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

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

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

Research Objectives

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising natural products (i.e. botanicals, probiotics, and products marketed as dietary supplements) for which there is compelling preclinical or preliminary clinical evidence for potential health benefit. NCCIH is particularly committed to identifying effective complementary health approaches for management of symptomatic conditions that are commonly treated in primary care such as sleep disturbance, pain, or mild mental health conditions (e.g., mild to moderate depression, anxiety, and post-traumatic stress). In addition, NCCIH is interested in examining the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system.

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 replicable biological effects. Biological signatures of the natural products may be an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes. It is recognized that for certain conditions (e.g., pain), a direct biological effect or biological signature may not be possible or practical with human participants. In these cases, investigators should contact a Program Director at NCCIH to discuss which funding mechanism (e.g., U01 PAR-17-216) can be used, with appropriate justification as to why measurement of a biological signature is impossible or impractical. In all cases, a measure of bioavailability of the natural product in human volunteers is required. A careful translational research process is as important for trials of natural products as it is for the study of conventional pharmaceuticals. Critical to this process is the development of measures of a biological effect and refinement of appropriate outcome measures for a clinical condition.

A clinical trial is defined by NIH as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.

Investigators considering applying to the NCCIH for a clinical trial award should refer to the NCCIH Clinical Trials Policy web site. Information about NCCIH Policies, Guidelines and Sample Templates for Clinical Trials at: http://www.NCCIH.nih.gov/Funding/Clinical_Research/NCCIH_guidelines.asp. 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).

Investigators must 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 for both the R61 and R33 phases.

NCCIH has designed its natural products clinical trials program to support investigator-initiated studies with funding mechanisms appropriate to the stage of the translational research process. This includes pre-clinical/animal studies (which may use Parent R21 or R01 FOAs), human mechanistic studies to determine and replicate the biological effect of a given natural product (phased innovation awards using R61/R33), clinical trials to determine the optimal dose and/or determine which patient phenotypes will be responders versus non-responders (this FOA uses the U01 funding mechanism), and multi-site clinical trials to perform definitive efficacy studies (UG3/UH3 funding mechanism).

The following research funding mechanisms have been established by NCCIH to assist in supporting research and development of a natural product along a translational research continuum from early exploratory pre-clinical or first in human research through multi-site efficacy trials. Depending on the extant evidence and research for a given natural product, applicants may use the appropriate FOA to support the next step in clinical trial research.

Clinical Trial Planning Phase - Determining and Replicating Biological Signature (R61/R33, PAR-17-319, R33, PAR-17-318)

To maximize the impact of a natural product clinical trial, it is highly desirable to establish an objective measure of the impact of the natural product, hence forth known as a biological signature. In general, a research grant application submitted under the R61/R33 (or R33) should precede submission of a U01 Clinical Trial Implementation Cooperative Agreement, although this is not a requirement and such data may be available or can be obtained through other means. The biological signature may be a measure of the postulated mechanism of action by which the natural product may ultimately modify the clinical condition or symptom(s) of interest. Biological signatures may be an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.

The R61/R33 should be used to measure the impact of the natural product on a biological signature, replicate the impact on and determine the reproducibility of the biological signature in a separate study; determine the bioavailability and pharmacokinetics of the natural product; and possibly determine the dose of the natural product that optimizes its impact on the biological signature. The data collection supported under the R61/R33 should be finished and the data analysis completed before the U01 or UG3/UH3 is submitted. Investigators are expected to implement the activities of the proposed U01 or UG3/UH3 application at the time of award.

Natural Product Phase II Clinical Trial Cooperative Agreement Award (U01, PAR-17-216)

The Phase II Clinical Trial Award FOA is intended to build upon work that has identified and replicated a biological signature of the a given natural product and complete collections of the necessary preliminary data needed to inform the design of a fully powered multi-site efficacy trial. Investigators should only apply for the U01 Natural Product Phase II Clinical Trial Cooperative Agreement after they have strong evidence that the proposed biological signature of the natural product can be reliably assessed for a condition of interest in the designated clinical population. It is recognized that for certain conditions (e.g., pain), a direct biological effect or biological signature may not be measurable in human participants for a variety of reasons. In such instances, a strong justification for why including a biological signature is not possible or impractical with human participants is required. In these cases, investigators should consider including other objective measures that may be a marker of the mechanism of action and provide evidence of a biological or behavioral effect of the natural product in human participants. The U01 clinical trial FOA will support natural product clinical trials (phase II) such as dosing and formulation optimization of the natural product to be used in a future multi-site randomized clinical trial; collecting additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, and complete collection of follow-up data; or determining which patient phenotypes will be likely responders versus non-responders to the natural product to inform inclusion/exclusion criteria of a future multi-site efficacy trial.

Multi-Site Investigator-Initiated Clinical Trials Cooperative Agreement Award (UG3/UH3, PAR-17-174 and U24, PAR-17-172 )

The UG3/UH3 FOA will support applications to implement a multi-site clinical trial of a natural product (Phase III and beyond). Under this phased award, the UG3 phase supports the planning and development of resources necessary to the perform the efficacy trial. If the UG3 phase successfully meets all planning milestones, the UH3 phase is awarded to implement the efficacy clinical trial. Under this phased award, the UG3 phase supports the planning and development of resources necessary to perform the trial. The UG3/UH3 award is used to implement a Clinical Coordinating Center (CCC) for investigator-initiated multi-site clinical trials of natural products (Phase III and beyond). In addition, multi-site clinical trials require a companion Data Coordinating Center (DCC) application (U24) be submitted with and linked to the CCC application. Both applications undergo peer review simultaneously. Multi-site clinical trials are defined as trials that enroll from two or more recruitment sites. Multiple sites are necessary for efficacy trials to increase generalizability of findings and enhance recruitment efficiency as well as representativeness of the participants. Multi-Site clinical trials are expected to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. The Clinical Coordinating Center for Multi-Site Trials FOA (UG3/UH3) runs in parallel with a companion FOA that solicits applications for the companion DCC (U24). Multi-site trials will be expected to achieve the required phase III trial requirements of NIH (see: https://humansubjects.nih.gov/glossary, and http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm)

Purpose of the NCCIH Natural Product Phase I-IIa Clinical Trial Phased Innovation Award (R61/R33)

The objective of this FOA is to support clinical trials to increase the evidence base for a natural product. The following are examples of types of clinical trials (phase I-IIa) appropriate for this FOA:

• Studies to demonstrate that when used by humans the natural product alters the biological signature(s) or mechanism(s) (thus providing an initial proof of principle) in the R61 phase
• Studies to replicate the impact of the natural product on the biological signature(s) in the R33 phase
• Studies to demonstrate human bioavailabiltiy of the natural product and or/its active metabolites
• Studies to measure the pharmacokinetics of the natural product
• In addition to the bullets above, investigators can also collect additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, demonstrate tolerability and initial safety of the natural product, and complete collection of follow-up data

An application submitted to this FOA must propose a way to measure the effect of the natural product on a biological signature when the natural product is used by humans. This biological signature should 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 objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.

The R61 Phase

The R61 phase must focus on testing whether, when used by human participants, the proposed natural product actually alters the presumed biological signature or mechanism of action. It may be necessary to include a placebo control in this phase of testing to determine whether the natural product is responsible for the change in the biological signature instead of regression to the mean. Additional testing in the R61 phase could include assessing whether the product is bioavailable in humans, and short-term testing of pharmacokinetics, pharmacodynamics, safety, and/or toxicity. Applicants should propose a go no/go decision rule for continuing to the R33 phase based on the robustness of the measure of the biological signature. For each proposed biological signature(s), applications must propose a priori definitions of the magnitude of change that will be sufficient to recommend further study in the subsequent R33 phase.

The specific activities and milestones appropriate for the R61 phase will depend on the specific natural product under study and its stage of development. Generally, these activities and milestones for the R61 phase 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 to provide a basis for future subsequent 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) 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;

5) demonstration of the ability of the investigative team to recruit and retain participants in the R61 trial;

6) NCCIH approved protocol, and data and safety monitoring plan for the planned R33 phase project; and

7) completion of necessary regulatory approvals for proposed R33 clinical studies (e.g., IRB, FDA IND).

Go/No-Go Criteria

In the R61 phase application, investigators are required to describe a set of Go/No-Go Criteria (for detailed instructions please see: Section IV.2 Other Attachments, 4. Milestones and Go/No-Go Criteria ) that will allow for a definitive assessment of whether the R61 phase provides sufficient evidence to support the subsequent replication study that would be conducted during the R33 phase of the grant application. Key evidence in the Go/No-Go Criteria includes:

• Detect a clear effect size in the primary biological signature(s) (mechanistic outcome measure) by the natural product.
• Provide adequate preliminary data (short-term pharmacokinetics and/or bioavailability) to justify conducting the proposed replication study under the R33 phase.
• Demonstrate the safety and tolerability of the natural product used in the trial by a set of metrics.
• Demonstrate the ability to recruit and retain subjects in the clinical trial with a pre-planned timeline for reaching the randomization target and estimated drop-out rate.
• By month 20 of the R61 award, submit R33 clinical trial protocols, Study Accrual and Retention Plan, and Data and Safety Monitoring Plan to NCCIH for review and approval.
• By month 21 of the R61 award, submit to NCCIH a R33 Transition Request Application .

While not required, investigators may also propose to evaluate how dose or formulation variations of the natural product may have differential impact on the biological signature(s).

The R33 Phase

Funding for the R33 phase is contingent on successfully meeting the milestones in the R61 phase, as well as other factors as described in Section VI. Award Administration Information, 1. Award Notices. Milestones accomplishments under the R61 phase will be administratively reviewed by NCCIH staff to determine whether transition to and funding for the R33 will occur.

For transition to an R33, the R33 phase must propose to replicate the impact of the natural product on the biological signature(s) demonstrated in the R61 phase and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Pilot studies supported by the R33 should not be statistically powered to assess 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. Again, a placebo can be used to confirm that the replicated changes measured in the biological signature are due to the natural product and not regression to the mean or natural history of the condition. In addition to the primary aim of assessing the association between the biological signature and functional or clinical outcomes, secondary aims in the R33 phase may include the following:

1) further testing of the intervention’s feasibility, safety, and acceptability;

2) determine the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the impact on the biological signature in response to multiple doses of the natural product;

3) determine the pharmacokinetics of the dose and 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 all assessments and samples, adhere to the study protocol, and report of adverse events; and

5) develop 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, the stage of the study proposed, and available preliminary data on the natural product. The R33 milestones should be clearly aligned with the aims associated with the R33 phase. The milestones should be feasible, well developed, and quantifiable with regard to the specific aims.

Subsequent Studies

The objective of this NCCIH R61/R33 funding opportunity is to improve the knowledge for natural product clinical trials 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 R61/R33 award could lead to the realization that the product does not warrant further study; additional studies must be completed before proceeding to a full-scale multi-site efficacy trial; or the data generated under this phased award are informative and sufficient to warrant moving ahead with a well-executed clinical trial. If warranted by the results of studies conducted, R61/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 R61 does not guarantee transition to and support of the R33 phase of the application. Transition to the R33 phase of the project will occur only if an NCCIH administrative review process determines that the R61 milestones and Go/No-Go criteria have been successfully met, and if funds are available. In addition, funding of an R61/R33 does not guarantee that NCCIH will accept, or support, a subsequent full-scale multi-site clinical efficacy trial application.

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 determine which natural products should or should not be further tested. This FOA uses a phased innovation approach (R61/R33) to manage the risk by requiring a demonstration R61 phase to test a natural product’s bioavailability and pharmacodynamic effects on a biological signature in human participants before moving to the R33 phase of the award to attempt to replicate the effect and measure the association between the biological signature and the clinical outcome changes.

Preliminary data requirements.

Applications should be based on a clear scientific premise and compelling rationale, for the proposed study, which may include preliminary data from animal studies that demonstrate biological mechanisms suggesting clinical benefit; alternatively, the empirical basis may be based on previous human clinical studies. Regardless, there must be a strong scientific premise and rationale as to why the specific natural product proposed is likely to benefit the clinical condition or indication under study.

NCCIH Priorities for Developing and Pilot-testing Natural Products

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

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

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

Clinical Trials Not Supported by this FOA

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

• Applications that do not propose giving the natural product to human participants in both the R61 and R33 phases.
• Applications that propose only the R61 phase or only the R33 phase.
• Applications that do not propose in the R33 phase to replicate the impact of the natural product on the biological signature(s) demonstrated in the R61 phase and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population.
• Clinical trials designed 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.
• Phase III trials of efficacy (such studies should use the Natural Product UG3/UH3 FOA, PAR-17-174).
• Single or multi-site observational studies that do not meet the NIH definition of a clinical trial (such studies should use the Parent R21 or R01 FOAs).
• Trials that propose to test natural products for the treatment or prevention of cancer. (Investigators interested in cancer treatment or prevention trials should contact the National Cancer Institute).

Consultation with NCCIH

Applicants are strongly encouraged to consult with the NCCIH Scientific/Research contacts for the area of science for which they are planning to develop an application prior to submitting to this FOA. Early contact (12 weeks prior to submission is encouraged) provides an opportunity for NCCIH staff to discuss the scope and goals, and to provide information and guidance.

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

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 not allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The letter of intent should be sent to:

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
6707 Democracy Blvd, Suite 401
Bethesda, MD 20892 (Express Mail Zip: 20817)
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 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 trial. Specifically, applicants must provide evidence that each recruiting center in the 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.

Other Attachments:

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

1. Clinical Protocol Synopsis

A Clinical Protocol Synopsis must be provided as an attachment called "Clinical Protocol Synopsis.pdf" and must not exceed 12 pages.

The synopsis will provide a concise snapshot of the overall R61 phase trial. It will be considered by reviewers, in addition to the aspects of the regular application. The synopsis is meant to supplement the information provided in the Research Strategy. The Clinical Protocol Synopsis should represent the protocol that would be implemented at a specific site. It is meant to summarize the necessary elements of the clinical trial.

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, parallel group or factorial, double-blind, and the Phase)
• 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 Sites: A list of enrollment/participating sites 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, event rate, power and the statistical methods (per protocol, intent-to-treat) to compare groups with respect to the primary outcome measure. 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.
• A Recruitment and Retention Plan describing the following: 1) the planned recruitment methods including use of contact lists, databases or other pre-screening resources, advertisements, outreach, media / social media and referral networks or groups; 2) if there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success; 3) contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks; 4) participant retention and adherence strategies; 5) possible competition from other trials for study participants; 6) safeguards for vulnerable populations as appropriate (e.g., children, pregnant women); and 7) strategies for outreach to minorities and women. Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP).

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

A Regulatory Communication Plan must be provided as an attachment called "Regulatory Communication Plan.pdf" and must not exceed 3 pages of a written description. Additional pages can include copies of correspondence from the FDA indicating whether the proposed study will require an IND/IDE or not.

The Regulatory Communication plan should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct of the trial, and associated timeline. For trials using an FDA-regulated product that require an Investigational New Drug (IND) application, the grant application must include evidence regarding the outcome of a pre-IND meeting, or other evidence of communication with FDA. 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. 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. See additional requirements regarding IND submission in Section 6.

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 must 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)

4. Milestones and Go/No-Go Criteria Plan

A Milestones and Go/No-Go Criteria Plan must be provided as an attachment called "Milestones and Go*No-Go Criteria.pdf" and must not exceed 3 pages.

The milestone plan should describe the key milestones that need to be met for each phase of the application (R61 and R33) to ensure its success; the processes that will be used to reach the milestones; and a timetable identifying when each of these key milestones will be met.

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

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

• For the R61 phase obtain NCCIH approval of the 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 that must be achieved. This will need to be agreed to before starting the R61 trial.
• Complete final, detailed clinical protocol approved by NCCIH prior to starting recruitment for the R61 clinical trial
• Complete Final Informed consent(s) and, if applicable, assent forms
• Final Data and Safety Monitoring Plan approved by NCCIH prior to starting recruitment for R61 clinical trial
• Submission of an approved Study Accrual and Retention Planned by the Authorized Business Official prior to starting both the R61 and R33 phases (https://nccih.nih.gov/grants/policies/SARP).
• Agreements in place for product supply
• Comprehensive laboratory plan (if applicable)
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training plan for clinical site(s)
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of all regulatory approvals
• IRB approval for clinical site(s)
• Assessment of site(s) protocol implementation performance
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date
• Data sharing plan for study data and biospecimens (if applicable)
• Prior to submitting the transition request for the R33 phase
• Obtain NCCIH approval for R33 phase protocol, data and safety monitoring plan, and study accrual and retention plan
• Complete necessary regulatory approvals for proposed R33 clinical trial (e.g., IRB, FDA IND).

In addition, Go/No-Go Criteria for transition from R61 to R33 phase must be included. Applications must provide this information in a section indicated by the heading "Go/No-Go Criteria for R61":

a. A clear effect size in changes in the primary biological signature(s) (mechanistic outcome measure) by the proposed natural product. Please specify the primary biological signature(s) and any clinical outcome(s) quantitatively. For each proposed primary biological signature, provide references to describe and justify the measure.

i) A clear, definitive, and quantitative set of rules for the primary biological signature (s) to determine whether the natural product has a measurable effect on the biological signature and the metrics/thresholds of No-Go criteria regarding the primary biological signature(s) for the R33 phase.

ii) A clear and definitive decision rule should be provided to prioritize the biological signatures if more than one is proposed, specify the direction of natural product induced changes proposed, and how contradictory changes in the measures would be handled.

b. Adequate preliminary data (collected through prior studies, other concurrent studies, or the R61 phase study) to justify the proposed replication study in the R33 phase. This preliminary data should include short-term pharmacokinetic data and bioavailability of the proposed natural product. If the preliminary data for the replication study is to be collected in other concurrent studies or the R61 phase of this application, a brief description of the planned experiments to generate such data and the anticipated outcomes that can justify the proposed R33 phase must be described.

c. Demonstrate the safety and tolerability of the natural product used in the study by a set of metrics.

e. Demonstrate the ability to recruit and retain subjects in the clinical trial with a pre-planned timeline for reaching the randomization target and drop-out rate.

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 trial. 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.

Budgets for both the R61 and R33 phases must be included in the application.

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

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

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

Specific Aims: In the single Specific Aims attachment, include headers titled R61 Specific Aims and R33 Specific Aims, and state the specific objectives of the research effort in each of the two phases of this project. The primary and major secondary hypotheses to be evaluated must be clearly stated.

Research Strategy:

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

The following criteria should be addressed:

Significance: The significance of the proposed clinical trial and importance of the question should be clearly stated. The application should provide rigorous preclinical or clinical preliminary data to support the study rationale. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. The application should describe how the proposed project will advance knowledge of the underlying mechanism(s) of the clinical condition or disease under study or the mechanism of the investigated natural product. 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 needed or justified, and/or provide evidence that additional studies must be completed before proceeding to a full-scale efficacy trial. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance. The applicant should provide a precise response to the following 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?

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

Approach: The research approach section should include a description of the supporting data, clinical trial experience, the experimental approach, and a brief summary of the milestone and go/no-go criteria plan referring to the required attachments as appropriate.

Supporting Data: The application should provide data from preclinical or clinical studies that led to the proposed clinical trial, which should demonstrate the need for and the feasibility of the proposed early phase trial. Additional supporting data from other research should be included so that the approach chosen is clearly justified and adequately framed. Applications should address the rationale for choosing the natural product to study. 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.

Experimental Approach: The proposed experimental approach should include an appropriate study design and the rationale for the design chosen. The experimental approach description should include:

• A project timeline (this can be provided as a table or graph), which should also reference the Milestones and Go/No-Go Criteria Plan (see Other Attachments).
• A description of the study population and why it is the most appropriate group to answer the question, and how or if results will generalize to a broader population.
• A description and rationale for the research hypothesis(es), methods of randomization if applicable, primary and secondary outcome measures, intervention(s), measurement of the replicable biological signature of the natural product, and participant follow-up procedures.
• Describe the R61 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. Information on measurement validity and reliability should be included in the application. Describe measurement schedules that are suitable for detecting that the clinically meaningful changes in the biological signature are due to the natural product and not regression to the mean or natural history of the condition. The approach should be summarized clearly in the application, with specific references to the Clinical Protocol Synopsis (which is to be submitted as an Other Attachment (see "Other Attachment" section above)).
• Describe the R33 phase methodology, including: a) how the investigators will replicate the impact of the natural product on the biological signature, extend the findings from the R61 phase, and determine the impact is due to the natural product and not regression to the mean or the natural history of the condition; and b) how the investigators will evaluate associations between the changes in the biological signature and changes in clinical or functional outcomes. 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.
• A description of the natural product and matching placebo (if applicable) 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).
• Provide a brief summary of the agreements that have been established for provision of the naturla product and any matching placebo. Note that all necessary agreements for the 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 third parties such as 1) executing necessary agreements, 2) providing natural product and matching placebo, and 3) permission to reference an open IND drug master file (if available). This should also be referenced to the Milestones and Go/No-Go Criteria Plan (see Other Attachments).
• A description and justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems) need to be described. A description of the laboratory evaluations (as appropriate) and plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate should be provided.
• Data Management and Quality Control: Details of efficient data management and methods for monitoring quality; Statistical Methods: Discussion of sample size justification to be powered on changes expected in the biological signatures are due to the natural product) and not powered to detect impact on clinical outcomes; study outcome measures; plans for interim (if any, with cogent justification) and final analyses for each aim; methods of bias control (e.g. use of matched placebo); and methods for handling missing data.
• A description of the future clinical trial beyond the R61/R33: A concise summary of the subsequent anticipated future trial should be provided including the study design.
• Discussion of the challenges expected in implementing the research and how these might be overcome.
• The strategy for timely publication and dissemination of results

Data and Safety Monitoring Plan

In addition to the NIH application requirements for data and safety monitoring for clinical trialsNCCIH 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 independent monitoring committee (IMC) or data and safety monitoring board (DSMB) will have the responsibility to review interim and final data, and recommend whether the protocol should be modified, and, at each meeting, whether the study should be continued or should be terminated early. Thus, its ethical responsibilities, to the participants as well as to the integrity of the study, are of paramount importance to the NCCIH. The IMC/DSMB will meet in person or by phone at least twice a year. Applicants should not appoint IMC/DSMB members in advance of the peer review, or even inquire about the interest of possible DSMB members, because anyone so contacted would not be eligible to serve as a member of the peer reviewer committee that will evaluate the applications for scientific merit.

Letters of Support:

Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided. 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; that the supplier will meet and provide details regarding Chemistry Manufacturing and Controls specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.

If parts of the costs of the trial are to be provided by sources other than NCCIH, provide Letter(s) of Support signed by an authorized representative.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, 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 will be submitted to the FDA prior to any award. The details of the IND status of the natural product should be provided in the attachment entitled "Regulatory Communication Plan". If the FDA has granted a waiver for either trial proposed in the application (R61 or R33 phase), the applicant can provide this letter as part of the "Regulatory Communication Plan". If the protocol is conducted under a non-US regulatory agency, equivalent determinations and documentation must be provided to NCCIH prior to a grant award. Funding will be restricted or the award may not be made until the necessary regulatory approvals are in place for the conduct of the proposed clinical trial.

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 the policy.

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

For this particular announcement, note the following:

The R61/R33 phased award 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. 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 R61 and R33 phases.

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

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

Does the project address an important problem or a critical barrier to progress in the field? 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?

Specific to this FOA:

Is there a sufficient body of preclinical or clinical research of high scientific rigor to support the study rationale? Why is this clinical trial necessary to generate preliminary data to inform the design and implementation of the future efficacy trial of the natural product 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 those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA:

How strong is the application in demonstrating that the PDs/PIs and Key Personnel have the experience and capability to conduct the proposed trial and meet milestones and timelines? How well defined are their roles and responsibilities? How well does the application provide evidence of necessary expertise about the natural product and study population? What evidence is provided to ensure that the investigators will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? Does the investigative team have a track record of conducting, completing, and publishing the results of clinical trials? What evidence is provided to demonstrate that the investigative team has 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?

Specific to this FOA:

For these early phase clinical trials, how will the proposed clinical trial inform the design of the future efficacy trial so that it can change clinical practice or practice guidelines? 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 less 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 human subjects?

How does the proposed study ensure that the underlying hypothesized biological signature is appropriate and relevant, and will be rigorously tested by giving the product to humans and assessing the impact on the biological signature? Is the need for the R61 phase well justified?

Does the R33 phase include sound methodology for (a) replicating and extending the initial impact of giving the natural product to humans on the hypothesized biological signature from the R61 phase, 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?

What strengths and weaknesses are there in the study design? How appropriately is the study designed to answer the research question, test the proposed hypothesis/hypotheses, and collect the necessary data? How efficient is the trial design? How strong is the evidence for equipoise? How well does the Clinical Protocol Synopsis attachment describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented? Is the natural product appropriately characterized?

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 adequate and well described?

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?

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

R61 Milestones: Are quantitative criteria pre-specified and rigorously defined to assess milestone achievement, Go/No-go criteria, and operational feasibility relevant to advancing from the R61 to the R33 phase? Are R61 milestones feasible, well developed and quantifiable and consistent with the specific aims? Is the timeline feasible? Specifically, will the investigators and NCCIH Program Officials be able to determine whether the project succeeded in: (a) demonstrating that when used by humans the natural product 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 milestones include quantifiable Go/No-go criteria for continuing to the R33 phase if the measure of biological signature is sufficiently robust? 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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Not Applicable.

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

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

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

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see 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.

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

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

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

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

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

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

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

Email: support@grants.gov

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.