what extent does this team of investigators show a significant measure of success in experimental approaches to biomarker discovery and development for assessment, detection, diagnosis and prognosis of early cancers? Do the investigators have extensive expertise in human cancer biospecimen collection, handling, characterization, assay development? To what extent are the key personnel and team organization suitable for integrating the BDL and BRL functions and meeting the goals of the BCC as well as the Network? Is the commitment of the PDs/PIs and other key personnel in line with the scope of the proposed project? Is there evidence that the PDs/PIs and other team members have effectively worked together in the past? How well do the proposed interactions and collaborations among the BCC PDs/PIs and other key personnel unite the components and advance the biomarker development effort?

Innovation

Does the application propose novel organizational concepts and biomarker development strategies in coordinating the research network the Center will serve? Are the strategies novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of biomarker development strategies proposed?

Specific to this FOA: If applicable, how clearly does the applicant delineate the integration of molecular, imaging and/or clinical information toward biomarker discovery?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the research network the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the network, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the network is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the network? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

Specific to this FOA:

To what extent are the target population and clinical setting for the intended use of the biomarker clearly defined?

How strong is the rationale for the product development/proposed deliverables? How clearly has the applicant described the source of high quality, clinically-annotated biospecimens?

Do the biospecimens meet the requirements of PRoBE or a similar rigorous study design?

Is it clear how the marker performance will be evaluated?

To what extent are parameters, such as sensitivity, specificity and predictive value, chosen to characterize the biomarkers/reagents sufficient and appropriate?

To what extent are the provided milestones and timelines appropriate for the success of the product development strategy and do they allow for an evaluation of the progress of the BCC on the proposed product development?

To what extent are the knowledge base and practices of biomarker discover/development and assay validation adequate for meeting the requirements of the BCC? How adequate are the plans for effective interaction and coordination with other Network units (i.e., CVCs, DMCC), the Steering Committee, and the NCI?

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?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research network it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling

Specific to this FOA:

To what extent are the primary resources for the proposed study within the laboratory under the direct oversight of the PDs/PIs?

To what extent are appropriate facilities and infrastructure (including equipment for high-throughput testing) available to the applicant’s team?

If collaboration with a private sector entity is proposed, will such collaboration be beneficial to the BCC goals and to the mission of EDRN? To what extent will the proposed BCC be a truly integrated entity, rather than a collection of unrelated research ventures and support services?

How well does the BCC organization promote scientific and administrative integration, synergy and a cohesive research goal?

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.

Review Criteria - Administrative Core

Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• To what extent are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the BCC?
• How well will the structure of the Administrative Core promote communication with other BCCs, CVCs, DMCC and the NCI?

Review Criteria - BDL

Reviewers will provide only one overall numerical score for the BDL (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• How well are the BDL leads, collaborators, and other researchers suited to the goals of the BDL?
• How well do the preliminary data demonstrate the capabilities of the BDL for the proposed biomarker development plan? Has the applicant provided adequate scientific evidence from epidemiologic, model systems (cell culture, animal models), or clinical studies warranting the success of the proposed study?
• To what extent are the target population and clinical setting for the intended use of the biomarker clearly defined?
• How well is the biomarker development plan described and explained? Are the selected technologies state of the art?
• Are the samples to be used in the proposed BDL appropriate for the requirements of the PRoBE study design or a similar design?
• Are considerations given to minimize bias, chance, overfitting, and reproducibility issues in the proposed study design?
• Is it clear how the marker(s) performance will be evaluated and triaged? Are parameters, such as sensitivity, specificity and predictive value, chosen to characterize the biomarkers/reagents sufficient and appropriate?
• How well are the potential problems, alternative strategies, and benchmarks for success presented?

Review Criteria - BRL

Reviewers will provide only one overall numerical score for the BRL (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• How well are the BRL leads, collaborators, and other researchers suited to the goals of the BRL? Do they have broad/diverse expertise to meet the Network needs and services for assay development/validation that goes beyond the scope of the proposed BCC research?
• Has the applicant provided assay development practices that are rigorous and robust including the ability for high volume assays?
• Does the BRL have access to CLIA or CAP laboratories (or equivalent) practicing GLP or GMP guidelines?
• Has the BRL described a collaboration with an industry partner? If yes, is the proposed plan for protocol or assay development aligned with the EDRN data/resource sharing requirements?
• To what extent are the proposed approaches suitable for clinical testing of biomarkers/reagents for a variety of early cancers?
• How well are the potential problems, alternative strategies, and benchmarks for success presented?

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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.

Vertebrate Animals

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.

Biohazards

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

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable.

Revisions

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.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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.

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 appropriate national Advisory Council or 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 and whether it addresses portfolio gaps in breast and other lethal cancers.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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

Recipients must comply with any funding restrictions described in Section IV.6. 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.

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

Prior Approval of Pilot Projects

Recipient-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The recipient institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The recipient institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, 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 (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. 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 https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/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. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals 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 information on an institution's specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, 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, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; 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.

• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws 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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 and 2 CFR 200, and other DHHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients 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 BCC, 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 U2C mechanism in accordance with the terms and conditions that are stated in this FOA.
• Committing and maintaining throughout the life of the BCC 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 BCC.
• 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 or a senior investigator and an early-stage/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 BCC efforts within EDRN and cooperating with the other 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 BCC award among all institutions/organizations participating in each BCC, 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 BCC 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 BCC and the overall EDRN program. The BCC Administrative Core should coordinate participation in program evaluation activities, including progress reports and site visits.
• 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 duplications of effort 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 U2C/U01/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 U2C/U01/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 development and clinical application of biomarkers developed through the Network. The NCI Project Coordinator, members of the NCT, 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, 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 MOP (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, recipients 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. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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 the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 75and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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: 301-480-7075

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]

Sharmistha Ghosh-Janjigian, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7122
Email: [email protected]

Matthew Young, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5846
Email: [email protected]

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

Amy R. Bartosch
National Cancer Institute (NCI)
Telephone: 240-276-6912
Email: [email protected]

Section VIII. Other Information

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

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 and 2 CFR Part 200.