PAR-27-026-Revised-Full-Announcement.html

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)

Note: Not all NIH Institutes, Centers, and Offices (ICOs) participate in Announcements. Applicants should carefully note which ICOs participate in this announcement and view their respective areas of research interest at the ICO-Specific Scientific Interests website. ICOs that do not participate in this announcement will not consider applications for funding.

Funding Opportunity Title

Avant Garde/Avenir Awards for Investigators Conducting High Risk/High Reward Research on HIV and Substance Use (or Substance Use Disorders) (DP1 Clinical Trial Optional)

Activity Code

DP1 NIH Director's Pioneer Award (NDPA)

Announcement Type

Reissue of

PAR-23-125

Reissue of

PAR-25-261

Related Notices

Funding Opportunity Number (FON)

PAR-27-026

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.279

Funding Opportunity Purpose

The purpose of this notice of funding opportunity (NOFO) is to support innovative basic, clinical, translational, and implementation science research relevant to HIV and substance use. This initiative encourages high risk high impact transformative studies that advance knowledge and strategies for HIV prevention, diagnosis, treatment and virus suppression in people who use substances and/or have a substance use disorder.

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 outcome, including HIV/AIDS.

Key Dates

Posted Date

June 09, 2026

Open Date (Earliest Submission Date)

August 25, 2026

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

September 25, 2026 *

Not Applicable

Not Applicable

July 2027

September 25, 2027 *

Not Applicable

Not Applicable

July 2028

September 25, 2028 *

Not Applicable

Not Applicable

July 2029

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.

Expiration Date

September 26, 2028

Due Dates for E.O. 12372

Not Applicable

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 How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information Key Dates Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

The National Institute on Drug Abuse (NIDA) Avant-Garde and Avenir Awards Program for HIV Research supports exceptionally creative scientists, who propose high-impact studies that open new areas of HIV research in the context of substance use and Substance Use Disorders (SUD) and/or lead to new avenues for HIV prevention, treatment and cure in people with SUD.

This notice of funding opportunity (NOFO) supports basic, clinical, translational and implementation science research addressing critical problems at the intersection of HIV and substance use. The term "Avant-Garde" refers to highly innovative ideas and/or approaches that have the potential to be transformative. The term "Avenir" refers to future and accordingly, Avenir awards are meant to support early stage investigators (ESI) who propose creative solutions to critical problems at the nexus of HIV and substance use. This combined NOFO fulfills NIDA's priority to accelerate scientific discoveries by supporting innovation.

Applicants responding to this NOFO must propose pioneering research that aligns with the National Institutes of Health (NIH) HIV/AIDS Research Priorities as described in NOT-OD-20-018. The purpose of this program is to support visionary concepts and approaches to research on HIV. Therefore, proposed research cannot be an expansion of an ongoing funded project. Rather, it should reflect ideas and approaches that are substantially different from those currently being pursued by the investigator or others in the field. This announcement defines biomedical and behavioral research broadly, with the emphasis on creativity and potential impact rather than a particular discipline or research area. The award is meant to support individuals who intend to pursue research directions relevant to the NOFO that are not readily supported by other NIH research grant activity codes. Applicants are required to clearly define the nexus with substance use in their HIV research projects.

Some examples of research studies include:

NIDA requires the applications to explain 'how' and 'why' substance use is considered in the research project by either addressing aspects of substance use in the research and analysis plan or by making clear the implications of the research for people who use drugs or have an SUD. The research plan must clearly explain:

Special Considerations NIDA applicants are strongly encouraged to review the guidelines and adhere to the requirements applicable to their research listed in the Special Considerations for NIDA Funding Opportunities and Awards. Upon award, these considerations will be included in the Notice of Grant Award.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources (https://researchmethodsresources.nih.gov/) website for information about developing statistical methods and study designs.

Non-responsiveness criteria:

Applications focusing solely on alcohol use in the context of HIV will be considered non-responsive and will be withdrawn from review.

Studies that evaluate, support, or promote SUD harm reduction models will be considered non-response and will be withdrawn from review.

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

Funding Instrument

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

Application Types Allowed

New

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

Clinical Trial?

Optional: Accepting applications that either propose or do not propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are limited to $700,000 in total costs per year for established investigators. For early stage investigators (ESIs) application budgets are limited to $375,000/year in total costs.

Award Project Period

The maximum project period allowed is 5 years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

Federal Governments

Eligible Agencies of the Federal Government

U.S. Territory or Possession

Other

Independent School Districts

Public Housing Authorities/Indian Housing Authorities

Native American Tribal Organizations (other than Federally recognized tribal governments)

Faith-based or Community-based Organizations

Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Organizations)

Foreign Organizations/Foreign Collaborations

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.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16.8 Collaborative International Research Awards.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Required Registrations

Applicant Organizations Applicant organizations must complete and maintain the following registrations as described in the How to Apply - Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference 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. Foreign organizations must obtain a NATO Commercial and Government Entity (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.

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.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

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.

Established investigators are required to commit at least 35% or 4.2 person months of their research effort to activities supported by the DP1 award. ESIs are required to commit at least 25% or 3 person months of their research effort to activities supported by the DP1 award.

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

3. Additional Information on Eligibility Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

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 (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

Instructions for Application Submission

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

SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.

Agency Routing Identifier: Enter N/A.

Type of Application: Must be New.

Proposed Project: Start date: April 1st Total Federal Funds Requested: Enter $3,500,000 for established investigators, $1,875,000 for ESIs.

Total Non-Federal Funds: Enter $0.

Total Federal & Non-Federal Funds: Enter $3,500,000 for established investigators, $1,875,000 for ESIs. (See note below.)

Estimated Program Income: Enter $0.

Note: The Budget Request is entered only in the fields for "Total Federal Funds Requested" and "Total Federal & Non-Federal Funds" as described above. Funds may be requested for personnel (including collaborators), supplies, equipment, sub-contracts, and other allowable costs. Only the five-year total - $3.5 million for established investigators or $1.875 million for ESIs - should be entered in the fields for "Total Federal Funds Requested" and "Total Federal & Non-Federal Funds". Applicable Facilities and Administrative (F&A) costs will be determined at the time of award and should not be included in the budget request. A detailed budget is not requested and will not be accepted.

Cover Letter: Provide names and affiliations of significant collaborators for the Avant-Garde/Avenir Award project. Biographical Sketch Common Forms of collaborators are not allowed as they are not considered Senior/Key Persons for this program. Provision of names here is only to help exclude conflicts during reviewer assignment. Information regarding any collaborators may be included in the Essay.

SF424(R&R) Project/Performance Site Locations

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

Profile Project Director/Principal Investigator Field - The PD/PI must submit a Current and Pending (Other) Support Common Form.

Research and Related Senior/Key Person Profile (Expanded) - Additional Senior/Key Person Profiles(s): DO NOT USE. Only the PD/PI may serve as senior/key personnel.

R&R Budget

Do not provide budget forms.

R&R Subaward Budget

Do not provide budget forms.

PHS 398 Cover Page Supplement

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims: Do not use.

Research Strategy: Upload the Essay here. Describe the applicant's innovative vision for, and the significance of, the HIV biomedical or behavioral problem to be addressed, and the applicant's qualifications to engage in groundbreaking research. The essay should describe the individual's view of the major challenges in HIV biomedical or behavioral research to which he/she can make seminal contributions. No detailed scientific plan should be provided since the Research Strategy is expected to evolve during the tenure of the grant. The essay should include the following sections in the order given with the headings as shown below:

Project title: The project title must be included at the beginning of the essay.

Statement of research effort commitment: A statement must be included that, if chosen to receive an award, the applicant will commit a minimum of 35% or 4.2 person months of his/her research effort to the project supported by the NIDA DP1 award. Applicants who are early stage investigators must commit a minimum of 25% or 3 person months of his/her research effort to the project proposed for the NIDA DP1 award. Applications without such a statement will be considered incomplete and will be returned without review.

Project description: What is the scientific problem or challenge that will be addressed, and why is this important? What are the pioneering, and possibly high-risk, approaches that, if successful, might lead to groundbreaking or paradigm-shifting results, and how might these results benefit people who use substances? If the initial strategy/approach does not work out as planned, what alternative strategies/approaches might be employed?

Evidence of Innovation: What concrete evidence can you provide for your claim of innovation in the project? For example, qualities common to many highly innovative people include an interest in, and the ability to integrate, diverse sources of information; an inclination to challenge paradigms and take intellectual risks; persistence in the face of failure; an ability to be flexible and a willingness to take a new view of a vexing problem; an ability to attract the right collaborators; and the energy and concentration necessary to plan and execute effective strategies for accomplishing goals.

How the planned research differs from your past or current work (required): Describe how the proposed ideas and approaches represent a new and distinct direction for your research, or the work of others in the field.

Compatibility with the goal of the Avant-Garde/Avenir Award Program for HIV Research: Why is the planned research uniquely suited to the stated goal of the DP1 Program for HIV Research, rather than a traditional NIH grant mechanism e.g. R01? How will the planned research move the field forward in a truly transformative way that would benefit people who are at risk or living with HIV and use substances and experience SUDs?

Information on collaborations may be included in the essay. Literature references are not required, but, if included, must fit within the page limit. Figures and illustrations may be included, but must also fit within the page limit. Do not include links to websites to provide further information.

Letters of Support: Provide letters of support from significant collaborators for the DP1 Award project. Note that Letters of support are not Reference letters and collaborators or personnel involved in the DP1 project cannot provide reference letters.

Applicants responding to this NOFO must clearly define the nexus with substance use in their HIV research projects. NIDA requires the applications to explain 'how' and 'why' substance use is considered in the research project by either addressing aspects of substance use in the research and analysis plan or by making clear the implications of the research for people who use drugs or have an SUD. The research plan must clearly explain:

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.

Other Plan(s):

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

A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format. Where the DMS Plan Format Page requires a "Yes or No" response, no additional narrative is allowed. The Data Management and Sharing (DMS) Plan must be provided in the Overall component.

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply - Application Guide must be followed.

PHS Assignment Request Form

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

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

4. Submission Dates and Times Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply – Application Guide.

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

6. Funding Restrictions All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Letters of Reference Letters of reference are an important part of the Pioneer Award application. PD/PIs must arrange to have three (and only three) letters of reference submitted on their behalf. Applications that are missing letters of reference will be considered incomplete and will not be reviewed. Late letters will not be accepted. PD/PIs are responsible for monitoring the submission of letters in their Commons account to ensure that three letters have been submitted prior to the submission deadline. Referees who submitted letters for Pioneer Award PD/PIs in prior years must submit new letters of reference this year. Previously submitted letters will not be retrieved.

Letters of reference are confidential; PD/PIs will not have access to the letters. PD/PIs should not upload letters of reference on behalf of their referees. Confirmed receipt of letters of reference will be sent via email to both the PD/PI and the referee. The confirmation sent to the PD/PI will include the referee's name and the date and time the letter was submitted. The confirmation sent to the referee will include the referee and PD/PI's names, a confirmation number, and the date and time the letter was submitted.

Instructions to Referees

Required Referee Information (the individual providing the letter of reference):

Required PD/PI Information (PD/PI must provide this information to their referees):

Please see the detailed instructions on submitting letters of reference and Frequently Asked Questions on the Pioneer Award website. Send questions to PioneerAwards@mail.nih.gov.

Mandatory Disclosure

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

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

Section V. Application Review Information

1. Criteria Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

NIDA HIV Avant-Garde/Avenir Award (DP1) applications are meant to support individual scientists of exceptional creativity who propose pioneering and possibly transforming approaches that, if successful, will have a major impact on a broad area of biomedical, clinical, and/or behavioral research. These DP1 applications do not require preliminary data, scientific aims, or a detailed research plan. Accordingly, reviewers will provide comments emphasizing the following:

Applications that are complete will be reviewed by a multidisciplinary scientific review group of outside experts convened by the Center for Scientific Research in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the stated review criteria. Final selection of awardees will be made by the Director, NIDA, NIH, based on the outcome of the peer review, concurrence of the National Advisory Council on Drug Abuse, and programmatic considerations.

All discussed applications will receive summary statements and a numerical Overall Impact score. Applications that are "Not Discussed" and will not receive a numerical Overall Impact score but will receive summary statements.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

In addition, for applications involving clinical trials Does the application adequately address the following, if applicable Study Design Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, sex, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Study Timeline

Specific to applications involving clinical trials Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Human Subjects Policies

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for inclusion. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the American Veterinary Medical Association (AVMA) Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions (as applicable), the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

For Renewals (as applicable), the committee will consider the progress made in the last funding period.

Revisions

For Revisions (as applicable), the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following…