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

The National Center for Complementary and Integrative Health (formerly the National Center for Complementary and Alternative Medicine) is committed to the rigorous investigation of promising natural products, including herbal medicines, botanicals, products marketed as dietary supplements, and probiotics. Products with high research priority include those for which there is compelling preclinical evidence for potential health benefit, and/or products that are widely used by the American public. Clinical trials of natural products are maximally informative if they incorporate well-formulated biological hypotheses, are built on a sound foundation of basic mechanistic and pharmacologic understanding, and incorporate assessment of defined signatures of biological effects. Thus, the design of maximally informative clinical efficacy trials of natural products requires mechanistic insight as a first step.

For this funding opportunity, the term natural products refers to botanicals, dietary supplements, and/or probiotics. This funding opportunity addresses the next steps in research for natural products that have shown clear-cut preliminary benefit using in vitro, animal models, and/or human models to determine whether they provide definitive benefit in humans or have any deleterious side effects. For larger clinical trials to be impactful, they must be well designed and include biological hypotheses that will inform decisions about the appropriate use of the natural product. A series of early-phase clinical trials may be required to gather the necessary preliminary data to design large and rigorous efficacy studies. The purpose of this Funding Opportunity Announcement (FOA) is to encourage Phased Innovation (R21/R33) grant applications that focus on the early phases of natural product development, during which basic and mechanistic research is translated into clinically testable hypotheses and tested in healthy volunteers or a clinical population. In this approach, clinical studies and trials should be designed to increase knowledge of the use of the intervention, the underlying condition and the mechanism of action through which the natural product produces clinical benefit.

Although the scientific literature may provide the rationale for conducting a clinical trial, investigators often lack critical information about the bioavailability, pharmacokinetics, and/or the mechanism of action to achieve a clinically meaningful effect. Exploratory clinical studies and trials supported under this FOA can fill this information gap. To elucidate the optimal clinical research strategy, a number of preliminary steps may be necessary. These steps may include demonstrating bioavailability in humans; providing pharmacokinetic or pharmacodynamic data to optimize the dose of the product; determining the appropriate biological marker(s) or objective outcome measures; establishing safety parameters in a new patient population; or providing additional pre-clinical work required by the Food and Drug Administration for the Investigational New Drug documentation.

A study submitted to this FOA must propose a way to measure the effect of the natural product in humans as a biological signature. This biological signature may be a measure of the postulated mechanism of action by which the natural product might ultimately modify the clinical condition or symptom(s) of interest. Biological signatures may be molecular/cellular, neural circuit, tissue/organ, somatic, commensurate with the natural product and specific aims of the study.

Exploratory intervention trials submitted to this FOA should not be scaled down randomized controlled trials (RCTs) that propose to test the efficacy of the natural product on clinical outcomes. It is expected, however, that results obtained under this NCCIH R21/R33 FOA could lead to submission of subsequent grant applications to support such studies. Indeed, as described below, depending on the stage of intervention development, the R21/R33 project might not involve randomization to a placebo, but rather might focus on earlier stages, such as dose escalation, pharmacokinetics, or pharmacodynamics studies. Investigators should keep in mind the future envisioned trial in designing the R21/R33 to provide the necessary supporting data for a future efficacy trial.

Applications should be based on a clear and compelling rationale for pursuing the study and developing the intervention, including other critical aspects of the research design (e.g., dose, dosing frequency and duration, choice of endpoints of interest, etc.). There should be a rigorous empirical basis for the proposed study, which may be based on animal studies that demonstrate biological mechanisms suggesting clinical benefit; alternatively, the empirical basis may be based on human clinical studies. Regardless, there must be a strong rationale as to why the specific natural product proposed is likely to benefit the clinical condition or indication under study. Studies must include an examination of a defined biological signature, based on empirical evidence of biologic processes and a clear hypothesis about how the natural product will alter the biological signature and lead to functional improvement and/or clinical benefit(s).

This FOA provides support for up to two years (R21 phase) for milestone-driven testing of bioavailability, short term pharmacokinetics and toxicity testing, and/or demonstration of the natural product’s effect on a well-defined, hypothesized biological signature or mechanism of action. If the R21 milestones are successfully achieved, there is a possibility of support of up to 3 additional years (R33 phase) for studies to confirm the natural product's effect on the biological signature in a larger sample and to assess the relationship between the biological signature and changes in functional outcomes or clinical symptoms. If an R33 is awarded, the results from the R33 phase studies should provide evidence to inform a decision about whether further clinical testing of the natural product is warranted.

This FOA encourages highly innovative projects, with the recognition that such projects may entail a greater failure rate. NCCIH values this early, efficient, and objective testing of an intervention’s proposed mechanism of action to better define which natural products should or should not be further tested. This FOA uses a phased innovation approach (R21/R33) to manage the risk by requiring a demonstration of the intervention’s direct effects on a biological signature, and human bioavailability before moving into the R33 phase of the award.

Potential applicants are encouraged to contact Scientific/Research staff as far in advance as possible to discuss the match between potential research applications and current NCCIH priorities.

Traditionally, exploratory clinical trials of natural products involve subjects selected on the basis of clinical indications and outcomes focused on symptom reduction. Such trials, whether positive or not with respect to symptom change, deliver little information about how the natural product might work in relation to the underlying cause of the clinical condition and therefore provide little guidance for further natural product research. Consequently, NCCIH intends to support clinical research that studies natural products in stages. The first stage is to demonstrate that the natural product is bioavailable in humans and exerts some measurable effect on a hypothesized biological signature or mechanism of action; the natural product is used as a probe with the immediate goal of determining whether the natural product affects a biological signature rather than attempting to demonstrate a clinical treatment effect. Biological signatures may be molecular/cellular, neural circuit, tissue/organ, somatic, commensurate with the natural product and specific aims of the study. Once bioavailability and impact on a biological signature are demonstrated, measures of the biological signature can then be related to clinical outcomes to test the hypothesis that the biological signature is relevant to the clinical condition under study.

As NCCIH’s clinical research portfolio matures, NCCIH has identified certain areas of high priority. Particular focus is management of conditions for which natural products are used by the public and have biologic plausibility. For this FOA, NCCIH considers the following two general topic areas to have high program priority:

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

NCCIH also encourages applications to this FOA that address health disparities, symptom management in patients with HIV/AIDS, and/or utilize special populations such as older adults, children, individuals in the military, or veterans.

This NCCIH R21/R33 FOA will not support studies that only utilize in vitro or animal models (i.e., studies involving human participants must be included in the application); nor will it support fully-powered randomized trials designed to test efficacy or effectiveness. For product dosing studies, randomization to a placebo treatment may be employed if a zero dose is needed for analytic comparisons. Other FOAs should be considered for applications with aims to assess efficacy. Applications proposing research in topics not identified above as high programmatic priority will be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce the likelihood of funding.

Examples of studies that would be considered non-responsive to this FOA and will not proceed to review include:

• Clinical trials solely to estimate intervention effect size or power calculations for a future trial.
• Applications that do not propose to measure biological signatures or mechanisms of action.
• Clinical trials proposing to test efficacy or effectiveness.
• Applications that propose to test natural products for the treatment or prevention of cancer (Investigators interested in cancer treatment or prevention should contact the National Cancer Institute).

The R21 phase focuses on testing whether the proposed natural product actually alters the presumed biological signature or mechanism of action, whether the product is bioavailable in humans, and short-term testing of pharmacokinetics, pharmacodynamics, safety, and/or toxicity. The specific activities and milestones appropriate for the R21 phase will depend on the specific natural product under study and its stage of development. Generally, these activities and milestones include: 1) operational definition and objective measures of the biological signature in humans (i.e., the hypothesized mechanism of action); 2) evidence that the operational mechanism of action measures can be reliably and validly manipulated in humans; 3) demonstration of adequate impact on the biological signature to provide a basis for future subsequent dosing studies in humans; 4) demonstration of human bioavailability of the natural product (if necessary for biological effect), and short term human pharmacokinetic data as a basis for subsequent human dosing studies; 5) feasibility data to indicate that an adequate dose of the natural product (defined by biological signature) can be applied in the select human population with adequate safety and tolerability; 6) protocol, data and safety monitoring plan, and manual of operations/procedures development for the planned R33 phase project; and 7) completion of necessary regulatory approvals for proposed R33 clinical studies (e.g., IRB, FDA).

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 and NCCIH s policy on natural product integrity (http://NCCIH.nih.gov/research/policies/naturalproduct.htm)

Applications that propose only the R21 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-16-002 "Exploratory Clinical Trials of Natural Products in NCCIH High Priority Research Topics (R33)".

Investigators must contact the US Food and Drug Administration (FDA) prior to submitting an application, to determine if an Investigational New Drug (IND) application is necessary for the proposed clinical research.

Applicants should refer to 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 trial and 2) the proposed trial is innovative.

Funding for the R33 phase is contingent on successfully meeting the milestones in the R21 phase, as well as other factor as described in Section VI. Award Administration Information, 1. Award Notices. Milestones completion will be administratively reviewed by NCCIH to determine whether R33 funding will be awarded.

The R33 phase should confirm the link between the degree of the impact on the biological signature and mechanism-based functional outcomes in a patient population. Pilot studies supported by the R33 should not be powered as strong tests of clinical efficacy, but rather should test a hypothesis about the intervention’s mechanism of action and inform a decision about whether the natural product warrants further study. In addition to prior demonstration of impact on the biological signature, preliminary data for proposed R33 studies should include pharmacokinetics, initial safety, and tolerability data, as appropriate, to justify the stage of the study. In addition to the primary aim of linking the biological signature and functional outcomes, secondary aims in the R33 phase may include: 1) further testing of the intervention’s feasibility, safety, and acceptability; 2) evaluation and optimization of the natural product dose to impact the biological signature; 3) determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the biological signature; 4) preliminary testing of the association between a change in the biological signature and clinical outcomes; 5) evaluating the feasibility of recruitment, randomization (if appropriate), retention, assessments, and reporting of adverse events; and 6) developing functional biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials. The specific activities appropriate for the R33 phase will depend on the natural product under study and the stage of the study proposed.

The objective of this NCCIH R21/R33 funding opportunity is to increase the evidence base on which high priority natural product clinical trials are planned. Investigators are encouraged to include relevant stakeholders (e.g., patients, providers, health care systems, etc.) in the planning and execution of exploratory and larger clinical trials. The outcomes of a successful R21/R33 award period are the data necessary to design and carry out a well-executed clinical trial, a decision whether a subsequent study is justified, and/or evidence that additional studies must be completed before proceeding to a full-scale trial. If warranted by the studies conducted, R21/R33 awardees may prepare and submit an application for a subsequent clinical trial during the final year of the R33 award period.

Prospective applicants should note that funding of an R21/R33 does not guarantee support of the R33 phase of the application. Transition to the R33 phase of the project will occur only if an administrative review process recommends that the R21 milestones have been successfully met, and if funds are available. In addition, funding of an R21/R33 does not guarantee that NCCIH will accept, or fund, a subsequent full-scale clinical trial application.

Applicants are encouraged to consult with NCCIH Scientific/Research staff as investigators plans 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 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 allowed.

See NCCIH's guidance on International Health Research http://NCCIH.nih.gov/research/international

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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: 301-451-6570
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.

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

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

Biographical Sketches: Document the Program Director s/Principal Investigator’s experience in leading clinical trials and expertise in the content area of the study or trial, as well as experience conducting trials under an FDA IND. Biographical sketches for all key personnel must be provided. Even exploratory clinical studies will require a multidisciplinary team (clinician, biostatistician, data manager, study coordinator, etc.) and the application should reflect their hands-on involvement in the design and implementation of the study protocol. Applicants are encouraged to provide strong evidence of the study team's qualifications and ability to conduct the proposed as well as future research, experienced investigative team members, and previous investigative experience in related clinical trials.

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

Budget Justification: For each budget year, indicate if the requested budget is for the R21 phase or the R33 phase.

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: Include headers titled R21 Specific Aims and R33 Specific Aims and state the specific objectives of the research effort in the two phases of this project. The primary and major secondary hypotheses to be evaluated must be clearly stated.

Research Strategy:

Clinical Significance and Biological Relevance: Applicants must provide a clear and compelling rationale for pursuing the proposed early-phase clinical studies and development of the intervention, as well as for other critical aspects of the research design. There must be a strong rationale as to why the specific natural product proposed is likely to benefit the clinical condition under study. The application should describe how the proposed project will advance knowledge of the mechanism of the clinical condition or disease under study.

The clinical significance and, when applicable, the biological relevance of the future clinical trial must be clearly stated. It is particularly important that there be discussion of how the results of the proposed research (positive or negative) will guide decisions about whether a subsequent study is feasible or justified, and/or provide evidence that additional studies must be completed before proceeding to a full-scale trial. Objective, quantifiable, and reproducible measures of both biological signature and the natural product’s clinical effects should be detailed in any application submitted to this FOA. A successful application should provide a rigorous response to these two questions: 1) Will the result, whether positive or negative, be informative and provide a definitive test of the hypothesis? 2) Will the results be informative about the potential role of the biological signature in the clinical condition?

Prior Studies and Rationale for Development: The major findings of the preclinical and clinical studies that led to the proposed research should be described. Justification for the study from preliminary data may be presented as results from previous animal studies that demonstrate biological mechanisms and clinical benefits in disease models, or human clinical studies conducted by the investigative team or from the scientific literature. Pilot studies that show the need for, and the feasibility of the trial should also be discussed. Study conceptualization and planning must be at a stage sufficient to allow an assessment of the likelihood of trial success.

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

Study Design: A summary of the proposed protocol for each phase of the application should be presented in the Research Strategy and must include the items listed below:

• Future Clinical Trial beyond the R21/R33: A concise summary of the subsequent proposed trial should be provided including the study design (efficacy, effectiveness, pragmatic, controlled cohort, or case-control study).
• Preliminary data to justify the selection of the specific natural product from available options to be used in the study.
• A description of the natural product to be tested including: name of the product, ingredients of the product, rationale for the product and supplier, proposed methods for product characterization and standardization, rationale for selection, and percentages of marker compounds if applicable. See the NCCIH Policy on Natural Product Integrity for more information (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).
• A description of the target population, why it is an appropriate group to address the proposed hypotheses, and how or if results will generalize to a broader population.
• A description of the study design proposed for each phase of the application (R21 and R33) (e.g., bioavailability, pharmacokinetics, pharmacodynamics, dosing studies, etc.) and the rationale for each study design choice.
• Describe the R21 methodology including: a) the scientific rationale for the measures used to assess the link between the hypothesized biological signature and functional or clinical effect; b) the measures proposed to assess the biological signature. Information on measurement validity and reliability should be included in the application. Describe measurement schedules that are suitable for detecting relevant changes in the biological signature. The approach should be summarized clearly in the application, with specific references to the protocol to be submitted as an appendix (see "Appendix" below).
• Describe the R33 phase methodology, including: a) how the replication and extension of the initial impact on the biological signature findings from the R21 phase will be conducted and b) how this phase will evaluate associations between the biological signature and subsequent clinical or functional change. Describe how sufficient data will be collected in the R33 phase in order to inform a decision about whether further clinical study is warranted. Describe how each proposed measure will contribute to assessment of the relationships between intervention, biological signature, mechanism-based functional outcomes, and/or clinical outcomes.
• A description of all assessments 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 (e.g., telephone, mobile devices, or web-based systems) should be considered if appropriate.
• Descriptions of the organization of the research and how it will be managed.
• Discussion of the challenges expected in implementing the research and how these might be overcome.
• Data Management and Quality Control: Details of efficient data management and methods for monitoring quality; and methods for monitoring the quality and consistency of intervention administration.
• Statistical Methods: Discussion of sample size justification; study outcome measures; plans for interim (if any, with cogent justification) and final analyses; methods of bias control; and methods for handling missing data.
• Milestones and Timeline: For each phase of the application (R21 and R33), applicants should include proposed milestones and a proposed timeline for reaching those milestones such as: a) obtaining regulatory approval of the final protocol; b) establishing agreements with participating industry partners, if indicated; c) finalizing the study procedures and training participating clinical site staff; d) enrolling 25%, 50%, 75%, and 100% of the targeted sample size; and (e) completing all subject follow-up and data collection activities.
• At the time the application is submitted, there must be either an open Investigational New Drug (IND) application, a documented FDA-submitted application for an IND, or a specified plan for an IND submission prior to award. The grant application should describe the status of any such pending regulatory submissions. All necessary agreements for use of the natural product in the study, including clinical research agreements and licensing agreements must be executed prior to grant award. A timeline should be included in the application showing activities with 3rd parties, such as: 1) executing necessary agreements, 2) providing natural product, and 3) permission to reference an open IND.

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 subjects protections section should also provide the following:

• A list of participant eligibility criteria or group eligibility criteria.
• Participant recruitment and retention plans, including a discussion of the availability of participants for the proposed study and the ability of enrollment sites to recruit and retain the proposed number of participants, including women and minority participants. Data supporting recruitment and retention estimates must be provided.
• Methods for ensuring participant confidentiality.

Letters of Support: Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating center. In addition, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; the supplier will meet CMC specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.

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 submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.

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 additional documents should be submitted in the Appendix:

• Draft Clinical Protocol for the activities proposed for the R21 phase. A study protocol must be included as Appendix I. Applications that do not include a draft protocol are incomplete and will not be reviewed.
• 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.

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 R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R21/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. 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 R21 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 natural products? Is it clear why the proposed exploratory research is essential to inform the design and implementation of subsequent steps in the evaluation of the natural product? 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 clinical trials previously completed? Has the investigative team successfully recruited the study population in previous clinical trials? Has the investigative team successfully conducted clinical trials under an Investigational New Drug (IND) application?

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 the field (e.g., by breaking ground for future trials in this area) even if (a) the proposed study design, methods, and intervention are not innovative, and/or (b) the results indicate that further clinical development of the intervention is unwarranted?

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?

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?

Does the proposed study ensure that the underlying hypothesized biological signature is appropriate and relevant, and will be rigorously tested? Is the need for the R21 phase well justified?

Does the R33 phase include sound methodology for (a) replicating and extending the initial impact on the biological signature from the R21 phase, and (b) evaluating associations between biological signature and subsequent clinical or functional change?

Does the applicant describe how the proposed study relates to a larger strategy for research of this natural product 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?

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 information provided in the application give reasonable assurance that the target sample size can be enrolled in the timeframe proposed? Does the application document the availability of the requisite eligible subject pool in proposed clinical center(s)? Is there documentation of the commitment of any 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.

Milestones and Timeline

R21 Milestones: Are quantitative criteria pre-specified and rigorously defined to assess milestone achievement and operational feasibility relevant to advancing from the R21 to the R33 phase? Are success criteria defined in terms of outcomes achieved rather than as tasks completed? Are R21 milestones feasible, well developed and quantifiable with regard to the specific aims of each stage? Is the timeline feasible? Specifically, will the investigators and NCCIH Program Officials be able to determine if the project succeeded in (a) demonstrating that the intervention alters the biological signature or mechanism (thus providing an initial proof of principle), (b) demonstrating human bioavailability of the natural product and/or its active metabolites, and (c) providing preliminary evidence that the intervention can be applied in a clinical population with adequate acceptability and tolerability to patients? Do the interim milestones include a futility analysis to assess feasibility for continuing the study if a measure of biological signature is not sufficiently robust to inform dose selection for a potential R33 phase? Does the application specify conditions under which they would not proceed to the R33 phase? Are likely problems anticipated?

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 whether further clinical testing 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 Wide Association Studies (GWAS) /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 National Advisory Council for Complementary and Integrative Health . The following will be considered in making funding decisions:

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

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.

Prior to funding an application, the NCCIH Program Officer will contact the applicant to discuss the proposed milestones and any changes suggested by the review panel as indicated in the Summary Statement. The Program Officer and the applicant will negotiate and agree on a final set of R21 milestones.

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.

The PD/PI will submit a progress report to the Program Officer upon completion of the R21 milestones. Receipt of this progress report will trigger an administrative program review that will determine whether or not the R33 should be awarded. Key criteria for the approval of R33 phase award include at a minimum: 1) Adequate demonstration of impact on the biological signature; 2) human bioavailability of the natural product or its active metabolites (if necessary for activity); and 3) NCCIH and regulatory approval of the planned R33 activities (study documents, IRB, and IND). The release of R33 funds will be based on successful completion of negotiated scientific milestones, on program priorities, and on the availability of funds.

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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

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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)
Telephone: 301-710-0267
Email: GrantsInfo@nih.gov

Wendy Weber, ND, PhD, MPH
National Center for Complementary and Integrative Health (NCCIH) Telephone: 301-402-1272
Email: weberwj@mail.nih.gov

Dale L. Birkle Dreer, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-6570
Email: birkled@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 Parts 74 and 92.