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

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

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

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



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background 

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions). These mind and body interventions are widely used by the public, and they are increasingly recognized as a nonpharmacologic approach to symptom management (e.g., chronic pain, mild depression, anxiety). These approaches can be used by individuals to help prevent, treat, or self-manage various conditions, and they can be complementary to conventional health care.  

There is a need for research to evaluate mind and body and/or multi-component approaches as they are used and delivered to determine whether they are safe and efficacious or effective for given conditions or disorders. For clinical trials to address this need, they must be well-designed and test hypotheses that will guide decisions about the inclusion of these interventions or approaches into the delivery of health care for a given condition or disorder. To accomplish this goal, multisite clinical trials are needed to determine the efficacy or effectiveness in a fully powered clinical trial. NCCIH utilizes the UG3/UH3 funding mechanism to support the Clinical Coordinating Center (CCC) for the trial and the companion U24 funding mechanism to support the independent Data Coordinating Center (DCC). 

Overview of NCCIH Mind and Body Clinical Trials Research Funding Opportunities  

NCCIH has designed a framework for research to describe the broad spectrum of complementary and integrative health research it supports (https://www.nccih.nih.gov/grants/nccih-research-framework). NCCIH supports investigators working on the continuum of the research framework, from basic science and feasibility research  through high-impact clinical trials as well as research on dissemination and implementation (https://www.nccih.nih.gov/grants/funding/clinicaltrials). We encourage investigators to examine the full suite of notices of funding opportunities (NOFOs) to determine which one best aligns with the proposed stage of intervention development and testing.

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.

Prior to submitting an application, NCCIH strongly encourages consultation with the NCCIH Scientific/Research contacts relevant to the area of science for which they are planning to develop an application. Early contact provides an opportunity for NCCIH staff to discuss the scope and goals, and to provide information and guidance.  

Research Objectives of the Clinical Coordinating Center (CCC; UG3/UH3) and the Data Coordinating Center (DCC; U24) for Multisite Investigator-Initiated Clinical Trials of Mind and Body or Multicomponent Interventions 

NCCIH requires companion applications for a CCC and DCC to support multisite investigator- initiated clinical trials to test the efficacy or effectiveness of mind and body or multi-component interventions. 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 multisite clinical trial. The DCC has expertise in clinical trial design and conduct and is responsible for overall project coordination  and administrative, data management, and biostatistical support for the proposed clinical trial, including sample size calculations and data analysis plan. NCCIH requires that the DCC be independent from the CCC (e.g., not include overlapping personnel) in order to provide for central coordination of study activities across multiple sites while ensuring the integrity of the intervention delivery, data collection, and study blinding. 

Research Objectives for the CCC (this NOFO) 

This NOFO invites cooperative agreement applications for investigator-initiated fully powered multisite efficacy, effectiveness, or pragmatic clinical trials (Phase III and beyond) to study the effects of complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind-body interventions) or multi-component interventions that include physical, psychological, and/or nutritional approaches in NCCIH- designated areas of high research priority. CCCs should develop and implement the proposed multisite clinical trial. Proposed clinical trials may utilize a design anywhere along the continuum between explanatory and pragmatic. For this NOFO, 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. 

For this NOFO, multisite clinical trials are defined as trials that enroll from at least three geographically distinct recruitment sites. Two sites will be permitted if there is a strong justification for how fewer sites can still achieve generalizability and meet the National Institutes of Health (NIH) diversity and inclusion requirements for a  Phase III clinical trial. Multiple sites are necessary in efficacy trials to increase generalizability of findings and ensure appropriate size and diversity of eligible participants. 

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. This CCC NOFO runs in parallel with a companion NOFO (PAR-24-087) for a corresponding DCC application. Both a CCC application and a corresponding DCC application need to be submitted simultaneously for consideration by NCCIH. 

Considerations for Selection of Study Design 

Power Recommendations

The choice of study design (e.g., standard efficacy, effectiveness, and/or pragmatic randomized control trial) should be justified scientifically and designed with a minimum of 90% power to estimate treatment effects. Investigators may propose fully powered adaptive designs or optimization designs, depending on their research question. In some cases, a stepped-wedge design may be the only practical way to generate the appropriate data. Nevertheless, considering the practical, ethical, and analytical challenges as outlined by the NIH Pragmatic Trials Collaboratory, stepped-wedge designs should be avoided when another rigorous study design is feasible and will answer the study question. If proposed, a strong justification for a stepped-wedge design should be provided, including why an alternative design is not superior. In all cases, there should be strong rationale for the proposed comparator condition(s) (e.g., time and attention control, usual care, standard of care, sham condition, and/or active comparator(s)) based on the research question you plan to address. Due to lack of rigor and potential expectancy effects, NCCIH will not support studies proposing a waitlist comparator condition. 

Group-Based Interventions

For interventions that either are or can be delivered in groups, investigators should provide a strong rationale for the choice of trial design. The selection of study design should be guided by decisions about how best to deliver the intervention and by concerns such as contamination and logistics. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions. Additional information is available at https://researchmethodsresources.nih.gov/ 

In traditional randomized clinical trials (RCTs), individual participants are randomized to receive an intervention that is delivered individually (e.g., spinal manipulation, acupuncture, or individually delivered hypnosis). When an intervention can be delivered in a group format, there are several methods of randomizing participants to the intervention. The first option is an individually randomized group treatment trial (IRGT), where individual participants are randomized to one of the interventions, but the intervention is delivered in small groups (e.g., yoga, mindfulness- based stress reduction, or tai chi classes). The second option is a group-randomized trial (GRT), also called cluster-randomized controlled trial (cRCT), where groups of participants are randomized to study conditions, often defined by their workplace, school, primary care provider, or community. In cRCT, the intervention provided to the randomized groups can be delivered individually, in small groups, or to the entire group. 

The study team biostatistician will need to justify the study design, data analysis, and sample size estimates. The justification should include discussion of the positive intraclass correlation expected in data obtained from participants in the same groups, or clusters (IRGT cRCT, or GRT). In general, these types of studies need to consider how the data analysis and sample size addresses the extra variation expected in the data and the degrees of freedom available to estimate that extra variation. Failure to account for this variable in the sample size calculation can result in under powered studies. Regardless of the choice of study design, the proposed multisite clinical trial is expected to be highly impactful, contribute to the evidence base for important health matters of relevance to the research mission of NCCIH, and be designed with a minimum of 90-percent power to test the primary hypothesis. These trials are expected to achieve the Phase III trial requirements of NIH as well (see https://grants.nih.gov/policy/clinical-trials/glossary-ct.htm and https://grants.nih.gov/policy/inclusion/women-and-minorities.htm). 

For applications that propose the use of a dietary supplement, drug, or device as part of the intervention, the applicants must contact the U.S. Food and Drug Administration (FDA) prior to applying to determine whether an Investigational New Drug (IND) or an Investigational Device Exemption (IDE) application is necessary for the proposed clinical research.  Applicants proposing to test a natural product in the intervention will need to address NCCIH's Natural Product Integrity Policy (see: https://www.nccih.nih.gov/research/nccih-policy-natural-product-integrity)

For applications that propose the use of an app or clinical decision support software, applicants must consult with their institutional review board (IRB) to determine whether the approach may qualify as a medical device. If so, applicants must contact the FDA prior to applying to determine whether an IDE application is necessary for the proposed clinical research (https://www.fda.gov/medical-devices/software-medical-device-samd/your-clinical-decision-support-software-it-medical-device).  

Mechanistic Measures 

There are often questions about whether efficacy, effectiveness, or pragmatic trials should include any mechanistic aims to evaluate how interventions work. Mechanistic outcomes could be included in trials submitted under this NOFO, if a strong rationale is provided such as the need to assess whether the effect of the intervention is mediated or moderated via the measured mechanism. The inclusion of mechanistic outcomes should not introduce significant burden for participants or utilize a significant portion of the budget. NCCIH has other funding mechanisms to support basic, mechanistic and translational research (NOT-AT-21-006).   

Preliminary Data Requirements  

This NOFO is appropriate when there is a clear and compelling rationale, a rigorous empirical basis, and a scientific premise to conduct multisite efficacy, effectiveness, or pragmatic clinical trials. Preliminary data from published data are required that address the following:  

• Evidence that an intervention similar to the one proposed is well tolerated (does not produce frequent severe adverse events) in pilot human studies.  
• Extant pilot multisite supportive feasibility data on a similar intervention and clinical population (e.g., a proposed study to examine vinyasa yoga in adults with anxiety may cite pilot work on hatha yoga in a population of adults with depression and anxiety). 
• Demonstrated adherence to and fidelity of the intervention (e.g., cite a pilot study of a similar duration with sufficient adherence and fidelity to the intervention across sites).  
• Demonstrated participant retention for a similar intervention and study duration (e.g., cite a pilot study that retained a sufficient percentage of participants at the primary outcome time point).  
• Demonstration that the primary outcome is a valid measure for the proposed condition and population.  
• Information that justifies how the intervention is delivered (format of delivery, duration of individual intervention, frequency of delivery, and timeline of intervention delivery to achieve clinical benefit) in the study. For example, the intervention could be delivered as a single 30-minute session once a week for 8 weeks, or as self-paced 5-minute modules over 10 weeks. Preliminary data therefore should demonstrate that the frequency and duration of the intervention are feasible and likely to have the greatest impact on clinical outcome and minimize participant burden and the risk of adverse events.  
• For applications that include a natural product as part of a multi-component intervention, the application must provide published data that the formulation of the natural product proposed has demonstrated efficacy for the condition being studied from at least one fully powered placebo-controlled trial. 

Preliminary Data about the Team 

In addition, the following information demonstrating the team’s collective experience conducting clinical trials is required:  

• Delivered a similar intervention via the same delivery mode in a clinical trial with fidelity across multiple sites.  
• Successfully recruited and accrued similar participants across multiple sites. 
• Successfully randomized participants to similar intervention and control conditions across multiple sites.  
• Achieved adherence to a similar intervention study protocol by research staff across multiple sites.  
• Retained participants for a similar study duration across multiple sites.   
• Completed collection of follow-up data with consistency and minimal missing data across multiple sites.  
• Published results from previous completed trials across multiple sites. 

Structure 

This NOFO will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to 1 year (UG3) and a full enrollment and clinical trial execution phase (UH3). There should be clear objectives for both the UG3 and UH3 phases. 

Phases of Award 

The UG3 phase will support the development of and preparation for the clinical trial including: establishing case report forms and other resources necessary to the performance of the trial; further interaction and finalization of study partnerships, including contracts with performing clinical sites; single IRB approval; establishing a data and safety monitoring board (DSMB); NCCIH approval of study protocol, study accrual and retention plan, and data safety and monitoring plan; finalization and IRB approval of the study protocol and informed consent form(s); review and completion of manual of operations; and completion of clinical trial project management plans. Applications are expected to provide a clinical trial project management plan that delineates how the study will monitor and evaluate critical processes impacting trial launch, conduct, and completion, coupled with on-time and on-budget performance milestones. All regulatory approvals should be obtained prior to the end of the UG3 award. Training of intervention providers, training of comparison group intervention providers, or plans for distribution of other resources (e.g., training materials, fidelity checklists) should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. Subject to NCCIH funding availability and scientific priorities, UH3 awards will be made after administrative review of a transition application with particular attention to the extent to which agreed-upon milestones have been met during the UG3.  

Investigators will need to submit their UH3 phase transition application 2 months before the end of the UG3 award.  The UG3 phase milestones therefore should be completed 2 months prior to the proposed UH3 start date. All UG3 milestones must be achieved prior to transition to the UH3 phase. Continued support for both the DCC and CCC will be contingent on the extent to which agreed-upon UG3 milestones have been met in the first year and on the availability of funds and scientific priorities to continue the project. 

Milestones 

Establishing and completion of study milestones is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Plans should be guided by milestones that will need to be reached at the end of the UG3 phase. Milestones are objective and performance-based events that are needed to prepare for and achieve completion of the trial on time and on budget (see example milestones at https://www.nccih.nih.gov/grants/toolbox#milestone). UG3 projects that have met milestones will be assessed administratively to determine eligibility for transition to the UH3 implementation phase. 

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

NCCIH Priorities for Clinical Trials of Mind and Body Interventions 

NCCIH has identified targeted areas of investigation to align with the NCCIH Strategic Plan (https://www.nccih.nih.gov/about/strategic-plans-and-reports). For this funding opportunity, applications will be considered high programmatic priority if they address one of following criteria related to the intervention of study:

• The complementary or integrative approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions) should include one or more of the following:   
  • Physical approaches such as spinal manipulation or mobilization, massage, tai chi, qi gong, yoga, acupuncture; or
  • Psychological approaches such as hypnosis, guided imagery, breathing exercises, progressive relaxation, meditation, biofeedback, mindfulness techniques, music or other art-based therapies
  • Multi-component interventions such a naturopathic medicine, traditional Chinese medicine, Ayurvedic medicine, chiropractic care, or a combination of two or more of the specific complementary health approaches (e.g., massage and biofeedback, or natural product and mindfulness); or integrated approaches to care in which a complementary health approach is used in combination with standard care (e.g., mindfulness or yoga as augmentation to conventional medications); or
  • Multilevel intervention level (patient, caregivers of patient, clinicians, and health care system) where at least one level of intervention includes a mind and body intervention. 
     
• In addition, proposed projects could include an outcome measure(s) that relates to at least one of the following high-priority topic areas:
  • Promotion of health behaviors, health restoration, emotional well-being, or resilience;
  • Prevention or treatment of symptoms such as sleep disorders or disturbances, depression, anxiety, chronic stress, post-traumatic stress (disorder), obesity, and acute and chronic pain conditions;   
  • Whole person health outcomes including multisystem or multilevel outcomes;
  • Minority health and reduction of disparities¹ in areas such as pain, obesity, mental and emotional behavioral health, and maternal health;   
  • Social and structural determinants of health (https://www.ninr.nih.gov/researchandfunding/nih-sdohrcc);
  • Enhancement of adherence to medications or prescribed behavioral approaches (e.g., physical activity and healthy eating);   
  • Reduction or deprescribing of inappropriate use of medications or  other substances (e.g., drugs of abuse or medications that are contraindicated in specific patient populations); or   
  • Reduction in risk for/incidence of HIV, or comorbidities, coinfections and complications from HIV (https://abs2.od.nih.gov/Docs/NIH_StrategicPlan_FY2021-2025.pdf)   

When evidence justifies, NCCIH encourages applications to conduct studies in a way that assesses the impact of integrating interventions into relevant settings (e.g., health care systems, schools, Federally Qualified Health Centers, military or veteran health care delivery organizations, community organizations, justice systems, or homeless shelters).

All NIH -funded research must adhere to the Code of Federal Regulations, which outlines specific requirements to enhance protections for pregnant women, human fetuses, and neonates; children; and prisoners (https://grants.nih.gov/policy/human subjects/policies-and-regulations/vulnerable-populations.htm). It is the policy of NIH that individuals of all ages, including children (i.e., individuals under the age of 18) and older adults, must be included in all human subjects research, conducted or supported by NIH, unless there are scientific or ethical reasons not to include them (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html).   

Applications proposing research topics not identified above as high programmatic priority can be submitted but are likely to be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce the likelihood of funding. Applications proposing research studies using an intervention and patient population that are the same as or very similar to those used in studies already in progress, conducted, or published by other groups are likely to be lower programmatic priority.

¹ NIH-designated health disparity populations include racial and ethnic minorities (African Americans/Blacks, Hispanics/Latinos, American Indians/Alaska Natives, Asian Americans, Native Hawaiians, and Other Pacific Islanders), sexual and gender minorities, socioeconomically disadvantaged populations, under-served rural populations, and people with disabilities.

Clinical Trials Not Responsive to This NOFO 

Applications that include any of the following types of clinical trials or methods are not responsive to this NOFO and applications proposing such activities will be deemed non-responsive and will not be reviewed: 

• Single site trials. 
• Studies that do not have a primary aim to assess clinical efficacy or effectiveness of the intervention.  
• Fully remotely delivered clinical trials.  
• Studies that do not include a mind-body intervention.  
• Studies that propose a waitlist control.  
• Studies that are geographically limited (e.g., recruiting from one city or region).  
• Trials that propose to test interventions for the treatment or prevention of cancer (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute). 

Plan for Enhancing Diverse Perspectives (PEDP)

•  This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, 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 material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

Specific Areas of Research Interest 

Applicants are strongly encouraged to consult with the NCCIH Scientific/Research contacts overseeing the relevant area of science prior to submitting an application under this NOFO. Early contact provides an opportunity for IC staff to provide guidance on the scope and goals of the application and provides the applicant sufficient time submit their application. It is recommended that engagement begin at least 12 weeks prior to submission of the application.  

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

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

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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

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

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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. 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 SF424 (R&R) Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

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

This NOFO only accepts applications that are part of a collaborative set of multiple applications. A set must contain one application to this NOFO and one application to PAR-24-087.

Applications with Foreign components are encouraged to read NCCIH International Health Research page. Foreign components can include foreign collaborators or consultants, but should not include foreign sites outside of the U.S. or Canada, according to NCCIH’s policy.

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 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 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, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: jessica.mcklveen@nih.gov 

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 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 application 1 of 2 for the CCC of the set. The DCC application will be labeled 2/2.) Titles may not exceed 200 characters in length, including the tag, e.g., 1/2, at the beginning of the title. 

Cover Letter Attachment: 

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 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., "1/2"), and 3) the applicant institution. Each application 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. 

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

Project Management Plan

A Project Management Plan must be provided as an "other attachment" called "CCC 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 to ensure that the unique goals of the clinical trial are met. 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 the planning team and identify control points and processes that are key to 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 key 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 DCC, will proactively evaluate and prioritize issues that jeopardize study goals and development of corrective responses 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 to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time. The project management plan should include risk mitigation or contingency plans. 

Plan for Enhancing Diverse Perspectives

• "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity
• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section
• 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 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review

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

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruiting of women and individuals from groups historically under-represented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.  

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see https://braininitiative.nih.gov/about/plan-enhancing-diverse-perspectives-pedp

SF424(R&R) Senior/Key Person Profile

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

The application for the CCC must include only the personnel and corresponding biographical sketches for the key personnel for that application. All Key Personnel involved in the conduct of the clinical trial must provide an NIH Biosketch regardless of whether they are budgeted. The PD/ Pl (or Multi-PDs/Pls) for the companion DCC cannot be listed as key personnel in the CCC application. 

Biographical Sketches: Document the experience of the PD/PI(s) in leading clinical trials and expertise in the content area of the trial (intervention, study population, and research methods).  

All trials will require a biostatistician, and the application should reflect their hands-on involvement in the design and implementation of the study protocol. Applicants are encouraged to provide strong evidence of the study team's qualifications and ability to conduct the proposed research, and previous investigative experience in related clinical trials. 

R&R Budget

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

Budgets should request only the costs that will be required for the activities to be performed in a given year. Generally, NCCIH expects the requested costs in year 1 (UG3) to be lower than in the following years, depending on recruitment targets. It is also expected that the CCC budget will be lower in the final year. 

This application must include only its own budget, including any subcontract budgets associated with it. The application must provide detailed annual budgets that will enable the CCC to meet its milestones. In the budget justification, provide the detailed budget needs (per year for each site and total) and an implementation and cost management plan (e.g., capitation instead of salary support at sites). Do not include budget support for the DSMB. 

Separate itemized budgets must be prepared for each subcontract and/or for each collaborating clinical site or core, if multiple sites or cores are proposed. 

Include budget support for personnel to travel to a yearly in-person steering committee and/or other meetings of investigators and NCCIH. In addition, include budget support for personnel to attend the semi-annual DSMB meetings/calls. 

Include budget support for enrolling diverse and non-English speaking participants. Costs may include, but are not limited to recruitment and retention costs, translation services and/or interpreters, and costs for using validated measures in multiple languages. 

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 specific term and condition in the Notice of Award. If the third-party support ceases and the trial is no longer tenable without the third-party support, a close-out plan may be requested. Applicants are reminded that although cost share is not required, if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NCCIH. 

Include budget support for the publication and dissemination of findings. 

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Research Strategy 

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application should present a concise overview of the state of the science and relevance of the trial, a discussion of the specific protocol, and the approach to data collection, analysis, and dissemination. 

The following criteria should be addressed: 

Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. 

It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and how or why there is clinical equipoise. The application should make clear the need for and timeliness of the study, with emphasis on how the results will address an evidence-gap and therefore advance knowledge of theory and practice in this area. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance. 

Applications should address the reasons for selection of the intervention. This may include public health impact if subsequent efficacy trials are conducted and positive, ethical dimensions, and patient perspectives on acceptability of the proposed intervention. Characteristics of any preliminary research results provided in support of the proposed project, whether conducted by the applicant or others, should be described in the application so that peer reviewers may evaluate the strength of the supporting evidence. The applicant should also discuss the limitations of those data. 

Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms or guidelines. 

Approach: The research approach section should include a description of the supporting data, clinical trial experience, the experimental approach. 

Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies conducted by the team or published in the literature that demonstrate the need for and the feasibility of the trial at multiple sites should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified and adequately framed. Applications must include the following preliminary data from human studies (preferably published in the literature) using a similar intervention in a similar patient population to the one proposed in the current study. 

Preliminary Data About the Intervention: 

The following preliminary data from previous human studies (from published literature or the team’s previous research) on a similar intervention and in a similar patient population and age group as proposed in the current application are required: 

• Demonstration that an intervention similar to the one proposed in the trial is well tolerated (does not produce frequent severe adverse events) in pilot human studies. 
• Pilot multi-site feasibility data on a similar intervention in a clinical population similar to the one that will be studied in the proposed trial (e.g., a proposed study to examine vinyasa yoga in adults with anxiety may cite pilot work on hatha yoga in a population of adults with depression and anxiety) 
  • Demonstrated adherence and fidelity (e.g., cite a pilot multi-site study of a similar duration with sufficient adherence and fidelity to the intervention across sites/instructors). 
  • Demonstrated retention of participants for a similar study duration (e.g., cite a pilot multi-site study that retained a sufficient percentage of participants at the primary outcome time point). 
• Demonstration that the primary outcome is a valid measure for the proposed condition and population 
• Information to justify the selection of how the intervention is delivered (e.g., format of delivery, duration of individual intervention, frequency of delivery, and timeline of intervention delivery to achieve clinical benefit) in the study. For example, the intervention could be delivered as a single 30-minute session once a week for 8 weeks, or as self-paced 5-minute modules over 10 weeks. Preliminary data should demonstrate that the selected doses are feasible and likely to have the greatest impact on clinical outcome and minimize the risk of adverse events. 
• For applications that include a natural product as part of a multi-component intervention, the application must provide published data that the formulation of the natural product proposed has demonstrated efficacy for the condition being studied from at least one fully powered placebo-controlled trial. 

Preliminary Data about the Team: 

In addition, all of the following preliminary data demonstrating the team’s collective experience conducting clinical trials are required: 

• Delivered a similar intervention via the same delivery mode in a clinical trial with fidelity across multiple sites. 
• Successfully recruited and accrued similar participants across multiple sites. 
• Successfully randomized participants to similar intervention and control conditions across multiple sites. 
• Achieved adherence to a similar intervention study protocol by research staff across multiple sites. 
• Retained participants for a similar study duration across multiple sites. 
• Completed collection of follow-up data with consistency and minimal missing data across multiple sites. 
• Published results from previous completed trials across multiple sites. 

Experimental Approach: A summary of the proposed multi-site efficacy, effectiveness, or pragmatic trial protocol should be presented in the Research Strategy and should include the items listed below. 

• A summary of the proposed efficacy, effectiveness, or pragmatic trial protocol should be presented in the Research S trategy and should include the items listed below.   
• A rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), and participant follow-up procedures.  
• A description of why the target population is an appropriate group to address the proposed hypotheses and how or if results will generalize to a broader population.  
• A description of the mind and body or multicomponent intervention to be tested including elements of the intervention, proposed methods of assessing fidelity of intervention delivery and intervention performance, time duration of delivery (for clinician provided interventions) or participant practice (in group or individual/home settings), and frequency of delivery or practice.  
• A description of the required training and/or licensure/credentialing of individuals providing the intervention across proposed site(s) if necessary.  
• A summary of the necessary agreements for the delivery of the intervention and comparison intervention by given clinicians or appropriately trained/certified instructors at given facility(ies)  
• A description and justification for assessments, including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes. Use of patient reported outcomes, including those available through the Patient-Reported Outcomes Measurement Information System (PROMIS), NIH Toolbox, and Quality of Life in Neurological Disorders (NeuroQoL), as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) need to be described. A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided.  
• Investigators should utilize instruments validated in multiple languages representing the diversity of their participant population. 
• A description of the commitment to engagement of the clinical community that will play a critical role in the recruitment, retention, and overall conduct of the clinical trial, including how this clinical trial will be prioritized in the context of other, overlapping clinical research.  
• Discussion of potential challenges expected in implementing the trial and how these might be overcome.  
• Contingency plans if the effect size or event rate is underestimated.  
• A timeline, which could be provided as a table or graph, for reaching important study milestones such as: (a) obtaining regulatory approval of the final protocol; (b) establishing agreements with participating partners, if relevant; (c) finalizing the study procedures and training participating clinical site staff; and (d) starting enrollment and completing all subject follow-up and data collection activities.  
• A description of the strategy for timely publication and dissemination of results.  

Investigators should check https://reporter.nih.gov/ and https://clinicaltrials.gov/ to provide justification that the work proposed is not duplicative of completed or ongoing trials. Applicants should not propose work that duplicates other studies already funded or other trials that are underway using a similar intervention in a similar population.  

For applications that propose the use of an app or clinical decision support software, applicants must consult with their Institutional Review Board to determine whether the approach may qualify as a medical device. If so, or if in doubt, applicants should contact the FDA prior to applying to determine whether an IDE application is necessary for the proposed clinical research (https://www.fda.gov/medical-devices/software-medical-device-samd/your-clinical-decision-support-software-it-medical-device).  

Letters of Support: 

Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided from all participating sites. 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 cosigned by the business official of the collaborating center. 

If parts of the costs of the trial are to be provided by sources other than NCCIH, provide Letter(s) of Support signed by an authorized representative. 

In addition, if utilizing a natural product as part of a multicomponent intervention, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; the supplier will meet CMC specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH policies and FDA regulations. Documentation should include a letter of agreement from the 3rd party supplying the natural product. 

For renewal applications, a summary of progress made during the initial funding period must be included.

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.

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

All instructions in the SF424 (R&R) 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 SF424 (R&R) 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 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.

Section 2 - Study Population Characteristics 

2.4 Inclusion of Women and Minorities 

Describe strategies for outreach to minorities and women. 

2.5 Recruitment and Retention Plan 

Describe the following: 1) the planned remote recruitment methods, including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants. Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan policy (https://nccih.nih.gov/grants/policies/SARP). 

Applicants must provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations. Documentation of availability of eligible subjects at clinic sites, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the clinical study or trial. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information must be provided for each participating site. 

2.7 Study Timeline 

Include a table or graph of the overall study timeline. This is expected to be a visual representation (such as a Gantt chart) of core milestones and key project management activities. A narrative is not expected in this section. 

The CCC and DCC are expected to provide the same overall study timeline to reach the same major milestones. The study timeline should include core milestones that need to be met throughout the lifecycle of the clinical trial (to include both the UG3 and UH3 phases) to ensure its success, and the subtasks that will be used to reach the milestones. It is expected that the overall timeline will clearly indicate which subtasks will be performed by the CCC and which subtasks will be performed by the DCC. In the timeline, the study duration is expected to be displayed in months. The timeline should include, but is not limited to, the following: 

(a) When the study opens to enrollment 

(b) When core milestones (see below) are met  

(c) What subtasks are needed to reach the core milestones 

(d) When final transfer of the data to the DCC will occur 

(e) When analysis of the study data will occur 

(f) When the primary study manuscript will be submitted for publication 

Section 3 - Protection and Monitoring Plans 

3.3 Data and Safety Monitoring Plan 

In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) , as well as the NCCIH Guidelines for Data and Safety Monitoring (http://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. NCCIH will determine if the DSMB will be appointed and established by NCCIH or by the Investigator team, in accordance with NIH and NCCIH policies.  The initial DSMB or Protocol Review Committee meeting is during the UG3 phase, and the DSMB will review the awardee’s protocol and potentially recommend modifications. The DSMB should approve the protocol prior to submitting it to the single IRB. Subsequently, the DSMB will monitor and review study recruitment and retention as well as other study information including adverse events, unanticipated problems, demographic trends, 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, the DSMB’s 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 once a year, generating a recommendation for study continuance, alteration or stopping.  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. 

3.5 Overall Structure of the Study Team 

Include a description of the following: 

• The role of the Executive Committee and Steering Committee as well as any internal or external advisory committees 
• The oversight, responsibilities, communication with, and coordination of any sites or cores proposed 
• The role of any sub-contractors or providers of services, personnel, or facilities 
• How these functions will integrate with the organizational framework described in the collaborating DCC application 
• How the CCC and DCC will coordinate leadership for clinical trial implementation and communications 
• The coordination between the separate components and NCCIH 
• Key channels used to reach and inform each stakeholder group and receive feedback 
• How disputes among the CCC, DCC, and all stakeholders will be resolved 

Section 4 - Protocol Synopsis 

4.1.a. Detailed Description 
Describe the protocol to be followed in each arm of the trial. Include a brief description of how the CCC will standardize and optimize adherence to the protocol at the sites. Specify concomitant interventions, if applicable. Describe the proposed experimental design, including a discussion of the clinical trial design and the rationale for the particular design chosen (pragmatic, explanatory, cluster-randomized, adaptive, etc.). 

4.1.c Interventions 
Describe the rationale for the choice of the intervention including such specific information as dose, period of administration, choice of formulation, device specifications, and key characteristics of other forms of proposed approaches such as diagnostic tests and behavioral interventions. 

4.3 Statistical Design and Power 
Include a brief statement indicating that the CCC has worked closely with the DCC to ensure that the number of expected subjects, the expected effect size, the power (minimum of 90 percent), and the statistical methods (with respect to each outcome measure) have been adequately addressed. In addition, clearly state that the Statistical Design and Power attachment is being submitted in its entirety as a part of the collaborating DCC application. 

4.5 Will the study use an FDA-Regulated intervention? 

4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status 

If the proposed clinical trial will use a device, natural product (such as a botanical, herbal, dietary supplement, probiotic, vitamin, or mineral), or drug, this attachment should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial and associated timeline. For trials using an FDA-regulated product that requires an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with the FDA. If the protocol is conducted under a non-U.S. regulatory agency, the applicant should submit a plan for attaining regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided as part of the PDF file attachment. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease, it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed clinical trial, the IND must be submitted to the FDA with no clinical hold imposed by the FDA prior to the application being funded. 

4.7 Dissemination Plan 
The information provided for Dissemination Plan must be the same as that provided in the collaborating DCC application. 

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 cooperative agreement application. Attachments permit expansion 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 demonstrate Key Personnel experience in trial coordination in the last 5 years. One table must be provided for each study record with a unique filename for each study record as an attachment (e.g., "Clinical Trial Experience1.pdf", "Clinical Trial Experience 2.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) was/were completed on schedule or not 
• Publication reference(s) 

2. Milestone Plan 

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

The plan should describe the key milestones that need to be met throughout the lifecycle of the clinical trial (UG3 and UH3 phases) to ensure its success, the processes that will be used to reach the milestones, and a timetable identifying when each of these key milestones will be met (this can be provided as a table or a graph). 

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. UH3 milestones should address overall recruitment and retention goals. The Terms and Conditions for a UG3 award under this NOFO will include a milestone plan that is mutually agreed upon by the investigators and NCCIH. 

CCC milestones of particular interest during the UG3 phase that should be described in the application may include but are not limited to: 

• Successfully complete pilot vanguard study and meet benchmarks, if applicable 
• Complete finalized clinical protocol approved by NCCIH and Protocol Review Committee/DSMB 
• Final informed consent form(s) and, if applicable, assent forms 
• Agreements in place for product supply or trained intervention providers 
• Comprehensive laboratory plan 
• Pharmacy/laboratories identification (as applicable) 
• Contracts/Third Party Agreements (if applicable) 
• Training plan for clinical sites 
• Final Management/Communication Plan 
• Final Data and Safety Monitoring Plan (DSMP) 
• Site Performance Plan 
• Data Completeness and Quality Monitoring Reporting Plan 
• Completion of regulatory approvals 
• Single IRB approval for clinical sites with reliance agreements established 
• Submission of UH3 transition request 2 months prior to the requested transition date 

The application should also include a series of milestones for the completion of the specific aims of the clinical trial (UH3) phase and contingency plans. Milestones for the UH3 phase may need to be revised and finalized at the time of the UG3/UH3 transition. Investigators and NCCIH will review and mutually agree upon a final revised UH3 milestone plan that will be included in the Terms and Conditions of the UH3 grant (if awarded). CCC milestones of particular interest during the UH3 phase that should be included in the application include but are not limited to: 

• Target dates for enrollment of 10, 25, 50, 75 and 100 percent of the projected recruitment for all study participants, including women, minorities, and children (as appropriate) 
• Assessment of site(s) protocol implementation performance and fidelity of intervention delivery 
• Collection of data related to primary and secondary endpoints and database lock 
• Submission of primary manuscript to peer-reviewed scientific journal 
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date 
• Data Management and  Sharing plan for study data and biospecimens (if applicable) 

During the award phase, achievement of each milestone for the UG3 and UH3 phases will need to be communicated to the NCCIH Program Officer listed on the Notice of Award. Award continuation, even during the period recommended for support, is conditional upon satisfactory progress. If, at any time, recruitment, as defined in the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP), falls significantly below projections, or core milestones mutually agreed upon by the PD/PI and NCCIH, are not met, the Center may consider ending support and negotiating an orderly phase-out of the award. NCCIH retains the option of periodic external peer review of progress. NCCIH staff will closely monitor progress at all trial stages, including milestones, accrual, and safety. 

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

PHS Assignment Request Form

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 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:

• For trials using an FDA regulated product and requiring an IND application, the applicant must either hold or be able to reference an open IND for the trial, or the applicant must obtain an IND with no clinical-hold from the FDA prior to any award. The details of the IND status of the natural product should be provided in the attachment included in the study record for section 4.6. If the FDA has granted a waiver for either trial proposed in the application , then the applicant can provide this letter as part of the response to item 4.6 in the study record. If the protocol is conducted under a non-US regulatory agency, then equivalent determinations and documentation must be provided to NCCIH prior to a grant award. Funding will not be made until the necessary regulatory approvals are in place for the conduct of the proposed clinical trial. If the product to be studied is on the Drug Enforcement Agency (DEA) controlled substance list, the applicant must describe the DEA license and registrations necessary to complete the proposed trial. Again, no awards will be made until all necessary DEA licenses and registrations are in place. 
• 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 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 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 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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive 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 jessica.mcklveen@nih.gov when the application has been submitted. Please include the NOFO 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. 

This policy applies when the combined budget for the collaborative DCC and CCC applications exceeds $500,000 in direct costs in any year (https://nccih.nih.gov/grants/policies/over500k-clinical-trials). 

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described 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 CCC Milestone 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).  
• Updates to section 4.6 on communications with the FDA in regard to IND/IDE requirements   
• Revised CCC 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). 

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. 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 withdrawn before review. Applications must include clinical experience table as attachment. Applications that fail to include clinical experience table will be considered incomplete and will be withdrawn.

Section V. Application Review Information

1. Criteria

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

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

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 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. 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 as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

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

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

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

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

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

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

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

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

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

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to 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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) 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 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 reside 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: 

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. 

Establishing 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. 

Working with the DCC to implement the core data collection method and strategy. 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. 

Working with the DCC to establish 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  

Sharing data, resources and software according to the approved sharing policies for NIH. 

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." 

Submitting a detailed transition request for the UH3 phase 2 months before the end of the UG3 phase, outlining UG3 progress and how negotiated UG3 Milestones have been met, as well as detailed plans, budget and annual milestones for the UH3 phase. Note that funding of the UG3 phase cooperative agreement does not guarantee support of 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 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. 

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. 

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 patients 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 therecipient 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 staff will conduct an administrative review of the UH3 transition request to determine whether the project will transition to UH3 funding. Criteria for transition to the UH3 phase used in the NIH administrative review include successful achievement of the UG3 milestones, potential for successfully meeting the UH3 implementation phase plans and milestones, demonstrated ability of the team to work within the consortium arrangement, and the availability of funds. 

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. NCCIH 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. The DSMB is expected to regularly review study progress, participant safety, the quality of accumulating data, and interim data. The DSMB will provide recommendations to NCCIH.  The study team will provide periodic data reports, as requested, to the DSMB

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 recipient '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.

• When multiple years are involved, recipient s will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
• Recipient s 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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (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 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

Elizabeth Ginexi, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-827-0160
Email: elizabeth.ginexi@nih.gov

Jessica McKlveen, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-8018
Email: jessica.mcklveen@nih.gov  

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 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.