Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility (R21 and R01 - Clinical Trial Not Allowed)

Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility (R21 and R01 - Clinical Trial Not Allowed) is sponsored by National Institutes of Health (NIH) / National Cancer Institute (NCI). Promotes etiologic research investigating novel and innovative hypotheses on emerging risk factors (biological, environmental, and social) and their interplay with established risk factors (e. g.

Expired PA-25-123: Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility (R21 Clinical Trial Not Allowed) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Cancer Institute ( NCI ) Funding Opportunity Title Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility (R21 Clinical Trial Not Allowed) R21 Exploratory/Developmental Research Grant 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) Companion Funding Opportunity See Section III. 3.

Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this Notice of Funding Opportunity (NOFO) is to promote epidemiologic research investigating novel and innovative hypotheses on emerging risk factors (biological, environmental, and social) and their interplay with established risk factors (e.g., viral hepatitis) associated with the development of liver cancer (hepatocellular carcinoma and other histological subtypes) in the United States.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) The following table includes NIH standard due dates marked with an asterisk. Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed 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.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - 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 1. Overview Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description The overarching objective of this Notice of Funding Opportunity (NOFO) is to enhance population-based research on liver cancer in the United States (U.S.).

Specifically, this liver cancer NOFO seeks to support epidemiologic research to expand our understanding of the etiology of the malignancy, including expanding investigations on unanswered questions related to viral hepatitis-associated liver cancer, and exploring emerging and novel risk factors that may contribute to the rising burden of liver cancer in the U.S. The funded projects will contribute to the body of evidence needed to inform evidence-based prevention and control strategies of liver cancer.

While hepatocellular carcinoma (HCC; ICD10 code C22. 0) accounts for approximately 85-90% of all primary liver cancer, this NOFO will also include support of applications seeking to better understand the etiology of other histological subtypes such as cholangiocarcinoma, hepatoblastoma, and angiosarcoma of liver. These subtypes are rare but add to the burden of primary liver cancer and have been under-investigated.

This NOFO will utilize the Research Exploratory/Developmental Research Grant (R21) mechanism and runs in parallel with a companion NOFO of identical scope, which utilizes the Research Project Grant (R01) mechanism. Liver cancer incidence and mortality rates in the United States (U.S.) are increasing.

Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer while cholangiocarcinoma (also called cancer of the bile duct) is a distant second. The established risk factors for HCC include viral hepatitis (hepatitis B [HBV] and hepatitis C viruses [HCV]), alcohol abuse, and environmental factors (e.g., smoking and aflatoxin B1).

Despite this, it has been estimated that 15%-50% of HCC cases do not have evidence of viral hepatitis or heavy alcohol consumption as risk factors. For cholangiocarcinoma, the primary established etiologic risk factor is infection of Opisthorchis veverrini or Clonorchis sinensis , also known collectively as liver fluke.

However, it is unclear why Americans who have never been exposed to high endemic areas of liver fluke (e.g., Thailand) would develop cholangiocarcinoma, thus suggesting that other etiologic factors exist. Collectively, there are marked disparities in liver cancer incidence, associated risk factors, and rates of progression to liver cancer by sex, age, race/ethnicity, and geographic areas.

The incidence of liver cancer, particularly HCC, is expected to increase further, and the health impact of this increase is being compounded by an overall 5-year survival of just 18%. Historically, a notable proportion of HCC has been attributed to Asian Americans and foreign-born persons that immigrated from countries where HBV is highly prevalent.

Recent epidemiologic evidence suggests that non-viral factors may contribute significantly, independently, and/or in concert with viral hepatitis, to the observed increase in liver cancer incidence.

These non-viral factors differentially affect different sub-populations in the U.S. These emerging non-viral factors include non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, diabetes, metabolic syndrome, and environmental factors such as Poly- and perfluoroalkyl substances (PFAS).

Obesity, diabetes, and metabolic syndrome may contribute significantly to the observed rise in HCC incidence in the U.S., particularly non-Asian American populations. Moreover, with the rise in the prevalence of obesity and metabolic syndrome, NAFLD and NAFLD-associated liver diseases have been increasing among Americans.

NAFLD may progress to NASH (non-alcoholic steatohepatitis), and it is estimated that 6-8% of the U.S. population have NASH. Between 70-90% of HCCs develop in people with liver cirrhosis (affecting 633,000 Americans), which is considered the penultimate step of the multistage pathogenesis of HCC. NAFLD-associated HCC can also occur in a liver without underlying cirrhosis.

Although individuals with non-viral risk factors are at a lower risk for developing cirrhosis and HCC than those infected with HCV or HBV, there is greater prevalence of these underlying liver diseases in the U.S. population.

Novel hypotheses underlying liver carcinogenesis also have emerged in recent years, including the influence of the microbiome in the liver-gut axis and liver-related malignancies and the microvesicles as a potential biomarker for HCC. Environmental exposures such as ambient air pollution, toxic metals, and PFAS may contribute to the etiology of liver cancer.

Additionally, there may be social and geospatial drivers that contribute to the differential incidence and mortality rates observed across U.S. regions and populations. Because the liver’s main job is to filter the blood coming from the digestive tract, it seems likely that circulating factors in the blood, such as immunological cells and inflammatory proteins, may play a role in liver cancer risk and progression.

These lines of scientific inquiry have not been fully examined. Overall, the etiologic role of these non-viral factors associated with liver cancer is still in its early stage of investigation compared to viral-related research. Little is known about the independent role of non-viral factors in liver carcinogenesis or how they may interact with viral hepatitis or serve as a co-factor to increase susceptibility.

This FOA seeks to facilitate focus on novel inquiries in liver cancer etiology using population-based studies research. This NOFO seeks applications focusing on epidemiologic research investigating emerging and new etiologic factors and liver cancer risk in populations relevant to the United States. Applications to this NOFO should include, when possible, relevant biospecimens to evaluate associated risk factors and liver cancer risk.

Applications that include an investigation on viral-associated liver cancer must provide strong rationale that outlines the added innovation or new knowledge to be gained from the current evidence of viral-associated liver cancer etiology. Appropriate research applications also include those that seek to understand the interplay of multiple factors that cause liver cancer across different U.S. populations.

For example, metabolic syndrome may accelerate the progression of liver disease in patients with chronic HBV infection and synergistically induce HCC development. As noted, studies responding to this announcement should be epidemiology research, but may include aspects of basic and behavioral research, if relevant, to elucidate underlying mechanisms in humans and improve targeted prevention in high-risk populations, respectively.

Applicants are strongly encouraged to leverage existing resources such as case-control and prospective cohort studies, and databases to utilize data and biological specimens to test the proposed hypotheses. Proposed projects can involve primary and/or secondary data collection and analysis. Projects should involve collaborations among investigators in the U.S., when possible.

Given that the etiology of liver may differ across U.S. populations, applicants may need to collaborate with international researchers, if directly relevant for the proposed research. Applicants can engage in collaborations with international partners, but the research must have direct application to the liver cancer etiologies found in U.S. populations.

Areas of research interest include, but are not limited to the following: The role of non-viral risk factors (e.g., obesity, diabetes, NAFLD, NASH, metabolic syndrome, alcohol consumption, and other environmental factors) and liver cancer (HCC and non-HCC) risk; The role of metabolic syndrome, obesity, diabetes, and influence of other risk factors in the progression of fatty liver, NASH, and cirrhosis to the development of liver cancer; The interactions of multiple risk factors (e.g., hepatitis B, hepatitis C, HIV, metabolic syndrome, smoking, host genomics and immunologic responses) in the etiology of liver cancer; The role of social, behavioral, and host factor determinants in explain differences in incidence and mortality rates for liver cancer across multiple populations; Examination of novel hypotheses, risk factors, and biomarkers of liver carcinogenesis (e.g., cellular factors, telomere maintenance and length, metabolites, microbiome signatures, epigenomic alternations, gene expression and protein expression); The role of pharmacologic factors (e.g. statin and metformin) and non-pharmacological supplements in liver cancer using population-based studies; The role of blood circulating factors, possible biomarkers, and liver cancer development and progression; and Investigation of factors that contribute to the differential risks of liver cancer between men and women Non-Responsive Applications Applications that propose the following will be deemed non-responsive to the goals of this NOFO and will not be reviewed: Focus on investigation of the etiologic link between HBV or HCV and liver cancer only Seek infrastructure support for the establishment of a new cohort or follow-up visits of an existing cohort See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information 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 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. Not Allowed: Only accepting applications that do not propose clinical trials.

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. The combined budget for direct costs for the two-year project period may not exceed $275,000.

No more than $200,000 may be requested in any single year. The maximum project period is 2 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 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 (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession 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 Non-domestic (non-U.S.) Entities (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. 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 .

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.

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. 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 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. 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: National Cancer Institute 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. 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. All instructions in the How to Apply- Application Guide must be followed.

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.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: 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.

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. 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-definedclinical 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.

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 (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement , and procedures for foreign institutions 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. 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 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. 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. 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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 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: 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).

An application does not need to be strong in all categories to be judged likely to have a major scientific impact. Reviewers will consider 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 factor score.

Factor 1: Importance of the Research 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. 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 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). 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. 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 a study population that appropriately models the target population.

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 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.

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 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.

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)