It is critical that applicants follow the instructions in the Research Instructions for the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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

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

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising natural products, which include 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 Announcement (FOA) the term natural products refers to botanicals, dietary supplements, and/or probiotics. This FOA will support the next steps in clinical research for natural products that have shown clear-cut preliminary benefit using in vitro, animal models, and/or human models. 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 are required to gather the necessary preliminary data to design subsequent large and rigorous efficacy studies. The purpose of this FOA is to encourage exploratory (R33) clinical trial grant applications that focus on the early phases of natural product clinical testing, during which basic and mechanistic research is translated into clinically testable hypotheses and tested in healthy volunteers or a clinical population. Using this approach, clinical trials should be designed to increase knowledge about the use of the natural product, the underlying condition to be treated with the product, and the mechanism of action through which the natural product may produce clinical benefit.

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, provide 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 it affects a biological signature rather than attempting to demonstrate a clinical treatment effect. 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.

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 that must be engaged to achieve a clinically meaningful effect. Exploratory clinical trials supported under this FOA can fill this knowledge gap. To elucidate a subsequent optimal clinical efficacy trial design, a number of preliminary steps may be necessary. These steps may include demonstrating bioavailability in humans; providing pharmacokinetic or pharmacodynamic data to assure proper dosing of the product; determining the appropriate biological marker(s) or objective outcome measures; demonstrating a replicable impact on a biological signature or mechanism of action when used by humans; 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.

Applications submitted under this FOA should have preliminary data, preferably published in the scientific literature, demonstrating that the natural product has an impact on a biological signature when used by humans and that the natural product is bioavailable to exert this effect in humans. This FOA provides support for studies to replicate the impact of the natural product on the biological signature(s) when used by humans and to assess the association between the degree of impact on the biological signature and functional or clinical outcomes in a patient population.

Exploratory trials submitted under 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 FOA could lead to submission of subsequent grant applications for support of such studies. Indeed, as described below, depending on the stage of intervention development, the project might focus on dose escalation, pharmacokinetics or pharmacodynamics studies. Investigators should keep in mind the future envisioned trial in designing the study to provide the necessary supporting data for a future efficacy trial.

Applications should be based on a clear scientific premise, and compelling rationale and a rigorous empirical basis for the proposed study, which should include preliminary data from human studies that demonstrate biological mechanisms via measurement of a biological signature, which may suggest clinical benefit. 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.

This FOA provides support for studies to replicate the natural product's effect on the biological signature in another human study and to assess the relationship between the biological signature and changes in functional outcomes or clinical symptoms. The results from the 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.

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 its mechanism of action and potential clinical benefit. 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, or mental health conditions such as those commonly managed in primary care (e.g., mild to moderate depression, anxiety, and post-traumatic stress).
• Studies to examine the effects of probiotics and other natural products on gut microbiome interactions with the brain or the immune system, for example. Of particular interest are biological signatures that may be impacted by probiotics that could be linked to biological signatures and symptoms associated with symptoms associated with depression, anxiety, or chronic pain.

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

This FOA will not support studies that utilize in vitro or animal models; 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.

The following types of clinical trials will not be supported by this FOA:

• Applications lacking preliminary data demonstrating that the specific natural product under study impacts the proposed biological signature when used by humans.
• Applications lacking preliminary data demonstrating that the natural product is bioavailable in humans. Note that for probiotics this may be demonstrated by documenting short-term retention in the gastrointestinal tract.
• Clinical trials solely to estimate intervention effect size or power calculations for a future trial.
• Applications that do not propose to give the natural product to human participants and measure the impact on a biological signature(s) 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).

Studies under this FOA should propose to replicate the natural product's effect, when used by human participants, on the biological signature or mechanism of action; and relate it to clinical outcomes to test the hypothesis that the biological signature is relevant to the clinical condition under study. The specific activities that are appropriate will depend on the specific natural product under study and its stage of development. Information for describing and supporting the rationale for study may include: 1) operational definition and objective measure(s) of the biological signature(s) that will be measured in humans (i.e., the hypothesized mechanism of action) and definition of a clinically meaningful change for each measure; 2) demonstration of adequate impact on the biological signature when the natural product is used by humans to provide a basis for future studies in humans; 3) 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; 4) preliminary feasibility, safety, and tolerability data to indicate that an adequate dose of the natural product can be given to the select human population; 5) demonstration of the ability of the investigative team to recruit and retain participants in previous clinical trials; 6) draft protocol and data and safety monitoring plan for the planned clinical project; and 7) completion of necessary regulatory approvals for proposed clinical studies (e.g., IRB, FDA IND).

The studies under this FOA should propose to replicate the impact of the natural product on the biological signature(s) when used by humans and assess if there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Exploratory studies supported by this FOA should not be powered as strong tests of clinical efficacy, but rather should test a hypothesis about the natural product’s mechanism of action and inform a decision about whether the natural product warrants further study. In addition to the primary aim of assessing the association between the biological signature and functional or clinical outcomes, secondary aims of the application may include: 1) further testing of the intervention’s feasibility, safety, acceptability, and pharmacokinetics; 2) determine the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the biological signature in response to multiple doses of the natural product; 3) determine the formulation of the natural product to be used in future trials to justify the frequency of dosing; 4) demonstrate the study team’s ability to recruit, randomize (if appropriate), retain, collect study assessments and samples, adhere to the study protocol, and report adverse events; and 5) develop functional biological signature measures and clinical outcome measures feasible for use in larger efficacy trials. The specific activities appropriate for this FOA will depend on the natural product under study, the stage of the study proposed, and available preliminary data on the natural product.

Investigators should contact the US Food and Drug Administration (FDA) prior to submitting an application, to determine whether an Investigational New Drug (IND) application is necessary for the proposed clinical research. When communicating with the FDA, applicants should describe the series of phased human studies that would be conducted if all milestones are met and the eventually future efficacy trial is pursued. Applicants are encouraged to ask the FDA at what point in the series of human studies would an IND be needed and if the proposed designs of each study will provide sufficient data to the FDA, such that they would allow the subsequent proposed study to be conducted under the IND.

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.

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).

This FOA will support research that proposes to replicate and extends human studies that have demonstrated the impact of the natural product on a biological signature and the bioavailability of the natural product in humans. Applicants who do not have this preliminary data can apply to PAR-16-418 "Phased Innovation Award for Exploratory Clinical Trials of Natural Products in NCCIH High Priority Research Topics (R61/R33)".

The objective of this funding opportunity is to improve the knowledge for high priority natural product clinical planning. 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 R33 award could lead to the realization that additional studies must be completed before proceeding to a full-scale efficacy trial or the data generated under the award are informative and sufficient to warrant moving ahead with a full-scale efficacy trial. If warranted by the results of studies conducted, 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 R33 award does not guarantee that NCCIH will accept, or fund, a subsequent full-scale clinical efficacy 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.

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

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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

Applicant Organizations

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

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

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

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

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

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

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

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

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

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

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

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

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

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

The letter of intent should be sent to:

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

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

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

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

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

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

Facilities and Other Resources: Applicants should 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 trial. Specifically, applicants must provide evidence that each recruiting center in the trial has access to a sufficient number of study participants who meet the eligibility criteria as defined in the submitted protocol. For multi-site applications, information must be provided for each site participating in the trial.

Other Attachments: Attachments listed below must be provided or the application will not be peer reviewed.

1. Clinical Protocol Synopsis

The filename "Clinical Protocol Synopsis.pdf" should be used and attached.

The synopsis will provide a concise snapshot of the overall trial to be completed during the R33 phase. It will be considered by reviewers, in addition to the Research Strategy. The synopsis is meant to supplement the information provided in the Research Strategy and may not exceed 12 pages. The Clinical Protocol Synopsis should represent the protocol that would be implemented at each site.

The Clinical Protocol Synopsis is expected to include the following information:

• Brief and/or Official Protocol Title
• Focus of the Study
• Objectives: A brief description of objectives, including the primary objective and secondary objectives (in a few sentences).
• Study Design: A brief description of the study design (e.g., randomized, double-blind and the Phase (Phase I or II))
• Intervention to Be Tested: A description of the intervention to be tested, and a brief description of the protocol to be followed in each arm of the trial and the adherence assessment. Specify concomitant interventions, if applicable.
• Primary and Important Secondary Endpoints: Specify the endpoints for the primary and, if applicable, important secondary endpoints.
• Provide schedule of clinical and laboratory evaluations.
• Study Population: A brief description of the study population, including the sample size, gender, age, demographic group, required health status, and geographic location.
• Enrollment Site(s): A list of enrollment/participating site(s) and their expected enrollment. Briefly describe plans for IRB approval.
• Statistical Design and Power: Specify the number of subjects to enroll, the expected effect size the study will be powered to detect for the biological signature, power of the study to detect impact on biological signature, and the statistical methods (per protocol, intent-to-treat) to compare groups with respect to the primary outcome measure and associate it with functional or clinical outcomes. Specify criteria for intervention discontinuation and stopping guidelines.
• Group Assignment: Methods of assignment of participants to study groups and of randomization
• Subject Participation Duration: Time it will take for each individual participant to complete all subject visits.
• Study Duration: Estimated time (in months) from when the study opens to enrollment until: (1) completion of data collection; and (b) final data analyses.

2. FDA or Other Applicable Regulatory Agency Strategy and Communication(s) (if applicable)

The filename Regulatory Communication Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers. This Regulatory Communication plan must be 3 pages or less in length and reflect the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial; and associated timeline. For trials using an FDA regulated product that require an IND application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. If the protocol is conducted under a non-US regulatory agency the applicant should submit a plan for attaining those regulatory approvals. If the protocol is exempt from an IND, a copy of the exemption letter from the FDA should be provided. Investigators are encouraged to inform the FDA of the subsequent studies they plan to pursue if all aims are achieved in the clinical studies (i.e. an efficacy trial), when they are asking if an IND is needed for the proposed human studies. Provide a brief description of the status of all necessary agreements for use of the natural product in the study, including clinical research agreements and licensing agreements. A timeline should be included showing activities with 3rd parties, such as: 1) executing necessary agreements, 2) providing natural product, and 3) permission to reference an open IND.

3. Clinical Trial Experience

Applicants must provide a detailed table listing the characteristics of trials that demonstrate experience in trial coordination in the last 5 years. The table must be provided as an attachment called "Clinical Trial Experience.pdf" and may not exceed 3 pages.

The table columns should include:

Column A: clinical trial title

Column B: applicant's role in the trial

Column C: a brief description of the trial design

Column D: planned enrollment

Column E: actual enrollment

Column F: number of sites

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

Column H: publication reference(s)

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

Biographical Sketches: Documentation of the Program Director s/Principal Investigator’s experience in leading clinical trials and expertise in the content area of the trial, as well as experience conducting trials under an FDA IND. Biographical sketches for all key study 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.

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:

Research Strategy:

Clinical Significance and Biological Relevance: Applicants must provide a clear and compelling rationale for pursuing the proposed early-phase clinical trial and testing of the natural product, as well as for other critical aspects of the research design. There must be a strong rationale for 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 trial (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 efficacy trial. Objective, quantifiable, and reproducible measures of both biological signature and the natural product’s clinical effects should be detailed. 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 clinical trial should be described. Justification for the study from preliminary data must be presented as results from previous human clinical studies demonstrating impact of the natural product on the proposed biological signature conducted by the investigative team or from the scientific literature as well as bioavailability of the natural product in humans. 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 natural product. 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 exploratory trial protocol should be presented in the Research Strategy and must include the items listed below:

• Future Clinical Trial: A concise summary of the subsequent anticipated future trial should be provided including the study design
• Preliminary data to justify the selection of the specific natural product and formulation 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).
• Describe the methodology including: a) the scientific rationale for the measure(s) used to assess the impact of giving the natural product to humans on the hypothesized biological signature; b) the measure(s) proposed to assess the biological signature; c) how the replication and extension of the initial impact on the biological signature findings from preliminary findings will be conducted; and d) how the investigators will evaluate associations between the biological signature and clinical or functional outcomes. Information on measurement validity and reliability should be included in the application. Describe measurement schedules that are suitable for detecting clinically meaningful changes in the biological signature. Describe how sufficient data will be collected in the R33 phase in order to inform a decision about whether further clinical study of the natural product is warranted. Describe how each proposed measure will contribute to assessment of the relationships between natural product, biological signature, mechanism-based functional outcomes, and/or clinical outcomes. The approach should be summarized clearly in the application, with specific references to the Clinical Protocol Synopsis to be submitted as an Other Attachment (see "Other Attachments" section above).
• 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, biosensors, or web-based systems) should be considered if appropriate.
• 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,methods for monitoring quality, and tools for data management and study oversight
• Statistical Methods: Discussion of sample size justification to be powered on changes expected in the biological signature(s) and not on clinical outcomes; study outcome measures; plans for interim (if any, with cogent justification) and final analyses for each aim; methods of bias control; and methods for handling missing data.
• Milestones and Timeline: Applicants should include proposed milestones and a 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.

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; the supplier does not anticipate to change the product formulation for the duration of the study; 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, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

For trials using an FDA regulated product and requiring an IND application, the applicant must either hold or be able to reference an open IND for the trial, or the applicant must have documentation that an IND application was submitted to the FDA. If the FDA has granted a waiver for the trial proposed in the R33, the applicant can provide this letter as part of the other attachment, "Regulatory Communication Plan". If the protocol is conducted under a non-US regulatory agency, equivalent determinations must be provided to NCCIH prior to a grant award.

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

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.

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? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Is there a sufficient body of preclinical or clinical research of high scientific rigor to support the study rationale? Is this clinical trial necessary to generate preliminary data to plan for testing the safety, efficacy, or effectiveness of an intervention that could lead to a change in clinic practice, community behaviors or health care policy? 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 trial 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 natural product, 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? With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have clinical trial-specific expertise and experience; the ability to organize, manage and implement the proposed clinical trial and meet study milestones and timelines? Do they have appropriate capacity in study coordination, data management and statistics? 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 exploratory trial 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 of the trial 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? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of 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?

Does the application include sound methodology for (a) replicating and extending the initial impact of giving the natural product to humans on the hypothesized biological signature(s) from the preliminary data findings, and (b) evaluating associations between biological signature and subsequent clinical or functional outcomes?

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

Are appropriate, evaluative milestones clearly defined for the aims associated with the proposed clinical trial? Are 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 to inform a decision whether further clinical testing is warranted? Are likely problems anticipated?

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

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

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

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

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

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 (GDS).

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

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

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

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

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

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

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: https://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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: 301-945-7573

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

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

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

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

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