Part 1. Overview Information

Key Dates

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.

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.

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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



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

Clinical research is a significant NIAMS investment aimed at answering critical questions about a particular disease or disease process. It is essential to support clinical trial studies to test promising new interventions with the potential to improve health and impact clinical care. NIAMS is committed to improving health through effective approaches for arthritis and musculoskeletal and skin diseases and disorders. Improving health through the generation of high-quality data from well-designed and executed clinical trials is a high priority for NIAMS.

A clinical trial is defined by NIH as "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes."

NIAMS has designed its clinical research program to support a broad spectrum of clinical research and trial designs by offering funding opportunities that are tailored to different stages of study development:

• Clinical Observational studies (studies that do not involve an intervention) that aim to obtain information necessary for designing future clinical research studies;
• Exploratory Clinical Trial grants for studies with a relatively small number of subjects and short-term intervention;
• Phased Clinical Trial Implementation Cooperative Agreements for trials involving greater number of subjects, greater complexity, or higher risk.

Please see the NIAMS Clinical Research webpage for a listing of Investigator-Initiated clinical research opportunities.

Large, more complex trials require substantial planning and preparation prior to beginning enrollment of human subjects, and investigators are expected to be ready to begin milestone completion for the start of the trial when the UG3 phase is awarded. NIAMS strongly encourages prospective applicants to pay special attention to advanced preparation and planning in order to avoid delaying: (1) the conduct of these important studies, and (2) analysis of data and dissemination of results.

All prior planning and preparation for the trial must be completed prior to applying for the phased UG3/UH3 award. The 1-year UG3 phase is milestone driven and will allow an investigator to accomplish the final activities (e.g., establishing the single IRB (sIRB), contracts and reliance agreements with sites, hiring of staff, etc.) that are often necessary prior to implementing the clinical trial when transitioning to the UH3 phase. Investigators who feel that they have already completed planning activities are strongly encouraged to consult with NIAMS staff in advance. Investigators considering applying to NIAMS for a clinical trial award should refer to the information found on the NIAMS Clinical Trial Policies, Guidelines, and Templates webpage.

Structure

This NOFO will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and clinical trial execution phase (UH3). There should be clear objectives for both a UG3 and a UH3 phases.

Phases of Award

The UG3 phase will support the development of case report forms and other resources necessary to the performance of the trial; further development and finalization of study partnerships including signed contracts with performing clinical sites; single Institutional Review Board approval as well as NIAMS appointed Data and Safety Monitoring Board approval of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. Applications are required to provide a clinical trial project management plan that delineates how the study will monitor and evaluate critical processes impacting feasibility of trial launch, conduct, and completion, coupled with on-time and on-budget performance milestones. All regulatory approvals should be obtained prior to the end of the UG3 award. Procurement of the necessary drugs, matched placebos, or other resources should be planned for availability at the start of the UH3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. Subject to NIAMS funding availability and scientific priorities, UH3 awards will be made after administrative review of a transition application with particular attention to the extent to which agreed upon milestones have been met.  The UG3 award supports the planning period and is not designed for the collection of preliminary data (neither clinical nor pre-clinical studies) about the efficacy or effectiveness of an intervention, or the collection of prospective data to support the rationale for a clinical trial.

Investigators will be asked to submit their UH3 phase transition application 2 months prior to transition, so the majority of UG3 phase milestones should be completed 2 months prior to transition to the UH3 phase. All milestones must be achieved prior to transition to the UH3 phase.

Milestones

The use of milestones is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Plans must be guided by milestones that will be reached at the end of the UG3 phase. Milestones are to be objective and performance-based to achieve completion of the trial on time and on budget. UG3 projects that have met milestones will be assessed administratively to determine eligibility for transition to the UH3 implementation phase. In situations when the milestones are not met, the transition will either be delayed until the milestones are completed and/or subsequent funding years may not be approved and may lead to phasing out the award. 

This NOFO will support applications that include a series of milestones for completion of the clinical trial (UH3 phase) and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Continuation of the award is conditional upon satisfactory progress, availability of funds, and scientific priorities of NIAMS. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NIAMS will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NIAMS staff will closely monitor progress at all stages, milestones, accrual, and safety.

UG3 Phase Milestones (as applicable)

1. Development of data management system, and case report forms; 
2. Development of tools for data and quality management; 
3. Enrollment, retention, plans to minimize losses to follow-up, and acceptable attrition rates;
4. Development of recruitment and retention strategies; 
5. Finalization of protocol, manual of procedures, and consent forms;
6. Finalization of statistical analysis plan (including interim analyses, if appropriate); 
7. Initiation of contracts and training of clinical site personnel (NIAMS expects the initiation of all study sites to occur in the start-up stage; if a large number of sites is needed, a plan that describes how additional sites will be added after the initiation of the study should be included); 
8. Initiation of processes for including proposed international clinical sites, if applicable; 
9. Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable; 
10. Protocol approval from IRB and NIAMS appointed Data and Safety Monitoring Board.

UH3 Phase Milestones (as applicable)

1. Begin enrollment and follow-up of all subjects; 
2. Register trial at www.clinicaltrials.gov; 
3. Register results with www.clinicaltrials.gov as per FDAAA 801 requirements; 
4. Submit the primary publication within one year of completion of subject follow-up; 
5. Provide a complete, cleaned, and de-identified dataset and any supporting documentation (including but not limited to the study protocol, statistical analysis plan, and data dictionary) required for the analysis of the data within one year of the primary publication or within 18 months of the last study visit of the last subject, whichever occurs first. See the NIH guidelines on sharing research data.

Adaptive Designs 

The use of innovative and efficient study designs, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, or futility designs, is encouraged.

Engaging People with Lived Experience and Other Collaborators 

People with lived experience (e.g., patients, patient advocates, caregivers, families, community leaders) have important insights that can improve meaningful outcomes, uptake of research findings, and health equity across the continuum of research from basic through implementation studies. The perspectives of other relevant collaborators (e.g., health service providers, payors, public health agencies, community-based organizations, biotech, pharma) can further improve research impact. This announcement strongly encourages applicants to specify their plan for meaningful engagement of people with lived experience and other collaborators in the research process. Meaningful engagement will vary with the focus of the research but should at minimum ensure that researchers are connecting with relevant collaborators and incorporating their perspectives throughout the conception, implementation, and dissemination of the research. Meaningful engagement should address what the researchers will learn and how the people with lived experience and/or collaborators will benefit from the partnership. To promote health equity, as is relevant for the research proposed, it is recommended that at least two people with lived experience from populations who experience health disparities should be meaningfully engaged in these efforts (see NIH’s Notice of Interest in Diversity for more information: NOT-OD-20-031).  

See this resource for more information in engaging people with lived experience: https://aspe.hhs.gov/lived-experience.

Submitting an Application for Clinical Trial Implementation

Consultation with NIAMS staff prior to submitting the UG3/UH3 Clinical Trial Implementation Cooperative Agreement application is highly recommended. 

Applications that propose multi-site studies with multiple domestic sites are subject to the NIH sIRB policy as well as the sIRB requirement under the cooperative research provision (45 CFR 46.114).

Information to guide investigators for preparation of clinical trial implementation can be obtained from the NIAMS Scientific/Research staff. NIAMS clinical research policy and guidance information as well as NIAMS templates for writing the manual of operating procedures and the data and safety monitoring plan are available at the NIAMS Clinical Study Tools and Templates website.

Examples of studies that might be supported by this NOFO include, but are not limited to:

• Clinical trials focusing on the prevention or treatment of a rheumatic, musculoskeletal, or skin disease or disorder;
• Clinical trials to investigate safety, efficacy, or effectiveness of novel therapeutic approaches for a rheumatic, musculoskeletal, or skin disease or disorder;
• Clinical trials testing methods to increase preventive health behaviors for a rheumatic, musculoskeletal, or skin disease or disorder.

Applications Not Responsive to this PAR:

• Studies involving animals are not responsive.
• Studies involving only Basic Experimental Studies Involving Humans (BESH) are not responsive.
• Applications that include intervention data collection in the UG3 phase are not responsive. 

See Section VIII. Other Information for award authorities and regulations.

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

Section II. Award Information

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

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) 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 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 NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply - Application Guide.

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:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the 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.

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

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply - Application Guide must be followed.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

If parts of the costs of the trial are to be provided by sources other than NIAMS, these contributions must be presented in detail in the budget justification. Third party support of the proposed research activity (if approved) will be incorporated as a specific term and condition in the Notice of Award. If the Third Party support ceases and the trial is no longer tenable without the Third Party support, a close-out plan may be requested. Applicants are reminded that although Cost Share is not required; if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NIAMS.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan

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

Specific Aims: The goals of the trial and the expected outcome(s) should be concisely stated in the Specific Aims section. The specific objectives of the trial must be clearly and concisely presented, including a specification of the primary and major secondary endpoints to be measured. There should be a clear explanation of the importance of various endpoints.

Research Strategy: The Research Strategy should include the following information:

Note: Discuss the following without duplicating information collected in the PHS Human Subjects and Clinical Trials Information Form.

Award Phases:

UG3:

• Describe the milestones to be completed during this 1-year time, including their rationale and justification. These can include, for example, establishing the sIRB, contracts and reliance agreements with sites, production of case report and consent forms, and hiring of staff. 

UH3: 

• The research approach section should include 
  • A description of the supporting data (including strengths and weaknesses of the published literature), the study team's clinical trial experience, the experimental approach, and a milestone plan; 
  • A discussion of the overall strategy, methodology for the proposed research, and the types of analyses that will be conducted; 
  • A discussion of the significance of the problem being studied and how the study will test the hypothesis(es) proposed. Address the need for this clinical trial to test either the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy; 
  • A discussion of the scientific rationale and how it supports the need to test the proposed hypothesis or intervention. The scientific rationale should be well-supported by preliminary data, information in the literature or knowledge of biological mechanisms; 
  • A discussion of potential biases or challenges in the study and how they will be addressed; 
  • A description of how the study organizational structure and administration, including external committees, will contribute to the success of the project. Discuss the impact of the organizational structure and administration on the scientific goals of the project; 
  • A description of any ethical issues surrounding the trial and the disease or condition under study; and
  • If proposing an NIH-defined Phase III clinical trial, a review of the evidence to show whether or not clinically important sex/gender and racial/ethnic differences in the intervention effect are to be expected. The application must address plans for the valid analysis of group differences on the basis of sex/gender, race, and ethnicity unless there is clear evidence that such differences are unlikely to be seen. Further, if the NIH-defined Phase III trial also meets the definition of an applicable clinical trial, additional requirements for reporting results of valid analyses in clinicaltrials.gov must be followed. See NOT-OD-18-014.

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): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. 

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply - Application Guide must be followed.

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-Related Attachments

The application must contain the following information, according to the instructions below, to provide evidence that the investigator(s) has planned a feasible clinical trial. The information provided here supports the Research Strategy and should not duplicate it. The following documents must be uploaded as separate .pdf files with the names indicated below. Attachments may be appended as needed for each study record (e.g., "Clinical Monitoring Plan1.pdf" for study record 1, etc.).

1. Clinical Monitoring Plan: The Clinical Monitoring Plan is a required attachment and must use the filename "Clinical Monitoring Plan.pdf." Applications lacking this attachment will be considered incomplete and will not be reviewed.  

The purpose of the Clinical Monitoring Plan is to verify that the clinical trial is being conducted and documented in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s):

• Describe the persons/entity responsible for conducting the clinical monitoring (e.g., contracted Clinical Research Associate, Data Coordinating Center, independent study monitor from the Clinical Coordinating Center);
• Describe the frequency of planned monitoring activities (e.g., study initiation, interim visits, study close out), locations where the monitoring will occur (e.g., participating clinical sites, data center, clinical coordinating center), and what data will be reviewed;
• Provide an overall description of the monitoring plan to ensure adherence to the protocol, adequate documentation of the consenting process, and the quality and consistency of the study intervention(s), including fidelity monitoring for behavioral interventions. Include methods to monitor study data collected and systems to record and manage exceptions and deviations. If applicable, describe monitoring of participating facilities, such as labs or pharmacies for adequate handling and storage of investigational product(s) and study specimens. Include a description to assure that the investigational product(s) accountability and reconciliation are performed adequately during and at the end of the trial per applicable regulatory requirements;
• Describe plans for handling any deficiencies that are uncovered and in cases of serious deficiencies the appropriate reporting to relevant authorities, including but not limited to the IRB of record, data and safety monitoring body, FDA if applicable, OHRP, institutional officials, and NIH;
• Describe methods and systems to ensure confidentiality and subject privacy; 
• Describe process for locking the final trial datasets.

2. Study Timeline: Applicants should provide detailed project performance objectives and corresponding timeline. The proposed milestones must include achievable goals for each stage of the project as follows:

For the UG3 Phase:

1. Development of data management system and case report forms; 
2. Development of tools for data and quality management; 
3. Enrollment, retention, plans to minimize losses to follow-up, and acceptable attrition rates; 
4. Development of recruitment and retention strategies; 
5. Finalization of protocol, manual of procedures, and consent forms; 
6. Finalization of planned analyses (including interim analyses, if appropriate); 
7. 8. Protocol approval from IRB and DSMB; 
9. Initiation of contracts and training of clinical site personnel (NIAMS expects the initiation of all study sites to occur in the start-up stage; if a large number of sites is needed, a plan that describes how additional sites will be added after the initiation of the study should be included); 
10. Initiation of processes for including proposed international clinical sites, if applicable; 
11. Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable; 
12. Completion of start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, etc.) 

For the UH3 Phase:

1. Earliest possible enrollment date;
2. Enrollment of 25%, 50%, 75% and 100% of the targeted sample size;
3. If an adaptive design is to be used, indicate when adaptions will be considered; 
4. Completion of all study data collection;
5. Completion of primary endpoint and secondary endpoint data analyses;
6. Completion of final study report;
7. Publication of primary study results;
8. Reporting of results in ClinicalTrials.gov;
9. Submission of final public use dataset to an appropriate repository.

Milestones and associated timelines will be refined and finalized in consultation with NIAMS Program staff at the time of award. 

Proposed milestones should be included for the entire trial, including any time beyond the six-year award. This information will be used for planning purposes and to support the rationale for the full trial but does not guarantee continued funding beyond the initial funding cycle. Applications that lack a Timeline Document attachment outlining the timeline for the proposed milestones will be considered incomplete and will not be reviewed.

3. Plan to Include Lived Experience: In an "Other Attachment" entitled"Plan to Include Lived Experience” all applicants must include a 1-page summary of strategies to advance the scientific and technical merit of the proposed project through expanded consideration for lived experience. The Plan will be considered as part of the scientific and technical peer review evaluation, as well as at the programmatic level with respect to funding decisions.

Investigators are encouraged to engage the people with lived experience/collaborators in a way that informs the scientific aims of the application and increases or validates the potential impact of the application. The Plan will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured. Examples of items that advance the inclusion of people with lived experience in research and may be part of the plan can include, but are not limited to:

• Discussion of engagement with users and/or caregivers/partners such as focus groups that enable incorporation of lived experience from multiple individuals.
• Description of the plan to incorporate People with Lived Experience (PWLE) in a way that informs the scientific aims of the application and increases or validates the potential impact of the application.

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.

The UH3 study should not be considered a delayed onset trial as it is expected that the proposed study can be described in the application.

PHS Assignment Request Form

All instructions in the How to Apply - Application Guide must be followed.

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.

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:

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.

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).

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.

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.

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.

Clinical Monitoring Plan

• Are the procedures for clinical monitoring activities adequate? Are standardized systems and methods in place to ensure adherence to the protocol, appropriate documentation, and quality of the interventions?

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIAMS, in accordance with NIH peer review policy and procedures, 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 the appropriate NIH Institute or Center. 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 National Arthritis and Musculoskeletal and Skin Diseases Advisory Council (NAMSAC). The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information

1. Award Notices

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. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding. 

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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).

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, 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.

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.

HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. 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 addition to the information available in the responsibility/qualification records in SAM.gov, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 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.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at  2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies. 

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below. 

The PD(s)/PI(s) will have the primary responsibility for:

• All aspects of the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators, including setting up and convening any external advisory or steering committees.

The recipient agrees to accept close coordination, cooperation, and participation of NIAMS staff in those aspects of scientific and technical management of the study as stated in these terms and conditions:

• Meeting NIAMS policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. The full NIAMS Data and Safety Monitoring policy and guidelines are available; 
• Upon implementation of the protocol, each site, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, patient management, data collection, and quality control; 
• Managing involvement of industry or any other third party in the study. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIAMS. Third party support of the proposed research activity (if proposed, accepted and approved) will be incorporated as a Special Award Condition in the NoA. Recipients will be responsible for ensuring third party compliance. If the third party support is no longer available and not replaceable in a timely fashion, negotiated phase-out of the award may occur. Cost share is not a requirement for this program; however, if cost share is proposed, peer reviewed, and accepted by NIAMS, it will become a Special Award Condition in the NoA. 
• Making all study materials and procedure manuals available in the public domain. Recipients are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by NIAMS/NIH; 
• Submitting monthly enrollment updates as specified by NIAMS; 
•  Ensuring compliance with all negotiated milestones.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. The Project Scientist (PS) has substantial scientific involvement in project activities and generally is not involved in normal programmatic stewardship of the award. A PS has a collaborative relationship with the investigators and participates/collaborates on the work being done. 

The NIAMS Project Scientist will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. The Project Scientist may use information obtained from the data for the preparation of internal reports on the activities of the study. However, recipients will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. In addition, the NIAMS Project Scientist may:

• Communicate regularly with the PD/PI and study team, which may include attendance at the safety monitoring body meetings (DSMB or SO) and related external advisory committee meetings or steering committee meetings; 
• Participate as a voting member on committees, such as steering committees and sub-committees, central to the research activity; 
• Participate in protocol design or development;
• Help to select contractors or other project staff; 
• Coordinate or participate in data collection, analysis, and interpretation;
• Coordinate or provide training of project staff in recipientinstitutions;
• Participate in selection and approval of data analysis mechanisms;
• Coauthor papers.

Program Officer/Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Additional considerations:

NIAMS may terminate or curtail the study in the event of (a) failure to obtain regulatory approval, or implement the study protocol, (b) a substantial shortfall in participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIAMS does not concur, or (d) human subject safety and ethical issues that may dictate a premature termination. 

In addition, NIAMS may end support for the study early if the study reaches a major study objective substantially ahead of schedule with persuasive statistical evidence. 

Areas of Joint Responsibility include:

Data and Safety Monitoring Oversight: An independent Data and Safety Monitoring Board (DSMB) or Safety Officer (SO) will be appointed by NIAMS to serve as an advisory body to the Institute. The DSMB/SO will review study progress, safety data, and interim/final results as outlined in the data and safety monitoring plan (DSMP) and the monitoring body charter and report their finding and recommendations to the NIAMS Program Official. The NIAMS Program Official will report in writing to the PD/PIs on the deliberations of the DSMB/SO reviews and NIAMS concurrence/non-concurrence of the DSMB/SO recommendations. The PD/PIs will comply with the DSMB/SO recommendations and assume responsibility for reporting the outcome of the monitoring body's reviews and NIAMS recommendations to their respective Institutional Review Boards (IRBs). 

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16. 

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

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.

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. 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.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (Responsibility/Qualification in SAM.gov, formerly FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

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)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Rheumatic Diseases:
Yan Wang, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 594-5032
Email: wangy1@mail.nih.gov 

Osteoarthritis and Diagnostic Imaging:
Xincheng Zheng, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: (301) 594-4953
Email: xincheng.zheng@nih.gov

Muscle Diseases:
Emily Carifi, Ph.D. 
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: emily.carifi@nih.gov

Orthopaedics:
Chuck Washabaugh, Ph.D
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: washabac@mail.nih.gov

Bone Diseases:
Faye H. Chen, Ph.D. 
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-9997 
Email: chenf1@mail.nih.gov

Skin Diseases:
Ricardo Cibotti, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-451-5888
Email: ricardo.cibotti@nih.gov

Kathy Salaita, ScD
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Email: salaitak@mail.nih.gov

Sarisa Kowl
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Email: sarisa.kowl@nih.gov

Section VIII. Other Information

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.