Key words
pharmacognosy - pharmacology - clinical studies - natural products analysis - molecular
targets and activities
Introduction
NIH, which resides within the U. S. Department of Health and Human Services, is the
largest funder of biomedical research in the world. NIH comprises 27 Institutes and
Centers, each focused
on a specific area of research. The NCCIH is the lead agency within NIH for research
on complementary and integrative health practices, but the NCCIH budget is less than
1% of total NIH
appropriations. Fortunately, many other NIH components also fund research on complementary
and integrative health approaches. In fiscal year 2020, NCCIH awarded nearly $130
million in research
grants while the rest of NIH awarded more than $350 million in additional research
funding on complementary and integrative health research [1].
A wide range of complementary and integrative health approaches are used in the United
States by an equally diverse collection of consumers and practitioners. NCCIH defines
and groups these
approaches based on the therapeutic input involved: nutritional, physical, or
psychological. Traditionally, physical and psychological inputs were classified as
mind and body approaches
whereas nutritional inputs were classified as natural products. The NCCIH website
(https://www.nccih.nih.gov/grants/natural-products-research-information-for-researchers) defines natural
products as “a large and diverse group of substances from various natural sources
such as plants, bacteria, fungi, insects, arachnids, marine organisms, and higher-order
animals. The term
‘natural products’ also refers to complex mixtures from these products and the
isolated compounds derived from them. In addition, the NCCIH definition also includes
vitamins, minerals,
probiotics–i.e., live microorganisms, bacteria in most cases, that are intended
to have health benefits–and special diets for medical conditions or health outcomes”.
Under either the new or
old classifications, about half of NCCIH research funding is devoted to grants
for physical and psychological input (i.e., mind and body) research and about half
is devoted to grants for
nutritional input (i.e., natural products) research. It is noteworthy that NCCIH
is the only grant making NIH component for which natural product research is an explicit
part of its
mission.
NIH maintains a public database of all funded research, the Research Portfolio Online
Reporting Tools (RePORT) (https://reporter.nih.gov/advanced-search), that can be mined for information
about NIH support on any topic. Capturing all natural products funding using this
database is challenging because of the incredible breadth of research endeavors that
could be classified under
that topic. An approximation can be made by combining search terms, but it certainly
underestimates the true investment. For example, using a combination of the search
terms “herbal”, “natural
product”, “natural products”, “botanical”, “botanicals”, “dietary supplements”,
“probiotics”, “herb-drug”, “medicinal herbs”, “medicinal plants”, and “phytochemical”
for fiscal year 2020
yields more than $530 million in NIH grant funding. Of this sum, NCCIH provided
more than $36 million which represented the fourth largest investment among NIH Institutes
and Centers [1]. Thus, although NCCIH has the 23rd largest budget, the Center provides a disproportionate
amount of funding for natural products research.
In early 2021, NCCIH issued its new strategic plan [2] (https://www.nccih.nih.gov/about/nccih-strategic-plan-2021-2025) which laid out a new and bold vision for
the next 5 years. In particular, the new plan includes a renewed focus on whole
person health. This is not new for NCCIH. The Centerʼs mandate has always included
research on the whole person.
What is new in this plan is an effort to explicitly study how the nutritional,
physical and psychological components of complementary and integrative health approaches
can work together across
multiple organ systems to move the whole person towards health restoration, also
known as salutogenesis [3]. In addition to laying out a range of scientific
research priorities, the plan also includes a specific objective focused on improving
workforce diversity. NCCIH wishes to emphasize support for groups underrepresented
in the sciences,
including racial and ethnic minorities, a position that aligns well with the NIH-stated
interest in diversity (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-20-031.html). Although
the plan is comprehensive in scope, this perspective focuses on how the plan shapes
NCCIH priorities for natural products research.
Rigor, Reproducibility, and Regulations
Rigor, Reproducibility, and Regulations
Underlying all research funded by NCCIH is adherence to the highest standards for
research integrity and quality. Within the Centerʼs natural products research portfolio,
these standards are
embodied by NCCIHʼs Natural Product Integrity Policy (https://www.nccih.nih.gov/research/nccih-policy-natural-product-integrity). Instituted more than 15 years ago, this policy requires that
investigators describe specific details about the identity, source, handling,
and chemistry of the products used in NCCIH-funded research. This information is required
before any award is
made. Given the inherent heterogeneity of natural product preparations, even within
the same botanical species, the information provided becomes critical for proper interpretation
of the
resulting data when comparing them with other research using similar products.
These details also provide the necessary blueprint for reproducing the results, if
necessary.
It is also important to note that NCCIH works collaboratively with various U. S. regulatory
bodies to make sure the research we fund adheres to all relevant federal regulations.
This
collaboration becomes particularly important if the research involves a controlled
substance (https://www.dea.gov/drug-information/drug-scheduling), such as cannabis, or involves a clinical
trial that may use the natural product as a drug as defined by the U. S. Food
and Drug Administration (FDA). In these instances, NCCIH also requires that the researcher
demonstrate compliance
with regulations established by the U. S. Drug Enforcement Administration (DEA)
for use of controlled substances or the FDA for clinical trials.
Methodology
NCCIH has a long-standing interest in improving the tools and methodologies used by
natural products researchers. This priority was based on a desire to break through
the persistent
bottlenecks that prevented rapid identification of compounds responsible for activity
in an extract. Over the past 7 years, NCCIH has supported the Center for High Content
Functional
Annotation of Natural Products (https://hifan2.sites.ucsc.edu/) which is dedicated to development of novel methods for the chemical and biological
characterization of natural products. The new
NCCIH strategic plan extends the Centerʼs interests to development and application
of novel computational, artificial intelligence, and systems biology methods to model,
predict, and quantify
complex interactions of natural products across multiple biological systems.
NCCIH support for innovative methodology applies to the Centerʼs clinical natural
product research portfolio as well in which NCCIH is interested in studies that test
the reliability and
validity of diagnostic systems used by multicomponent therapeutic approaches such
as traditional Chinese and Ayurvedic medicines. These studies may involve omics approaches
that measure
systems level changes in response to treatments. Studying such multicomponent
interventions and multisystem outcomes may also require innovative clinical trial
designs and advanced statistical
methods to explore which components are responsible for an observed effect. Machine
learning using big data and systems science has the potential to further unlock these
complex interactions
and may identify subpopulations for which certain interventions may be more effective.
Mechanistic Research
The NCCIH strategic plan highlights several priorities related to mechanistic natural
products research. The most common type of mechanistic research determines the effect
of a natural
product on a mechanistic measure assessed at a biological, behavioral, psychological,
or social level, either in a model system or in human subjects. NCCIH is interested
in how natural
products, including pre- and probiotics work together across multiple biological
systems to elicit biological effects, with special focus on health and on resilience
against various
environmental, biological, and psychological stressors. There are several types
of mechanistic studies relevant to natural product research. The first type of mechanistic
study has the
objective to understand the mechanism(s) of action of an intervention, a biological
or behavioral process, or the pathophysiology of a disease or condition. In such studies,
the primary
outcomes are mechanistic. The second type of mechanistic study involves the prospective
use of a natural product where the intent is to obtain biospecimens or other psychosocial
or
environmental factors to identify genetic risk associations and novel biomarkers,
examine the disease process, characterize therapeutic responses, or predict treatment
outcomes, using
preclinical models or human participants. Some mechanistic studies may use a natural
product to answer basic science questions about normal physiological function or the
pathophysiology of a
disorder, but do not aim to demonstrate efficacy on clinical outcomes. Studies
to develop, validate, and/or apply novel measures contributing to healthy behaviors
in humans, or biomarkers of
physiological or pathological processes, are also important examples of mechanistic
research relevant to natural products. For studies that involve human subjects, especially
in a specific
patient population, there is a need to distinguish clinical mechanistic studies,
which could be any one of the mechanistic study types described earlier, from those
clinical studies geared
toward safety, tolerability, feasibility, efficacy and/or effectiveness.
Many natural products are consumed as complex mixtures. The NCCIH mechanistic research
program also supports studies that aim to identify the active components of these
mixtures and better
understand how they interact with each other and potentially multiple biological
targets. These mechanistic insights are necessary for the design of maximally informative
clinical trials.
Importantly, NCCIH includes probiotics in our definition of natural products.
Thus, NCCIH is equally interested in furthering knowledge of the mechanisms through
which the gut microbiome
interacts with pre- and probiotics to influence health outcomes. In the current
strategic plan, NCCIH places emphasis on gaining mechanistic insight into how natural
products can influence and
improve salutogenesis, well-being, and resilience. On the bidirectional continuum
between health and sickness there exists pre-disease states. On that continuum, a
phase also exists during
which an acute injury or exposure transitions to a more chronic condition. Natural
product interventions may be particularly helpful during these critical time points.
NCCIH encourages basic
and mechanistic research in this window where functional or biochemical abnormalities
exist but are still reversible.
Clinical Research Priorities
Clinical Research Priorities
The NCCIH strategic plan outlines several priorities for clinical research on natural
products. NCCIH continues to place emphasis on studying products that have compelling
preclinical
evidence of potential biological activity or products that are widely used by
the American public. NCCIH has designed its funding opportunities to support all phases
of clinical research from
Phase I trials through fully powered Phase III efficacy trials. 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 signatures of biological effects. Consistent
with NIHʼs goals for rigor
and reproducibility, NCCIH requires that the signature of biological effects be
reproducible in two independent clinical trials before it will support efficacy trials,
unless the biological
impact of a natural product is impossible or impractical to measure directly.
Priorities include clinical trials for isolated natural product compounds as well
as for the complex mixtures from
which they originate.
In addition to its interest in the classic clinical trial designed to assess the effect
of a single natural product on a single primary outcome, NCCIH is interested in studying
the effect of
natural products on interconnected systems and multi-organ outcomes (e.g., on
the nervous, gastrointestinal, and immune systems). NCCIH also has interest in studying
the effects of
multicomponent interventions which may include one or more natural products on
single outcomes or on multi-system outcomes. Multicomponent therapeutic systems such
as traditional Chinese
medicine, naturopathy and Ayurvedic medicine often use a package of treatment
approaches that frequently include one or more natural product. NCCIH supports research
that defines and develops
treatment algorithms from these therapeutic systems to establish if they can be
delivered with fidelity and reproducibility.
Investigators proposing research hypotheses to examine multicomponent interventions
or multisystem outcomes will likely need to use more advanced analytic techniques
and may incorporate
computational or machine learning approaches. Once multicomponent interventions
have demonstrated efficacy or effectiveness, the question then becomes how to accomplish
adoption,
implementation and sustainability of these interventions into health care delivery.
To address these questions, pragmatic trials or implementation science trials can
be done to assess the
effectiveness of the multicomponent intervention or the strategies used to integrate
the intervention into health care delivery. It is critical that the participants in
clinical trials
represent the racial and gender diversity of the population with the study condition
in the United States.
As described above, the strategic plan emphasizes the study of natural products on
whole person health. Some of the outcomes relevant to whole person health include
health promotion and
restoration, resilience, and disease prevention across the lifespan. Many Americans
use natural products to promote their overall health and NCCIH is interested in supporting
clinical research
that will develop and validate measures of health as well as evaluate the safety
and efficacy of natural products to improve these measures of health. In addition
to promoting health, natural
products are used by the public to address the symptoms of pain, anxiety, depression,
and sleep difficulties. For the management of these symptoms, clinical research that
identifies
biologically active natural products and evaluates the safety and efficacy of
these products is of high priority to NCCIH.
NCCIH Peer Review Alignment with Strategic Plan Priorities
NCCIH Peer Review Alignment with Strategic Plan Priorities
Peer review across NIH is framed by policies that promote the fair and unbiased evaluation
of applications submitted in response to funding opportunity announcements (FOAs).
Applications
focused on natural products are reviewed at the Center for Scientific Review (CSR)
or NCCIH based on the locus of review for the relevant FOA. To reflect its strategic
plan for natural
products research, NCCIH has added additional review language to many of its FOAs.
For example, for the PAR-20-228 (Pilot Projects Increasing the Impact of the NIH Centers
for Advancing
Research on Botanicals and Other Natural Products, R03) FOA, reviewers evaluate
how rigorously the experimental design addresses similarities to or differences from
humans. In the review
language, the emphasis on translational validity at the pilot stage is reflects
the strategic plan objectives for advancing research on the whole person. In particular,
the plan prioritizes
conducting clinical and translational research on multicomponent interventions
and studying the impact of these interventions on multiple physiological systems (NCCIH
strategic plan, objective
2, strategies 1 and 2).
Reviewers also evaluate, for example, whether a proposed study responding to the PAR-20-218
and PAR-20-217 (Natural Product Early Phase Clinical Trial Phased Innovation Award,
R61/R33) FOA
could advance knowledge of the natural productʼs effect on a biological signature,
whether the results are positive or negative. This additional review language reflects
NCCIHʼs prioritization
of support for trials of natural products that assess whether the effects of these
products on biological signatures are reproducible (NCCIH strategic plan objective
2, strategy 2). Reviewers
evaluate appropriate characterization of the natural product in proposed studies
responding to the aforementioned FOAs (i.e., PAR-20-218, PAR-20-217, PA-20-228) which
reflects the NCCIH
Natural Product Integrity Policy of ensuring that natural products used in NCCIH-supported
research are fully identified, characterized, and standardized.
Conclusion
The NCCIH strategic plan sets a bold and ambitious vision for the next 5 years. The
goals and strategies of the plan influence all aspects of NCCIH research priorities.
Within its natural
products portfolio, NCCIH will continue to adhere to the highest standards of
rigor and reproducibility through the implementation of the long-standing Natural
Product Integrity Policy. NCCIH
continues to support research on complex natural product mixtures as well as on
identification of active components within those mixtures. NCCIH is especially interested
in exploring and
better understanding how the components of natural product mixtures work together
to elicit biological effects in both mechanistic and clinical settings. Furthermore,
NCCIH will prioritize
research investigating how natural products can improve whole person health and
increase resilience through coordinated effects on multiple biological systems. NCCIH
looks forward to working
with the investigator community to enact these priorities.
Contributorsʼ Statement
Conception of the work: P. Still, W. Chen, W. Weber, D. C. Hopp; data collection:
P. Still, W. Chen, W. Weber, D. C. Hopp; drafting the manuscript: P. Still, W. Chen,
W. Weber, D. C. Hopp;
critical revision of the manuscript: P. Still, W. Chen, W. Weber, D. C. Hopp.
