Journal of Clinical Trials, Pathology and Case Studies | Volume 4 | Issue 1 | 2019-05-11

Traditional System of Medicine and Nutritional Supplementation: Use Vs Regulation

AK Mohiuddin

Abstract

Food is the major source for serving the nutritional needs, but with growing modernization some traditional ways are being given up. Affluence of working population with changing lifestyles and reducing affordability of sick care, in terms of time and money involved, are some of the forces that are presently driving people towards thinking about their wellness. There has been increased global interest in traditional medicine. Efforts to monitor and regulate traditional herbal medicine are underway. Ayurveda, the traditional Indian medicine, remains the most ancient yet living traditions. Although India has been successful in promoting its therapies with more research and science-based approach, it still needs more extensive research and evidence base. Increased side effects, lack of curative treatment for several chronic diseases, high cost of new drugs, microbial resistance and emerging, diseases are some reasons for renewed public interest in complementary and alternative medicines. Numerous nutraceutical combinations have entered the international market through exploration of ethnopharmacological claims made by different traditional practices. This review gives an overview of the Ayurvedic system of medicine and its role in translational medicine in order to overcome malnutrition and related disorders. Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

Keywords: Dietary supplements, Food supplements, Supplement science, Scientific challenges, Regulatory challenges, Natural health product, Complementary medicine, Traditional medicines, National Institutes of Health, Office of Dietary Supplements

Full text

India is known for its traditional medicinal systems Ayurveda, Siddha, and Unani. Medical systems are found mentioned even in the ancient Vedas and other scriptures. The Ayurvedic concept appeared and developed between 2500 and 500 BC in India. The fundamental challenge in any discussion about the regulation of dietary supplements is that there is no global consensus on how the category of products known variously as dietary supplements, natural health products (NHPs), complementary medicines or food supplements in different countries is defined. For example, a product considered to be a dietary supplement and regulated as a food in the USA, in another jurisdiction may be considered a food supplement or a therapeutic good (complementary medicine) or a therapeutic good (prescription medicine) or potentially even a controlled substance. The situation is even more complicated when countries like China or India that have an existing regulatory framework for traditional medicine or phytomedicine that includes crude botanicals are considered. To add further to the confusion, many regulatory frameworks are changing. Another challenge is that while all regulatory scientists want to protect consumers from harm, ensure that consumers have the ability to make informed choices about the products they use, and do the right thing, the scientific challenges and regulatory systems that have arisen to deal with them vary greatly from country to country. Even in countries with similar cultures, legal systems, and levels of economic development, regulations applying to dietary supplements vary considerably. Some of these differences are explored below, using examples from Australia, Canada and the USA, all English-speaking countries with largely similar cultures and legal systems to illustrate this point. The discussion of other countries with similar legal systems such as the United Kingdom, New Zealand and South Africa or other nations in the Americas, Europe, Africa and Asia, often with different cultures, legal systems, and levels of economic development is left for others with greater expertise and experience. A final challenge is that dietary supplement health products are often very emotive and polarizing topics, evoking a diverse range of opinions and viewpoints. While some observers may contend that these products should be considered in a similar fashion to conventional drugs and foods, others believe that a more tailored approach is necessary since there is often a traditional or historical evidence base and products often contain multiple ingredients. Increasingly, this situation has become even more complex because of the lucrative nature of the global dietary supplement sector, increased involvement of a growing industry sector producing them, and the introduction of many new and innovative products onto the market. A detailed discussion of the politics of the subject is outside the scope of this paper. However, it must be recognized that politics may play both a positive and negative role in shaping both regulatory frameworks and research agendas. Irrespective of the reader s point of view, this context is important in any discussion of dietary supplement products. Figure 1: Dietary Supplements. Herbal supplements are regulated by the FDA, but not as drugs or as foods. They fall under a category called dietary supplements. Manufacturers don t have to seek FDA approval before selling dietary supplements. Companies can claim that products address a nutrient deficiency, support health or are linked to body functions if they have supporting research and they include a disclaimer that the FDA hasn t evaluated the claim. The FDA is responsible for monitoring dietary supplements that are on the market. If the FDA finds a product to be unsafe, it can take action against the manufacturer or distributor or both, and may issue a warning or require that the product be removed from the market. These regulations provide assurance that: Herbal supplements meet certain quality standards; The FDA can intervene to remove dangerous products from the market (Source: Herbal supplements: What to know before you buy. MAYO CLINIC Nov. 08, 2017). Figure 2: Planning and development of new herbal preparation. Analysis of active substances in the selected plant raw materials and quality control prescribed by Pharmacopoeia or another relevant document are performed. Then, the quality control of semifinal product is conducted. In the case of capsules, the analysis of the active substance in dry extract is performed, and also the analysis of other parameters that define its quality, and that is defined by Pharmacopoeia monographs or summarized in an internal specification or a certificate. Afterwards, the preparation formulation is conducted (formulation of teas or herbal drops, herbal creams, capsules, etc.). In addition to the main plant raw materials, secondary raw materials are selected, which will synergistically facilitate the functioning of the dominant plant drugs, and auxiliary pharmaceutical raw materials are selected. Auxiliary raw materials are used as the basis for semi-solid galenic forms (creams, ointments, and gels), and capsule fillers (Djordjevic SM. From Medicinal Plant Raw Material to Herbal Remedies. In: IntechOpen LimitedDOI: 10.5772/66618). Importance of Research on Dietary Supplements Internationally, herbal products are regulated under different classifications, some of which are: complimentary medicines; natural health products; prescription medicines; over the counter medicines; supplements; traditional herbal medicines, etc. Until relatively recently, there was limited scientific research on dietary supplements and so little was known about them [1] . However, the prevalence of supplement use has increased dramatically over the past 20 years [2] , and they have become a matter of consumer interest [3,4] . At the same time, the application of state-of-the art scientific methods to explore issues involving dietary supplements has advanced rapidly. The other invited articles in this special issue illustrate progress in our understanding of supplement science as it applies to several nutrients, including vitamin D, iron, omega-3 fatty acids, and iodine. Progress on botanicals and other non-nutrient ingredients (e.g., glucosamine, methyl-sulfonyl-methane (MSM), coenzyme Q10) has been more challenging [5] . There is no global consensus in terminology for the category of products known variously as dietary supplements, NHPs, and food supplements in different countries and while we recognize this limitation, for the purpose of this article the term dietary supplement will be used to refer to such products as nutritional supplements, herbal medicines and traditional medicines. This article summarizes some of the scientific challenges in supplement research and some resources that may be useful in studying them. Most of the scientific challenges in supplement science are ubiquitous and global, so it is vital for scientists to collaborate across nations to help meet them without duplicating effort. A case study is provided by the work of the NIH Office of Dietary Supplements (ODS) which has been pursuing this goal since 2000. Some freely available resources and tools that ODS has developed for advancing health-related scientific knowledge on supplements are presented. The supplement marketplace is increasingly international, making collaboration between regulators essential since national decisions have international implications. Since products are consumed world-wide, calls for global quality standards are emerging. The remainder of the article focuses on regulatory challenges involving dietary supplements, and perspectives on how the regulatory systems in a number of different countries deal with them. Key resources for learning more about these approaches are provided. Exhibit 1. International Regulatory Overview of Herbal Supplements India Herbal drugs are regulated under the Drug and Cosmetic Act (D and C) 1940 and Rules 1945 in India, where regulatory provisions for Ayurveda , Unani , Siddha medicine are clearly laid down. Malaysia Herbal products in Malaysia fall under the category of regulated products. Any marketer intending to place the herbal products in the market require to register the product first. The applicant is required to be registered with the Malaysia Registrar of Business or Suruhanjaya Syarikat Malaysia under two classifications Philippines The Bureau of Food and Drugs (BFAD), who are the regulators in the country, mandate registration of the traditionally used herbal products before manufacture, import or market. The extent of control of BFAD includes the brand names of the traditional herbal products as well, and their prior clearance is required, before filing for product registration. Nigeria Nigeria, the trade of herbal products is regulated by National Agency for Food and Drug Administration and Control (NAFDAC) who has classified these products as Herbal Medicines and Related Products. Premarketing registration of herbal medicines and related products is mandatory in Nigeria. No advertisement can be made as a cure for any disease conditions listed in Schedule 1 to the Food and Drug Act 1990. Australia Complementary medicines which do not require medical supervision are permitted and have to be entered on the Australian Register for Therapeutic Goods (ARTG) before marketing. The low-risk medicines require to be listed while the medicines for comparatively higher risk therapeutic conditions require registration on the ARTG. Only evidence-based claims which are entered on the ARTG are allowed. United States As per FDA, the drug must be marketed under an approved New Drug Application (NDA). FDA regulates the dietary supplements under the Dietary Supplement Health and Education Act of 1994. The claims need to comply with the regulatory guidelines issued by the FDA. The manufacturing of dietary supplements should be done as per the current GMP for dietary supplements. Canada Complete data on product composition, standardization, stability, microbial and chemical contaminant testing methods and tolerance limits, safety and efficacy along with ingredient characterization, quantification by assay or by input needs to be submitted to Natural Health Product Directorate (NHPD). The authority mandates that NHPs must comply with the contaminant limits and must be manufactured as per the GMP norms. European Union The European Medicine Agency have laid down two ways of registration of herbal medicinal products: (1) A full marketing authorization by submission of a dossier, which provides the information on quality, safety and efficacy of the medicinal products including the physicochemical, biological or microbial tests and pharmacological, toxicological and clinical trials data; under directive 2001/83/EC. (2) For traditional herbal medicinal products, which do not require medical supervision, and where evidence of long traditional of use of medicinal products exists, and adequate scientific literature to demonstrate a well-established medicinal use cannot be provided, a simplified procedure under directive 2004/24/EC exists. Source: Sharma S. Current status of herbal product: Regulatory overview. J Pharm Bioallied Sci. 2015;7(4):293-6. Areas of Scientific Consensus about Supplement Science Although there is broad consensus on the need for advances in science to make progress, opinions vary on the best paths to take and on priority areas for consideration. Quality: The supply of ingredients used in supplements has outpaced the availability of methods and trained personnel to analyze them [6] . For example, in 1994, when the Dietary Supplement Health and Education Act (DSHEA) first became law in the USA, about 600 U.S. manufacturers of supplements were producing an estimated 4000 products. By 2000, more than 29,000 supplement products were on the US market but few documented analytical methods or reference materials (RM) were available for these products. This growth in the market has also been evident internationally. For example, there are anecdotal reports that over 100,000 product license applications have been approved in Canada since the Natural Health Products Regulations came into force in 2005. The need for improving quality continues today, since now there are estimated to be more than 85,000 supplement products in the US marketplace and concerns about ingredient misidentification, safety concerns, and quality assurance / control problems continue to be important for the industry and the public [7,8] . The first step in characterizing supplement products is generally identifying the ingredients [9] . Plant identification is a particular challenge. Even when easily identified whole plants or plant parts are used, unless the chain of custody is tight, and the exact manufacturing process is known and well characterized, the quality of extracts and blends such as those found in many botanical products is difficult to ascertain. Reliable analytical methods to characterize the bioactive components in supplements are helpful, but even for the nutrients in supplements, specific analytical chemistry methods must be often developed [10] . The bio-actives in supplements differ from those in foods in their matrices in that the forms, combinations, and doses in which they are consumed, and the circumstances under which they are used are likely to differ. Analytical techniques for other bio-actives in supplements are further complicated because the active compound(s) are often unknown, and even when they are known, validated analytical methods may not exist for determining their content. Reference materials are often unavailable to compare results between different laboratories for research purposes and to monitor data and supplement quality. Safety: Manufacturers are prohibited from marketing supplement products that are unsafe or contain unsafe ingredients. This includes assuring that safe upper levels of intake for nutrients or maximum dosages for other constituents are not exceeded and ensuring that toxic contaminants are absent. Improved accuracy and precision of the nutrient measurements, bioactive marker compounds for other ingredients, natural toxins, toxic elements and/or pesticides in dietary supplement ingredients and finished products will be helpful to regulatory agencies. Efficacy: Demonstration of efficacy typically depends on a number of research approaches ranging from basic in-vitro research on the mechanisms of action to animal and human studies. For example, in the past, large and expensive clinical trials using poorly characterized herbal supplement products for which the mechanisms of action were not understood were performed, leading to results that were inconclusive and irreproducible [11-13] . These experiences led publishers and funders to demand better product characterization and funders to demand more mechanistic evidence of bioactivity. Once mechanistic plausibility is established, animal and small phase 1 and phase 2 trials should precede the launch of large phase 3 studies of efficacy. More and better clinical studies of the safety and efficacy of dietary supplements on hard health outcomes are also sorely needed. Health outcomes such as changes in validated surrogate markers for performance, functions, morbidity, and mortality from diseases or conditions are required rather than changes in biochemical measures in blood with unvalidated surrogate markers. The question of the use of evidence from traditional forms of health and healing such as Traditional Chinese Medicine (TCM) makes the question of efficacy often more complex. This is briefly explored in the regulatory section below. Exhibit 2. Parameters of quality control for Herbal Preparations Herbal drugs 1. Definition: the name of the herbal drugs and content of active substances 2. Characters: appearance, taste, odor, solubility 3. Identification: macroscopic and microscopic examination, TLC 4. Tests: water, loss on drying, total ash, foreign matter, insoluble matter, extractable matter, swelling index, microbiological purity, bitterness value, broken drug 5. Assay: essential oils, tannins, declared active substances (GC, LC, UV-VIS) Herbal drug preparations Dry extract ( Extractumsiccum ) 1. Definition: standardized dry extract prepared from..., content of active substances 2. Production: method of extraction and solvents 3. Characters: appearance 4. Identification: TLC 5. Tests: loss on drying, total ash, microbiological purity 6. Assay: declared active substances (LC) Liquid extract ( Extractumfluidum ) 1. Definition: liquid extract produced from , and content of active substances 2. Production: method of extraction and solvents 3. Characters: appearance, taste, odor 4. Identification: TLC 5. Tests: ethanol, methanol and 2-propanol, loss on drying, microbiological purity 6. Assay: declared active substances (LC, UV-VIS) Tincture ( Tinctura ) 1. Definition: tincture produced from , and content of active substances 2. Production: method of extraction and solvents 3. Characters: appearance, taste, odor 4. Identification: TLC 5. Tests: ethanol, methanol and 2-propanol, dry residue, microbiological purity 6. Assay: declared active substances (LC, UV-VIS) Essential oil ( Aetheroleum ) 1. Definition: essential oil obtained by , and content of dominant components 2. Production: method of extraction and solvents 3. Characters: appearance, odor, solubility 4. Identification: TLC and chromatographic profile (GC and GC-MS) 5. Tests: relative density, refractive index, optical rotation, chromatographic profile Translation of the Science: Widespread consensus exists on the need to translate the scientific evidence on supplements into appropriate recommendations, regulations, and policies that ensure the public health. Population-based prevalence estimates of supplement use are needed to estimate total exposures to nutrients or other bioactive that can be related to health outcomes [14] . Monitoring is especially important when supplementation is used as a public health strategy to fill nutrient gaps in deficient populations. It is also needed in other countries such as the USA where use of certain supplements is high, and where substantial proportions of total intakes of nutrients such as vitamin D and calcium come from supplements, especially among older adults [15] . Exhibit 3. Parameters of quality control of phyto -preparation Phyto -preparations Parameters of quality control Mono-component tea and tea mixture 1. Identification 2. Appearance 3. Verification of components, declared mass ratio of components 4. Verification of package weight 5. microbiological purity Liquid herbal preparations (liquid extracts, tinctures, and mixtures of extracts or tinctures), herbal drops, solutions, syrups 1. Identification 2. Appearance 3. Loss on drying 4. Content of ethanol 5. Relative density 6. Refractive index 7. Verification of package weight 8. Qualitative and quantitative analysis 9. microbiological safety and/or complete health safety control Semi-solid forms (herbal gels, cream, and unguent) 1. Identification 2. Appearance 3. Verification of package weight 4. pH value 5. microbiological safety and/or complete health safety control Solid-dosage forms (capsules, tablets, etc.) 1. Identification 2. Appearance 3. Declared mass of single-dose preparations 4. Disintegration 5. Qualitative and quantitative analysis of the declared active components 6. microbiological safety and/or complete health safety control Challenges and Resources: Regulatory Perspectives: As with other categories of regulated goods such as foods and drugs, the development of regulations is a balancing act where many different factors need to be taken into account. Notable among these are ensuring that products are of high quality and safe, that any claims made are truthful and not misleading, and that there is reasonable and appropriate access to the marketplace. All regulatory scientists want to both protect consumers from harm and support them in making informed choices about the products they include or as importantly do not include in their healthcare options. Appropriate regulatory oversight of this category is very challenging, and requires that scientists and regulators work together, as the former director general of the World Health Organization, Margaret Chan, MD urged [16] . This section provides a concise overview of how these regulations have been developed, and common themes as well as challenges faced in a global market. Figure 3: Postgenomic era (PGE) and the associated new disciplines of study. Firstly, in this postgenomic era, the screening of herbal ingredients should be accelerated. Due to the development of related disciplines in the postgenomic era, the pace of drug discovery from herbal medicine is likely to be hastened and become more efficient than ever, with a resultant higher success rate. Unlike synthetic drugs, drugs derived from herbal medicine are developed by isolating and identifying the active chemical entities in the crude herbal extract, rather than by going through processes of drug design and synthesis. Although many aids and tools for advanced drug design are now available and the in vivo properties of a drug can also be predicted using quantum mechanics and statistical mechanics, the complexity of biological systems often defies some of the basic assumptions of rational drug design. As such, it is impossible to estimate all drug-related parameters in an accurate manner during the pregenomic era. It is estimated that a single herbal preparation may contain more than 100 active compounds, and their bioactivities and/or drug-like properties are difficult to be accurately identified and evaluated by conventional pharmacological methods or drug screening approaches (Source: Pan SY, Zhou SF, Gao SH, et al. New Perspectives on How to Discover Drugs from Herbal Medicines: CAM s Outstanding Contribution to Modern Therapeutics. Evid Based Complement Alternat Med. 2013;2013:627375). Definition of Dietary Supplements : Although the definition of dietary supplement within a specific jurisdiction such as the USA is quite precise [17,18] . a fundamental challenge to any discussion on regulation is that there is no global consensus on either what falls within this category or even what the category is called. Intuitively many equate a dietary supplement in the USA with a NHP in Canada or a traditional herbal medicine in the European Union or a complementary medicine in Australia, but this is not the case. For example, while melatonin is regulated in the USA as a dietary supplement and in Canada as a NHP, in Australia it is considered as a prescription medicine [19-21] . Dehydroepiandrosterone (DHEA) is readily available as a dietary supplement in the US, while in many other jurisdictions it is regulated as a controlled substance and is subject to significant regulatory oversight [22] . This situation is even more complicated when one considers that in addition to dietary supplements such as vitamins and minerals, many of these products come from traditional systems of health and healing such as TCM in China and Ayurvedic / Unani / Siddha medicine in India. For this reason, we must differentiate between the manner in which nations regulate the practice of medicine and the manner in which they regulate marketed products used in medical practice or as foods. In the U.S., the practice of medicine is regulated by the states, while marketed food and drug products in interstate commerce are regulated by the Federal government. Approaches and regulatory frameworks in many parts of the world, notably in Asia, reflect this fact with terminology and categories developed accordingly [23] . To assist in development of its Traditional Medicine Strategy 2014 2023, the World Health Organization refers to this category as Traditional and Complementary Medicines (T & CM) [16] . Although this classification does have significant limitations, it recognizes the fact that definitions for this category vary significantly globally. Descriptions of specific national / regional definitions and categories can be found through the list of resources in Table 1. Table 1: Useful Global Resources on Dietary Supplement Regulatory Issues and Definitions Name URL Comments USA FDA Food and Drug Administration Dietary Supplements www.fda.gov/food/dietarysupplements/ Details on regulations, policies and guidelines dealing with dietary supplements Australia Therapeutic Goods Administration (TGA) www.tga.gov.au/complementary-medicines Details of existing complementary medicine regulations, policies and guidelines Food Standards Australia and New Zealand www.foodstandards.gov.au/Pages/default.aspx Details on food standards, policies and guidelines. Canada Health Canada www.canada.ca/en/health-canada/services/drugshealth-products/natural-non-prescription.html www.canada.ca/en/health-canada/services/foodnutrition/legislation-guidelines/guidancedocuments/category-specific-guidance-temporarymarketing-authorization-supplemented-food.html Details on the existing NHP regulations, policies and guidelines as well as work underway with regards to a comprehensive approach to self care products Information on supplemented food category. EU European Union EU Parliament and Council ec.europa.eu/health/human-use/ herbalmedicines_en Details on the traditional herbal medicine directive re: member states. European Food Safety Authority (EFSA) www.efsa.europa.eu Provides details and links to regulation of foods and food supplements. China China Food and Drugs Administration (CFDA) eng.sfda.gov.cn/WS03/CL0755/ Information on health food regulations including blue hat process. (Note: English translation was not available). China Special Administrative Region of Hong Kong Health Ministry Chinese Medicine Division www.cmd.gov.hk/html/eng/important_info/ regulation.html Information on policies and regulation related to Chinese proprietary medicines. Japan www.mhlw.go.jp/english/topics/foodsafety/fhc/02.html Singapore Health Sciences Authority www.hsa.gov.sg/content/hsa/en.html Information on policies, regulation and guidelines related to health products and Chinese proprietary medicines. As a member state, resource to access work on regulatory harmonization of products within Association of South East Asian Nations (ASEAN). New Zealand Medsafe www.medsafe.govt.nz/regulatory/ DietarySupplements /Regulation.asp Provides information related to regulation, policies and guidelines dealing with dietary supplements. India Food Safety and Standards Authority of India (FSSAI) fssai.gov.in/home Government direction, standards and regulation of health supplements and nutraceuticals . New regulations published in November 2016 take effect in January 2018. Health supplements are intended to supplement the diet of healthy individuals over 5 year, and levels of nutrients should not exceed RDA amounts. Ministry of Ayurveda , Yoga, Unani , Siddha and Homeopathy (AYUSH) ayush.gov.in Policies, guidelines and regulations dealing with Indian traditional medicines. WHO who.int/medicines/areas/traditional/en/ Provides links to on-going work by the WHO including the Traditional Medicine Strategy 2014-2023, the International Regulation on the Cooperation of Herbal Medicines and various technical guidelines. World Self Medication Industry www.wsmi.org Industry association website providing details on international approaches to over-the-counter medicines including dietary supplements. International Alliance of Dietary/Food Supplement Associations (IADSA) www.iadsa.org Industry association website providing details on international approaches to dietary supplements. While it would be easy just to consider that the substance itself is the defining factor in determining whether or not a product is a dietary supplement, this is not the case. Two other important factors considered are the claim that the product is making and how the product is supplied or recommended (intended use). In many jurisdictions such as the USA, Canada and Australia, dietary supplements are considered suitable for self-selection without the need for the intervention of a practitioner or prescription. Here the claims that can be made are limited to minor conditions and to the support of health and wellness depending on the jurisdiction [24,25] . In other jurisdictions, notably those where a traditional form of health and healing is recognized, traditional and complementary medicine products are often prescribed, and in some cases supply is limited only to trained practitioners. Exhibit 4. An overview of the regulatory options for regulating practitioners of traditional/complementary medicine Area of regulation Regulatory options Education and training Type of qualification: university education, specific training for practitioners of traditional/complementary medicine and for conventional health care practitioners Educational setting: schools, colleges or universities Specify standards in terms of length of training vs content of core curriculum Shared biomedical curriculum vs alternative curriculum Private/professional associations accredit courses vs independent accreditation (by registering body or government) Training component of conventional medical training aimed at familiarization vs integration Licensing and registration Individual registration vs associations of practitioners register (and all membersautomatically registered) Automatic registration with accredited qualification vs licensing exam vs both Recognition of prior non-accredited training or experience vs licensing exam Lifetime membership vs re-licensing (associated with continuing medical education) Joint or dual licensing of practitioners of traditional/complementary medicine and conventional medical practitioners practicing traditional/complementary medicine vs no additional licensing requirements for conventional medical practitioners Practice Generic laws that also cover the practice of traditional/complementary medicine vs specific traditional/complementary medicine legislation De-criminalization of practice vs professionalization of practice Mono-therapeutic (that is, individual traditional/complementary medicine practitioner regulators) vs multi-therapeutic (that is, umbrella regulator for all such practitioners) vs integrated (that is, single regulator for traditional/ complementary and conventional medicine practitioners) National vs regional/local standards of practice Setting specific standards (for example, hospital vs primary care; public hospital vs private practice) Delegate standard setting to professionals vs specify in legislation Statement of minimum standards vs statement of limits of practice Protection or title vs protection of practice Regulatory Models: As with the definition of the products themselves, there is no consistent global approach to regulation, with many different frameworks developed that largely reflecting national and regional priorities and needs. That being said, there are a number of common themes and approaches that have been taken internationally. Where Does the Category Fall within Existing Legislation?: With a few exceptions, notably where traditional forms of health and healing exist, most countries do not regulate dietary supplements as a stand-alone category. Rather, they include them as a subset of existing legislation [17,18] . That is, they hang from the hook that is set in existing legislation. In the past, this was largely a question of whether these products should be considered a subset of drugs or foods; increasingly though, a third option is to capture them under existing regulations for biologics. It is important to note that overarching legislation is often one of the most important factors impacting the type of claim that can be made and what level of scrutiny and oversight will exist. For example, countries that regulate these products as a subset of drugs or therapeutic goods such as Australia, Canada and the European Union (EU) for traditional herbal medicines allow far more specific clinical claims to be made than in a jurisdiction such as the USA, where dietary supplements are captured in regulations under the existing food legislation, with their advertising regulated by trade regulations [20,25,26] . Should They Be Regulated as a Group?: As noted above in many jurisdictions dietary supplements are simply captured under the existing food or drug regulations and legislation with no specific consideration for these products, in some cases specific regulations have developed to reflect the category. In these cases, two different regulatory models have typically been adopted that reflect their domestic use, national priorities and public health needs. In many jurisdictions, the first model applies. Dietary supplements are simply captured under the existing food or drug regulations and legislation. In that model, a wide range of products (typically herbal medicines, traditional medicines and dietary or nutritional supplements) reside under an umbrella term such as dietary supplements in the USA, complementary medicines in Australia or NHP in Canada [20,24,25] . In the second model, specific regulations are developed to deal with these products. In this case, specific categories are developed with very structured regulatory frameworks for specific types of T&CMs. This is particularly the case in countries with a strong traditional form of health and healing such as Chinese proprietary medicines in China (TCM), Ayurvedic medicines in India and Kampo medicines in Japan [23] . Irrespective of the approach taken, it is rare that one set of regulations will encompass all products commonly considered to be dietary supplement-like. Typical examples of this are guidelines and legislation related to advertising that apply irrespective of whether or not a product is considered to be a dietary supplement. Common Elements of Regulatory Frameworks: As with other forms of regulations, independent and irrespective of the approach taken, frameworks that deal with dietary supplements may contain a number of common elements, in this case often specifically developed to reflect the challenges and nature of the products. These common elements include: process for approval of a product to be sold; provisions related to manufacture and Good Manufacturing Practices (GMPs); reporting of adverse events; controls on labeling related to indications, contraindications and warnings; and, where claims are permitted, the type and quality of supporting evidence required. Again, the number and nature of these elements applied are determined by the specific regulations in place. Risk-Based Approach: Operationally, the regulation of dietary supplements faces a number of issues and challenges not shared with conventional drugs or even food products. Notable amongst these are the sheer number of individual dietary supplements on the domestic markets, often numbering in the tens of thousands, and the fact that the sector contains many different types of products often posing very different risks that are grouped together often by the fact that they do not fit under any other regulatory regime. In particular, considerable challenges are posed especially by herbal and traditional medicine products that contain crude botanicals and a complex milieu of potentially active moieties, unlike conventional allopathic pharmaceuticals. While a completely pre-market approach, where all products and manufacturing sites are approved before the dietary supplement is marketed would be the optimal situation, given the challenges mentioned above, this is often impractical. This has led to the development of regulatory frameworks that increasingly blend elements looking at products and sites both before they come to market as well as once they are available to consumers, or post-market. This regulatory oversight is sometimes referred to as a life-cycle approach. Examples of post-market regulatory approaches (i.e., once the dietary supplement is on the market) include target audits where dietary supplements already on the market are analyzed for quality or manufacturers are requested to submit evidence they may hold that supports a specific claim. The determining factor on which approach is applied is largely determined by risk posed to the consumer. Since most dietary supplements when appropriately manufactured are considered to be inherently low risk, increasingly regulatory frameworks are increasingly focused more on post-market review than pre-market licensure. Even in countries that are in many ways socially, economically and legally similar, different approaches to the definition and regulation of dietary supplement health products are evident although they contain some common elements. Illustrative examples of this are evident in the different regulatory frameworks in place in the United States, Australia and Canada. In the United States, dietary supplements are regulated under the Dietary Supplements Health Education Act of 1994 (DSHEA) as a subset of foods and limited to those taken orally. This approach is primarily post-market in nature. However, it does contain pre-market elements. For example, manufacturers must hold evidence to support their claims and they cannot make specific disease treatment claims but only claims related to nutritional support (which includes physiological structure and function [20] . All products must carry a disclaimer on the label stating that claims have not been reviewed by the US Food and Drug Administration (FDA). Provisions also include a post-market site audit process for manufacturing sites for Good Manufacturing Practice compliance and mandatory reporting of serious adverse effects by manufacturers. Companies must notify the Food and Drug Administration before marketing products with new dietary ingredients (NDI) [27] . There is at present no indication that DSHEA will be substantially changed or modified by Congress, in recent years the regulatory authority has given more attention to the notification and classification of NDIs as well as the importance of Good Manufacturing Practices (GMP) [20] . In Australia, although a small number of these products are captured by a food standard, most are regulated as therapeutic goods under the Australian Therapeutic Goods Act. Products are referred to as complementary medicines and are legally defined as being a listed therapeutic good or a registered therapeutic good. The legislation itself does not define these terms, but a comprehensive set of guidelines describes how they are considered. Most complementary medicines are listed medicines and are managed through an online portal called the Electronic Listing Facility (ELF). Permitted claims are limited to minor, self-limited considerations and those traditional forms of health and healing such as traditional Chinese medicine. Evidence for efficacy is assured through a random and targeted post-market audit system and new listable substances are evaluated pre-market. As with all registered therapeutic goods, registered complementary medicines are evaluated pre-market for safety, quality and efficacy. Manufacturers of either finished listed or registered complementary medicines must undergo an on-site audit to ensure GMP [28] . In 2014, complementary medicines were included within a comprehensive review of regulations for all therapeutic goods and medical devices to be conducted by an external expert panel [29] . The Commonwealth government accepted the majority of the recommendations from the panel and preliminary draft legislation was made public in September 2017. Although one of the recommendations was to keep complementary medicines as a distinct category, some significant changes are proposed, allowing mid-level claims through a new third regulatory route between the listed and registered therapeutic goods process as well as changes to how advertising is approved and compliance management [25-30] . In Canada, the majority of these dietary supplement products are referred to as natural health products (NHPs) and are considered a subset of drugs under a specific set of regulations the Natural Health Products Regulations. Products must undergo a premarket assessment for safety, quality and efficacy. This is done in part through an online submission process with permissible claims supported by Health Canada monographs. Producers of NHPs who wish to make novel claims not supported through the monograph process must submit a full dossier of evidence for review. The products can make therapeutic claims, but their use is limited to self-care situations. While manufacturers are required to have a valid site license following approved GMP guidelines, no pre-market site audit is needed; the process being primarily paper based [24] . To address the growing number of NHPs sold in a food-like format, Health Canada has created a new category of food currently defined through regulatory policy called supplemented foods . The category does allow for some health claims, but they are limited reflecting the nature of the products [31] . Unlike Australia, Canada is proposing to take different approach and rather than keeping NHPs as a distinct category, will include them in a self-care health product category together with non-prescription medicines and cosmetics. The intent of this initiative is to support informed consumer choice through a more consistent regulatory approach to these product categories that is based on risk. Key questions being explored deal with topics including evidence needed to support claims, provisions ensuring safety and quality and introduction of cost recovery framework [34] . The overviews above are brief and concise with more detailed information on these country specific approaches to be found through the list of resources in Table 1. Competing Types of Evidence: While it is clear that high quality scientific evidence is always required to support the quality of a dietary supplement, from a regulatory perspective the same may not always be true with regard the type and nature of the evidence required to support a product claim. Given the nature of the dietary supplement sector and the fact that it often encompasses traditional medicines with a long history of use, the question faced by regulators is how to balance the need for robust scientific evidence with a respect for diverse forms of health and healing. Globally, no consistent approach has been taken in answering this question. In some jurisdictions such as Canada and Australia, the approach has been to link the form of evidence, whether it be traditional or evidence based from scientific research, to the level and type of claim that can be made. In these cases, typically products based on traditional evidence making traditional health care claims are approved according to pre-cleared and approved sources of information such as monographs or labeling standards. For products making higher level, clinical claims, in a way similar to that for conventional pharmaceuticals, companies must supply a full dossier with appropriate supporting evidence such as that from randomized controlled trials (RCTs) [24-28] . In many countries such as the United States with no pre-market approval framework system, claims that can be made are more limited [17,18] . In countries with long-established traditional forms of medicines such as in China, India, and Japan, specific regulatory frameworks have been developed for these types of products with the type of claim that can be made and the evidence required to reflect this approach [23] . As the dietary supplement sector matures and develops and the market for raw ingredients becomes more global, establishing a balance between evidence generated by scientific research and that coming from traditional forms of health and healing is becoming increasingly demanding. This will be discussed later. Evolving Regulatory Landscape Challenging Issues: International regulatory frameworks are still considered by many to be a new and novel sector, although many of them are now more than two decades old. They were developed to reflect a time when the sector and nature of the market, not to mention the needs and demands of the consumer, were very different. This has meant that some decisions made in the past around policies and regulatory decisions may need to be revisited. These include the need to evaluate evidence of the grandfathering of dietary supplements already on the market when new regulations were implemented, the need to ensure that approaches are sustainable through cost-recovery mechanisms and the more global nature of the market place. Table 1 provides links to some of the regulatory frameworks of different countries that provide insights into the ways issues are dealt with in them. Some of the key issues that commonly arise are detailed in the next session. Evaluating Evidence for Product Claims: As the market for dietary supplements has increased, so has the amount and diversity of scientific evidence and research to support, or not support, their use. This market is made more complex when there are conflicting evidence bases and conflicting ways for evaluating them. For example, how, or should, traditional evidence be evaluated within the framework of traditional healing theories or those of allopathic evidence based medicine; what should be done when evidence from traditional forms of health and healing are not supported by more conventional evaluation mechanisms such as randomized clinical trials; and how can consumers, often wanting to explore both conventional and traditional medicine, be supported in making informed choices about including, or not including, these products in their health care options. The original concept of Evidence Based Medicine is based on three basic premises individual clinical expertise, the best external evidence and patients values and expectations [33] . The challenge faced by the regulator is to ensure that these are in play and to support consumers in making informed choices that are often made in a self-care setting. Questions at the Regulatory Interface: It has never been easy to distinguish between a dietary supplement and other categories such as conventional foods, drugs and biologics. As all these sectors have evolved, this question of product classification has become even more complex. Two of the main questions at the regulatory interface are: what are the boundaries are between dietary supplements and conventional foods and between dietary supplements and over-the-counter drugs? As the popularity of dietary supplements available in a food-like format such as a pre-prepared drink or bar has increased, the line between what a consumer would understand to be a food as compared to a dietary supplement has become increasingly blurred. In essence, how does the regulator provide for appropriate regulatory oversight? This has been particularly challenging for those jurisdictions that consider these products as a sub-set of drugs with regulation and often legislation governing them that is very different from that for foods. In these cases, the regulatory frameworks are more specific to such dosage forms as capsules, tablets and tinctures. The challenge is one primarily of balance in providing a regulatory approach that is appropriate and not unnecessarily restrictive with the need to ensure that consumers are aware that these food-like dietary supplements that they are considering are not typical foods. This lack of clarity is also challenging for the private sector in determining what regulatory framework applies to a product, either food or drug, that they wish to develop and bring to market. In Canada, this concern required the government to create a new category called supplemented foods distinct from NHPs where products in a food like format are considered as a subset of foods and not as natural health products [31] . In other jurisdictions such as Australia, authority has been given to the respective regulators to deem something to be either a therapeutic good or a food based a specific set of criteria [34] . The challenge at the over-the-counter (OTC) / dietary supplement interface is even more pronounced. A number of herbal medicines with a long history of use within the conventional health care model, such as senna and cascara, are regulated in most countries as OTC drugs rather than dietary supplements. As described above, Health Canada is proposing to address this issue in part by considering both NHPs and OTC drugs within a single regulatory approach for self-care products [32] . Working on the Global Stage: Although science and research may be global, regulations are still made primarily to reflect domestic needs and pressures. This poses a challenge regarding dietary supplements and dietary supplement ingredients that are now often sourced and/or manufactured outside of the country where they are sold. In spite of calls for regulatory harmonization, examples of true harmonization are limited to regions such as countries in the Association of South East Asian Nations (ASEAN) with the lack of a coherent and consistent regulatory approach prohibiting this globally [35] . Even if regulatory harmonization is not possible, regulatory cooperation is often a viable option, taking into account inputs from stakeholder groups such as industry and not just governments. For example, to support cooperation between regulators, in 2005 in Ottawa, the World Health Organization supported the creation of the International Cooperation on Herbal Medicine (IRCH). IRCH now has over twenty members and provides a forum and mechanism for regulators to share information on safety issues and common challenges they all face [36] . Increasingly governments are working together as well as with other stakeholders such as industry and consumers to address common problems and in some cases to provide regulatory decisions in one jurisdiction that can be used as a basis for action in another. Strengthening Product Quality: As the dietary supplement market has become more global and lucrative, so have the importance of ensuring product quality and the challenges in doing so. There are increasing numbers of cases of adverse reactions and some fatalities due to contaminants or adulterants in the product rather than in the dietary supplement ingredients themselves. In some cases this has been due to intentional fraud by producers of these poor quality products who have developed sophisticated methods for overcoming existing regulations and oversight. This situation is explored in greater depth elsewhere in this paper. Need for Continued Science in Support of Regulation: Irrespective of whether the goal is to support production of high quality products or to develop, apply or modify methods for evaluation of evidence in support of claims, the need for robust and relevant science and research on dietary supplements has never been more necessary. As regulatory frameworks evolve, many of the questions posed above will need to be addressed, balancing the need for robust science with a respect for traditional forms of health and healing. Challenges: Scientific Perspectives Issues Involving Human Requirements: Scientists often disagree about definitions of human requirements for bioactives and the implications for supplements. They differ on whether some non-nutrient bioactives are required for certain population subgroups and also on the health effects associated with the use of non-nutrient bioactives. It has been known for over 100 years that inborn errors of nutrient metabolism exist that can be remediated by supplying the lacking nutrient that has become conditionally essential. However, it is not clear that such a model based on single gene defects is useful for the amelioration of multigenic complex diseases. It is unclear that there are large numbers of individuals with common diseases and conditions such as type 2 diabetes or depression whose unique genetic characteristics cause them to have special nutritional requirements requiring supplements or medical foods [37] . Discoveries of genetic polymorphisms and the advent of inexpensive genetic tests that are widely available to consumers have nutritional implications. They have led to the rise of personalized or precision nutrition [38] and to the proliferation of boutique personalized eating plans and precision dietary supplements supposedly tailored to an individual s genetic profile. The extent to which such supplements are efficacious in reducing chronic degenerative disease remains to be determined. Supplement Quality, Safety and Efficacy: Challenges remain on the appropriate means for assuring supplement quality, safety and efficacy. Quality: Regulators, health professionals and manufacturers often disagree on how much quality testing is necessary for supplements. This is echoed by the World Health Organization s Strategy on Traditional Medicines 2014 2023 [39] where quality is seen as a cornerstone of the sector. Botanical extracts and blends present particular challenges for detecting misidentification and contamination. The presence of adulterants and contaminants of both a biological and chemical nature in supplements is also challenging. Certain categories of supplements, such as athletic performance, sexual performance, and weight loss products, are particularly prone to the deliberate spiking with unlabeled extraneous or synthetic substances to confuse analytical techniques and even occasionally the addition of active synthetic drugs. Purity is a special problem for individuals with inborn errors of metabolism for specific nutrients such as vitamin B-6 or choline who require reliable, high quality sources of the nutrient. In countries that do not require that added nutrients be pharmaceutical grade or provide nutrients free to such patients, afflicted individuals must buy products that vary greatly in their quality on the open market. The scientific challenges involved in all of the problems cited above depend in part on the adequacy and application of analytical methods. Analytical methods and reference standards are lacking for many of the thousands of different bioactive ingredients in dietary supplements. There is still disagreement about whether only a single officially endorsed method of analysis is acceptable. Any analytical method that is appropriately calibrated to a recognized reference standard should suffice but the onus is on the user of the method to demonstrate that affirmative requirements are met and that the method is suitable for its intended use and yields results that are accurate and precise. Methods that are suitable for foods may not be so for dietary supplements. Opinions also differ on whether government or the private sector is responsible for developing reference standards and analytical methods, and, if the private sector develops them, how they can be both kept independent and objective and made publicly available to avoid duplication of effort while preserving the marketing advantage of the developer. Tension also exists between researchers who desire ever more precise analytical methods for ingredients in dietary supplements and manufacturers who are concerned about the expertise and monetary costs required to apply some of the methods. A balance needs to be struck between the two. Safety: Apart from concerns related to product quality, the safety of dietary supplements depends largely on dose. High doses of some nutrients are more likely to pose problems than others, although there is disagreement about the levels at which problems arise. For example, some dialysis patients who are receiving very large doses of calcium and the active form of vitamin D on a chronic basis may exceed the Tolerable Upper Level (UL) and incur adverse effects on health, including calcification of the soft tissues [40] . Very high doses of vitamin D may also cause adverse effects in people with normal kidney function [41] . There is little evidence that usual doses and forms of these nutrients give rise to health problems [42] . The possibilities of excessive intakes of nutrients from dietary supplements are greater in countries with programs to fortify their food supplies than in others, and therefore they must also be evaluated [43-46] . Dose-response data for establishing safe levels of intakes of non-nutrient bioactives in supplements is frequently lacking [47,48] . Some dietary supplements containing non-target herbs added intentionally ( like germander as an adulterant for skullcap), or others such as black cohosh, kava extract, green tea and others have been associated with liver injures of various types even after taking into account concomitant use with acetaminophen and alcohol and consumption while fasting [49] . Extracts that are used in bodybuilding and weight loss have also been linked to liver injury. This has led to studies of the composition of different supplements [50,51] . Causes of liver toxicity from supplements appear to be due to insufficient regulatory authority, inaccurate product labeling, adulterants and inconsistent sourcing of ingredients [52] . There is controversy about whether evidence of causality is sufficient for regulators to take action against supplements that seem to pose a hepatotoxic risk [53] . Some possible actions include requirements for warning labels with usage instructions as is done for drugs, or/and removal of products from the market. Adulterated or fraudulent tainted products sold as dietary supplements are already illegal and subject to recall [54] . Interactions of some ingredients in supplements with other dietary supplements, nutrients, prescription or over-the-counter drugs are well documented. Of particular concern are adverse reactions occurring with commonly used medications, such as anti-hypertensive and cardiovascular preparations [55] . In addition, much interest focuses around concomitant use of herbal medicines such as St. John s Wort which has been shown to alter drug metabolism of a number of drugs notably those used in the treatment of HIV/AIDS, warfarin, insulin, aspirin and digoxin [56] . Efficacy: Among the most hotly debated issues in supplement research is the type and amount of evidence needed to demonstrate the efficacy of dietary supplements. Many of the issues involving efficacy include those common in testing of all medications such as study designs, significance testing, appropriate outcomes, effect sizes, acceptable biomarkers of effect, and the differences between statistical and clinical significance. In order to be efficacious, dietary supplements must be bioavailable, and yet in some countries regulations do not require testing of supplements for disintegration and dissolution and some products on the market fail such tests. This is a matter of concern both to researchers and regulators since such results have a negative impact on studies of dietary supplement efficacy. In-vitro methods are available for testing disintegration and dissolution of drugs, and these are adaptable for use with dietary supplement products. Regulators in some countries insist on changes in health outcomes or in validated surrogate biochemical markers of effect on the causal pathway to a health or performance outcome. Others accept changes in intermediary biochemical markers that may or may not be surrogates of health outcomes. These considerations have come to the fore because supplements on the market in some countries apparently have little or no demonstrated efficacy. For example, one recent review of 63 randomized,...