- May 20, 2020 - This PAR has been reissued as PAR-20-217.
- August 23, 2019 - Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137.
- July 26, 2019 - Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128.
- January 11, 2019 - Notice of Updated Application Forms Package for PAR-18-828. See Notice NOT-AT-19-018.
- November 26, 2018 - NIH & AHRQ Announce Upcoming Updates to Application Instructions and Review Criteria for Research Grant Applications. See Notice NOT-OD-18-228.
PAR-18-829, R61/R33 Exploratory/Developmental Phased Award
PAR-18-125 , U01 Research Project Cooperative Agreement
PAR-18-696, UG3/UH3 Exploratory/Developmental Cooperative Agreement
This FOA will provide up to 3 years support for studies to replicate the impact of the natural product on the biological signature(s) when used by humans and assess whether there is an association between the degree of the impact on the biological signature and functional or clinical outcomes in a patient population. Applications can design studies to determine how to optimize the impact of the natural product on the biological signature by (1) optimizing the delivery of the natural product by dose or formulation; (2) combine the natural product with another treatment approach that is known to impact the same biological signature; or (3) study the impact of the natural product in a target population that is more responsive. Clinical trials submitted under this FOA are expected to be hypothesis based, milestone-driven, and directly related to the research priorities and mission of NCCIH. This R33 funding mechanism is intended to accelerate the translation of emerging basic science findings about natural products into early stage clinical testing to determine whether continued clinical research is warranted. This FOA will not support efficacy or effectiveness trials, nor will it support trials to test natural products for the treatment or prevention of cancer.
Key Dates
Resubmission Applications: September 7, 2018; February 21, 2019; and October 22, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.
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.
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.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
- Use the NIH ASSIST system to prepare, submit and track your application online.
- Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
- Go to Grants.gov to download an application package to complete the application forms offline or create a Workspace to complete the forms online; submit your application to Grants.gov; and track your application in eRA Commons.
Part 1. Overview Information
Part 2. Full Text of the Announcement
Section
I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission
Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
Research Objectives
The National Center for Complementary and Integrative Health (NCCIH) is committed to the rigorous investigation of promising natural products (i.e., botanicals, probiotics, and products marketed as dietary supplements) for which there is compelling preclinical or preliminary clinical evidence 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.
Subsequent Studies
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:
- Human studies demonstrate biological mechanisms via measurement of the impact of the natural product on the biological signature(s) proposed in the application
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:
- 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.
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.
?ODS Priorities
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:
- Applications lacking preliminary data demonstrating that the specific natural product under study impacts the proposed biological signature when used by humans.
- Applications lacking preliminary data demonstrating that the specific natural product is bioavailable in humans. Note that for probiotics this may be demonstrated by documenting short-term retention in the gastrointestinal tract.
- Clinical trials designed solely to estimate intervention effect size or power calculations for a future trial.
- Applications that do not propose to give the natural product to human participants and measure the impact on a biological signature(s) or mechanisms of action.
- Phase III trials of efficacy (such studies should use the Natural Product UG3/UH3 FOA, PAR-18-869).
- Observational studies that do not meet the NIH definition of a clinical trial (such studies should use the Parent R21 or R01 FOAs).
- Trials that propose to test natural products for the treatment or prevention of cancer.
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.
Resubmission
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Need help determining whether you are doing a clinical trial?
1. Eligible Applicants
- Public/State Controlled Institutions of Higher Education
- Private Institutions of Higher Education
- Hispanic-serving Institutions
- Historically Black Colleges and Universities (HBCUs)
- Tribally Controlled Colleges and Universities (TCCUs)
- Alaska Native and Native Hawaiian Serving Institutions
- Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)
- Nonprofits 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)
- Small Businesses
- For-Profit Organizations (Other than Small Businesses)
- 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
- Independent School Districts
- Public Housing Authorities/Indian Housing Authorities
- Native American Tribal Organizations (other than Federally recognized tribal governments)
- Faith-based or Community-based Organizations
- Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.
Applicant organizations 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.
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.
2. Cost Sharing
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.3. Additional Information on Eligibility
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)
1. Requesting an Application Package
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.2. Content and Form of Application Submission
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide 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.
Letter of Intent
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.
Telephone: 301-594-34-56
Email: [email protected]
Document the Program Director's/Principal Investigator's experience in leading clinical trials and expertise in the content area of the trial. Even exploratory clinical studies will require a multidisciplinary team (clinician, biostatistician, data manager, study coordinator, etc.) and the application should reflect their hands-on involvement in the design and implementation of the study protocol. Applicants are encouraged to provide strong evidence of the study team's qualifications and ability to conduct the proposed as well as future research, experienced investigative team members, and previous investigative experience in related clinical trials.
All instructions in the SF424 (R&R) Application Guide must be followed.
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. The application should provide rigorous preclinical or clinical preliminary data to support the study rationale. It is particularly important that there be a discussion of how the trial will test the proposed hypotheses and why there is clinical equipoise. The application should make clear the need for and timeliness of the study with emphasis on how the results will address an evidence gap and therefore advance our knowledge of theory and practice in this area. The application should describe how the proposed project will advance knowledge to determine if the natural product can reproducibly modify a biological signature, so that future clinical trials can determine if the biological signature is a mediator of clinical benefit. It is particularly important that there be discussion of how the results of the proposed trial (positive or negative) will guide decisions about whether a subsequent study is needed or justified, and/or provide evidence that additional studies must be completed before proceeding to a full-scale efficacy trial. A discussion of the costs and benefits of the study should be included for evaluation of the trial's significance. The applicant is expected to provide a precise response to the following two questions: 1) Will the result, whether positive or negative, be informative and provide a definitive test of the hypothesis? 2) Will the results be informative about the potential role of the biological signature in the clinical condition?
Innovation: Explain how the application challenges and seeks to shift current research or clinical practice paradigms or guidelines.
Approach: The research approach section should include a description of the supporting data, clinical trial experience, the experimental approach, and a milestone plan.
Supporting Data: The application should describe data from preclinical and/or clinical studies that led to the proposed clinical trial, which should demonstrate the need for, and the feasibility of, the proposed early phase trial. 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:
- Human study(ies) demonstrates biological mechanisms via measurement of the impact of the natural product on the biological signature(s) proposed in the application
Experimental Approach: The proposed experimental approach should include an appropriate study design and the rationale for the design chosen. The experimental approach description should include:
- A rationale of why the study population is the most appropriate group to answer the question, which can refer to the description and details in the PHS Human Subjects and Clinical Trials Information form as appropriate.
- A 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. This rationale can refer to the description and details in the PHS Human Subjects and Clinical Trials Information form as appropriate.
- A rationale for the natural product and matching placebo (if applicable) to be tested including: name of the product, ingredients of the product, rationale for the product and supplier, proposed methods for product characterization and standardization, rationale for selection, and percentages of marker compounds if applicable. See the NCCIH Policy on Natural Product Integrity for more information (http://NCCIH.nih.gov/research/policies/naturalproduct.htm).
- A summary of the necessary agreements for the use of the natural product and any matching placebo. Note that all necessary agreements for the use of the natural product in the study, including clinical research agreements and licensing agreements must be executed prior to grant award. A timeline should be included in the application showing activities with third parties such as 1) executing necessary agreements, 2) providing natural product and matching placebo, and 3) permission to reference an open IND drug master file (if available).
- A justification for all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. A rationale for the use of patient reported outcomes as well as non-traditional data collection approaches (e.g., telephone, mobile devices, or web-based systems). This justification can refer to the description and details in the PHS Human Subjects and Clinical Trials Information form as appropriate.
- A description of the future clinical trial beyond the R33: A concise summary of the subsequent anticipated future trial should be provided including the study design.
- Discussion of the challenges expected in implementing the research and how they will be addressed.
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.
The following modifications also apply:
- All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions:
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 instructions in the SF424 (R&R) Application Guide must be followed.
3. Unique Entity Identifier and System for Award Management (SAM)
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.gov4. Submission Dates and Times
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.
5. Intergovernmental Review (E.O. 12372)
This initiative is not subject to intergovernmental review.6. Funding Restrictions
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.
7. Other Submission Requirements and Information
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.
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.
Section V. Application Review Information
Important Update: See NOT-OD-18-228 for updated review language
for due dates on or after January 25, 2019.
1. Criteria
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.Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?
Specific to this FOA:
Is there a sufficient body of preclinical or clinical research of high scientific rigor to support the study rationale? Why is this clinical trial necessary to generate preliminary data to inform the design and implementation of the future efficacy trial of the natural product that could lead to a change in clinical practice, community behaviors or health care policy? Does the applicant provide justification as to why it is important to perform the future larger clinical study in the context of the present knowledge on clinical research in natural products? Is it clear why the proposed exploratory trial is essential to inform the design and implementation of subsequent steps in the evaluation of the natural product? Is the proposed project likely to yield clear answers needed to proceed to the next step of research as proposed in this application? Will the proposed study advance knowledge of intervention or disease mechanisms, whether the results are positive or negative?
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?
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?
Specific to this FOA:
For these early phase clinical trials, how will the proposed clinical trial inform the design of the future efficacy trial so that it can change clinical practice or practice guidelines? Does the proposed exploratory trial have the potential to advance the field (e.g., by breaking ground for future trials in this area) even if (a) the proposed study design, methods, and intervention are less innovative, and/or (b) the results of the trial indicate that further clinical development of the intervention is unwarranted?
Study Design:
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
For this specific FOA:
How does the proposed study ensure that the underlying hypothesized biological signature is appropriate and relevant, and will be rigorously tested by giving the product to humans and assessing the impact on the biological signature?
Does the application include sound methodology for (a) replicating and extending the initially observed impact of giving the natural product to humans on the hypothesized biological signature(s) described in the preliminary data section of the application, and (b) evaluating associations between biological signature and subsequent clinical or functional outcomes? If optimization studies are described, will the methods proposed allow investigators to design a future study with a more impactful intervention by selecting the dose, formulation, patient population, or combination treatment that has the greatest effect on the biological signature while maintaining safety?
Does the applicant describe how the proposed study relates to a larger strategy for research of this natural product and will it provide pilot and feasibility data needed to advance that strategy? Does the application demonstrate the feasibility of methods for developing tools for data management and study oversight, finalizing protocol documents and manuals, as well as addressing appropriate regulatory requirements (FDA, IRB)? How well justified are the outcome measures, dose/duration of study, appropriateness of inclusion/exclusion criteria, and sample size for the early phase study?
What strengths and weaknesses are there in the study design? How strong is the evidence for equipoise? How well does the study record attachment describe the necessary elements of the clinical trial and how likely is it that the protocol can be efficiently implemented? How strong are the formative clinical studies, including any pilot studies, underpinning the trial? Is the natural product appropriately characterized?
Is there a clear strategy for tracking recruitment and facilitating retention? Will sufficient and appropriate data be collected to inform a decision whether further clinical testing is warranted? Are likely problems anticipated?
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center 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?
Study Timeline
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)?
2. Review and Selection Process
- 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.
- 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.
3. Anticipated Announcement and Award Dates
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.
1. Award Notices
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.
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).
2. Administrative and National Policy Requirements
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.
3. Reporting
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 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.
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]
GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-402-1272
Email: weberwj@mail.nih.gov
Barbara Sorkin, Ph.D
Office of Dietary Supplements
Telephone: 301-435-3605
Email: [email protected]
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3456
Email: schmidma@mail.nih.gov
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov
