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 nutritional therapeutic inputs (often called natural products). Promising natural products (i.e. botanicals, probiotics, and products marketed as dietary supplements) have compelling preclinical or preliminary clinical evidence for potential health benefit. For this notice of funding opportunity (NOFO), natural products include promising nutritional regimens that standardize the amount of a specific naturally occurring nutritional compound (e.g., omega-3 fatty acids, anthocyanidins, or polyphenols) and have compelling preliminary evidence suggesting potential benefit in treating a condition, disorder or disease.

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

Clinical trials of natural products are maximally informative if they incorporate well-formulated hypotheses built on a sound foundation of basic mechanistic and pharmacologic understanding. The first step in clinical trials of natural products is to demonstrate that the intervention exerts a measurable effect on a hypothesized “target” or mechanism of action rather than just focusing on demonstrating a change in clinical symptom(s). “Target engagement” refers to verification that the intervention has had the predicted effect on the target. Targets may be molecular, cellular, circuit, biological, tissue, organ, somatic, psychological, behavioral, or interpersonal. Following the initial demonstration of target engagement, the next step of novel intervention development involves replicating target engagement and evaluating whether intervention-induced changes in the target are associated with clinical benefit. In some cases, a fundamental understanding of a given natural product’s biologic target, or mechanism of action has been clearly established (e.g., compound’s affinity for a specific receptor is well established). It is also recognized that for certain conditions (e.g., pain), demonstrating target engagement may not be possible or practical with human participants. When a mechanism of action has already clearly been established or when measuring target engagement is not possible, investigators should contact a Program Officer at NCCIH to discuss what funding mechanism is appropriate.

There is a need to determine whether natural products are safe and efficacious or effective for given conditions or disorders. To accomplish this goal, multi-site 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 for the trial and the companion U24 funding mechanism to support the independent Data Coordinating Center (PAR-24-313) 

Overview of NCCIH Natural Products 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 demonstrating reproducible impact on a target engagement measure, through high impact efficacy trials (https://www.nccih.nih.gov/grants/funding/clinicaltrials). We encourage investigators to examine the full suite of natural product research 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 for clinical research.        

Prior to submitting and 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 Multi-Site Investigator Initiated Clinical Trials of Natural Products

NCCIH requires companion applications to support a CCC and DCC for multi-site investigator initiated clinical trials to test the efficacy or effectiveness of natural products. The CCC and DCC will need to collaborate closely to develop the study protocol and select the most rigorous trial design. The CCC should have clinical content expertise to conduct the proposed intervention for a  study population and is responsible for implementing the proposed multi-site clinical trial. The DCC should have 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 of the CCC (i.e., 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 invites cooperative agreement applications for investigator-initiated fully powered multi-site, efficacy or effectiveness clinical trials (Phase III and beyond) to study the effects of natural products in NCCIH designated areas of high research priority. The CCC should develop and implement the proposed multi-site 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 efficacy trials do so under more controlled conditions. The trial design should be appropriate for the study question.

For this NOFO, multi-site clinical trials are defined as trials that enroll research participants 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 NIH diversity and inclusion requirements for a phase III clinical trial. Multiple sites are necessary in efficacy trials to increase generalizability of findings, and assure adequate number and diversity of eligible participants to enhance recruitment efforts.  

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 and a companion Data Coordinating Center (DCC) NOFO (PAR-24-313). Both a CCC application and a corresponding DCC application need to be submitted simultaneously for consideration by NCCIH.

Considerations for Selection of Study Design and Power

The choice of study design (e.g., standard efficacy, effectiveness, and/or pragmatic randomized control trial) should be justified scientifically. Investigators may propose fully powered adaptive designs or optimization designs, depending on their research question. The natural product UG3/UH3 NOFO supports multi-site clinical trials (Phase III and beyond) and is appropriate once there is sufficient data on a natural product’s mechanism of action, dosing and safety, and optimal study processes and/or outcomes assessments to facilitate successful implementation of a fully-powered efficacy trial. The proposed multi-site clinical trial is expected to 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 (see https://grants.nih.gov/policy/clinical-trials/glossary-ct.htm and https://grants.nih.gov/policy/inclusion/women-and-minorities.htm). 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 wait-list comparator condition. 

Target Engagement Measures

There are often questions about whether efficacy, effectiveness, or pragmatic trials should include the target engagement measures previously demonstrated. Mechanistic outcomes should be included in trials submitted to this NOFO to assess whether the effect of the natural product is mediated or moderated via the target engagement measures proposed. The inclusion of target engagement measures 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).

Regulatory Requirements to Consider:

The U.S. Food and Drug Administration (FDA) establishes and enforces the regulatory requirements for clinical research on natural products when they may be used as drugs. Because NCCIH is a Federal agency, any research supported with NCCIH funding must adhere to relevant FDA regulations. Prior to submitting an application Investigators must contact the FDA to determine whether an Investigational New Drug (IND) application is necessary for the proposed clinical research. 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 prior to any award. If the FDA has granted a waiver for the trial proposed in the application, the applicant can provide this letter as part of the Regulatory Communication Plan. Guidance on the IND evaluation process can be found in the NCCIH Natural Products Clinical Trials web page: Resource https://www.nccih.nih.gov/grants/natural-products-clinical-trials-resource.

For applications that propose the use of a mobile device, similar 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, 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). 

Preliminary Data Requirements:

This NOFO is appropriate when there is a clear and compelling rationale, a rigorous empirical basis, and scientific premise to conduct a natural product multi-site efficacy or effectiveness clinical trials. The following preliminary data from human studies (published and citable data from the peer-reviewed literature) on the same natural product and specific formulation as proposed in the current application are required:

• Demonstration that the natural product can produce a clinically meaningful and measurable change in target engagement (e.g., mechanism of action) in the human population of interest. There must also be evidence that the change in target engagement has been replicated in a separate human study with the same natural product to be used in the proposed project, unless it is impossible or impractical to do so or when a mechanism of action has been clearly established.
• Evidence that the specific natural product is bioavailable in humans. Note that for prebiotics or probiotics this may be demonstrated by documenting short-term retention in the gastrointestinal tract.
• Information to justify the selection of the dose(s) of the product proposed to be used in the study. Data should demonstrate that the selected doses are likely to have the greatest impact on target engagement and minimize the risk of adverse events.
• Evidence that evaluates the pilot study data for strength of correlation between the impact on target engagement and changes in the clinical outcomes that will be studied in the proposed clinical trial.
• Pharmacokinetic (PK) data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and demonstrate initial safety of the product. PK studies are not required for natural products that do not require absorption for their intended effect (e.g. prebiotics and probiotics).
• Evidence that the natural product does not produce frequent or severe adverse events in human pilot trials.
• For applications that include a mind and body approach as part of a multi-component intervention, the application must provide published data that the mind and body intervention proposed has demonstrated efficacy for the condition being studied from at least one fully powered controlled trial.

For the purposes of this NOFO, it is preferred that there be an established, measurable, reproducible, well-characterized target engagement measure for a given natural product in human subjects. However, NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the target engagement on a natural product. In these circumstances the study should be justified by: (1) a clear rationale for why studying target engagement in human participants is impossible or impractical; (2) potentially proposing other objective, reproducible measures, that may be proxy to, or indicative of target engagement of the natural product; and (3) strong compelling preliminary data to warrant further study of a natural product in clinical studies. In other cases, a fundamental understanding of a given natural product’s biologic target, or mechanism of action has been clearly established (e.g., compound’s affinity for a specific receptor is well established). In these situations, investigators are also encouraged to contact NCCIH Scientific/Research staff to determine whether the UG3/UH3 is the appropriate NOFO for the proposed clinical 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 across multiple sites.
• Successfully recruited and accrued similar participants across multiple sites.
• Successfully randomized participants across multiple sites.
• Achieved adherence to a similar 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 one year (UG3) and a full enrollment and clinical trial execution phase (UH3). There should be clear objectives for both a UG3 and a UH3 phases.

Phases of Award

The UG3 phase will support the development of case report forms and other resources necessary to the performance of the trial; further development and finalization of study partnerships including signed contracts with performing clinical sites; single Institutional Review Board approval as well as Data and Safety Monitoring Board approval of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. Applications are required to provide a clinical trial project management plan that delineates how the study will monitor and evaluate critical processes impacting feasibility of trial launch, conduct, and completion, coupled with on-time and on-budget performance milestones. All regulatory approvals should be obtained prior to the end of the UG3 award. Provision of the necessary natural products, matched placebos, or other resources 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.

Investigators will be asked to submit their UH3 phase transition application 2 months prior to transition, so the majority of UG3 phase milestones should be completed 2 months prior to transition to the UH3 phase. All milestones must be achieved prior to transition to the UH3 phase. Continued support for both the DCC and CCC will be contingent on the extent to which agreed-upon milestones have been met in the first year and on the availability of funds and scientific priorities to continue the project.

Milestones

The use of milestones is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Plans must be guided by milestones that will be reached at the end of the UG3 phase. Milestones are to be objective and performance-based to achieve completion of the trial on time and on budget (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.

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

NCCIH Priorities for Developing and Pilot-testing Natural Products 
As NCCIH’s clinical research portfolio matures, NCCIH has identified targeted areas of investigation to align with the NCCIH Strategic Plan (https://www.nccih.nih.gov/about/strategic-plans-and-reports). Focus is on management of conditions for which natural products are used by the public and where there is evidence of postulated mechanism of action. For this NOFO, NCCIH considers the following topic areas to have high program priority: 

• Symptom management, particularly the use of natural products for sleep disorder/disturbance, management of pain conditions, common gastrointestinal disorders, post-acute sequelae SARS-CoV-2 infection (PASC), or mental health conditions such as those commonly managed in primary care (e.g., chronic stress, depression, anxiety disorders, and post-traumatic stress). 
• Studies that examine the effects of prebiotics/probiotics and other natural products on gut microbiome-brain interactions. Of particular interest are studies of prebiotics/probiotics for depression, anxiety disorders, irritable bowel syndrome (IBS), or chronic pain. 
• Studies that examine the effects of cannabinoids and terpenes in conditions noted above. 
• Studies that examine the effects of naturally occurring psychedelics and entheogens in conditions noted above 
• Studies that address minority health and reduce disparities in conditions noted above. 
• Studies that examine the effects of natural products to address comorbidities, coinfections and/or complications from HIV (https://abs2.od.nih.gov/Docs/NIH_StrategicPlan_FY2021-2025.pdf) 
• Trials that examine the effects of natural products across the continuum of background dietary intake
• Trials that evaluate whether nutritional status moderates target engagement or clinical outcomes

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/humansubjects/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 the 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).    

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. 

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. Applications that do not address dietary intake and nutritional status when appropriate will also be deprioritized.

Clinical Trials Not Responsive to this NOFO

The following types of clinical trials are not responsive to this NOFO and applications proposing such activities will be deemed non-responsive and will not be reviewed:

• Studies that are geographically limited (e.g., recruiting from only one city or region).
• Studies that do not have a primary aim to assess clinical efficacy of the natural product.   
• Fully remotely delivered clinical trials
• Trials that do not include a natural product or standardized nutritional regimen
• Trials utilizing a natural compound that has been synthetically modified (e.g., conjugates, derivatives, or pro-drugs)
• Studies that propose a waitlist control
• Animal studies
• Trials that propose to test natural products 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)

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

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

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

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

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the 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 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

This NOFO only accepts applications that are part of a collaborative set of multiple applications. A set must contain 2 applications, 1 UG3/UH3 application to this NOFO TEMP-26943 and 1 U24 application to TEMP-27798.

Applications with Foreign components are encouraged to read the NCCIH International Health Research page. Foreign components can include foreign collaborators or consultants, but should not include foreign sites outside of the United States 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: [email protected] 

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

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

Descriptive Title of Applicant's Project:

To allow NIH to identify a group of applications as a related set of collaborative applications, the titles for each application in the set must have the following format: a “1/N” indicator + Identical Title (e.g., “1/2”, where the 1/2 means this is site 1 of the clinical coordinating center of the set. The data coordinating center site will be labeled 2/2). Titles may not exceed 200 characters in length, including the tag, e.g., 1/2, 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 site should submit an identical listing. If applicable, the letter should indicate the name of the NCCIH program officer with whom the project has been discussed.

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

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

Project Management Plan Attachment:

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 lead to the 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 (PEDP)

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

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

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

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

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex.
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex.

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

SF424(R&R) Senior/Key Person Profile

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

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

The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of clinical trials and have expertise in the content area of the trial, as well as experience conducting trials under an FDA IND. The experience of all key personnel must be carefully documented. Most clinical trials will require a multidisciplinary team (clinician, data manager, study coordinator(s), etc.) and the application should reflect their roles and responsibilities in the design and implementation of the study protocol. 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 How to Apply- Application Guide must be followed.

PEDP implementation costs:

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

R&R Subaward Budget

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

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.  An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, the NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by the NCCIH and budget support for the DSMB will be provided by NCCIH.

Separate itemized budgets must be prepared for each subcontract and/or for each collaborating clinical site or core .

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy

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

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

The following criteria must be addressed:

Importance of Research: The significance and innovation of the proposed clinical trial and importance of the question must be clearly stated. 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 our 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 the required 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. 

Explain how innovation influences the importance of undertaking the proposed research and how the application applies novel concepts, methods or technologies or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Rigor and Feasibility: The research approach section should include a description of the supporting data (including strengths and weaknesses of the published literature), clinical trial experience, the experimental approach, and a milestone plan.

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

Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies that show the need for and the feasibility of the trial should also be presented in the application. 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 of the same product and specific formulation as proposed in the current application (preferably published in the peer-reviewed literature):

1. Demonstration that the natural product can produce a clinically meaningful and measurable change in target engagement (e.g., mechanism of action) in the human population of interest. There must also be evidence that the change in target engagement has been replicated in a separate human study with the same natural product to be used in the proposed project, unless it is impossible or impractical to do so or when a mechanism of action has been clearly established.
2. Evidence that the specific natural product is bioavailable in humans. Note that for prebiotics or probiotics this may be demonstrated by documenting short-term retention in the gastrointestinal tract.
3. Information to justify the selection of the dose(s) of the product proposed to be used in the study. Data should demonstrate that the selected doses are likely to have the greatest impact on target engagement and minimize the risk of adverse events.
4. Evidence that evaluates the pilot study data for strength of correlation between the impact on target engagement and changes in the clinical outcomes that will be studied in the proposed clinical trial.
5. Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and demonstrate initial safety of the product. PK studies are not required for natural products that do not require absorption for their intended effect (e.g. prebiotics and probiotics).
6. Evidence that the natural product does not produce frequent or severe adverse events in human pilot trials.
7. For applications that include a mind and body approach as part of a multi-component intervention, the application must provide published data that the mind and body intervention proposed has demonstrated efficacy for the condition being studied from at least one fully powered controlled trial.

If it is impractical/impossible to measure the impact of the natural product on target engagement or when there is a fundamental understanding of the product’s mechanism of action, such that it is not possible to provide item 1, applicants must provide the following:

• Justification for why studying target engagement in human participants is impossible or impractical;
• Consider proposing other objective, reproducible measures, that may be proxy to, or indicative of target engagement for the natural product;
• Provide strong compelling preliminary data to warrant further study of a natural product in clinical studies

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 across multiple sites.
• Successfully recruited and accrued similar participants across multiple sites.
• Successfully randomized participants across multiple sites.
• Achieved adherence to a similar 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: The proposed experimental approach should include an appropriate design and the rationale for the particular design chosen (e.g. explanatory, cluster-randomized, pragmatic). The experimental approach description should include:

• A rationale of why the study population is the most appropriate group to answer the question, and how or if results will generalize to a broader population.
• A rationale for the research hypothesis(es), methods of randomization, primary and secondary outcome measures, intervention(s), measurement of the replicable target engagement of the natural product, and participant follow-up procedures.
• A rationale, including supporting data, for the natural product to be tested including: dose and frequency of dosing to be used, name and ingredients of the product, rationale for the supplier, proposed methods for product characterization and standardization, and rationale for selection of and specified percentages or levels of marker compounds if applicable. See the NCCIH Policy on Natural Product Integrity for more information (https://nccih.nih.gov/research/policies/naturalproduct.htm).
• A discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. 
• A summary of the necessary agreements for the use of the natural product in the study, including clinical research agreements and licensing agreements must be executed prior to grant award. A timeline should be included in the application showing activities with third parties such as: 1) executing necessary agreements, 2) providing natural product and matching placebo, and 3) permission to reference an open IND drug master file (if available).
• A description of the commitment to engagement of the clinical community that are playing a critical role in the recruitment, retention and overall conduct of the clinical trial including the prioritization of this clinical trial in the context of other overlapping clinical research.
• A justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. 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 discussion of potential challenges in implementing the research protocol and how they will be addressed.
• 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. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating center.

In addition, 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 Chemistry Manufacturing and Controls (CMC) specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.

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.

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 How to Apply- Application Guide.

Other Plan(s): 

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

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

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics 

2.5 Recruitment and Retention Plan

Describe the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants; Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (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 a data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (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. As part of the collaborative activities under this cooperative agreement, the NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by the NCCIH. At the first meeting in the UG3 phase, the DSMB will review the awardee’s protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. Thus, its ethical responsibilities, to the participants as well as to the integrity of the study, are of paramount importance to the NCCIH. The DSMB will meet in person or by phone at least twice a year. Applicants should not propose DSMB members in the application, or even inquire about the interest of possible DSMB members, because anyone so contacted would not be eligible to serve as a member of the peer reviewer committee that will evaluate the applications for scientific merit. For renewal applications, applicants should provide a list of the DSMB members in the application.

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, frequency of dosing to be used, choice of formulation, name and ingredients of the product, rationale for the supplier, proposed methods for product characterization and standardization, and rationale for selection of and specified percentages or levels of marker compounds if applicable.

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

The proposed clinical trial must use a natural product (such as botanical, herbal, dietary supplement, probiotic, vitamin or mineral) for this NOFO. The attachment in this section 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 conduct the trial; and associated timeline to complete these approvals. For trials using an FDA regulated product that require an IND/IDE application, the cooperative agreement application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-US regulatory agency the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided or a copy of correspondence with the FDA indicating an IND is not required. The FDA has provided guidance indicating that when substances that are Generally Recognized as Safe (GRAS) are used in a clinical trial to evaluate the product's ability to diagnose, cure, mitigate, treat, or prevent disease it may require an IND under part 312 (https://www.fda.gov/media/79386/download). If an IND is required by the FDA for the proposed trial, the IND must be submitted to the FDA with no clinical-hold imposed by the FDA prior to the application being funded.

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", etc.) and must not exceed 3 pages.

The table columns should include:

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

2. Milestone Plan

One Milestone Plan must be provided for each study record with an unique filename for each study record (e.g. "CCC Milestone Plan1.pdf", "CCC Milestone Plan 2.pdf", etc.) and must not exceed 5 pages.

The plan should describe the key milestones that need to be met throughout the lifecycle of the clinical trial (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:

• Complete finalized clinical protocol approved by NCCIH and Protocol Review Committee/DSMB
• Final Informed consent(s) and, if applicable, assent forms
• Agreements in place for product supply
• 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
• Final Study Accrual and Retention Plan
• Site Performance Plan
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• sIRB 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% of the projected recruitment for all study participants, including women, minorities and children (as appropriate)
• Assessment of site(s) protocol implementation performance
• 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

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 the NCCIH, are not met, the Center may consider ending support and negotiating an orderly phase-out of the award. The NCCIH retains, as an option, 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 How to Apply- Application Guide must be followed.

PHS Assignment Request Form

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

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 4.5. If the FDA has granted a waiver for the trial proposed in the application, then the applicant can provide this letter as part of the response to item 4.5 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 trials in the UG3 and UH3 phases. 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

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

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

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NCCIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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 facilities and administrative) must contact a Scientific/Research Contact at least 126 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 How to Apply-Application Guide and the NCCIH policy. (https://www.nccih.nih.gov/grants/policies/nccih-policy-applications-for-large-budget-clinical-trials-over-500000-in-direct-costs-in-any-year)

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

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

Post Submission Materials

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

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 Milestones Plan (e.g. due to the hiring, replacement, or loss of an investigator; change to sites participating in the trial; or change in IT infrastructure)
• Updates to section 4.5 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).

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.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed).  An application does not need to be strong in all categories to be judged likely to have a major scientific impact. As part of the overall impact score, reviewers should consider and indicate how the Plan for Enhancing Diverse Perspectives affects the scientific merit of the project.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

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

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, consistent with applicable law.

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

Please note that reviewers will not consider race, ethnicity, age, or gender of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

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

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

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

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

2. Administrative and National Policy Requirements

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

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

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

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR 200 and other DHHS, 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.
• Provide updates at least annually on progress in PEDP implementation.  

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

• NIH will assign a Project Scientist as the point of contact to work with the PD(s)/PI(s) and participate in the Trial Management Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the recipient, although specific tasks and activities will be shared among the recipient and the NIH Project Scientist. With the agreement of the PD(s)/PI(s), the NCCIH Project Scientist or designee may assist in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and/or in the publication of results.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the notice of award.
• 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 the recipients’ 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.

Joint Responsibilities:

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

Dispute Resolution:

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

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

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

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

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

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

Debbie Chen 
National Center for Complementary and Integrative Health (NCCIH) 
Telephone: 301-594-3788 
Email: [email protected]  

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.