Discovery and Development of Novel Therapeutics for Select Fungal Pathogens (R21/R33 Clinical Trial Not Allowed)

Discovery and Development of Novel Therapeutics for Select Fungal Pathogens (R21/R33 Clinical Trial Not Allowed) is sponsored by National Institute of Allergy and Infectious Diseases (NIAID). This is a Fiscal Year 2026 NIAID research initiative focused on antimicrobial resistance, specifically the discovery and development of novel therapeutics for select fungal pathogens.

Expired RFA-AI-24-065: Discovery and Development of Novel Therapeutics for Select Fungal Pathogens (R21/R33 Clinical Trial Not Allowed) This notice has expired. 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 Institute of Allergy and Infectious Diseases ( NIAID ) Funding Opportunity Title Discovery and Development of Novel Therapeutics for Select Fungal Pathogens (R21/R33 Clinical Trial Not Allowed) R21 / R33 Phased Innovation Award 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 Part 2, 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 support milestone-driven, early-stage translational research focused on drug discovery and development of novel therapeutics against select fungal pathogens including: Candida species , specifically Candida auris; Aspergillus fumigatus; Coccidioides; and Mucorales .

This NOFO will use a milestone-driven, biphasic award mechanism. Transition to the R33 phase will depend on the successful completion of specific milestones during the R21 phase.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 30 days prior to the application due date 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 Invasive fungal infections (IFIs) are significant causes of morbidity and mortality worldwide, leading to an estimated one and a half million deaths per year.

Only three major classes of antifungals are in use clinically and the treatment of IFIs remains challenging due to limited options, toxicities, drug-drug interactions, restricted routes of administration, limited central nervous system (CNS) penetration, and emerging resistance.

Despite increased emphasis on development of new drugs and therapeutic approaches to augment clinical options and combat antimicrobial resistance, the discovery and development of novel therapeutics against fungal pathogens largely fall behind that for other pathogens.

Advances of in vitro and in vivo assay development for fungal pathogens coupled with recent progress in understanding the molecular and genetic mechanisms that contribute to antifungal resistance offer unique opportunities for therapeutic target identification and therapeutic discovery for fungal pathogens.

This initiative aims to advance antifungal development for pathogens highlighted on the NIAID Biodefense and Emerging Infectious Disease Pathogens webpage , and in the Centers for Disease Control and Prevention’s Antibiotic Resistance Threats report (2019) and The WHO fungal priority pathogen list (2022).

Research Objectives and Scope This initiative will support research projects focused on discovery and development of novel therapeutics against select fungal pathogens of clinical concern. Applications must target at least one of the following priority fungal pathogens: Candida species, specifically Candida auris; Aspergillus fumigatus; Coccidioides; and Mucorales.

A novel therapeutic is defined as an agent with a mechanism of action that differs from existing agents; an agent against a non-traditional target; an agent against a traditional target but with significantly improved safety and tissue distribution; or an agent that can circumvent known resistance mechanisms associated with a traditional target.

It is anticipated that this initiative will provide additional and improved therapeutic starting points and accelerate preclinical development of candidates. Examples of potential approaches to be supported include, but are not limited to: Discovery and validation of novel fungal pathogen-specific or host-specific therapeutic targets using synthetic disease models or animal models.

Exploitation of targets common to yeasts, dimorphic fungi and molds is strongly encouraged. Identification and/or development of novel compounds that circumvent resistance mechanisms. Identification and/or development of novel compounds with broad-spectrum activity against select fungal pathogens.

Characterization/down-selection of novel compounds and/or preclinical development of lead candidates. Due to the high-risk, high-impact nature of the research, this NOFO will use the R21/R33 Exploratory/Developmental Phased Award activity code.

During the R21 phase, support will be provided for up to two years for milestone-driven research that enables proof-of-concept for novel therapeutic targets and/or candidate therapeutics specific to select fungal pathogens and describe how the therapeutic concept/candidate will be further developed in the R33 phase.

During the R33 phase, support will be provided for an additional three years to engage in additional activities as appropriate, such as expanded development of the candidate therapeutics developed during the R21 phase. It is expected that candidate therapeutics will be at the preclinical development stage by the end of R33 phase. Proposed transition milestones will be reviewed and negotiated prior to award.

Before the end of the R21 phase, recipients will submit the R33 transition package, which includes a detailed progress report describing advancement toward the transition milestones and a description of how the completed work justifies continuation with the originally proposed R33 studies. These materials will be evaluated by NIH Program staff.

Awards selected for continued funding will transition to an R33 award without the need to submit a new application. Transition to the R33 phase is neither automatic nor guaranteed. R33 funding decisions will be based on the original R21/R33 peer review recommendations, successful completion of transition milestones, program priorities, and availability of funds.

It is expected that approximately 50% of awards funded in the R21 phase will transition to the R33 phase. Applications proposing the following will be considered non-responsive and will not be reviewed : Projects not targeting at least one of the following priority fungal pathogens: Candida species, specifically Candida auris; Aspergillus fumigatus; Coccidioides; and Mucorales. Projects proposing to develop vaccine agents or adjuvants.

Projects proposing to conduct Investigational New Drug (IND)-enabling studies. Projects proposing to conduct Good Manufacturing Practices (GMP) manufacturing. Applications without a section with proposed transition milestones.

Projects that propose clinical trials. However, clinical development strategies may be included within an overall project. 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 NIAID intends to commit $2. 4 million in FY 2026 to fund 8-10 awards.

Application budgets are limited to $275,000 in direct costs over the two-year R21 project period, with a maximum of $200,000 in direct costs allowed in any single year. For the R33 award phase, a pplication budgets are not expected to exceed $300,000 in direct costs per year and should reflect the actual needs of the project.

Applicants may request up to two years of support for the R21 phase and up to 3 years of support for the R33 phase. The maximum project period for an application submitted in response to this NOFO cannot exceed five years total. 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 The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: Hispanic-serving Institutions Historically Black Colleges and Universities (HBCUs) Tribally Controlled Colleges and Universities (TCCUs) Alaska Native and Native Hawaiian Serving Institutions Asian American Native American Pacific Islander Serving Institutions (AANAPISIs) Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (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 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.

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the 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: Annie Walker-Abbey, Ph. D.

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: Specific Aims: State in clearly marked sections the overall objective(s) and specific aims for both the R21 and R33 phases of the proposed research. Applicants must submit a single application that includes both the R21 and R33 phases.

For each phase (R21 and R33), describe the planned research approach and explain how this approach will enable the successful achievement of the aims. Do not repeat information or experimental details in the R33 section that are already described in the R21 section.

For the R21 Phase: Describe a research plan that addresses the strategies to be employed in enabling proof-of-concept for novel therapeutic targets and/or candidate therapeutics specific to select fungal pathogens.

For the R33 Phase: Describe a research plan for the application of developments from the R21 phase that will address how the therapeutic concept/candidate will be further developed, building upon the outcomes from the R21 phase milestones. Transition Milestones (required): Applicants must include a section entitled Transition Milestones and provide milestones for the R21 phase of the award within the research strategy.

Within this section, provide milestones that address critical aspects of the research proposed in the R21 phase, and a discussion of the rationale for the proposed milestones, as well as the implications of successful completion of these milestones for the proposed R33 phase. Transition milestones should be specific, quantifiable, rigorous, and scientifically justified; they should not be simply a restatement of the R21 specific aims.

Include a Gantt chart or equivalent that outlines the sequence and timeline of the proposed research to illustrate the project schedule and the relationships between individual activities. The timeline should include the R21 phase and transition milestones. Applications without a Transition Milestone section in the R21 phase will be considered non-responsive and will not be reviewed.

Milestones for the R33 phase are not required in the application but may be provided at the discretion of the applicant. If included, R33 milestones should be clearly labeled within the Milestones section of the Research Strategy under a separate heading for the R33 phase.

Although preliminary data are not required for an R21/R33 application, they may be included if they support or justify the proposed hypothesis, rationale, or development. 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-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.

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.) 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. 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 the National Institute of Allergy and Infectious Diseases, 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: The R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research.

An R21/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work should be provided through literature citations, data from other sources, or, when available, from investigator-generated data.

Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.

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.

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) 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 well the outcome from this project is likely to lead to development of a novel therapeutic against select fungal pathogens. Factor 2. Rigor and Feasibility (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). 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 an appropriately diverse population of participants.

Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, racial, ethnic, and sex/gender categories. For clinical trial applications, evaluate whether the study timeline and milestones are feasible. Evaluate the extent to which the R21 phase Transition Milestones are defined and adequately described, with quantifiable criteria.

Evaluate whether the timelines are reasonable. Evaluate how clearly the R33 phase of the study will build on the R21 phase if the R21 phase milestones are achieved. Factor 3.

Expertise and Resources (Investigator(s) and Environment) 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 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