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 NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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. Notice of Funding Opportunity Description

Purpose

Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) intends to support the discovery and development of novel natural products that are safe, non-toxic, and efficacious for cancer interception and prevention. Given the broad chemical diversity of natural products, they provide an opportunity for discovering biologically active compounds with unique structures and mechanisms of action, only a small percentage of which have been screened and evaluated. Hence, natural products could be a valuable source of chemical diversity for the discovery of novel targeted agents using high-throughput screening (HTS) strategies. Samples showing activity in the HTS could be further fractionated and re-screened to support the bioassay-directed characterization of the active constituents. At the termination of the HTS campaign, the purified active compounds may then be prioritized for medicinal chemistry efforts to maximize pharmaceutical properties and potentially define synthetic routes for scaled-up production.

The NCI Program for Natural Product Discovery has created one of the world’s largest, most diverse libraries of pre-fractionated natural products (~500,000 semi-purified natural product samples) that are readily available to the research community for use. The NCI can provide the pre-fractionated library to screening centers and researchers to accelerate natural product drug discovery, and high-throughput screening support for researchers to enable targeted cancer interception discovery efforts, and faster analytical resources (isolation, structure elucidation, re-supply) to expedite translational pipelines. The development of HTS-amenable assays that are predictive of a desirable cancer interception endpoint continues to be an area of need. The current NOFO will encourage the adaptation of newer model systems for HTS.

Awards made under this NOFO will initially support a three-year maximum, milestone-driven UG3 phase with a possible transition to a two-year maximum UH3 phase. Progression to the UH3 phase is based on an administrative review and is dependent on meeting UG3 milestones and additional criteria outlined in this NOFO, availability of funds, and NCI programmatic priorities. Only UG3 grants that have met scientific milestones and feasibility requirements related to the HTS strategy or that meet National Center for Advancing Translational Sciences (NCATS) HTS requirements will be considered for transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application following the instructions described in this NOFO.

Background

Progress in cancer reduction is highly dependent on the discovery and development of effective intervention agents. To this end, NCI supports a number of drug development efforts through a variety of funding mechanisms. While such initiatives have led to substantial progress in establishing novel therapeutic drugs, a critical shortcoming still persists in the discovery, screening, and development of novel naturally occurring agents for cancer interception and prevention. Natural products (i.e., purified compounds derived from extracts of plants, marine organisms, microbial or other natural sources) have long been an important source of medicinal agents and continue to be a rich source for modern drug discovery due to their structural diversity and diverse biologic activities. Some widely studied natural products, including curcumin, resveratrol, EGCG, quercetin, sulforaphane, etc., have been reported to exert anticancer chemopreventive activities. However, most of these are Pan-assay interference compounds (PAINS) that often give positive results in high-throughput screens as they react nonspecifically with numerous biological targets rather than specifically affecting one desired target. Natural products do present challenges for drug discovery, such as technical barriers to screening, isolation, characterization, and optimization.

In recent years, several technological and scientific developments have addressed such challenges, opening up new opportunities. Classical natural product-based drug research starts with the biological screening of crude extracts to identify a bioactive hit extract, which is further fractionated to isolate the active products. Bioactivity-guided isolation is a laborious process with a number of limitations, but various strategies and technologies such as metabolomics (fingerprinting, footprinting, profiling, or target analyses), bioassays and detection technologies, other omics techniques such as transcriptomics and proteomics, and/or imaging-based screens, higher-field NMR instruments and probe technology can overcome these limitations. Microcrystal electron diffraction (MicroED) recently emerged as a cryo-electron microscopy-based technique for unambiguous structure determination of small molecules, which also can be used to address some challenging molecules. To create libraries compatible with high-throughput screening, crude extracts can be pre-fractionated into sub-fractions that are suitable for automated liquid handling systems. In addition, fractionation methods can be adjusted so that sub-fractions preferentially contain compounds with drug-like properties (typically moderate hydrophilicity). Such approaches increase the number of hits compared to using crude extracts, as well as enable a more efficient follow-up of promising hits.

Although there has been a growing interest in discovering novel natural product-derived potential agents, there are no programs within NCI for screening natural products for specific clinically relevant pathways and targets for cancer interception and prevention. The NCI has already developed libraries of pre-fractionated natural products that are readily available to the research community for use. Hence, the development of a robust HTS strategy is a key requirement for natural product drug discovery for specific targets and exploitable pathways. The aim of this NOFO is to evaluate specific clinically relevant cancer interception targets with the potential for HTS and discovery of cancer preventive interventions in the UG3 phase, followed by full-scale HTS, characterization, efficacy testing, and development of the screened agents in the UH3 phase of the grant.

Proposed studies should focus on selection of clinically relevant cancer interception pathways and targets, development of primary and secondary assays and HTS strategy that meets robust HTS requirements before conducting full scale HTS and bioassay testing of screened leads. Specifically, projects submitted in response to this NOFO should be designed to generate data of sufficient quality to support successful advanced preclinical testing and for filing an IND application with the FDA. At minimum, the selected interception target candidates (no more than 5) for a project must have data showing clear clinical relevance in relevant in vitro and in vivo systems. In addition, applicants will provide disease-specific knowledge and expertise and access to models/assays.

Specific Research Objectives and Requirements

Through this NOFO, NCI solicits applications that propose the identification of cancer preventive natural products using the commercial natural product libraries or investigator owned libraries or the NCI Program for Natural Product Discovery (NPNPD) Pre-fractionated Natural Product Library and the NCATS resources.

Specific areas of focus that could be proposed in response to this NOFO include (but are not limited to):

1. Identification and selection of clinically relevant cancer interception pathways and targets, and the development of robust high-throughput screening strategies. Development of specific cell-based and/or cell-free assays to screen non-toxic natural agents.
2. High-throughput screening, purification, and structure elucidation of active natural compounds. Medicinal chemistry or other novel strategies such as click chemistry development for optimization of any drug leads.
3. Development of models with predictive value for positive efficacy outcomes in the clinic that could be used to guide the selection of preventive agents active in HTS assays.

Applicants are expected to propose to identify and select clinically relevant targets, development and validation of assays for bioactivity as well as toxicity screening applying HTS and novel technologies using the readily available NCI or other libraries, full-scale evaluation of screened individual agents, active sample prioritization, and determining the optimal dose for subsequent studies and safety testing.

UG3/UH3 Cooperative Agreement Award Mechanism

This NOFO will utilize a two-phase cooperative agreement (UG3/UH3) mechanism. Awards made under this NOFO will initially support a three-year maximum, milestone-driven UG3 phase, initial target selection, verification in clinical samples and preclinical in vivo studies, assay development, and/or assay validation for bioactivity as well as toxicity screening, and pilot screening of natural agents, with a possible transition to a two-year maximum UH3 phase for a full-scale screening (larger initial screening and identification of the crude fractions and sub-fractions for further investigation) to characterize, evaluate pharmacokinetics, bioavailability, and assessment of the natural product’s effect (i.e., a measure of the mechanism of action) in vitro and in vivo. The outcomes of UG3 phase experiments will be the central determining factors for the activation of the UH3 Phase.The UG3/UH3 application must be submitted as a single application following the instructions described in this NOFO. Milestones to be accomplished in the UG3 phase for transition to the UH3 phase as well as annual milestones for the UH3 phase must be proposed by the PI in the application. Ultimately, this UG3/UH3 NOFO is intended to accelerate the screening and development of natural agents for translating into novel interventions that can be efficiently tested for their promise in cancer interception and prevention. A maximum of 5 years will be supported by the two phases of the UG3/UH3 award. Once promising interventions with in vivo efficacies and lack of toxicities are identified, these natural agents can enter the NCI PREVENT pipeline for advanced preclinical development followed by moving to clinical trials through DCP CP-CTNet program.

UG3 Phase

The UG3 phase of the application must describe all preparatory activities necessary for full scale HTS activities and secondary testing of screened leads during the UH3 phase.

Specific activities related to UG3 phase include (but are not limited to):

• Selection and verification of the clinically relevant cancer interception pathways and critical targets in appropriate in vitro and in vivo systems, and clinical samples
• Assay development and optimization (cell-free, cell-based, and/or short-term in vivo assays)
• Development of pilot screening assay and conduct of pilot screens
• Pilot-scale screening using commercial libraries, investigator-developed libraries and/or the NCI NPNPD natural product libraries (~1,500 samples)
• Generation of research plan for UH3 phase
• Development of prototype HTS
• Development of secondary assays for selectivity and toxicity
• Development of mechanistic assays to characterize screening leads
• Development of robust HTS strategy as proposed or that meets NCATS robotic HTS requirements

Specific activities related to UH3 phase include (but are not limited to):

• HTS technology transfer to NCATS with NCI assistance (not applicable for applications that propose to use commercial or investigator developed robust HTS strategies)
• Conduct full scale evaluation of the Natural Products Libraries independently or at the NCATS through NCI assistance (350,000 - 500,000 natural product samples/fractions) in HTS compatible screens designed to identify potential cancer preventive agents.
• Development/optimization of animal models for efficacy studies
• Bioassay-directed isolation and structural elucidation of active natural products by active sample prioritization, orthogonal assays/hit prioritization, Hit-to-lead progression/lead optimization with NCI collaboration
• Conduct/collaboration on medicinal chemistry/formulation of purified natural products with NCI/NCATS assistance
• Full scale evaluation of screened natural product leads, Mechanistic characterization of screening leads
• Conduct/collaborate with NCI/NCATS to characterize, and evaluate pharmacokinetics, bioavailability, and assessment of the lead natural product’s effect (i.e., a measure of the mechanism of action) in vitro and/or in vivo (cancer preventive efficacy testing)
• Determine the optimal dose for subsequent studies and further testing safety and acceptability.

UG3 Phase to UH3 Phase Transition

Utilization of milestones is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline signifying the completion of a major project stage or activity. Applications must include well-defined milestones for the UG3 phase and annual milestones for the UH3 phase. Milestones for the UG3 phase must be objectively defined and quantifiable with clear go/no-go criteria to ensure clear demonstration that the proposed milestones were met at the time of the transition request. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UG3 and UH3 milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a final set of approved UG3 milestones. These milestones will be the basis for judging the successful completion of the work proposed in the UG3 stage and progress towards interim milestones in the UH3 stage. Only projects that meet their UG3 milestones will have an opportunity to move to the UH3 phase. UH3 milestones will be the basis for judging progress towards and completion of the UH3 phase.

At the completion of the UG3 phase, the applicant will be required to submit a detailed transition request to the UH3 phase. An administrative review will be conducted by NCI program staff to decide whether a UG3 phase grant will be transitioned into a UH3 phase grant based on the following criteria:

• Successful achievement of defined milestones in the UG3 phase;
• Specific molecular target defined, verified/validated;
• Successful completion of all preparatory activities necessary including target selection, verification, bioassay development and pilot screening for launching the full scale HTS at the beginning of the UH3 phase;
• Screen development (necessary reagents such as recombinant proteins, materials, engineered cell lines, etc.), qHTS techniques aimed at accurately predicting and assessing toxicity, availability of reliable toxicity metrics & HT-ADME Assays, characterization (pilot screening confirmation of hits/secondary testing retention of mechanism);
• primary assay meets NCATS requirements for HTS, potential for scale-up to meet NCATS criteria;
• Secondary assays identified to further interrogate potential active compounds;
• Assays perform with consistency, reproducibility, robustness and accuracy in initial/pilot HTS;
• Potential for full scale screening of large natural product libraries during the UH3 phase;
• Availability of funds; and
• Programmatic priorities.

UH3 Phase

The UH3 phase of the application must include research plans to test the cancer interception effects of the screened leads. The application must contain detailed information about the proposed UH3 activities.
The UH3 phase will include activities necessary to achieve the following goals:

• Successfully conduct and complete all aspects of the proposed goals, including full-scale screening of the NCI libraries, full-scale characterization of the screened leads, selection and/or optimization of the animal model, in vivo efficacy testing, and development of the screened agents, MOA in vitro and in vivo; and
• Identify potential targeted natural product lead for cancer interception and prevention.

Leveraging Existing Research Resources

Applicants are strongly encouraged to leverage existing NCI and the NCATS resources and infrastructure, whenever possible. NCI will provide prototype natural product libraries for pilot screening (NCI), provide NCI libraries (~500,000 semi-purified natural product fractions) for full scale HTS efforts, assistance with technology transfer to NCATS, support conduct of primary HTS of the NCI Natural Products Library (NCATS), provide direct support for the isolation, identification, and structural characterization of bioactive fractions/active natural products throughout the purification process.

Non-Responsive Applications

The following types of activities remain outside the scope of this NOFO. Applications proposing them will be considered non-responsive to this NOFO and will not be reviewed.

• Identify potential targeted natural product lead for cancer interception and prevention;
• Applications that propose clinical trials;
• Applications that do not propose clinically relevant cancer interception pathways/targets;
• Applications that do not propose to screen/test natural products;
• Applications that propose to screen/test natural products for cancer therapies;
• Applications lacking milestones for the UG3 phase and UH3 phase.
• Applications seeking NCATS support but failing to obtain a letter of collaboration from the Scientific Director of NCATS Division of Preclinical Innovation

Additional Information

Pre-application Information Session: NIH staff will hold a Webinar for potential applicants to answer questions related to this NOFO. Webinar information will be posted on the NCI Division of Cancer Prevention website.

Prior Consultation

Potential applicants are encouraged to consult with the Program Staff early on in the planning of an application. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of the project, potential NIH support for the project, and the intent of this NOFO. Further, potential applicants seeking NCATS support are required to consult and obtain a letter of collaboration from the Scientific Director of NCATS Division of Preclinical Innovation to be included in their application. For additional information, see the NCATS Early Translation Branch (see: https://ncats.nih.gov/etb) and Letters of Support section.

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

Section II. Award Information

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

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 Government

• 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 Grants.gov registration; 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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

2. Cost Sharing

This NOFO 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 NOFO. 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 notice of funding opportunity 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:

Altaf Mohammed, PhD
Division of Cancer Prevention
National Cancer Institute (NCI)
Telephone: 240-276-6082
Email: [email protected]

All page limitations 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 an application to this NOFO.

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

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

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

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

R&R Budget

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

R&R Subaward Budget

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

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

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

Specific Aims: Describe the overall goals for the entire application. Provide a rationale and description of how the application addresses a gap in the discovery and development of natural products for cancer interception and prevention, and how addressing that gap will impact public health. Include distinct aims for the UG3 phase and the UH3 phase, and clearly label them as UG3 specific aims and UH3 specific aims.

Research Strategy: Applicants should describe both the UG3 phase and the UH3 phase using the standard sub-sections of Research Strategy defined in more detail in the SF424 Application Guide with additional guidance below.

Significance: Explain the significance of the selected organ site cancer and justify why the proposed target and the screening and development of natural products is likely to have an impact on the cancer interception and prevention. Explain why the specific interception intervention addresses an unmet medical need, global burden of disease; which patients will benefit; how patients will benefit; the potential public health impact if the proposed research successfully translates to the clinic. Which patients benefit if the screened lead compound is successfully translated to the clinic; How would be the proposed HTS strategy lead to screening of a superior agent to an existing standard natural products (side-by-side comparision with a known standard agent within the proposed pathway/targets)? The clinical relevance of the target class for the proposed indication, or how the mechanism of action of the proposed target and the agents has been understudied for the indication; and If the same target/mechanism of action has been studied in the proposed patient population, discuss the value added for the proposed studies.

Investigator: Demonstrate that the research team has the multidisciplinary scientific expertise necessary to develop and characterize an HTS. Demonstrate that the research team has expertise in the target area. Demonstrate that the appropriate collaborators are involved in the proposed study, and provide evidence of successful collaboration between the research team and the proposed key partners.

Innovation: Discuss how the proposal fills a gap in the targeted cancer interception discovery research and the high need for initial screening efforts to identify new modalities to change the current trajectory of cancer interception and prevention research. Provide compelling information (and include data, where applicable) that demonstrates that the proposed targeted discovery research for natural product screening and development is missing, largely absent, or underrepresented. How this project shifts translational science paradigms: Address any ways that the project will generally improve the success or efficiency of translational science. Discuss the ways in which any learnings from the current natural product discovery and development campaign could be applied to other translational science efforts.

Approach: This section should include a description of the approach needed to accomplish the objectives for the UG3 phase and the UH3 phase.

Overall Strategy and Analyses: Projects should have clear, testable hypotheses and the research plan should use quantifiable measures for making a go/no-go decision. A statistician should be consulted to make sure all experiments have adequate power and statistical rigor. Justification and statistical calculation for the proposed number of animals for applicable in vivo models should be included.

The approach should be divided into the UG3 phase and the UH3 phase and address the following for each phase:

UG3 Phase: The UG3 part of the application must describe the proposed cancer interception pathways and the clinically relevant targets, development of screens and HTS strategies and the activities associated with preparing for the full scale HTS of the natural product libraries and development of lead screen in the UH3 phase. Specifically, the application should:

• Describe the clinical relevance of the pathway and the selection of the associated targets;
• Provide evidence that the proposed targets are appropriate for the target population and the setting, and the evidence of knowledge of molecular class of target and its affected pathway;
• Describe the approaches for target verification/validation in both clinical samples and in the preclinical in vitro and in vivo samples;
• Describe the detailed strategies for primary assay development and assay optimization for screening natural products in cell-based screens and/or cell-free assay technologies;
• Describe details to assess if the proposed assay performs with consistency, reproducibility, robustness, and accuracy in initial HTS and whether primary assay determined to be targeted to cancer interception and prevention;
• Provide evidence of capability to screen for perturbation of target;
• Provide details to assess whether primary assay meets requirements for full scale robotic HTS;
• Describe secondary assays to further interrogate potential active compound;
• Describe and justify the design for the development of prototype HTS;
• Describe the availability of reliable toxicity metrics & in vitro/in vivo HT-ADME Assays;
• Provide detailed strategies on the pilot evaluation of existing NCI NPNPD natural product libraries or investigator-developed libraries in HTS compatible screens.

UH3 Phase: The UH3 part of the application must describe the proposed full scale HTS of the NCI libraries or investigator owned or commercial libraries and development of screened lead for cancer interception and prevention. Specifically, the application should:

• Describe strategies for the full-scale evaluation of natural product libraries in HTS compatible screens designed to identify potential cancer preventive agents;
• Describe how the developed assay performs with consistency, reproducibility, and accuracy in initial HTS and provide statistically significant data to direct active fractions;
• Describe how the hit list will be further prioritized (previous activity, toxicity screening, known chemistry) with NCI input prior to secondary purification of active compound;
• Describe the strategies for active sample prioritization, orthogonal assays/hit prioritization, compound isolation and structure elucidation, hit-to-lead progression/lead optimization;
• Describe strategies to determine if sub-fractions recapitulate identified activity in initial fraction in a dose-response manner;
• Provide plans to characterize, and evaluate pharmacokinetics, bioavailability, and assessment of the lead natural product’s effect (i.e., a measure of the mechanism of action) in vitro and/or in vivo;
• Describe the plan to determine the optimal dose or formulation of the product for subsequent studies and further testing safety and acceptability;.
• Use reliable and validated measures to assess the cancer interception in vivo efficacy;
• Describe reference compounds for assessing efficacy of screened lead compound.

Milestones and Timelines

A timeline including milestones is required for all phases of the application (UG3/UH3). A milestone is defined as a scheduled event in the project timeline signifying the completion of a major project stage or activity. Milestones will be used to evaluate the application in peer review as well as in consideration of the awarded project for funding of non-competing award years.

The application must include a section of proposed milestones that are clearly specified, well-defined, quantifiable, scientifically justified, and include objective criteria to allow for assessment of progress and success. For UG3 milestones, applicants should delineate what they propose to achieve in order to proceed to the UH3 phase. The milestones should also include a timeline, a discussion of the suitability of the milestones for assessing success in the UG3 phase, and a discussion of the implications of successful completion of these milestones for the proposed UH3 phase. Annual milestones for the UH3 phase must also be included in the application.

Letters of Support: Applications must include letters of support from key collaborators collaborating on the project. Potential applicants seeking NCATS support are required to consult and obtain a letter of collaboration from the Scientific Director of NCATS Division of Preclinical Innovation to be included in their application. For additional information, see the NCATS Early Translation Branch at https://ncats.nih.gov/etb and the Letters of Support section below.

Collaboration Plan and Agreement. Applications seeking NCATS support must describe the partnership in a Collaboration Plan that will be included in the application. Applications for this program will be submitted by the extramural institution with the NIH intramural scientist(s) integrated into the application as described in the Collaboration Plan. Annual progress reports will be prepared and submitted by the extramural institutions, with the participation and input of the program staff and intramural investigator(s) and should include the project findings, publications, data and resource-sharing and impact of the collaborative project. This collaborative translational research between NCATS intramural scientists and extramural investigators will involve either a Cooperative Research and Development Agreement (CRADA) or Research Collaboration Agreement (RCA), which will need to be executed for projects deemed scientifically meritorious by peer review. NCATS will provide CRADA or RCA template documents to help streamline the interaction between NCATS intramural scientists and extramural investigators. These template agreements can be found on https://ncats.nih.gov/alliances/forms. Questions regarding any of these agreements can be referred to the NCATS Office of Strategic Alliances at [email protected]. Applicants should review this document and consult with their institutes about their willingness to agree to the conditions well in advance of submitting an application to this NOFO. The CRADA or RCA will need to be executed after the application has been identified for funding. While the CRADA or RCA may not be in place before the award is made, it will be useful to have a statement from the applicant’s Sponsored Research Office that they agree, in principle, to the conditions of the CRADA/RCA.

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.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

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.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

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

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.

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

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

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 NOFO 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 reviewed 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.

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.

For this particular announcement, note the following:

Applications in response to this NOFO will include two phases: the UG3 phase and the UH3 phase. Milestones to be accomplished in the UG3 phase for transition to the UH3 phase must be proposed by the Principal Investigator in the application and will require NCI administrative review and approval before the UH3 grant is awarded.

Overall Impact

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

Scored Review Criteria

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

Significance

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

Specific for this NOFO:

• How well does the application provide an explanation and justification for and development of novel cancer interception natural products?
• How well are the scientific rationale and need for a large scale natural product screening to test the proposed hypothesis supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms?
• What is the likelihood that the proposed research will substantially advance the understanding of cancer interception targets in higher-risk populations and the discovery and development of novel targeted natural products for cancer interception and prevention?
• How well does the proposal address a research issue that could not be addressed previously?

Investigator(s)

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

Specific for this NOFO:

• How well does the application provide evidence that the investigative team has scientific expertise in the cancer prevention, proposed pathway/target area, and/or develop and characterize an HTS and their ability to organize, manage and implement the proposed studies and meet milestones and timelines?

Innovation

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

Specific for this NOFO:

• How well does the application demonstrate that the proposed cancer interception-prevention targets/pathways are clinically relevant?
• How well does the proposed studies explore innovative biological concepts to improve the understanding and knowledge of cancer preventive or interceptive targets and to discover novel targeted natural products for cancer interception and prevention?
• How novel are the research methods proposed to validate potential targets and discover efficacious molecularly or immunologically targeted natural products for higher-risk populations?
• How well does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge?

Approach

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

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

Specific for this NOFO:

• How well does the application describe the scientific rationale/premise of the study based on previous preclinical and/or clinical research?
• How well does the application describe the proposed cancer interception pathways and the clinically relevant targets, development of screens and HTS strategies and the activities associated with preparing for the full scale HTS of the natural product libraries and development of lead screen?
• How well does the application describe and justify the full scale HTS strategies and development of safe and efficacious targeted natural product for cancer interception and prevention?
• How adequately does this application describe testable hypotheses and the research plan with clarity using quantifiable measures having adequate power and statistical rigor for making a go/no-go decision?
• How well is the Collaboration Plan defined with identifiable responsibilities for the NIH intramural investigator and the extramural applicant?

Environment

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

Additional Review Criteria

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

Milestones Plan

• To what extent do the proposed milestones provide sufficient detail for the planned tasks?
• To what extent are the milestones clearly defined, feasible, and quantifiable with respect to the proposed activities within the proposed timeframe?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications will receive a written critique.

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

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

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

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Compliance with resource sharing policies.

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal wide 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 will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. 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 NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/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 religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) 2 CFR Part 200 Administrative Regulations, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, NIH Grants Policy Statement (which implements the aforementioned HHS Regulations (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 recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

Primary Responsibilities of PD/PIs

The PD(s)/PI(s) of each award will have the primary authority and responsibility for the project as a whole, including determining research approaches, designing protocols, setting project milestones in consultation with NCI staff, ensuring scientific rigor, conducting specific studies, analysis and interpretation of research data, and preparation of publications.

Specific rights and responsibilities will include the following:

• Overseeing the overall budget, activities, and performance of the project;
• Conducting the scientific research in the project, reporting progress and milestones or objectives to NCI staff, reporting results to the scientific community, and disseminating approaches, methods, models, and tools broadly;
• Participating in a cooperative, interactive, and collaborative manner with NCI staff, including those outlined below under NIH Responsibilities ;
• Submitting a detailed transition request for the phase, outlining progress, accomplishment of milestones, and detailed plans, budget, and annual milestones for the phase.
• Submitting materials and updates to the NCI on study progress, accomplishments, and challenges as requested;
• Facilitating the public release and dissemination of results, data, and other products generated through this award in a timely manner. All PDs/PIs are expected to share data and resources generated through this award in accordance NIH sharing policies and the goals of the NOFO;
• Complying with OHRP and FDA regulations concerning the protection of human subjects;
• Assuming responsibility and accountability to the applicant organization officials for the performance and proper conduct of the research and administrative functions supported under this NOFO in accordance with the terms and conditions of the award, as well as all pertinent laws, regulations, and policies; and
• Operating in accordance with processes and goals as delineated in the NOFO.
• Recipients(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.

In addition to standard annual Research Performance Progress Report (RPPR) submissions, PDs/PIs may be expected to supply additional progress-related information to the NCI and participate in the meetings as needed.

Primary Responsibilities of NCI program Staff

NCI program staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The substantially involved NCI program staff member(s), acting as Project Scientist(s), will coordinate in a centralized fashion various activities of the recipients.

Specific responsibilities of the NCI Project Scientist(s) will include, but will not be limited to:

• Provide scientific input and advice on development of high-throughput screening assays
• Advice and assistance with generation of key reagents
• Provision of natural product libraries for pilot screening and full scale HTS (if applicable)
• Advice on optimization of screening assay for technology transfer to HTS laboratory at NIH (if applicable)
• Assistance with technology transfer to NCATS (if applicable)
• Provide direct support for the isolation, identification, and structural characterization of bioactive fractions/active natural products throughout the purification process (if applicable)
• Conduct of full scale HTS of the NCI Natural Products Library at the NIH laboratory (if applicable)
• Assistance with follow-up testing to support bioassay-directed isolation of active natural products (if applicable)
• Assistance with medicinal chemistry/formulation support for isolated natural products (if applicable)
• Providing scientific input on the design of the secondary screens to prove the specificity of active compounds
• Providing input on scientific milestones and decisions regarding their finalization;
• Promoting collaborative research efforts by facilitating interactions with relevant NCI- and NIH-sponsored programs, projects, and centers; and
• Contributing to scientific manuscripts and other scientific and scholarly activities (e.g., conference presentations) resulting from the project.

Additionally, an NCI Program Director acting as the NCI Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The NIH staff (NCI and NCATS) is expected to have responsibility for a substantial portion of the proposed research and provide advice and technical assistance as needed. The NIH staff will also participate in the analysis, interpretation, and reporting of findings in the scientific literature, to the community at large and to the public policy community within the Federal government through various media, as appropriate. The NIH staff is subject to the same publication/authorship policies as the official NIH publication policy.

Areas of Joint Responsibility

The Natural Products Steering Committee (NPSC) will serve as the main governing board for this initiative. Awardees will join NPSC, which will continue to serve as the main governing board of this initiative.

Voting members for the NPSC include:

• NIH Project Scientists (collective one vote) and one representative from each new UG3/UH3 award (a PI or their designee) will be voting members; and
• Other PD(s)/PI(s) can participate in NPSC meetings as non-voting members ;

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

• Conducting monthly teleconferences or virtual meetings;
• Establishing policies and procedures for collaborative projects and protocols;
• Developing guidelines for the distribution of materials for collaborative research;
• Identifying impediments to success and developing strategies to overcome them;
• Serving as a nucleus for a broader outreach to the entire extramural natural products research community;
• The SC may decide to establish sub-committees for specific purposes and NIH Project Scientists will serve on such sub-committees, as they deem appropriate.
• Participate in monitoring of intellectual property arising from the project.

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: one NIH designee and two designees with expertise in the relevant area, chosen by the NCI Cohort Consortium Steering Committee. This special dispute resolution procedure does not alter the recipient'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.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. 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 NOFOs 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 $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.

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: https://www.era.nih.gov/need-help (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]

Altaf Mohammed, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6082
Email: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: [email protected]

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.