Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Center for Complementary and Integrative Health (NCCIH)

Funding Opportunity Title
Clinical Coordinating Center for NCCIH Multi-Site Investigator-Initiated Clinical Trials of Mind and Body Interventions (Collaborative UG3/UH3 Clinical Trial Required)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
Reissue of PAR-18-662
Related Notices

None

Funding Opportunity Announcement (FOA) Number
PAR-21-243
Companion Funding Opportunity
PAR-21-240 , R34 Planning Grant
PAR-21-241 , R01 Research Project
PAR-21-242 , U24 Resource-Related Research Project (Cooperative Agreements)
Assistance Listing Number(s)
93.213
Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) encourages applications for investigator-initiated multi-site clinical trials (e.g. efficacy, effectiveness or pragmatic trials) to study the effects of complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions) in NCCIH designated areas of high research priority. Clinical Coordinating Centers should develop and implement the proposed fully powered multi-site clinical trial. The objective of a Clinical Coordinating Center application is to present the scientific rationale and a comprehensive scientific and operational plan for the clinical trial. Clinical Coordinating Center applications are expected to describe plans for project management, participant recruitment and retention strategies, performance milestones, scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) funding mechanism.

In addition, an accompanying Data Coordinating Center application (U24), submitted under PAR-21-242 proposing a data analysis and data management plan for the clinical project is required. Both a Clinical Coordinating Center application and a corresponding Data Coordinating Center (DCC) application need to be submitted simultaneously for consideration by NCCIH. For additional information about the mission, strategic vision, and research priorities of the NCCIH, applicants are encouraged to consult the NCCIH website: (https://nccih.nih.gov/about/plans).

Applicants are encouraged to contact the appropriate the Scientific/Research contact for the area of science for which they are planning to develop an application prior to submitting to this FOA.

Key Dates

Posted Date
June 14, 2021
Open Date (Earliest Submission Date)
September 20, 2021
Letter of Intent Due Date(s)

30 days prior to application date.

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
October 20, 2021 October 20, 2021 November 15, 2021 March 2022 May 2022 July 2022
February 18, 2022 February 18, 2022 March 11, 2022 July 2022 October 2022 December 2022
June 20, 2022 June 20, 2022 July 22, 2022 November 2022 January 2023 April 2023
October 19, 2022 October 19, 2022 November 14, 2022 March 2023 May 2023 July 2023
February 21, 2023 February 21, 2023 March 10, 2023 July 2023 October 2023 December 2023
June 20, 2023 June 20, 2023 July 22, 2023 November 2023 January 2024 April 2024
October 20, 2023 October 20, 2023 November 14, 2023 March 2024 May 2024 July 2024
February 20, 2024 February 20, 2024 March 11, 2024 July 2024 October 2024 December 2024

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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.

Expiration Date
March 12, 2024
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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

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

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

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.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

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

There is a need for research to evaluate mind and body approaches as they are used and delivered to determine whether they are safe and efficacious or effective for given conditions or disorders. For clinical trials to address this need they must be well designed and test hypotheses that will guide decisions about the inclusion of these interventions or approaches into the delivery of health care for a given condition or disorder. To accomplish this goal, 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.

For more information about NCCIH recommendations for the multi-stage process or developing and testing physical and/or psychological therapeutic input (mind and body interventions), see the NCCIH website (https://nccih.nih.gov/research/blog/clinical-mind-body;https://nccih.nih.gov/grants/funding/clinicaltrials).

Overview of NCCIH Mind and Body Clinical Trials Research Funding Opportunities

NIH defines a clinical trial as "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes."

NCCIH has designed its Clinical Trials Program to support a range of investigator-initiated studies with funding mechanisms tailored to address different scientific questions and levels of study complexity from early stage discovery research through large-scale efficacy or effectiveness trials. For complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind and body approaches), this pipeline of research is supported under funding opportunities that include the following options:

i) Pre-clinical/animal studies (which may use Parent R21 or R01 FOAs).

ii) Mechanistic studies focused on the fundamental science of mind and body approaches (which may use Parent R21 or R01 FOAs).

iii) Human feasibility and intervention refinement studies to obtain preliminary data on novel interventions, new multicomponent interventions that need to be protocolized, or existing interventions requiring substantial adaptations; to assess the ability to recruit/randomize and accrue participants; to evaluate the fidelity of delivering the intervention; to assess participant adherence to the intervention and study procedures; to reliably collect outcomes data for follow-up durations; and to assess retention of participants (which may use R34 PAR-21-240). Feasibility studies are not needed when published literature or previous studies by the investigators demonstrate the feasibility of a similar intervention trial in a similar population.

iv) Multi-site feasibility clinical trials to demonstrate delivery of the intervention with fidelity across at least two geographically distinct sites; to assess adherence to the study protocol across sites; to evaluate the ability to recruit and retain participants consistently across sites; to perform minimal adaptation to the intervention when needed; and to collect data with consistency across sites (which may use R01 PAR-21-241). Multi-site feasibility studies are not needed when published literature or previous studies that demonstrate that a similar intervention in a similar population can be delivered with fidelity across sites, and the investigative team has experience conducting multi-site trials.

v) Multi-site clinical trials to determine efficacy or effectiveness of an intervention in a fully powered clinical trial. Trials must be conducted across at least three distinct geographic regions and adhere to NIH policy for enrollment of diverse populations in Phase III trials. An independent DCC is required for multi-site trials (which may use this UG3/UH3 for the CCC PAR-21-243 with the companion U24 for the DCC PAR-21-242).

vi) Remotely delivered and conducted clinical trials to determine efficacy or effectiveness of complementary and integrative health interventions in a representative sample (which may use R01 PAR-20-154).

vii) Dissemination and implementation science trials to support innovative approaches to identifying, understanding, and developing strategies for overcoming barriers to the adoption, adaptation, integration, scale-up and sustainability of evidence-based complementary and integrative health interventions, tools, policies, and guidelines. Hybrid Type 1 and Type 2 effectiveness-implementation studies should use the multi-site clinical trial pathway described above in item v. Hybrid Type 3 effectiveness-implementation studies should use the NIH-wide FOAs (R21 PAR-19-275 or R01 PAR-19-274).

Research Objectives of the Multi-Site Investigator Initiated Clinical Trials (UG3/UH3)

This FOA invites cooperative agreement applications for investigator-initiated fully powered multi-site clinical trials (e.g., efficacy, effectiveness or pragmatic trials) to study the effects of complementary and integrative health approaches with physical and/or psychological therapeutic inputs (often called mind and body interventions) in NCCIH designated areas of high research priority. CCCs 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 FOA, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances. The trial design should be appropriate for the study question.

For this FOA, multi-site clinical trials are defined as trials that enroll from at least three geographically distinct recruitment sites. Two sites will be permitted if there is a strong justification for how fewer sites can still achieve generalizability and meet the NIH diversity and inclusion requirements for a phase III clinical trial. Multiple sites are necessary in efficacy trials to increase generalizability of findings, representativeness of the participants, and the size and diversity of the pool of eligible participants to enhance recruitment efforts. In addition to more standard efficacy, effectiveness, and/or pragmatic randomized control trial designs, investigators may propose fully-powered adaptive designs, such as sequential, multiple assignment, randomized trials (SMARTs) which are designed to determine the treatment options at decision points, possible tailoring variables, or a sequence of decision rules depending on the research question they seek to address. Investigators may also choose to use fully powered optimization designs if they fit their research question, such as a multiphase optimization strategy (MOST) design to determine how to optimize the intervention by evaluating which elements of a complex intervention are impactful. Regardless of the choice of study design, the proposed multi-site clinical trial is expected to be highly impactful, contribute to the evidence base for important health matters of relevance to the research mission of NCCIH and be designed with a minimum of 90% power to test the primary hypothesis. 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 FOA runs in parallel with a companion FOA (PAR-21-242) for a corresponding DCC application. Both a CCC application and a corresponding DCC application need to be submitted simultaneously for consideration by NCCIH.

If the study design will use a natural product, device, or mobile application, investigators must contact the US Food and Drug Administration (FDA) prior to submitting an application to determine whether an Investigational New Drug (IND) or Investigational Device Exemption (IDE) application is necessary for the proposed clinical research.

Investigators are encouraged to review the NCCIH Clinical Research Toolbox (https://www.nccih.nih.gov/grants/toolbox). to learn more about NCCIH's requirements for clinical research. Information about NCCIH policies, guidelines and sample templates for clinical trials can be found on the website at: https://www.nccih.nih.gov/grants/toolbox. Clinical trials supported by this FOA will have to adhere to the NIH Policy on Good Clinical Practice Training https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html.

It is strongly recommended that investigators contact an NCCIH Scientific/Research contact to discuss at an early stage the development of a concept for a given clinical study. The Scientific/Research contact can provide feedback on whether a given concept is well-aligned with NCCIH research priorities, and whether the available preliminary data appear sufficient for a given phase of a study.

Preliminary data requirements

This FOA is appropriate when there is a clear and compelling rationale, a rigorous empirical basis, and a scientific premise to conduct a large-scale efficacy, effectiveness, or pragmatic clinical trial. The following preliminary data from previous human studies (preferably published in the literature) on a similar mind and body intervention and in a similar patient population and age group as proposed in the current application are required:

All of the following preliminary data about the intervention or outcome measure (from published literature or the team’s previous research):

  • 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.
  • Demonstration that the proposed clinical trial is feasible.
  • Pilot 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).
  • A pilot study that achieved adherence and fidelity to a similar intervention study protocol by study participants across at least two sites (e.g. cite a pilot study of a similar duration with sufficient adherence and fidelity to the intervention across sites).
  • A pilot study that 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).
  • Pilot data to demonstrate that the primary outcome is a valid measure for the proposed condition and population.

All of the following preliminary data demonstrating the team’s collective experience conducting clinical trials:

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

Additionally, it is highly desirable, though not required, that:

  • A similar intervention can produce a clinically meaningful change in a measurable biological signature or psychological process (e.g., mechanism of action) in the population similar to the one of interest. Additionally, there is evidence that the change in biological signature or psychological process measure has been replicated in a separate human study with an intervention similar to the one to be used in the proposed trial.
  • Evidence is provided that evaluates the pilot study data for strength of correlation between the impact on the biological signature or psychological process and changes in the clinical outcomes that will be studied in the proposed clinical trial.
  • The intervention has been optimized to enhance the impact on the biological signature or psychological process (e.g., mechanism of action).

Structure

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

Phases of Award

The UG3 phase will support the development of 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 (IRB) approval of the study; Data and Safety Monitoring Board (DSMB) approval of the trial protocol; and finalization of the informed consent form(s), manual of operations, and clinical trial project management plans. Applications are expected to provide a clinical trial project management plan that delineates how the study will monitor and evaluate critical processes impacting 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. Training of intervention providers, training of comparison group intervention providers, or plans for distribution of other resources (e.g., training materials, fidelity checklists) should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. Although not required, investigators may propose a vanguard pilot study if needed during the UG3 planning phase with specific milestones for defining success. A vanguard pilot study can provide an opportunity to make minor adaptations to enhance feasibility of the intervention or when investigators are citing published literature but do not have direct previous experience with the intervention. If a vanguard study is proposed, it is recommended that this study involve at least two of the study sites. 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 9 months into their UG3 phase award, so the majority of UG3 phase milestones should be completed within 9 months of initial funding. All milestones must be achieved prior to transition to the UH3 phase.

Milestones

Use of milestones is a key characteristic of this FOA. 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 FOA 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 priorites of NCCIH. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NCCIH will consider ending support and negotiating an orderly phase-out of the award. NCCIH retains the option of periodic external peer review of progress. NCCIH staff will closely monitor progress at all stages for milestones, accrual, and safety.

NCCIH Priorities for Clinical Trials of Mind and Body Interventions

As its 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). For this funding opportunity, applications will be considered of high programmatic priority if they meet at least one element in each of the following criteria:

  • 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: specific approaches such as spinal manipulation or mobilization, massage, tai chi, qi gong, yoga, acupuncture*, hypnosis, guided imagery, breathing exercises, progressive relaxation, meditation, biofeedback, mindfulness techniques, or music or art therapies; multicomponent interventions such as naturopathic medicine, traditional Chinese medicine, Ayurvedic medicine, chiropractic care, or a combination of two or more of the specific complementary health approaches; or integrative approaches to care in which a complementary health approach is used in combination with standard care (e.g. cognitive behavioral therapy combined with mindfulness or yoga).
  • In addition, proposed projects should study a mind and body or integrated approach for one of the following high priority topic areas and should include at least one outcome measuring the topic: promotion of whole person health, health restoration, emotional well-being, or resilience; prevention or treatment of symptoms including sleep disorders or disturbances, depression, anxiety, post-traumatic stress (disorder), obesity, and pain conditions; improving minority health and eliminating disparities in priority health conditions; the role of social and structural determinants of health; enhancement of adherence to medications or prescribed behavioral approaches (e.g., physical activity and healthy eating); reduction of inappropriate use of medications or substances (e.g., substance use disorder or medications that are contraindicated in specific patient populations); or symptom management among individuals living with HIV/AIDS.

NCCIH strongly encourages applications to this FOA that conduct studies in diverse settings1 or include of health disparity and vulnerable populations.2

1Examples of diverse settings include families, schools, Federally Qualified Health Centers, child welfare and juvenile justice systems, and homeless shelters).

2NIH-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, and under-served rural populations. Other vulnerable populations include high-risk pregnant women, homeless youth, individuals with disabilities, children who have experienced abuse, older adults, veterans, military personnel, and military families)

*Applicants proposing acupuncture as an intervention should consult the NCCIH website (https://www.nccih.nih.gov/grants/acupuncture-research-areas-of-high-and-low-programmatic-priorities) to determine whether the proposed study is aligned with NCCIH's updated priorities for acupuncture research.

Applications proposing research topics not identified above as high programmatic priority can be submitted but are likely to be considered 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.

Considerations for Selection of Study Design

For interventions that either are or can be delivered in groups, investigators must 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.

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

The study team biostatistician will need to consider how the chosen study design led to the proposed data analysis and sample size estimates. The justification should include discussion of the positive intraclass correlation expected in data obtained from participants in the same groups, or clusters (IRGT cRCT, or GRT). In general, these types of studies need to consider how the data analysis and sample size addresses the extra variation expected in the data and the degrees of freedom available to estimate that extra variation. Failure to account for this variable in the sample size calculation can result in underpowered studies. Regardless of the choice of study design, the proposed multi-site clinical trial is expected to be highly impactful, contribute to the evidence base for important health matters of relevance to the research mission of NCCIH and be designed with a minimum of 90 percent power to test the primary hypothesis.

Design, Analysis, and Sample Size for Studies to Evaluate Group-Based Interventions: 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. Such studies may propose a parallel group- or cluster-randomized trial, an IRGT trial, a stepped-wedge design, or a quasi-experimental version of one of these designs. In these studies, special methods may be warranted for analysis and sample size estimation. 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/.

Clinical Trials Not Responsive to This FOA

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

  • Phase I (first-in-human) trials whether single or multi-site
  • Single site trials
  • Mechanistic studies on the fundamental science of mind and body approaches (Such studies should use the Parent R01 or R21 FOAs).
  • Studies to determine a biological signature or psychological process measure (mechanism) of a complementary or integrative health approach that do not have a primary outcome to assess efficacy or effectiveness on a clinical outcome
  • Studies to assess feasibility of a complementary or integrative health approach (Such studies should use the R34 PAR-21-240 for initial feasibility or the R01 PAR-21-241 for multi-site feasibility.)
  • Fully remotely delivered clinical trials (Such studies should use the R01 PAR-20-154).
  • Natural product, pharmacologic, or device safety trials
  • Natural product or pharmacologic clinical trials that do not include a mind and body element in the intervention or comparison group
  • Single or multi-site observational studies that do not meet the NIH definition of a clinical trial (Such studies should use the Parent R21 or R01 FOAs).
  • Trials that propose to test interventions for the treatment or prevention of cancer (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute)

Specific Areas of Research Interest

Applicants are strongly encouraged to consult with the NCCIH Scientific/Research contacts for the area of science for which they are planning to develop an application prior to submitting to this FOA. Early contact (12 weeks prior to submission is encouraged) provides an opportunity for IC staff to discuss the scope and goals, and to provide information and guidance.

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New
Resubmission

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are not limited but need to reflect the actual needs of the proposed project.

The combined budgets of the CCC and DCC will be used to determine whether the policy regarding direct costs of $500,000 or more in any year will be applied (https://nccih.nih.gov/grants/policies/over500k-clinical-trials).

Award Project Period

The scope of the proposed project should determine the requested project award period.

The project period for the UG3 phase will be up to 1 year.

The period of award for the UH3 phase is expected to be 4 years. With strong justification, up to 6 years for the UH3 may be requested.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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
Foreign Institutions

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

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

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

Required Registrations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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.  This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

This FOA only accepts applications that are part of a collaborative set of multiple applications. A set must contain one application to this FOA and one application to PAR-21-242.

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement 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 Institute or Center staff to estimate the potential review workload and plan the review.

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

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

The letter of intent should be sent to:

Martina Schmidt, Ph.D.
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

Descriptive Title of Applicant's Project:

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

Cover Letter Attachment:

The Cover Letter is one pdf file only. The following collaborative information is required in the cover letter: a listing of all the applications that are part of the set of collaborative applications being submitted, including for each: 1) the PD/PI(s) name(s), 2) the Title (including the tag, e.g., "1/2"), and 3) the applicant institution. Each application should submit an identical listing. If applicable, the letter should indicate the name of the NCCIH program officer with whom the project has been discussed.

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

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

A Project Management Plan must be provided as an "other attachment" called "CCC Project Management Plan.pdf" and must not exceed 3 pages. The Project Management Plan should describe the evidence-based strategy that will be used throughout the project to ensure that the unique goals of the clinical trial are met. Project management planning should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. The project management plan should describe the planning team and identify control points and processes that are key to scientific and fiscal performance. This will include a description of the organizational strategy that defines internal control points and business roles. A description of the key methodology, standards, and processes governing resource management, study deployment, operations/execution, and study closure should be included. The management plan should also describe how the team, in collaboration with the DCC, will proactively evaluate and prioritize issues that jeopardize study goals and development of corrective responses to resolve fiscal and logistical issues (risk planning) in a timely manner. Describe processes required for orderly project closure. In summary, the project management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time. The project management plan should include risk mitigation or contingency plans.

SF424(R&R) Senior/Key Person Profile

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

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

Biographical Sketches: Document the experience of the PD/PI(s) in leading clinical trials and expertise in the content area of the trial (intervention, study population, and research methods). Most clinical trials will require a multidisciplinary team (clinician, biostatistician, data manager, study coordinator, etc.) 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 as well as future research, experience as investigative team members, and previous investigative experience in related clinical trials.

R&R Budget

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

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

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

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

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

If parts of the costs of the trial are to be provided by sources other than NCCIH, these contributions must be presented in detail in the budget justification. Third party support of the proposed research activity (if approved) will be incorporated as a specific term and condition in the Notice of Award. If the third party support ceases and the trial is no longer tenable without the third party support, a close-out plan may be requested. Applicants are reminded that although cost share is not required, if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NCCIH.

Include budget support for the publication and dissemination of findings.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy

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

The following criteria should be addressed:

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

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

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

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

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

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

All of the following preliminary data about the intervention (from published literature or the team’s previous research):

  • 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.
  • Demonstration that the proposed clinical trial is feasible.
  • Pilot study included 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 cites pilot work on hatha yoga in a population of adults with depression and anxiety).
  • A pilot study that achieved adherence to a similar intervention study protocol by study participants across multiple sites (e.g., cite a pilot study of similarduration with sufficient adherence to the intervention).
  • A pilot study that 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).

All of the following preliminary data demonstrating the collective team’s experience conducting clinical trials:

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

Additionally, it is highly encouraged, though not required that:

  • A similar intervention can produce a clinically meaningful change in a measurable biological signature or psychological process (e.g., mechanism of action) in a population similar to the one of interest. Additionally, there is evidence that the change in biological signature or psychological process has been replicated in a separate human study with a similar intervention to be used in the proposed trial.
  • Evidence is provided that evaluates the pilot study data for strength of correlation between the impact on the biological signature or psychological process and changes in the clinical outcomes that will be studied in the proposed clinical trial.
  • The intervention has been optimized to enhance the impact on the biological signature or psychological process measure (e.g., mechanism of action).

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

  • A rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), measurement of the replicable biological signature or psychological process measure of the mind and body intervention (if available), and participant follow-up procedures.
  • A description of why the target population is an appropriate group to address the proposed hypotheses and how or if results will generalize to a broader population.
  • A description of the mind and body 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 group or individual/home settings), and frequency of delivery or practice.
  • A summary of the necessary agreements for the delivery of the intervention and comparison intervention by given clinicians or appropriately trained/certified instructors at given facility(ies).
  • A description and justification for assessments, including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes. Use of patient reported outcomes, including those available through the Patient-Reported Outcomes Measurement Information System (PROMIS), NIH Toolbox, and Quality of Life in Neurological Disorders (NeuroQoL), as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) needs 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.
  • Engagement of the clinical community 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. Description of this commitment should be provided.
  • Discussion of potential challenges expected in implementing the trial and how these might be overcome.
  • Contingency plans if the effect size or event rate is underestimated
  • If a pilot vanguard study is proposed in the UG3 phase, the approach must detail a strong rationale for the pilot work, the study methods, and specific milestones for defining success. Only minor adaptations to existing interventions should be proposed in this pilot work.
  • 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.
  • Descriptions of the organization of the study and how the trial will be managed.
  • The strategy for timely publication and dissemination of results.

Letters of Support:

Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided from all participating sites. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be cosigned by the business official of the collaborating center.

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

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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.4 Inclusion of Women and Minorities

Describe strategies for outreach to minorities and women.

2.5 Recruitment and Retention Plan

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

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

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

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

(a) When the study opens to enrollment
(b) When core milestones (see below) are met
(c) What subtasks are needed to reach the core milestones
(d) When final transfer of the data to the DCC will occur
(e) When analysis of the study data will occur
(f) When the primary study manuscript will be submitted for publication

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), as well as the NCCIH Guidelines for Data and Safety Monitoring (https://www.nccih.nih.gov/grants/policies/data-and-safety-monitoring-of-nccihfunded-clinical-research). An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by NCCIH. At the first meeting in the UG3 phase, the DSMB will review the awardee’s protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim 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 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 review committee that will evaluate the applications for scientific merit.

3.5 Overall Structure of the Study Team

Include a description of the following:

  • The role of the Executive Committee and Steering Committee as well as any internal or external advisory committees

  • The oversight, responsibilities, communication with, and coordination of any sites or cores proposed

  • The role of any sub-contractors or providers of services, personnel, or facilities

  • How these functions will integrate with the organizational framework described in the collaborating DCC application

  • How the CCC and DCC will coordinate leadership for clinical trial implementation and communications

  • The coordination between the separate components and NCCIH

  • Key channels used to reach and inform each stakeholder group and receive feedback

  • How disputes amongthe CCC, DCC, and all stakeholders will be resolved

Section 4 - Protocol Synopsis

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

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

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

4.5 Will the study use an FDA-Regulated intervention?

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

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

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

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

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

1. Clinical Trial Experience

Applicants must provide a detailed table listing the characteristics of trials that demonstrate Key Personnel experience in trial coordination in the last 5 years. One table must be provided for each study record with a unique filename for each study record as an attachment (e.g., "Clinical Trial Experience1.pdf" , "Clinical Trial Experience 2.pdf") and must not exceed 3 pages.

The table columns should include:

  • Clinical trial title

  • Applicant's role in the trial

  • A brief description of the trial design

  • Planned enrollment

  • Actual enrollment

  • Number of sites

  • Whether the trial(s) was/were completed on schedule or not

  • Publication reference(s)

2. Milestone Plan

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

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

All applicants must use the following definition of a milestone in their application: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, achievable, and measurable. The milestone plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. UH3 milestones should address overall recruitment and retention goals. The Terms and Conditions for a UG3 award under this FOA will include a milestone plan that is mutually agreed upon by the investigators and NCCIH.

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

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

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

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

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission. Each application of a collaborative set must be on-time. Considerations for late applications that are based on the institution or PD/PI apply only to his/her individual application.

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) 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.

Specific to this FOA:

  • Awards issued under this FOA will be incrementally funded for up to 7 years. These will not be Multi-Year Funded.
  • Awards issued under this FOA will be excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
  • Awards issued under this FOA will not be provided the authority to automatically extend the final budget period. All extensions, including the first, will require NCCIH prior approval.
  • Awards issued under this FOA will be excluded from SNAP.
7. Other Submission Requirements and Information

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

Each application of a collaborative set must be complete, compliant, and responsive.

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

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

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

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

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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

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

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.

Overall Impact

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).

Scored Review Criteria

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

Significance

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

Specific to this FOA:Has the applicant provided the required preliminary data that has sufficient scientific rigor to support the study rationale? If the primary outcomes of the trial are achieved, how critical will the information be to addressing the evidence gap and advancing knowledge of theory and practice? Is there sufficient demonstration for the presence of equipoise?

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

Investigator(s)

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

Specific to this FOA:Does the investigative team have a track record of completing and publishing the results of clinical trials? Based on the clinical experience attachment, has the investigative team successfully recruited a similar study population in previous single or multi-site clinical trials? Does the team meet the preliminary data requirements of experience delivering a similar intervention with fidelity in previous multi-site clinical trials? How strong is the plan for leadership and coordination of roles/responsibilities for CCC leadership?

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

Innovation

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

Specific to this FOA: Have the investigators sufficiently described how will the proposed clinical trial inform clinical practice or practice guidelines? Does the proposed research have the potential to advance the field even if the proposed study design, methods, and intervention are not innovative?

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

Approach

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

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

How appropriately is the study designed to answer the research question, test the proposed hypothesis/hypotheses, and collect the necessary data? How efficient is the trial design? How well does the Clinical Protocol Synopsis attachment describe the necessary elements of the clinical trial at all of the sites? How strong are the formative clinical studies, including any pilot studies, underpinning the trial? Is the mind and body intervention appropriately characterized? How well are the clinical outcome measures, dose/duration of intervention, and sample size justified and explained? What evidence is there that the study population has been appropriately defined? Are there plans for adverse events to be appropriately captured and monitored? How clear is the communication plan between DCC and CCC leadership and is it appropriate for implementing and conducting the trial? What is the quality of the DSMP to monitor sites/centers, and participating facilities (labs, pharmacies)? Have the investigators described how they will follow GCP, GLP, and GMP as appropriate? If a pilot/vanguard study is proposed in the UG3 phase, is it well justified and well designed to inform the UH3 phase study?

If the clinical trial is Phase III, does the application include all relevant data to assess whether the trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses?

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Environment

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

Specific to this FOA: Have investigators demonstrated that the available facilities and resources are adequate to coordinate multi-sites clinical trials? Is there strong evidence that the institutions have the available resources needed to conduct a multi-site trial at the CCC and the performance sites? Does the application document the availability of the requisite eligible subject pool at the proposed clinical site(s)? Is there documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel and facilities?

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

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

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

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

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

Additional Review Criteria

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.

Milestones

How strongly do the milestones address the specific aims of each phase? Are the listed milestones appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused, and timebound? How effectively does the Project Management Plan address contingency plans in the event the UG3 and/or UH3 milestones are not achieved?

Data and Safety Monitoring

Is the proposed DSMP appropriate for the proposed clinical trial?

Study Timeline

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications 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. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council for Complementary and Integrative Health. 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 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.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to the NCCIH Guidelines for Data and Safety Monitoring (https://www.nccih.nih.gov/grants/policies/data-and-safety-monitoring-of-nccihfunded-clinical-research). The Independent Monitoring Committee (IMC) or DSMB will have 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 NCCIH. The IMC/DSMB will meet in person or by phone at least twice a year. Applicants should not appoint IMC/DSMB members in advance of peer review, 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.

Investigational New Drug (IND) or Investigational Device Exemption (IDE) 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 an FDA IND or IDE if required by the FDA.

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 awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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

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

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

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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. The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility reside with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees 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 Steering Committee to coordinate and manage the project. The PD(s)/PI(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Study investigators will be required to accept and implement the common protocol and procedures approved by the Steering Committee.
  • Working with the DCC to implement the core data collection method and strategy collectively decided upon by the Steering Committee. It is the responsibility of each clinical site to ensure that data will be submitted in a timely way to the study’s data entry system according to the study protocol. Additionally, sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.
  • 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 professionalsand 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) or Steering Committee, as applicable. NIH policies governing possible co-authorship of publications with NIH staff will apply in all cases. In general, to warrant co-authorship, NIH staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts
  • Overseeing the overall budget, activities and performance of the cooperative agreement. Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices of NCCIH Sharing data, resources and software 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 3months 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 function may be performed by the recipientorganization or by subrecipient organization.
  • Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

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

Areas of Joint Responsibility include:

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

  • The Steering Committee has primary responsibility to design research activities; establish priorities; develop common protocols and manuals, questionnaires, and other data recording forms; establish and maintain quality control among recipients; review progress; monitor patient accrual; coordinate and standardize data management; and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NCCIH Program Officer and will provide periodic supplementary reports upon request.
  • The Steering Committee will be composed of the PD(s)/PI(s) and co-investigators as deemed necessary, such as the study biostatistician and trial manager, the NCCIH Project Scientist, and additional designees of NIH. The NCCIH Project Scientist or designee will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NCCIH Program Officer will serve as an “ex officio” member of the Steering Committee. The Steering Committee will typically meet in-person or via videoconference twice in the first year of the award and then at least yearly thereafter. More frequent phone meetings will occur as required during the award period. The first in-person meeting will occur before clinical activities begin.
  • The Steering 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 Steering Committee will develop appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health.
  • A DSMP will be required for both phases of the project. An independent DSMBwill be appointed and established by NCCIH for the clinical trial, in accordance with NIH and NCCIH policies for monitoring (https://www.nccih.nih.gov/grants/policies/data-and-safety-monitoring-of-nccihfunded-clinical-research) https://nccih.nih.gov/grants/policies/data-safety-monitoringhttps://nccih.nih.gov/grants/policies/data-safety-monitoring).
  • 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 awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR.

3. Reporting

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

Application Submission Contacts

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: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Lanay Mudd, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-9346
Email: lanay.mudd@nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Shelley Headley
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.


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