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

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

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

The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising natural products, including herbal medicines, botanicals, products marketed as dietary supplements, and probiotics. Products with high research priority include those for which there is compelling preclinical and 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 signatures of biological effects. Biological signatures of the natural products effect 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 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. 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.

NCCIH has designed its natural products clinical trials program to support investigator initiated studies with funding mechanisms appropriate to the stage of the translational process. This includes pre-clinical/animal studies (which may use Parent R21 or R01 mechanisms), 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 (Phase II Clinical Trial Cooperative Agreement U01), and multi-site clinical trials to perform definitive efficacy studies (UG3/UH3 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 Biological Signature (R61/R33, PAR-16-418 and PAR-16-419)

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 or a UG3/UH3 Multi-Site Clinical Trial, although such data may be available or can be obtained through other means. This 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 a 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 (U01, PAR-17-216)

The Phase II Clinical Trial Award FOA is intended to build upon work identifying a biological signature for a given natural product, and begins the next stage of work - namely collecting any final preliminary data needed to inform the design of a fully powered multi-site efficacy trial. Investigators should only apply for the U01 Phase II Clinical Trial Cooperative Agreement after they have strong evidence that the proposed the 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 is needed for why including a biological signature is not possible or impractical with human participants. 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 objective of the NCCIH U01 funding opportunity is to increase the evidence base on which high priority natural product clinical trials are based prior to funding multi-site clinical trials (if necessary). 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; 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)

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 perform the trial. If the UG3 phase successfully meets all planning milestones, the UH3 phase is awarded to implement the clinical trial. The UG3/UH3 award, therefore, is used to implement a clinical Coordinating Center (CCC) for investigator-initiated multi-site clinical trials of natural products. 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 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 runs in parallel with a companion FOA (PAR-17-172) that encourages applications for the companion DCC. 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).

This FOA invites cooperative agreement applications for investigator-initiated multi-site clinical trials (Phase III and beyond) to study the effects of natural products in NCCIH designated areas of high research priority. The Clinical Coordinating Center (CCC) will have plans to develop and implement the proposed multi-site clinical trial. Proposed clinical trials may utilize a design anywhere along the continuum between explanatory and pragmatic. For this FOA, pragmatic trials are considered those that test an intervention under the usual clinical conditions in which it will be applied, while explanatory trials do so under more idealized circumstances. The trial design should be appropriate for the study question.

This CCC FOA runs in parallel with a companion FOA (PAR-17-172) that encourages applications for a corresponding Data Coordinating Center (DCC). Both a CCC application and a corresponding DCC application need to be submitted simultaneously for consideration by NCCIH.

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.

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). Clinical trials supported by this FOA will have to adhere to the NIH Policy on Good Clinical Practice Training (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-148.html).

Preliminary data requirements

This FOA is appropriate when there a clear and compelling rationale, a rigorous empirical basis, and scientific premise, which should include preliminary data from animal studies and previous human studies. The following preliminary data from human studies (preferably published in the literature) on the same product and specific formulation as proposed in the current application are required:

• Demonstration that the natural product can produce a clinically meaningful change in measurable biological signature (e.g. mechanism of action) in the human population of interest. There must also be evidence that the change in biological signature has been replicated in a separate human study with the same natural product to be used in the proposed project.
• Information to justify the selection of the dose(s) of the product proposed to be used in the study. Data should demonstrate that the selected doses are likely to have the greatest impact on the biological signature and minimize the risk of adverse events.
• Evidence that evaluates the pilot study data for strength of correlation between the impact on the biological signature and changes in the clinical outcomes that will be studied in the proposed clinical trial.
• Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and demonstrate initial safety of the product.
• Demonstration that the natural product does not produce frequent or severe adverse events in human pilot trials.

For the purposes of this FOA, it is preferred that there be an established, measurable, reproducible, well characterized biological signature for a given natural product in human subjects. However, NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the biological impact of a natural product. In these circumstances the study should be justified by: (1) a clear rationale for why studying a biological signature in human participants is impossible or impractical; (2) potentially proposing other objective, reproducible measures, that may be proxy to, or indicative of a biological or behavioral effect for the natural product; and (3) strong compelling preliminary data to warrant further study of a natural product in clinical studies. In these situations, investigators are also encouraged to contact NCCIH Scientific/Research staff to determine whether the UG3/UH3 is the appropriate funding opportunity for the proposed clinical trial.

Structure

This FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and clinical trial execution phase (UH3). There should be clear objectives for both a UG3 and a UH3 phases.

Phases of Award

The UG3 phase will support the development of case report forms and other resources necessary to the performance of the trial; further development and finalization of study partnerships including signed contracts with performing clinical sites; Institutional Review Board/Data and Safety Monitoring Board approval of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. Applications that provide a clinical trial project management plan that delineates how the study will monitor and evaluate critical processes impacting feasibility of trial launch, conduct, and completion, coupled with on-time and on-budget performance milestones are strongly encouraged. All regulatory approvals, should be obtained prior to the end of the UG3 award. Provision of the necessary natural products, matched placebos, or other resources should be planned at the start of the UH3 award to allow for the successful launch and execution of the proposed clinical trial in the UH3 phase. Subject to NCCIH funding availability and scientific priorities, UH3 awards will be made after administrative review with attention to the extent to which agreed upon milestones have been met.

Milestones

Utilization of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Plans must be guided by milestones that will be reached at the end of the UG3 phase. Milestones are to be performance-based to achieve completion of the trial on time and on budget. UG3 projects that have met milestones will be assessed administratively to determine eligibility for transition to the UH3 implementation phase.

This FOA will support applications that include a series of milestones for completion of the clinical trial (UH3 phase) and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Continuation of the award is conditional upon satisfactory progress and subject to availability of funds. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NCCIH will consider ending support and negotiating an orderly phase-out of the award and retains, as an option, periodic external peer review of progress. NCCIH staff will closely monitor progress at all stages, milestones, accrual, and safety.

NCCIH Priorities for Clinical Trials of Natural Products

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 widely used by the public and where there is evidence of postulated mechanisms 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-brain interactions. Of particular interest are studies of probiotics for depression, anxiety, or chronic pain.

Applications proposing research 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.

Clinical Trials Not Supported by this FOA

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

• Phase I (first-in-human) trials whether single or multi-site (such studies should use the Natural Products R61/R33, PAR-16-418 and PAR-16-419)
• Single site trials
• Drug or device safety trials
• Studies to determine or replicate the effect of a natural product on a biological signature (such studies should use the Natural Products R61/R33 FOA, PAR-16-418 and PAR-16-419)
• 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 proposing to use products that do not have evidence that the change in biological signature has been replicated in two independent human studies using the same natural product to be used in the proposed project
• Trials that propose to test natural products for the treatment or prevention of cancer

Specific Areas of Research Interest

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 IC 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 allowed.

In general, the National Center for Complementary and Integrative Health (NCCIH) support of investigator-initiated clinical trials that study an intervention delivered to human subjects will be limited to studies carried out within the United States and Canada, except in special settings (https://nccih.nih.gov/grants/internationalclinicaltrials

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.
Office of Scientific Review
National Center for Complementary and Integrative Health
6707 Democracy Blvd, Suite 401
Bethesda, MD 20892 (Express Mail Zip: 20817)
Telephone: 301-594-3456
Email: [email protected]

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.

Descriptive Title of Applicant's Project:

To allow NIH to identify a group of applications as a related set of collaborative applications, the titles for each application in the set must have the following format: a 1/N indicator + Identical Title (e.g., 1/3 , where the 1/3 means this is site 1 of 3 sites in the set. The other sites will be labeled 2/3, etc.) Titles may not exceed 200 characters in length, including the tag, e.g., 1/3, at the beginning of the title.

Cover Letter Attachment:

The Cover Letter is one pdf file only. The following collaborative information is required in the cover letter: a listing of all the applications that are part of the set of collaborative applications being submitted, including for each: 1) the PD/PI(s) name(s), 2) the Title (including the tag, e.g., "1/2"), and 3) the Applicant institution. Each site should submit an identical listing. If applicable, the letter should indicate the name of the NCCIH program officer with whom the project has been discussed.

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

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

Facilities and Other Resources:

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

Other Attachments:

The following attachments must be included as a part of the cooperative agreement application. Attachments permit expansion of certain elements that cannot 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 trial. It will be considered by reviewers, in addition to the components 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 each 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., multicenter, randomized, double-blind and the Phase (Phase III or beyond))
• 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 Policy (https://nccih.nih.gov/grants/policies/SARP).

2. Study Organization Plan

A Study Organization Plan must be provided as an attachment called "Study Organization Plan.pdf" and must not exceed 6 pages. The Study Organization plan should describe the study organization and administration, and include a communication plan. The Study Organization plan can include, but is not necessarily limited to: a description of committee structures needed to manage the complexity of the trial; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed; and the role of any sub-contractors or providers of services, personnel, or facilities. The plan should explain how these will integrate with the organizational framework described in the collaborating DCC application and should address how the CCC and DCC will coordinate leadership for clinical trial implementation. The communication plan should include a description of the coordination between the separate components including NCCIH and identify the key channels used to reach and inform each stakeholder group and receive feedback. The organization plan should also describe how disputes will be resolved between the CCC, DCC and all stakeholders.

3. 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 IND/IDE 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/IDE, a copy of the exemption letter from the FDA should be provided. See additional requirements regarding IND submission in Section 6. If the proposed clinical trial does not include a device, natural product, or drug, this document should provide a brief statement as to why FDA regulation is not applicable.

4. 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)

5. CCC Project Management Plan

A Project Management Plan must be provided as an attachment called "CCC Project Management Plan.pdf" and must not exceed 3 pages. The Project Management Plan should describe the evidence-based strategy that will be used throughout the project to ensure that the unique goals of the clinical trial are met. Project management planning should directly support the needs of scientific study leadership to identify barriers, make timely responses, and optimize the allocation of limited resources to meet pre-defined study objectives. The project management plan should describe the planning team and identify control points and processes that are key to scientific and fiscal performance. This will include a description of the organizational strategy that defines internal control points and business roles. A description of the key methodology, standards, and processes governing resource management, study deployment, operations/execution, and study closure should be included. The management plan should also describe how the team, in collaboration with the DCC, will pro-actively evaluate and prioritize issues that jeopardize study goals and lead to the development of corrective responses to resolve fiscal and logistical issues (risk planning) in a timely manner. Describe processes required for orderly project closure. In summary, the project management plan should provide sufficient detail to demonstrate the ability to achieve the goals of the clinical trial on-budget and on-time. The project management plan should include risk mitigation or contingency plans.

6. Timeline and Milestone Plan

A Timeline and Milestone Plan must be provided as an attachment called "CCC Timeline and Milestone Plan.pdf" and must not exceed 5 pages.

The plan should describe the key milestones that need to be met throughout the lifecycle of the clinical trial (UG3 and UH3 phases) 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 (this can be provided as a table or a graph).

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 milestone plan should include anticipated challenges to meeting milestones and propose potential mitigation or corrective actions strategies. UH3 milestones should address overall recruitment and retention goals. The Terms and Conditions for a UG3 award under this FOA will include a milestone plan that is mutually agreed upon by the investigators and NCCIH.

CCC milestones of particular interest during the UG3 phase that should be described in the application may include but are not limited to:

• Complete finalized clinical protocol approved by NCCIH and Protocol Review Committee/DSMB
• Final Informed consent(s) and, if applicable, assent forms
• Agreements in place for product supply
• Comprehensive laboratory plan
• Pharmacy/Laboratories Identification (as applicable)
• Contracts/Third Party Agreements (if applicable)
• Training plan for clinical sites
• Final Management/Communication Plan
• Final Data and Safety Monitoring Plan
• Site Performance Plan
• Data Completeness and Quality Monitoring Reporting Plan
• Completion of regulatory approvals
• IRB approval for clinical sites (if less than 100%, the percent of sites will be negotiated prior to UG3 award)
• Submission of UH3 transition request 2 months prior to the requested transition date

The application should also include a series of milestones for the completion of the specific aims of the clinical trial (UH3) phase and contingency plans. Milestones and timelines for the UH3 phase may need to be revised and finalized at the time of the UG3/ UH3 transition. Investigators and NCCIH will review and mutually agree upon a final revised UH3 milestone plan that will be included in the Terms and Conditions of the UH3 grant (if awarded). CCC milestones of particular interest during the UH3 phase that should be included in the application include but are not limited to:

• Target dates for enrollment of 10%, 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and children (as appropriate)
• 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)

During the award phase, achievement of each milestone for the UG3 and UH3 phases 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. If, at any time, recruitment, as defined in the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP), falls significantly below projections, or core milestones mutually agreed upon by the PD/PI and the NCCIH, are not met, the Center 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.

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

The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of clinical trials and have expertise in the content area of the trial, as well as experience conducting trials under an FDA IND. The experience of all key personnel must be carefully documented. Most clinical trials will require a multidisciplinary team (clinician, statistician, data manager, study coordinator(s), etc.) and the application should reflect their roles and responsibilities in the design and implementation of the study protocol.

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

Separate itemized budgets must be prepared for each subcontract and/or for each collaborating clinical site or core, if multiple sites or cores are proposed.

Include budget support for personnel to travel to a yearly in-person steering committee and/or other meeting of investigators and NCCIH. In addition, include budget support personnel to attend the semi-annual DSMB meeting/calls.

If parts of the costs of the trial are to be provided by sources other than NCCIH, these contributions must be presented in detail in the budget justification.

Include budget support for the publication and dissemination of results

Note: Do not include budget support for the DSMB. An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, the NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by the NCCIH and budget support for the DSMB will be provided by NCCIH.

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

The Research Strategy should be organized in a manner that will facilitate peer review. The body of the application must 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 must be addressed:

Significance: The significance of the proposed clinical trial and importance of the question must be clearly stated. 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. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance.

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

Approach: The research approach section should include a description of the supporting data, clinical trial experience, the experimental approach, and a milestone plan.

Supporting Data: The studies that led to the proposed clinical trial should be presented. Data from pilot studies which show the need for and the feasibility of the trial should also be presented. Additional supporting data from other research should be included so that the approach chosen is clearly justified and adequately framed. Applications must include the following preliminary data from human studies of the same product and specific formulation as proposed in the current application (preferably published in the literature):

• Demonstration that the natural product can produce a clinically meaningful change in measurable biological signature (e.g. mechanism of action) in the human population of interest. There must also be evidence that the change in biological signature has been replicated in a separate human study with the same natural product to be used in the proposed project.
• Information to justify the selection of the dose(s) of the product proposed to be used in the study. Data should demonstrate that the selected doses are likely to have the greatest impact on the biological signature and minimize the risk of adverse events.
• Evidence that evaluates the pilot study data for strength of correlation between the impact on the biological signature and changes in the clinical outcomes that will be studied in the proposed clinical trial.
• Pharmacokinetic data on the specific natural product and formulation to be used in the proposed trial to justify the dosing frequency in the proposed trial and demonstrate initial safety of the product.
• Demonstration that the natural product does not produce frequent or severe adverse events in human pilot trials.

For the purposes of this FOA, it is preferred that there be an established, measurable, reproducible, well characterized biological signature for a given natural product in human subjects. However, NCCIH acknowledges that for some conditions, it may be impossible or impractical to directly measure the biological impact of a natural product. In these circumstances the applicant should: (1) provide a clear rationale and justification for why studying a biological signature in human participants is impossible or impractical; (2) consider proposing other objective, reproducible measures, that may be proxy to, or indicative of a biological or behavioral effect for the natural product; and (3) provide strong compelling preliminary data to warrant further study of a natural product in clinical studies.

Experimental Approach: The proposed experimental approach should include an appropriate design and the rationale for the particular design chosen (e.g., pragmatic, explanatory, cluster-randomized). The experimental approach description should include:

• 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.
• A description of the natural product to be tested including: dose and frequency of dosing to be used, 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).
• 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).
• Engagement of the clinical community that are playing a critical role in the recruitment, retention and overall conduct of the clinical trial including the prioritization of this clinical trial in the context of other overlapping clinical research. Description of this commitment should be provided.
• 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.
• A description of the approach to obtain regulatory approvals - NCCIH strongly encourages the use of a central IRB.
• A discussion of potential challenges in implementing the research protocol and how they will be addressed.
• Contingency plans if the effect size or event rate is underestimated
• The strategy for timely publication and dissemination of results

Data and Safety Monitoring Plan

In addition to the NIH application requirements for a data and safety monitoring for clinical trials (https://grants.nih.gov/grants/how-to-apply-

application-guide/forms-d/general/g.400-phs-398-research-plan-form.htm#Human), NCCIH requires independent monitoring for research involving human subjects. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) , as well as the NCCIH Guidelines for Data and Safety Monitoring (http://nccih.nih.gov/grants/policies/data-safety-monitoring). An independent DSMB will be established to monitor data and oversee participant safety in the clinical trial. As part of the collaborative activities under this cooperative agreement, the NCCIH will collaborate with the awardees to appoint and/or agree upon a single DSMB for monitoring the clinical trial. The DSMB will be appointed by the NCCIH. At the first meeting in the UG3 phase, the DSMB will review the awardee’s protocol and potentially recommend modifications. Subsequently, the DSMB will monitor and review recruitment, adverse events, data quality, outcome data, and overall awardee performance. The DSMB has the responsibility to review interim data 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 DSMB will meet in person or by phone at least twice a year. Applicants should not propose DSMB members in the application, 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. For revision applications, applicants should provide a list of the DSMB members in the application.

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; the supplier will meet CMC specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.

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.
• All applications must address how datasets will be made available as appropriate and consistent with achieving the goals of the program..
• Describe how the CCC will facilitate and support timely publication and dissemination of results as appropriate and consistent with achieving the goals of the program..

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 UG3/UH3, the applicant can provide this letter as an 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.

Specific to this FOA:

• Awards issued under this FOA will be incrementally funded for up to 7 years. These will not be Multi-Year Funded.
• Awards issued under this FOA will be excluded from automatic carryover. All carryover actions will require NCCIH prior approval.
• Awards issued under this FOA will not be provided the authority to automatically extend the final budget period. All extensions, including the first, will require NCCIH prior approval.
• Awards issued under this FOA will be excluded from SNAP.

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NCCIH Program Staff (See https://nccih.nih.gov/grants/policies/over500k) at least 8 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

This policy applies when the combined budget for the collaborative DCC and CCC applications exceeds $500,000 in direct costs in any given year.

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:

For the purposes of peer review and funding the collaborative applications will be submitted on the same due date. Reviewers will consider the overall feasibility of the project and whether the clinical trial will answer a key scientific question and be completed on time and within the proposed budget.

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:

If the primary outcomes of the trial are achieved, how critical will the information be to addressing the evidence gap and advancing knowledge of theory and practice? Could results of the trial have a significant influence on clinical care and improve health? Is there sufficient demonstration for the presence of equipoise? Is there a sufficient body of preclinical or clinical research of high scientific rigor to support the study rationale?

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 multi-center trial and meet milestones and timelines? How well defined are their roles and responsibilities? What evidence is provided to ensure that the clinical centers will employ the appropriate personnel to recruit subjects and implement the clinical protocol? How strong is the plan for leadership and coordination of roles/responsibilities for CCC leadership? How well does the application provide evidence of necessary experience and expertise of the investigators with the natural product, the study population, and the research methods to be employed? What evidence is provided to ensure that the clinical centers will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? Does the investigative team have a track record of publishing the results of clinical trials previously completed? 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 Phase III clinical trials, how will the proposed clinical trial change clinical practice or practice guidelines? Does the proposed research have the potential to advance the field even if the proposed study design, methods, and intervention are not innovative?

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?

Specific to this FOA:

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 at all of the sites? How strong are the formative clinical studies, including any pilot studies, underpinning the trial? Is the natural product appropriately characterized? How well are the clinical outcome measures, biological signature, dose/duration of study and follow up, appropriateness of inclusion/exclusion criteria, and sample size justified and explained? What evidence is there that the study population has been appropriately defined? How well does the Recruitment and Retention plan provide evidence that the accrual goals can be reached within the proposed timeline? How appropriate is the plan to monitor accrual? Is the study timeline appropriate to complete the goalsand address the scientific question(s)? Are adverse events appropriately captured and monitored? How effectively does the Project Management Plan identify and describe risks to implementation and how well are contingency plans described? How clear is the communication plan between DCC and CCC leadership and is it appropriate for implementing and conducting the trial?

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?

Specific to this FOA:

What evidence is provided that the planned analyses are appropriate for the proposed study design? Since this is a multi-center application, is there evidence of the ability of the individual centers to (1) enroll the proposed numbers, (2) adhere to the protocol, (3) collect and transmit data in an accurate and timely fashion, and (4) operate within the proposed organizational structure? If the clinical trial is Phase III, does the application include all relevant data to assess whether or not the trial should include adequate numbers of subgroups of participants to allow for separate and adequately powered analyses?

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?

Specific to this FOA:

What facilities and resources are available to adequately coordinate multi-sites clinical trials? Is there strong evidence that the institutions have the available resources needed to conduct a multi-site trial at the CCC and the performance sites? Does the application document the availability of the requisite eligible subject pool in proposed clinical site(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

How strongly do the milestones address the specific aims of each phase? Are the listed milestones appropriate for the goals of the project? To what extent are the milestones relevant, measurable, achievable, result-focused and time-bound? Does the application address contingency plans in the event the UG3 and/or UH3 milestones are not achieved?

Data and Safety Monitoring

• Is the proposed Data and Safety Monitoring Plan appropriate for the proposed clinical trial? What is the quality of the DSM Plan to monitor sites/centers, and participating facilities (labs, pharmacies)?

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.

Not Applicable

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.

For Renewals, the committee will consider the progress made in the last funding period.

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Research design and protocol development, including definition of objectives and approaches, planning, implementation, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.
• Establishing a Steering Committee to coordinate and manage the project. The PD(s)/PI(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Study investigators will be required to accept and implement the common protocol and procedures approved by the Steering Committee.
• Working with the DCC to implement the core data collection method and strategy collectively decided upon by the Steering Committee. It is the responsibility of each clinical site to ensure that data will be submitted in a timely way to the study’s data entry system according to the study protocol. Additionally, sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.
• Working with the DCC to establish mechanisms for quality control and monitoring. The recipients are responsible for ensuring accurate and timely assessment of the progress of the study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) as simple as appropriate in order to encourage maximum participation of physicians and patients and to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions.
• Establishing procedures, where applicable, for all participating institutions to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.
• Cooperating in the reporting of the study findings. The NIH will have access to and may periodically review all data generated under an award. Where warranted by appropriate participation, plans for joint publication with NIH of pooled data and conclusions are to be developed by the Principal Investigator or Steering Committee, as applicable. NIH policies governing possible co-authorship of publications with NIH staff will apply in all cases. In general, to warrant co-authorship, NIH staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; and (c) preparation and authorship of pertinent manuscripts
• Overseeing the overall budget, activities and performance of the cooperative agreement. Accepting the participatory and cooperative nature of the collaborative research process and complying with policies and practices of NCCIH
• Sharing data, resources and software according to the approved sharing policies for the NIH.
• Cooperating with the NIH staff and contracted on-site monitors in the design and conduct of protocols, analysis of data, and reporting of results of research.
• Agreeing to accept close coordination, cooperation and management of the project with NIH, including those outlined below under "NIH Responsibilities."
• Awardees will submit a detailed transition request for the UH3 phase, outlining UG3 progress, how negotiated UG3 Milestones have been met, as well as detailed plans, budget and annual milestones for the UH3 implementation phase. Note that funding of the UG3 phase cooperative agreement does not guarantee support of the UH3 phase.
• Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NCCIH or other NIH Institute or Center support; or special access to study results, data, findings, or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIH.
• Any of the above function may be performed by the applicant organization or by subcontract to the applicant organization
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIH will assign a Project Scientist as the point of contact to work with the PD(s)/PI(s) and participate in the Steering Committee to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist. With the agreement of the Principal Investigator, the NCCIH Project Scientist or designee may assist in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and/or in the publication of results.
• The NIH will assign a Program Officer who will be responsible for retaining overall programmatic responsibility for the award, and will clearly specify to the recipient the name(s) and role (s) of any additional individuals with substantial involvement in the project and the lines of reporting authority.
• NCCIH may designate additional staff to provide advice to the recipient on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Analyst, who will provide direct technical assistance to the recipients to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.
• Prior to the start of clinical activities, NIH staff will review and approve study protocols to insure they are within the scope of peer review and for safety considerations, as required by Federal regulations. NIH will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; and (f) emergence of new information that diminishes the scientific importance of the study question. The NIH will not permit further expenditures of NIH funds for a study after requesting closure (except for patients already on-study).
• Serve as a resource with respect to other ongoing NIH activities that may be relevant to the protocol to facilitate compatibility and avoid unnecessary duplication of effort.
• NIH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his/her staff, periodic site visits for discussion with the awardees research team, observation of field data collection and management techniques, fiscal reviews, and other relevant stewardship activities. NCCIH may designate NIH staff or contractors to conduct site initiation, interim and close out site-visits
• The NIH reserves the right to terminate or curtail the award (or an individual component of the award) in the event of inadequate progress or data reporting.
• NIH staff will provide input, expert advice, and suggestions in the design, development, and coordination and implementation of the study objectives.
• NCCIH staff will make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.
• NIH staff will conduct an administrative review of the UH3 transition request to determine whether the project will transition to UH3 funding. Criteria for transition to the UH3 phase used in the NIH administrative review include: successful achievement of the UG3 milestones, potential for successfully meeting the UH3 implementation phase plans and milestones, demonstrated ability of the team to work within the consortium arrangement, and the availability of funds.

Areas of Joint Responsibility include:

• Steering Committee organized by the Principal Investigator will be the main oversight body of the study.
• The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among recipients, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NCCIH Program Officer, and will provide periodic supplementary reports upon request.
• The Steering Committee will be composed of the PI(s)/PD(s) and co-investigators as deemed necessary, such as the study biostatistician and trial manager, the NCCIH Project Scientist, and additional designees of NIH. The NCCIH Project Scientist or designee will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NCCIH Program Officer will serve as an ex officio member of the Steering Committee. The Steering Committee will typically meet in-person twice in the first year of the award and then at least yearly thereafter. More frequent phone meetings will occur as required during the award period. The first in person meeting will occur before clinical activities begin.
• Ensuring that sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes, but is not limited to those relating to human subjects protections, informed consent, and reporting of adverse events.
• Jointly developing appropriate confidentiality procedures for data collection, processing, storage and analysis to ensure the confidentiality of data on individual health.
• A Data and Safety Monitoring Plan will be required for both phases of the project. An independent Data and Safety Monitoring Board will be appointed and established by NCCIH for the clinical trial, in accordance with NIH and NCCIH policies for monitoring (https://nccih.nih.gov/grants/policies/data-safety-monitoring). The Data and Safety Monitoring Board will play a crucial role in ensuring safety and welfare of patients enrolled in the trial and will regularly review study progress and some interim data; and will provide recommendations to NIH. During the award the recipient will provide interim data and reporting, as requested, to the Board as outlined in NCCIH Guidelines (https://nccih.nih.gov/research/policies/datasafety

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

The institution must submit a transition request as the progress report of the UG3 activities to NCCIH upon completion of the UG3 milestones. Submission of this report will trigger an administrative review that will determine whether the UG3 milestones have been achieved and whether the UH3 will be awarded.

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.

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Wendy Weber, N.D., Ph.D., M.P.H.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: [email protected]

Martina Schmidt, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: [email protected]

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: [email protected]

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.