Improving natural product research translation: From source to clinical trial

Abstract

While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

Keywords: clinical predictive validity; dietary supplements; model systems; rigor and replicability; value of information.

Figure 1.. Critical information for the design, implementation and interpretation of natural product clinical trials.

Elucidating details (light bulbs) of molecular mechanisms of action prior to initiating a NPCT can help “de-risk” the planned trial by both providing evidence for the hypothesized outcome and its underlying causes, and supporting the development of methods to test that hypothesis, e.g., by measuring in vivo target engagement. It is good practice for researchers to establish standard procedures for product preparation (A), that are optimized for bioactivities and stability, and methods, preferably validated, for thorough characterization of product chemistry and stability. Elucidation of the bioactive NP constituents or metabolites (B) is critical for quality control, for assessing bioavailability, PK and PD, and determining whether minimal effective concentrations of bioactives have been achieved in plasma or at the targets (C). These data can support the development of methods to test mechanistic hypotheses, e.g., by measuring in vivo engagement of the putative targets, proximate bioactivities, or PD, and/or assessing the relationships between these and (D) the primary and secondary NPCT outcomes, and any adverse events.

Figure 2.. Good practices for actionable results in future translation of Natural Products research to Clinical Trials (NP2CT).

Translation is most informative and cost-effective when CT Phase (I vs. II) and design (e.g. RCT, adaptive) decisions are built on a solid and rigorous evidence base (pyramid and tabletop). The choice to proceed to an NPCT and the determination of the most appropriate trial type (examples on sphere) depends on the extent and strength of supporting data available (table legs and segments). If multiple supporting data elements are missing or weak, an earlier phase CT may be more informative and cost-effective than a Phase III CT. If a substantial number of CT design choices or parameters lack supporting evidence, a more useful next step may be research addressing those gaps via either preclinical research or a mechanistic or early phase NPCT.