NIH – Botanical Dietary Supplements Research Centers (BDSRC) (U19 Clinical Trial Optional)

Plants and plant-derived products are widely consumed for basic nutrition, and to promote health and well-being, worldwide and in the U.S. Nevertheless, there is only a partial understanding of what effects (beneficial or adverse) many of these products have on human health and well-being. To the extent that these products may have clinical efficacy, the underlying mechanisms of action are rarely fully understood. The challenges of doing research on these complex and inherently variable materials contribute to slow progress towards a definitive understanding of these issues.

Randomized, controlled clinical trials (RCTs) are the most widely accepted standard for assessing the efficacy of an intervention, but the majority of RCTs (whether of botanicals or of pharmaceuticals) fail to reject the null hypothesis (i.e., they fail to provide evidence supporting the tested hypothesis). Given the substantial cost of Phase III RCT, they should be undertaken selectively, with their initiation generally limited to situations where there is a body of rigorous and compelling evidence, consistent over a range of research approaches and/or distinct preclinical and/or clinical models, that:

  1. supports the likelihood of seeing the hypothesized effect in humans,
  2. indicates the proposed intervention(s) are unlikely to expose trial participants to inappropriate risks, and
  3. is sufficient to inform and justify design of the trial protocol, such that if the completed trial fails to provide evidence of the hypothesized effect, it is difficult to blame that failure on those design decisions.

In addition, it is preferable to conduct large RCTs only when the level of preliminary data is sufficient to support design of a trial where, regardless of the results of the completed trial, they are expected to be useful to rigorously inform decisions about further research on, or use of the product. In general, such preliminary data will include compelling evidence on the bioactive components of the product, their bioavailability, mechanism(s) of action, etc.

Research Objectives

Achievement of the Specific Aims of the transdisciplinary research centers responsive to this FOA must address the most critical gaps in information needed for future design (by the applicant or others) of optimally informative clinical trials. Taking into consideration that each clinical trial entails myriad design decisions, some of which will likely have stronger effects on trial outcomes than others, applicants must set forth an evidence-based case that achieving the proposed Specific Aims will provide key information towards design decisions for the anticipated, future RCT, and that the future RCT is likely to rigorously inform practice or other health-critical next steps.

Past clinical trials of botanicals have been criticized for real or imagined design flaws. The objective of these BDSRC is to obtain evidence to inform critical clinical trial design decisions, presumably enhancing the chances that a future RCT rejects the null hypothesis, but also making it more difficult to discount the result in the event of a failure to do so. Objectives of the BDSRC might therefore include, but are not limited to, optimizing the composition or formulation of the botanical intervention, optimizing dose or dose timing, assessing bioavailability and pharmacokinetics of bioactive components, elucidating proximate biological effects underlying the health outcome of interest, elucidating individual determinants of response, or optimizing outcome measures. BDSRC researchers must monitor, and may focus on, evidence relevant to safety of human use. In addition, BDSRC Specific Aims should generate information that will allow confirmation or falsification of a detailed mechanism of action hypothesis during a future RCT. The BDSRC might, for example, aim to obtain information necessary to allow monitoring the concentration of a bioactive component at its target(s), or the extent to which the proximate biological effect is generated and correlated with the outcome.

The two research projects and the Botanical Core are expected to apply – and, where appropriate, develop – rigorous, state-of-the-science approaches to understanding the potential to affect human biological or cognitive/behavioral resilience of the complex botanical product(s) studied.

The BDSRC may include certain clinical trials (as defined by NIH; https://grants.nih.gov/policy/clinical-trials.htm), including, but not limited to, assessments of bioavailability, pharmacokinetics of a product component, or approaches to predict responsive individuals (where there is evidence that response is heterogeneous).

The BDSRC may NOT include applications proposing clinical trials of efficacy and/or effectiveness. Such applications will be considered nonresponsive and withdrawn without review. Future RCTs building on the BDSRC findings may be supported in a variety of ways, including, but not limited to, FOAs such as NCCIH’s PAR 17-172 and 17-174.

Clinical research may be included in the Research Projects or the Botanical Core, but may not be included in an Administrative Core.

BDSRC Structure

Each BDSRC will be required to include a Botanical Research Core and two research projects that all synergize with each other, and will, separately and together, provide information that will fill in the most critical gaps in the existing body of data relevant to the optimal design of a future clinical trial of the effects on human resilience of orally consumed, complex botanical products. We define synergy, in this context, as collaboration of the various projects and Cores, such that data or methods from each component inform the others, and the scientific contributions of the Center as a whole are greater than the sum of outcomes of the individual projects and Cores in the absence of intensive collaboration.

The Botanical Core of each proposed BDSRC must be responsible for ensuring product integrity and providing in sufficient amounts materials used by both research projects and any collaborating projects within the CARBON Program, and for advancing understanding of the chemistry of the product(s). If a broad, non-targeted approach has not previously been applied to the product(s) to be studied, then the Botanical Core must include one or more Specific Aims to rigorously assess the potential presence in the product of additional bioactive components which may synergize with or add to the proposed (known) bioactives, counteract them, or have quite different bioactivities, including in vivo targets not previously noted for the product studied. Such aims may include the use of untargeted screening platforms or other approaches, as appropriate.

BDSRC must have clearly delineated plans for a governance and organizational structure. An Internal Steering Committee (ISC) and an External Advisory Committee (EAC) are required (please see Section VI. of this FOA). An Administrative Core is allowed, but is not required. The planned governance and organizational structure must encompass processes for making decisions on scientific direction in conjunction with the EAC, and procedures for resolving conflicts.

BDSRC must develop and regularly update a BDSRC website providing information on (at least) the U19 supported research, research publications and research presentations.

BDSRC should be strong environments for research career development and must have plans for obtaining funds (or utilizing existing resources) to provide graduate students and post-doctoral fellows with training and career development opportunities in transdisciplinary approaches to understand the biological and/or cognitive/behavioral effects of complex botanicals.

Collaboration beyond, as well as within each BDSRC is expected to be a critical contributor to the Program’s success. Therefore BDSRC are expected to interacti with other components of the CARBON, including through a pilot project component, to be described later. Such collaborations are expected to include, where appropriate and productive, collaborative demonstration projects with the concurrently awarded Centers for Natural Product Technology, Methodology and Productivity Optimization and must include participation of key personnel in meetings, including, but not limited, to the annual meetings of the CARBON.

Participation of younger investigators, including post-doctoral fellows and students in the annual CARBON meetings is also strongly encouraged.

Specific Areas of Research Interest

The purpose of this BDSRC FOA is to support research to develop additional information most critical to the optimal design of, and decision-making for clinical trials of the effects of ingested, complex botanical products on quantitative, objective, well-validated indicators relevant to biological or cognitive/behavioral resilience. Responsive applications must provide rigorous evidence supporting a biologically and mechanistically plausible, reproducible effect, the magnitude of which is sufficient to justify a human intervention trial. The evidence provided, whether newly developed or in peer-reviewed research publications, must be consistent across at least two independent and scientifically distinct (e.g., orthogonal) lines of evidence, and must include data that address causality (e.g., results of knock-out and/or over-expression designs). For example, data from an in vitro model (using a physiologically relevant product and concentration) supporting a mechanism of action, and data from an early-phase clinical trial, consistent with the in vitro results, as well as with a correlation between the mechanism of action and the physiological or cognitive/behavioral outcome of interest, would be responsive. Data from two different product doses, both in the same pre-clinical model, would not be sufficient support for a responsive application.

Responsive BDSRC applications must include rigorous evidence that the presence of one or more proposed bioactive components (or precursors thereof) in the intervention is necessary for a relevant proximate biological effect, health outcome, or both, and of the applicants’ ability to meaningfully monitor product quality, bioavailability, and pharmacokinetics based on one or more of these proposed bioactives. In addition, responsive applications must include rigorous evidence of bioactive bioavailability, i.e., that, following product ingestion, the bioactive components (which may be metabolites of the product) can reach a concentration in vivo, preferably at the presumed proximate target, that is sufficient for the activity of interest.

Successful BDSRC applications must have made a compelling case that achieving the proposed Specific Aims will significantly enhance the design of a future clinical trial of the product (or an optimized form of it), such that that future RCT is expected to be highly informative whether or not it rejects the null hypothesis, as described in Section II.1 (Research Objectives) above.

Products appropriate for applications responsive to this FOA will be limited to complex botanical products for which there is rigorous, but not definitive, evidence supporting a clinically or public health significant and reproducible effect (as described above) on quantitative, objective outcomes relevant to human biological or cognitive/behavioral resilience. Applications in which a purified phytochemical is the main focus, or in which the focus is not on effects of oral intake, will be considered nonresponsive to the FOA and withdrawn without review.

Research objectives supported by this FOA may include, but are not limited to:

  • Obtaining additional data on the causal, molecular mechanism through which the bioactive component(s) of the product act(s) on the proximate in vivo target(s). Model systems used, whether in silicoin vitro or in vivo, must be well-validated and well-justified as appropriate for the research question posed.
  • Obtaining data on genetic or epigenetic sources of diversity in human responses to the intervention, and their underlying causal, molecular mechanisms. The contributions of age, sex, diet, and/or differences in gut microbiota to such differences are of particular interest.
  • Further elucidation of the mechanisms through which the proximate biological activity(ies) of the product are effected, or through which they generate the hypothesized health outcome.
  • Generation of data on dose-response, optimal product composition, pharmacokinetics/pharmacodynamics (PK/PD) and optimal dose regimen, and/or optimization of circadian timing of intervention.
  • Generation of data on the time course of a health effect.

Resilience

For the purposes of the BDSRC FOA, resilience is defined as capacity to withstand and successfully adapt to change, disturbance, stress, etc., or to recover efficiently from disturbance, challenge, illness, etc. Applicants must use models in which resilience can be measured quantitatively and objectively over relatively short time frames appropriate for a 5-year award. Examples of such outcomes include, but are not limited to, restoration, in initially healthy individuals, of baseline microbiome ecology after disturbance, HbA1c levels, response to vaccine or viral challenge, time to return to initial or normal/healthy levels of inflammatory cytokines or blood glucose after a perturbation, or measures of fatigability.

Botanicals of interest

Terrestrial plants, algae or macroscopic fungi (and products derived from them) are included within the purview of this FOA. Applications that include experiments using purified entities found in, or synthetic compounds derived from, botanical sources will be considered only where such research is necessary to elucidate the mechanisms of action or activities of the complex botanical. This FOA supports research on traditional herbal medicines as well as on foods of plant origin that are proposed to contain bioactive components beyond basic nutrients. While optimization of product formulation based on the results of the proposed research are appropriate for this FOA, applications focused on methods to improve large scale production of individual natural products or their derivatives, or on tools to synthetically modify natural products to improve bioavailability or potency, will be considered nonresponsive and will not be reviewed.

Investigators wishing to propose research that doesn’t meet the strict eligibility criteria for this FOA may wish to consider submitting applications to NCCIH’s R61/R33, PAR 18-828, and PAR 18 -829 instead.

Each BDSRC Botanical Core will be responsible to:

  • ensure product integrity and consistent availability in sufficient quantity, of materials used by both research projects and any collaborating projects within the CARBON,
  • implement, and where necessary, develop rigorous, cutting-edge methods for assessing composition, stability, bioavailability, pharmacokinetics, etc., of the products used in the BDSRC,
  • advance understanding of the chemistry of the product(s). If a broad, non-targeted approach has not previously been applied to the product(s) to be studied, then the Botanical Core must include Specific Aims to rigorously assess the potential presence in the product of additional bioactives, which may synergize with or add to the proposed (known) bioactives, counteract them, or have quite different bioactivities, including in vivo (animal) targets not previously noted for the product studied. Such aims may include unbiased screening platforms, as well as other approaches, as appropriate. High-throughput, high-content approaches including but not limited to in vitro as well as in vivo (e.g., Drosophila, Caenorhabditis, or Danio) are encouraged.

In addition, Botanical Core Specific Aims may include:

  • Generation of modified versions of the products, based on data produced through the research projects (e.g., enriched or depleted in putative bioactives),
  • Rigorous and specific quantitation of the (known) bioactives or relevant metabolites thereof in vivo or in relevant biological specimens.
  • Clinical assessment of pharmacokinetics and pharmacodynamics.
Excluded Research Areas

Projects proposing any of the following research will be considered nonresponsive and will not be reviewed:

  • Projects lacking evidence for a biologically and mechanistically plausible, reproducible effect(s) relevant to human resilience, with the effect(s) consistent across at least two independent and scientifically distinct lines of evidence.
  • Projects lacking justification for the importance of achieving the Specific Aims to the future design of a follow-on clinical trial.
  • Research involving models of chronic diseases or conditions where the focus is solely on treatment rather than on outcomes relevant to risk reduction, health maintenance or resilience.
  • Applications in which the Specific Aims do not focus on quantitative, objective outcomes relevant to human resilience.
  • Projects proposing clinical trials of efficacy or effectiveness.
  • Applications proposing to focus on parenteral or topical administration of interventions are generally beyond the scope of this FOA, as dietary supplements are intended to be orally ingested and swallowed. Applications proposing parenteral or topical administration may be considered responsive only where the outcome is demonstrably applicable to understanding the mechanism of action of orally ingested product.
  • Projects lacking rigorous data identifying one or more components of the botanical product or their metabolites as bioavailable and required for an in vivo bioactivity.
  • Projects lacking a proposed unbiased and rigorous approach to assess the potential presence of additional bioactives or in vivo targets, beyond those previously described, except where data from such an approach are previously reported and/or included as preliminary data.
  • Projects where the focus is a small number of largely purified phytochemicals. Minimally processed botanicals are within scope.
  • Projects focused on classical drug development.
  • Research on bacterial or yeast fermentation products as the delivered intervention. Aims focused on bioactives generated within a human or other animal by its microbiota would be in scope.
  • Research focused on the development of methods to improve large scale production of individual botanicals or their derivatives, or on synthetic approaches to modify botanicals or their components to improve bioavailability or potency.

Deadline:  April 15, 2019 (letters of intent due 30 days prior to the deadline)

URL:  https://grants.nih.gov/grants/guide/rfa-files/RFA-OD-19-001.html