NIH – NCCIH Natural Product Phase II Clinical Trial Cooperative Agreement (U01)

March 10, 2017 by School of Medicine Webmaster

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 and preliminary clinical evidence for potential health benefit. NCCIH is particularly committed to identifying effective complementary health approaches for management of symptomatic conditions that are commonly treated in primary care such as sleep disturbance, pain, or mild mental health conditions (e.g., mild to moderate depression, anxiety, and post-traumatic stress). In addition, NCCIH is interested in examining the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system.

Clinical trials of natural products are maximally informative if they incorporate well-formulated biological hypotheses, are built on a sound foundation of basic mechanistic and pharmacologic understanding, and incorporate assessment of defined replicable biological effects. Biological signatures of the natural products may be an objective single measure, proxy, correlate or combination of molecular/cellular, psychological, neural circuit, tissue/organ, and/or somatic changes. It is recognized that for certain conditions (e.g. pain), a direct biological effect or biological signature may not be measurable in human participants for a variety of reasons.  In such instances, a strong justification for why including a biological signature is not possible or impractical with human participants is required. In these cases, investigators should consider including other objective measures that may be a marker of the mechanism of action and provide evidence of a biological or behavioral effect of the natural product in human participants. In all cases, a measure of bioavailability of the natural product in human volunteers is required. A careful translational research process is as important for trials of natural products as it is for the study of conventional pharmaceuticals.  Critical to this process is the development of measures of a biological effect and refinement of appropriate outcome measures for a clinical condition.

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

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

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), clinical trials to determine the optimal dose and/or determine which patient phenotypes will be responders versus non-responders (this FOA 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.

Clinical Trial Planning Phase – Determining Biological Signature (R61/R33, PAR-16-418)

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

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

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

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

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

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

Deadlines:

  • New Applications: June 7, 2017; October 6, 2017; June 7, 2018; February 7, 2019; and October 8, 2019
  • Resubmission, Revision, and Renewal Applications: October 20, 2017; June 21, 2018; February 21, 2019; and October 21, 2019
  • Letters of intent are due 30 days prior

URL:  https://grants.nih.gov/grants/guide/pa-files/PAR-17-216.html

Filed Under: Funding Opportunities