Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Funding Opportunity Announcement.

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from 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

This Funding Opportunity Announcement (FOA) is soliciting applications for a Liver Cancer Consortium focused on advancing translational research in the early detection of liver cancer. Translational Research Centers (TRCs) will conduct studies to improve the surveillance of liver cancer in members of high-risk populations, increase the fraction of liver cancer detected at an early stage, and better stratify patients at risk of developing liver cancer. A major collaborative effort of the TRCs will be establishing an integrated blood and image repository with annotated clinical data from patients found to have indeterminate nodules during liver cancer surveillance. To achieve these goals, each proposed TRC should include laboratory and clinical researchers with multi-disciplinary expertise in such areas as early cancer detection, biomarkers, cancer surveillance, imaging, and biospecimen science.

To achieve these goals, each proposed TRC should include laboratory and clinical researchers with multi-disciplinary expertise in such areas as early cancer detection, biomarkers, surveillance, imaging, and biospecimen science.

The Consortium will consist of several Translational Research Centers (TRCs, to be supported by this U01 FOA) and a Data Management and Coordinating Center (DMCC, to be supported through a companion U24 FOA, RFA-CA-22-032). The TRCs will be expected to interact closely with the DMCC and engage in collaborative activities with other members of the Liver Cancer Consortium.

Background

Worldwide, liver cancer is the second most common cause of cancer-related death, and it is a rising cause of cancer-related deaths in the United States (U.S.) The incidence of hepatocellular carcinoma (HCC) is three times higher in men than women, and there are racial and ethnic differences in liver cancer occurrence. The liver cancer burden is higher in African Americans, Hispanics, and Asians. The etiological/risk factors for liver cancer include viral hepatitis (Hepatitis B virus and Hepatitis C virus), non-alcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD). Approximately 80-90% of HCC occurs in patients with underlying liver cirrhosis. In patients with cirrhosis, the 5-year cumulative risk of liver cancer ranges from 5-30%, depending on the etiology, and patients with advanced cirrhosis represent a high-risk group for liver cancer and are recommended for surveillance.

Viral hepatitis is a major etiologic factor for liver cancer in the U.S. Hepatitis C virus (HCV) infects approximately 1% of the U.S. population and approximately 50-60% of the patients with HCC are infected with HCV. Direct-acting antivirals are successful in the treatment of chronic HCV infections, but the risk of developing HCC is not completely eliminated. Globally, Hepatitis B virus (HBV) is the most frequent underlying cause of liver cancer. In the United States, approximately 20% of the HCC cases are attributable to HBV. There is a need for effective surveillance, early detection, and improved screening technologies for HBV-associated liver cancer.

It is estimated that currently, 25% of the U.S. population has NAFLD (Non-alcoholic fatty liver disease) which can progress to NASH. Cirrhosis can develop in patients with NASH resulting in an increased risk for HCC. Alcoholic liver disease (ALD) is a burden in Western countries and is rising worldwide. Heavy alcohol abuse results in liver cirrhosis which greatly increases the risk for liver cancer. With the increase in obesity and metabolic syndrome, there is a greater prevalence of these underlying liver diseases in the U.S. population, and in the future more HCC may be attributable to NASH.

The prognosis of patients with HCC largely depends on the tumor stage at the time of diagnosis. If detected early, liver cancer patients can undergo transplantation or resection and achieve 5-year survival of 70%. In contrast, patients with advanced stage HCC are only eligible for palliative treatments and have a median survival of less than one year. Unfortunately, current surveillance protocols do not detect many HCCs until they are late stage. In the U.S. and Europe, surveillance guidelines for patients with cirrhosis is hepatic ultrasound every 6 months. Ultrasound has a sensitivity of approximately 60% for early-stage HCC and a specificity of approximately 85-90%. The performance of ultrasound is operator-dependent, which reduces its reproducibility, and is less accurate in obese patients. Improved biomarkers and imaging methods are needed that can enhance surveillance, better stratify patients, and increase the fraction of HCC detected at an early stage.

The following aspects reflect major unmet clinical needs related to HCC and should be viewed as high-priority areas for translational research.

• A major unmet clinical need is the ability to differentiate whether an indeterminate nodule identified during HCC screening is benign or malignant. Indeterminate nodules (defined as LiRAD 3 or 4 lesions [LR3/LR4]) are found in approximately 20% of patients undergoing HCC screening. Current guidelines recommend these nodules to be evaluated by continual surveillance (CT or MRI) or biopsy until an HCC diagnosis. A study that will leverage the diverse (race/ethnicity and etiologies) population of cirrhosis patients is needed to address this clinical need. In addition, a combination of clinical parameters, along with blood-based biomarkers, and imaging can be utilized to address the risk of HCC among patients with cirrhosis and indeterminate nodules found during HCC screening.
• Access to large cohorts of patients with cirrhosis attributable to viral hepatitis [HBV or HCV], NASH, or ALD is a challenge that needs to be addressed to identify biomarkers and clinical parameters associated with the different etiologies for the early detection of HCC in these patients.
• The liver cancer burden is higher in minority populations, i.e., African Americans, Hispanics, and Asians. The performance of biomarkers in different racial and ethnic populations needs to be better understood.

Specific Objectives and Requirements

Main Areas of Research Focus. Each Translational Research Center proposed in response to this FOA must focus on research relevant to one or more of the main goals for the liver cancer consortium, which comprise the following areas:

• Area 1: Improving the surveillance for liver cancers in patients with cirrhosis, including imaging approaches;
• Area 2: Increasing the detectability of liver cancers at early stages, including imaging approaches; and/or
• Area 3: Approaches to better stratify patients with cirrhosis, who are at risk of developing liver cancer.

Examples of specific directions relevant to these broad areas include, but are not limited to, the following research activities:

• Prospective collection and analysis of samples and/or images from cirrhotic patients with LR3/LR4 nodules to determine the likely progression to liver cancer within a defined period of time;
• Integration of imaging approaches with biomarkers; and/or
• Improve imaging modalities for surveillance and early detection of liver cancer;
• Identifying and/or validating biomarkers for HCC associated with racial and/or ethnic differences;
• Establishing cohorts of cirrhotic patients to study risks for liver cancer associated with viral infections (HCV or HBV), NASH, or ALD;
• Stratifying cirrhotic patients to identify those patients at the highest risk for progression to liver cancer;
• Identifying and/or validating biomarkers for HCC arising from different etiologies (e.g., viral and NASH, or ALD);

Roles of the Translational Research Centers in the Liver Cancer Consortium

• Individual Research Projects. Each proposed Translational Research Center for support through this FOA must include a well-developed individual research project. The projects should be based on appropriate available biospecimen resources and capability for the inclusion of patients with different racial or ethnic backgrounds. The proposed project must have a clear translational potential for and relevance to at least one of the main Research Areas defined above. Each project should also be founded on evidence-based rationale and preliminary data.
• Trans-Network Activities. In addition to conducting an individual research project, the Translational Research Center investigators will be required to engage in various trans-Network activities, which are expected to include:
  • Participating in collaborative Network projects with other Consortium recipients ;
  • Contributing to the establishment of a Network biospecimen repository and database;
  • Engaging, as appropriate, in other collaborative activities, sharing resources and expertise, etc.; and
  • Submitting data (e.g., biomarker, imaging, Common Data Elements, etc.) to the Data Management and Coordinating Center.
  • Interactions with Data Management and Coordinating Center (DMCC). Each U01 recipientwill be required to interact closely with DMCC, including working jointly on processing and analyses of various types of TRC-generated data as well as clinical annotations (e.g., biomarker, imaging, Common Data Elements, etc.)

Biomarker-based Research Approaches

Regardless of the specific area(s) of research proposed, all research projects should include biomarker-based research approaches. Although the degree of emphasis on that aspect may vary (depending on project objectives), it is a general expectation that biomarker-based approaches will be a prominent element of all studies.

Accordingly, all the proposed Translational Research Centers must have appropriate capabilities to achieve their research goals through systematic, evidence-based development and validation of biomarkers. Generally, such activities are expected to be aligned with the five-phase approach outlined below. The full details are available on the following link: https://edrn.nci.nih.gov/docs/EDRN5.pdf. (see page 18 for a listing and description of the 5 phases).

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

Biomarker research proposed for this FOA should mainly focus on Phases 2, 3, and/or 4, as indicated above. Therefore, for all biomarkers proposed for further exploration, preliminary data covering at least the pre-clinical exploratory phase (Phase 1) are required.

Sources of Biospecimens and Clinical Data. Research activities outlined above require that all applicants have adequate access to samples from existing cohorts of high-risk individuals (e.g., cirrhotic patients), prospective collection of serial biospecimens, and clinical imaging data. Imaging data in combination with biospecimens is preferable. Investigators with existing biospecimens are encouraged to share these resources with the consortium, if appropriate and feasible. For specimens collected under the U01 award, the investigators must be willing to aid in the recruitment of sufficient numbers of patients with different etiologies (i.e., viral and non-viral) and different ethnic and racial backgrounds and share these biospecimens with the consortium. This will help ensure consortium access to these resources.

Note on Biospecimen Sources: To the extent possible, investigators will be expected to leverage resources, such as established relevant cohorts from domestic and/or foreign collaborators, if relevant. There will be limited resources for the establishment of new patient cohorts, so the leveraging of supplementing existing cohorts is encouraged. For example, PAR-22-171, NIDDK Central Repositories Non-renewable Sample Access (X01), allows investigators to apply for samples and data from numerous clinical studies.

Composition of Translational Research Teams. For the outlined goals and activities, it is anticipated that each Translational Research Center proposed will need to include translational and clinical researchers with multi-disciplinary expertise in the areas of early detection, biomarkers, cancer surveillance, imaging, and biorepositories.

Note: If directly relevant to the proposed research, applicants can engage in collaborations with international partners, but the research must have direct application to the liver cancer etiologies found in the U.S. populations (i.e., HCV, HBV, NASH, and ALD).

Non-responsive Research Projects

This FOA will not support the types of studies listed below. Applications proposing such studies will be viewed as non-responsive and will not be reviewed.

• Studies not directly relevant to at least one of the three Main Areas of Research Focus defined above;
• Projects focused on the discovery of new biomarkers without any translational component;
• Studies on biomarkers that are not directly relevant to early HCC detection (such as biomarkers of treatment outcomes); and
• Studies aimed at understanding fundamental biological mechanisms, such as growth regulation, cell cycle control, or other basic studies.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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.

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.

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, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

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:

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

Page Limitations

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

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

Instructions for Application Submission

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Cover

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

a) The contact PD/PI must commit a minimum of 1.8 person-months effort per year to the U01 award. The commitment cannot be reduced in later years of the award. The other PD(s)/PI(s) (if designated) must devote a minimum of 1.2 person-months effort per year to their respective projects.

b) Applicants must budget for travel and per diem expenses for Steering Committee meetings. In the first year, applicants should plan for at least two senior investigators (all PDs/PIs, if desirable, or the PD/PI and a senior investigator if multi-PD(s)/PI(s) option is not used), to attend a Planning Meeting and one Steering Committee Meeting. In the second and subsequent years, applicants should plan for at least two senior investigators (all PDs/PIs, if desirable, or the PD/PI and a senior investigator if multi-PD(s)/PI(s) option is not used) to attend one Steering Committee meeting per year.

c) Restricted Network Collaborative Fund. Starting in Year 2, Applicants must set-aside $100,000 of their annual direct budget for future joint trans-Network activities (such as collaborative studies). The use of these funds will be restricted to activities reviewed and recommended by the Steering Committee. The set-aside amount should be listed in the Other Expenses category under the heading Restricted Network Collaborative Fund.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Outline the overall goals for the proposed Translational Center and define the goals and specific aims of the individual research project.

Research Strategy: Research Strategy must consist of the Sub-sections, A-D, as defined below. Applicants must address all aspects indicated but additional aspects may also be included.

Sub-section A. Translational Center Overview

• Outline how the proposed Translational Center will advance at least one of the three Priority Areas identified in Section I;
• If more than one of these Priority Areas is to be addressed, provide rationale and explain succinctly how the efforts will be balanced/integrated and how the broader scope is expected to help advance the overall goals; and
• Summarize the main collective strengths of the team (without repeating information in individual biosketches) and, as applicable, explain the roles of vital collaborations (e.g., longitudinal collection and analysis of samples and/or images from cirrhotic patients with LR3/LR4 nodules to determine the likely progression to liver cancer) and other key aspects pertinent to Center goals. The planned interactions among the members of the collaborative should be outlined. The ability of the investigators to work as a team and to contribute to the goals of the consortium should be stated.

Sub-section B. Significance and Background

• Relevance to Liver Cancer.
• Outline the significance of the proposed research project in the context of the overall translational potential and the anticipated outcomes; and
• Describe clearly the relevance to cancer surveillance, early detection and/or risk stratification for liver cancer, identifying a specific unmet clinical need(s) that will be addressed.
• Background and Preliminary Data.
• Summarize the current state-of-the-science in the specific research direction pursued;
• Describe preliminary findings on which the proposed project is based; and
• For biomarkers proposed to be studied, provide preliminary data on their performance characteristics (including sensitivity and specificity) and other relevant information, if available (e.g., on differences in their performance associated with different HCC etiology and/or patient race/ethnicity).

Sub-section C. Approach

In addition to standard aspects for the Approach section, applicants must specifically address all the items listed below using the headings identified.

Patient Cohorts and Biospecimens. The applicants should identify the specific cohort(s) of cirrhotic patients to be included in the proposed project (i.e., HCV, HBV, NASH or ALD) and their relevance to the proposed research. Provide a detailed description of the biospecimen resources available. Include both prospective and/or retrospective collections of biospecimens, as well as secured access to existing biospecimen repositories. Include the following information:

• Summary tables with information on the available, existing repositories. Include the types of patients (e.g., cirrhotic patients with viral or non-viral etiologies), clinical information and types of specimens collected (serum, plasma, DNA, other) and the number of available specimens.
• Ability to recruit a set number of patients with specific clinical parameters (e.g., cirrhotic patients with viral or non-viral etiologies).
• Access to existing available biorepositories with the appropriate clinical parameters (e.g., cirrhotic patients with viral or non-viral etiologies).

Biomarkers. Describe the proposed biomarker research activities in terms of Phases 2, 3 and/or 4 of the five-phase approach (as defined in Section I). The description should include, at a minimum, the following elements.

• With the focus on Phases 2, 3 and/or 4, identify the biomarkers for which preliminary data document their appropriate performance characteristics:
• Describe analytical studies needed to establish and compare the sensitivity and specificity as well as the predictive accuracy of biomarkers in a clinical context, including inter- and intra-laboratory comparison studies.
• When describing study design for individual proposed research, indicate how statistical power is defined in multiple tests (biomarker) 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 nonzero effect; (b) the probability to detect all nonzero effects; and (c) true discovery rate, etc. For case-control study designs, define clearly whether matching is involved, what cofounders are adjusted for (and why), and specify other relevant factors. Biomarkers and/or imaging modalities should be verified in prospectively-collected samples and/or images from cirrhotic patients to determine the likely progression to liver cancer within a defined period of time (e.g., 1-3 years).

Sub-section D. Anticipated/Potential Contributions to Collaborative Trans-Network Activities

Outline how the proposed TRC can participate in collaborative efforts with other TRCs. Consider addressing, as appropriate, such aspects as:

• List areas in which your TRC team may be able to collaborate, share resources (biospecimens, procedures, bioinformatic tools, etc.) with other TRCs.
• Prospective collection and analysis of samples and/or images from cirrhotic patients with LR3/LR4 nodules to determine the likely progression to liver cancer within a defined period of time (e.g., 1-2 years).

Letters of Support: In addition to letters from collaborators and consultants, applicants must include letters provided by biospecimen repositories or cohorts on specimens and associated information available for the purposes of the proposed studies. Letters of collaboration from investigators directly involved in relevant cohort studies should clearly indicate their planned commitment level to the consortium.

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.

The following modifications also apply:

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

Software Dissemination Plan: A software dissemination plan, with appropriate timelines, is expected to be included in the application. There is no prescribed single license for software produced through grants responding to this announcement. However, NCI does have goals for software dissemination and the plan should address the following:

Prior to funding, program staff may negotiate modifications of software sharing plans with the applicant. Any software dissemination plans represent a commitment by the institution (and its subcontractors, as applicable), to support and abide by the plan. The final version of any accepted software sharing plans will become a condition of the award.

• The software should be freely available to biomedical researchers and educators in the non-profit sector, such as institutions of education, research institutions, and government laboratories.
• The terms of software availability should permit the dissemination and commercialization of enhanced or customized versions of the software, or incorporation of the software or pieces of it into other software packages.
• To preserve utility to the community, the software should be transferable such that another individual or team can continue development in the event that the original investigators are unwilling or unable to do so.
• The terms of software availability should include the ability of researchers to modify the source code and to share modifications with other colleagues.
• To further enhance the potential impact of their software, applicants may consider proposing a plan to manage and disseminate the improvements or customizations of their tools and resources by others. In support of this goal, recipientsare encouraged to manage and disseminate their source code through an open revision control and source code management system such as GitHub.

Appendix:

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

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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). 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.

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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. See Section III of this FOA for information on registration requirements.

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 (CSR) 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

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials:

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

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

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

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.

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.

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

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to NCI's program priorities.

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 the NIH Grants Policy Statement.

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

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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: 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 identify, 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 and 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.htmlandhttps://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 OMB administrative guidelines, HHS grant administration regulations at 45 CFR Part 75, 2 CFR Part 200 and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH's purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility reside 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 PD(s)/PI(s) will have the primary responsibility for:

The PD/PI (or multiple PDs/PIs, if applicable) under the Consortium auspices will have primary responsibilities in the following areas:

• Defining objectives and approaches, overseeing the planning and conducting of experiments, analyzing and interpreting results, and publishing reports of studies conducted under this award.
• Assuming responsibility and accountability to the applicant organization and to the NCI for the performance and proper conduct of the research in accordance with the terms and conditions of the award;
• Serving as voting members of the Consortium Steering Committee. In accordance with this cooperative agreement, the PD/PI and another senior investigator (or two PD(s)/PI(s) for multi-PD/PI awards) from each Consortium award (U01) and U24 Data Management and Coordinating Center will be required to attend Steering Committee meetings once a year;
• Accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee to the extent consistent with applicable grant regulations;
• Coordinating efforts and cooperating with the other components of the Consortium and with NCI Program staff, including participation in collaborative Consortium research activities; and
• Implementing the approved research resource sharing plan.

In addition:

• All institutions/organizations participating in the Consortium will be expected to share with each other knowledge, data, research materials, and any other resources necessary and relevant to the Consortium; and
• Each Consortium recipient and the entire Consortium programmatic initiative will be subject to external evaluation (coordinated by the NIH). Consortium recipientswill be expected to participate in such evaluations.

Additional Responsibilities of U01 Recipients

• Participation in collaborative Network projects with other Consortium recipients;
• Contributions to the establishment of a Network biospecimen repository;
• Follow biospecimen collection protocol and collect the same common data elements that will be established by the Consortium's Steering Committee; and
• Submit data (e.g., biomarker, imaging, Common Data Elements etc.), generated by the studies, to the Data Management and Coordinating Center.

Recipientswill 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.

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

Designated NCI Program Directors serving as a Project Scientist(s) and a Project Coordinator(s) will be involved in assisting and coordinating interactions and collaborations among the various investigators.

Additionally, an NCI Program Director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Specific activities of substantially involved NCI Project Scientist will include:

• Advising the recipients on specific scientific issues as well as programmatic priorities;
• Facilitating access to NCI resources, expertise, etc.;
• Serving as the liaison between the Consortium investigators and NCI staff members;
• Monitoring the scientific progress of the entire Consortium and the entire program;
• Promoting collaborative research efforts that involve interactions with other NCI-sponsored programs, projects, and centers;
• In cooperation with the NCI Center for Bioinformatics, ensuring that there are effective mechanisms to enable the transfer of network-generated data from the Consortium Units to the NCI;
• Coordinating external evaluation of the Consortium;
• Assisting the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action;
• To facilitate communications among the participants in the Consortium and between the Consortium and the NCI, the NCI will establish and maintain an internet-based information technology solution for rapid data and document transmission and electronic communications for the Consortium; and
• Developing working groups and trans-project efforts as needed.

Areas of Joint Responsibility include:

Steering Committee: The Steering Committee will be the main governing body for the Consortium. The Steering Committee will be composed of the following voting members:

• Two representatives from each Consortium U01 Translational Research Center and U24 Data Management and Coordinating Center award (the PD(s)/PI(s) or a PD/PI and a designated senior investigator) who will have one vote each; and
• NCI Project Coordinator (who will have one vote).

Assigned Project Scientists will participate in Steering Committee meetings as non-voting members. Additional NIH staff members, serving in an advisory capacity, may participate in these meetings as non-voting members. This decision will be made by the existing voting members of the Steering Committee. These members may include representatives from NCI extramural divisions and a representative from the NCI CBIIT.

The Chair of the Steering Committee will be selected from the representatives of all recipients.

In addition, Chairs of other NIH programs may serve on the Consortium Steering Committee as ex officio members.

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

The Steering Committee may decide to establish sub-committees for specific purposes. The NCI Project Coordinator and the NCI Project Scientist will serve on such sub-committees, as they deem appropriate.

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

• Setting the overall research priorities for the Consortium and identifying emerging research opportunities which can be best explored through a joint collaborative effort via the Consortium;
• Establishing general Consortium policies and procedures;
• Establishing policies and procedures for collaborative projects, protocols, and Consortium-defined projects, including defining how such collaborative activities/ studies (to be supported by the restricted set-aside funds on each award) will be initiated, formulated, and presented to the Steering Committee for recommendations regarding collaborative execution;
• Reviewing (with the help of external reviewers if needed), prioritizing, and recommending for activation trans-Network collaborative activities to be supported by these restricted set aside funds; and
• Developing guidelines for the collection and distribution of specimen reference sets for collaborative research.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to 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 recipient. This special dispute resolution procedure does not alter the recipient'sright to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

When multiple years are involved, 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 75.113 and 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 75 and 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]

For scientific inquiries, address questions to:

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

Jo Ann Rinaudo, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-7133
Email:rinaudoj@mail.nih.gov

For administrative, letter of intent, and FOA-related inquiries:

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]

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
E-mail: [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.