PAR-25-070: Mechanisms that Impact Cancer Risk with Use of Incretin Mimetics (R01 Clinical Trial Optional)

PAR-25-070: Mechanisms that Impact Cancer Risk with Use of Incretin Mimetics (R01 Clinical Trial Optional) is sponsored by National Institutes of Health (NIH). Investigates how incretin mimetics affect cancer risk.

PAR-25-070: Mechanisms that Impact Cancer Risk with Use of Incretin Mimetics (R21 Clinical Trial Not Allowed) 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. 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 Mechanisms that Impact Cancer Risk with Use of Incretin Mimetics (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 Through this notice of funding opportunity (NOFO), the National Cancer Institute (NCI) invites applications for investigator-initiated studies addressing mechanisms by which incretin mimetics, specifically glucagon-like peptide ( GLP)-1 or dual GLP-1/glucose-dependent insulinotropic polypeptide ( GIP)-1 receptor agonists (RAs), impact cancer risk.

The focus on these agents is due to their reported effects on thyroid, prostate and other cancer risks, and the generally more favorable efficacy and side effect profile compared to other classes of incretin mimetics. In addition, this NOFO seeks to draw in talented scientists to the cancer biology field who may study incretin mimetic effects on diseases other than cancer.

Open Date (Earliest Submission Date) 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.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. 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 Through this notice of funding opportunity (NOFO), the National Cancer Institute (NCI) invites applications for investigator-initiated studies addressing mechanisms by which incretin mimetics, specifically glucagon-like peptide ( GLP)-1 or dual GLP-1/ glucose-dependent insulinotropic polypepide ( GIP)-1 receptor agonists (RAs), impact cancer risk.

The focus on these agents is due to their reported effects on thyroid, prostate and other cancer risks, and the generally more favorable efficacy and side effect profile compared to other classes of incretin mimetics. In addition, this NOFO seeks to draw in talented scientists to the cancer biology field who may study incretin mimetic effects on diseases other than cancer.

Investigators wishing to study incretin mimetics other than GLP-1 RAs or GLP-1/GIP-1 RAs, such as dipeptidyl peptidase (DPP)-4 inhibitors, must justify why the agent(s) they propose to study are more effective and/or have a more favorable side effect profile than GLP-1 or GLP-1/GIP-1 RAs. Route of agent administration (oral vs. other) is, by itself, not an adequate justification.

Whereas this NOFO is for pilot/exploratory projects, the companion NOFO (R01) is for well-developed projects. Almost 40% of U.S. adults are obese, including 35% of cancer survivors. Obesity increases the risk of death from cancer by 52% among men and 62% among women.

Our focus is on the class of agents known as incretin mimetics. These agents mimic incretin hormones such as glucagon-like GLP-1. They stimulate glucose-dependent insulin release , suppress appetite and inhibit glucagon secretion.

Current FDA approved incretin mimetics for type 2 diabetes mellitus (T2DM) or obesity in the absence of T2DM are receptor agonists (RA)s of GLP-1 and, more recently, GLP-1. These RAs have demonstrated dramatic weight loss in overweight and obese individuals, with or without T2DM.

Treatment is associated with improvements in T2DM, lower CV risk and kidney protection, although GLP-1RA/GIP-1RAs seem to be less effective for weight loss in people with than in those without T2DM. T2DM is associated with insulin resistance, a risk factor for cancer, that is exacerbated by increasing obesity. The U.S. GLP-1/GIP-1 RA market was valued at $11.

3 billion in 2019 and is anticipated to grow annually by over 6% during the next five years. The impact of these agents on cancer risk is understudied. Both thyroid cancer and aggressive prostate cancer are associated with obesity, but preliminary data show RAs have differential effects in these tumors.

RAs are contraindicated in patients with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN)2, and there are early signs that the agents may increase the overall risk of thyroid cancer. On the other hand, preliminary evidence suggests RAs may reduce the risk of prostate cancer.

There are GLP-1 and GIP-1 receptors in most human organs, suggesting that these agents might provide off-target effects unrelated to hunger suppression. While the incretin effects of GLP-1 RAs have been studied in some detail, far less is known about how dual GLP-1/GIP-1RAs work to promote weight loss, or the role of GIP-1RAs in cancer, alone or with GLP-1RAs.

Overall, this class of drug is growing in clinical use but understudied in terms of cancer related mechanisms and cancer risk. Preclinical evidence for agent mechanism(s) of action on cancer endpoints : There is increasing evidence that these agents downregulate inflammation within adipocytes.

In obese mice, semaglutide, a GLP-1 RA, reduced plasmatic cytokines, and proinflammatory gene expression of tumor necrosis factor-alpha, interleukin (IL)-6, IL-1 beta, and monocyte chemoattractant protein-1. The agents have also been shown to downregulate the pro-inflammatory interferon-γ. However, these analogs have been shown to activate macrophages toward an M2 (protumor) phenotype.

The GLP-1 RA exendin (ex)-4 decreased the proliferation of multiple prostate cancer (PCa) cell lines and the growth of murine LNCaP xenografts. Ex-4 decreased extracellular signal–regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation both in vitro and in LNCaP tumors. The GLP-1R is also expressed in human breast cancer tissue and cell lines.

When ex-4 was added to breast cancer cells, proliferation slowed in a dose-dependent manner. Xenograft tumors from MCF-7 cells shrank in response to ex-4 associated with inhibited nuclear factor (NF)-kB expression as well as decreased Akt and IkB phosphorylation.

Liraglutide not only improves blood glucose levels, but also dyslipidemia in mice fed a HFD In mice fed a HFD, liraglutide administration led to decreases in weight, total cholesterol (TC) and low-density lipoproteins, and increases in high-density lipoprotein cholesterol (HDL) levels.

The beneficial effects on circulating lipids may depend on gut microbial metabolic actions, since liraglutide treatment promotes the growth of beneficial microbes associated with lipid metabolism ( Akkermansia, Lactobacillus, Parabacteroides, Oscillospira , etc.), and inhibited the growth of harmful microbes.

Preliminary clinical findings on cancer risk : A real world study compared cancer risk among individuals using GLP-1RAs vs. metformin users based on data from an electronic health database and validated using data from the FDA Adverse Event Reporting System (FDA FAERS). Findings indicate that regular GLP-1RA use was associated with decreased risk of colon, lung, and PCa compared to metformin, and benefit increased over time.

However, there was a significant 65% increase in thyroid cancer risk. There was not an association with any other cancer. Additionally, a nested case-control analysis of individuals with T2DM in the French national health insurance database treated with GLP-1RA or not for 1-3 years observed an increased risk of all thyroid cancer of 58%, with risk of medullary thyroid cancer increased by 78%.

GLP-1 RA and dual GIP/GLP-1 RA FDA approved agents carry a black box warning prohibiting their use in patients with MTC and MEN2 syndrome, which includes tumors of the thyroid, parathyroid, and adrenal gland. Analysis of 4 randomized controlled trials (RCTs) involving patients with T2DM demonstrated an almost 50% reduction in PCa risk with GLP-1 RA administration.

A cohort study using the UK Clinical Practice Research Datalink also showed a lower risk of PCa among men taking GLP-1 RAs vs. sulfonylureas, with the benefit starting after 30 months on treatment. Research Objectives for this NOFO General Areas of Research Mechanistic questions that could be addressed include, but are not limited to: Is there a role for these agents in cancer risk reduction?

If so, what preclinical models or human studies are appropriate to study the molecular mechanism(s) associated with risk? What are the incretin mimetic-induced changes in the immune system, metabolome, hormones, cytokines, or other signaling molecules that alter cancer risk? In what organ, tissue, or cell type do they originate?

Do the changes occur prior to weight loss? Which cancers (or cancer subtypes, such as medullary vs. well differentiated thyroid) are impacted by these agents, either favorably or unfavorably, and if so, what are the mechanism(s)? Are there certain groups (sex, age, ethnicity or race) that would benefit from RAs more or less than others?

Are there off-target effects that alter cancer risk? Are these off-target effects impacted by dose? If so, what are their mechanisms?

Does the specific agent within the GLP-1, GIP-1, or dual agent list, influence the cancer promoting or tumor preventative impact? If so, what are the mechanism(s) driving the impact difference? Scope of Work and Additional Guidance The animal model and/or human studies should clearly indicate the population focus and provide a justification for that focus.

It is anticipated that studies will evaluate animal models where a significant proportion of the animals develop cancer. Human studies involving individuals who will or have received GLP-1 or dual GLP-1/GIP1 RAs are also encouraged, so long as within the cohort a substantive proportion of otherwise healthy individuals after starting the incretin mimetic subsequently develop cancer.

When feasible, investigators should evaluate mechanisms influenced by incretin mimetics in an animal model of cancer and evaluate potential changes in humans due to the medication. We define “mechanism” as a biologic endpoint based on analyzed samples from an incretin mimetic animal model or from subjects who have or are planning to receive incretin mimetics.

This NOFO does not support studies where an epidemiological endpoint is the primary aim of the project. The mechanism(s) to be studied should evaluate samples collected from animals or humans who have received incretin mimetics. For animal studies, a cancer endpoint is required.

For human studies, a cancer biomarker endpoint(s) is(are) allowed, so long as the biomarker(s) has(have) clearly been associated with the development of cancer. This NOFO is not intended for epidemiologic studies, where the primary endpoint is the assessment of cancer in a cohort of animals or humans which has received an incretin mimetic.

The following types of studies are not responsive to this NOFOapplications proposing such activities will be deemed non-responsive and will not be reviewed: A project which focuses entirely on in vitro investigations; Epidemiologic investigations as the primary focus of the project; Animal or human studies that do not evaluate tissue and/or bodily fluid samples collected from participants who have received incretin mimetics, some of which developed cancer after starting the agent; Projects that include a clinical trial.

If a clinical trial is planned, please use the companion NOFO PAR-23-279. Additional Considerations Applicants to this NOFO are strongly encouraged to contact NCI staff as soon as possible in the development of the application (preferably no later than 12 weeks prior to the application due date). A webinar may be held before the first grant deadline to address questions that investigators may have.

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 awards.

Application budget direct costs are limited to $275,000 over a maximum two year period, with no more than $200,000 in any single year. The proposed project period must not exceed 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. 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: All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Research Strategy: The entire Research Strategy must address the following specific aspects.

Explain how this project, if successful, will contribute to advancing our understanding of mechanism(s) driving the impact of incretin mimetics on cancer risk Describe how the project addresses an important aspect of how incretin mimetics impact mechanism(s) of cancer risk which is(are) not currently known or adequately addressed.

The description in this subsection must address and provide the necessary supporting details explaining how the proposed project will meet the following key requirements: The study must evaluate one or more mechanism(s) that impact cancer risk. Does the mechanism(s) being studied impact cancer prevention or cancer promotion? Describe in detail the study timeline, taking into account start-up activities.

Discuss if the projected timeline is feasible and well justified. Discuss how the project incorporates efficiencies and utilizes existing resources to increase the efficiency. Discuss the potential challenges and possible corresponding solutions.

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 (CSR), and responsiveness by the NCI, 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.

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. Evaluate how the proposed work will help in evaluating the association of incretin mimetics with cancer risk and/or impact clinical care of the patient. 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