Required Application Instructions

It is critical that applicants follow the 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

Understanding the mechanisms by which complementary or integrative mind and body interventions exert their clinical effects is critical for the development of optimized interventions that target specific conditions and disorders. A phased research plan offers an excellent opportunity to dissociate exploratory mechanistic studies from clinical trials fully powered for efficacy or effectiveness.

The purpose of this funding opportunity announcement (FOA) is to encourage the use of a phased research approach to strengthen our understanding and utilization of the underlying mechanisms and processes associated with mind and body interventions. This FOA will support two-phased research applications to (1) uncover the underlying biological, neurological, physiological, and/or behavioral mechanisms or processes relevant to mind and body interventions (e.g. meditation, spinal manipulation, massage, yoga, tai chi, hypnosis, acupuncture) and then, (2) to utilize the results from the initial phase to improve, refine, enhance, or strengthen the identified mechanisms or processes through either rigorous validation and refinement of the intervention, or using combined approaches that, together, will modulate the underlying mechanism or process. This second phase should also be able to provide preliminary evidence that the mechanism or process modulated by the intervention is associated with a functional outcome or clinical benefit for a specific condition or disorder.

The first phase in the form of an R61 will provide funding for up to two years to support hypothesis-driven pilot testing and assessment of an intervention’s mechanisms of action. The second phase in the form of an R33 will provide up to three years of support for the larger scale validation and/or optimization incorporating the initial findings. Subject to the availability of funds, transition from the R61 to the R33 phase of the award will be administratively reviewed and determined by successful completion of the Go/No-Go Criteria that need to be clearly specified in the R61 phase. This FOA is not appropriate for clinical trials with the primary objectives to determine efficacy or effectiveness. The ultimate goal of this R61/R33 funding mechanism is to facilitate the direct translation of basic mechanistic research to clinical application.

The National Center for Complementary and Integrative Health (NCCIH, formerly the National Center for Complementary and Alternative Medicine) is committed to the rigorous investigation of mind and body interventions to determine their usefulness and safety. Mind and body interventions cover a variety of procedures or techniques administered by a trained practitioner, taught by a teacher, or self-administered to improve function (e.g., improve motor control and balance), and to modulate or reduce symptoms (e.g., pain and anxiety). 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 recruit volunteers selected on the basis of clinical indications and outcomes are 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. The intent of this FOA, therefore, is to encourage clinical research that studies mind and body interventions in two phases: the first phase is to explore and identify the underlying mechanisms of action for a mind and body intervention and to develop methods to assess those mechanisms; and the second phase is to focus on how the putative mechanism or process may be improved, refined, enhanced, or strengthened in relation to a functional outcome or clinical benefit of these interventions. NCCIH views the early-phase R61 of this grant award as an efficient and objective means for examining a proposed mechanism or process that could then directly be applied to improving and optimizing the benefit of mind and body interventions in the second R33 phase.

For this FOA, the putative mechanisms or processes underlying interventions should be studied in volunteers who are the intended beneficiaries of the proposed interventions. The mechanisms or processes could be derived using, but not limited to, epigenetic, biochemical, molecular, cellular, physiological, neurophysiological 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.

Applications submitted to this FOA are likely to cover a large and diverse group of interventions, practices, and disciplines. NICCIH 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, and anxiety; or
• behavior change to promote healthy behaviors such as healthy eating and physical exercise.

The following types of applications will be considered non-responsive and will be withdrawn without being reviewed:

• 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 R21 FOA, PA-13-303).
• 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 Scientific/Research 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 considered as responsive to this FOA.
• Applications that propose only the R61 phase or only the R33 phase will not be accepted under this FOA. (Applicants who already have sufficient preliminary data to progress to the R33 phase should apply directly to RFA-AT-16-006 (R33) " Innovation Award for Mechanistic Studies of Mind and Body interventions in NCCIH High Priority Research Topics)".

Applicants should 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.

Investigators are encouraged to review the NCCIH Clinical Research Toolbox (http://NCCIH.nih.gov/grants/toolbox) to learn more about NCCIH's requirements for clinical research.

Prospective applicants should note that funding of an R61/R33 does not guarantee support of the R33 phase of the application. In addition, funding of an R61/R33 does not guarantee that NCCIH will accept, or fund, a subsequent full-scale clinical trial application or future mechanistic studies.

Additional information for FDA-regulated interventions

If a device is used as part of the mind and body intervention, investigators must contact the US Food and Drug Administration (FDA), prior to submitting an application, to determine if an Investigational Device Exemption (IDE) application is necessary for the proposed clinical research.

If a device is proposed to enhance the mind and body intervention in the R33 phase, the investigators must contact the FDA prior to the transition to the R33 phase to determine if an IDE application is necessary for the proposed clinical research.

The R61 Phase

The primary goal of the R61 phase supported under this FOA is to identify and pilot test the hypothesized mechanisms of action affected by the proposed mind and body intervention in healthy subjects or a targeted clinical population. A randomized intervention design, although not required, is encouraged for this phase of study. An intended clinical or functional outcome for the proposed intervention is not required for the R61 phase, but may be included to give a preliminary assessment of the relevance of the presumed mechanism to the intended clinical outcome. The effects of the intervention on the proposed mechanisms should be adequately powered statistically.

At the completion of the R61 phase, investigators are expected to provide the following as appropriate:

• Adequate evidence that the operational mechanism of action measures can be reliably and validly monitored and manipulated in humans;
• Demonstration of adequate impact on the mechanism by the proposed intervention to provide a basis for subsequent clinical studies;
• Development of the protocol, data and safety monitoring plan, and manual of operations/procedures development for the planned R33 phase project; and
• Completion of necessary regulatory approvals for proposed R33 clinical studies (e.g., IRB, FDA).

The R33 Phase

The success of the R61 phase completion will be administratively reviewed by NCCIH and funding for the R33 phase is contingent on the following: 1) meeting the Go/No-Go Criteria articulated in the R61 phase; 2) the availability of funds; and 3) NCCIH and regulatory approval of the planned R33 activities (study documents, IRB, and if applicable IDE).

The primary goal of the R33 phase is to validate the measures of the hypothesized mechanisms or to optimize the effects on the postulated mechanisms developed in the R61 phase. In most cases, a randomized clinical design will be appropriate for the R33 phase, with the choice of the control group determined by the needs for testing the specific mechanism or process. Blinding of subjects and objective methods of assessment using blinded raters should be employed whenever possible. Due to the pilot nature of the R33 phase, the proposed study is not expected to be fully powered for efficacy or effectiveness of the clinical outcome. Instead, the minimal requirement for the R33 studies is that they should be statistically powered for the effect on the postulated mechanism. Nevertheless, examination of the correlation with clinical outcome(s) is of value for decisions about follow-on studies.

Examples of validation and optimization strategies appropriate for the R33 phase may include, but are not restricted to:

• Validation of the robustness and/or consistency of the relationship(s) between the intervention-induced mechanism(s) and clinical/functional outcome(s) in a more targeted, or a broader, or a larger population
• Development of an approach to modify specific components of the mind and body intervention to enhance the postulated mechanism
• Development or testing a non-invasive device, pharmacologic or behavioral intervention (e.g. therapy) that may augment or modulate the same hypothesized mechanism

Secondary aims in the R33 phase may, but are not required to, include: 1) further testing of the intervention’s feasibility, safety, and acceptability; 2) evaluation and optimization of the frequency or intensity of the intervention/ dose to impact the proposed mechanism or action; and/or 3) developing functional biological signature or psychological process measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials.

This FOA provides support for up to two years (R61 phase) for Go/No-Go Criteria -driven testing of the intervention’s effect on a well-defined, hypothesized biological signature or mechanism of action. If the R61 Go/No-Go Criteria are successfully achieved, there is a possibility of support of up to three additional years (R33 phase) for studies to probe the utility of the proposed mechanism of action to enhance functional outcomes in a larger sample or clinical symptoms. If an R33 is awarded, the results from the R33 phase studies should provide evidence to inform a decision about whether the proposed modifiable mechanism of the intervention is or is not correlated with the clinical outcome of interest. If the proposed mechanism is correlated with the outcome of interest, the results of the R33 would further inform whether the mechanistic insight and the strategy to manipulate the mechanism should be incorporated into further testing to optimize the efficacy or effectiveness of the intervention in a full scale clinical trial.

The application must propose and articulate a well-defined set of Go/No-Go Criteria for the R61 phase. The proposed milestones for the R33 phase may be revised in accordance with activities carried out in the R61 phase.

At the completion of the R61 phase, the applicant will need to submit a transition request for the R33 phase. R33 transition requests will undergo an administrative review to determine whether the Go/No-Go Criteria and other required conditions have been met, pending the availability of funding. In view of the exploratory nature of R61 studies funded via this FOA, it is anticipated that not all funded R61 projects will transition to the R33 phase.

Applicants are encouraged to consult with NCCIH Scientific/Research staff as investigators plan for applications are being developed (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.

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:

• 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

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 not 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).

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the 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:

Dale L. Birkle Dreer, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-480-9483
Email: birkled@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.

Other Attachments: Applicants must upload a single attachment including the following information relevant to the proposed R61 and R33 phases of the study. This attachment must be no more than 5 pages. Applications that exceed this limit will not be reviewed. Applicants should use the headers below in their description. Applications that lack this attachment will be considered incomplete and will not be reviewed.

I. Study Participant and Recruitment Descriptors. Applications must provide a clear description of:

• Recruitment and Referral sources, including detailed descriptions of the census/rate of new cases and anticipated yield of eligible participants from each source;
• Procedures that will be used to monitor enrollment and track/retain participants for follow-up assessments;
• Strategies that will be used to ensure a diverse, representative sample;
• Potential recruitment/enrollment challenges and strategies that can be implemented in the event of enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources);
• Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts employing similar referral sources and/or strategies.

II. Milestones and Timeline: Applications must provide a timeline for reaching important study milestones such as: (a) finalizing the study procedures and training participating clinical site staff; (b) finalizing the intervention manual and assessment protocols, including fidelity measures/procedures, where applicable; (c) enrollment milestones; (d) completing all subject assessments and data collection activities, including data quality checks; (e) analyzing and interpreting results; and (f) preparing de-identified data and relevant documentation to facilitate data sharing, as appropriate.

III. Additional Information for FDA-regulated Pharmacological and Device-based Interventions: For studies using pharmacologic compounds and devices, at the time of the application’s submission, there must be either an open Investigational New Drug application (IND), Investigational Device Exemption (IDE), or a documented FDA-submitted application for an IND or IDE. The grant application should describe the status of any such pending regulatory submissions. If the investigation of the intervention (e.g., drug product, device) meets all requirements for exemption from the IND or IDE regulations and, therefore, an IND or IDE is not required to conduct the investigation, this information should be clearly stated in the grant application. All necessary agreements for use of the compound or device in the study, including clinical research agreements and licensing agreements, must be executed prior to grant award. For pharmacological compounds, there must be documentation of sufficient compound supply and matching placebo (if applicable) available for testing at the time of award, including expiration date. Documentation should include a letter of agreement from the 3rd party supplying the compound or device, if applicable. A timeline should be included in the application showing activities with 3rd parties, such as: 1) executing necessary agreements, 2) providing compound or device, and 3) permission to reference an open IND. Note: Trials to test pharmacological compounds or devices under regulatory control will not be awarded if additional preclinical research needs to be performed prior to conducting the trial.

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.

The R61 and R33 cannot be funded in the same fiscal year.

Budget Justification: For each budget year, indicate if the requested budget is for the R61 phase or the R33 phase. Describe the staffing for conducting the study as proposed and within specified timelines.

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: Applicants should provide brief background information to justify the importance of the topic area and rationale for the proposed hypotheses. This section should also include headers titled R61 Specific Aims and R33 Specific Aims with brief descriptions of key hypotheses, major research approaches, expected outcomes, and alternative interpretations or strategies for each aim in the two phases of this project.

Research Strategy:

Clinical Significance and Biological or Psychological Relevance: Applicants should provide a clear and compelling rationale for pursuing the mechanism of action of the intervention and the proposed clinical impact. There must be a strong rationale as to why the specific complementary and integrative intervention proposed is likely to impact the biological or psychological signature and potentially benefit the clinical condition under study. The application should describe how the proposed project will advance knowledge of the mechanism of action of the intervention.

The clinical significance and relevance of the future clinical trial must include a discussion of how the results of the proposed research (positive or negative) will guide decisions about further clinical studies.

Experimental Design: A proposed protocol for each phase of the application should be presented in the Research Strategy and should include the items listed below as appropriate:

• Preliminary Data: 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
• Intervention: 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; key quantifiable functional or clinical outcome measures to be studied, justification of the target population, and how results may generalize to an extensive population beyond the proposed target population in this study.
• R61 Methodology: a) scientific rationale or preliminary data for the proposed mechanisms; b) justification of the measures to assess the hypothesized mechanism, including how these measures may relate to functional or clinical outcomes to be studied in the R33 phase; c) detailed description of measures to assess the mechanism of action, including quantification method, and test of validity and reliability of the measures. (Note: The protocol may be submitted as an appendix).
• R33 Methodology: a) rationale, justification, and/or preliminary data for the proposed manipulation of the hypothesized mechanism(s) from the R61 phase; b) detailed description of the manipulation process, including justifications for and relevant information about dosing, dose response, intensity, duration, frequency, grouping, initial safety, and/or tolerability ; c) detailed analytic plan to assess the relationship between the mechanistic measures and the clinical or functional outcomes; d) description of the key information to be generated in the R33 phase to justify future large scale mechanistic or efficacy/effectiveness studies. (Note: The protocol may be submitted as an appendix).
• Assessment: description of all 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.
• Management: description of the organization of the research and how it will be managed.
• Data Management and Quality Control: data management and methods for monitoring quality; and methods for fidelity monitoring.
• Statistical Methods: sample size justification; outcome measures; plans for interim and final analyses; methods of bias control; and handling missing data.
• Go/No-Go Criteria for R61: Applications must provide this information in a section indicated by the heading "Go/No-Go Criteria for R61". Adequate effect on the proposed mechanism(s) must be a key criterion of a "go/no-go" decision to move from the R61 to R33 phase. This section should include a clear description of the R61 phase criteria that, if met, will justify taking the proposed intervention into the R33 pilot study. The criteria proposed in the application must be objective, quantifiable, and scientifically justified to allow program staff to assess progress in the R61 phase of an award. The criteria must specify the measures by which they will evaluate whether the intervention affects the mechanism(s) as hypothesized. Criteria must include a description of specific, quantitative threshold values for any measures proposed for go/no-go decision-making. The proposed criteria should describe projected specific, measureable and achievable progress throughout the project period, which can be used as an indicator of success.
• Subsequent Studies beyond the R61/R33: A brief summary of the subsequent studies, either with clinical efficacy as the primary goal or with further mechanistic investigation as the goal.

As outlined above, applicants should provide a clear and logical rationale for: (1) why the proposed mechanisms or processes are relevant to the mind and body intervention to be studied, (2) how mechanisms or processes are related to the clinical condition or outcome associated with the intervention, and (3) how understanding such mechanisms or processes could improve the intervention and lead to enhanced clinical outcomes.

As outlined above, the proposed mechanisms or processes would need to be assessed using objective, quantifiable, and reproducible measures. Applicants should provide detailed descriptions of the measures and a strong rationale for choosing such measures. In addition, applicants should discuss or present evidence on whether the proposed mechanism or process can be manipulated directly or indirectly in human subjects by other approaches beyond the original mind and body intervention.

As outlined above, applicants should provide separate but related objectives for the R61 and the R33 phases of research. The applicant must justify the need for the R61 phase. The Go/No-Go Criteria in the R61 phase should be clearly described and defined to allow for the determination of the continuation to the R33 phase. The implications of the R33 results for future research should be clearly described.

Human Subjects Protections: Applications must include a Data and Safety Monitoring Plan (DSMP)

that is commensurate with the study size, complexity, and risks posed to study participants (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html). The DSMP provides a general description of a monitoring plan that will serve as the overall framework for data and safety monitoring of the study. The DSMP must be included in the study protocol and address the following elements:

• Who will perform the monitoring?
• What data will be monitored?
• What is the planned frequency of monitoring?
• What policies and procedures will be implemented to ensure confidentiality of subject identifiers and accuracy/completeness of accumulating data throughout the monitoring process?
• What are the timeframes for reporting unanticipated problems and serious adverse events to NCCIH and applicable regulatory agencies?

As part of general oversight and scientific leadership of the study, the study’s PD/PI is expected to play an integral role in the data and safety monitoring of the study. In addition, 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 human subject protections section must also provide the following:

• A list of participant eligibility criteria or group eligibility criteria.
• Methods for ensuring participant confidentiality.

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..

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.

The following documents may be submitted as an appendix of the application:

• Draft study/clinical protocols for the activities proposed for the R61 and R33 phases.
• Draft informed consent form(s) (ICFs) and, if applicable, assent form(s). The applicant should consider including language in the ICF to allow broad data and specimen access for subsequent research in order to maximize the value of subject samples and data and accelerate progress beyond the trial itself.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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 R61/R33 phased innovation grant supports investigation of novel scientific ideas as applied to new or existing interventions, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R61/R33 grant application need not have preliminary data, extensive background material, or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data, to strengthen the proposal hypothesis. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R61 and R33 phases.

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

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

Does the project address an important problem or a critical barrier to progress in the field? 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 there a sufficient body of preclinical or clinical research of high scientific rigor to support the study rationale? Does the applicant provide justification as to why it is important to perform the future larger clinical study in the context of the present knowledge on clinical research in mind and body interventions? Is it clear why the proposed exploratory research is essential to inform the design and implementation of subsequent steps in the evaluation and optimization of the intervention? Is the proposed project likely to yield clear answers needed to proceed to the next step of research as proposed in this application? Will the proposed study advance knowledge of intervention or disease mechanisms, whether the results are positive or negative?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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? Has the investigative team have adequate experience in recruiting clinical populations?

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? Is proposed research highly innovative and have the potential to advance or transform the field by breaking ground for future clinical research with high public impact?

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

Does the proposed study ensure that the underlying hypothesized mechanism of action is appropriate and relevant, and will be rigorously tested? Is the need for the R61 phase well justified?

Does the R33 phase include sound methodology for (a) enhancing the initial impact on the mechanism of action from the R61 phase, and (b) evaluating associations between biological or psychological mechanisms and subsequent clinical or functional change?

Does the applicant describe how the proposed study relates to a larger strategy for research of this intervention and will it provide pilot and feasibility data needed to advance that strategy? Does the application demonstrate the feasibility of methods for developing tools for data management and study oversight, finalizing protocol documents and manuals, as well as addressing appropriate regulatory requirements (FDA, IRB)? Are the outcome measures, dose/duration of study, appropriateness of inclusion/exclusion criteria, and sample size clearly justified and explained in the application? Is the proposed design feasible and adequate to provide interpretable results?

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?

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?

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.

R61 Go/No-Go Criteria: Are quantitative criteria pre-specified and rigorously defined to assess achievement and operational feasibility relevant to advancing from the R61 to the R33 phase? Are the R61 Go/No-Go Criteria feasible, well developed, and quantifiable? Specifically, will NCCIH officials be able to determine if the project succeeded in accomplishing its specific aims. Does the application specify conditions under which they would not proceed to the R33 phase?

R33 Milestones: Are appropriate, evaluative milestones clearly defined for the aims associated with the R33 phase? Are R33 milestones feasible, well developed, and quantifiable with regard to the specific aims? Is the timeline feasible? Are the plans for sample size and timely recruitment of subjects feasible? Is there a clear strategy for tracking recruitment and facilitating retention? Will sufficient and appropriate data be collected in the R33 phase to inform a decision on whether further clinical efficacy or effectiveness testing or additional mechanistic investigation is warranted?

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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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.

Not Applicable

Not Applicable

Not Applicable

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.

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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.

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.

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.

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.

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

eRA Commons Help Desk (Questions regarding 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 CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (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

Dale L. Birkle Dreer, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-480-9483
Email: birkled@mail.nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCHI)
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.