Development of Medications to Prevent and Treat Substance Use Disorders and Overdose (UG3/UH3 - Clinical Trial Optional)

Development of Medications to Prevent and Treat Substance Use Disorders and Overdose (UG3/UH3 - Clinical Trial Optional) is sponsored by National Institutes of Health (NIH). This funding opportunity supports research on the discovery and development of interventions to prevent and/or treat substance use disorders (SUDs) and overdose, including medications and medical devices.

Expired PAR-25-329: Development of Medications to Prevent and Treat Substance Use Disorders and Overdose (UG3/UH3 - Clinical Trial Optional) 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 Institute on Drug Abuse ( NIDA ) Funding Opportunity Title Development of Medications to Prevent and Treat Substance Use Disorders and Overdose (UG3/UH3 - Clinical Trial Optional) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement Notices of Special Interest associated with this funding opportunity September 10, 2025 - This PAR has been reissued as PAR-25-446 .

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 National Institute on Drug Abuse (NIDA) seeks research for the discovery and development of medications to prevent and treat substance use disorders (SUDs) and overdose.

The UG3/UH3 Phased Innovation Awards Cooperative Agreement funding mechanism involves 2 phases. The UG3 is to support a project with specific milestones to be accomplished by the end of the 2-year period. The UH3 is to provide funding for 3 years to a project that successfully completed the milestones set in the UG3.

UG3 projects that have met their milestones will be administratively considered by NIDA and prioritized for transition to the UH3 phase. Investigators responding to this FOA must address both UG3 and UH3 phases. Application may include preclinical or clinical research studies that will have high impact and quickly yield the necessary results to advance closer to or to FDA approval.

The compounds to be evaluated can be small molecules or biologic and may focus on the development of new chemical entities, new formulations of marketed medications available for other indications, or combinations of medications. Through this funding opportunity, NIDA seeks to fast-track the discovery and development of medications to prevent and treat SUDs and overdose and to advance them in the FDA's pathway.

Funding Opportunity Goal(s) To support basic, clinical, translational, and implementation research in the field of substance use. To develop new knowledge and approaches for the prevention, diagnosis, and treatment of drug use, misuse, and addiction, drug overdose, and related health outcomes, including HIV/AIDS.

Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 30 days prior to submission 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 Drug overdose is the leading cause of accidental death in the United States, with an estimated 106,850 deaths in 2022. Deaths involving synthetic opioids other than methadone (primarily fentanyl), psychostimulants (primarily methamphetamine), and cocaine were estimated to be 71%, 33%, and 27%, respectively.

Furthermore, 48% of the 2022 overdose deaths were attributed to a synthetic opioid and another substance (i.e., polysubstance overdose). Although there are safe and effective pharmacotherapies to treat opioid use disorder (OUD) and to prevent/reverse overdose, their utility is impaired by inherent limitations of the medications combined with underutilization.

Methadone and buprenorphine are approved by the FDA to treat OUD, but long-term efficacy and treatment adherence are sub-optimal. Naltrexone is approved by the FDA to prevent opioid use relapse in people with no physical dependence to opioids but initiation and adherence to treatment are low.

Naloxone is approved to reverse opioid overdose, but it may precipitate opioid withdrawal, and its relatively short duration of action may put naloxone-rescued individuals at risk of a subsequent overdose or renarcotization. Lofexidine is FDA-approved for the treatment of opioid withdrawal in adults, but it is not approved to treat pregnant women or neonatal opioid withdrawal syndrome.

Unfortunately, there are no FDA-approved medications to treat overdose or SUDs associated with stimulants, cannabis, benzodiazepines, or polysubstance use. Therefore, there is an urgent need to develop safe and effective medications to prevent and treat SUDs and overdose.

Advances in the understanding of SUDs and overdose provide new opportunities to improve the treatment of these disorders and may ultimately contribute to reducing the current drug overdose crisis. Some of these advances include the new findings of receptors, neurotransmitters, neuromodulators, and brain circuits associated with these disorders.

These advances have led to a greater understanding of endogenous systems and well as risk/protective factors for the onset and progression of these disorders. Application of these findings has led to new targets, formulations, and delivery systems to be evaluated.

Furthermore, advances in the development of biologics offer an opportunity to investigate vaccines and monoclonal antibodies for the prevention or treatment of SUDs and drug overdose. Therefore, multiple therapeutic approaches may be poised for the next step in the FDA approval process and concerted efforts are needed to advance these potential pharmacotherapies to approval.

The National Institute on Drug Abuse (NIDA) seeks preclinical and clinical research studies that will have high impact and quickly yield the necessary results to advance candidate medications for SUD and overdose closer to FDA approval.

Applications should focus on studying new chemical entities (NCEs), medications already marketed for other indications, biologics (e.g., vaccines, monoclonal antibodies), natural products, or combinations of medications.

Topics that are considered to be within the scope of this notice of funding opportunity (NOFO) include, but are not limited to: Preclinical evaluation of new chemical entities at a preclinical or late preclinical IND-enabling stage; Early clinical evaluation of drug candidate at early clinical development stages: FIH, SAD/MAD, PK/PD, drug-drug interaction studies with morphine or cocaine, translational clinical studies in patient populations, testing the target for safety and early evidence of efficacy signal to de-risk further clinical development; Repurposing of marketed medications that are used for a non-SUD indication can include: preclinical and clinical safety evaluation (drug-drug interaction studies with the drug of use / misuse); clinical translational studies in early phase of clinical development, and/or proof-of-concept (POC) study assessing the pharmacologically best dose, efficacy and safety endpoints for the drug in preparation for phase III; Phase III clinical stage drug candidates can include clinical development plans with the preparations for an end of phase II meeting with the FDA and phase III development program studies layout, where, if needed, the FDA feedback could be incorporated.

Use of Artificial Intelligence/Machine Learning (AI/ML) tools for chemistry, preclinical, and clinical medications development for SUDs.

For example, use of AI/ML for de novo design of new molecules, virtual screening and drug-drug interaction studies, or use of AI in clinical trial design/analysis, etc. There is particular interest in the development of compounds for: Prevention of initiation of SUDs Prevention of progression of the severity of SUDs Reduction of the dose of opioids analgesics Improvement of SUD treatment adherence Facilitation of opioid agonist discontinuation Treatment of drug withdrawal Treatment of neonatal drug withdrawal Reduction of lethality of overdose Reduction of overdose relapse Reduction of the risk of substance-induced respiratory depression Applications Not Responsive to this NOFO The following types of studies are not responsive to this NOFO and will not be reviewed: Applications focusing solely on novel target identification/validation, generation of new animal models, development/testing of new human laboratory models Applications focusing on mechanistic studies of the neurobiology of addiction Applications that address alcohol as the only substance of use.

Because the development of medications is likely to be high risk, grant applications must provide clear milestones to be accomplished at the end of the UG3 phase. It is anticipated that there will be attrition of some projects that do not meet the of milestones the UG3.

Objective milestones of success and go/no-go rules for medications development progression will be required, and both should have quantitative criteria associated with them.

Some examples of Milestones include: Compound(s) identified, and confirmed, with at least micromolar affinity for the target and some selectivity vs. counter targets Chemical structure identified that can serve as a starting point for SAR to improve potency, selectivity, and/or pharmacokinetic parameters Single compound identified with adequate affinity, selectivity, pharmacokinetic and toxicological properties to initiate advanced toxicology/safety/drug-drug interaction studies Investigational New Drug application submitted to FDA with no clinical-hold imposed by the FDA Phase I SAD/MAD successfully completed Completion of initial single and multiple dose clinical studies with no significant medical safety or pharmacokinetic issues identified Phase Ib Translational Clinical Study successfully completed Completion of initial clinical efficacy testing in patients with no significant medical safety issues identified and preliminary efficacy signal evidence Phase II Clinical study successfully completed Completion of clinical studies in intermediate-size patient groups with safety and efficacy demonstrated Phase III Clinical study(s) successfully completed Completion of clinical studies in large patient groups with safety and efficacy demonstrated.

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

Section II. Award Information Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

See Section VI. 2 for additional information about the substantial involvement for this NOFO. 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. Optional: Accepting applications that either propose or do not propose clinical trial(s). Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are limited to $3 million per year for direct costs. The maximum period of support is 5 years.

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

Eligibility Information 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: [email protected] 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. Target Product Profile (Optional): Applicants may include a target product profile for therapeutic candidates. This may not exceed one page in length.

Interactions with FDA (Optional): Applications may include a summary of interactions with FDA, which may not to exceed two pages in length. Applications exceeding the above page limitations or including other information in these attachments, will be withdrawn without review. 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: Without duplicating the information provided in Section 2. 7 Study Timeline from PHS Human Subjects and Clinical Trials Information Form, include a study timeline that relates to the anticipated completion of Aims and/or milestones.

Applications must provide a decision tree for the compound testing, with appropriate go/no-go decision points. They must also provide the entry and exit points of the proposed compound in the FDA's medications development continuum, if applicable. Milestones and UG3/UH3 Transition : Applicants must plan and submit the application for both a UG3 and a UH3 phases.

The section describing the research to be conducted under the UG3 must include a description of an entry point and the milestone(s) that will be reached at the end of this phase. To successfully transition to the UH3 phase, the project must reach the milestones outlined in the application. The application must provide quantifiable metrics to determine success of the UG3.

Additional milestone(s) may be negotiated before or after funding decisions have been made. All clinical trial applications must include methods to evaluate subjects' compliance with the study medications. If applicable, investigators must include male and female samples and data analysis to evaluate potential sex differences.

When samples or analysis are not proposed, scientific justification must be provided. 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 NIDA, 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 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 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,