Naturally complex: Perspectives and challenges associated with Botanical Dietary Supplement Safety assessment

Highlights

• The use of botanical dietary supplements is widespread in the United States.

• High quality botanicals research requires accurate characterization of products.

• The complexity and variability of these supplements present many challenges.

• Both manufacturers and regulators are responsible for the safety of these products.

• Addressing the challenges in botanical safety is an important public health goal.

Abstract

Due to the extensive use of botanical dietary supplements by consumers in the United States, there is a need for appropriate research and data to support safety assessments. Complexity and variability, both natural and introduced, of botanical dietary supplements make research on these products difficult. Botanical dietary supplements are regulated by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the 1994 Dietary Supplement Health and Education Act (DSHEA). They are regulated as a category of food, which differs from the regulation of pharmaceutical products. Both manufacturers and the FDA are faced with the challenge of determining the best approaches for evaluating and monitoring the safety of botanical products. High quality botanicals research requires accurate identification and characterization of the material being studied. Inconsistent results in efficacy studies of botanical dietary supplements have led to efforts to improve the rigor and reproducibility of research in the field. Addressing the challenges associated with botanical dietary supplement safety is a global effort requiring coordination between numerous stakeholders, including researchers, suppliers, manufacturers, and regulators, all of whom play a role in ensuring that high quality products are available on the market.

Introduction

Dietary supplements, as defined by the Dietary Supplement Health and Education Act of 1994 (DSHEA) in the United States, are products intended to supplement the diet that contain vitamins, minerals, amino acids, other dietary substances, and/or herbs or other botanicals (Abdel-Rahman et al., 2011). They are further defined as only including products intended for ingestion, not representing a conventional food or complete nutritional source, and requiring labeling as a dietary supplement. The DSHEA legislation was aimed at balancing access to dietary supplements with public safety and amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to provide a clear definition of dietary supplements and a regulatory framework for evaluating safety and claims associated with activity (Abdel-Rahman et al., 2011). The focus herein is on a subset of dietary supplements, those containing herbs or other botanicals, that are collectively referred to as botanical dietary supplements or, simply, botanicals. It is important to note that use patterns and regulatory guidance for botanical dietary supplements differ around the world. While this manuscript focuses primarily on the United States, recent reviews offer comparisons of global regulatory paradigms (Enioutina et al., 2017; Low et al., 2017). Furthermore, the challenges in assessing the safety of botanical dietary supplements discussed within are universally relevant.

Botanical dietary supplements are generally available as whole plants, plant parts, powdered plant material, or plant extracts. These supplements are marketed in various forms, including as powders, tablets, capsules, gummies, teas, tinctures, and essential oils. A variety of botanical dietary supplements are used in complementary and integrative health practices (https://nccih.nih.gov/health/integrative-health). Although there is overlap in the botanical species used in dietary supplements and other forms of complementary medicine, such as Ayurveda and Traditional Chinese Medicine, the applications can vary widely, and safety considerations associated with these practices are beyond the scope of the current work.

Botanical dietary supplements are widely available in the United States. According to the 2012 National Health Information Survey, an estimated 18% of adults in the United States used dietary supplements that were not vitamin- or mineral-based (Clarke et al., 2015). Although this value is not specific to botanical dietary supplements (also includes fish oil, glucosamine, etc.), it provides an informative estimate about consumer use of these types of products. This is consistent with findings from the 2007 National Health Information Survey, in which an estimated 18% of adults and 4% of children used non-vitamin, non-mineral natural products at least once during the 12 months preceding the survey (Barnes et al., 2008). According to the Dietary Supplement Label Database, there are currently over 20,000 dietary supplements in the botanical ingredient category available in the United States marketplace (https://dsld.nlm.nih.gov/dsld/). Furthermore, it was estimated that approximately $7.5 billion was spent on botanical dietary supplements in 2016 (Smith et al., 2017). Extensive use of botanical dietary supplements, combined with a paucity of toxicity data, has fueled interest in developing approaches for ensuring the safety of botanical dietary supplements (Job et al., 2016; Marcus, 2016; van Breemen, 2015).

Many different stakeholders recognize the importance of ensuring the quality and safety of botanical dietary supplements (e.g., the public, suppliers and manufacturers, regulators, healthcare providers, researchers). This endeavor is multi-dimensional and involves consideration of the chemical properties and toxicological profiles of the raw botanical ingredient(s), excipients present in the finished product, and reagents involved in the processing or manufacturing of the finished product, as well as possible sources of contamination at any step along the process from harvest of the raw ingredients to storage of the finished product (Fig. 1).

A complicating factor in the evaluation of botanical quality and safety is their inherent complexity. Botanical dietary supplements are typically complex mixtures and can display a high degree of variability (both natural and introduced) (Tanko et al., 2005). Sources of variability in finished products can range from compositional differences between batches of raw materials to differences in processing and manufacturing of the source biomass (Pferschy-Wenzig and Bauer, 2015). The constituents of individual batches may differ based on factors such as geographical location where the plant material is grown (e.g., altitude (Rieger et al., 2008), climate (Melito et al., 2016)), season or growth stage at harvest (Galasso et al., 2014; Pacifico et al., 2016). Furthermore, the processes and practices that individual manufacturers use are often unique to the company and proprietary, so while batch-to-batch variation within a company may be minimal, variability between products that are nominally the same from different companies may be considerable. Due to this widespread variability, chemical evaluation of composition has joined botanical morphology as an important tool in the manufacture, study and regulation of these products (Schilter et al., 2003). Standardization, a process that measures and adjusts the amount of and ratio between key constituents has been adopted as a means of controlling batch-to-batch variability.

Due to the complexity and variation in botanical dietary supplement composition, there are significant issues with comparing test articles across studies and, therefore, reproducibility in botanicals research is a challenge. Protocols for dietary supplement research must take many different factors into consideration, including populations (generalizability), responders vs. non-responders, timing and duration of exposure, endpoints of concern, dose levels, and earlier phase studies. Data from exploratory clinical trials and studies of natural products have been highly inconsistent, and there are many problems replicating the effects of botanicals that have been reported in the literature. NIH's National Center for Complementary and Integrative Health (NCCIH) has long recognized these issues, and has had a natural product integrity policy in place since 2007 (https://nccih.nih.gov/research/policies/naturalproduct.htm) and a requirement to address composition of research materials in grant applications has been added to NIH-wide grant policies (https://www.nih.gov/research-training/rigor-reproducibility). Clinical research to evaluate the efficacy of a botanical product in “curing, treating, or mitigating a disease” shifts the botanical from the dietary supplement category to the drug category and must be conducted under the umbrella of the Investigational New Drug process administered by the Food and Drug Administration/Center for Drug Evaluation and Research (FDA/CDER). The clinical research process requires exhaustive characterization of product composition, but compositional details are proprietary and known only to the study sponsor and the FDA.

Inconsistencies in study design and knowledge about product composition have contributed to a low level of confidence in published data on potential biological targets of botanical dietary supplements (Landis et al., 2012). As part of efforts to standardize botanical quality, there are now many publications that set out minimum quality standards for botanical raw materials and very simple finished products. These include the European Pharmacopoeia, the United States Pharmacopeia (USP), Pharmacopoeia of the People's Republic of China, the Hong Kong Materia Medica Standards, and others. These science-based, quality monographs for botanicals contain specifications on the identity, content and composition, purity, and performance of individual botanicals. These publications set out specifications and tests for use in Good Manufacturing Practice (GMP) settings, but are not mandatory for dietary supplement products in the United States (www.usp.org).

In 2016, the National Toxicology Program (NTP) hosted a workshop entitled “Addressing Challenges in the Assessment of Botanical Dietary Supplement Safety”. The goal of the workshop was to bring together stakeholders with varying expertise and discuss best strategies for: 1) developing methods for assessing phytoequivalence of botanicals, 2) identifying the active constituent(s) or patterns of biological response of botanicals, and 3) assessing the absorption, distribution, metabolism, and elimination (ADME) of botanicals (NTP, 2016). This manuscript will serve to expand on the three primary challenges associated with botanical supplement safety including the complexity of botanical dietary supplements, the struggle for reproducibility in botanicals research, and the regulatory issues relevant to botanicals; additional companion manuscripts will expand further on the three key topics outlined above (Catlin et al., 2018; Roberts et al., 2018; Waidyanatha et al., 2018).