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 rigorous investigation of promising complementary and integrative health interventions with physical and/or psychological inputs (often called mind and body approaches), and nutritional approaches, including natural products. For the purposes of this notice of funding opportunity (NOFO), nutritional approaches include botanicals, probiotics, and products marketed as dietary supplements; mind and body approaches include meditation approaches (e.g., mindfulness), hypnosis or guided imagery, meditative movement approaches (e.g., yoga, tai chi, qi gong), body-based approaches (e.g., progressive muscle relaxation, acupressure), music or art-based therapy; or a combination of these approaches (e.g., mindfulness-based stress reduction). These approaches are often widely used by the public, and they are increasingly recognized to provide a complementary approach to symptom management (e.g., chronic pain, mild depression, anxiety). These approaches can be used by individuals to help prevent, treat, or self-manage various conditions, and they can be complementary to conventional health care. 

Overview of NCCIH Mind and Body Clinical Trials Research Funding Opportunities:

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

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

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

Overview of Remotely Delivered Interventions:

Increasingly, researchers are incorporating mobile health (mHealth) technologies to remotely deliver interventions, including complementary and integrative health interventions. These remotely delivered interventions may utilize phone delivery, app-based approaches, video delivery, web-based platforms, wearable devices, and/or new technologies. The rapid expansion of mHealth technologies makes it possible to digitally transmit participant data from remote areas to centrally based researchers and interventionists, deliver feedback, and capture all interactions in a database. Additionally, these mHealth technologies have the potential to improve and increase access to complementary and integrative health approaches to address existing health disparities and promote health equity. 

Many commercially available mHealth complementary and integrative health approaches already exist. However, rigorously designed research is needed to test the usefulness and safety of remotely delivered complementary and integrative interventions for given conditions/disorders and/or for health promotion. For clinical trials to address this need, they must be well-designed and appropriately powered to test clinically relevant hypotheses. To that end, before proposing an efficacy or effectiveness clinical trial, it is necessary to conduct early-phase clinical trials to collect the multiple types of preliminary feasibility data needed to rigorously design a definitive clinical trial.  Applications submitted under this NOFO would be appropriate when there is a clear and compelling rationale, a rigorous empirical basis, strong feasibility and safety data, and scientific premise to conduct a fully powered remotely delivered efficacy, effectiveness, or pragmatic clinical trial. 

Research Objectives of Remotely Delivered mHealth Complementary and Integrative Health Interventions (R01):

This NOFO supports remotely delivered clinical trials (e.g., efficacy, effectiveness or pragmatic trials) to study the effects of complementary and integrative health interventions in NCCIH-designated areas of high research priority. 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 conditions in which it will be applied in the ‘real world' while explanatory trials do so under more idealized circumstances. For example, pragmatic trials may employ interventions that would not require research staff to interact directly with participants, such as clinician decision support tools embedded in the electronic health record, system changes within the health care system, or when complementary interventions are implemented and delivered within the health care setting. The trial design should be appropriate for the study question.  

Study Design Considerations: 

For this NOFO, the proposed trial must study an intervention that can be delivered in a fully remote manner, and all data collected remotely (i.e., no in-person contact between research staff and study participants). The application should propose to recruit a representative sample for the population and condition of interest, and to conduct all study activities, including recruitment, intervention delivery, and data collection, remotely. The proposed remotely delivered clinical trial should utilize methods that allow for the participation of geographically diverse participants (e.g., not limited to a single city or location). Applications to this NOFO should be based on a strong rationale for the need of a fully remotely delivered design as opposed to a multi-site in-person clinical trial. Trials supported under this NOFO are expected to contribute to research topics relevant to the mission of NCCIH and be designed with a minimum of 90-percent power to test the primary hypothesis.  The choice of study design (e.g., standard efficacy, effectiveness, and/or pragmatic randomized control trial) should be justified scientifically. In all cases, there should be strong rationale for the proposed comparator condition(s) (e.g., time and attention control, usual care, standard of care, sham condition, and/or active comparator(s)) based on the research question you plan to address. Due to lack of rigor and potential expectancy effects, NCCIH will not support studies proposing a waitlist comparator condition. 

Group-Based Interventions:

In some cases, investigators who wish to evaluate the effect of an intervention on a health-related biomedical or behavioral outcome may propose a study in which (1) groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention, or (2) participants are assigned individually to study arms but receive at least some of their intervention in a real or virtual group or through a shared facilitator. Investigators should provide a strong rationale for the choice among trial design options. The selection of study design should be guided by decisions about how best to deliver the intervention and by concerns regarding contamination and logistics. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions. Additional information is available at https://researchmethodsresources.nih.gov/. 

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

The study biostatistician will need to consider how the chosen study design led to the proposed data analyses and sample size estimations. The justification should include discussion of the positive intraclass correlation expected in data obtained from participants in the same groups or clusters (IRGT, GRT, or cRCT). In general, these types of studies need to consider how the data analyses and sample size addressed the extra variation in the data and degrees of freedom available to estimate that extra variation. Failure to account for this variable in sample size calculations can result in underpowered studies.

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. 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).

For applications that propose the use of a dietary supplement, drug, or device as part of the intervention, the applicants must contact the U.S. Food and Drug Administration (FDA) prior to applying to determine whether an Investigational New Drug (IND) or an Investigational Device Exemption (IDE) application is necessary for the proposed clinical research. This NOFO will not support trials of natural products that are regulated by the Drug Enforcement Agency (DEA) as a controlled substance.

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

Mechanistic Measures

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

Preliminary Data Requirement 

Preliminary Data About the Intervention: 

This NOFO is appropriate when there is a clear and compelling rationale, a rigorous empirical basis, and a scientific premise to conduct a remotely delivered efficacy, effectiveness, or pragmatic clinical trial. The following preliminary data from previous human studies (from published literature or the team’s previous research) on a similar intervention and in a similar patient population and age group as proposed in the current application are required:

• Demonstration that an intervention similar to the one proposed in the trial is well tolerated (does not produce frequent severe adverse events) in pilot human studies.
• Pilot feasibility data on a similar intervention in a clinical population similar to the one that will be studied in the proposed trial (e.g., a proposed study to examine vinyasa yoga in adults with anxiety may cite pilot work on hatha yoga in a population of adults with depression and anxiety)
  • Demonstrated adherence and fidelity (e.g., cite a pilot study of a similar duration with sufficient adherence and fidelity to the intervention across sites/instructors).
  • Demonstrated retention of participants for a similar study duration (e.g., cite a pilot study that retained a sufficient percentage of participants at the primary outcome time point).
  • Demonstrated remote recruitment methods that meet data security standards for collecting and accessing individual-level data.
• Demonstration that the primary outcome is a valid measure for the proposed condition and population.
• Information to justify the selection of how the intervention is delivered (e.g., format of remote delivery, duration of individual intervention, frequency of delivery, and timeline of intervention delivery to achieve clinical benefit) in the study. For example, the intervention could be delivered as a single 30-minute session once a week for 8 weeks, or as self-paced 5-minute modules over 10 weeks. Preliminary data should demonstrate that the selected doses are feasible and likely to have the greatest impact on clinical outcome and minimize the risk of adverse events.
• Demonstration from pilot studies that potential adverse events can be monitored and addressed remotely.

Preliminary Data about the Team: 

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

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

Natural Products Preliminary Data:

In addition, for applications utilizing a natural product, the following preliminary data from human studies (published and citable data from the peer-reviewed literature) on the same 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 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 this NOFO is the appropriate funding opportunity for the proposed clinical trial. 

Timeline  

Investigators should design a realistic timeline for the startup and completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances to the planned trial. 

NCCIH Priorities for Clinical Trials of Mind and Body Interventions

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

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

NCCIH Priorities for Clinical Trials of Natural Products

NCCIH has identified targeted areas of high program priority for clinical trials on natural products. 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, or post-traumatic stress).
• Studies to 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 to address minority health and reduce disparities in conditions noted above.
• Studies to 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)

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

All NIH-funded research must adhere to the Code of Federal Regulations, which outlines specific requirements to enhance protections for pregnant women, human fetuses, and neonates; children; and prisoners (https://grants.nih.gov/policy/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 NIH, unless there are scientific or ethical reasons not to include them (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-18-116.html).    

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

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

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 not reviewed:

• Clinical trials with any in-person contact of research staff with research participants. 
• Studies that do not have a primary aim to assess efficacy or effectiveness of the intervention. 
• Clinical trials proposing to deliver an intervention to participants outside the United States or Canada. 
• Studies that are geographically limited (e.g., recruiting from one city or region).  
• Studies that propose a waitlist control. 
• Trials that include a natural product that is regulated by the DEA as a controlled substance.
• Trials that propose to assess efficacy or effectiveness of interventions for the treatment or prevention of cancer. (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute.) 

Plan for Enhancing Diverse Perspectives (PEDP)

 This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV).

 Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information

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

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

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

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

Plan for Enhancing Diverse Perspectives

• "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate.
• Where possible, applicant(s) should align their description with these required elements within the research strategy section
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured
• The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review

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

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

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

SF424(R&R) Senior/Key Person Profile

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

The Principal Director(PD)/ Principal Investigator (PI) (or Multi-PDs/PIs) of the clinical trial must be experienced in the conduct of remotely delivered clinical trials and have expertise in the content area of the trial. We strongly encourage that all clinical trials include a biostatistician and the application should reflect their roles and responsibilities 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 or Modular Budget

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

The budget for the first year of the grant should reflect the implementation timeline. 

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 NIH, these contributions must be presented in detail in the budget justification. Include budget support for the publication and dissemination of findings. 

The applicationshould include in their budget all costs associated with preparation of materials for DSMB meetings and travel for key personnel to all in person DSMB meetings. This includes the costs for preparing reports for open and closed portions of DSMB meetings. Budgets should include costs for unmasked biostatistician(s) for generating the randomization scheme and preparing unmasked DSMB reports in addition to the study’s masked biostatistician who will conduct study analyses at the end of the trial and prepare open reports for the DSMB. An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. 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. Applicants should provide areas of expertise of DSMB members, but 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.

PEDP implementation costs

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application must 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: 

Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. The application should make clear the need for and timeliness of the study, with emphasis on how the results will address an evidence gap and therefore advance 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.  

Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms. Describe plans to include mechanisms for leveraging novel collaboration and/or study oversight strategies. 

Approach: The research approach section should include a description of the supporting data, clinical trial experience, the experimental approach, and a milestone plan. The application should provide justification for a remotely delivered design. 

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

• Demonstration that an intervention similar to the one proposed in the trial is well tolerated (does not produce frequent severe adverse events) in pilot human studies. 
• Pilot feasibility data on a similar intervention in a clinical population similar to the one that will be studied in the proposed trial (e.g., a proposed study to examine vinyasa yoga in adults with anxiety may cite pilot work on hatha yoga in a population of adults with depression and anxiety)  
• Demonstrated adherence and fidelity (e.g., cite a pilot study of a similar duration with sufficient adherence and fidelity to the intervention across sites/instructors). 
• Demonstrated retention of participants for a similar study duration (e.g., cite a pilot study that retained a sufficient percentage of participants at the primary outcome time point). 
• Demonstrated remote recruitment methods that meet data security standards for collecting and accessing individual-level data. 
• Demonstration that the primary outcome is a valid measure for the proposed condition and population.  
• Information to justify the selection of how the intervention is delivered (e.g., format of remote delivery, duration of individual intervention, frequency of delivery, and timeline of intervention delivery to achieve clinical benefit) in the study. For example, the intervention could be delivered as a single 30-minute session once a week for 8 weeks, or as self-paced 5-minute modules over 10 weeks. Preliminary data should demonstrate that the selected doses are feasible and likely to have the greatest impact on clinical outcome and minimize the risk of adverse events. 
• Demonstration from pilot studies that potential adverse events can be monitored and addressed remotely. 

Preliminary Data about the Team: 

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

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

Natural Products Preliminary Data:

In addition, for applications utilizing a natural product, the following preliminary data from human studies on the same product and specific formulation as proposed in the current application are required: 

• Demonstration that the natural product can produce a clinically meaningful change in measurable biological signature (e.g., measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, behavioral and/or somatic changes) in the human population of interest. There must also be evidence that the change in biological signature has been replicated in a separate human study with the same natural product to be used in the proposed project. 
• 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 the biological signature and minimize the risk of adverse events. 
• Evidence that demonstrates a strong correlation between the impact of the natural product on the biological signature and changes in the clinical outcomes that will be studied in the proposed clinical trial. 
• 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 (if applicable). 

NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the impact of a natural product on a biological signature. In these circumstances, the study should be justified by: (1) a clear rationale for why studying a biological signature in human participants is impossible or impractical; (2) potentially proposing other objective, reproducible measures, that may be proxy to, or indicative of a biological or behavioral effect for the natural product; and (3) strong compelling preliminary data to warrant further study of a natural product in clinical studies. In these situations, investigators are also encouraged to contact NCCIH Scientific/Research staff to determine whether this NOFO is the appropriate funding opportunity for the proposed clinical trial. 

Conceptualization and planning must have progressed to a stage sufficient to allow for an overall assessment of the likelihood of the success of the trial. 

Experimental Approach: The proposed experimental approach should include an appropriate design and the rationale for the particular design chosen (e.g., pragmatic, explanatory, cluster-randomized). The experimental approach description should include: 

• A description 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 if applicable, primary and secondary outcome measures, intervention(s), and participant follow-up procedures. 
• A description of the required training and/or licensure/credentialing of individuals remotely providing the intervention across geographic locations if necessary. 
• A rationale for the remote-delivery mode and the complementary and integrative health intervention to be tested, including: elements of the intervention, proposed methods for assessing fidelity of intervention delivery and intervention performance, time duration of delivery (for clinician-provided interventions) or participant practice (in remote groups or individual/home settings), and frequency of delivery or practice. 
• A summary of the necessary agreements for the remote delivery of the intervention and comparison intervention by given clinicians or appropriately trained/certified instructors (if applicable). 
• A description and justification for all assessments, including clinical, laboratory, physiological, behavioral, patient centered, or other outcomes addressing the primary and secondary research questions. Remote data-collection methods should be described. 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., electronic health records, 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. 
• A description and justification of remote recruitment and consenting methods, including methods to confirm the authenticity of participants (e.g., not fictious or bot enrollees)
• A description of methods to protect participant confidentiality that meet data security standards for collecting, transferring and accessing individual-level data remotely.
• 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 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).  

Letters of Support 

Letters of support from clinicians, clinical department chairs, and/or health care systems whose support is necessary to the successful conduct of the trial should be provided (if applicable). Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants. Letters of commitment must be co-signed by the business official of the collaborating center. In addition, if utilizing a natural product, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; the supplier will meet CMC specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH 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 SF424 (R&R) Application Guide.

The following modifications also apply: 

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

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

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

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics 

2.4 Inclusion of Women, Minorities, and Children 

Describe strategies for outreach to minorities and women. 

2.5 Recruitment and Retention Plan 

Describe the following: 1) the planned remote recruitment methods, including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; and 5) possible competition from other trials for study participants; Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (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 the availability of eligible participants must be provided. The application must provide relevant information that addresses the feasibility of recruiting a representative sample of eligible participants nationwide utilizing remote methods. 

2.7 Study Timeline 

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

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The research plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. Milestones should address overall recruitment and retention goals. 

Milestones of particular interest that should be described in the application may include, but are not limited to, the following: 

• Complete finalized clinical protocol 
• Final informed consent(s) and, if applicable, assent forms 
• Agreements in place for product supply 
• Comprehensive laboratory plan (as applicable) 
• Pharmacy/Laboratories Identification (as applicable) 
• Contracts/Third Party Agreements (as applicable) 
• Training plan for study staff/interventionists 
• Final Data and Safety Monitoring Plan 
• Data Completeness and Quality Monitoring Reporting Plan 
• Completion of regulatory approvals 
• A Study Accrual and Retention Plan with target dates for percent enrollment of 10, 25, 50, 75, and 100% of the projected recruitment for all study subjects, including women, minorities, and children (as appropriate) 
• Remote 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 
• Biospecimens (if applicable) 

During the award phase, achievement of each milestone 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 Policy, falls significantly below projections, or core milestones mutually agreed upon by the PD/PI and NCCIH, are not met, NCCIH may consider ending support and negotiating an orderly phase-out of the award. 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. 

Section 3 - Protection and Monitoring Plans 

3.3 Data and Safety Monitoring Plan 

In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), as well as the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring). An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. NCCIH will determine if the DSMB will be appointed and established by NCCIH or by the Investigator team, in accordance with NIH and NCCIH policies.  The initial DSMB or Protocol Review Committee meeting will review the awardee’s protocol and potentially recommend modifications. The DSMB should approve the protocol prior to submitting it to the single IRB. Subsequently, the DSMB will monitor and review study recruitment and retention as well as other study information including adverse events, unanticipated problems, demographic trends, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim data and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. Thus, the DSMB’s ethical responsibilities to the participants as well as to the integrity of the study are of paramount importance to NCCIH. The DSMB will meet in person or by phone at least once a year, generating a recommendation for study continuance, alteration or stopping.  Applicants should not propose DSMB members in the application, or even inquire about the interest of possible DSMB members, because anyone so contacted would not be eligible to serve as a member of the peer reviewer committee that will evaluate the applications for scientific merit. 

Section 4 - Protocol Synopsis 

4.3 Statistical Design and Power

Applicants must describe the Statistical Analysis Plan (SAP). If the SAP is not a part of the DCC application, both the CCC and the DCC applications will be deemed incomplete and will not proceed to peer review. The SAP should correspond to major aims of the study, and include plans for randomization, final statistical analyses; and methods for handling missing data.The power calculations must be linked to the study endpoints and to the hypothesis(es) being tested. The power calculation description should be detailed enough to allow replication of the analysis by an independent statistician. NCCIH requires a minimum of 90% power for the primary outcome. Multiplicity adjustment should be made if there are multiple primary outcomes. The effect size used in power calculations should be clinically meaningful.

Plans for interim analyses should be described in detail and include plans to assess futility based on the inability of successfully completing the trial, due to poor enrollment or poor adherence to the intervention; conditions for early stopping due to such futility or early achievement of primary clinical outcomes; plans to assess safety; and while not common, any plans to reassess or recalculate power, or modify sample size (e.g., confirm expected event rate during the trial or confirm expected Intra-class Correlation (ICC) for cluster-randomized trials). If the application is not proposing interim analyses, the application should justify why they are not planned. For phase III clinical trials, the SAP must address plans for the analysis of intervention effect differences required by the policy unless there is clear evidence that such differences are unlikely to be seen (https://grants.nih.gov/policy/inclusion/women-and-minorities.htm). Studies with adaptive designs should include a pre-specified adaptation plan that specifies design type, adaptable element(s), clear decision rules and pre-specified statistical analysis boundaries. 

4.5. Will the study use an FDA-Regulated intervention? 

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

Section 5 - Other Clinical Trial-related Attachments 

5.1 Other Clinical Trial-related Attachments 

The following attachment must be included as a part of the 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. 

Clinical Trial Experience 

Applicants must provide a detailed table listing the characteristics of trials that demonstrate the experience of the study Key Personnel in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf" and must not exceed 3 pages. If applicants propose more than one clinical trial study and are submitting more than one study records, they must use unique file names for each study record (e.g. “Clinical Trial Experience for Study Record 1.pdf”, “Clinical Trial Experience for Study Record 2.pdf”, etc) to avoid errors uploading attachments. 

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) 

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Do not enter a delayed onset study. 

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Specific to this NOFO: 

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

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

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

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

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

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

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

Post Submission Materials

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

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

All post-submission materials must be received by the Scientific Review Officer (SRO) no later than 30 calendar days prior to the peer review meeting. 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 Milestones Plan (e.g., due to the hiring, replacement, or loss of an investigator; change to health care systems participating in the trial; or change in electronic health record or IT infrastructure) 
• Updates to section 4.6 on communications with the FDA in regard to IND/IDE requirements 

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review. Applications must include a clinical trial experience table. Applications that fail to include a clinical trial experience table will be considered incomplete and withdrawn.

Section V. Application Review Information

1. Criteria

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

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

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

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

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

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCCIH, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons. 

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

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

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

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

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Data Management and Sharing

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

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

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

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

Section VII. Agency Contacts

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

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

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

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

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

Beda Jean-Francois, Ph.D.  
National Center for Complementary & Integrative Health (NCCIH) 
Phone: 202-313-2144 
Email: beda.jean-francois@nih.gov 

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

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

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.