Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
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 (i.e., botanicals, probiotics, and products marketed as dietary supplements) for which there is compelling preclinical or preliminary clinical evidence of 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 when they incorporate well-formulated biological hypotheses, are built on a sound foundation of basic mechanistic and pharmacologic understanding and incorporate assessment of defined replicable biological effects. Biological signatures of the natural products may be an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes. 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
Overview of NCCIH Natural Products Clinical Trials Research Funding Opportunities
NCCIH has designed its natural products clinical trials program to support investigator-initiated studies with funding mechanisms appropriate to the stage of the translational research process. This includes pre-clinical/animal studies (which may use Parent R21 or R01 FOAs), human mechanistic studies to determine and replicate the biological effect of a given natural product (phased innovation awards using R61/R33 or R33 alone), clinical trials to determine the optimal dose and/or determine which patient phenotypes will be responders versus non-responders (using the U01 funding mechanism), and multi-site clinical trials to perform definitive efficacy studies (UG3/UH3 funding mechanism).
The following research funding mechanisms have been established by NCCIH to assist in supporting research and development of a natural product along a translational research continuum from early exploratory pre-clinical or first in human research through multi-site efficacy trials. Depending on the extant evidence and research for a given natural product, applicants may use the appropriate FOA to support the next step in clinical trial research.
Natural Product Early Phase Clinical Trial - Determining and Replicating Biological Signature (R61/R33, PAR-18-829 and, R33, PAR-18-828)
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, henceforth known as a biological signature. In general, a research grant application submitted under the R61/R33 (or R33) should precede submission of a U01 Clinical Trial Implementation Cooperative Agreement, although this is not a requirement and such data may be available or can be obtained through other means. The biological signature may be a measure of the postulated mechanism of action by which the natural product may ultimately modify the clinical condition or symptom(s) of interest. Biological signatures may be an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes.
The R61/R33 should be used to measure the impact of the natural product on a biological signature (R61 phase); replicate the impact and determine the reproducibility of the biological signature in a separate study (R33 phase); 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 (R33 phase). The data collection supported under the R61/R33 (or R33 if pilot data is available demonstrating the initial impact of the natural product on the biological signature) should be finished and the data analysis completed before the U01 or UG3/UH3 is submitted.
Natural Product Phase II Clinical Trial Cooperative Agreement Award (U01, PAR-18-125 )
The Phase II Clinical Trial Award FOA is intended to build upon work that has identified and replicated a biological signature of a given natural product and complete collections of the necessary preliminary data needed to inform the design a fully powered multi-site efficacy trial. Investigators should only apply for the U01 Natural Product Phase II Clinical Trial Cooperative Agreement after they have strong evidence that the proposed biological signature of the natural product can be reliably assessed for a condition of interest in the designated clinical population. It is recognized that for certain conditions (e.g. pain), a direct biological effect or biological signature may not be measurable in human participants for a variety of reasons. In such instances, a strong justification for why including a biological signature is not possible or impractical with human participants is required. In these cases, investigators should consider including other objective measures that may be a marker of the mechanism of action and provide evidence of a biological or behavioral effect of the natural product in human participants. The U01 clinical trial FOA will support natural product clinical trials (phase II) such as dosing and formulation optimization of the natural product to be used in a future multi-site randomized clinical trial; collecting additional data documenting ability to recruit/accrue participants, achieve adherence to the study protocol, retain participants during study, and complete collection of follow-up data; or determining which patient phenotypes will be likely responders versus non-responders to the natural product to inform inclusion/exclusion criteria of a future multi-site efficacy trial.
Multi-Site Investigator-Initiated Clinical Trials Cooperative Agreement Award (UG3/UH3, PAR-18-696 and U24, PAR-18-697 )
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 efficacy trial. If the UG3 phase successfully meets all planning milestones, the UH3 phase is awarded to implement the efficacy 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 (Phase III and beyond). In addition, multi-site clinical trials require a companion Data Coordinating Center (DCC) application (U24) be submitted with and linked to the CCC application. Both applications undergo peer review simultaneously. Multi-site clinical trials are defined as trials that enroll from two or more recruitment sites. Multiple sites are necessary for efficacy trials to increase generalizability of findings and enhance recruitment efficiency as well as representativeness of the participants. Multi-Site clinical trials are expected to contribute to the evidence base for important health matters of relevance to the research mission of NCCIH. In addition to scientific relevance and excellence, these clinical trials are expected to be conducted with a high degree of efficiency, with streamlined administrative procedures wherever possible. The Clinical Coordinating Center for Multi-Site Trials (UG3/UH3) FOA runs in parallel with a companion FOA that encourages applications for the companion DCC (U24). Multi-site trials will be expected to achieve the required phase III trial requirements of NIH (see: https://humansubjects.nih.gov/glossary, and http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm)
Purpose of the NCCIH Natural Product Early Phase Clinical Trial Award (R33) (This FOA)
This FOA provides support for studies to replicate the impact of the natural product on the biological signature(s) when used by humans and assess if there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Exploratory studies supported by the R33 should not be powered to assess clinical efficacy, but rather should test a hypothesis about the natural product’s mechanism of action and inform a decision about whether the natural product warrants further study. A placebo arm can be used and is usually needed to confirm that the replicated changes measured in the biological signature are due to the natural product and not regression to the mean or natural history of the condition.
In addition to the primary aims of replicating the impact of the natural product on the biological signature and assessing the association between the biological signature and functional or clinical outcomes, secondary aims in the R33 may include:
1) further testing of the intervention’s feasibility, safety, and acceptability;
2) determine the optimal dose or formulation of the product for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of the impact on the biological signature in response to multiple doses of the natural product;
3) determine the pharmacokinetics of the dose and formulation of the natural product to be used in future trials to justify the frequency of dosing;
4) combine the natural product with another treatment approach that is known to impact the same biological signature to optimize its impact;
5) optimize the impact of the natural product by studying it in a more responsive target population;
6) demonstrate the study team’s ability to recruit, randomize (if appropriate), retain, collect all assessments and samples, adhere to the study protocol, and report of adverse events; and
7) develop functional biological signature measures and clinical outcome measures feasible for use in larger efficacy and effectiveness trials.
The specific activities appropriate for the R33 will depend on the natural product under study, the stage of the study proposed, and available preliminary data on the natural product.
The objective of this NCCIH R33 funding opportunity is to improve the knowledge for natural product clinical trials planning. Investigators are encouraged to include relevant stakeholders (e.g., patients, providers, health care systems, etc.) in the planning and execution of exploratory and larger clinical trials. The outcomes of an R33 award could lead to the realization that the product does not warrant further study; additional studies must be completed before proceeding to a full-scale multi-site efficacy trial; or the data generated under this phased award are informative and sufficient to warrant moving ahead with a well-executed clinical trial. If warranted by the results of studies conducted, R33 awardees may prepare and submit an application for a subsequent clinical trial during the final year of the R33 award period. Prospective applicants should note that funding of an R33 does not guarantee that NCCIH will accept, or fund, a subsequent full-scale clinical efficacy trial application.
Preliminary Data Requirements
This FOA is appropriate when there are 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 peer-reviewed literature) on the same product and specific formulation as proposed in the current application are required:
NCCIH Priorities for Developing and Pilot-testing 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 used by the public and where there is evidence of postulated mechanism of action. For this FOA, NCCIH considers the following two general topic areas to have high program priority:
NCCIH also encourages applications to this FOA that address the above priorities as well as health disparities, symptom management in patients with HIV/AIDS, and/or utilize special populations such as older adults, children, underrepresented minorities, individuals in the military, or veterans.
This FOA will not support studies that utilize only in vitro or animal models; nor will it support fully-powered randomized trials designed to test efficacy or effectiveness. Applications proposing research in topics not identified above as high programmatic priority will be considered of lesser or low programmatic priority, which will significantly influence programmatic relevance and reduce the likelihood of funding.
The Office of Dietary Supplements (ODS) is interested in supporting early phase clinical trials of the effects of dietary supplements (or their ingredients or bioactive metabolites) on objective outcomes relevant to health maintenance (e.g., measures relevant to metabolic, cognitive, immune, anti-inflammatory, and/or aging processes) or resilience (the capacity to withstand and successfully adapt to change, disturbance, stress, etc.) where there is rigorous evidence that a specific chemical component or components are required for the proposed bioactivity(ies). Relevant biomarkers of resilience in the context of this FOA might include (but are not limited to) gut microbiome diversity, or effects on specific cognitive or immune measures of sleep disruption, or other biological or psychosocial stressors. Research on effects of treatment is inconsistent with the ODS mandate and cannot be supported by ODS unless the data to be collected are demonstrably relevant to health maintenance.
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:
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 NCCIH staff to discuss the scope and goals, and to provide information and guidance.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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.
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.
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.
Experimental Approach: The proposed experimental approach should include an appropriate study design and the rationale for the design chosen. The experimental approach description should include:
Letters of Support:
Letters of support from clinicians or clinical department chairs whose support is necessary to the successful conduct of the trial should be provided. Applicants are also encouraged to include documentation of the commitment of any subcontractors and consultants, as well as service agreements for personnel or facilities. Letters of commitment must be co-signed by the business official of the collaborating center. In addition, a letter of support should document that sufficient supply of the natural product will be available for testing at the time of award, including expiration date; that the supplier will meet and provide details regarding Chemistry Manufacturing and Controls specifications; and the supplier will provide the data necessary for the investigator to adhere to NIH and FDA policies. Documentation should include a letter of agreement from the 3rd party supplying the natural product.
If parts of the costs of the trial are to be provided by sources other than NCCIH, provide Letter(s) of Support signed by an authorized representative.
Section 2 - Study Population Characteristics
2.4 Inclusion of Women, Minorities, and Children
Describe the following: 1) safeguards for vulnerable populations as appropriate (e.g., children, pregnant women); and 2) strategies for outreach to minorities and women.
2.5 Recruitment and Retention Plan
Describe 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; and 5) possible competition from other trials for study participants; Investigators are encouraged to review the NCCIH Study Accrual and Retention Plan (https://nccih.nih.gov/grants/policies/SARP).
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 multisite applications, information must be provided for each participating site.
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
In addition to the NIH application requirements for a data and safety monitoring for clinical trials, 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).
Section 4 - Protocol Synopsis
4.6. Will the study use an FDA-Regulated intervention?
4.6.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status
The proposed clinical trial must use a natural product (such as botanical, herbal, dietary supplement, probiotic, vitamin or mineral) for this FOA. The attachment in this section should describe correspondence from the FDA indicating whether the proposed study will require an IND/IDE. Investigators should describe the process that will be used for attaining all necessary FDA or other applicable regulatory agency approvals necessary to the conduct the trial; and associated timeline to complete these approvals. 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.
4.7 Dissemination Plan
Describe how the investigators will facilitate and support timely publication and dissemination of results as appropriate and consistent with achieving the goals of the program.
Section 5 - Other Clinical Trial-related Attachments
5.1 Other Clinical Trial-related Attachments
The following attachment must be included as a part of the cooperative agreement application. The attachment permits expansion of certain elements that cannot be appropriately described in the Research Strategy. The attachment listed below must be provided or the application will not be peer reviewed.
1. Clinical Trial Experience
Applicants must provide a detailed table listing the characteristics of trials that demonstrate Key Personnel experience in past trial coordination in the last 5 years. The table must be provided as an attachment and must not exceed 3 pages.
The table elements should include:
Element A: clinical trial title
Element B: applicant's role in the trial
Element C: a brief description of the trial design
Element D: planned enrollment
Element E: actual enrollment
Element F: number of sites
Element G: whether the trial(s) were completed on schedule or not
Element H: publication reference(s)
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.
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.
Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.
Specific to this FOA:
How well defined are the PD/PI roles and responsibilities? How well does the application provide evidence of necessary expertise about the natural product and study population? What evidence is provided to ensure that the investigators will employ the appropriate personnel to recruit subjects and design/implement the clinical protocol? Does the investigative team have a track record of conducting, completing, and publishing the results of clinical trials? What evidence is provided to demonstrate that the investigative team has successfully conducted clinical trials under an Investigational New Drug (IND) application?
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs,
practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
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.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.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 https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/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 https://www.hhs.gov/ocr/about-us/contact-us/index.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.
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.