The purpose of this Funding Opportunity Announcement (FOA) is to support collaborative research projects designed to address adverse sequelae of cancer therapies that persist and become chronic comorbidities or develop as delayed posttreatment effects. This FOA supports basic, translational, and clinical research projects that seek to identify the mechanisms of therapy-induced adverse sequelae, clinically characterize the adverse sequelae, or translate the mechanistic understanding into therapeutic approaches to prevent or minimize the development of long-term sequelae. Research projects should focus on mechanistic studies with translational endpoints and longitudinal clinical phenotyping to identify and validate clinical endpoints (biomarkers, imaging, patient-reported outcomes, or combined elements) for future use in clinical trials that will evaluate the efficacy of interventions designed to prevent or reduce specific adverse sequelae.

PAR-25-145: Clinical Characterization of Cancer Therapy-induced Adverse Sequelae and Mechanism-based Interventional Strategies (R01 Clinical Trial Optional)

Posted Date: November 06, 2024 Expiration Date: January 08, 2028

This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

Part 1. Overview Information

Participating Organization(s): National Institutes of Health (NIH) Components of Participating Organizations: National Cancer Institute (NCI)

Funding Opportunity Title: Clinical Characterization of Cancer Therapy-induced Adverse Sequelae and Mechanism-based Interventional Strategies (R01 Clinical Trial Optional)

Activity Code: R01 Research Project Grant

Announcement Type: Reissue of PAR-21-329

Related Notices:

• March 31, 2025: This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.
• April 4, 2024: Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084.
• August 31, 2022: Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
• August 5, 2022: Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.

Funding Opportunity Number (FON): PAR-25-145

Companion Funding Opportunity: None

Number of Applications: See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s): 93.393

Funding Opportunity Purpose: The purpose of this Notice of Funding Opportunity (NOFO) is to promote research studies designed to address adverse sequelae of cancer therapies that persist and become chronic co-morbidities or develop as delayed posttreatment effects. This NOFO supports basic, translational, and clinical research projects that seek to identify the mechanisms of therapy-induced adverse sequelae, clinically characterize the adverse sequelae, and translate the mechanistic understanding into therapeutic approaches to prevent or minimize the development of long-term sequelae. The scope of research projects includes mechanistic studies with translational endpoints and longitudinal clinical phenotyping to identify and validate clinical endpoints (biomarkers, imaging, patient-reported outcomes or combined elements) for future use in clinical trials that will evaluate the efficacy of interventions designed to prevent or reduce specific adverse sequelae.

Key Dates:

• Posted Date: November 06, 2024
• Open Date (Earliest Submission Date): January 05, 2025

The following table includes NIH standard due dates marked with an asterisk.

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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose: The purpose of this Notice of Funding Opportunity (NOFO) is to promote research studies designed to address adverse sequelae of cancer therapies that persist and become chronic co-morbidities or develop as delayed posttreatment effects. This NOFO supports basic, translational, and clinical research projects that seek to identify the mechanisms of therapy-induced adverse sequelae, clinically characterize the adverse sequelae, and translate the mechanistic understanding into therapeutic approaches to prevent or minimize the development of long-term sequelae. The scope of research projects includes mechanistic studies with translational endpoints and longitudinal clinical phenotyping to identify and validate clinical endpoints (biomarkers, imaging, patient-reported outcomes or combined elements) for future use in clinical trials that will evaluate the efficacy of interventions designed to prevent or reduce specific adverse sequelae.

Research projects may be conducted in basic science and/or clinical settings. Successful applications should identify the specific adverse sequelae, which may include a cluster of adverse events that occur sequentially or in tandem with rationale for the cluster. The adverse sequelae may be chronic, progressive or later adverse effects for which current management or treatment strategies are limited or ineffective.

Background: Many advances have been made in the treatment of cancer, with an increasing number of treatment options available to cancer patients, including surgery, radiation, and/or systemic therapy (chemotherapy, immunotherapy, targeted or hormonal therapies), from which severe adverse sequelae may result. The number of cancer survivors continues to grow, with more than 18 million alive today, of which 47% have lived more than 10 years since diagnosis. Often, the extent of the toxicity burden is unknown until the therapy is administered to a large population of “real-world” patients with comorbidities who were not included in the definitive clinical trials. Cancer registries do not typically collect information on treatment-related adverse effects, and identifying chronic or late-onset adverse effects can be challenging.

Commonly, systemic cancer treatment can result in acute, cumulative, progressive and/or chronic toxicities. Some acute drug-related adverse events (e.g., acute nausea and vomiting, neutropenia infections) can be mitigated by implementing evidence-based treatments or altering treatment doses and will resolve once therapy has been completed. Similarly, acute inflammatory responses resulting from immunotherapy can be managed by discontinuing therapy or treating with immunosuppressive corticosteroids. Other adverse effects persist after completion of therapy or develop as late effects of therapy. For radiation therapy, adverse effects can develop acutely, resulting in dosing modifications, or occur as an intermediate or late effect. Adverse sequelae that result in dose modifications or discontinuation of therapy may have a negative impact on cancer outcomes. Some of the chronic or late adverse effects may reduce the overall benefit from therapy by reducing patient quality of life following therapy and/or introducing additional morbidities that impair overall survival. These adverse sequelae include, but are not limited to, therapy-induced peripheral neuropathy, neurocognitive impairments, cardiovascular toxicity, lymphedema of the upper and/or lower extremities, pulmonary fibrosis, arthralgias, fatigue, nephrotoxicity, ototoxicity, and various immune system-related adverse events. While a variety of acute inflammatory adverse reactions have been reported with anti-checkpoint immunotherapy, the long-term consequences of checkpoint blockade or cellular immunotherapy are not known.

With the introduction of newer treatment approaches, whether drugs, radiation therapy, immunotherapy or novel combinations, adverse events not seen with older therapies are emerging. A careful assessment of pretreatment baseline characteristics may not be completed, impairing the ability to understand individual variability and subclinical risk factors. To date, little is known about the rates and severity of these newer adverse effects, particularly for immunotherapy agents and combination therapies involving immunotherapies. Further, it is unknown how age, race/ethnicity, and co-morbid conditions will affect the development, progression or severity of these adverse events. In some cases, it is not a single adverse event, but a cluster of events that may herald the development of significant sequelae.

Given the high prevalence and significant impact of cancer treatment-related adverse effects, there is a need to understand both the mechanisms for their acute development and the clinical trajectory of the events that become chronic sequelae, including the variability in severity and duration of specific chronic or late effects. For most of the cancer treatment-related adverse effects, no approved mitigating therapies or evidence-based management strategies are in place. Efforts to develop nontoxic interventions to relieve treatment-related toxicities are hampered by a lack of mechanistic insight into these adverse events, difficulties in objectively measuring treatment-related toxic effects, insufficient characterization of the clinical phenotype, and insufficient studies validating preclinical biomarkers in the clinical setting.

Specific Areas of Research Interest: NCI is interested in pre-clinical and clinical grant applications that extend the mechanistic understanding of cancer therapy-induced adverse sequelae to address one or more of the research gap areas outlined below. Applications should address hypotheses supported by mechanistic data focused on clinical and translational outcomes in adult or pediatric populations. Applications may focus on adverse sequelae that persist and become chronic comorbidities or develop as delayed posttreatment effects related to radiation and/or systemic therapy (chemotherapy, immunotherapy, targeted or hormonal therapies). Collaborations between clinical and basic science investigators are encouraged, and projects that couple the mechanistic knowledge with clinical phenotype will be prioritized. It is highly recommended that preclinical studies validate their findings in human tissue or human-derived cells with direct applicability to human conditions. A focus on understudied and underserved cancer populations and emerging cancer treatments is encouraged.

Research areas of interest include, but are not limited to, the following:

• Clinical characterization/phenotyping of chronic or progressive cancer therapy-induced adverse events or cluster of events
• Investigation of the trajectory of adverse sequelae that progress or become chronic
• Development and/or validation of objective measures of treatment-related adverse events
• Validation of clinical markers (biomarkers, imaging, patient-reported outcomes) of adverse sequelae in the clinical setting
• Conducting translational research to evaluate prevention or mitigation strategies
• Identification of risk factors and/or individual differences that contribute to the trajectory of adverse sequelae
• Examining the effect of the interaction between cancer treatment and cancer/tumor biology on adverse sequelae
• Translating knowledge of known and emerging clinical and genetic profiles and biological mechanisms into improvements in risk stratification, prevention, and detection

Non-responsive Applications: Applications with the following attributes will be deemed non-responsive and will not be reviewed:

• Studies focused on acute, reversible, and non-progressive adverse sequelae;
• Exploring resistance to cancer treatment;
• Using Pre-clinical models to determine adverse events of non-FDA approved anti-cancer agents; and
• Exploring the development of symptomatic adverse events in non-cancer conditions.

See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

Funding Instrument: Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed:

• New
• Resubmission

The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial? Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards: The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget: Application budgets are not limited but need to reflect the actual needs of the proposed project.

Award Project Period: The scope of the proposed project should determine the project period. The maximum project period is 5 years.

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

Eligible Organizations:

• Higher Education Institutions
  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education
• Nonprofits Other Than Institutions of Higher Education
  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• For-Profit Organizations
  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)
• Local Governments
  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
• Federal Governments
  • Eligible Agencies of the Federal Government
• U.S. Territory or Possession
• Other
  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)
  • Foreign Organizations
  • Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.
  • Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
  • Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations:

Applicant Organizations: Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• 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 registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov: Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

Eligible Individuals (Program Director/Principal Investigator): 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. 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 How to Apply-Application Guide.

2. Cost Sharing: This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

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 NIH Grants Policy Statement Section 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 NIH Grants Policy Statement 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 How to Apply - 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.

Page Limitations: All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission: The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

• SF424(R&R) Cover: All instructions in the How to Apply - Application Guide must be followed.
• SF424(R&R) Project/Performance Site Locations: All instructions in the How to Apply- Application Guide must be followed.
• SF424(R&R) Other Project Information: All instructions in the How to Apply- Application Guide must be followed.
• SF424(R&R) Senior/Key Person Profile: All instructions in the How to Apply- Application Guide must be followed.
• R&R or Modular Budget: All instructions in the How to Apply- Application Guide must be followed.
• R&R Subaward Budget: All instructions in the How to Apply-Application Guide must be followed.
• PHS 398 Cover Page Supplement: All instructions in the How to Apply- Application Guide must be followed.
• PHS 398 Research Plan: All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: The Research Strategy should clearly describe the following within the appropriate section (i.e., Factor 1: Importance of the Research; Factor 2: Rigor and Feasibility): Information to be included in each grant application, but not limited to bulleted items, are listed below:
  • Factor 1: Importance of the Research (Significance, Innovation)
    • Succinctly discuss how the proposed research clinically characterizes adverse sequelae and how it can be translated into developing therapeutic approaches to prevent or minimize the development of long-term sequelae.
    • Summarize how the proposed research utilizes mechanistic knowledge of adverse sequelae to bring novel insight and understanding to preventing or minimizing long-term adverse sequelae.
    • Discuss how any advances in the mechanistic understanding of specific adverse sequelae could be ultimately applied to clinical phenotyping and/or the development of biomarkers that could be used in clinical trials.
    • Summarize how the mechanistic knowledge is being used to evaluate the acute development and/or clinical trajectory of events that become chronic sequelae in the proposed research.
    • Summarize how the proposed research uses novel methodology for clinical phenotyping.
    • Discuss and highlight the innovative aspects of the research design.
  • Factor 2: Rigor and Feasibility (Approach)
    • The approach and methodology proposed will be unique to the clinical need specifically addressed by each application. It is strongly encouraged that the proposed approach be succinctly described in detail and that it addresses possible weaknesses while clearly stating the clinical impact.
    • The potential difficulties and limitations of the proposed methodology and alternative approaches to achieve the aims should be identified and succinctly discussed.
    • Describe and define the specific adverse event or cluster of events being studied in the proposed research.
• Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide. The following modifications also apply:
  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Other Plan(s): All instructions in the How to Apply-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.
  • A Data Management and Sharing Plan is not applicable for this NOFO.
• Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide. No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.
• PHS Human Subjects and Clinical Trials Information: When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- 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 How to Apply- Application Guide must be followed.
    • Section 2 - Study Population Characteristics:
      • 2.5 Recruitment and Retention Plan:
        • Recruitment and referral sources: include the number of potentially available participants per proposed site annually;
        • Enrollment rate (e.g., number of participants meeting eligibility criteria for enrollment per month);
        • Discussion of potential recruitment delays or challenges and alternative strategies that can be implemented if there are enrollment delays or shortfalls;
        • Procedures to monitor enrollment and track/retain participants for follow-up assessments;
        • Evidence to support the feasibility of enrollment, including prior experience and yield from research efforts using similar referral sources and/or strategies;
        • Strategies to ensure the study population has scientifically appropriate complexity and representativeness;
        • Decision points for terminating the trial.
    • 2.7 Study Timeline: The study timeline should describe key milestones throughout the project and trial that need to be met to achieve the goals of the study. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a project stage or activity. Applicants are required to provide detailed project performance and timeline objectives as outlined below. Investigators must indicate where within the Plan the clinical trial or trials are scheduled and when the required documents will be available if not included at the time of submission. Program staff will review the milestones and timelines which can be negotiated, as needed, at the time of the award. This section should include an estimated timeline for the following general milestones, as applicable:
      • Complete finalized Clinical Trial Protocol for submission to NCI;
      • Registration of clinical trial in ClinicalTrials.gov;
      • Completion of regulatory approvals;
      • Enrollment of the first subject;
      • Enrollment of 25%, 50%, 75%, and 100% of the projected recruitment for all study participants including women, minorities, and individuals across the lifespan (as appropriate);
      • Completion of data collection time period;
      • Completion of primary endpoint and secondary endpoint data analyses;
      • Completion of final report of the primary outcome;
      • Reporting of results in ClinicalTrials.gov;
      • Status of the FDA-regulated product requiring IND or IDE if applicable. In addition to meeting the above recruitment and other targets, applicants should give contingency plans if they do not meet the milestones and address other implementation activities necessary such as start-up tasks to achieve trial completion. Future year support is contingent on satisfactory achievement of performance milestones. If milestones are not achieved fully, NCI may request development of a remedial plan and more frequent monitoring of progress, and/or take other remedial actions.
    • Section 3 - Protection and Monitoring Plans:
      • 3.3 Data and Safety Monitoring Plan: In addition to the description of safety monitoring, address plans to monitor trial performance, including plans to assure fidelity to the protocol and integrity of the data. Information about Data and Safety Monitoring Plans are available at https://humansubjects.nih.gov/data_safety.
      • 3.5 Overall Structure of the Study Team: In addition to the standard requirements for this item, provide a description of methods to identify additional collaborators, including enrollment/participation sites, if applicable. Investigators who are new to the conduct of clinical trials should identify an appropriate mentor and establish the right composition for the clinical trial team (e.g., trial manager, statistician, data manager, study coordinator(s), research assistants, institutional review board [IRB] and ethics coordinator, etc.). In this situation, only the names and titles of key team members should be listed in a table.
    • Section 4 - Protocol Synopsis:
      • 4.1.a Detailed Description: It should summarize the necessary elements of the trial and supplements the Research Strategy, which includes an overview of the state-of-science and relevance of the trial and is meant to justify the need, its potential impact, and provide supporting preclinical and/or clinical evidence to justify the proposed trial, its design, and likelihood of successful completion. Applications submitted without the Clinical Protocol Synopsis are considered incomplete and will not be reviewed.
      • 4.1.c Interventions: Please include the dose and intensity of the intervention in the description, if applicable.
      • 4.1.d Study Phase: Applicants proposing behavioral intervention research are encouraged to use an existing framework, such as the ORBIT model for developing behavioral treatments (http://dx.doi.org/10.1037/hea0000161), to determine the clinical trial phase being proposed and for guidance on study designs and methods appropriate for early-phase (Phase I and II) translational behavioral research.
      • 4.3 Statistical Design and Power: The sample size and statistical power calculations should contain enough detail, including sufficient information on the assumptions made, so that a reviewer can readily duplicate the projected sample size for primary and secondary endpoints. The power analysis should include a discussion of non-compliance, potential cross-over (if applicable), account for rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts. A discussion of how missing data will be handled should be included. Planned interim analyses for safety, efficacy, and/or futility should be described, if applicable. For single-case design and other small-N study designs where traditional power analyses may not be applicable, provide a detailed description of the approach to sample size and analysis being used.
    • Section 5 - Other Clinical Trials-Related Attachments:
      • 5.1 Other Clinical Trials-related Attachments: For applications that have the complete Clinical Trial Protocol available, submit the Clinical Trial Protocol as a single PDF that combines all clinical documents.
      • Applicants should provide a list of clinical trials that demonstrate their experiences in trial coordination over the last 5 years, without duplicating information in biosketches. The table should be provided as an attachment using the filename Clinical Trial Experience. The table should also include the following for each trial listed: start and completion date; percent of target accrued; whether the trials reached completion; and, if applicable, the date of first publication.
  • 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 How to Apply- Application Guide must be followed.
• PHS Assignment Request Form: All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations: Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM): See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

4. Submission Dates and Times: Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372): This initiative is not subject to intergovernmental review.

6. Funding Restrictions: All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information: Applications must be submitted electronically following the instructions described in the How to Apply - 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 How to Apply - 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. Applications that are incomplete, or non-compliant, and/or nonresponsive will not be reviewed.

Requests of $500,000 or more for direct costs in any year: Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Mandatory Disclosure: Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35. Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected]

Post Submission Materials: Applicants are required to follow the instructions for post-submission materials, as described 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.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Scored Review Criteria: Reviewers will evaluate Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate criterion score.

• Factor 1. Importance of the Research (Significance and Innovation):

  • Significance: Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance. Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g., prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.
  • Innovation: Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field. Evaluate whether the proposed work applies novel concepts, methods or technologies or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

• Factor 2. Rigor and Feasibility (Approach):

  • Approach: Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).
    • Rigor:
      • Evaluate the potential to produce unbiased, reproducible, robust data.
      • Evaluate the rigor of experimental design and whether appropriate controls are in place.
      • Evaluate whether the sample size is sufficient and well-justified.
      • Assess the quality of the plans for analysis, interpretation, and reporting of results.
      • Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
      • For applications involving human subjects or vertebrate animals, also evaluate:
        • the rigor of the intervention or study manipulation (if applicable to the study design).
        • whether outcome variables are justified.
        • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
        • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
      • For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.
    • Feasibility:
      • Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances.
      • For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain an appropriately diverse population of participants. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, race, ethnicity, and sex.
      • For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

• Factor 3. Expertise and Resources (Investigator(s) and Environment):

  • Investigator(s): Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.
  • Environment: Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

Additional Review Criteria: As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

• 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, 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, 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.
• Vertebrate Animals: When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals 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. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.
• Biohazards: When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.
• Resubmissions: As applicable, evaluate the full application as now presented.
• Renewals: As applicable, evaluate the progress made in the last funding period.
• Revisions: As applicable, evaluate the appropriateness of the proposed expansion of the scope of the project.

Additional Review Considerations: 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.

• Authentication of Key Biological and/or Chemical Resources: For projects involving key biological and/or chemical resources, evaluate the brief plans proposed for identifying and ensuring the validity of those resources.
• Budget and Period of Support: Evaluate 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 CSR, 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. Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. 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, consistent with applicable law.

• 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.

Please note that reviewers will not consider race, ethnicity, age, or sex of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions. 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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding. Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

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 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices: A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official. 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. Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk. For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process. Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

• ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
• Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
• Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
• Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements: The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
• HHS recognizes that NIH 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.
• All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.
• Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. NIH may terminate awards under certain circumstances. See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support.

Cooperative Agreement Terms and Conditions of Award: Not Applicable

3. Data Management and Sharing: Consistent with the 2023 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 Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting. 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 Section 8.6 Closeout. 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 2 CFR Part 200.301.

Section VII. Agency Contacts

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

Application Submission Contacts:

• 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]

Scientific/Research Contact(s):

• Kelly Filipski Ph.D., M.P.H National Cancer Institute (NCI) Telephone: 240-276-6841 Email: [email protected]
• Rachel Altshuler, Ph.D. National Cancer Institute (NCI) Telephone: 240-276-5873 Email: [email protected]

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

Financial/Grants Management Contact(s):

• Dawn Mitchum National Cancer Institute (NCI) Telephone: 240-276-5699 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.

Authority and Regulations: 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 2 CFR Part 200.

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