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
Investigator Initiated Clinical Trials of Complementary and Integrative Interventions Delivered Remotely or via mHealth (R01 Clinical Trial Required)
Activity Code
R01 Research Project Grant
Announcement Type

New

Related Notices
July 26, 2019- Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128

August 23, 2019- Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137

Funding Opportunity Announcement (FOA) Number
PAR-20-154
Companion Funding Opportunity

None

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.213?

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) encourages applications for investigator-initiated fully remotely delivered and conducted clinical trials to assess the efficacy or effectiveness of complementary and integrative health interventions in NCCIH designated areas of high research priority. Applications submitted under this FOA are expected to propose a remotely delivered and conducted clinical trial with no in-person contact between research staff and study participants and may utilize mHealth tools or technologies. To justify the proposed remotely delivered efficacy or effectiveness clinical trial, applications must have sufficient preliminary data that includes: demonstration of feasibility of remote recruitment and accrual of participants; demonstration of participant adherence to the intervention as well as retention of participants throughout the study; completion of final data collection from any related studies; demonstration of the safety of the intervention; and evidence that the intervention has promise of clinical benefit.

Applicants are encouraged to contact the appropriate NCCIH 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

March 30, 2020

Open Date (Earliest Submission Date)
May 05, 2020
Letter of Intent Due Date(s)

Not Applicable?

Application Due Date(s)

Standard dates apply.

The first standard due date for this FOA is June 5, 2020.

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.

AIDS Application Due Date(s)

Standard AIDS dates apply.

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

The first AIDS due date is September 7, 2020.

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.

Scientific Merit Review
Advisory Council Review
Earliest Start Date
Expiration Date
May 08, 2023
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 rigorous investigation of promising complementary and integrative health interventions, including natural products and mind and body approaches. For the purposes of this funding opportunity announcement (FOA), natural product approaches include botanicals, dietary supplements, and probiotics; mind and body approaches include meditation approaches (e.g., mindfulness), hypnosis or guided imagery, meditative movement approaches (e.g., yoga, tai chi, qi gong), body-based approaches (e.g., progressive muscle relaxation, acupressure), music or art-based therapy, or a combination of these approaches (e.g., mindfulness based stress reduction). These approaches are often widely used by the public, and they are increasingly recognized to provide a complementary approach to symptom management (e.g., stress, chronic pain, mild depression, anxiety, etc) and health promotion.

Increasingly, researchers are incorporating mobile health (mHealth) technologies to remotely deliver interventions, including mindfulness, deep breathing, progressive muscle relaxation, and other complementary and integrative health interventions. These remotely delivered interventions may utilize phone delivery, app-based approaches, video delivery, web-based platforms, wearable devices and/or new technologies. The rapid expansion of mHealth technologies makes it possible to digitally transmit participant data from remote areas to centrally based researchers and interventionists, deliver feedback, and capture all interactions in a database.

The use of the pragmatic trial design is another method of conducting informative effectiveness studies that can be conducted with remote delivery of the intervention and data collection. This FOA will also support pragmatic clinical trials to assess the effectiveness of complementary and integrative health interventions when the trial design does not require in-person contact with study participants for delivery of the intervention or collection of data. For example, pragmatic trials may employ interventions that would not require research staff to interact directly with participants, such as clinician decision support tools embedded in the electronic health record, system changes within the health care system, or when complementary interventions are implemented and delivered within the health care setting. These types of pragmatic trials allow for investigators to coordinate delivery of the intervention centrally and capture of data from the electronic health record or via remote data collection.

Remotely delivered interventions such as pragmatic trials or trials utilizing mHealth tools/technologies have the potential to increase the reach of complementary and integrative health interventions, and many commercially available mHealth approaches already exist. However, rigorously designed research is needed to test the usefulness and safety of remotely delivered complementary and integrative health interventions for given conditions/disorders and/or health promotion. For clinical trials to address this need, they must be well designed and appropriately powered to test clinically relevant hypotheses. To that end, before proposing an efficacy or effectiveness clinical trial, it is necessary to conduct early-phase clinical trials to collect the multiple types of preliminary data needed to rigorously design a definitive clinical trial. For more information about what NCCIH recommends for the multi-staged process for intervention development and testing, see the NCCIH website (https://nccih.nih.gov/grants/funding/clinicaltrials).

This FOA is appropriate when there is a clear and compelling rationale, a rigorous empirical basis, strong feasibility and safety data, and scientific premise to conduct a large-scale remotely delivered efficacy, effectiveness, or pragmatic clinical trial.

Considerations for Selection of Study Design

For complementary and integrative interventions that either are or can be delivered in groups, investigators must provide a strong rationale for the choice among trial design options. If group delivery is selected, investigators should describe how this will be accomplished remotely in a secure fashion. 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., a specific natural product, individually delivered hypnosis, massage). When an intervention can be delivered in a group, there are several methods of randomizing participants. The first option is an individually randomized group treatment trial (IRGT, where individual participants are randomized to one of the interventions, but the intervention is delivered in small groups (e.g., Mindfulness based Stress Reduction or tai chi classes). The second option is a group-randomized trial (GRT), also called a cluster randomized trial (cRCT), where groups of participants are randomized to study conditions, often defined by their workplace, school, primary care provider, or community. In cRCTs, the intervention provided to the randomized groups can be delivered individually, in small groups, or the entire randomized group.

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

Overview of NCCIH Clinical Trials Research Funding Opportunities

NCCIH has designed its Clinical Trials Program to support a wide 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, effectiveness, or pragmatic clinical trials. This pipeline of research is supported under a range of funding opportunities that are detailed on the NCCIH Clinical Trials Funding webpage (https://nccih.nih.gov/grants/funding/clinicaltrials). Briefly, funding options include:

  • Preclinical/animal studies (which may use Parent R21 or R01 FOAs)
  • Human studies on the fundamental science of complementary and integrative health approaches (R21 and R01)
  • Human mechanistic studies to determine and verify the biological signature or psychological process of a given mind and body approach and then optimize the impact, or to determine bioavailability, pharmacokinetics, and biological signature of a natural product and then replicate and optimize the impact (R61/R33 or R33)
  • Human feasibility studies to demonstrate the ability to recruit and randomize participants, fidelity of delivering the study conditions, participant adherence to study conditions, data collection rates, and follow-up retention rates (R34)
  • Clinical trials to determine or optimize dosing, develop and test adaptive intervention strategies, and demonstrate fidelity and feasibility of study conditions across multiple sites for mind and body intervention delivered in person (U01)
  • Phase II clinical trials of natural products (U01)
  • Multi-site Phase III clinical trials to determine efficacy/effectiveness of natural product or mind and body interventions delivered in person in a representative sample (UG3/UH3) with an independent data coordinating center (U24)
  • Remotely delivered and conducted clinical trials to determine efficacy/effectiveness of complementary and integrative health interventions in a representative sample (this R01)

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

This FOA supports remotely delivered clinical trials (e.g., efficacy, effectiveness or pragmatic trials) to study the effects of complementary and integrative health interventions in NCCIH-designated areas of high research priority. Proposed clinical trials may utilize a design anywhere along the continuum between explanatory and pragmatic. For this 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, the proposed trial must study an intervention that can be delivered in a fully remote manner and all data collected remotely (i.e., no in-person contact between research staff and study participants). The application must propose to recruit a representative sample for the population and condition of interest, and conduct all study activities, including recruitment, intervention delivery, and data collection, remotely. Applications to this FOA should be based on a rationale for the need for a fully remotely delivered design as opposed to a multi-site in-person clinical trial. For study designs that require in-person participant contact, other funding mechanisms are available (https://nccih.nih.gov/grants/funding/clinicaltrials). Trials supported under this FOA are expected to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. These trials are expected to achieve the Phase III trial requirements of NIH (see https://grants.nih.gov/policy/clinical-trials/glossary-ct.htm and https://grants.nih.gov/policy/inclusion/women-and-minorities.htm).

For applications that propose the use of a dietary supplement, drug, or device as part of the intervention, the applicants must contact the U.S. Food and Drug Administration (FDA) prior to applying to determine whether an Investigational New Drug (IND) or an Investigational Device Exemption (IDE) application is necessary for the proposed clinical research.

Investigators are strongly encouraged to review the NCCIH Clinical Research Toolbox (https://nccih.nih.gov/grants/toolbox) to learn more about NCCIH's policies for clinical research and to review our guidelines and sample templates. Clinical trials supported by this FOA will have to adhere to all NIH Policies on clinical trials (https://grants.nih.gov/policy/clinical-trials.htm).

It is strongly recommended that investigators contact the 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 Requirement

The following preliminary data from previous human studies (preferably published in the peer-reviewed literature) on the specific intervention utilizing the same remote delivery mode and in the same population with the same condition as proposed in the current application will provide a strong justification for the proposed work:

  • Demonstration that the specific intervention proposed in the trial does not produce frequent severe adverse events in pilot human studies, and is minimal risk;
  • Demonstration that the proposed clinical trial is feasible. There should be pilot data on the specific intervention in the clinical population that will be studied in the proposed trial and utilizing the same remote-delivery methods. Pilot data should demonstrate the investigator's ability to recruit and accrue participants, successfully randomize participants, achieve adherence to the study protocol by staff and participants, retain participants during the study, and complete collection of follow-up data. Remote data collection methods should meet data security standards for collecting and accessing individual-level data.
  • Information to justify the selection of how the intervention is delivered (format of remote delivery, duration of individual intervention, frequency of delivery, and timeline of intervention delivery to achieve clinical benefit) in the study. For example, the intervention could be delivered as a single 30-minute session once a week for 8 weeks, or as self-paced 5-minute modules over 10 weeks. Data should demonstrate that the selected doses are feasible and likely to have the greatest impact on clinical outcome and minimize the risk of adverse events.

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

  • Demonstration that the natural product can produce a clinically meaningful change in measurable biological signature (e.g., measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, behavioral and/or somatic changes) in the human population of interest. There must also be evidence that the change in biological signature has been replicated in a separate human study with the same natural product to be used in the proposed project.
  • Information to justify the selection of the dose(s) of the product proposed to be used in the study. Data should demonstrate that the selected doses are likely to have the greatest impact on the biological signature and minimize the risk of adverse events.
  • Evidence that evaluates the pilot study data for strength of correlation between the impact on the biological signature and changes in the clinical outcomes that will be studied in the proposed clinical trial.
  • Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and demonstrate initial safety of the product.

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

In addition, for applications utilizing a mind and body approach, it is highly desirable, though not required that:

  • The intervention can produce a clinically meaningful change in a measurable biological signature or psychological process (e.g., mechanism of action) in the population of interest; Additional evidence that the change in biological signature or psychological process measure has been replicated in a separate human study with the same 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 (e.g., mechanism of action).

NCCIH Priorities for Clinical Trials of Mind and Body Interventions

As NCCIH's mind and body clinical research portfolio matures, NCCIH has identified targeted areas of investigation. For this FOA, applications involving remotely delivered mind and body interventions will be considered of high programmatic priority if they meet the following two criteria:

  • The mind and body or integrated approach includes one or more of the following: massage, tai chi, qi gong, yoga, acupressure, hypnosis, guided imagery, breathing activity, progressive relaxation, meditation, biofeedback, mindfulness techniques, or music or art-based therapy. Integrated approaches to care must include one or more of these complementary health approaches added to standard care or other interventions such as a natural product, pharmacological approach, and/or another conventional behavioral approach (e.g., health coaching, physical activity, or nutritional recommendations).
  • The study proposes to address one or more of the following high priority topic areas: symptom management - particularly for chronic pain syndromes; reduction of prescription drug (opioid) use or abuse in patients with chronic pain; enhancement of medication adherence; treatment or prevention of post­ traumatic stress (disorder), traumatic brain injury, sleep disorders or disturbances, anxiety, depression, obesity, and smoking; promotion of psychological resilience or wellbeing; and promotion of healthy eating and physical activity.

NCCIH Priorities for Clinical Trials of Natural Products

NCCIH has identified targeted areas of high program priority for clinical trials on natural products. Focus is on management of conditions for which natural products are used by the public and where there is evidence of postulated mechanism of action. For this FOA, NCCIH considers the following two general topic areas to have high program priority:

  • Symptom management, particularly the use of natural products for sleep disturbance, management of pain conditions, or mental health conditions such as those commonly managed in primary care (e.g., mild to moderate depression, anxiety, and post-traumatic stress).
  • Studies to examine the effects of probiotics and other natural products on gut microbiome-brain interactions. Of particular interest are studies of probiotics for depression, anxiety, or chronic pain.

NCCIH encourages applications for this FOA that meet the above criteria for either mind and body interventions and/or natural products interventions and also address health disparities, address symptom management in patients with HIV/AIDS, and/or utilize special populations such as older adults, children, under-represented minorities, individuals in the military, or veterans.

Applications proposing research topics not identified above as high programmatic priority will be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce the likelihood of funding.

Clinical Trials Not Supported by this FOA

The following types of clinical trials are not intended to be supported by this FOA and applications proposing such clinical trials will not be considered for funding:

  • Phase I (first-in-human) trials whether single or multi-site
  • Studies to determine biological signature or psychological process measure (mechanism) of a mind and body approach, or bioavailability, pharmacokinetics, or biological signature of a natural product (such studies should use R61/R33 FOAs)
  • Studies to assess initial feasibility of a mind and body approach delivered remotely or in-person (such studies should use R34 FOA)
  • Studies designed to evaluate how to optimize the intervention or to determine the treatment options at decision points, possible tailoring variables, or a sequence of decision rules (MOST or SMART designs)
  • Drug or device safety trials
  • 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)
  • Phase II or Phase III natural product or pharmacological clinical trials with in-person participant contact (such studies should use the U01 or UG3/UH3 FOAs)
  • Multi-site efficacy or effectiveness trials of mind and body interventions with in-person participant contact (such studies should use the UG3/UH3 FOA)
  • Clinical trials with any in-person contact with research participants
  • Clinical trials proposing to deliver an intervention to participants outside the U.S. or Canada
  • Trials that propose to test interventions for the treatment or prevention of cancer (investigators interested in a cancer treatment or prevention trial 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 provides an opportunity for NCCIH 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

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
Revision
New
Renewal
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.
Award Project Period

The scope of the proposed project should determine the project period. The maximum project period is 5 years.

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)

Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession
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

 

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)

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 Guideexcept 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.
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.
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.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.

The Principal Director(PD)/ Principal Investigator (PI) (or Multi-PDs/PIs) of the clinical trial must be experienced in the conduct of remotely delivered clinical trials and have expertise in the content area of the trial. The experience of all Key Personnel must be carefully documented. Most clinical trials will require a multidisciplinary team (clinician, statistician, data manager, study coordinator, etc.), and the application should reflect their roles and responsibilities in the design and implementation of the study protocol.

 

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

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

If parts of the costs of the trial are to be provided by sources other than NIH, these contributions must be presented in detail in the budget justification. Include budget support for the publication and dissemination of findings.

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:

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

The following criteria must be addressed:

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

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

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

Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies that show the need for and the feasibility of the trial should also be presented. 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):

  • Demonstration that the specific intervention proposed in the trial does not produce frequent severe adverse events in pilot human studies and is minimal risk;
  • Demonstration that the proposed clinical trial is feasible. There should be pilot data on the specific intervention in the clinical population that will be studied in the proposed trial and utilizing the same remotely delivery methods. Pilot data should demonstrate the investigator's ability to recruit and accrue participants, successfully randomize participants, achieve adherence to the study protocol by staff and participants, retain participants during the study, and complete collection of follow-up data. Remote data collection methods should meet data security standards for collection and accessing individual-level data.
  • Information to justify the selection of how the intervention is delivered (format of remote delivery, duration of individual intervention, frequency of delivery, and timeline of intervention delivery to achieve clinical benefit) in the study. For example, the intervention could be delivered as a single 30-minute session once a week for 8 weeks, or as self-paced 5-minute modules over 10 weeks. Data should demonstrate that the selected doses are feasible and likely to have the greatest impact on clinical outcome and minimize the risk of adverse events.

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

  • Demonstration that the natural product can produce a clinically meaningful change in measurable biological signature (e.g., measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, behavioral and/or somatic changes) in the human population of interest. There must also be evidence that the change in biological signature has been replicated in a separate human study with the same natural product to be used in the proposed project.
  • Information to justify the selection of the dose(s) of the product proposed to be used in the study. Data should demonstrate that the selected doses are likely to have the greatest impact on the biological signature and minimize the risk of adverse events.
  • Evidence that evaluates the pilot study data for strength of correlation between the impact on the biological signature and changes in the clinical outcomes that will be studied in the proposed clinical trial.
  • Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and demonstrate initial safety of the product.

NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the biological impact of a natural product. In these circumstances, the study should be justified by: (1) a clear rationale for why studying a biological signature in human participants is impossible or impractical; (2) potentially proposing other objective, reproducible measures that may be proxy to or indicative of a biological or behavioral effect for the natural product; and (3) strong compelling preliminary data to warrant further study of a natural product in clinical studies. In these situations, investigators are also encouraged to contact NCCIH Scientific/Research staff to determine whether this R01 is the appropriate funding opportunity for the proposed clinical trial.

In addition, for applications utilizing a mind and body approach, it is highly desirable, though not required that:

  • The intervention can produce a clinically meaningful change in a measurable biological signature or psychological process measure (e.g., mechanism of action) in the human population of interest; additional evidence that the change in biological signature or psychological process measure has been replicated in a separate human study with the same 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 measure 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).

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

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

  • A rationale of why the study population is the most appropriate group to answer the question, and how or if results will generalize to a broader population.
  • A rationale for the research hypothesis(es), methods of randomization 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 rationale for the remote-delivery mode and the complementary and integrative health intervention to be tested, including: elements of the intervention, proposed methods for assessing fidelity of intervention delivery and intervention performance, time duration of delivery (for clinician-provided interventions) or participant practice (in remote groups or individual/home settings), and frequency of delivery or practice.
  • A summary of the necessary agreements for the remote delivery of the intervention and comparison intervention by given clinicians or appropriately trained/certified instructors (if applicable).
  • A justification for all assessments, including clinical, laboratory, physiological, behavioral, patient­ centered, or other outcomes addressing the primary and secondary research questions. Remote data-collection methods should be described. Use of patient reported outcomes as well as non-traditional data collection approaches (e.g., electronic health records, telephone, mobile devices, or web-based systems) need to be described. A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP), as appropriate should be provided.
  • A discussion of potential challenges in implementing the research protocol and how they will be addressed.

Letters of Support

Letters of support from clinicians, clinical department chairs, and/or health care systems whose support is necessary to the successful conduct of the trial should be provided (if applicable). Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants. Letters of commitment must be co-signed by the business official of the collaborating center. In addition, if utilizing a natural product, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; the supplier will meet CMC specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.

If parts of the costs of the trial are to be provided by sources other than NCCIH, provide Letter(s) of Support signed by an authorized representative.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

  • 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-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.4 Inclusion of Women, Minorities, and Children

Describe strategies for outreach to minorities and women.

2.5 Recruitment and Retention Plan

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

Applicants must provide strong evidence of the availability of appropriate institutional resources and suitable patient populations. Documentation of the availability of eligible participants must be provided. The application must provide relevant information that addresses the feasibility of recruiting a representative sample of eligible participants nationwide utilizing remote methods.

2.7 Study Timeline

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

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

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

  • Complete finalized clinical protocol
  • Final informed consent(s) and, if applicable, assent forms
  • Agreements in place for product supply
  • Comprehensive laboratory plan (as applicable)
  • Pharmacy/Laboratories Identification (as applicable)
  • Contracts/Third Party Agreements (as applicable)
  • Training plan for study staff/interventionists
  • Final Data and Safety Monitoring Plan
  • Data Completeness and Quality Monitoring Reporting Plan
  • Completion of regulatory approvals
  • A Study Accrual and Retention Plan with target dates for percent enrollment of 10, 25, 50, 75, and 100% of the projected recruitment for all study subjects, including women, minorities, and children (as appropriate)
  • Remote collection of data related to primary and secondary endpoints and database lock
  • Submission of primary manuscript to peer-reviewed scientific journal
  • Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date
  • Data sharing plan for study data and biospecimens (if applicable)

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

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

In addition to the NIH application requirements for data and safety monitoring for clinical trials, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), as well as the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring). The data and safety monitoring plan must explicitly describe plans to remotely monitor participant safety with appropriate safeguards to minimize risk. The Independent Monitoring Committee (IMC) or Data and Safety Monitoring Board (DSMB) will have the responsibility to review interim 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 the peer review, or even inquire about the interest of possible DSMB members, to avoid conflicts of interest in peer review.

Section 4 - Protocol Synopsis

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

If the proposed clinical trial will use a device, natural product (such as botanical, herbal, dietary supplement, probiotic, vitamin, or mineral), or drug, this attachment should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial and associated timeline. For trials using an FDA-regulated product that requires an IND/IDE application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-U.S. regulatory agency, the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND/IDE, a copy of the exemption letter from the FDA should be provided as part of the PDF file attachment.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

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

Clinical Trial Experience

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

The table columns should include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

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

Column H: publication reference(s)

Delayed Onset Study

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

Do not enter a delayed onset study.

PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

4. Submission Dates and Times

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

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

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

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

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 excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
  • Awards issued under this FOA will not be provided the authority to automatically extend the final budget period. All extensions, including the first, will require NCCIH prior approval.
Awards issued under this FOA will be excluded from SNAP.

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

 

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

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

All post-submission materials must be received by the Scientific Review Officer (SRO) no later than 30 calendar days prior to the peer review meeting. In addition to the NIH policy allowed post-submission materials in NOT-OD-19-083, the follow post-submission materials are allowed:

  • Clinical Trial Experience Table (e.g., due to updated enrollment numbers, publication of trial results, or newly started clinical trials)
  • Milestones Plan (e.g., due to the hiring, replacement, or loss of an investigator; change to health care systems participating in the trial; or change in electronic health record or IT infrastructure)
  • Updates to section 4.6 on communications with the FDA in regard to IND/IDE requirements

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.

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.

 

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

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

Specific to this FOA:

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? Could results of the trial have a significant influence on clinical care and improve health? Is there sufficient demonstration for the presence of equipoise?

Is there adequate justification for a remotely delivered design? For pragmatic studies that integrate an intervention into health care delivery, how strong is the evidence of efficacy or effectiveness for the intervention? For studies that propose to improve adherence to established guidelines, how strong is the evidence for the guidelines that are being used? Is there adequate justification for the potential of study outcomes to provide clinically meaningful information to stakeholders?

 

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

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

Specific to this FOA:

How well defined are their roles and responsibilities? How well does the application provide evidence of necessary expertise about the complementary and integrative health intervention, remote-delivery methods, and the study population? How strong is the evidence provided that the investigators will employ the appropriate personnel and strategies to recruit subjects and design/implement the remotely delivered clinical protocol? Does the investigative team have a track record of conducting, completing, and publishing the results of clinical trials?

In addition, for studies proposing pragmatic trials within health care systems: Do teams include appropriate collaborators from the participating health care systems? Do the PD(s)/PI(s) and Key Personnel have the necessary expertise in design and implementation of large-scale clinical studies within a health care system? For example, do they have expertise in using electronic health records for recruitment and outcomes assessment? Do the PD(s)/PI(s) have a track record of successful remote recruitment and retention in prior studies, investigative collaborations or partnerships with (within) health delivery organizations in conducting clinical studies within a health care system?

 

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

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

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

Specific to this FOA:

Does the application include mechanisms for leveraging novel collaboration and study oversight strategies?

 

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?

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?

In addition, for studies proposing pragmatic trials within health care systems: Are the projections for recruitment, ongoing engagement, attrition, and effect size estimations based on data in the proposed health care setting or similar settings? Is the degree of pragmatic aspects of the approaches, measures, design and outcomes well justified for the design elements of the proposed study? Will the results provide relevant information and adequate data for other potential adopting health care settings to determine applicability? Will rigorous controls be included in the design? Will broad but adequate eligibility criteria be used, as proposed? Can interventions be easily implemented? How will the approaches proposed overcome barriers to research in the health care system setting?

Specific to this FOA:

What strengths and weaknesses are there in the study design? 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 strong is the evidence for equipoise? How well does the Clinical Protocol Synopsis describe the necessary elements of the clinical trial and how likely is it that the protocol can be implemented for a fully remotely delivered design? Is the complementary and integrative health intervention appropriately characterized? How well are the clinical outcome measures, dose/duration of intervention and follow up, appropriateness of inclusion/exclusion criteria, and sample size justified and explained? Did the applicant appropriate define the study population? How well does the Recruitment and Retention plan provide evidence that the accrual goals can be reached? Are there adequate plans to recruit a generalizable sample of participants utilizing remote methods? Are there plans for adverse events to be appropriately captured and monitored? Have the investigators described how they will follow Good Clinical Practices, Good Laboratory Practices, and Good Manufacturing Practices as appropriate?

Is there evidence of the ability of the investigators to: (1) enroll the proposed numbers, (2) deliver the intervention, and (3) collect and transmit data in an accurate and timely fashion, all with remote methods?

If the clinical trial is Phase III, does the application include all relevant data to assess whether or not the trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses?

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?

 

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

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

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

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

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

Specific to the FOA:

Is there strong evidence that the environment has the resources necessary to conduct a remotely delivered intervention with remote recruitment, intervention delivery and data collection in a safe, secure, and timely fashion?

For studies proposing pragmatic trials within health care systems: Does the application provide sufficient rationale for the health care system(s) selected for the project? Is commitment from the HCS to the project evident? Has/have the health care system(s) successfully conducted clinical studies, such that there are sufficient infrastructure and expertise (e.g., clinical investigators, informaticists) to implement the proposed pragmatic trial within all proposed health care systems?

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.

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? Does the application address contingency plans in the event the milestones are not achieved?

Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial? Are any safety concerns related to the remote-delivery methods adequately addressed? Are there appropriate safeguards in place to minimize risk?

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)?

 

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

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

 

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.

 

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.

 

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.

 

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.

 

For Renewals, the committee will consider the progress made in the last funding period.

 

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

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.

 

Not Applicable.

 

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).

 

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).

 

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.

 

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications:
  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
  • Will receive a written critique.
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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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

Section 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 grantee’s business official.

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

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

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

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that 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.

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

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

2. Administrative and National Policy Requirements

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

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

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

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
Not Applicable

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 agreementsare required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Application Submission Contacts
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)

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

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

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

Section VIII. Other Information

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