- What does the product do?
- What can be claimed about the product?
- Is the evidence supporting the claims sufficient?
- How safe is the product?
- Who will benefit from the product?
- How is the dosage determined?
- Are the ingredients available at an acceptable quality, cost and volume?
Scientific Publications on Natural Products, including Food, Medicine and Dietary Supplements: With a focus on Good Manufacturing Practices (GMP) for Natural Products, Quality Management Systems, and Good Agricultural and Collection Practices (GACP)
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- A Field Guide to Herbal Dietary Supplements, AHPA-ERB Foundation, http://www.ahpafoundation.org/fieldguide.pdf
- A Harvester’s Handbook to Wild Medicinal Plant Collection in Kosovo (2003). Lonner J. and Thomas M. Source: http://www.gowildconsulting.com/wp-content/uploads/2011/02/harvesters_handbook.pdf
- AHPA-AHP Good Agricultural and Collection Practice for Herbal Raw Materials, December 2006. (Updated draft 2016)
- AHPA Botanical Identity References Compendium, http://www.botanicalauthentication.org/index.php/Main_Page
- AHPA Guidance Policies, http://www.ahpa.org/Portals/0/PDFs/Policies/AHPA_Guidance_Policies.pdf
- Aspects of sustainable wild plant collection (2012) Rodina K, WWF Hungary/TRAFFIC
- Biological Diversity Act 2002 (India)
- BRC’s Global Standard for Food Safety
- Canadian Herb, Spice and Natural Health Product Coalition (CHSNC) Good Agriculture and Collection Practices (GACP). Kehler C. Source: https://www.cotr.bc.ca/webs_media/Creston/_docManager/docs/Good%20Agricultural%20and%20Collection%20Practices(1).pdf
- Canadian Horticultural Council OFFS (CanadaGAP)
- Code of Good Agricultural Practices of Georgia (2007). Ministry of Agriculture of Georgia. Source: http://iwlearn.net/iw-projects/633/reports/aret-code-of-good-agriculture-practices-of-georgia
- Code of hygienic practices for spices and dried aromatic herbs. (2014) Codex Alimentarius Commission, CAC/RCP 42-1995
- Codex Alimentarius Commission Recommended International Code of Practice – General Principles of Food Hygiene CAC/RCP1-1969, Rev. 4 -2003
- Current good manufacturing practice in manufacturing, packaging, labeling or holding operations for dietary supplements (21 CFR 111)
- Current good manufacturing practice, hazard analysis and risk-based preventive controls for human food (21 CFR 117)
- Development of a Good Agricultural Practice Approach. November 5, 2003. Source: http://www.fao.org/prods/GAP/archive/GAPCONCEPT12_en.pdf.
- Development of Good Wildcrafting Practices and Wildcrafter Certification for Medicinal Plants. (2006) Howe A. Source: http://www.bestlibrary.org/best_teachers/files/Wildcraftingfinalreport.pdf
- Dietary Supplement Ingredient Database, https://dietarysupplementdatabase.usda.nih.gov/
- Dietary Supplement Label Database, https://ods.od.nih.gov/factsheets/DietarySupplements-HealthProfessional/
- Dietary supplement laboratory quality assurance program: the first five exercises. Phillips MM, Rimmer CA, Wood LJ, Lippa KA, Sharpless KE, Duewer DL, Sander LC, Betz JM. J AOAC Int 2011;94:803-14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173719/
- Dietary Supplement Online Wellness Library (OWL), Council for Responsible Nutrition (CRN), http://www.supplementowl.org/
- EFSIS Safe & Legal: https://www.saiglobal.com/assurance/food-safety/SafeandLegal.htm
- Ensuring the Compliance of Raw Herbal Materials stemmed from China with European Good Agricultural and Collection Practice. Philippe A. et al. Chinese Herbal Medicine, (2011) 3(4): 251-256
- FairWild Standard, Version 2.0 (2010).
- FairWild Standards Map. Source: http://search.standardsmap.org/assets/media/FairWild/English/AtAGlance_EN.pdf
- FDA Food Safety Modernization Act http://www.fda.gov/Food/GuidanceRegulation/FSMA/
- FDA Dietary Supplement Labeling Guide, http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/DietarySupplements/ucm2006823.htm
- Field Techniques Used by Missouri Botanical Garden. Compiled by R. Liesner with suggestions from MO staff and others. Source: http://www.mobot.org/MOBOT/molib/fieldtechbook/pdf/handbook.pdf
- GAP Production of TCM Herbs in China (2010) Zhang B. et al. Planta Med 2010 76:1948-1955
- General guidelines for good agricultural practices: spices. International Organisation of Spice Trade Associations (IOSTA) (2013). Source: http://www.esa-spices.org/download/iosta-gap-final.pdf
- Global GAP, http://www.globalgap.org/uk_en/
- Good Agricultural and Collection Practices – Guidelines for the cultivation and collection of herbal medicines. (2012) Republic of Kenya.
- Good agricultural and collection practices for medicinal plants: Illustrated booklet for farmers and collectors. Source: http://www.dmapr.org.in/Downloads/Illustratedbooklet.pdf
- Good Agricultural and Wild Collection Practice (GACP) of Medicinal Plants in Europe, EUROPAM,( EHGA), c/o Veterinaerplatz, Vienna.
- Good Agricultural Practice (GAP) – Does It Ensure a Perfect Supply of Medicinal Herbs for Research and Drug Development? (2008) Leung PC and Cheng KF. Int J. App. Res. Nat. Prod. 1(2);1-8.
- Good Agricultural Practices and Good Handling Practices: Audit Verification Program. (2011) USDA Source: https://www.ams.usda.gov/sites/default/files/media/GAPGHP_Audit_Program_User%27s_Guide%5B1%5D.pdf
- Good Agricultural Practices and Good Handling Practices: Risk Mitigation in Edible Horticultural Production Systems (2015) Urbanowitz S and Bishop C. Source: https://www.unce.unr.edu/publications/files/ag/2015/cm1501.pdf
- Good agricultural practices for Artemisia (2014) ICAR Directorate of Medicinal and Aromatic Plants Research, Anand, Gujarat, India. Source: http://www.dmapr.org.in/publications/bulletine/artemisia%2016-1-15.pdf
- Good Agricultural Practices for Chinese Crude Drugs (Interim) (2002). Source: http://eng.sfda.gov.cn/WS03/CL0768/61642.html
- Good Agricultural Practices for Medicinal Plants (2009) National Medicinal Plant Board (NMPB), Department of AYUSH, India and World Health Organization Source: http://nmpb.nic.in/WriteReadData/links/8527013542Good%20Agricultural%20Practicies%20(GAPs)%20Booklet%20-%20Part%20-%20I.pdf
- Good Agricultural Practices for Plantago ovate Forsk. National Medicinal Plant Board (NMPB), Department of AYUSH, India and World Health Organization Source:
- Good agricultural practices for senna (2015) ICAR Directorate of Medicinal and Aromatic Plants Research, Anand, Gujarat, India. Source: http://www.dmapr.org.in/publications/bulletine/Good%20Agricultural%20Practices%20for%20Senna.pdf
- Good agricultural practices for small diversified farms, Carolina Farm Stewardship Association. Source: http://www.carolinafarmstewards.org/wp-content/uploads/2013/07/CFSA_GAPS-web.pdf
- Good agricultural practices for sustainable cocoa production: a guide for farmer training. Asare R and Sonii D. (2010) University of Copenhagen
- Good Practices for Plant Identification for the Herbal Industry (2004), Saskatchewan Herb and Spice Association, National Herb and Spice Coalition (Canada)
- Grocery Manufacturers Association (GMA-SAFE)
- Guidance for Implementing the International Standard for Sustainable Wild Collection of Medicinal and Aromatic Plants (ISSC-MAP). (2008) Leaman and Cunningham.
- Guidance for Industry: Botanical Drug Products (2004) FDA.Source: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070491.pdf
- Guidance Manual for Organic Collection of Wild Plants (2005) Swiss Import Promotion Programme (SIPPO).
- Guideline on good agricultural and collection practice (GACP) for starting materials of herbal origin. London, 20 February 2006. Doc. Ref. EMEA/HMPC/246816/2005 Source: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003362.pd
- Guidelines for good agricultural and hygiene practices for raw materials used for herbal and fruit infusions (GAHP). [Former EHIA Document], Version 6, 2014 Source: http://www.thie-online.eu/fileadmin/inhalte/Publications/HFI/2_2014-06_PU_GAHP_Version_6.pdf
- Guidelines for good agricultural and wild collection practices for medicinal and aromatic plants (2010). EUROPAM the European Herb Growers Association Brussels, November, 2010; EUROPAM GACP‐MAP 8.0
- Guidelines for identification and collection of medicinal plants in Bhutan. 2008.
- Guidelines for the Sustainable Harvesting of Traditional Medicinal Plants in Zimbabwe ( ). Khumalo SG, Frode A, Sola P. Research and Development Section Southern Alliance for Indigenous Resources (SAFIRE). Source: http://projects.nri.org/adappt/docs/HarvestingGuidelines.pdf
- Hand book of domestic medicine and common Ayurvedic remedies. Source: http://niimh.nic.in/ebooks/ayuhandbook/index.php
- Heavy metals: analysis and limits in herbal dietary supplements, http://www.naturalhealthresearch.org/wp-content/uploads/2013/02/09_1214_AHPA_Heavy-Metals-White-Paper-Revised.pdf
- Herbs of Commerce, American Herbal Products Association, Second Ed. (First Ed., 1992 available here: https://law.resource.org/pub/us/cfr/ibr/001/ahpa.herbs.1992.pdf )
- In search of comprehensive standards for nontimber forest products in the botanicals trade. PIERCE, A.R. and S.A. LAIRD. (2003). International Forestry Review 5(2):138-147.
- International Labour Organization: Labour Principles of the United Nations Global Compact
- International Standard for Sustainable Wild Collection of Medicinal and Aromatic Plants (ISSC-MAP) (2007) Version 1.0 Source: http://www.floraweb.de/map-pro/Standard_Version1_0.pdf
- ISO /TS 22003:2007 Food safety management systems – Requirements for bodies providing audit and certification of food safety management systems
- ISO 22000:2005 Food safety management systems – Requirements for any organization in the food chain
- ISO 9000:2005 Quality management systems – Fundamentals and vocabulary
- ISO 9001:2008 Quality management systems – Requirements
- ISO/IEC 17000:2004 Conformity assessment – Vocabulary and general principles
- ISO/IEC 17011:2004 Conformity assessment – General requirements for accreditation bodies accrediting conformity assessment bodies
- ISO/IEC 17021:2006 Conformity assessment – Requirements for bodies providing audit and certification of management systems
- ISO/IEC Guide 65:1996 General requirements for bodies operating product certification systems
- Legal and regulatory frameworks governing the growing, packing and handling of fresh produce in countries exporting to the U.S. (2010) Produce Safety Project, Pew Charitable Trust, Georgetown University. Source: http://www.pewtrusts.org/~/media/legacy/uploadedfiles/phg/content_level_pages/reports/psprptlegalregexportspdf.pdf
- National Advisory Committee on Microbiological Criteria for Foods Hazard Analysis and Critical Control Point Principles and Application Guidelines, August 1997.
- Office of Dietary Supplements, Background Information on Dietary Supplements, https://ods.od.nih.gov/factsheets/DietarySupplements-HealthProfessional/
- Pesticide Analytical Manual, Vol I, FDA. Source: http://www.fda.gov/downloads/Food/FoodScienceResearch/ucm113702.pdf
- Pesticide Analytical Manual, Vol II, FDA. Source: http://www.fda.gov/downloads/Food/FoodScienceResearch/ucm113721.pdf
- Pesticide chemicals in processed foods (21 CFR 170.19)
- Phytomedicine 101: plant taxonomy for preclinical and clinical medicinal plant researchers. Bennett, BC, Balick MJ. J Soc Integr Oncol 2008;6:150-157. https://www.ncbi.nlm.nih.gov/pubmed/19134447
- Quality assurance of cultivated and gathered medicinal plants. Mathe and Mathe, Source: http://www.mtk.nyme.hu/fileadmin/user_upload/kornyezet/Mathe/Quality_assurance.pdf
- Quality control methods for medicinal plant materials (1998) World Health Organization
- Recommendations for microbial limits in herbal products, American Herbal Products Association, http://www.ahpa.org/Portals/0/PDFs/Policies/14_0206_AHPA_micro_limits_comparisons.pdf
- Research and implementation of good agricultural practice for traditional Chinese medicinal materials in Jilin Province, China. (2014) Li C, Yan Z, Zhang L, Li Y. Ginseng Res. 38;227-232 Source: http://www.ginsengres.com/article/S1226-8453(14)00062-1/pdf
- Safe Quality Food, Edition 7.0. (SQF 2000 Levels 1, 2 & 3)
- Selection and authentication of botanical materials for the development of analytical methods. Applequist WL, Miller JS. Anal Bioanal Chem 2013;405):4419-28. https://www.ncbi.nlm.nih.gov/pubmed/23224664
- Standard operating procedure for the collection and preparation of voucher plant specimens for use in the nutraceutical industry. Hildreth J, Hrabeta-Robinson E, Applequist W, Betz J, Miller J. Anal Bioanal Chem. 2007 Sep;389(1):13-7. Epub 2007 Jun 16.
- Standardization of herbal medicines – A review. Kunle O.F. et al, (2012) Int. J Biodiv and Conserv. 4(3) 101-112. Source: http://www.academicjournals.org/article/article1380017716_Kunle%20et%20al.pdf
- Suggested Good Agricultural and Collection Practices for North Carolina Medicinal Herbs (2016) Davis J. Source: http://content.ces.ncsu.edu/suggested-good-agricultural-and-collection-practices-for-north-carolina-medicinal-herbs
- Suggested guidelines for articles about botanical dietary supplements. Swanson CA. Am J Clin Nutr 2002;75:8-10, https://www.ncbi.nlm.nih.gov/pubmed/11756054
- The Ayurvedic Pharmacopoeia of India, 5 Volumes, Ministry of Health and Family Welfare, Govt. of India, New Delhi, 1989-2005
- The Chinese Approach to Medicinal Plants – Their Utilization and Conservation. Pen-Gen X. (1991) In: Akerle, O., V. Heywood, and H. Synge (eds.). Conservation of Medicinal Plants. Cambridge University Press, Cambridge, UK.
- The Drugs and Cosmetics Act and Rules (as amended up through 30 June 2005. New Delhi: Department of Health. 2005.Schedule T: Good Manufacturing Practices (GMPs) for Ayurveda, Siddha and Unani Medicines.
- The Global Food Safety Initiative: GFSI Guidance Document, 6th Version 6.3
- The Indian Forest Act, India, 1927
- The NIH analytical methods and reference materials program for dietary supplements. Betz JM., Fisher KD., Saldanha LG, Coates PM. Anal Bioanal Chem 2007; 389:19-25. https://www.ncbi.nlm.nih.gov/pubmed/17541565
- The Siddha Pharmacopoeia of India, Part I(1), Ministry of Health and Family Welfare, of India, New Delhi, 2007
- The Unani Pharmacopoeia of India, Part-I, Ministry of Health and Family Welfare, Govt. of India, New Delhi
- Trainer’s manual on good agricultural and collection practices for medicinal plants: Source: http://www.dmapr.org.in/Downloads/Trainersmanual.pdf
- U.S. Customs & Border Protection, (C-TPAT)
- USDA (National Organic Program), https://www.ams.usda.gov/about-ams/programs-offices/national-organic-program
- USP Food Fraud Mitigation Guidance, http://www.usp.org/food/food-fraud-mitigation-guidance
- USP <2750> Manufacturing Practices for Dietary Supplements.
- USP <467> Residual Solvents
- USP <561> Articles of Botanical Origin
- Voluntary Sustainability Standards (Draft), United Nations Forum on Sustainability Standards Source: https://unfss.org/documentation/general-documentation/
- WHO guidelines on good agricultural and collection practices (GACP) for medicinal plants (2003). Source: http://apps.who.int/iris/bitstream/10665/42783/1/9241546271.pdf
- WHO Traditional Medicine Strategy 2002-2005. World Health Organization, Geneva.
- Wild Life (Protection) Act, India, 1972
Dietary Supplements: Regulatory Challenges and Research Resources
Johanna T. Dwyer, Paul M. Coates, and Michael J. Smith
Nutrients 2018, 10, 41; doi:10.3390/nu10010041 (Open Access)
Abstract: 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
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.
1.1. Importance of Research on Dietary Supplements
Until relatively recently, there was limited scientific research on dietary supplements and so little was known about them . However, the prevalence of supplement use has increased dramatically over the past 20 years , 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, methylsulfonylmethane (MSM), coenzyme Q10) has been more challenging . 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.
1.2. 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.
The supply of ingredients used in supplements has outpaced the availability of methods and trained personnel to analyze them . 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 . 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 . The bioactives 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 bioactives 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.
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.
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.
1.2.4. 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 bioactives that can be related to health outcomes . 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 .
2. 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 . 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.
2.1. 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 .
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 .
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) . 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.
EU Parliament and Council
European Food Safety Authority (EFSA)
China Food and Drugs Administration (CFDA)
Health Ministry—Chinese Medicine Division
Food Safety and Standards Authority of India (FSSAI)
Ministry of Ayurveda, Yoga, Unani, Siddha and Homeopathy (AYUSH)
WHO World Health Organization
World Self Medication Industry
International Alliance of Dietary/Food Supplement Associations (IADSA)
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.
2.2. 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.
2.2.1. 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].
2.2.2. 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 .
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.
2.2.3. 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.
2.2.4. 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) . 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) . 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) .
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 .
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 . 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 . 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 .
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 .
2.2.5. 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 .
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.
2.3. 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.
2.3.1. 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 . 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.
2.3.2. 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 . 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 .
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 .
2.3.3. 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 . 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 . 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.
2.3.4. 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.
2.4. 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.
3. Challenges: Scientific Perspectives
3.1. 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 .
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”  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.
3.2. Supplement Quality, Safety and Efficacy
Challenges remain on the appropriate means for assuring supplement quality, safety and efficacy.
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  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.
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 . Very high doses of vitamin D may also cause adverse effects in people with normal kidney function . There is little evidence that usual doses and forms of these nutrients give rise to health problems . 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 . 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 . There is controversy about whether evidence of causality is sufficient for regulators to take action against supplements that seem to pose a hepatotoxic risk . 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 .
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 . 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 .
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, placebo-controlled clinical trials of dietary supplements in Western adults found that in 45 of them no benefits were found, 10 showed a trend toward harm and 2 showed a trend toward benefit, while 4 reported actual harm, and 2 both harms and benefits; only vitamin D and omega 3 fatty acids had strong enough benefits and lack of harm to suggest possible efficacy . This is an area of controversy that is highly polarized with questions being raised that depend on the type of dietary supplement being used, notably herbal medicines, the quality of the studies included in the review, and additional factors such as product quality of the supplement being evaluated that need to be taken into account .
3.2.4. Standards of Efficacy for Traditional Natural Products
The traditional use of Chinese medicines, Ayurvedic medicines and other remedies is embedded in larger healing systems and cultural or metaphysical beliefs that are part of users’ larger and more holistic world views. Should usual standards for efficacy should apply to them when they are used in the traditional manner? Clearly such uses are quite different than the use of a single product or ingredient at much higher traditional doses and without such a cultural context.
Although policy issues arise with all types of dietary supplements, the examples below will focus on nutrient-containing dietary supplements since these are particularly germane to discussions of nutritional status.
3.3.1. Nutrient Supplements Are Only One of Many Strategies for Improving Nutrient Intakes
There are many strategies for filling nutrient gaps in dietary intakes. They include nutrition education on appropriate food choices, fortification and enrichment that add nutrients to staple foods, genetic engineering that increases the nutrient content of a commodity itself either by genetic engineering/biotechnology, biofortification involving conventional breeding, and the use of nutrient containing dietary supplements. Dietary supplements provide concentrated sources of bioactives that are low or lacking in some individuals’ ordinary dietary intakes. The supplements can be used selectively by those whose diets have gaps in them. However, supplements have disadvantages. Their use depends upon individual motivations. Because they provide concentrated sources of bioactives at relatively high levels, they may increase the risks that some individuals will ingest excessive quantities and suffer health risks. Moreover, since dietary supplements can contain ingredients that lack a history of safe use, their long-term health effects may be unknown. The advantages and disadvantages of dietary supplements as a strategy to improve dietary intakes therefore must be carefully considered.
3.3.2. Supplementation as a Strategy to Achieve Nutritional Adequacy
The cost-effectiveness of using supplements to fill gaps in nutrient intakes as opposed to other means such as fortification or nutrition education varies from one nutrient to another and by country, and so each situation is unique and must be evaluated independently. There are also questions about what the supplement should be, if supplementation is chosen. In countries where nutrient containing dietary supplements are common, the use of multivitamin-multi-mineral (MVM) supplements is often associated with a greater proportion of the population reaching the estimated average requirement (EAR) for nutrients . However, for some of these nutrients, intakes are already adequate, so that the increased intakes may do little good, and in some cases supplements may increase the risk of exceeding the upper safe level (UL) of intakes.
3.3.3. Monitoring of Supplement Use
Monitoring of supplement use is particularly important in countries where premarket approval is not required to detect potential adverse reactions. Dietary indicators are known to be imprecise and estimates of usual intake are lacking for many nutrients . Biochemical indicators of deficiency are often not well linked with adverse health outcomes, underscoring the need for more attention to be paid to the development of agreed on measures of deficiency and excess . Recent work on key nutrient biomarkers is now available, facilitating the monitoring of high risk groups, such as pregnant women for folate status [61,62].
3.3.4. Authoritative Recommendations for Dietary Supplements
Health and nutrition experts differ on whether it is appropriate to include recommendations for nutrient containing dietary supplements in national health promotion and disease prevention recommendations. Many countries opt to recommend that adequate nutrient intake for the general public be achieved solely from foods, and reserve recommendations of specific nutrient supplements for specific subgroups in the population. Others recommend only food alone with no recommendations for special populations.
3.3.5. Inclusion of Dietary Supplements in Food Programs to Reduce Malnutrition
There is pressure by industry to include MVM or other dietary supplements in food programs. However, there is little evidence that the target groups are deficient in the ingredients in the supplements, nor has it been demonstrated that provision of a supplement leads to better health outcomes.
3.3.6. Stimulating Innovation
The development of new and more highly bioavailable forms of the nutrients, timed release, dosage forms, novel bioactive constituents and the appropriate application of new technologies such as nanotechnology are all important, but some pose new scientific and regulatory challenges.
4. Case Study: Office of Dietary Supplements (ODS), National Institutes of Health (NIH), USA
This case study highlights some examples of dietary supplement research supported by or conducted at the ODS, and provides some research tools it has developed that may be useful resources for scientists both there and abroad.
Since its establishment in 1995 as part of the implementation of the Dietary Supplement and Health Education Act [17,18] of 1994, the ODS is the lead federal agency devoted to the scientific exploration of dietary supplements. Its mission is to support, conduct and coordinate scientific research and provide intellectual leadership to strengthen the knowledge and understanding of dietary supplements in order to enhance the US population’s health and quality of life. ODS’s four goals are to: expand the scientific knowledge base on dietary supplements by stimulating and supporting a full range of biomedical research and by developing and contributing to collaborative initiatives, workshops, meetings and conferences; enhance the dietary supplement research workforce through training and career development; foster development and dissemination of research resources and tools to enhance the quality of dietary supplement research; and translate dietary supplement research findings into useful information for consumers, health professionals, researchers, and policymakers.
Several of its major initiatives that have expanded the scientific knowledge base on dietary supplements are described elsewhere in this special issue of NUTRIENTS. They include studies to clarify the implications for public health of omega-3 fatty acids , iodine , vitamin D , and iron .
4.2. Research Resources and Tools
This section provides the details on freely available research resources developed by ODS that are available for scientists to use to enhance the quality of dietary supplement research and meet public health priorities, with a focus on those that may be useful to scientists in other countries.
4.3. Analytical Methods for Dietary Supplements
The rigorous assessment of dietary supplement ingredients requires accurate, precise and reliable analytical methods and matching reference materials. The ODS Analytical Methods and Reference Materials program accelerates the creation and dissemination of validated methods and reference materials. It provides resources for characterization and verification of supplement product content that enhance the reliability and reproducibility of research using these products and supports product quality .
The genesis of the program was the paucity of publicly available methods for the analysis of supplement ingredients [68,69]. In 2000, the US dietary supplement community tended to use proprietary or compendial methods for quality control operations, and scientists and laboratories often kept their proprietary methods to themselves. Negative publicity about discrepancies between label claims and the results of product testing performed by third parties led to some unsuccessful efforts on the part of the industry to pay a laboratory to develop and validate methods through the Association of Official Analytical Chemists International (AOACI). The program was not successful for several reasons, including lack of expert technical guidance and conflicting sponsor priorities. However, this early effort led to a collaboration between trade associations, ODS, the AOACI, the United States Pharmacopoeia (USP), NSF International, and others in an attempt to establish standard methods for dietary supplement analysis. The ODS became involved because explicit wording in DSHEA required the Government to use “publicly available” analytical methods for enforcement actions involving dietary supplements. In response to the need for such publicly available methods and to support efforts to validate methods used in biomedical research on dietary supplement ingredients, ODS established the Analytical Methods and Reference Materials (AMRM) program in 2002.
ODS has been involved in sponsoring the creation of AOAC Official Methods of Analysis for dietary supplements and in the development and dissemination of numerous analytical methods and reference materials for 15 ingredients in dietary supplements in the USA, 32 botanical identification and documentation projects, and 45 studies determining contamination and adulterants. It has also helped to develop guidance on the validation of identity methods for botanical ingredients  and the conduct of single-laboratory validation studies for dietary supplements, Appendix K, AOAC Official Methods of Analysis, and provided guidance to evaluation of the literature on botanical supplements [71,72]. The portion of the ODS website includes a searchable database of analytical methods; these can be accessed at: https://ods.od.nih.gov/Research/AMRMProgramWebsite.aspx.
ODS also supports the Dietary Supplement Laboratory Quality Assurance Program in which participants measure concentrations of active and/or marker compounds and nutritional and toxic elements in practice and test materials. Exercises have included water and fat-soluble vitamins, nutritional and toxic elements, fatty acids, contaminants (e.g., aflatoxins, polyaromatic hydrocarbons (PAH’s)) and botanical markers (e.g., phytosterols and flavonoids).
4.4. Reference Materials
ODS supports the development of certified reference materials for dietary supplement ingredients with assigned values for concentrations of active and/or marker compounds, pesticides, and toxic metals to assist in the verification of product label claims and in quality control during the manufacturing process. A reference material is a material that is sufficiently homogeneous and stable with respect to one or more specified properties, which have been established to be fit for its intended use in a measurement process. A certified reference material (CRM) is a reference material characterized by a metrologically valid procedure for one or more specified properties, accompanied by a certificate that provides the value of the specified property, its associated uncertainty, and a statement of metrological traceability. Certified reference materials can be used for laboratory proficiency studies, methods development, method verification, and method validation studies. Calibration standards are the single chemical entities necessary for construction of calibration curves for quantitative analysis and for confirming analyte identity. Several processes are used to produce calibration standards. ODS provided funding to the U.S. Department of Commerce’s National Institute of Standards and Technology (NIST) for the development and distribution of calibration standard solutions and matrix standard reference materials (SRM®; a NIST-trademarked type of CRM). The materials fall into one of the following categories: (1) pure chemical entities or their mixtures, including many nutrients and other ingredients in dietary supplements for use in establishing analyte identity and for calibrating instruments; (2) natural matrix materials that represent the supply chain of a particular dietary supplement, e.g., biomass (ginkgo leaves and powder), processed botanical ingredient (ginkgo extract), finished product; (3) natural matrix materials that cover a range of analytes including nutritional compounds, botanical marker compounds, and compounds with known health concerns (heavy metals, pesticides, plant toxins); and (4) Clinical materials that can be used to assist clinical laboratories assess nutrient status or exposure, such as the measure of measure of vitamin D status commonly used around the world, serum 25-hydroxyvitamin D [73–75]. ODS is now expanding efforts to develop biomarkers of nutrient exposure and status in blood and other biological specimens in relation to chronic disease risk in individuals and populations. ODS has worked with NIST to produce and make available reference materials for calibration of various laboratory methods. Supplementary Table S1 shows NIST Standard Reference Materials (SRM®) now available. Supplementary Table S2 shows dietary supplement and nutritional assessment SRMs that are currently in progress.
4.5. Dietary Supplement Databases
Two databases have been developed by ODS that are described elsewhere in detail [76–80]. The goal of the Dietary Supplement Label Database (DSLD) is to include labels for virtually all dietary supplements sold in the USA. This provides all the information on the product label including composition, claims, and manufacturer contact information. It now contains over 72,000 dietary supplement labels, with new labels added at the rate of 1000 per month. Used together with food composition databases it is possible to estimate total daily intakes of nutrients and other bioactive ingredients from both foods and dietary supplements. A mobile version of DSLD is now available for use on smartphones to enhance consumer access to it [78,80]. It is primarily aimed at researchers and so contains information about products that are currently on the market, as well as those that have been removed from the market.
The Dietary Supplement Ingredient Database (DSID) provides analytically derived information on the amount of labeled ingredients of a representative sample of commonly used categories of supplement products sold in the USA, including adult, child and prenatal MVM supplements and omega-3 fatty acids. DSID is now being expanded to examine botanicals and other ingredients in supplements that are of public health interest, such as green tea products. Calculators included with the DSID permit a consumer to examine how closely the labeled contents of a nutrient in a product compare to chemical analyses of all products in the category .
4.6. Nutrition Research Methods and Review Methodology
Systematic reviews of dietary supplements require special techniques. ODS has sponsored a series of technical reports on the application of review methodology to the field of nutrition and dietary supplements [81–86]. Staff have also collaborated in performing systematic reviews with other groups [87,88].
4.7. Population-Based Monitoring of Dietary Supplement Use
In collaboration with the National Health and Nutrition Examination Survey (NHANES) of the National Center for Health Statistics, ODS investigates patterns of dietary supplement use using national and other large cohorts, and assesses supplements’ effects on total nutrient intakes. Several studies have focused on adults , children [90,91], and others in the population and their supplement use. Other studies have focused on the contributions to total intakes of nutrients made by dietary supplements. Investigators at ODS have been active in funding monitoring efforts on the links between intakes of folic acid and health . They have devoted particular attention to blood levels of folic acid and dietary intake patterns that are associated with very low and very high intakes of the nutrient [93–95]. The survey methods used are well documented and they may be useful for those in other countries planning similar population-based surveys to consult .
The motivations for use of dietary supplements are also documented; they often differ from those specified in regulations. NHANES contains several items that are consumer tested and available for use in other surveys on motivations. Knowledge of motivations can improve understanding of how people use these products and may provide clues for encouraging appropriate supplement use.
4.8. Translation of Supplement Science for Health Professionals and the Public
ODS has produced and periodically updates a library of more than two dozen fact sheets on the ingredients in supplements such as vitamin D, magnesium, and special products such as MVM supplements and products marketed for weight loss. There is a detailed version for professionals that is complete with detailed references, as well as easy-to-read versions for consumers in both English and Spanish. ODS also works with the National Library of Medicine (NLM) to produce and update a Dietary Supplement Subset of NLM’s PubMed. The National Center for Complementary and Integrative Health (NCCIH) at NIH produces a series of fact sheets on many botanicals and other non-nutrient bioactives in supplements that are also useful. They can be accessed at https:
//www.nccih.nih.gov. ODS also hosts an intensive, free 3-day course on issues in dietary supplement research annually for researchers. Further information about these and other projects is accessible at:https://www.ods.od.nih.gov.
4.9. Other Resources
In order to foster the development of appropriate study methods for dietary supplement research, ODS sponsors workshops on the latest knowledge and emerging approaches to the study of dietary supplements. It also supports the development of cutting–edge approaches to elucidate the mechanisms of action of complex botanical dietary supplements. It co-funds the Centers for Advancing Research on Natural Products (CARBON) with the NCCIM, including its program to develop high content high throughput methods to rapidly generate hypotheses on active compounds and the cellular targets. These and other resources are announced as they become available on the ODS website.
4.10. Fostering Use of Systematic Evidence Reviews in Policy Making and Clinical Practice
ODS has strengthened the scientific framework for developing dietary recommendations by encouraging the incorporation of systematic reviews into the development of the DRI. It has sponsored 18 systematic reviews on topics related to dietary supplements. These include ephedra, B vitamins, MVM supplements, omega-3 fatty acids, soy, probiotics, and vitamin D. The ephedra systematic review was helpful to the US government in banning ephedra products from the US market. The systematic reviews of omega-3 fatty acids funded over a decade ago and more recent updates on their associations with cardiovascular disease and infant health outcomes have been useful for planning intervention programs as well as for regulatory purposes. Current AHRQ reviews are available on the AHRQ website (https://www.ahrq.gov).
5. Future Needs
Attitudes toward safety, efficacy, and values about what is important in food and life will be important in determining future needs involving supplement science in the countries we have discussed and perhaps elsewhere in the world. Safety is critical, and requires better chains of custody and product characterization that exists at present for these products, particularly those involving global markets. Efficacy, that is that the health promotion claims for the product are true and not misleading is also critical. Demonstrating efficacy requires clinical studies with well defined products and rigorous experimental designs, and the studies must be replicable. To that end, many publishers now require that submitted manuscripts comply with established guidelines for the reporting of clinical trial results (e.g., CONSORT guidelines), while funders require demonstration of product integrity by applicants [97,98]. Finally there are issues of personal choice and values, sometimes involving the efficacy of supplements as complementary and alternative therapies that are part of a larger philosophical or religious world views and systems. These must be accommodated without abandoning safety.
Both basic and more applied challenges will continue well into the future. Much remains to be learned about the effects of bioactive constituents such as flavonoids in foods and dietary supplements on health outcomes, as many recent papers in Nutrients and elsewhere indicate [99–101]. More and better biomarkers need to be developed and their associations with health outcomes clarified . Supplements intended to enhance sports performance  botanicals used for disease treatment  and those ingredients thought to slow aging  all require identification of valid biomarkers of efficacy as well as of exposure. The role of supplements and the gut microbiome also must be explored for its associations with common diseases and conditions . The associations between supplement ingredients and health outcomes in chronic degenerative disease must be clarified [47,105,107–109]. High risk groups need more attention Certain subgroups within the population such as athletes consume very high amounts of some supplements and it is important to monitor them to prevent adverse outcomes and study the effects, if any, on athletic performance . Others use supplements in the hope that they will improve cognitive performance . Those who practice polypharmacy with prescription, non-prescription drugs and dietary supplements represent another high-risk group, and interventions to limit the potential for adverse events are needed [111,112]. Collaborations among scientists in many countries are needed to drive supplement science forward.
Irrespective of the type of health product, high quality science is fundamental to the success of any regulatory framework. Assessments of the safety, quality and efficacy of nutrients and other bioactives are needed to provide the scientific information that regulators need . As mentioned earlier, the nature and diversity of the sector means that regulators face a number of very specific challenges for these low risk products. These include evaluating traditional evidence, dealing with products that contain multiple bio-actives and addressing the growing challenges of ensuring product quality. It is critical that scientists and regulators work together and learn from each other in both identifying issues and developing ways in which they can be addressed. Although regulatory challenges must be met at the national level, there must be due regard paid to the fact that national regulatory decisions about supplements have global implications.
Science is vital in regulatory settings, and there is no reason that science and regulation should be incompatible . The challenges in supplement science and its regulation provide new opportunities for scientists and regulators to work together both nationally and internationally, to learn from each other, and to cooperate and when appropriate harmonize approaches to improve the public health.
Supplementary Materials: The following are available online at www.mdpi.com/2072-6643/10/1/41/s1, Tables S1 and S2 Table S1 Standard Reference Materials (SRM®) available from the National Institute of Science and Technology, US Department of Commerce. Table S2 Dietary supplement and nutritional assessment Standard Reference Materials (SRM®) currently under development at the National Institute of Science and Technology, US Department of Commerce (as of December 2016).
Acknowledgments: Funded by the National Institutes of Health, Bethesda, MD, USA. We thank Joseph M. Betz, Leila Saldanha, Cara Welsh, for their thoughtful and critical reviews of the manuscript, and Joyce Merkel, for technical editing and support.
Author Contributions: J.T.D. and P.M.C. developed the concept for the manuscript. J.T.D., P.M.C. and M.J.S. wrote the manuscript.
Conflicts of Interest: Johanna T. Dwyer holds stock in several food and drug companies, and serves on the scientific advisory boards of Conagra Foods, McCormick Spices, and as a consultant for Gerber/Nestle. She accepted partial travel and per diem expenses to speak at a symposium on dietary supplements sponsored by the International Association of Dietary/Food Supplement Associations at the International Congress of Nutrition in Buenos Aires, Argentina in October 2017. Michael J. Smith holds stock in several food and drug companies as well as acting as a consultant with clients in both the private and public sector including companies in dietary supplement and natural health products sector. He sits on the scientific advisory board of ISURA and the advisory board of the American Botanical Council. Paul M. Coates reports no conflicts of interest.
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- Gahche, J.J.; (NIH Office of Dietary Supplements, Bethesda, MD, USA). Personal communication, 2017.
- NIH National Center for Complementary and Integrative Health. NCCIH Policy: Natural Product Integrity. Available online: https://nccih.nih.gov/research/policies/naturalproduct.htm (accessed on 7 November 2017).
- NIH Office of Extramural Research. Grants & Funcing—Rigor and Reproducibility. Available online: https://grants.nih.gov/reproducibility/index.htm#guidance (accessed on 7 November 2017).
- Sebastian, R.S.; Wilkinson Enns, C.; Goldman, J.D.; Moshfegh, A.J. Dietary flavonoid intake is inversely associated with cardiovascular disease risk as assessed by body mass index and waist circumference among adults in the United States. Nutrients 2017, 9, 827. [CrossRef] [PubMed]© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
We often get asked what we think of a product concept. The thought process to develop an answer is generally similar, regardless of the type of product, and whether its a consumer packaged good (CPG) or finished product, or an ingredient or raw material.
A number of considerations go into developing and producing successful, effective, safe and compliant dietary supplements, foods, and food and dietary ingredients. These include:
The 7 Steps to Dietary Supplement Product Development
There are seven basic elements to developing a groundbreaking product:
- Begin with the finished product in mind. Determine in full detail how the product will be marketed, what the desired product claims will be, and how the product will address an unmet market need.
- Intimately understand the product value and market positioning compared to the competition. How will the product address an unmet need, or be different than what is already found on the market? How will the product be priced compared to the competition? A full competitive analysis is important to determine positioning.
- What language will be used to describe the product? (This language, found on product labels and on webpages, is considered to be part of product claims.)
- In what country(s) will the product be marketed? Regulations in different countries vary, and it is important to understand the unique requirements of each location.
- How will it be sold? Online, Amazon, Whole Foods, health food stores, clubs, MLM and practitioner channels have distinct customer needs, pricing and positioning requirements
- Evaluate the regulatory landscape. What steps need to be taken to access the market? What gaps need to be filled in order to be compliant with the regulations?
- Evaluate ingredients and suppliers. An ingredient that is processed in a way that makes it different than material used in studies will negate the supporting evidence. And, an ingredient that does not meet GMP and quality requirements under FDA is illegal to sell. Don’t go far down the path of product development without a rigorous evaluation of supply and ingredients.
Product Development Planning
Working backwards from the product claim may sound simple, but it is an analytical process that benefits greatly from industry experience and forethought. A solid plan is what separates a rocket from a dud.
Sufficient time spent in the planning phase is the difference between success and failure.
Product development plans often coordinate the knowledge of supplement consultants and experts, review regulatory status of the product and evaluate the available scientific evidence. A good development plan will identify not only opportunities, but also gaps and risks that may prevent success.
Dietary Supplement Label Review Checklist
⊗ PACKAGING REQUIREMENTS
Five general requirements for labels include: 1) the statement of identity (name of the dietary supplement), 2) the net quantity of contents statement (amount of the dietary supplement), 3) the nutrition labeling (Supplement Facts Panel), 4) the ingredient list, and 5) the name and place of business of the manufacturer, packer, or distributor.
⊗ LABEL STATEMENTS
You must place all required label statements either on the front label panel (the principal display panel) or on the information panel (usually the label panel immediately to the right of the principal display panel, as seen by theconsumer when facing the product), unless otherwise specified by regulation(i.e., exemptions).
⊗ SUPPLEMENT FACTS PANEL
Total calories, calories from fat, total fat, saturated fat, cholesterol, sodium, totalcarbohydrate, dietary fiber, sugars, protein, vitamin A, vitamin C, calcium, andiron must be listed when they are present in measurable amounts. Calories from saturated fat and the amount of polyunsaturated fat, monounsaturated fat, soluble fiber, insoluble fiber, sugar alcohol, and other carbohydrate may be declared, but they must be declared when a claim is made about them.
⊗ INGREDIENT LIST
When present, you must place the ingredient list on dietary supplementsimmediately below the nutrition label, or if there is insufficient space belowthe nutrition label, immediately contiguous and to the right of the
⊗ WARNING STATEMENT
FDA requires warning statements related to safety and special precautions that, if not followed, could make the product unsafe.
⊗ UNITS OF MEASUREMENT
Proper units of measurement must be used, for example milligrams (mg), micrograms (mcg) or other appropriate units
⊗ PERCENTAGE DAILY VALUE (DV)
The % DV must be declared for all dietary ingredients for which FDA has established Daily Values, except that 1) the percent for protein may be omitted, and 2) on the labels of dietary supplements to be used by infants, children less than 4 years of age, or pregnant or lactating women, you must not list any percent for total fat, saturated fat, cholesterol, total carbohydrate,dietary fiber, vitamin K, selenium, manganese, chromium, molybdenum,chloride, sodium, or potassium.
⊗ DOMESTIC ADDRESS OR PHONE NUMBER
The label of a dietary supplement being marketed in the United States must include a domestic address or domestic phone number through which the responsible person may receive a report of a serious adverse event with such dietary supplement. If the label does not include the required domestic address or phone number, the dietary supplement is misbranded.
⊗ UPC BAR CODE
The UPC bar code may be obtained from the Uniform Code Council (www.uc-council.org)
⊗ NATURAL AND ARTIFICIAL FLAVORS
You must declare these ingredients in ingredient lists by using either specific common or usual names or by using the declarations “natural flavor” or “artificial flavor,” or any combination thereof.
⊗ CHEMICAL PRESERVATIVES
You must list the common or usual name of the preservative, which may be followed by a description that explains its function e.g., “preservative,” “to retard spoilage,”“a mold inhibitor,” “to help protect flavor,” or “to promote color retention.”
⊗ OTHER DIETARY INGREDIENTS
You must list “other dietary ingredients” by common or usual name in acolumn or linear display. FDA has not specified an order that you must follow. You must list the quantitative amount by weight per serving immediately following the name of the dietary ingredient or in a separate column. You must place a symbol in the column for “% Daily Value” that refers to the footnote “Daily Value Not Established,” except that the symbol must follow the weight when you do not use the column format.
⊗ LIQUID EXTRACTS
You must list liquid extracts using the volume or weight of the total extract and the condition of the starting material prior to extraction when it was fresh. You may include information on the concentration of the dietary ingredient and the solvent used. The solvent must be identified in either the nutrition label or ingredient list.
⊗ DRIED EXTRACTS
For dietary ingredients that are extracts from which the solvent has been removed, you must list the weights of the dried extracts.
You may list constituents of a dietary ingredient indented under the dietary ingredient and followed by their quantitative amounts by weight per serving. You may declare the constituents in a column or in a linear display.
⊗ PROPRIETARY BLENDS
You must identify proprietary blends by use of the term “Proprietary Blend” or an appropriately descriptive term or fanciful name. On the same line, you must list the total weight of all “other dietary ingredients” contained in the blend. Indented underneath the name of the blend, you must list the “other dietary ingredients” in the blend, either in a column or linear fashion, in descending order of predominance by weight. These ingredients should be followed by a symbol referring to the footnote “Daily Value Not Established.”Dietary ingredients having RDIs or DRVs must be listed separately and the individual weights declared.
⊗ PRODUCT CLAIMS
Claims come in four basic varieties:
- structure/function claims
- disease claims
- health claims and qualified health claims
- content claims
Basically, dietary supplements cannot make “disease” claims (for example: “treats cancer”). Dietary supplements that make disease claims are considered by FDA as drugs.
Dietary supplements can make “structure/function” claims (for example, “calcium builds strong bones”). A structure/function claim describes the product’s role in maintaining the “structure or function of the body,” or “general well-being.”
The Federal Trade Commission (“FTC”) has overlapping jurisdiction with the federal Food and Drug Administration (“FDA”), and focuses more on whether advertising is truthful, or false and misleading. Thus, it is important to respect nuanced labeling rules, including those regarding the statement of the identity.
The regulation states that the term “high potency” may be used in a claim on the label or in labeling to describe individual vitamins or minerals thatare present at 100 percent or more of the Reference Daily Intakes (RDI) per reference amount customarily consumed (21 CFR 101.54(f)(1)(i)). This means a supplement may be labeled as “high potency” for each nutrient(s) that is present at 100% of the RDI per serving.
⊗ ANTIOXIDANT NUTRIENT CONTENT CLAIMS
A claim that describes the level of antioxidant nutrients present in a food is a nutrient content claim and may be used on the label or in the labeling of a food when the conditions of use in the regulation are met (21 CFR 101.54(g)).
The antioxidant nutrient must meet the requirements for nutrient content claims in 21 CFR 101.54.
A dietary supplement may include claims in labeling such as “sugar free,” “no sugar,” or other claims provided it meets all of the eligibility criteria set forth in the regulation.
Among other requirements, a food must be labeled as “low calorie” or “reduced calorie” or bear a relative claim of special dietary usefulness. However, a dietary supplement that is prohibited from bearing a “low calorie”or “reduced calorie” claim can still use a sugar-free claim provided it meets the “low calorie” requirement in 21 CFR 101.60.
⊗HIGH OR GOOD SOURCE CLAIMS
You may make a “high” claim when your dietary supplement contains atleast 20% of the Daily Value (DV) (i.e. the Reference Daily Intake (RDI) or Daily Reference Value (DRV)) of the nutrient that is the subject of the claim perreference amount customarily consumed. You may make a “good source”claim when your dietary supplement contains 10 to 19% of DV.
⊗ LOW OR FREE-FROM CLAIMS
If a similar dietary supplement is normally expected to contain a nutrient and your dietary supplement is specially processed, altered, formulated, or reformulated as to lower the amount of the nutrient in the food, remove the nutrient in the food, or not include the nutrient, then you are permitted to make a “low” or “free” claim as applicable.
⊗ LOW CALORIE CLAIMS
A “low calorie” claim may not be made on dietary supplements, except when an equivalent amount of a dietary supplement that the labeled dietary supplement resembles and for which it substitutes (e.g., another protein supplement), normally exceeds the definition for “low calorie.”
⊗ QUALIFIED HEALTH CLAIMS
FDA will permit the use of a qualified health claim provided that 1) FDA hasissued a letter stating the conditions under which we will consider exercisingenforcement discretion for the specific health claim, 2) the qualified claim is accompanied by an agency-approved disclaimer, and 3) the claim meets all the general requirements for health claims in 21 CFR 101.14, except forthe requirement that the evidence for the claim meet the validity standard for authorizing a claim, and the requirement that the claim be made in accordance with an authorizing regulation.
This guidance was prepared by the Office of Nutritional Products, Labeling and Dietary Supplements (ONPLDS) in the Center for Food Safety and Applied Nutrition (CFSAN) at the U.S. Food and Drug Administration.
There’s a lot of detail required for dietary supplement labels. Between supplement facts, structure-function health claims, and required formatting, it’s easy to overlook some of the FDA requirements for labeling.
Dietary Supplement Facts and Label Review
As part of our Label Review services, NaturPro helps clients develop, review and suggest improvements to dietary supplement labels, to ensure compliance with FDA regulatory requirements
Our clients enjoy the following benefits:
- Reliability: 100% accuracy and FDA compliance
- Experience: 15+ years of experience reviewing supplement labels
- Science-driven: Our reviews are based on the most current, reliable information, techniques and evidence
- Perspective: We have experience on the business side of the industry, so we know what the law is, whether it’s followed, and what is likely to happen if you don’t.
Updated 2018 Pricing:
Label Review: $400-600 ea. (Volume discounts may apply for similarly labeled products.)
Marketing Review: Contact for Pricing
FDA Dietary Supplement Labeling Guidelines
The following outlines some of the most frequently asked questions (FAQ) for dietary supplement labels:
- How are dietary supplements defined?Dietary supplements are defined, in part, as products (other than tobacco) intended to supplement the diet that bear or contain one or more of the following dietary ingredients:
- A vitamin;
- A mineral;
- An herb or other botanical;
- An amino acid;
- A dietary substance for use by man to supplement the diet by increasing the total dietary intake; or
- A concentrate, metabolite, constituent, extract, or a combination of any ingredient mentioned above.Further, dietary supplements are products intended for ingestion, are not represented for use as a conventional food or as a sole item of a meal or the diet, and are labeled as dietary supplements.
- What label statements are required on the containers and packages of dietary supplements?Five statements are required: 1) the statement of identity (name of the dietary supplement), 2) the net quantity of contents statement (amount of the dietary supplement), 3) the nutrition labeling, 4) the ingredient list, and 5) the name and place of business of the manufacturer, packer, or distributor.
- Where do I place the required label statements?You must place all required label statements either on the front label panel (the principal display panel) or on the information panel (usually the label panel immediately to the right of the principal display panel, as seen by the consumer when facing the product), unless otherwise specified by regulation (i.e., exemptions).
- What label statements must I place on the principal display panel?You must place the statement of identity and the net quantity of contents statement on the principal display panel. Where packages bear alternate principal display panels, you must place this information on each alternate principal display panel.
- How do I locate the principal display panel?The principal display panel of the label is the portion of the package that is most likely to be seen by the consumer at the time of display for retail purchase. Many containers are designed with two or more different surfaces that are suitable for use as the principal display panel. These are alternate principal display panels.
- What label statements must I place on the information panel?You must place the “Supplement Facts” panel, the ingredient list, and the name and place of business of the manufacturer, packer, or distributor on the information panel if such information does not appear on the principal display panel, except that if space is insufficient, you may use the special provisions on the “Supplement Facts” panel in 21 CFR 101.36(i)(2)(iii) and (i)(5). See questions 46 and 56 in Chapter IV for more details.
- Where is the information panel?The information panel is located immediately to the right of the principal display panel as the product is displayed to the consumer. If this panel is not usable, due to package design and construction (e.g. folded flaps), the panel immediately contiguous and to the right of this part may be used for the information panel. The information panel may be any adjacent panel when the top of a container is the principal display panel.
- What name and address must I list on the label of my product?You must list the street address if it is not listed in a current city directory or telephone book, the city or town, the state, and zip code. You may list the address of the principal place of business in lieu of the actual address.
- May I place intervening material on the information panel?No. You may not place intervening material, which is defined as label information that is not required (e.g., UPC bar code), between label information that is required on the information panel.
- What type size, prominence and conspicuousness am I required to use on the principal display panel and the information panel?You are required to use a print or type size that is prominent, conspicuous and easy to read. The letters must be at least one-sixteenth (1/16) inch in height based on the lower case letter “o,” and not be more than three times as high as they are wide, unless you petition for an exemption in accordance with 21 CFR 101.2(f). The lettering must contrast sufficiently (it does not need to be black and white) with the background so as to be easy to read. See Chapter IV for the type size requirements for the nutrition label.
- Do I need to specify the country of origin if my product, or the ingredients in my product, is not from the United States?Yes. Unless excepted by law, the Tariff Act requires that every article of foreign origin (or its container) imported into the United States conspicuously indicate the English name of the country of origin of the article.
- What is the nutrition label for a dietary supplement called?The nutrition label for a dietary supplement is called a “Supplement Facts” panel.
- You must list dietary ingredients without RDIs or DRVs in the “Supplement Facts” panel for dietary supplements. You are not permitted to list these ingredients in the “Nutrition Facts” panel for foods.
- You may list the source of a dietary ingredient in the “Supplement Facts” panel for dietary supplements. You cannot list the source of a dietary ingredient in the “Nutrition Facts” panel for foods.
- You are not required to list the source of a dietary ingredient in the ingredient statement for dietary supplements if it is listed in the “Supplement Facts” panel.
- You must include the part of the plant from which a dietary ingredient is derived in the “Supplement Facts” panel for dietary supplements. You are not permitted to list the part of a plant in the “Nutrition Facts” panel for foods.
- You are not permitted to list “zero” amounts of nutrients in the “Supplement Facts” panel for dietary supplements. You are required to list “zero” amounts of nutrients in the “Nutrition Facts” panel for food.How does “Supplement Facts” differ from “nutrition facts?”The major differences between “Supplement Facts” panel and “Nutrition Facts” panel are as follows:
- What information must I list in the “Supplement Facts” panel?You must list the names and quantities of dietary ingredients present in your product, the “Serving Size” and the “Servings Per Container.” However, the listing of “Servings Per Container” is not required when it is the same information as in the net quantity of contents statement. For example, when the net quantity of contents statement is 100 tablets and the “Serving Size” is one tablet, the “Serving Per Container” also would be 100 tablets and would not need to be listed.
- How must I display the “Supplement Facts” panel?The “Supplement Facts” nutrition information (referred to as a panel) must be enclosed in a box by using hairlines. The title, “Supplement Facts,” must be larger than all other print in the panel and, unless impractical, must be set full width of the panel. The title and all headings must be bolded to distinguish them from other information.
- How must I present the information in the “Supplement Facts” panel?You must present all information using the following:
- A single easy-to-read type style;
- All black or one color type, printed on a white or neutral contrasting background, whenever practical;
- Upper- and lowercase letters, except that you may use all uppercase lettering on small packages (i.e., packages having a total surface area available to bear labeling of less than 12 square inches);
- At least one point leading (i.e., space between lines of text); and
- Letters that do not touch.
- What are the type size requirements for the “Supplement Facts” panel?Except as provided for small and intermediate-sized packages, you must set information other than the title, headings, and footnotes in uniform type size no smaller than 8 point. You also must use a type size larger than all other print size in the nutrition label for the title “Supplement Facts.” You may set the column headings and footnotes in type no smaller than 6 point type. See the section on “Special Labeling Provisions” for the exceptions for small and intermediate-sized packages.
For more information, visit FDA Dietary Supplement Labeling Guide
Testing Foods, Supplements and Ingredients
NaturPro offers independent laboratory support for food & supplement testing for natural products.
Why Testing is Important: Supplement and natural product testing with a compliant laboratory is required by FDA for foods, dietary supplements and ingredients to ensure they meet standards for safety, quality and effectiveness. For example, identity, potency and purity are quality control parameters needed to legally sell a natural product as an ingredient, food or dietary supplement.
NaturPro Scientific is driven to achieve the right answers for our clients. Some have even called us the UnLab. Why?
Being independent means that we do not own or have interest in any laboratory, which means we are free to pick from the top scientific experts for each type of test or analysis. As a result, we are truly able to work on behalf of our clients, to ensure that correct methods are used and results are obtained.
We know which labs are experienced with ginseng, but not with ginkgo — and this can mean a world of difference in test results.
11 reasons to use a supplement testing consultant for natural products:
- To ensure analytical methods used are valid and fit for purpose
- To make sure laboratories don’t take shortcuts with your sample
- To determine if results are precise and accurate
- To replicate the results of another lab
- To resolve out-of-specification test results
- To resolve disputes in data reports
- To determine if “dry-labbing” may be occurring
- To have an independent expert to review methods and results
- To perform due diligence on a supplier or partner
- To eliminate the potential for perceived conflict of interest when testing own products
- To qualify a lab as a good partnership choice.
3 main benefits of food and natural products testing consultants:
- Better analysis and testing validity for reliable, replicable and defensible results.
- Fast turnaround and lower testing costs.
- Reduced retesting, rejections, production delays and product recalls.
Bottom Line – NaturPro knows the right methods and labs to use, and the right questions to ask. We know the shortcuts that testing labs can take, and how to prevent that from happening to you, to ensure testing gives the most scientific, accurate and defensible results possible.
NaturPro Contributes to Expert Panel Receiving AOAC Award: “ERP of the Year” to Kombucha Alcohol Group
The AOAC Expert Review Panel (ERP) charged with reviewing methods of analysis for ethanol in kombucha initially met in September 2016 to review methods against AOAC SMPR 2016.001 (Determination of Ethanol in Kombucha). At this meeting, the ERP adopted an Official Method of Analysis for First Action status, AOAC 2016.12 (Determination of Ethanol in Kombucha) using gas chromatography with flame ionization detection (GC-FID). The selection and validation of this method was coordinated by NaturPro Scientific and performed by Covance Laboratories, Wisconsin.
AOAC states: “The ERP’s work directly impacts the resolution of urgent and key issues identified by industry, and serves as a forum where both the kombucha industry and government work together.
“The ERP was selected because its open and thorough scientific scrutiny of methods and its output clearly demonstrate the culmination of an industry-wide effort that facilitates regulatory and industry engagement for addressing urgent analytical disputes and facilitating trade. All ERP members receive the award, and publicly receiving the award on behalf of the group is the ERP chair, Sneh Bhandari.
“The Expert Review Panel (ERP) of the Year Award recognizes an ERP for achieving and completing signicant milestone(s) (e.g., Final report, First Action Method, Final Action Method), highlighted by some unique or particularly noteworthy aspect of a review panel report, such as innovative technology or application, breadth of applicability, critical need, difficult analysis, or timeliness.
“The report demonstrates significant merit as to the scope of the project, diversity of the panel, or an innovative approach to difficult analytical challenges. The report must have been submitted within the last 3 years.”
Knowing whether a material will be able to be made into a product is a key step to product development. A lot of natural products are unstable, insoluble, non-flowable, terrible tasting, or otherwise challenging to mix into the desired product form.
In today’s ‘clean label’ demanding market, many of the additives used to make a high quality tablet or beverage are no longer salable.
Food and Supplement Product Manufacturing Feasibility
Related to the exercise of understanding manufacturing feasibility, we also offer a number of production-related services:
- Source and qualify bulk raw materials
- Raw material quality verification program
- Supplier verification program
- Facility design and GMP
- Formula/recipe development
- Project management
- Manufacturing process design
- Equipment qualification, sourcing, IQ/OQ/PQ
- Contract manufacturer qualification
- Materials selection & sourcing
- Packaging & label development
- Documentation & systems
NaturPro’s core experiences are in understanding how to make better products and better ingredients. Contact us to learn more.
In the United States, dietary supplements and their ingredients are subject to a patchwork of regulations, industry guidance, voluntary certifications and audit programs. With some exceptions, few standards for dietary supplements have been developed with expert consensus and broadly implemented by the dietary supplement industry.
FDA’s dietary supplement GMPs (good manufacturing practices) are part of the exception and have made today’s supplement products generally a higher level of quality than at any time before.
Making A Quilt from the Regulatory Patchwork: What Successful, Resourceful Firms Do
Yet few industry standards are clearly understood, consistently applied and sufficiently comprehensive to cover all the ground.
One primary example is the gap between compliance requirements for dietary ingredients (under food GMPs) and dietary supplements, whose GMP framework is derived from that for pharmaceuticals. The underlying litmus test for the level of safety demanded for supplements and foods are different—that of “non-adulteration” versus “safe for human consumption,” Respectively. Maybe due to the differences, supplement GMP audit programs can overlook the food GMPs that govern ingredients. It is not uncommon for a manufacturer and a supplier to speak completely different quality languages. Audits for supplement GMPs are frequently unable to determine to a reasonable degree of certainty whether a particular ingredient, based on its certificate of analysis (CoA), should be expected to meet supplement requirements once it is placed inside a capsule or tablet.
As could be expected, an unintended consequence of this major gap is the common practice of a raw material CoA being duplicated as the manufacturer’s raw material specification.
In this scenario, an ingredient specification has been developed according to food requirements and, often without further analysis or verification, it is assumed to meet the requirements of the finished supplement. The result is a supplement that is essentially of no better quality than the “food-grade” ingredients put into it.
Especially for botanicals and animal-derived raw materials: cultivation, harvesting and processing before the final ‘transformation’ adds another dimension..
Confirming identity and purity is a complicated problem, particularly for a global supply chain of agricultural materials susceptible to contaminants during farming, harvesting, processing, storage or transportation to the ingredient processing facility.
In many poorer countries, the supply chain, and contaminants are not as well regulated as in advanced nations, and are freely shipped with no knowledge of their destination. Likewise, the final manufacturer or end user may have no information on the source of the material beyond the previous dock. In an uncomfortable way, the U.S., with its more lax regulations, often receives the materials rejected by Europe. Thus, potential contaminants may not be necessarily listed on the specification or controlled by the food GMPs, yet they can cause the products to which they are added to be adulterated.
Dozens of standards have been written for agricultural products, many of which don’t (or can’t) apply to the small family farmers who are a predominant source of botanical raw materials. In addition to recent requirements for fresh produce established by the Food Safety Modernization Act (FSMA), which don’t really apply to dried agricultural materials, we also have: USDA good agricultural practices (GAPs), which are intended for large farms and seldom fully practiced in the United States; certified organic, which requires no testing for contaminants like pesticides that may cause a product to be adulterated; independent farm standards like Global GAP, which arealso intended for large, modernized industrial farms; and, dozens of good agricultural and collection practices (GACPs) for medicinal plants that have been independently written by various nations and trade groups.
Some experts say the mess of standards, the dynamics of the industry and the law of entropy do not support the possibility of a clear and unified regulatory structure.
Others recognize the limitations, yet remain busy sewing the patches together into a quilt that is greater than the sum of its parts.
initiatives are in process or recently completed that contribute to the integrity of our industry quilt and have provided free information. Just in the past couple years:
• The U.S. Pharmacopoeia (USP) and American Herbal Pharmacopoeia (AHP) developed monographs and methods for testing dietary supplement ingredients.
• USP also developed a Food Fraud Mitigation Database that lists adulterants common for food ingredients.
• AOAC International developed analytical methods for dietary supplement ingredient potency and contaminants.
• The National Institutes of Health’s (NIH) Office of Dietary Supplements (ODS) website became a valuable source of information and resources.
• Trade groups such as the American Herbal Products Association (AHPA) and American Botanical Council (ABC) made enormous efforts to educate and guide the industry on issues around botanical dietary ingredients and adulteration, including a recently updated draft GACP from AHPA, and the ABC-AHP-National Center for Natural Products Research (NCNPR) Botanical Adulterants Program.
• The Supplement Online Wellness Library (OWL) was established by the Council for Responsible Nutrition (CRN), to allow labels for supplement products on the U.S. market to be put into in one place.
• The Supplement Safety and Compliance Initiative (SSCI) was formed as a broad industry initiative, with wide support from trade associations, to address some of the gaps for supplements that aren’t sufficiently covered under other standards. SSCI is led by experienced players in retail, manufacturing and supply, and includes a focus on identity, risk assessment and quality for raw materials.
• In response to consumer demand, leading retailers, manufacturers and ingredient suppliers invested significant resources into traceability and quality, and are now able to make meaningful claims to these effects that are not only important to consumers, but also serve as a reliable way to differentiate from the competition.
Today’s movement toward a greater level of education and transparency includes a firming of the gaps, especially where raw material traceability and quality are concerned. Successful companies across the entire supply chain are actively improving and adopting new standards, building a level of quality and integrity that provides lasting value to their business. Those who are upping their game are piecing together a quilt of their own, leveraging their quality advantages into claims that deliver marketing value. On the other side, those who continue to rely on ignorance or a lack of regulatory clarity as reason to take no action are increasingly left behind.
In an industry where faceless online product marketers are more common than they should be, and where a list of the tens of thousands of products available on the market is just getting online, our combined efforts to fill in the gaps of the collective regulatory patchwork benefits everyone.
This article was previously published in Natural Products Insider, July 2017.