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

Research Objectives of the Clinical Coordinating Center (CCC; UG3/UH3) and the Data Coordinating Center (DCC; U24) for Multi-Site Investigator-Initiated Clinical Trials of Natural Products    

NCCIH requires companion CCC and DCC applications to support a multi-site investigator-initiated clinical trial to test the efficacy or effectiveness of natural products. The CCC and DCC will need to collaborate closely to develop the study protocol and select the most rigorous trial design. The CCC has clinical content expertise for the proposed intervention and study population and is responsible for implementing the proposed multi-site clinical trial. The DCC has expertise in clinical trial design and conduct and is responsible for overall project coordination that includes administrative oversight data management, and biostatistical support for the proposed clinical trial, including sample size calculations and developing data analysis plans. NCCIH requires that the DCC be independent of the CCC (i.e., not include overlapping personnel) while providing central coordination of study activities across multiple sites and ensuring the integrity of the intervention delivery, data collection, and study blinding.   

Research Objectives for the DCC 

This notice of funding opportunity (NOFO supports applications for a DCC to support a corresponding CCC investigator-initiated, multi-site efficacy or effectiveness clinical trial (Phase III and beyond). The DCC is integral to the proficient operation of a clinical trial. The DCC contributes to the study design; ensures appropriate adverse event monitoring and reporting; manages data, masking of staff to intervention assignment, and coordinates the randomization of research participants into the study arms; prepares interim data reports for the data and safety monitoring board (DSMB); conducts statistical analyses; and helps with the dissemination of the results. Clinical trials require the recruitment of research participants, and hence it is of foremost importance to ensure patient safety and the enrollment and retention of men, women, and children from diverse backgrounds in sufficient numbers for meaningful analysis among relevant subgroups. An independent DCC is critical to ensure central coordination these activities to maintain the integrity of the data collection and intervention delivery in a complex multi-site clinical trial. 

For this NOFO, multi-site clinical trials are defined as trials that enroll research participants from two or more recruitment sites. Two sites will be permitted if there is a strong justification for how fewer sites can still achieve generalizability and meet the NIH diversity and inclusion requirements for a Phase III clinical trial. Multiple sites are necessary in efficacy or effectiveness trials to increase generalizability of findings, and to obtain the sample size and diversity participants needed to complete the study. Trials for which this NOFO applies are expected to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH and meet the definition of an NIH clinical trial (see NOT-OD-15-015, https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html). For additional information about the mission, strategic vision, and research priorities of NCCIH, applicants are encouraged to consult the NCCIH website (https://www.nccih.nih.gov). In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. 

Proposed clinical trials may utilize a design anywhere along the continuum between efficacy and effectiveness. For this NOFO, effectiveness trials are considered those that test an intervention under the usual clinical conditions, while explanatory trials do so under more controlled conditions. The trial design should be appropriate for the study question. 

This DCC NOFO runs in parallel with companion NOFO (PAR-24-312) that supports applications for a collaborating CCC. A DCC application must be submitted in support of a collaborating CCC, and both applications must be submitted on the same due date for consideration by NCCIH. DCC applications submitted without a collaborative CCC (UG3/UH3) will be deemed incomplete and will not be reviewed. 

Structure 

This NOFO will utilize a collaborative resources-related cooperative agreement (U24) funding mechanism and will be milestone driven and performance based to achieve completion of the study on time and on budget. 

Phases of Award 

The first year of the DCC will correspond with the UG3 planning phase of the collaborative CCC application, which is considered a lead-in planning phase intended to support the development of case report forms, trial database, data quality assurance plan, coordinate recruitment of study partnerships, and finalize informed consent(s) and any Institutional Review Board, and DSMB issuesof the trial protocol; manual of operations, project management plans, and other activities and resources necessary to perform the clinical trial under the UH3 implementation phase of the CCC. DCC applications are expected to propose the design of a comprehensive clinical trial project management plan that includes consideration of feasibility of trial launch, conduct, and completion and on-time and on-budget performance milestones. As appropriate, all necessary regulatory approvals, as well as provision of the necessary natural products, intervention providers, and devices or other necessary resources, should be obtained by the end of the UG3 planning phase to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. Thus, proposed clinical trials are expected to be able to begin enrollment at the start of the second year of the CCC and DCC award. 

The second-year award and subsequent out years of the DCC is contingent on the successful completion of year one U24 milestones, the UG3 planning phase milestones of the collaborative CCC, and approved transition to the UH3 implementation phase of the CCC. The decision to proceed beyond the first year of the DCC award will be made after an NCCIH administrative review of the progress made by both the DCC and CCC at the end of their first year. Continued support for both the CCC and DCC will be contingent upon the extent to which agreed-upon milestones have been met in the first year and on the availability of funds and scientific priorities to continue the project. If agreed-upon milestones are not met in the U24 or either the UG3 or UH3 phase, NCCIH will work with the DCC and CCC to conduct an orderly phase-out of the project. 

Milestones 

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. Applications must be driven by the milestones that will be reached and completed at the end of the first year of planning prior to implementation of the clinical trial. Milestones are to be objective and performance-based goals needed to begin and complete the trial on time and on budget (see example milestones at https://www.nccih.nih.gov/grants/toolbox#milestone). Projects that have met the planning phase milestones will be administratively considered for continuation of the DCC U24 and transition from the UG3 planning phase to the UH3 implementation phase under the CCC. 

This NOFO will support applications that utilize a series of milestones that synchronize activities between the DCC and the collaborating CCC activities that are needed to support the successful completion of the clinical trial. NCCIH staff in collaboration with the awardee will closely monitor progress, milestones, accrual, and human subject safety at all stages of the project. It is strongly encouraged to develop contingency plans that can proactively confront potential delays or disruptions in attaining milestones. NCCIH staff will closely monitor progress toward milestones at all stages of the project including accrual rate, and participant safety and will retain the option of periodic external peer review of progress. If, at any time, recruitment falls significantly below the projected milestones, NCCIH will consider ending support of the trial and will negotiate a phase-out of the award.  

NCCIH has an oversight process to provide stewardship and maintain excellence, integrity, and rigor in our supported clinical studies (https://www.nccih.nih.gov/grants/toolbox). Investigators are encouraged to review the NCCIH Clinical Terms of Award for Human Subjects Research (https://www.nccih.nih.gov/research/nccih-clinical-terms-of-award-for-human-subjects-research) to learn more about NCCIH's requirements for clinical research.   

Specific Areas of Research Interest 

Prior to submitting an application to this NOFO, all applicants are strongly encouraged to consult with the Scientific/Research Contacts for the area of science of the CCC application for which a resource-related research grant is being submitted. Early contact (e.g., 12 weeks prior to submission) is encouraged. This period of time provides an opportunity for NCCIH staff to discuss the scope and goals and to provide information and guidance to the applicants. 

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

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex (including gender identify, sexual orientation, or transgender status) of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions.  Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materials.

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.

Multiple PDs/PIs are allowed on any single application. Because the NOFO already supports a team approach between groups of experts across sites and collaborating applications, the designation of multiple PDs/PIs on a single application may be less likely to apply. PD(s)/PI(s) from each linked application cannot be designated as multiple PDs/PIs on each application of a collaborative set 

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).

This NOFO only accepts applications that are part of a collaborative set of multiple applications. A set must contain 2 applications, 1 U24 application to this NOFO (PAR-24-313 and 1 UG3/UH3 to PAR-24-312).

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.

Letter of Intent 

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute or Center (IC) staff to estimate the potential review workload and plan the review. 

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information: 

• Descriptive title of proposed activity 
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) 
• Names of other key personnel 
• Participating institution(s) 
• Number and title of this funding opportunity 

The letter of intent should be sent to: 
Jessica McKlveen, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: [email protected]  

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.

Descriptive Title of Applicant's Project:

To allow NIH to identify a group of applications as a related set of collaborative applications, the titles for each application in the set must have the following format: a "1/N" indicator+ Identical Title (e.g., "1/2" where the 1/2 means this is site 1 for the CCC of the set. The DCC site will be labeled 2/2. Titles may not exceed 200 characters in length, including the tag, e.g., 1/3 at the beginning of the title.

Cover Letter Attachment:

A cover letter is required for each application submitted to this collaborative NOFO. The cover letter should include the following information: 1) names of the PD/Pl for both the collaborating CCC and DCC applications; 2) the title of the projects (which should be the same in both CCC and DCC applications and include the tag, e.g., “1/3”); and 3) the names of applicant institutions. Each site should submit an identical listing. If applicable, the letter should indicate the name of the NCCIH program officer with whom the project has been discussed.

If the direct costs of the combined DCC and CCC budgets equal or exceed $500,000 in any given year, a copy of the NCCIH permission to apply letter must be attached. (https://www.nccih.nih.gov/grants/policies/nccih-policy-applications-for-large-budget-clinical-trials-over-500000-in-direct-costs-in-any-year).

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.

Facilities and Other Resources:

Describe the facilities and resources available for the DCC infrastructure to support and enable the conduct of the research proposed in the multi-site clinical trial.

Other Attachments: The attachments listed below must be completed and attached or the application will not be peer reviewed.

Project Management Plan

A Project Management Plan must be provided as an "other attachment" called "DCC Project Management Plan.pdf' and must not exceed 3 pages. The Project Management Plan should describe the evidence-based strategy that will be used throughout the project by the DCC to ensure that the unique goals of the clinical trial are met within the constraints of time and funding permitted under this NOFO.

Project management planning should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet predefined study objectives. The project management plan should describe how the planning team will work together and identify control points and processes that are critical for scientific and fiscal performance. This will include a description of the organizational strategy that defines internal control points and business roles. A description of the methodology, standards, and processes governing resource management, study deployment, operations/execution, and study closure should be included. The management plan should also describe how the team, in collaboration with the CCC, will proactively evaluate and prioritize issues that could jeopardize study goals and how corrective responses will be developed to resolve fiscal and logistical issues (risk planning) in a timely manner. Describe processes required for orderly project closure. In summary, the project management plan should provide sufficient detail that demonstrates the ability to achieve the goals of the clinical trial on budget and on time. The project management plan should include risk management or contingency plans.

The plan should address how enrollment data will be shared on a regular basis with NCCIH, including any proposed use of electronic enrollment data reports sent directly to NCCIH's accrual monitoring system. 

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex (including gender identify, sexual orientation, or transgender status).
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex (including gender identify, sexual orientation, or transgender status).

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP guidance materials.

SF424(R&R) Senior/Key Person Profile

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

Biographical Sketches: The application for the DCC must include only the personnel and corresponding biographical sketches for the key personnel for that application. All key personnel must provide an NIH biosketch whether or not they are budgeted. The PD/Pl (or multi-PDs/Pls) for the companion CCC cannot be listed as key personnel in the DCC application.

R&R Budget

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

All costs requested and all changes in budgets after the first year should be clearly identified and justified. The DCC budget must be synchronized with the CCC budget.

If parts of the costs of the trial are to be provided by sources other than NCCIH, 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 Special Award Condition. 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 NCCIH.

The DCC should include in its budget all costs associated with preparation of materials for DSMB meetings and travel for key personnel to all in-person DSMB meetings. This includes the costs for preparing reports for the DSMB. An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by NCCIH. Other DSMB expenses and activities such as DSMB member travel costs, liability insurance, and conflict of interest assessment will be provided by NCCIH.

The DCC should budget for the attendance of their key personnel to all in-person, steering committee meetings in collaboration with the CCC.

Include budget support for publication, data sharing, and dissemination of results.

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

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:

Research Strategy

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

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application must present a discussion of the approach to coordination and administration, data management, biostatistical support, and data analysis.

The application from each site must contain a Research Strategy that clearly describes those aspects of the project that are common to all sites of the collaboration. All variations in the Research Strategy between sites, no matter how minor, should be highlighted in a subsection of the Research Strategy with the heading "Elements Unique to This Site." In this subsection, PDs/PIs should describe, for example, how the research site has a unique role in the collaboration, such as data coordination, statistical analyses, etc.

The following criteria must be addressed:

Significance: Explain why the chosen study design is optimal to answer the scientific question posed for the trial described in the CCC application. Justify the appropriateness of the study sample size, power, and effect size for the trial.

Innovation: Describe plans to employ unique or novel methodologies that will enhance the clinical trial design, management, or methods of data analysis. Describe innovation of planned approaches to project coordination and logistical support. Describe plans for utilization of current best practices to improve the knowledge and/or skills of the multi-site clinical trial.

Approach: Describe the planned approaches to study coordination, data management (including data security procedures), data monitoring and reporting, and biostatistical support and include a description of how these approaches will contribute to the success of the trial. Describe plans for coordination of the project, study design, data management and quality control, statistical analysis and milestone plans.

Nutritional intervention research in humans is complicated by the complex and varied background nutritional status and dietary intake of participants in clinical trials. To enhance rigor, reproducibility, and generalizability, it is important that trials of natural products that are part of the regular or occasional dietary intake include rigorous methods to account for the dietary intake and heterogeneity across participants (e.g., assessment of nutritional status; collection of data about dietary intake at baseline and throughout the trial; collection of data about factors that may impact absorption or metabolism of the natural product; rigorous study design to ensure balance across study arms with strategies such as stratified randomization; or rigorous statistical methods to examine treatment heterogeneity through prespecified subgroup analyses or analyses of effect modification by background nutritional status or other participant characteristics on target engagement or clinical outcomes).

Coordination: Describe plans for how the multi-site clinical trial will be coordinated, including plans for providing administrative and operational support. Describe how the DCC will interact and collaborate with the CCC and individual sites, including transmission of data in an accurate and timely fashion.

Study Design: Describe the proposed experimental approach, including a discussion of the clinical trial design and the rationale for the particular design chosen (efficacy, effectiveness, adaptive, etc.). Provide details of the randomization scheme.

Data Management and Quality Control: Describe the approach to data management, including data management systems, methods of data entry, case report forms, methods for assessing the quality and consistency of the intervention(s) and data collection, policies and methods for ensuring blinding of study results, and data confidentiality and subject privacy.

Letters of Support:

Letters of support from institutions with a key personnel in the study must be provided.

Letters of support from department chairs whose support are necessary for the functions of the DCC should be provided. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating organization.

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 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 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In addition to the NIH application requirements for a data and safety monitoring for clinical trials, NCCIH requires independent monitoring plan 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-17-038.html), as well as the NCCIH Guidelines for Data and Safety Monitoring (https://nccih.nih.gov/grants/policies/data-safety-monitoring). An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by NCCIH. At the first meeting in the UG3 phase, the DSMB will review the awardee's protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment adverse events, data quality, outcome data, and overall awardee performance.

The DSMB has the responsibility to review interim and final data and to recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or terminated early. Thus, its ethical responsibilities to the participants as well as to the integrity of the study are of paramount importance to NCCIH. The DSMB will meet in person or by phone at least twice a year. Applicants should not propose DSMB members in the application, or even inquire about the interest of possible DSMB members, because anyone so contacted would not be eligible to serve as a member of the peer reviewer committee that will evaluate the applications for scientific merit. For renewal applications, applicants should provide a list of DSMB members in the application.

Section 4 - Protocol Synopsis

4.3 Statistical Design and Power

Applicants must describe the Statistical Analysis Plan (SAP). If the SAP is not a part of the DCC application, both the CCC and DCC applications will be deemed incomplete and will not proceed to peer review. The calculations must be linked to the study endpoints and to the hypothesis(es) being tested. The power calculation description should be detailed enough to allow replication of the analysis by an independent statistician. NCCIH recommends a minimum of 90 percent power for the primary outcome. The plan should also include a description of the methods to be used in the analysis of the primary outcome data. The SAP should include plans for interim and final analyses, methods of bias control, and methods for handling missing data (as applicable). The SAP should take into account that nutritional intervention research in humans is complicated by the complex and varied background nutritional status and dietary intake of participants in clinical trials. To enhance rigor, reproducibility, and generalizability, it is important that trials of natural products that are part of the regular or occasional dietary intake include rigorous methods to account for the dietary intake and heterogeneity across participants (e.g., assessment of nutritional status; collection of data about dietary intake at baseline and throughout the trial; collection of data about factors that may impact absorption or metabolism of the natural product; rigorous study design to ensure balance across study arms with strategies such as stratified randomization; or rigorous statistical methods to examine treatment heterogeneity through prespecified subgroup analyses or analyses of effect modification by background nutritional status or other participant characteristics on target engagement or clinical outcomes). Power calculations should account for these analytic plans.

For Phase Ill clinical trials, the SAP should include plans for evaluation of the primary outcome(s) by race/ethnicity and sex/gender, and it should include all relevant data to assess whether the trial includes adequate numbers of subgroups of participants to allow for separate and adequately powered analyses. Adaptive designs should include a prespecified adaptation plan that allows for clear go/no-go decisions and prespecified analysis boundaries.

Section 5 - Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-Related Attachments

The following attachments must be included as a part of the collaborative application. Attachments permit expansion but not duplication of certain elements that cannot be appropriately described in the Research Strategy. All attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Trial Experience Table

Applicants must provide a detailed table listing the characteristics of trials that demonstrates experience of the study key personnel in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf" and must not exceed 3 pages.

The table columns should include:

• Clinical trial title
• Applicant's role in the trial
• A brief description of the trial design
• Planned enrollment
• Actual enrollment
• Number of sites
• Whether the trial(s) were completed on schedule or not
• Publication reference(s)

2. Milestone Plan

A Milestone Plan must be provided as an attachment called "DCC Milestone Plan.pdf" and must not exceed 5 pages.

The plan should describe the key milestones that need to be met throughout the lifecycle of the clinical trial to ensure its success and the processes that will be used to reach the milestones; the plan should provide a timetable identifying when each of these key milestones will be met.

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The Milestone Plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective action strategies. Milestones should address accrual goals for women, minorities and children and any other identified requirements for completion of the approved research. The Terms and Conditions for an award under this NOFO will include a Milestone Plan that is mutually agreed upon by the investigators and NCCIH.

The aim of the DCC milestone plan is to describe the milestones that need to be met by the DCC in coordination with the UG3/UH3 activities of the CCC. The DCC milestone plan should include key milestones that need to be met during the first phase of the trial (UG3 phase of the CCC) to allow for successful launch of the full trial in the second phase (UH3 phase of the CCC). The milestone plan also needs to describe the milestones that need to be reached in the second phase of the trial to ensure the successful completion of the clinical trial and dissemination of its results.

Since the DCC functions are developed and carried out in collaboration with the CCC, it is expected that milestones will be clearly delineated as to which will be met by the DCC and which will be the responsibility of the CCC. For those activities (e.g., protocol development) that require involvement of both the CCC and the DCC, the DCC milestone plan should address the aspect of the milestone that is relevant to the DCC. Synchronicity with the CCC milestone plan is expected (e.g., the timeline for finalization of the protocol should be the same in both the DCC and CCC milestone plans).

The application should describe DCC milestones for the planning phase (phase 1, up to 1 year) which may include but are not limited to the following:

• Final protocol and informed consent(s)
• Clinical sites identification, including potential back-up sites
• Final organization/communication plan
• Pharmacy/laboratories identification (as appropriate)
• Contracts/third party agreements
• Case report forms
• Final data management plan
• Final data and safety monitoring plan
• Site training plan
• Private website that provides a secure environment and the necessary data management system(s) and informatics support to acquire, store, catalogue, query, and distribute documents and materials required for the successful performance of the clinical trial.
• Final Manual of Procedures (MOP)
• Agreements in place for product supply or provider availability, including back-up plans (depending on the needs of the trial)
• Regulatory documentation needed before trial enrollment can occur, such as DSMB review, IRB approval(s), or other applicable regulatory agencies' requirements (e.g., FDA)
• Tracking of biological samples in place including metrics and quality control
• Listing with regular updates of clinical trial information on ClinicalTrials.gov, as per NIH policy.

DCC milestones of particular interest during the implementation phase that should be described in the application may include but are not limited to:

• Data safety and monitoring reports to the DSMB
• Completion of subject assessments and data collection
• Completion of data cleaning
• Completion of primary data analyses
• Completion of secondary data analyses
• Completion and submission of primary manuscript
• Update project status in ClinicalTrials.gov
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date

The aims of the DCC milestone plan are to describe the goals that need to be met by the DCC in coordination with the UG3/UH3 activities of the CCC.

Delayed Onset Study

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

PHS Assignment Request Form

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. Each application of a collaborative set must be on-time. Considerations for late applications that are based on the institution or PD/PI apply only to his/her individual application.

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.

Specific to this NOFO:

• Awards issued under this NOFO will be incrementally funded for up to 7 years. These will not be multi-year funded.
• Awards issued under this NOFO will be excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
• Awards issued under this NOFO will not be provided the authority to automatically extend the final budget period. All extensions, including the first, will require NCCIH prior approval.
• Awards issued under this NOFO will be excluded from Streamlined Noncompeting Award Process (SNAP)

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.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NCCIH, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed. Each application of a collaborative set must be complete, compliant, and responsive.

In order to expedite review, applicants are requested to notify the NCCIH Referral Office by email at [email protected] when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application.

Applications must include a project management plan as “Other Attachments” while the clinical trial experience table and milestone plan need to be submitted as “Other Clinical Trial attachments”. A cover letter is required for each application submitted to this collaborative NOFO. Applications that fail to include these attachments will be considered incomplete and will be withdrawn.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

The policy applies when the combined budget for the collaborative DCC and CCC applications exceeds $500,000 in direct costs in any year. Applicants requesting $500,000 or more in direct costs need to follow the NCCIH process for large budget grants to get permission to submit the application (https://www.nccih.nih.gov/grants/policies/nccih-policy-applications-for-large-budget-clinical-trials-over-500000-in-direct-costs-in-any-year).

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected]. 

Post Submission Materials

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

Any instructions provided here are in addition to the instructions in the policy.

In addition to the NIH policy-allowed post-submission materials in NOT-OD-19-083, the follow post-submission materials are allowed:

• Revised Clinical Trial Experience Table (e.g., due to updated enrollment numbers, publication of trial results, or newly started clinical trials).
• Revised DCC Milestones Plan (e.g., due to new recommendations from the DSMB; the hiring, replacement, or loss of an investigator; change to health care systems participating in the trial; or change in electronic health record or IT infrastructure).
• Revised DCC Project Management Plan (e.g., due to the hiring, replacement, or loss of an investigator; change to health care systems participating in the trial; or change in electronic health record or IT infrastructure).

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:

For the purposes of peer review and funding, the DCC and CCC applications will be reviewed together. Reviewers will emphasize the overall feasibility of the project and whether the clinical trial will answer a key scientific question and be conducted on time and within the proposed budget.

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).As part of the overall impact score, reviewers should consider and indicate how the Plan for Enhancing Diverse Perspectives affects the scientific merit of the project.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCCIH, 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 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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

Please note that the reviewers will not consider race, ethnicity, age, or gender (including gender identity, sexual orientation, or transgender status) of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors 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.

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

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).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• 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.

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.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

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:

• Working with the CCC to finalize research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.
• Working with the CCC to establish a Trial Management Committee to coordinate and manage the project. The PD(s)/PI(s) will name investigators and staff to serve as members on a Trial Management Committee (and other subcommittees as needed). Study investigators will be required to accept and implement the common protocol and procedures approved by the Trial Management Committee.
• Implementing the core data collection method and strategy collectively decided upon by the Trial Management Committee. It is the responsibility of each clinical site to ensure that data will be submitted in a timely way to the study’s data entry system according to the study protocol. Additionally, sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.
• Establishing mechanisms for quality control and monitoring. The recipients are responsible for ensuring accurate and timely assessment of the progress of the study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis, (2) as simple as appropriate in order to encourage maximum participation of health professionals and patients and to avoid unnecessary expense, and (3) sufficiently staffed across the participating institutions.
• Establishing procedures, where applicable, for all participating institutions to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.
• Cooperating in the reporting of the study findings. NIH will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIH of pooled data and conclusions are to be developed by the PD(s)/PI(s), as applicable. NIH policies governing possible co-authorship of publications with NIH staff will apply in all cases. In general, to warrant co-authorship, NIH staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts.
• Overseeing the overall budget, activities, and performance of the cooperative agreement. Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices of NCCIH
• Complying with the approved Data Management and Sharing Plan (DMS Plan), including sharing data, resources, and software according to NIH sharing policies
• Cooperating with NIH staff and contracted on-site monitors in the design and conduct of protocols, analysis of data, and reporting of results of research.
• Agreeing to accept close coordination, cooperation, and management of the project with NIH, including those outlined below under “NIH Responsibilities”"Managing support or other involvement of industry or any other third party in the study e.g., participation by the third party; involvement of study resources or citing the name of the study or NCCIH or other NIH Institute or Center support; or special access to study results, data, findings, or resources – which may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIH.
• Any of the above functions may be performed by the recipient organization or by subrecipient organization.
• 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.
• Provide updates at least annually on progress in PEDP implementation.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• NIH will assign a Project Scientist as the point of contact to work with the PD(s)/PI(s) and participate in the Trial Management Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the recipient, although specific tasks and activities will be shared among the recipient and the NIH Project Scientist. With the agreement of the PD(s)/PI(s), the NCCIH Project Scientist or designee may assist in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and/or in the publication of results.
• NIH will assign a Program Officer who will be responsible for retaining overall programmatic responsibility for the award and will clearly specify to the recipient the name(s) and role(s) of any additional individuals with substantial involvement in the project and the lines of reporting authority, and will be named in the notice of award.
• NCCIH may designate additional staff to provide advice to the recipient on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Analyst, who will provide direct technical assistance to the recipients to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.
• Prior to the start of clinical activities, NIH staff will review and approve study protocols to ensure they are within the scope of peer review and for safety considerations, as required by Federal regulations. NIH will monitor protocol progress and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete the study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. NIH will not permit further expenditures of NIH funds for a study after requesting closure (except for participants already on-study).
• NIH will serve as a resource with respect to other ongoing NIH activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.
• NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include regular communication with the PD(s)/PI(s) and their staff, periodic site visits for discussion with the recipient's research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship activities. NCCIH may designate NIH staff or contractors to conduct site initiation, interim, and closeout site-visits NIH reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting.
• NIH staff will provide input, expert advice, and suggestions in the design, development, and coordination and implementation of the study objectives.
• NCCIH staff will make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Study Team/NIH meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.NIH reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting.

Areas of Joint Responsibility include:

Close interaction between the participating grantee(s) and the PO/PS team will be required, to manage, assess, and implement the activities of the UG3 and UH3 phases.

A Trial Management Committee organized by the PD(s)/PI(s) will be the main oversight body of the study.

• The Trial Management Committee has primary responsibility to design research activities; establish priorities; develop common protocols and manuals, questionnaires, and other data recording forms; establish and maintain quality control among recipients; review progress; monitor patient accrual; coordinate and standardize data management; and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Trial Management Committee. The Trial Management Committee will document progress in written reports to the NCCIH Program Officer and will provide periodic supplementary reports upon request.
• The Trial Management Committee will be composed of the PD(s)/PI(s), co-investigators, or staff as deemed necessary, such as the study biostatistician and trial manager, the NCCIH Project Scientist, and additional designees of NIH. The NCCIH Project Scientist or designee will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NCCIH Program Officer will serve as an “ex officio” member of the Trial Management Committee.
• The Trial Management Committee will ensure that sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes but is not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
• The Trial Management Committee will develop appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health.
• A detailed data and safety monitoring plan (DSMP) will be required for the clinical trial(s) supported by the award.
• An independent data and safety monitoring board (DSMB) will be required for the UH3 phase clinical trial. Prior to award, NCCIH and the Investigator team will determine if the DSMB will be appointed and established by NCCIH or by the Investigator team, in accordance with NIH and NCCIH policies for monitoring (https://www.nccih.nih.gov/grants/policies/data-and-safety-monitoring-of-nccihfunded-clinical-research).
• The DSMB will play a crucial role in ensuring safety and welfare of patients enrolled in the trial, will regularly review study progress and some interim data, and will provide recommendations to NIH. During the award, the recipient will provide interim data and reporting, as requested, to the Board as outlined in NCCIH guidelines (https://www.nccih.nih.gov/research/guidelines-for-nccih-appointed-data-and-safety-monitoring-boards).

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel will be convened. It will have three members: 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 recipients's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR. 

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 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.

• Recipients will provide updates at least annually on implementation of the PEDP.

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.

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: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Wendy Weber, N.D., Ph.D. M.P.H
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: [email protected]

Jessica McKlveen, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: [email protected]  

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH) 
Telephone: 301-594-3788 
Email: debbie.chen@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.