Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

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

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Research Objectives

This FOA supports applications for a Data Coordinating Center (DCC) to support a corresponding investigator-initiated, multi site, 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 randomization; 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 human participants, and hence it is of foremost importance to ensure patient safety and enroll men, women, and children from diverse backgrounds and retain sufficient numbers for meaningful analysis among relevant sub-groups. An independent DCC is critical to the integrity of the data collection and intervention delivery because of the need for central coordination of these activities in complex multi-site clinical trials.

For this FOA, multi-site clinical trials are defined as trials that enroll volunteers from two or more recruitment sites. Trials for which this FOA 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 a 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 the NCCIH, applicants are encouraged to consult the NCCIH website (http://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 explanatory and pragmatic. For this FOA, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances. The trial design should be appropriate for the study question.

This DCC FOA runs in parallel with companion FOA (PAR-20-215) that encourages applications for a collaborating Clinical Coordinating Center (CCC). Both a DCC application and a collaborating CCC application 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 FOA 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 intended to support the development of case report forms, trial database, data quality assurance plan, study partnerships; informed consent(s); Institutional Review Board, and Data and Safety Monitoring Board approval of the trial protocol; manual of operations, project management plans, and other resources necessary to the performance of the actual clinical trial under the UH3, implementation phase of the CCC. Applications should 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, devices or other necessary resources, should be obtained by the start of the UH3 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 of the DCC is contingent on the successful completion of year 1 U24 milestones, the UG3 planning phase milestones of the collaborative CCC, and approved transition to the second 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 the CCC at the time of the transition request for the UG3/UH3. Continued support for both the CCC and DCC will be contingent on the extent to which agreed-upon milestones have been met in the first year, and on the availability of funds to continue the project. If agreed upon milestones are not met in the U24 or either the UG3 or UH3 phases, NCCIH will work with the DCC and CCC to conduct an early and orderly phase-out of the project.

Milestones

Delineation of milestones is a key requirement for applications submitted under this FOA. 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 at the end of the first year of planning that must be completed prior to implementation of the clinical trial. Milestones are to be performance-based goals to achieve completion of the trial on time and on budget. Projects that have met the planning phase milestones will be administratively considered for continuation of the U24 and transition of the CCC from the UG3 planning phase to the UH3 implementation phase.

This FOA will support applications that utilize a series of milestones that synchronize activities between the DCC and the collaborating CCC activities 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 to proactively confront potential delays or disruptions in attaining milestones. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NCCIH will consider ending support and will negotiate a phase-out of the award. Continuation of the award is conditional upon satisfactory progress in meeting milestones and on the availability of funds.

NCCIH policies regarding milestones and relevant clinical research/studies policies are described in NCCIH Accrual of Human Subjects (Milestones) Policy (https://nccih.nih.gov/grants/policies/SARP,) NCCIH Clinical Terms of Award for Human Subjects Research (https://nccih.nih.gov/research/policies/terms-of-awards.htm) and NCCIH Policy on Data and Safety Monitoring (https://nccih.nih.gov/grants/policies/data-safety-monitoring). Clinical trials supported by this FOA must adhere to the NIH Policy on Good Clinical Practice Training (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html).

Specific Areas of Research Interest

Prior to submitting to this FOA, 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.

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 FOA.

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)

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)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

• 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 Institutions) 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 SF 424 (R&R) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• 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.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

Multiple PDs/PIs are allowed on any single application. Because the FOA 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 should not be designated as multiple PDs/PIs on each application of a collaborative set

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. 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 NOT-OD-11-101)

This FOA only accepts applications that are part of a collaborative set of multiple applications. . A set must contain 2 applications, 1 U24 application to this FOA and 1 UG3/UH3 to TEMP-8095.

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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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 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:

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) 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 clinical coordinating center of the set. The data coordinating center 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 FOA. The cover letter should include names of the PD/Pl for both the collaborating CCC and DCC applications; the title of the projects (which should be the same in both CCC and DCC applications); and the names of applicant institutions. 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.

The Cover Letter is one pdf file only. The following collaborative information is required in the Cover Letter: a listing of all the applications that are a part of the set of collaborative applications being submitted, including for each: 1) the PD/PI(s) name(s), 2) the Title (including the tag, e.g., 1/3 ), and 3) the Applicant Institution. Each site should submit an identical listing.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) 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 attachment listed below must be completed and attached or the application will not be peer reviewed.

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 FOA.

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 pre-defined 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.

All instructions in the SF424 (R&R) 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 and must provide an NIH Biosketch whether or not they are budgeted. The Program Director (PD)/ Principal Investigator (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 SF424 (R&R) 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. 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 their 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, the 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 the NCCIH. Other DSMB expenses and activities such as DSMB member travel costs, liability insurance, 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.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) 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, as well as biostatistical support and include 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.

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 (pragmatic, explanatory, cluster-randomized, adaptive, etc.). Provide details of the randomization scheme, if applicable.

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; data confidentiality and subject privacy.

Letters of Support:

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

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed.

Only the following fields/attachments below may be submitted. Other fields/attachments may not be submitted:

• 1.1 Study Title
• 1.2 Is this Study Exempt from Federal Regulations?
• 1.4 Clinical Trial Questionnaire
• 2.1 Conditions or Focus of Study
• 2.4 Inclusion of Women, Minorities, and Children
• 3.1 Protection of Human Subjects
• 3.2 Is this a multi-site study that will use the same protocol to conduct non-exempt human subjects research at more than one domestic site?
• 3.3 Data and Safety Monitoring Plan
• 4.4 Statistical Design and Power
• 4.7 Dissemination Plan
• 5.1 Other Clinical Trial-related Attachments

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 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, the 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 the 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 data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. Thus, its ethical responsibilities, to the participants as well as to the integrity of the study, are of paramount importance to the 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

4.4 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 the 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% 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).

For phase Ill clinical trials, the SAP should include plans for evaluation of the primary outcome(s) by race/ethnicity and gender, and 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 pre-specified adaptation plan that allows for clear go/no-go decisions and pre-specified analysis boundaries.

4.7 Dissemination Plan

Describe how the CCC will facilitate and support timely publication and dissemination of results as appropriate and consistent with achieving the goals of the program.

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

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:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

Column G: whether the trial(s) were completed on schedule or not

Column H: 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; the processes that will be used to reach the milestones; and 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 actions 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 FOA 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 one 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 (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
• Implementation of Data Sharing Plan

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.

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 SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. 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. Overview Information 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 Policy on Late Application Submission.

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 SF424 (R&R) Application Guide.

"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. " after the template text "Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission."

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.

Specific to this FOA:

• Awards issued under this FOA will be incrementally funded for up to 7 years. These will not be Multi-Year Funded.
• Awards issued under this FOA will be excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
• Awards issued under this FOA 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 FOA will be excluded from SNAP.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) 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 Component of the SF424(R&R) Application Package. 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 FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) 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. Each application of a collaborative set must be complete and compliant.

In order to expedite review, applicants are requested to notify the NCCIH Referral Office by email at SchmidMa@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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 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:

• Clinical Trial Experience Table (e.g. due to updated enrollment numbers, publication of trial results, or newly started clinical trials)
• DCC Milestones 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

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.

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

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

For this particular announcement, note the following:

For the purposes of peer review and funding the 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.

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.

Significance

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

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

For this specific FOA:

Does the proposed Data Coordinating Center (DCC) address the needs of the research proposed clinical trial that it will coordinate? Is the scope of activities proposed for the DCC appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research clinical trial?

Investigator(s)

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

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

For this specific FOA:

Are the PD(s)/PI(s) and other personnel well suited to their roles in the DCC? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing data coordination for clinical trial research? Do the investigators demonstrate significant experience with coordinating collaborative clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the DCC? Does the applicant have experience overseeing selection and management of subawards, if needed?

Innovation

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

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

Specific to this FOA:

Does the application propose novel organizational concepts or management strategies in coordinating the clinical trial the DCC will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts or management strategies or instrumentation proposed?

Where appropriate, does the proposed DCC utilize current best practices to improve the knowledge and/or skills of the multi site clinical trial it will support?

Approach

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

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

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA:

Does the Project Management Plan adequately address the critical parameters to launch, conduct, and complete the study on time and on-budget? How effectively does the Project Management Plan identify and describe risks to implementation and how well are contingency plans described? Since this is a multi-site application, how strong is the evidence of the ability of the DCC to operate within the proposed organizational structure, communicate with the individual sites, and collect and transmit data in an accurate and timely fashion?

Environment

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

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

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

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

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

Specific to this FOA:

Will the institutional environment in which the DCC will operate contribute to the probability of success in facilitating the research clinical trial it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the DCC benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing central facilities , appropriate for the trial proposed? Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate? If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial? If multi-sites/centers, is there evidence of the ability of all of the individual sites or centers to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure? How strong is the evidence that the facilities and resources available for the DCC infrastructure will support and enable the conduct of the multi-site clinical trial?

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

Study Timeline

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

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

Milestones

Are the specific milestones proposed measurable, achievable, reasonable, so that the milestones will be achieved in the time frame proposed? Does the DCC application adequately address contingency plans in the event the CCC application is not succeeding in achieving its milestones? How well do the contingency plans proposed support the overall program if problems are encountered? Are the listed milestones appropriate for the DCC?

Organization

Is the proposed organizational structure appropriate? Does the applicant adequately address the integration of the DCC in the organizational structure and the impact it will have on the scientific goals of the project? What is the quality of the Project Management Plan? How well does the application provide details to facilitate clear communication and coordination between the DCC and CCC?

Protections for Human Subjects

For research that involves human subjects but does not involve one of thecategories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

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

Renewals

Not applicable.

Revisions

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

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.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

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 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:

• 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.
• Will receive a written critique.

• 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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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 grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. 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 FOA 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: Grantee 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 awardee 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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that 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 FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, 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 45 CFR Part 75.205 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 (0MB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, 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 awardees 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 award 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/Pl(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 Steering Committee to coordinate and manage the project. The PD(s)/Pl(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Study investigators will be required to accept and implement the common protocol and procedures approved by the Steering Committee.
• Implementing the core data collection method and strategy collectively decided upon by the Steering 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 physicians 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. The 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 Principal Investigator or Steering Committee, 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
• Sharing data, resources and software as appropriate and consistent with achieving the goals of the program and the approved sharing policies for the NIH.
• Cooperating with the 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."
• Awardees will submit a detailed transition request for the continuation of the collaborative UH3 implementation phase, outlining the DCC and CCC progress during the UG3 phase, how negotiated milestones have been met, as well as detailed plans, budget and annual milestones for the DCC activities to support implementation of the clinical trial. Funding of the UG3 phase cooperative agreement and first year of the DCC does not guarantee support of the continuation of the DCC and implementation of the clinical trial in the UH3 phase.
• 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 -- 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 function may be performed by the applicant organization or by subcontract to the applicant organization
• Awardees 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

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

• The NIH will assign a Project Scientist as the point of contact to work with the PD(s)/Pl(s) and participate in the Steering Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist. With the agreement of the Principal Investigator, 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.
• The 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.
• 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 insure 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 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. The NIH will not permit further expenditures of NIH funds for a study after requesting closure (except for patients already on-study).
• 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)/Pl(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/Pl(S) and his/her staff, periodic site visits for discussion with the awardees' 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 close out site-visits
• The 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 Steering Committee 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 staff will conduct an administrative review of the DCC and CCC's transition request to determine whether the project will transition to UH3 funding and U24 continuation to implement the clinical trial. Criteria for transition to the implementation phase used in the NIH administrative review include: successful achievement of the planning period milestones, potential for successfully meeting the clinical trial implementation phase plans and milestones, demonstrated ability of the team to work within the consortium arrangement, and the availability of funds.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• Steering Committee organized by the Principal Investigator will be the main oversight body of the study.
• The Steering 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 Steering Committee. The Steering Committee will document progress in written reports to the NCCIH Program Officer, and will provide periodic supplementary reports upon request
• The Steering Committee will be composed of the Pl(s)/PD(s) and co-investigators 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 Steering Committee. The Steering Committee will typically meet in-person twice in the first year of the award and then at least yearly thereafter. More frequent phone meetings will occur as required during the award period. The first in person meeting will occur before clinical activities begin.
• Ensuring 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.
• Jointly developing appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health.
• A Data and Safety Monitoring Plan will be required for both phases of the project. An independent Data and Safety Monitoring Board will be appointed and established by NCCIH for the clinical trial, in accordance with NIH and NCCIH policies for monitoring (https://nccih.nih.gov/grants/policies/data-safety-monitoring). The Data and Safety Monitoring Board will play a crucial role in ensuring safety and welfare of patients enrolled in the trial and 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://nccih.nih.gov/research/policies/datasafety).

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members 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 awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the 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.

3. Reporting

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, 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 (currently 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 45 CFR Part 75 Award Term and Conditions 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 threatensubmission by the due date, and post-submission issues)

Finding Help Online:http://grants.nih.gov/support/(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

Wendy Weber, N.D., Ph.D. M.P.H
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: weberwj@mail.nih.gov

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.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 45 CFR Part 75.