RFA-DA-28-011-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)

National Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Neurological Disorders and Stroke (NINDS)

National Center for Complementary and Integrative Health (NCCIH)

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

HEAL Initiative: Integrative Management of Chronic Pain and OUD for Whole Recovery (IMPOWR): Research Centers (RM1 Clinical Trial Required)

Activity Code

RM1 Research Project with Complex Structure

Announcement Type

Reissue of

RFA-DA-21-030

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

RFA-DA-28-011

Companion Funding Opportunity

RFA-DA-28-012

, U2C Resource-Related Research Multi-Component Projects and Centers Cooperative Agreements

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.279, 93.273, 93.866, 93.213, 93.853

Funding Opportunity Purpose

The National Institutes of Health (NIH) intends to renew the Integrative Management of chronic Pain and OUD for Whole Recovery (IMPOWR) research network. The goal of the network is to test new and improved approaches for people who have both chronic pain (CP) and opioid use disorder (OUD). These approaches should lead to meaningful improvements in how health systems deliver care.

The network will be part of the NIH's Helping to End Addiction Long-term (HEAL®) Initiative to speed the development and implementation of scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment and prevention of opioid misuse and OUD and (2) enhance pain management.

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

October 06, 2026

Open Date (Earliest Submission Date)

December 26, 2026

January 26, 2027

Not Applicable

Not Applicable

December 2027

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

January 27, 2027

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

Background The NIH Helping to End Addiction Long-term (HEAL) Initiative: This notice of funding opportunity (NOFO) encourages applications in support of the NIH's HEAL initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for overdose, opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/.

IMPOWR Background Recent estimates suggest that roughly 60% of people with opioid use disorder (OUD) also have chronic pain (CP), which is associated with substantial illness and death nationwide. Evidence-based treatments exist for both conditions, including behavioral therapies, nonpharmacological treatments, neuromodulation modalities, and medications. Service delivery approaches such as the Collaborative Care Model have also demonstrated effectiveness, particularly for individuals with co-occurring mental illness. Despite the high rate of co-occurrence, evidence remains limited on integrated service delivery packages and multi-component interventions that coordinate these evidence-based elements. Care is often fragmented across providers, health systems, and policy frameworks, creating barriers to access and continuity and leaving only a small fraction of the target population with high-quality care.

The Integrative Management of chronic Pain and OUD for Whole Recovery (IMPOWR) program (FY21) funded 10 clinical trials to evaluate psychosocial interventions, optimize Medications for Opioid Use Disorder (MOUD) dosing strategies, and test innovative care delivery models, informed by collaboration with people living with OUD/CP and practitioners. The IMPOWR network also developed a harmonized dataset capturing key measures across substance use, pain, quality of life, and co-occurring mental health conditions to characterize factors affecting treatment engagement and retention. Since IMPOWR Phase I, regulatory changes have expanded reimbursement pathways, workforce capacity, and service delivery options nationwide. Additionally, observational data suggests GLP-1 agonists and neuromodulation modalities may hold promise for CP and OUD, underscoring the need for data-driven insights to optimize care in this evolving landscape.

Purpose and Scope of Clinical Studies for IMPOWR Phase II Implementation determinants across clinical, health system, and contextual domains play a critical role in shaping how quickly evidence-based interventions are integrated into routine care. HEAL IMPOWR Phase II will fund studies that combine clinical intervention research with implementation science. These studies must use hybrid implementation-effectiveness designs that look at both patient outcomes and health system outcomes. The goal is to improve the reach, scalability, and long-term sustainability of integrated, evidence-based treatments for CP and OUD.

IMPOWR Phase II will support a single clinical trial per application that:

Areas of special interest include, but are not limited to:

Partner Engagement Evidence-to-Action Partner (EAP): Individuals at the state and local levels routinely make critical choices affecting access to and the availability, cost, quality, and effectiveness of addiction and pain treatment services. These could be enhanced if they were informed by timely, robust, and actionable health services research findings. Applicants are required to apply user-centered design principles to refine their research process to outline how the EAPs will utilize the data generated by the research study to improve health outcomes for this population.

OUD and Pain Partner (OPP): All projects must include an OUD and Pain Partner (OPP) Engagement Plan that incorporates perspectives from individuals living with CP/OUD to ensure that the study addresses real patient needs and priorities. Applicants will engage with these partners throughout the entire research process, from design through dissemination.

Network Structure and Participation IMPOWR Phase II will include 6–8 clinical studies to speed adoption of evidence-based treatments in routine care. A single Building Engagement, Assistance, Capacity, and Networks (BEACON) Coordination Center will provide network coordination and administrative support. Applicants are encouraged to review the companion BEACON NOFO (RFA-DA-28-012).

Investigators are expected to:

Pre-Application Consultation:

Potential applicants are strongly encouraged to consult with NIDA Program staff early in the application development process. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of the project relative to the intent of this NOFO. See Scientific/Program Contacts in Section VII.

Data Harmonization for Substance Use and Addiction via the PhenX Toolkit NIDA strongly encourages investigators involved in human-subjects studies to employ a common set of tools and resources that will promote the collection of comparable data across studies and to do so by incorporating the measures from the Core and Specialty collections, which are available in the Substance Abuse and Addiction Collection of the PhenX Toolkit. Please see NOT-DA-12-008 for further details.

For further information on special considerations for NIDA applicants, please see the Resources section on the NIDA Grants and Funding page.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Applications Not Responsive to this NOFO The following types of applications are not responsive to this NOFO and will not be reviewed:

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

Renewal

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?

Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The HEAL Initiative intends to commit $12,000,000 in FY 2027 to fund six-eight awards.

Award Budget

Direct costs are limited to $900,000 per year over the 5-year project period.

Award Project Period

The maximum project period 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

Foreign Organizations/Foreign Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

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. 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.

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.

SF424(R&R) Project/Performance Site Locations

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

R&R Budget

Requirements for Participating in Network Activities Budget time and funds for the required network meetings and reporting. Applicants must plan for:

Pilot Studies: Pilot studies are limited to $100K direct costs each year of the award.

R&R Subaward Budget

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: A 1-page Specific Aims is required. Applications must include the following functional and structural units. These units referred to as Sub-sections A-D must be clearly marked and include all information specifically requested for each component. The Research Strategy must consist of the following subsections with the indicated page limits:

Subsection A: Evidence-to-Action Partner (EAP) Engagement Plan (3 pages): required Subsection B: OUD and Pain Partner (OPP) Engagement Plan (3 pages): required Subsection C: Research Project (12 pages): required Subsection D: Pilot projects (6 pages): required Research Strategy:

Subsection A: EAP Engagement Plan All projects must include an EAP Engagement Plan. Audience examples include, but are not limited to, individuals responsible for resource allocation, health systems or community-based organizations that monitor or provide treatment services, local health/public health departments, or local services providers leaders. Examples of engagement include, but are not limited to: data collection that would guide intervention implementation in a clinic or community, direct resource allocation, improved efficiencies in integrated care delivery, refinements in insurance coverage and determination, and/or other actions impacting service provision for this population.

This plan should include:

Letters of Support: Letters of support are required from the EAP(s).

Subsection B: OPP Engagement Plan This plan should also detail how the proposed intervention and any implementation strategy benefits the patients. Relevant audiences can include: individuals with OUD and CP, members from patient advocacy groups, and/or caregivers. In addition to informing the research design, applicants are strongly encouraged to utilize OPP perspectives to inform intervention selection, subject recruitment, treatment retention, and engagement in follow-up care.

This plan should include:

Letters of Support: Letters of support are strongly encouraged from the OPP(s). If these partners are not pre-identified, include the number of slots and types of expertise sought to complement the research project.

Subsection C: Research Project HEAL IMPOWR Phase II prioritizes studies that balance clinical intervention innovation with implementation science. Applications must use hybrid implementation-effectiveness designs that address both patient-level and system-level needs to improve reach, scalability, and sustainability of integrated CP and OUD treatments. Multi-site clinical trial designs are strongly encouraged. Implementation emphasis should reflect existing evidence.

IMPOWR Phase II supports two categories of studies:

(a) testing implementation strategies for established interventions that address CP in the presence of comorbid OUD. Applicants are encouraged to use Hybrid Type II, Type III, or implementation clinical trial study designs

(b) providing effectiveness data for novel or emerging treatments not previously tested in IMPOWR Phase I that have the potential to meaningfully shift clinical practice. Applicants are encouraged to use a Hybrid Type I or Type II approach.

Provide a detailed overview of the study design and sample, including:

Subsection D: Pilot projects Applicants should plan to support 1-2 pilot projects per year, lasting no more than 2 years. At least 1 pilot project should be planned for the first year, with outyear projects permitted as delayed onset. Pilot projects may be led by new, early-stage investigators or partners to support:

All pilots must align with the grant scope, receive NIH/NIDA approval, and encourage network collaboration, particularly in outyears. Pilot projects cannot be used to supplement ongoing research or serve as bridge funding.

This plan should include:

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.

All applications should provide a plan for sharing data with other research sites within the application, and across awarded research centers, including the BEACON Center.

Applications must comply with Data Management and Sharing (DMS) and Genomic Data policies, methods and standards for scientific data.

HEAL Initiative Expectations All data from HEAL-funded projects must be shared through a HEAL-compliant data repository so the data can be accessed through the HEAL Data Ecosystem. The HEAL Initiative has additional requirements for awarded applications that must be addressed in the Data Management and Sharing Plan (refer to HEAL Data Sharing Requirements under Section VI.3 for details).

See guidance below for more information:

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

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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.

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?

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, orcommunity behaviors ? 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?

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,…