It is critical that applicants follow 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 the 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.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of Mind and Body Interventions to determine their safety and usefulness. For the purposes of this FOA, Mind and Body Interventions are non-pharmacological approaches that include mind/brain focused interventions (e.g., meditation, hypnosis), body-based approaches (e.g., acupuncture, massage, spinal manipulation/mobilization), meditative movement approaches (e.g., yoga, tai-chi, qigong), or some combinations of these approaches. More about the current Mind and Body Interventions supported by the NCCIH may be found at http://nccih.nih.gov/health/integrative-health.

Traditionally, exploratory clinical trials research of Mind and Body Interventions recruits volunteers selected based on clinical indications with outcomes focused on symptom reduction or improvement in some specified functional outcome. Such research, whether positive or negative with respect to an intervention’s ability to modulate symptoms or functional outcomes, provides little information about how the intervention might work in relation to the putative underlying cause or mechanisms associated with the clinical condition. Nor does it offer insight into how the interventions may be optimized or improved. Thus, mechanistic studies of Mind and Body Interventions are critically needed prior to a full-scale efficacy study.

Generally, mechanistic studies of Mind and Body Interventions comprise three key elements. The first key element is the intervention itself, which commonly contains complex procedures or techniques administered by a trained practitioner, a teacher, or is self-administered to improve function and/or to modulate or reduce symptoms with certain conditions such as pain and anxiety. The second key element is the biologically-based mechanism(s) or behavioral process(es) by which a given Mind and Body Intervention may exert its intended functional or clinical outcome. The mechanism(s) or process(es) may range widely from biochemical/molecular mechanisms to behavioral processes. Commonly studied mechanisms of action for Mind and Body Interventions include structural and/or functional changes in physiological systems, and networks including parasympathetic and sympathetic neural systems, cortical and subcortical neural networks, neuromuscular systems, or activation of endocrine, immunological, vascular and lymphatic systems. The third key element is the intended functional or clinical outcome for the intervention.

The intent of this FOA, therefore, is to support research that focuses on how an intervention's putative mechanism(s) or process(es) may be improved, refined, enhanced, or strengthened in relation to a functional outcome or clinical benefit. Overall, the goal of this R33 grant funding opportunity is to support research to improve and optimize the benefit of a Mind and Body Intervention.

The primary objective of this R33 FOA is to support research to develop and evaluate strategies to optimize previously demonstrated mechanisms or processes underlying proposed Mind and Body Interventions.

Applicants are expected to develop a detailed description of the Mind and Body Intervention they propose to use in this context. The mechanisms or processes to be optimized would need to be assessed using objective, quantifiable, and reproducible measures. Applicants are also expected to develop detailed descriptions of the measures and a strong rationale for choosing such measures. Prior evidence for the mechanistic effects to be studied under the R33 must be already be known and described from, for example, a well-controlled randomized interventional study. Applicants are encouraged to refer to http://www.ClinicalTrials.gov for a review of the registered trials already underway or completed to help determine whether: 1) the results of ongoing trials can inform the design of the proposed study, and 2) the proposed study is innovative.

In general, there are three major types of intervention optimization strategies for studying the proposed mechanisms or processes. The first type may focus on modifying the complex Mind and Body Interventions per se, so that the active components of the intervention may be enhanced while the inactive or irrelevant components of the intervention may be minimized. For this type of optimization strategy, a prior study must have demonstrated that a specific component of a complex Mind and Body intervention is at least moderately better than a well-controlled intervention that lacks this specific component(s). The second type of optimization strategy may enhance the mechanistic effects of the proposed Mind and Body Interventions by adding other interventions (e.g., non-invasive devices, natural products, or pharmacological interventions) that have been previously shown to modulate the same mechanisms or processes to explore possible additive or synergistic effects. The third type of optimization strategy would be to select a targeted population that might benefit from the hypothesized mechanisms or processes modulated by the intervention. For this type of optimization strategy, it is important to provide preliminary evidence that the hypothesized mechanisms or processes are relevant for the proposed clinical population. Based on such preliminary results, the grant application would examine whether the mechanisms or processes using the proposed intervention significantly change and possibly amplify the mechanistic effects in a target population. For the R33, investigators may choose to optimize the proposed Mind and Body Intervention using any one or a combination of these strategies.

The R33 studies are expected to adhere to clearly defined inclusion and exclusion criteria of study participants as well as feasible recruitment plans, milestones, and timeline. In addition, the R33 is expected to have justifications, as appropriate, for the proposed intervention's dose-response (i.e., frequency and duration of the intervention), initial safety, and tolerability data for the proposed intervention. Although not required, secondary aims in the R33 may include: 1) further testing of the intervention’s feasibility, safety, and acceptability; 2) evaluation and optimization of the frequency or intensity of the intervention to determine impact on the proposed mechanism or processes; and/or 3) development of functional biological signature or psychological process measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials. Research submitted under the R33 grant funding mechanism is expected to be fully powered to demonstrate an effect on the hypothesized mechanism or process using a proposed intervention with an appropriate comparison group. Applications submitted under the R33 grant funding mechanism, however, are not expected to be fully powered to determine efficacy or effectiveness of an intervention. Nevertheless, examination of clinical outcome(s) is of value for making decisions about follow-on studies. In most cases, a randomized clinical design will be appropriate for the R33, with the choice of the control group determined by the needs for testing the specific mechanism or process. Masking of subjects and objective methods of assessment using masked raters is expected to be employed whenever possible. Masking procedures are expected to be clearly specified for the study participants/patients, instructors/practitioners, outcome assessors, data analysts/statisticians, and principal investigators. Investigators are expected to review the NCCIH Study Accrual and Retention Policy (https://nccih.nih.gov/grants/policies/SARP).

All projects under this FOA will need to adhere to the US Food and Drug Administration (FDA) regulations if a device or drug will be used in the proposed research. In these cases, investigators must work with the FDA to determine if the study will need to be conducted under an Investigational New Drug application (IND) or Investigational Device Exemption (IDE).

This FOA supports research exploring putative mechanisms or processes underlying Mind and Body Interventions intended for human participants. The mechanisms or processes proposed for study could use epigenetic, biochemical, molecular, cellular, physiological, neurophysiological, or behavioral methods. They could be tissue- or organ- specific mechanisms or measures of psychosocial and behavioral processes, such as stress reactivity, self-regulation, sustained attention, or social, interpersonal, or somatic processes that are relevant to the proposed intervention. This FOA is not intended to support work exclusively focusing on the characteristics of practitioners or of health care settings in which the intervention is delivered. Such characteristics, however, may be included for study if a strong rationale can be made for their importance in modulating the putative underlying mechanism or process associated with an intervention.

Research applications submitted under this FOA are likely to cover a large and diverse group of complementary integrative health interventions, practices, and disciplines. NCCIH is, however, interested in: (1) interventions that have compelling evidence for potential health benefit; (2) interventions with evidence that they can exert a plausible and measurable biological or psychological effect; and (3) practices that are widely used by the American public. For this FOA, therefore, NCCIH considers the following topic areas/clinical outcomes to have high program priority for study with Mind and Body Intervention:

• pain and pain management;
• sleep and sleep disturbances;
• symptomatic conditions, such as those associated with menopause;
• management of mental health conditions commonly managed in primary care such as mild to moderate depression, or anxiety;
• behavior change to promote healthy behaviors such as healthy eating and physical exercise.

The following types of applications are not appropriate for this FOA:

• Exploratory studies that only utilize in vitro or animal models. (Basic mechanistic studies using in vitro or animal model systems are of high interest and priority to NCCIH; but at this time such applications should respond to the investigator-initiated R01 FOA).
• Clinical trials solely to estimate intervention effect size or power calculations for a future trial.
• Fully powered clinical trials proposing to test efficacy or effectiveness as the primary outcome. (Investigators aiming to test efficacy or effectiveness as the primary outcome should consult with NCCIH program staff and identify other appropriate FOAs to respond to).
• Applications that do not propose to measure mechanisms or processes as described above.
• Applications that propose to test Mind and Body Interventions for the treatment or prevention of cancer or symptom management in a cancer or cancer survivor population. (Investigators interested in cancer treatment or prevention or cancer treatment or survivor patient populations should contact the National Cancer Institute). However, studies using a cancer or cancer survivor population to explore mechanisms or processes of Mind and Body Interventions for high priority topics as described above, which could be potentially generalizable to other non-cancer populations, may still be appropriate for this FOA.

Applicants are encouraged to consult with NCCIH Scientific/Research staff before investigators begin developing their applications (see Section VII, Agency Contacts). This early contact will provide an opportunity to clarify NCCIH policies and guidelines for clinical research and determine whether the research topic is a fit with NCCIH's mission and priorities. Investigators are encouraged to review the NCCIH Clinical Research Toolbox (http://NCCIH.nih.gov/grants/toolbox) to learn more about NCCIH's requirements for conducting clinical research.

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

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. 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) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

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.

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

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).

Buttons to access the online ASSIST system or to download application forms 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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

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

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

The letter of intent should be sent to:

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

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

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.

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

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

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

All instructions in the SF424 (R&R) Application Guide must be followed. As appropriate, Senior/Key Personnel should demonstrate their expertise and track record in clinical research, including expertise in the recruitment and retention of human subjects and methodological and statistical expertise. Also include recent collaborative clinical research efforts among members of the proposed team, if any. Describe the expertise within the research team in the measurement methods proposed (e.g., PET, fMRI, MRS).

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

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

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

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

Specific Aims:

In the single attachment allowed for the specific aims, applicants should provide brief background information to define the proposed Mind and Body Intervention, justify the importance of the topic area, outline the knowledge gap relevant to the proposed study, and provide rationale for the proposed hypotheses. The investigators should clearly indicate the optimization strategy and a brief justification with either preliminary data or existing literature for such a strategy. This page should also include headers titled R33 Specific Aims with brief descriptions of key hypotheses, primary mechanistic measures, secondary/alternative mechanistic measures, major research approaches, associated clinical or functional outcomes, and alternative interpretations or strategies. The investigators should also have at least one statement about innovation of the proposed hypothesis, and the general impact of the proposed study.

Research Strategy:

Note: Discuss the overall approach but do not duplicate information collected in the PHS Human Subjects and Clinical Trials Information Form.

Clinical Significance, Rationale, and Biological or Psychological Relevance:

• Applicants should describe the general clinical significance of the proposed Mind and Body Intervention and a detailed definition of the proposed Mind and Body Intervention.
• Applicants should also describe and define the proposed primary mechanism to be optimized. There must be strong evidence, either based on relevant prior studies or the investigators own preliminary data, as to the impact of the specific mind and body intervention proposed on this mechanism or process as well.
• Applicants should provide theoretical rationale to support the proposed optimization strategy to enhance the impact of the specific mind and body intervention on the proposed mechanisms of action or processes. The application should also describe how the proposed project will advance knowledge of the mechanism of action of the intervention.
• Applicants should describe the relevance of the populations as well as associated clinical or functional outcomes to be studied in the R33 application to the proposed intervention and mechanisms. Applicants may include a discussion of how the results of the proposed research (positive or negative) will guide decisions about further clinical or mechanistic studies.

Approaches: This section should include the items listed below as appropriate:

• Intervention: Key preliminary data to justify the need to study the proposed mind and body intervention either based on the existing literature or from unpublished data.
• Primary Mechanisms: 1) Preliminary data and adequate justification based on relevant prior studies, either on biological mechanisms and clinical benefits in disease models, or from pilot human clinical studies conducted by the investigative team or from the scientific literature, should be presented as the evidence that the proposed mind and body intervention modulates the proposed mechanism of action or process. 2) Justification of the chosen measures to assess the proposed mechanism, including any preliminary data or existing literature to show how such a mechanism has been measured and studied, should be presented. 3) Detailed description of measures to assess the mechanism of action, including quantification method, and test of validity and reliability of the measures must be presented.
• Associated Functional/Clinical Outcomes: Preliminary data or existing literature to support the relevance of the functional or clinical outcomes to the proposed interventions and the hypothesized primary mechanisms.
• Methodology: 1) additional preliminary data or existing literature to support the proposed optimization strategy, including whether the proposed optimization strategy has been previously shown to modulate the same or related mechanisms of action or processes as the proposed mind and body intervention; 2) detailed description of the optimization strategy with a schematic diagram; 3) detailed analytic plan to assess the relationship between the mechanistic measures and the clinical or functional outcomes; 4) discussion of alternative interpretations of results and strategies.

Data Management and Quality Control: data management and methods for monitoring quality; and methods for fidelity monitoring.

Subsequent Studies beyond the R33: A brief summary of the subsequent studies, either with clinical efficacy as the primary goal or with further mechanistic investigation as the goal.

Letters of Support: Applicants are also encouraged to include documentation of the commitment of any collaborators, subcontractors, and consultants, as well as service agreements for personnel or facilities. Letters of commitment should be co-signed by the business official of the collaborating center.

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, with the following modification:

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

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a 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, with the following additional instructions:

3.3 Data Safety Monitoring Plan:

The investigators are encouraged to use the NCCIH template as a suggested format for the Data and Safety Monitoring Plan (DSMP).

In addition, NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring).

4.2. Study Design

Interventions: 1) justify the choices of the control groups and why such groups may adequately test the hypothesized mechanistic effects, including any preliminary data or evidence from the existing literature; 2) description of the mind and body intervention to be tested, including any relevant and known biological processes, choice of dosing, intensity, duration, frequency, and grouping as appropriate.

4.3 Outcome Measures

Associated Functional/Clinical Outcomes: 1) clear justification and description of the target population; 2) specification of the measures for the functional or clinical outcomes quantitatively, either based on preliminary data or existing literature, and how these measures may relate to functional or clinical outcomes.

Additionally, a description of all secondary assessments or measures including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes, including those available through PROMIS, NIH Toolbox, and NeuroQoL, as well as non-traditional data collection approaches are encouraged if appropriate.

4.4 Statistical Design and Power:

1) specify the effect change of the primary mechanistic measure and statistical analysis methods to be employed; 2) define the number of subjects per group and provide power calculation to demonstrate why the proposed numbers of subjects are sufficient to ascertain the effect of the proposed intervention on the hypothesized mechanism; 3) any additional statistical issues related to interim analysis and missing data handling.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

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.

This initiative is not subject to intergovernmental review.

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.

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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.

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

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. NCCIH Policy for applications requesting direct costs of $500,000 or more in any one year can be found at https://nccih.nih.gov/grants/policies/over500k.

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R33 FOA supports highly innovative mechanistic studies of Mind and Body Interventions allowing for rapid translation of prior mechanistic insights into clinically relevant optimization strategies. A R33 grant application must have adequate preliminary data to demonstrate that the proposed mind and body intervention and the proposed optimization strategy modulate the proposed mechanism or process, through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the level of innovation, the adequate premise of the preliminary data, the potential to significantly optimize the proposed intervention, and the rigor of the proposed experimental designs.

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).

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

Reviewers will 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 there a strong scientific premise for the project? 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?

Is the proposed optimization strategy likely to enhance the chosen Mind and Body Intervention on the proposed mechanism of action? Is the optimization strategy likely to improve the relationship between the chosen mind and body intervention and the associated clinical or functional outcomes? Are there enough preliminary data and/or evidence for the impact of the chosen mind and body intervention on the mechanism or process and the proposed optimization strategy to enhance the mechanistic effect?

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 the trial needed to advance scientific understanding?

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?

Does the application provide strong evidence of necessary experience and expertise with the intervention, the study population, and the research methods to be employed? Does the investigative team have a track record of publishing the results of previous studies in high impact journals? Does the investigative team have adequate experience in recruiting clinical populations?

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?

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 proposed research have the potential to advance or transform the field by breaking ground for future mind and body intervention research with high public impact? Is the proposed optimization strategy novel for strengthening the primary mechanism of action?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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?

1) Does the application include sound methodology for (a) enhancing the initial impact on the mechanism of action demonstrated in previous studies, and (b) evaluating associations between biological or psychological mechanisms and subsequent clinical or functional change? 2) Is the hypothesized mechanistic effect by the proposed optimization strategy statistically powered with adequate justifications? 3) Are the choices of control group(s) appropriate to test the proposed optimization strategy? 4) Are the outcome measures, dose/duration of study, appropriateness of inclusion/exclusion criteria, blinding, and sample size clearly justified and explained in the application? 5) Is the proposed design feasible and adequate to provide interpretable results? 6)) Does the application include clearly defined milestones with feasible timelines and rates of subject recruitment and retention?

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 children, justified in terms of the scientific goals and research strategy proposed?

Are the plans for recruitment outreach appropriate and are there follow-up procedures to ensure collection of data at stated intervals? Are the retention plans and practices described? Are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable:

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?

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?

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?

Does the application provide a reasonable assurance that the target sample size can be enrolled in the timeframe proposed? Does the application include information about the availability of the requisite subject pool in proposed clinical center(s)? If applicable, is there documentation of the commitment of any collaborators, subcontractors, and consultants, as well as service agreements for personnel and facilities?

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

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.

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 the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six 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 children 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.

Not Applicable

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.

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.

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.

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.

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.

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

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

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

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

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

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 law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. 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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Grants Info (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Wen G. Chen, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: chenw@mail.nih.gov

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

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

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

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