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

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

The purpose of this Funding Opportunity Announcement (FOA) is to advance our understanding of the role of the tumor niche or microenvironment in the risks, development, progression, and diagnosis of cancer observed in individuals with an underlying HIV infection or Acquired Immune Deficiency Syndrome (AIDS) through the creation of U54 Centers. For this purpose, the National Cancer Institute (NCI) will support several U54 Centers. Each U54 proposed must be centered on a specific, tumor-niche relevant scientific theme that will be pursued through two to three related collaborative scientific projects. In the FOA, these U54 Centers are referred to as "Research Centers".

The tumor niche for the purposes of this FOA is focused on an ecological niche, which in this case are the specific host environmental/microenvironmental conditions as the result of an underlying HIV infection that could be encountered by the host and establish an environment for tumor initiation and progression. The proposed research areas identify two main areas that most likely control the major activities for establishing and maintaining the tumor niche: the role of the AIDS retrovirus and the response of the host to HIV infection. These areas of research will advance our understanding of the contribution to the tumor niche in the context of an underlying HIV infection.

This initiative addresses the NIH high priority areas of HIV co-morbidities (NIH AIDS priorities) and the goals of the strategic plan for NIH's Office of AIDS Research (OAR) (FY2019-2020 Strategic Plan).

Key Terms for This FOA

Tumor Niche. For the purposes of this FOA, the term "tumor niche" refers to an ecological niche, which are the specific environmental/microenvironmental conditions encountered by the host as the result of an underlying HIV infection. Such altered/dysregulated microenvironment becomes a niche that may facilitate and support tumor initiation and/or progression.

HIV/AIDS and the Tumor Niche Research Center. A HIV/AIDS Tumor Niche Research Center to be proposed in response to this FOA denotes a multilateral partnership that involves at least one U.S. institution and institutions from other US-based or foreign institutions. Each proposed Research Center must be focused on one specific Scientific Theme relevant to HIV/AIDS and the tumor niche (see below). Together, Research Centers will form a network of U54 awardees dedicated to research on HIV/AIDS and the tumor niche.

Scientific Theme. A scientific theme for a given U54 Research Center is defined as an area of study that is relevant to a tumor niche for HIV-associated cancers and central to all research activities of that RESEARCH CENTER. Accordingly, each research project proposed must focus on specific research questions within the scientific theme that a given U54 RESEARCH CENTER has chosen to address. Scientific themes may be defined for various types of HIV/AIDS-defining or non-AIDS defining cancers.

This FOA is an expansion of the "HIV/AIDS and the Tumor Niche" initiative that has been originally supported through R01 awards under RFA-CA-17-030. The overarching goal of the initiative is to gain a better understanding of how HIV infection affects the composition, development, and function of the tumor environment in AIDS defining and non-AIDS defining cancers.

HIV/AIDS Effects on the Host Immune System. The host’s immune system is the first target of HIV. In response, the host generates an often-skewed response establishing a tumor niche that can produce excessive and/or inadequate regulatory responses. The immune responses generated in the excessive regulatory response scenario provide an excellent milieu for tumor development through co-infection with viruses in addition to HIV. Once viral co-infection is established, immune surveillance mechanisms, unable to clear the host of the pathogen, create a state of chronic inflammation that leads to cancer initiation and progression. Dysregulated immune responses may also produce inadequate regulatory responses, which create a suppressive tumor-promoting environment with expression of high levels of pro-inflammatory cytokines, which also establishes a niche for cancer initiation and progression. Cancers that arise in HIV-infected immunosuppressed individuals may be more antigenic and therefore more amenable to anti-checkpoint immunotherapeutic approaches to restore tumor immunity. Further, the effect of co-infection and long-term anti-retroviral therapy on cancer initiation and progression or the composition and function of stromal elements in the tumor environment (including immune cells) has not been rigorously investigated.

It is well established that HIV-induced immunodeficiency and inflammation are key factors leading to the increased risk of certain tumors. Several studies suggest that HIV may cause cancer, either directly or indirectly through other mechanisms. For example, an HIV-encoded Tat protein, a gene activator, can enter uninfected cells, enhance angiogenesis, and enhance infection of cells by Kaposi’s sarcoma-associated herpesvirus (KSHV). There is also recent evidence suggesting that the integration of HIV near certain oncogenes can lead to enhanced survival of the HIV-infected cells, which would establish a reservoir that could maintain the effect of HIV on the surrounding cells.

Immunodeficiency is a hallmark feature of HIV infection. Most tumors that are highly associated with HIV infection are caused by oncogenic viruses, such as Kaposi sarcoma-associated herpesvirus, and poor immunologic control of these viruses is a key element in tumor development. There is increasing recognition that systemic or local inflammation is an important contributor to cancer development in the general population. Patients with HIV infection have increased inflammation, even when their HIV infection is suppressed with antiretroviral therapy and they have little or no immunodeficiency. For example, they often have increased levels of interleukin-6 and other inflammatory cytokines, and increased levels of immunoglobulin. There is also an increasing body of evidence that many of the tumors whose incidence is increased in HIV infection, such as non-Hodgkin lymphoma, hepatocellular carcinoma, or lung cancer, are related to this increased inflammation.

Effects of HIV/AIDS on the Host. Combination antiretroviral therapy (cART) and aging may play a role in HIV-infected persons in establishing an environment for tumor initiation/progression or a tumor niche. cART improves immune function in HIV-positive individuals and as a result has reduced the incidence of some AIDS-defining malignancies (e.g. Kaposi’s sarcoma and non-Hodgkin lymphoma), especially those associated with profound immunodeficiency. However, there is increasing evidence that these patients are at increased risk for developing a number of other tumors, such as anal cancer, lung cancer, or hepatocellular carcinoma. Likewise, the number of older individuals (50 and older) living with HIV/AIDS has risen dramatically over the last decade, mainly due to the availability of cART. Moreover, there has been a substantial increase in the incidence of non-AIDS-defining cancers likely driven to a large extent by the growth and aging of the HIV/AIDS population. HIV-infected patients manifest certain aspects of accelerated aging, such as increased frailty or cognitive changes. However, little is understood on the interplay between HIV infection, aging, exposure to antiretrovirals or other drugs, and other risk factors that may establish a niche for initiation and progress of cancer.

Major Goal and Scientific Scope. The major goal of this FOA is to support, inter-disciplinary multi-project research efforts focused on tumor niche in HIV-associated or non-AIDS-defining cancers.

To be responsive to this FOA, research proposed for each U54 Center must be specifically focused on the exploration of the tumor niche in the context of HIV/AIDS. Therefore, it is a requirement that research of each proposed Center will be focused on one (or both) areas that most likely control the major activities for establishing and maintaining the tumor niche:

• Area 1: How HIV directs and establishes the tumor niche; and
• Area 2: How inflammation and decreases in immunosurveillance from the HIV-infected host direct and establish the tumor niche.

Central Research Theme. Each proposed U54 center is expected to identify a distinct research theme and focus its activities around that theme. The research theme for the proposed center may be in various areas relevant to HIV/AIDS and the tumor niche, provided that the theme aligns with the NIH-defined high-priority topics in HIV/AIDS research (NOT-OD-15-137). In addition to these high priority areas, basic research on Kaposi sarcoma-associated herpesvirus (KSHV) will be responsive.

Cancer Categories. There are no restrictions on cancer types to be studied. Both HIV/AIDS-defining or non-AIDS defining cancers are appropriate. It is expected, however, that each proposed Center and its research projects would either address multiple aspects in depth for a single HIV-associated cancer category or, alternatively, select few (e.g., 1-2) topics of fundamental significance, applicable to a larger group of HIV-associated cancer categories.

Appropriate Research Models

• Research Involving Human Specimens. Whereas clinical trials (as defined by NIH) are not permitted in response to this FOA, it is anticipated that projects proposed for the U54 Research Centers will generally involve human biospecimens. Access to specimens and other materials related to the proposed projects must be secured through appropriate arrangements or collaborations by the time of application submission. Prospective applicants are encouraged to consider the AIDS and Cancer Specimen Resource (ACSR) as a major source of relevant de-identified human samples.
• Animal, Cell Culture, and Ex Vivo Models. Projects proposed may use, as appropriate, various animal models and/or cell culture models, and/or ex vivo models. However, applications proposing only studies on animal models will not be responsive.

Examples of Possible Research Directions. Below are non-exhaustive lists of examples of potential research directions that can be addressed by U54 applications submitted in response to this FOA.

1. How HIV directs and establish the tumor niche.

• What other mechanisms, does HIV use to directly or indirectly establish a tumor niche?
• What is the significance of these mechanisms in the increased risk of various tumors in the HIV positive population?
• How is the stroma affected during acute or chronic HIV infection?

2. How inflammation and decrease in immune surveillance from the HIV-infected host direct and establish the tumor niche.

• What role does inflammation play in establishing a tumor niche?
• Does immunosuppression contribute to the tumor niche in a way that causes a markedly increased risk of developing otherwise rare AIDS-defining tumors or non-AIDS-defining tumors?
• Does co-infection of HIV-infected patients with infectious agents like hepatitis B and C viruses or human papillomavirus contribute to the establishment of the tumor niche and if so, how does this occur?
• What role does antiretroviral therapy play in altering the tumor niche or the environment for developing a variety of non-AIDs defining cancers?
• Do changes in immunosurveillance or defects of the HIV-infected host contribute to a tumor niche that permits the development of AIDS-defining and non-AIDS-defining cancers?
• How does aging or premature aging contribute to the tumor niche in the context of an underlying HIV infection?

Required Organization and Key Attributes of the U54 Research Centers

A proposed U54 Research Center is expected to be a multilateral partnership that involves one U.S. institution (lead institution serving as application submitting entity) and other partnering institutions that may be US-based and/or foreign. Foreign participants may be from any country. As appropriate for the Center's Scientific Theme, prospective applicants are encouraged to consider partnerships with institutions from countries particularly affected by the HIV/AIDS epidemic.

Each proposed U54 Research Center must include all the required components listed below.

Research Projects (required). Each proposed U54 Research Center must be based on two to three well defined research projects with the following characteristics:

• The proposed projects should be well integrated and synergistic with a common research theme.
• The proposed projects are expected to be well developed and generally supported by sufficient preliminary data from researchers laboratories (See Note below).
• Research approaches, methodologies, and background information should be well established.
• Each project must attempt to provide definitive, comprehensive, and thorough research answers to the problem or portions of the problem presented by a given research topic.
• Projects incorporated into a U54 Center may be basic, translational, epidemiological or combinations of them.
• Each project should have an appropriate set of specific benchmarks that can be used as measures of accomplishing the project's goals.

Note on projects not fully supported by preliminary data. Since research in HIV/AIDS and the tumor niche represents an understudied area, a particular novelty and significance of the concept to be explored may compensate for insufficiency in supporting preliminary data.

Therefore, one (and only one) of the required projects may be of exploratory nature. Such a project, however, can be proposed only if the concept to be explored is particularly novel or significant in terms of a truly transformative potential for the goals of this FOA. Such exploratory projects must still be conceptually well developed and supported by sound rationale based on data from all available sources.

Administrative Core (required) will be responsible for the overall administration, coordination, and management of the U54 Research Center.

Shared Resources Cores (optional). The Research Center may include the technical/research shared resource cores necessary to conduct the proposed research (e.g., data management). No more than two shared resources cores can be proposed, and any proposed core must support at least two of the research projects.

Trans-Network Activities

Each Research Center will be expected to engage in trans-network activities, e.g., exchanging expertise, resources (such as reagents or biospecimens). These interactions will include participation in the activities of the HTRNC Steering Committee and the annual Investigators meetings. (For details see Section VI.2 Cooperative Agreement Terms and Conditions).

Non-Responsive Applications

The following types of research activities are outside the scope of this FOA and will be considered non-responsive. (Non-responsive applications will not be reviewed.)

• Applications that are not clearly focused on the HIV/AIDS and the tumor niche (as reflected by the Center's Scientific Theme and the scope of Research Projects);
• Applications proposing more than one exploratory project (i.e., project that is not well supported by the applicants' preliminary data);
• Applications proposing only studies on animal models; and/or
• Applications proposing clinical trials.

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

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts

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

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

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

Applicant Organizations

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

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

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

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

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

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

All individuals designated as PDs/PIs must have appropriate expertise in HIV/AIDS-associated cancer research and organizational experience in multi-project collaborative research endeavors.

The use of multiple PDs/PIs option is encouraged. The primary appointment of the individual designated as contact PD/PI must be at the institution submitting the application (which must be a U.S. institution). Other PDs/PIs may be from other participating institutions (either domestic or foreign), as appropriate.

However, individuals designated as PDs/PIs on applications submitted in response to this FOA must not serve as PDs/PIs on R01 awards under the predecessor RFA-CA-17-030 (such individuals can still be collaborators on the U54 Research Center applications).

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

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

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

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

The application forms package specific to this opportunity must be accessed through ASSIST 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.

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.

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:

Elizabeth Read-Connole, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6190
Email: [email protected]

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12 pages
Admin Core (use for Administrative Core)	6 pages
Project (use for Research Projects)	12 pages per project
Core (use for shared Resources Core)	6 pages per core

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

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 1 Required
• Research Projects minimum of 2 required, maximum of 3
• Shared Resource Core (Optional): maximum of 2

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.

Complete entire form. The title of the application should reflect the major theme of the proposed Research Center.

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

Follow standard instructions.

Project Summary/Abstract: The Project Summary/Abstract should include the overall goals for the Research Center and the selected research theme related to HIV/AIDS and the tumor niche. Also include a description how it addresses the HIV research priorities identified by NIH. The Project Narrative should summarize how the proposed research theme will impact HIV/AIDS and the tumor niche.

Facilities and Resources: Include any information about available unique resources and/or special capabilities that may be relevant for collaborative studies. List all available resources pertinent to the research proposed in the application. Identify which partner is contributing which resources. Indicate which specific resources will be available to other partners in the Research Center (e.g. specific reagents, patient samples, and access to populations or data for epidemiologic studies).

Other Attachments: Attachments listed below must be provided or the application will not be peer reviewed.

Upload all the items listed below in one pdf file named "Supplementary Documentation".

Provide the following:

• Details of the Research Center structure and organization (including an organizational chart of the Research Center);
• Schemes for communication between investigators in the Research Center;
• Summary tables for responsibilities of investigators; and,
• (If applicable) a summary table for the past collaborations between the partnering institutions.

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.

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

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.

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.

Specific Aims: Describe the overall goals of the Research Center, including the integration of its components.

Research Strategy: Instead of the standard Research Strategy subsections, use the sub-sections A-C defined below.

Subsection A: Research Center Overview and Significance.

In this sub-section address the following aspects.

• Describe the overall vision for the Research Center and explain the significance of the chosen research theme;
• Outline how the proposed research projects align with HIV/AIDS and the tumor niche and how they address the NIH HIV/AIDS criteria for high priority research;
• Provide details on how the anticipated contributions of the Research Center to scientific knowledge about HIV/AIDS and the tumor niche that will improve understanding, prevention, diagnosis, and treatment;

Sub-section B: Collaborative Experiences and Research Center Makeup.

The following elements must be addressed:

Collaborative Experiences:

• Without repeating information in biosketches, explain the collective, collaborative experiences of the participating investigators in HIV/AIDS, cancer or other relevant research areas;
• Provide evidence that those collaborations have been productive; and
• Indicate how the collaborations among the partners involved have benefited past research efforts institution.

Research Center Makeup:

• Describe the structure of the Research Center, chain of command, and individual responsibilities for the Research Center leader(s);
• Provide clear evidence of equal and shared partnership (it is encouraged that such partnership is reflected by a balanced distribution of responsibilities and leadership of research projects and cores); and
• Outline the roles and responsibilities of the investigators in accomplishing the proposed research aims and in managing the Research Center.

Note: Project leaders and core directors can be either from the U.S. or foreign institutions (if appropriate, some components may be jointly led).

Sub-section C: Overall Strategy for Scientific Integration.

The following elements must be addressed:

• Explain how the scientific aims and goals of the Research Center will synergize;
• Outline how projects and cores will integrate scientifically;
• Provide expectations on how the Research Center will accelerate research for HIV/AIDS and the tumor niche;
• Indicate (as appropriate) how the Research Center may enhance research experiences within the Research Center and/or collaborations across other consortia;
• Mention other relevant existing research programs that the Research Center may consider interacting/partnering with; and
• Mention other NIH programs as well as non-NIH programs that may be beneficial to the proposed Research Center.

Letters of Support:

In addition to standard letters of collaborations, institutional commitments, etc., applicants should specifically provide letters presenting evidence that they have an agreement with their collaborator(s) for receiving appropriate samples/biospecimens for the studies proposed. All letters of Support for the entire application must be provided under Overall component.

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 Plan should be provided only under the Overall component, but it should cover all activities proposed for the entire U54 Research Center.

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

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

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.

Complete only the following fields:

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

Enter Human Embryonic Stem Cells in each relevant component.

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.

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 attachment for additional entries.

• 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.
• If multiple PDs/PIs are designated, it is expected the contact PD/PI will lead the Administrative Core.
• If multiple PDs/PIs are NOT designated, indicate clearly a senior investigator in the partnering institution who will serve as the main collaborator (select Other, and list their role as Key Collaborator".)

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

Include budgets for the following items in the Administrative Core budget.

PDs/PIs Effort. All PDs/PIs will be expected to have a significant effort commitment of at least 1.8 person-months for a contact PD/PI and 1.2 person-months for any additional PD/PI. Salary support for faculty and research staff must follow salary guidelines of a given institution.

Travel costs: Each application is required to budget for supporting travel to the annual meeting of the Research Center investigators. It is anticipated that every meeting will be attended by the PDs/PIs and selected project and core leaders (up to four leaders). In addition, other travel expenses may be proposed as needed relevant to the goals of the Research Center (e.g., for visits of PDs/PIs to the collaborating institutions, travel to scientific meetings, etc.). All the travel expenses combined must not exceed $10,000 (direct costs) annually.

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.

Specific Aims: Provide the strategies and goals for managing the Research Center.

Research Strategy: The Administrative Core is expected to oversee the overall administration, coordination and management of the Research Center. Use sub-sections A-B defined below to describe the following elements:

Sub-Section A: Administration Structure:

Outline the administrative infrastructure and explain how it will serve all Research Center components. Address all the aspects listed below:

• Provide details on how the Administrative Core will coordinate, supervise and manage all administrative activities;
• Articulate the process for communicating with partnering institutions, decision making, and conflict resolution;
• Outline the anticipated interactions of the Research Center with other existing relevant programs, including HIV/AIDS-oriented U.S.-foreign partnerships;
• Include contingency plans addressing solutions to possible setbacks (e.g., related to logistics, sub-contracting, ethical approvals, travel/visa issues, and other possible hurdles associated with multi-institutions/multi-national partnerships.

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 Plan should only be provided in the Overall component of the application.

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.

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

When preparing your application in ASSIST, use Component Type Project.

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

SF424 (R&R) Cover (Research Project)

Complete only the following fields:

• Applicant Information;
• Type of Applicant (optional);
• Descriptive Title of Applicant’s Project (start each title, as appropriate, with "Research Project 1:" or "Research Project 2:" or "Research Project 3:", if a given project is exploratory, add the word "Exploratory" in parenthesis after Project number;
• Proposed Project Start/Ending Dates.

PHS 398 Cover Page Supplement (Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Project)

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 Summary/Abstract: Provide a Project Summary/Abstract narrative for the proposed research project that includes the project goals, how it addresses the selected research theme of the application and the HIV research priorities identified by NIH as "high" priority.

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) (Research Project)

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 attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Project).

In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project 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.

Budget (Research Project)

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

Budgets for individual research projects are not restricted but the combined budget for all research projects must not exceed 60% of direct costs for the entire application.

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 (Research Project)

Specific Aims: Outline the specific aims of the proposed Research Project and explain how it fits into the overall research theme of the Research Center.

Research Strategy: Use Sub-Sections A-D defined below to describe research project. Explain clearly in relevant sub-sections how each project conforms to the general requirements outlined in Section I, including the NIH criteria for high priority research on HIV/AIDS defined in NOT-OD-15-137.

In addition to the standard items covered by applicable instructions in the SF424 (R&R) Application Guide, address the following aspects in sub-sections A-D:

Sub-Section A: Significance. Describe the central problem/hypothesis to address and describe how the proposed research will contribute to meeting the goals and objectives of the Research Center and its primary theme. Indicate the project's relevance to the specific situation of the partnering country (-ies) and how it will leverage and strengthen existing research capacity at the partnering foreign institution(s).

Sub-Section B: Rationale. Outline the rationale and summarize other information supporting the proposed hypothesis and/or focal point of the research project.

• For fully developed Projects: include any supporting original research preliminary data (required) and other relevant information enhancing the rigor of the study concept;
• If a given Project is designated as "Exploratory" (no more than one): Original research preliminary data are not required but encouraged if available. Regardless of the availability of applicants-generated preliminary data, provide justification that the project concept is scientifically mature and rigorous. Accordingly, for the rationale and concept justification, integrate to the extent possible the available relevant information from various sources.

Sub-Section C: Innovation. Describe how the research project may provide a novel or innovative approach that could have the potential to inform the HIV/AIDS research community about the impacts of HIV on the tumor niche. Include any novel concepts, approaches, tools or technologies for the proposed studies.

Sub-Section D: Approach. Describe the research design, conceptual procedures, and analyses to be used. Discuss the potential difficulties and limitations of the proposed procedures and alternative approaches to achieve the aims. As part of this section, provide a tentative sequence or timetable for the project as well as set of specific (if feasible quantitative) Benchmarks that will allow for an unambiguous assessment of the completion of Specific Aims.

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 Plan should only be provided in the Overall component of the application.

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

When preparing your application in ASSIST, use Component Type Shared Resource Core.

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

Optional Shared Resources Cores (not to exceed two) may be proposed as required for the proposed research projects (e.g. Clinical/Translational, Epidemiology, Biostatistics, or Laboratory Core).

SF424 (R&R) Cover (Shared Resources Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of the Core (starting with "Core 1:" or "Core 2:")
• Proposed Core Start/Ending Dates

PHS 398 Cover Page Supplement (Shared Resources Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Shared Resources 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 Summary/Abstract: Provide a project narrative/abstract for the proposed Shared Resources Core, including which research projects will be supported by the Core.

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) (Shared Resources 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 attachment for additional entries.

Research & Related Senior/Key Person Profile (Shared Resources 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 should be included in the Overall component and in the Personal Statement state role in the core.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Shared Resources Core)

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 (Shared Resource Core)

Specific Aims: Provide the specific aims for the particular core outlining which projects it will serve (must be a minimum of two projects).

Research Strategy: The Shared Resource Core can be a virtual (e.g. data management) or physical (e.g. viral vector lab) infrastructure that provides support to the research projects. Describe the intended function and rationale for the proposed core. The description of the core must contain the following information:

• Explanation how the proposed Core matches the research needs of Research Center;
• The scope of expertise available, including the level of skills of technical personnel, if applicable, who will be responsible for the day-to-day operation (and who may not be included under Senior/Key Persons);
• The key characteristics of the proposed Shared Resource Core (including approaches to ensure rigor and proper quality control) and anticipated benefits for the projects to be served; and
• The justification for the location of the Shared Resources Core.

A Shared Resources Core must support at least two of the research projects and must not duplicate an existing resource.

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 Plan should only be provided in the Overall component of the application.

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

PHS Inclusion Enrollment Report (Shared Resource Core)

Not Applicable

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

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) 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.

This initiative is not subject to intergovernmental review.

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

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

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

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 Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

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

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

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

For this FOA, note the following:

The emphasis of this FOA is on highly meritorious research efforts focused on the tumor niche in the context of an underlying HIV/AIDS infection.

Scoring: Reviewers will provide an overall impact score for the entire U54 Research Center (Overall). In addition, assigned reviewers will provide individual "criterion scores" for the Overall application but not for the other components.

Other components of the U54 Research Centers [i.e., Administrative Core, each individual Research Project, and optional Other Shared Resource Core(s)] will be evaluated but each will receive only one overall adjectival (not numerical) rating.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the U54 Research Centers 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 U54 Research Centers 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 U54 Research Center that by its nature is not innovative may be essential to advance a field.

Does the U54 Research Center address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the U54 Research Center are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA: How strong is the Center's Scientific Theme and research proposed in terms of focus on the exploration of the tumor niche in the context of HIV/AIDS? How relevant is this research to the areas that most likely control the major activities for establishing and maintaining the tumor niche?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the U54 Research Center? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI , do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA: Are the expertise and backgrounds of investigators from the lead U.S. institution and the partnering institutions complementary and appropriately balanced for the goals of the U54 Research Center and the goals of the entire initiative?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the U54 Research Center? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the U54 Research Center 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?

Specific to this FOA:

U54 Research Center Integration: How well are the overall goals and the scientific theme of the U54 Research Center addressed by individual research projects? Are the contributions of all components to the U54 Research Center clearly articulated and well-integrated?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Reviewers will consider each of the review criteria outlined below to assess the scientific merit of the Research Projects but will give only one adjectival rating for the entire project (criterion scoring is not used for this component). A project does not need to be strong in all categories to have major scientific impact. For example, a Research Project that by its nature is not innovative may be essential to advance the field.

Significance

Do the research projects address an important problem or a critical barrier to understanding HIV/AIDS tumor niche? How relevant is the project to the overall Center scientific theme? Is the prior research that serves as the key support for the proposed project rigorous? If the project is exploratory in nature and preliminary data are incomplete, how strong and compelling is the project concept?

Investigator(s)

Are the Project Leads, collaborators, and other researchers well suited for the projects proposed? If the project is collaborative, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Is the concept to be explored particularly novel or significant in terms of a truly transformative potential for the goals of this FOA (essential for exploratory projects, not fully supported by preliminary data)? What is the project potential to generate innovative approaches to study tumor niche?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success appropriate and sufficient? If the project is exploratory in nature, are the proposed approaches sufficient to establish the feasibility of the concept? Will particularly risky aspects be sufficiently managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If a given 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

What is the likelihood that the scientific environment of the proposed Research Center and its underlying partnerships will contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Reviewers will provide only one overall adjectival impact rating for the Administrative Core (criterion scoring is not used for this component). Reviewers will consider the following aspects while determining scientific and technical merit of this component:

• Is the proposed Administrative Core well matched to the needs of the U54 Research Center?
• Given the multi-institutional/multinational partnerships for U54 Centers, is the management proposed appropriate for scientific and fiscal administration, procurement, regulatory and personnel management?

Reviewers will provide only one overall adjectival impact rating for each Shared Resource Core (criterion scoring is not used for this component). Reviewers will consider each of the aspects below in the determination of the merit of a Shared Resources Core.

• How well is the proposed Shared Resource Core matched to the needs of the research being proposed by the U54 Research Center?
• How strong is the justification of research projects?
• What is the overall quality of the proposed core services? Are adequate quality control processes proposed?
• How strong are the qualifications, experience, and commitment of the Shared Resource Core Director(s) and other Core personnel adequate in the context of their ability to provide the proposed services?
• Is the environment for the shared resource core adequate to support the program as proposed?

As applicable for the U54 Research Centers 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.

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed U54 Research Centers involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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

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

Not Applicable

Not Applicable

Not Applicable

As applicable for the U54 Research Centers proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

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

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities. These priorities may include a sufficiently broad coverage of both non-AIDS-defining and AIDS-defining cancer types.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

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 awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Awardee-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 awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH s Instructions for Preparing the Human Subjects Section of the Research Plan.
• The awardee 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: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Defining the overall research objectives and approaches of the Research Center;
• Overseeing and coordinating the efforts of individual Research Center components and ensuring their optimal integration;
• Overseeing the conduct of Research Center research projects and ensuring their scientific rigor;
• Ensuring compliance with the applicable mandatory regulations (including protection of human subjects);
• Overseeing establishment and maintenance of appropriate quality control procedures;
• Overseeing final data analysis and interpretation and preparation of publications;
• Participating as voting members in the Network Steering Committee;
• Overseeing the Administration of the Research Center and logistical support for joint activities; and
• Overseeing the preparation of required reports and informing, as needed, the NIH Program staff members concerning Research Center progress in research projects and other activities.

All PDs/PIs will be expected to maintain significant effort commitment not smaller than that stated in the application (at least 1.2 person-months throughout the entire project period).

Participation in the Investigators Meetings: Investigators from all the individual U54 Research Centers will participate in annual meetings to present updates on progress, to exchange ideas, to develop inter regional collaboration and to discuss problems encountered. It is required that at least PDs/PIs, as well as project and core leaders will attend these meetings. Meetings of the U54 Center awardees supported under this FOA may be combined with subject-matter related scientific conferences if appropriate.

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.

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

A designated NCI Program Director, acting as a Project Scientist, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The NCI Project Scientist will be the main NCI contact for all facets of the scientific interaction with the awardees and will provide advice to the awardee on specific scientific and/or analytic issues in addition to programmatic issues. As needed, additional NCI scientific staff members with relevant expertise may also become substantially involved in the Consortia activities as Projects Scientists. The responsibilities of substantially involved NCI Program Staff members will include the following aspects.

• Providing technical assistance, scientific input, and assistance in effort coordination across the Research Center Network;
• Promoting collaborations across the different consortia;
• Facilitating interactions of the Research Centers with other ongoing programs and studies supported throughout the NIH to avoid duplication of effort and encourage sharing and collaboration among the different programs;
• Recommending additional research endeavors within the constraints of the approved research and negotiated budget of the Research Center;
• Convening and facilitating the annual Network Investigators Meeting; and
• Participating as a voting member(s) of the Network Steering Committee.

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

Areas of Joint Responsibility include:

Network Steering Committee. The Network of the U54 Research Centers will have a Steering Committee that will be responsible for guiding the overall scientific directions of the Research Centers, promoting collaborations across Research Centers, facilitating/coordinating, sharing of expertise, reagents, or specimens across Network, and other trans-network activities as needed.

The Steering Committee will be composed of the following voting members:

• PDs/PIs (or PD/PI plus designated senior investigators), so that each Research Center is represented by two representatives (who will jointly have one vote for a given Research Center);
• A representative of the AIDS Specimen Repository (ACSR); and
• The NCI Project Scientist(s) (who will collectively have one vote for the NCI).

In addition, Program Official and other NIH staff members may participate in Steering Committee meetings as non-voting members.

The Steering Committee will meet three times a year; twice by teleconference and once at the annual Network Investigators Meeting.

The Steering Committee may establish working groups/sub-committees as needed, e.g., to address specific scientific or administrative issues.

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 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 regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

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

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

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

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

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

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

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

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

Elizabeth L. Read-Connole, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6190
Email: [email protected]

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

Mutema Nyankale
National Cancer Institute (NCI)
Telephone: 240-276-5987
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.