Table 9.

Recommendations for the Path Forward for Safety and Efficacy Assessment of Bioactives

Goal	Objective	Comments
Improve Quality and Product Integrity	Accelerate botanical and chemical characterization of single ingredients and mixtures (Mudge et al. 2016).	Develop robust methods of analysis and reference materials especially for bioactives in proprietary blends, dietary supplements and traditional medicines. Characterized and standardized extracts of cocoa flavanols and robust methods of analysis were used in the recently completed COSMOS clinical trial (Bussy et al., 2022).
	Adopt standardized nomenclature for ingredients	Use a common terminology with standard names and definitions, expressed in the same units, especially for bioactives in natural products such as botanicals and medicinal plants (Frank et al., 2020). (National Academies of Science, Engineering, and Medicine, 2018).
	Develop databases of ingredients and products	Use databases for bioactives with possibly beneficial health effects to improve exposure estimates (Betz et al., 2018).
Ensure Safety Assessment	Elucidate mechanisms of action and pathways responsible for bioactives’ health effects (Ribeiro et al., 2019)
	Document pharmacokinetics, pharmacodynamics, and dose-response profiles of bioactives over a broad range of intakes for ingredients occurring alone and in combinations ( Cazarin and Bicas 2022 )	Associations between intakes and health effects may not be linear, as the U-shaped relationship between selenium intakes and type 2 diabetes mellitus exhibited(Cardoso et al., 2022).
	Encourage industry self-regulation	Examples include product integrity standards, third party certification and certificates of analysis required by some trade associations and internet marketers before products can use their platforms.
	Register ingredient lists of products with regulatory authorities	This is done for foods, but not yet for traditional medicines or dietary supplements
	Review amounts of bioactives originally approved compared to those used in herbal medicines and dietary supplements	Doses, matrices, and conditions of use of some bioactives differ from approved uses and may have adverse health effects.
	Enforce safety standards more vigorously at national and international levels	Methods include enhanced enforcement capacity, seizure of violative products and assets of offending companies, legislation stipulating premarket approval of products. Outside actors such as lawsuits against offenders by plaintiff’s lawyers might also enforce safety standards.
	Activate global frameworks for safety surveillance especially of bioactive ingredients and products marketed in many countries spanning different regulatory systems	Draw upon existing collaborations with the Food and Agricultural Organization, the World Health Organization, Codex Alimentarius and other groups that already exist between countries for foods (Thakkar et al.2020)
	Enhance surveillance of dietary supplements and traditional preparations marketed globally over the internet	Prioritize safety effort for global online sales of “nutraceuticals” and dietary supplements such as performance and weight-control drugs often spiked with active pharmaceuticals and otherwise adulterated(Low et al., 2017).
	Achieve consensus on safety assessment processes for bioactives in natural products	Modify existing processes or develop new ones to overcome their limitations(Wallace et al., 2015).
	Resolve discrepancies between countries in safety standards and placement in regulatory categories for traditional/herbal medicines, and dietary supplements	Simplify regulation and ease compliance of multinational marketers with local regulations
	Increase international collaboration in safety a surveillance to detect adulteration and fraud ( Low et al 2017 )	Highest priority is ingredients of safety concern in dietary supplements and traditional /herbal/medicines and botanicals
	Develop a tiered global system prioritizing “problem” bioactives likely to pose greatest safety risk and disseminate wisely	The top tier is ingredients and products most likely to pose greatest risk, such as pyrrolizidine alkaloids (Colegate et al., 2018). Wider dissemination of bioactives in dietary supplements and traditional medicines with safety concerns beyond the international regulatory community would be helpful, as is done with EFSA’s botanical compendium (Low et al., 2017).
	Work toward eventual adoption of global safety assessment processes and standards	Scientific and regulatory approval of food safety assessment standards, testing, inspection, data collection, monitoring and global harmonization activities are all essential
Improve Efficacy Assessment	Build in regulatory incentives to promote high quality clinical trials Prioritize promising “best bet” bioactive ingredients and preparations with strong ethnobotanical and preclinical evidence for assessment (Funk and Schneider, 2021).	These may be widely used traditional botanical preparations with strong ethnobotanical and preclinical evidence of efficacy
	Apply more rigorous standards in clinical trials of bioactives	Improve designs in studies of bioactives Develop supportive preclinical study data, use of appropriate animal models, dosing levels and routes of administration and predetermined endpoints to translate evidence from animal experiments appropriately for planning human clinical trials of bioactives in foods, dietary supplements and traditional medicines (Floyd et al., 2022 and Sorkin et al., 2020) (Floyd et al., 2022). Use biomarkers of exposure to the bioactive both before and after the intervention Adopt validated biomarkers of chronic disease outcome for assessing nutrient and non-nutrient compounds for decreasing chronic disease risk Use the same validated surrogate biomarkers of chronic disease prevention for both nutrient and non-nutrient bioactives (Institute of Medicine, 2010 and National Academies of Science, Engineering, and Medicine, 2017). Use validated qualified surrogate biomarkers of chronic disease risk Surrogate markers of chronic disease risk allow smaller clinical studies over a shorter time.(Sesso et al., 2022). They must be analytically validated, on a causal pathway in the pathogenesis of the disease and be significantly associated with the disease in the target population in a defined context of use. They must consistently change in response to the intervention with a change health outcome and explain a substantial proportion of the disease response to the intervention (Institute of Medicine, 2010 and National Academies of Science, Engineering, and Medicine, 2017). Develop validated intermediary surrogate biomarkers of decreased chronic disease risk Intermediary surrogate biomarkers must reflect critical intermediate steps in the bioactive’s metabolic activity, correlate with decreased disease risks, and measure all adverse effects associated with the bioactive.
	Improve communications about bioactive safety and efficacy to consumers
	Work toward developing guidance on bioactive intakes	Amass more information about the safety and efficacy of common bioactives to make it possible to frame evidence-based recommendations for their consumption in foods and dietary supplements (Weaver, 2014).