National Institutes of Health (NIH)
National Center for Complementary and Integrative Health (NCCIH)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Neurological Disorders and Stroke (NINDS)
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.
See Part 2, Section III. 3. Additional Information on Eligibility.
The NIH Helping to End Addiction Long-term® (HEAL) Initiative is releasing this Notice of Funding Opportunity (NOFO) to support a phased mechanistic clinical research program focusing on understudied biological mechanisms that drive joint pain. The phased projects supported by this program (of up to five years total in duration) will first identify and validate multi-tissue mechanisms underlying joint pain, then test non-pharmacologic or multimodal interventions that directly target these mechanisms. The initiative responds to priorities identified in the 2023 HEAL Whole Joint Pain Workshop and supports the broader goals of the NIH HEAL Initiative and the Make America Healthy Again vision by advancing safe, non-addictive, and prevention-oriented approaches to chronic pain.
NCCIH is the lead Federal agency for scientific research on the fundamental science, usefulness, and safety of complementary and integrative treatments and practices. To address the need for objective evidence on the fundamental science, safety and efficacy of complementary and integrative health approaches, NCCIH supports rigorous scientific investigation to better understand how these interventions impact health, for whom, and the optimal methods of practice and delivery.
| Application Due Dates | Review and Award Cycles | ||||
|---|---|---|---|---|---|
| New | Renewal / Resubmission / Revision (as allowed) | AIDS - New/Renewal/Resubmission/Revision, as allowed | Scientific Merit Review | Advisory Council Review | Earliest Start Date |
| October 30, 2026 | Not Applicable | Not Applicable | March 2027 | May 2027 | July 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.
Not Applicable
It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
Background
Joint pain is highly prevalent and disabling. It contributes substantially to chronic pain, reduced mobility, and diminished quality of life across the lifespan. Many individuals with joint pain do not achieve lasting relief despite extensive biomedical research and clinical investment. Continued reliance on reductionist approaches, which focus on single tissues or structures rather than on the joint as a dynamic, integrated system, contribute to this major challenge.
This initiative defines the "whole joint" as an integrated organ system. It includes articular tissues such as bone, cartilage, and synovium. It also includes periarticular tissues such as muscle, adipose tissue, ligaments, tendons, and fasciae. Peripheral physiological or neural systems include peripheral nerves, blood vessels, lymphatic structures, and endocrine tissues.
In July 2023, the NIH Helping to End Addiction Long-term® (HEAL) Initiative convened a workshop titled "Understanding and Restoring Whole Joint Health in Pain Management." The workshop assessed the current state of the science and identified critical gaps in joint pain research. Participants emphasized that joint pain arises from complex, interrelated processes involving articular and periarticular tissues. These processes include changes in biomechanics, metabolism, inflammation, neural signaling, and psychosocial influences. Participants acknowledged that researchers have not adequately studied many of these processes. Structural abnormalities identified through conventional imaging often correlate poorly with pain indicating additional factors might be involved. This gap underscores the need to study multi-tissue mechanisms and inter-tissue communication across the whole joint.
Participants also noted that pain prevention and joint restoration are likely to require attention to nutritional, psychological, and physical domains. Effective pain relief may require multimodal approaches, including non-pharmacologic interventions to effectively target multiple tissues and systems that comprise the whole joint. Recent advances now make this work feasible, including new imaging, computational modeling, tissue-specific -omics, and related tools and methods to study myofascial and nerve-tissue interactions. Together, these techniques will allow investigators to examine the joint as a complex organ and to capture dynamic changes associated with pain, healing, and functional recovery.
The goal of this NOFO is to advance the mechanistic understanding of interactions across these tissues and systems that together define the "whole joint" as one integrated organ. As such, this NOFO will support studies that identify and measure whole joint mechanisms, including at least one periarticular tissue and interactions with one or more articular tissues or peripheral physiological or neural systems. This NOFO will support studies that first examine how these interactions contribute to joint pain and reduced whole joint health and then determine how interventions modify mechanisms across multiple tissues and pathways to restore whole joint health.
Research Objectives
This two-phase NOFO will support well-powered, hypothesis-driven mechanistic clinical studies aligned with HEAL's whole joint health priorities.
R61 Phase (2 or 3 Years):
In the R61 phase, studies will test innovative whole joint mechanisms in healthy and clinical pain populations to generate strong preliminary data to support the R33 clinical trial. Studies will include one or more observational or mechanistic clinical study(ies) that measure whole joint mechanisms, including at least one periarticular tissue and the interactions with one or more articular tissue(s) and/or peripheral physiological or neural system(s), to demonstrate measurable differences in joint pain and pathophysiology between a clinical population with joint pain versus a healthy population with no joint pain.
This NOFO prioritizes innovation in the proposed measures of whole joint mechanisms. The inclusion of multiple tissues and mechanisms involved in whole joint function as well as joint pain and pathophysiology is considered a strength.
Specific Areas of Research Interest
Examples of innovative mechanisms include (but are not limited to):
This NOFO will also support studies that may incorporate innovative or cutting-edge imaging, biomarker profiling, neuromuscular assessment, and/or behavioral or environmental measures. Other multimodal approaches that meet NIH standards for rigor and reproducibility will also be supported.
R33 Phase (2 or 3 Years; Total Project Period 5 Years or less):
The R33 phase supports mechanistic clinical trials to test the effects of non-pharmacologic or multimodal interventions on the proposed mechanisms demonstrated in the R61 phase. The selected intervention and its expected mechanistic impact should be well-justified and coupled with a rigorous clinical trial design. The rationale for the proposed intervention may be based on prior work published in the literature or preliminary data generated in the R61 phase using appropriate models, organisms, or human populations.
Examples of appropriate non-pharmocologic interventions for joint pain include (but are not limited to):
This NOFO will support additional interventions if there is evidence provided supporting its relevance to the joint tissues studied in the R61 phase and if the intervention is likely to produce measurable mechanistic changes. Additional approaches may include devices, drugs, or other multimodal therapies.
Definitions and restrictions for this NOFO:
Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control(s)) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.
Applications Not Responsive to this NOFO
The following types of applications are not responsive to this NOFO and will not be reviewed:
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.
Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
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.
Required: Only accepting applications that propose clinical trial(s).
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets are not limited but need to reflect the actual needs of the proposed project. However, it is strongly recommended that applicants do not request a budget of more than $500k in direct costs per year for the R61 phase. For applications that propose a 3-year R33 project phase, it is strongly recommended that they budget no more than $700k in direct costs per year. For applications proposing a 2-year R33 phase, it is strongly recommended that they budget no more than $800k in direct costs per year.
The scope of the project should determine the project period for each phase. The maximum period of the combined R61 and R33 phases is 5 years, with 2 or 3 years for the R61 phase and 2 or 3 years for the R33 phase.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.
Higher Education Institutions - Includes all types
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Local Governments
Federal Governments
Other
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.
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 the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.
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.
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.
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:
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.
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 Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.
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.
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.
All instructions in the How to Apply- Application Guide must be followed.
All instructions in the How to Apply - Application Guide must be followed.
Its strongly recommended that applicants budget no more than $500k in direct costs per year for the R61 phase. For applications that propose a 3-year R33 project phase, it is strongly recommended that applicants budget no more than $700k in direct costs per year. For applications proposing a 2-year R33 phase, it is strongly recommended that applicants budget no more than $800k in direct costs per year.
All instructions in the How to Apply - Application Guide must be followed.
All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:
Specific Aims
The Specific Aims page should include a brief description of the following:
The objectives and hypotheses for the R61 and R33 phases should be clearly distinguished using appropriate headers.
Research Strategy
Importance of the Research
Background and Research Objectives
Approach
In general, the Research Approach must include relevant figures and clear descriptions of the study design and analytic plan for both phases. Applicants should organize the Research Approach to have distinct R61 and R33 phase plans, in separate sections. Quantitative details for the R61-to-R33 transition criteria should be provided in this part of the application, under a separate heading for "Go/No-Go Criteria", as detailed below. Applications should include a clear timeline for completing the R61 phase.
R61 Phase
R61-to-R33 Go/No-Go Transition
Provide this information under the heading: "Go/No-Go Criteria for R61."
R61/R33 Go/No-Go Transition Process
Transition between the R61 and R33 phases will be guided by clearly defined milestone-based transition criteria. These criteria should allow reviewers to determine whether the R61 phase provides sufficient evidence to proceed to the R33 phase. NIH does not negotiate benchmarks or milestones prior to application submission but may negotiate transition criteria and milestones prior to making an award.
The HEAL program team will review R61-phase progress administratively. NIH will not transition projects to the R33 phase if investigators do not meet the approved Go/No-Go criteria. NIH must approve these criteria before issuing the R61 award.
Note that not all R61 grants will transition to the R33 phase, even if milestones are met. NIH will also consider the quality of the planned R33 clinical trial, the clinical investigator team, available funds, program relevance and priority at the time of transition request.
R33 Phase
In the R33 phase, applicants must test the effect of the proposed intervention(s) on the hypothesized mechanistic measure(s) established during the R61 phase. Studies should propose separate clinical cohorts from the R61 phase to achieve a well-powered clinical trial.
Subsequent Studies Beyond the R61/R33
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:
All HEAL-funded studies must follow the HEAL data sharing requirements. Please refer to the the HEAL Public Access and Data Sharing Policy.
Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.
When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:
If you answered "Yes" to the question "Are Human Subjects Involved?" on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the How to Apply - Application Guide must be followed.
Section 2 - Study Population Characteristics
2.5 Recruitment and Retention Plan
Describe the following: 1) the planned recruitment methods, including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media/social media, and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants.
Applicants must provide strong evidence of the availability of appropriate institutional resources and suitable patient populations. Documentation of the availability of eligible participants must be provided. The application must provide relevant information that addresses the feasibility of recruiting a robust sample of eligible participants.
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH's policy on data and safety monitoring (https://grants.nih.gov/grants/guide/notice-files/not-od-00-038.html).
Section 4 - Protocol Synopsis
4.5. Will the study use an FDA-regulated intervention?
4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status
If the proposed clinical trial will use a device, natural product (such as botanicals, probiotics, and products marketed as dietary supplements), or drug, this attachment should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial and associated timeline. For trials using an FDA-regulated product that requires an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-U.S. regulatory agency, the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided as part of the PDF file attachment. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed trial, the IND must be submitted to the FDA with no clinical hold imposed by the FDA prior to the application being funded.
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.
All instructions in the How to Apply- Application Guide must be followed.
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
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.
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.
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.
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.
Applicants are required to follow the instructions for post-submission materials, as described in the policy
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:
Projects supported by this two-phase NOFO will support well-powered, hypothesis-driven mechanistic clinical studies that align with the HEAL Initiative's whole joint health priorities. Meritorious projects will identify and validate whole joint mechanisms underlying joint pain in the first phase, then test non-pharmacologic or multimodal interventions that directly target these mechanisms in the second phase. Please note that while applications can specify the length of time (two or three years) for each of the following study phases, the total project length cannot exceed 5 years.
High-priority programmatic considerations include, but are not limited to:
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.
Significance
Innovation
Specific to this NOFO
Evaluate the relevance and importance of the chosen tissue types in advancing knowledge of potential mechanistic targets involved in whole joint pain and pathophysiology.
Evaluate the significance and strength of the scientific rationale related to the non-pharmacologic or multimodal intervention(s) proposed in the R33 study and the potential impact of the intervention(s) on the proposed mechanistic measures developed during the R61 phase.
Approach
Rigor:
Feasibility:
Specific to this NOFO:
Evaluate how well the hypothesized primary mechanism(s) are described and defined, either based on relevant prior studies or preliminary data, and the appropriateness of the metrics or measures related to the proposed whole joint mechanism(s).
Evaluate the relevance of the populations and associated clinical or functional outcomes to be studied in the R61 and R33 phases to the hypothesized mechanisms and to the proposed intervention.
Evaluate the likelihood that the proposed measure(s) will differentiate healthy whole joint function from clinical joint pain phenotypes during the R61 phase, providing strong preliminary data for the proposed R33-phase clinical trial.
Evaluate if the listed Go/No-Go Transition Criteria are well-justified and well-defined, with specified threshold(s) to differentiate joint pain and/or pathophysiology in a chosen clinical pain population using the proposed measures.
Evaluate how useful the Go/No-Go Transition Criteria (as presented) would be in demonstrating the readiness of the project to advance from the mechanistic study R61 phase to the R33 intervention trial phase.
Investigator(s)
Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.
Environment
Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.
As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.
For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, evaluate the justification for involvement of human subjects and the proposed protections from 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, 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.
When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.
When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.
As applicable, evaluate the full application as now presented.
As applicable, evaluate the progress made in the last funding period.
As applicable, evaluate the appropriateness of the proposed expansion of the scope of the project.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
For projects involving key biological and/or chemical resources, evaluate the brief plans proposed for identifying and ensuring the validity of those resources.
Evaluate whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by CSR, in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.
As part of the scientific peer review, all applications will receive a written critique.
Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
Applications will be assigned to NCCIH upon receipt. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the NCCIH Advisory Council.
The following will be considered in making funding decisions:
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.
Prior to making an award, NIH reviews an applicant's federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant's integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.
A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient's business official.
In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.
Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk. For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:
All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.
By applying for or accepting federal funds from HHS, recipients certify compliance with all federal antidiscrimination laws and these requirements and that complying with those laws is a material condition of receiving federal funding streams. Recipients are responsible for ensuring subrecipients, contractors, and partners also comply.
Applicants and recipients are strongly encouraged to refer to the NIH Director's Statement of Priorities, entitled "Advancing NIH's Mission Through a Unified Strategy."
Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. Pursuant to 2 CFR 200.340, by accepting an NIH award, the recipient agrees that continued funding for the award is contingent upon the availability of appropriated funds, recipient satisfactory performance, compliance with the Terms and Conditions of the award, and may also otherwise be terminated, to the extent authorized by law, if the agency determines that the award no longer effectuates the program goals or agency priorities, in line with 2 CFR 200.340(a)(4).
Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.
Successful recipients under this NOFO agree that:
When recipients, subrecipients, or third-party entities have:
Cybersecurity plans and procedures must at minimum include the following:
All activities proposed in your application and budget narrative must align with applicable law, including but not limited to statutes, executive orders, federal regulations and applicable judicial holdings. Accordingly, discretionary awards shall not be used to fund, promote, encourage, subsidize, or facilitate; racial preferences or other forms of racial discrimination by the recipient, including activities where race or intentional proxies for race will be used as a selection criterion for employment or program participation; denial by the recipient of the sex binary in humans, or the belief that sex is a chosen or mutable characteristic; illegal immigration; or any other initiatives that compromise public safety. If an application does not align, the application will not receive funding to the extent permitted by law and applicable court orders.
For applications involving substance abuse, the application must not support harm reduction. Please see Updated Funding Guidance for Recipients on Supplies and Services.
For applications involving funding Medication-Assisted Treatment (MAT) or medications for opioid use disorder (MOUD), this funding should be used to provide comprehensive treatment and recovery support services rather than medication-only models for opioid use disorder. Services should include medications, where clinically indicated, in conjunction with psychosocial and other treatment and recovery support services. Funding can also be used to support individualized tapering and discontinuation of medications when clinically indicated. Please see Updated Funding Guidance for Recipients on MAT/MOUD.
As of October 1, 2025, HHS has adopted 2 CFR Part 200, with some modifications included in 2 CFR Part 300. These regulations replace those in 45 CFR Part 75. However, for NIH, under the Consolidated Appropriations Act for FY 2026, (P.L. 119-75, Division B, Title II, Sec. 224), the provisions relating to indirect costs in 45 CFR 75 continue to apply to NIH awards. Consistent with the statute, NIH will not apply updated thresholds outlined within 2 CFR Part 200, at this time.
In administering programs under this and all funding announcements, NIH prioritizes:
Not Applicable
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.
Please follow all instructions described in Section IV.2, "Other Plans" related to the HEAL Data Sharing Requirements (https://www.nih.gov/heal/heal-initiative-requirements/data-sharing-policy/complying-heal-public-access-data-sharing-policy).
When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.
This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://www.nih.gov/heal)" under award number, [include specific grant/contract/award number; for NIH grant number(s) use full format for the grant number, which includes application type, activity code, institute code, serial number, support year, and other suffixes as defined in Deciphering NIH Application/Grant Numbers. Example: 5R01GM987654-03S].
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. When contacting the email addresses below please add the NOFO number to the subject line to assist routing.
eRA Service Desk - Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues.
Grants.gov Support Center - Questions regarding Grants.gov registration and services (e.g., Workspace, subscriptions).
National Center for Complementary and Integrative Health (NCCIH)
Division of Extramural Research (DER)
Email: NCCIHDERFunding@nih.gov
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
E-mail: niams_pain@mail.nih.gov
National Institute of Dental and Craniofacial Research (NIDCR)
Email: NIDCR-HEAL@nih.gov
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Division of Neuroscience and Behavior
NIAAA-HEAL@mail.nih.gov
National Institute on Aging (NIA)
Email: NIA-NOFO-Scientific@nih.gov
Please include the NOFO number in the subject line when emailing.
National Institute of Neurological Disorders and Stroke (NINDS)
NCCIHDERFunding@nih.gov
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Email: NIBIB_HEAL@NIH.GOV
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Center for Scientific Review (CSR)
Email: NOFOReviewContact@csr.nih.gov
National Center for Complementary and Integrative Health (NCCIH)
Office of Grants Management (OGM)
Email: NCCIHDERFunding@nih.gov
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
E-mail: niamsgrants@nih.gov
National Institute of Dental and Craniofacial Research (NIDCR)
Email: deeranotifications@nidcr.nih.gov
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Grants Management Contact
Email: NIAAA-GMB@mail.nih.gov
National Institute on Aging (NIA)
Email: NIA-NOFO-Grants@nih.gov
Please include the NOFO number in the subject line when emailing.
Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Email: NIBIB_HEAL@NIH.GOV
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.