- Email: [email protected]
health supplements
CHAPTER
Global market entry regulations for nutraceuticals, functional foods, and dietary/food/health supplements
3
Andrew Shao Global Nutrition Solutions, LLC, Los Angeles, CA, United States
3.1 Introduction Policy that underlies regulations for any consumer product should appropriately balance benefit, consumer access, and choice with safety (risk). This principle should apply regardless of the regulatory category, whether a drug, device, food, supplement, or nutraceutical. Requiring a new promising treatment for cancer to be free of any side effects whatsoever may minimize risk to the public, but such a treatment would likely fail to reach the market; thus, it would do consumers little good, if any. In contrast, allowing an untested medical device to be placed on the market that provides little benefit, but poses high safety concerns, allows for open consumer access but does not balance risk appropriately. Starting with market entry, global regulations should aim to strike an appropriate balance between consumer access and risk (safety). For nutraceuticals, functional foods, and supplements, specific market entry requirements depend on the overall regulatory framework employed within a given country. For most countries, these frameworks are based on a food or drug, including an over the counter–based approach. Products that are regulated under a food-like category tend to be subjected to notification or registration-based systems, whereas products regulated under a drug-like category tend to be subjected to a premarket approval system. This chapter compares and contrasts the different approaches used globally and whether these approaches help to achieve the appropriate access– risk balance.
3.2 Market entry requirements For most countries worldwide, conventional and functional foods and supplements (including nutraceuticals) are regulated as a category of food. In some regions or countries, a specific set of regulations governs supplements (e.g., the United States, the European Union [EU], the Association of South East Asian Nations [ASEAN]) and nutraceuticals (India), which stems from a food-based regulatory Nutraceutical and Functional Food Regulations in the United States and around the World. https://doi.org/10.1016/B978-0-12-816467-9.00003-4 Copyright © 2019 Elsevier Inc. All rights reserved.
37
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Chapter 3 Global market entry regulations
Table 3.1 Global notification or registration for foods/supplements. Country/region
Notification/registration
Argentina Association of South East Asian Nations Australia Brazil Canada Chile China Colombia United States Japan Mexico Russia European Union
Registration Notification or registration Notification/listing Notification Registration Notification Both Registration Notification or none None Notification Registration Notification or none
paradigm. For most of these countries, some form of a notification- or registration-based system (or a combination of both) is required to bring new products to the market (Table 3.1). This approach is in contrast to the premarket approval approach required for drugs in most countries, and appropriately fits the category of foods, because these pose inherently low safety risks relative to drugs. China and Brazil are examples of two large markets that have revised regulations regarding market entry. In the case of Brazil, an entirely new regulatory framework governing supplements and functional foods was published as a series of six consultations in mid-2018.1 Regarding market entry, the Agência Nacional de Vigilância Sanitária (National Sanitary Surveillance Agency, ANVISA), which oversees supplements in Brazil, has exempted food supplements (with the exception of enzymes and probiotics) from the traditional registration process.2 The formal establishment of a legal and regulatory category for supplements in Brazil should have a positive effect on the market for responsible companies and should benefit consumers as well. A notification-based system will allow ANVISA to be aware of products entering the marketplace in Brazil, but it will reduce greatly the resources needed from both the agency and the industry to bring products to the market. Before Brazil, China’s Food and Drug Administration (CFDA) in 2016 relaxed its regulations allowing for the notification of vitamin and mineral-containing health foods (previously subject to burdensome registration requirements).3 Although some viewed this move as insufficiently progressive, this represents a significant step for a market with historically rigid requirements for health foods. The Chinese government has since undergone a substantial reorganization, resulting in the renaming of 1 http://portal.anvisa.gov.br/noticias?p_p_id=101_INSTANCE_FXrpx9qY7FbU&p_p_col_id=column-2&p_p_col_
count=2&_101_INSTANCE_FXrpx9qY7FbU_groupId=219201&_101_INSTANCE_FXrpx9qY7FbU_urlTitle=anvisaquer-regulacao-especifica-para-suplementos-alimentares&_101_INSTANCE_FXrpx9qY7FbU_struts_action=%2Fasset_ publisher%2Fview_content&_101_INSTANCE_FXrpx9qY7FbU_type=content. 2Resolution of the Board of Directors - RDC Nº 243, July 26, 2018. Brazilian Ministry of Health, National Health Surveillance Agency. 3China Food and Drug Administration. Detailed Rules on Health Food Registration Review and Approval Process 2016.
3.2 Market entry requirements
39
agencies and reallocation of resources. This includes the CFDA, which no longer exists. The State Administration for Market Regulation, a new government entity, will oversee health foods. What impact, if any, this government reorganization will have on the health food category in China remains to be seen.
3.2.1 Positive and negative ingredient lists The safety and acceptability of new products in the marketplace starts first with the ingredients. In most regions of the world, the safety and acceptability of excipients used in a given formula are governed via established food additive requirements. In the United States [1] (including Generally Recognized as Safe [GRAS] [2]) and the EU [3] there are well-established food additive regulations, and for countries that lack their own established approaches, many rely on standards set by the Codex Alimentarius [4]. Therefore, when evaluating the entry of new products into the marketplace, most regulators focus attention on the safety and acceptability of the active or driver ingredients. In many countries, regulators rely on established formal positive and/or negative ingredient lists or their derivations to guide evaluations. As their name implies, these lists indicate which ingredients are considered acceptable for use in foods and/or supplements and which are not allowed. Some countries will rely on only a positive list, and others only a negative list; some countries rely on both and some do not rely on a list but employ a broader approach. The basis for how ingredients are added to these lists varies widely around the world, and the formal role the lists have varies as well. An ingredient may be added to a negative (not allowed in foods) list based on well-established safety issues (e.g., a botanical with well-known toxic effects), or an ingredient may be added to the list based on the perception (often ill-conceived) or speculation about adverse effects. Ingredients known to be inherently safe, such as vitamins and minerals, will appear on most positive lists, or owing to their inherent safety, they may not appear on a list at all. Most regulatory agencies keep separate lists for botanicals allowable for use in foods and supplements. New botanicals or other novel ingredients may also be allowed and added to positive lists on a case-by-case basis after their formal evaluation. Whether an ingredient is considered new or novel depends on the specific policies and regulations of the given country or region. In Australia, the Therapeutic Goods Administration (TGA) regulates supplements under a Complementary Medicines category and maintains a positive list of allowable ingredients, including excipients and actives [5]. This list includes vitamins, minerals, and botanicals. China [6] is an example of a country that uses both a positive and negative list. China’s positive list includes ingredients that can be added to foods, drugs, and health foods, as well as a list of banned ingredients. Canada employs a unique monograph system: ingredients that comply with already established monographs have an easier path to market as Natural Health Products (NHPs), whereas those that have not yet been the subject of a monograph must go through a more formal approval process [7]. In the EU, the European Commission published a list of vitamin and mineral ingredients allowable in foods and food supplements [8]. Ingredients that have not been used for human consumption to a significant degree before May, 1997 are considered novel foods, requiring the marketer to apply for authorization [9]. There is an online catalog that uses a traffic light system to highlight whether the ingredient is novel, not novel, or can only be used in food supplements, or whether it is not yet certain [10]. For other physiologic substances, including botanicals, regulations in the EU for acceptable ingredients have not yet been harmonized. As a result, different positive lists have been developed by some individual member states. For example, Italy [11], Denmark [12], and the Czech Republic [13]
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Chapter 3 Global market entry regulations
Table 3.2 Countries/regions employing positive and/or negative ingredient lists. Market/region Argentina Australia Brazil Canada Chile China Colombia Mexico Paraguay Russia United States Uruguay Venezuela European Union Italy Denmark Czech republic Association of South East Asian Nations
Positive list
Negative list
Other
✓ ✓ Monograph system ✓
✓
✓ ✓ Generally Recognized as Safe, new/old dietary ingredients ✓ ✓ ✓ ✓ ✓
✓ Novel food
Restricted list
established their own versions of positive lists of substances that can be added to foods and/or supplements. Russia is an example of a non–member state with a positive list [14]. In the United States, the US Federal Food and Drug Administration (FDA) maintains a list of ingredients that are GRAS for use in foods [2]. In many cases, these ingredients are acceptable for use in dietary supplements as well, although the agency does not maintain a specific positive list of ingredients for supplements. Regarding ingredients not allowed for use in supplements, the FDA has published several rulings [15,16] and/or warning letters [17–19] indicating that certain ingredients are not acceptable for inclusion in dietary supplements or are unsafe for the public [20]. In the United States, the FDA must be notified of New Dietary Ingredients (NDI), whereas “old” dietary ingredients, or grandfathered ingredients (ingredients marketed before Oct., 1994) need not be notified. However, no formal list of grandfathered ingredients exists in the United States. In South America, the situation varies from country to country, with some not relying on a list (e.g., Argentina, Chile, Colombia), others a positive list (e.g., Brazil), and others both (e.g., Venezuela). Brazil updated its positive list to include acceptable forms of vitamins, minerals, and bioactive substances.4 The list excludes botanicals and probiotics. In the ASEAN, the region aims to establish a restricted list of substances allowed in traditional medicines and health supplements [21]. A brief summary of the different types of lists used in different countries or regions is summarized in Table 3.2. 4Normative
Instruction 28/2018. Lists of constituents, limits of use, claims and supplementary labeling of food supplements. July 27, 2018. Brazilian Ministry of Health, National Health Surveillance Agency.
3.2 Market entry requirements
41
3.2.2 Botanicals Botanicals can present unique regulatory, quality, and safety challenges and thus tend to be more restricted in many markets. Lack of understanding on the part of regulators, lack of transparency in the supply chain, and a less robust evidence base relative to vitamins and minerals serve to undermine the confidence of regulators in this category of ingredients. Thus, the appearance of botanical ingredients on positive lists is limited in many countries. In Brazil ANVISA, only water or ethanol-extracted botanicals are allowed in foods, and each product is evaluated on a case-by-case basis [22]. In Mexico, the Federal Commission for the Protection against Sanitary Risk maintains a positive and negative list for botanicals allowed in foods [23]. The agency proposed adding certain botanical ingredients with a long history of safe use to a negative list, including inulin and aloe [24], based on the belief that these have documented therapeutic uses (and thus are medicines, not acceptable for use in foods). In the EU, the European Food Safety Authority published a botanicals compendium [25] that includes a list of botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. Although this document does not have official regulatory standing, it could be interpreted as a form of negative list for the EU. However, other EU member states published and continue to update their own positive and negative botanical lists. Italy maintains a list of permitted botanicals with related health benefits [26] and one of nonpermitted botanicals [26]. Belgium has one list including permitted and nonpermitted botanicals and mushrooms with related maximum allowable levels for some botanicals [27]. Germany maintains a list that has been used by regulators as a guidance document to assess botanicals [28]. In these countries, whether a botanical appears on a positive or negative list for foods depends largely on whether it is perceived as medicinal. A plant may be judged medicinal if scientific data show an influence on physiological functions. When applicable, an assessment of the minimum dosage for such activity is determined. Therefore, traditional use has become an important resource for determining whether certain plants, plant parts, and preparations may be added to positive lists. One challenge that has arisen is the lack of consensus on what constitutes traditional use. Individually, experts seem to agree on its meaning, but this has not been codified in a globally recognized resource. Criteria that could be considered include widespread use (e.g., by large or multiple populations), long duration of use (e.g., over generations), and documented (e.g., in compendia) conditions of use (e.g., plant, plant part, preparation, dosage, indication, etc.). These are all aspects that would support a safe and efficacious history of use, which is the basis of many positive lists. Another check is whether the ingredient is novel, in which case the EU novel food catalog is consulted as a reference. Finally, the botanical may be checked against conformity with other approvals (e.g., additives) and whether the product would be considered as safe. If formal lists are to be in place, the preference should be for a negative list (i.e., limiting ingredients that are not allowed), which tends to be much shorter and easier to maintain and allows consumers access to a greater variety of products. If allowable ingredients are restricted to a positive list, this would limit the industry’s ability to bring novel products to market. Because of the inherent safety of most food and supplement ingredients, a negative list most appropriately balances consumer access with risk.
3.2.3 Notification versus registration Although there are some differences among countries, a notification-based system usually represents a means of informing the regulatory authorities of a product’s introduction to the marketplace or the intent to introduce a new product. Notifications tend to be composed of information about the manufacturer, product form, formulation, and label; these tend to be subjected to minimal review by regulators.
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Chapter 3 Global market entry regulations
Product ingredients must be derived from a positive list (if one exists), and the entry of the product into the marketplace does not signify or constitute an approval or authorization from regulators, but they have the authority to question or object to a notification. The notification results in the addition of the new product to a list that regulators maintain for enforcement purposes. The notification approach tends to be most efficient for getting new products to the market, for both industry and regulators, because minimal premarket resources are necessary. This approach also allows regulators to focus resources on enforcing critical postmarket activities, such as good manufacturing practices, and collecting, handling, and reporting adverse events. Notification is thus a proportionate approach to the low level of risk posed by these categories of food products. Registration-based approaches differ from notification-based ones in that they require more detailed information in the form of a registration dossier, intense review by regulators, and a lengthier and more resource intensive review process. A typical registration dossier requires much more detailed information than is found in a notification, including details about the specifications of the finished product, evidence supporting the safety and efficacy of the ingredients, a certificate of analysis, stability testing (to support shelf-life dating), the product label, a certificate of free sale, and a good manufacturing practice (GMP) certification or compliance statement. Although this approach allows regulators to scrutinize new products closely, in most countries that require registration, it is a slow and extremely resource-intensive process ranging from months to years. Lengthy registration time tends to result from a lack of resources and expertise, along with the obligation of regulators to approve or authorize product dossiers. A drawback of this approach is the length of time to market for products regardless of the risk they may pose, and even fewer resources for enforcement in other, potentially more critical areas. A comparison of notification versus registration appears in Table 3.3. Table 3.3 Notification versus registration submissions for foods, supplements, and nutraceuticals. Ingredients in accordance with applicable positive and negative lists Applicable good manufacturing practices Label according to regulation Detailed product specifications Certificate of analysis Claim substantiationa Shelf-life substantiation Certificate of free sale Implications Helps authority to process high volume of products Immediate access to market N/A, not applicable. aIn countries where claims are allowed.
Notification
Registration
Required
Required
Manufacturer expected to adhere to
Official certification or statement required with dossier Required Required Required Required Required
Required N/A N/A Manufacturer expected to have on file N/A or manufacturer expected to have on file N/A Surveillance and control regime Requires high government resources Slow access to market
Required Reduces postsurveillance and control regime
3.2 Market entry requirements
43
Table 3.4 Current health supplement market entry requirements for various Association of South East Asian Nations member countries. Premarketing registration Time line for evaluation <2 months 2–3 months 6 months 6–12 months
Brunei
Cambodia
Indonesia
Malaysia
Philippines
Singapore
Thailand
Vietnam
No
Yes
Yes
Yes
Yes
No
Yes
Yes
✓ ✓
✓ ✓
✓ ✓
The EU is an example of a region that uses the notification approach [29]. Although specific requirements differ among countries, of the 27 member states, 23 have opted to incorporate a notificationbased approach for new product entry. Austria, Holland, Sweden, and the United Kingdom are among those for which notification for new products is optional. In the ASEAN, the 10-member country region is in the process of finalizing harmonized regulations for traditional medicines and health supplements [30]. Currently, both registration and notificationbased procedures are used, depending on the country (Table 3.4). As with other regions, the specific requirements in each country vary [31]. For market entry of health supplements, the region will require a comprehensive product dossier as part of a registration-based process, with the emphasis on quality, safety, and efficacy. The United States represents a unique situation in which no product notification is required unless the product contains NDI [32]. If a new product does not contain NDI, no notification is required. If a new product contains NDI, notification to the FDA is required 75 days before the product enters the market. The basis of the notification is substantiation that the manufacturer or marketer believes the NDI are safe in the product under its intended conditions of use [33]. In Latin America, market entry requirements for foods and supplements vary. Notification-based approaches are employed in Mexico and Chile, whereas registration-based approaches are followed in Colombia, Brazil, and Argentina. In countries such as Brazil (ANVISA [34]), China (China State Food and Drug Administration [6]), and Taiwan (Taiwan Food and Drug Administration [35]), regulators require animal and/or human clinical studies for product registration for some, but not all, products. This requirement tends to be limited to products for which efficacy claims are intended. In Australia and Canada, supplements and nutraceuticals are regulated more closely to a drug than food category. The TGA in Australia regulates supplements under a Complementary Medicines category [36]. Premarket approval requirements for this category are comparable to registration requirements for foods and supplements in other countries [37], although other requirements such as GMPs tend to be more drug-like than food-like. In Canada, Health Canada (HC) regulates supplements under an NHP category [38]. Because of the allowance of medicinal or therapeutic claims for NHPs, HC takes a more rigorous approach to new product entry. The licensing process in Canada for NHPs is riskbased, with products posing the highest risk requiring the greatest premarket review by the agency.
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Chapter 3 Global market entry regulations
Although a variety of individual systems exists in various countries and regions worldwide, the approach to bringing new foods, supplements, or nutraceutical products to the market has begun to converge toward notification-based systems. The notification-based approach most optimally balances premarket resources, consumer access, and consumer safety. However, a key aspect to ensuring product safety and quality in the marketplace, regardless of premarket requirements, is robust postmarket surveillance.
References [1] FDA. Food additives. 2012. Retrieved from: http://www.fda.gov/Food/FoodIngredientsPackaging/ FoodAdditives/default.htm. [2] FDA. Generally recognized as safe (GRAS). 2012. Retrieved from: http://www.fda.gov/Food/ FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm. [3] European Commission. Food additives and flavourings. January 15, 2013. Retrieved from: http://ec.europa. eu/food/fs/sfp/flav_index_en.html. [4] JECFA. About Codex. Codex Alimentarius. 2013. Retrieved from: http://www.codexalimentarius.org/ scientific-basis-for-codex/jecfa/en/. [5] Therapeutic Goods Administration. Substances that may be used in Listed medicines in Australia. 2007. Retrieved from: http://www.tga.gov.au/pdf/cm-listed-substances.pdf. [6] SFDA. Regulations on supervision of functional foods (draft for approval). 2009. Retrieved from: January 15, 2013. [7] Natural Health Products Directorate. Compendium of monographs. Drugs and health products. 2009. Retrieved from: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/index-eng.php. [8] European Commission. Commission Regulation (EC) No 1170/2009 of 30 November 2009 amending Directive 2002/46/EC of the European Parliament and of Council and Regulation (EC) No 1925/2006 of the European Parliament and of the Council as regards the lists of vitamin and minerals and their forms that can be added to foods, including food supplements. Off J Eur Union 2009. L314/36. [9] European Commission. Novel foods and novel food ingredients. Food and Feed Safety 2012. Retrieved from: http://ec.europa.eu/food/food/biotechnology/novelfood/index_en.htm. [10] European Commission. Novel Food catalogue–Search. Food and Feed Safety January 15, 2013. Retrieved from: http://ec.europa.eu/food/food/biotechnology/novelfood/nfnetweb/mod_search/index.cfm. [11] della Salute M. Altri nutrienti e altre sostanze ad effetto nutritivo o fisiologico. January 15, 2013. Retrieved from: http://www.salute.gov.it/imgs/C_17_pagineAree_1268_listaFile_itemName_4_file.pdf. [12] Ministerialtidende. Bekendtgørelse om tilsætning af visse andre stoffer end vitaminer og mineraler til fødevarer. 2012. Retrieved from: https://www.retsinformation.dk/Forms/R0710.aspx?id=137299. [13] Sbírka Zákonů. Kterou se stanoví požadavky na doplňky stravy a na obohacování potravin. 2008. [14] Customs Union Commission. Uniform sanitary and epidemiological and hygienic requirements for products subject to sanitary and epidemiological supervision (control). 2010. [15] FDA. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Fed Regist 2004;69(28):6788–854. [16] CFSAN, FDA. CFSAN office of food additive safety. FDA response to OVOS natural health homotaurine petition. Washington, DC: Department of Health and Human Services; 2011. [17] FDA. FDA advises dietary supplement manufacturers to remove comfrey products from the market. 2001. [18] FDA. February 28, 2003 warning letter to powerhouse supplements. 2003. [19] FDA. Letter to Health Professionals regarding safety concerns related to the use of botanical products containing aristolochic acid. 2001.
References
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[20] FDA. Consumer advisory: kava-containing dietary supplements may be associated with severe liver injury. 2002. [21] ASEAN. Guiding principles for inclusion of active substances into the restricted list for traditional medicines and health supplements. TMHS; 2010. [22] ANVISA. Novos ingredientes aprovados. 2009. Retrieved from: http://portal.anvisa.gov.br/wps/content/ Anvisa+Portal/Anvisa/Inicio/Alimentos/Assuntos+de+Interesse/Novos+Alimentos+e+Novos+Ingredientes/ 29bd7700401adec6b403b654e035b7cb. [23] COFEPRIS. What is the COFEPRIS?. 2011. Retrieved from: http://www.cofepris.gob.mx/Paginas/Idiomas/ Ingles.aspx. [24] Asociacion Nacional de la Industria de los Suplementos Alimenticios. ANAISA noticias. 2013. Retrieved from: http://www.anaisa.mx/. [25] European Food Safety Authority. Compendium of botanicals reported to contain naturally occurring substances of possible concern for human health when used in food and food supplements. EFSA J 2012;10. [26] della Salute M. Disciplina dell’impiego negli integratori alimentari di sostanze e preparati vegetali (G.U. 21-7-2012 serie generale n. 169). 2012. [27] Belgian Health. F. C. S. E. Food supplements – enriched foodstuffs. 2012. Retrieved from: http://www. health.belgium.be/eportal/foodsafety/foodstuffs/foodsupplements/index.htm?fodnlang=en#Plants. [28] The Federal Office of Consumer Protection and Food Safety (BVL). Entwurf einer Liste für die Kategorie “Pflanzen und Pflanzenteile”. 2010. Retrieved from: http://www.bvl.bund.de/SharedDocs/Downloads/01_ Lebensmittel/stoffliste/stoffliste_pflanzen_pflanzenteile.html?nn=1406620. [29] European Commission. Directive 2002/46/EC of the european parliament and of the council. 2002. [30] ASEAN. Harmonization of standards and technical requirements in ASEAN. 2012. Retrieved from: http:// www.asean.org/news/item/harmonization-of-standards-and-technical-requirements-in-asean. [31] ASEAN. Profile of definition, terminology, and technical requirement of traditional medicines and health supplements among ASEAN member countries. 2006. [32] FDA. Draft guidance for industry: dietary supplements: new dietary ingredient notifications and related issues. 2011. Retrieved from: http://www.fda.gov/food/guidancecomplianceregulatoryinformation/guidancedocuments/dietarysupplements/ucm257563.htm. [33] FDA. New dietary ingredients in dietary supplements–background for industry. 2012. Retrieved from: http:// www.fda.gov/Food/DietarySupplements/ucm109764.htm. [34] ANVISA. Registration of Products: manual covering procedures for registration and exemption from registration of imported products. 2000. Retrieved from: http://www.anvisa.gov.br/eng/food/registration.htm. [35] TFDA. Food and drug administration, department of health. 2012. Retrieved from: http://www.taiwan.gov. tw/ct.asp?xItem=25613&ctNode=1957&mp=999. [36] TGA. The regulation of complementary medicines in Australia–an overview: pre-market assessment. 2012. Retrieved from: http://www.tga.gov.au/industry/cm-basics-regulation-overview.htm#pre. [37] TGA. Australian guidelines for complementary medicines (ARGCM) Part II: listed complementary medicines. 2011. [38] Health Canada. Natural health products. 2012. Retrieved from: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/ index-eng.php.
Global market entry regulations for nutraceuticals, functional foods, and dietary/food/health supplements
3
Andrew Shao Global Nutrition Solutions, LLC, Los Angeles, CA, United States
3.1 Introduction Policy that underlies regulations for any consumer product should appropriately balance benefit, consumer access, and choice with safety (risk). This principle should apply regardless of the regulatory category, whether a drug, device, food, supplement, or nutraceutical. Requiring a new promising treatment for cancer to be free of any side effects whatsoever may minimize risk to the public, but such a treatment would likely fail to reach the market; thus, it would do consumers little good, if any. In contrast, allowing an untested medical device to be placed on the market that provides little benefit, but poses high safety concerns, allows for open consumer access but does not balance risk appropriately. Starting with market entry, global regulations should aim to strike an appropriate balance between consumer access and risk (safety). For nutraceuticals, functional foods, and supplements, specific market entry requirements depend on the overall regulatory framework employed within a given country. For most countries, these frameworks are based on a food or drug, including an over the counter–based approach. Products that are regulated under a food-like category tend to be subjected to notification or registration-based systems, whereas products regulated under a drug-like category tend to be subjected to a premarket approval system. This chapter compares and contrasts the different approaches used globally and whether these approaches help to achieve the appropriate access– risk balance.
3.2 Market entry requirements For most countries worldwide, conventional and functional foods and supplements (including nutraceuticals) are regulated as a category of food. In some regions or countries, a specific set of regulations governs supplements (e.g., the United States, the European Union [EU], the Association of South East Asian Nations [ASEAN]) and nutraceuticals (India), which stems from a food-based regulatory Nutraceutical and Functional Food Regulations in the United States and around the World. https://doi.org/10.1016/B978-0-12-816467-9.00003-4 Copyright © 2019 Elsevier Inc. All rights reserved.
37
38
Chapter 3 Global market entry regulations
Table 3.1 Global notification or registration for foods/supplements. Country/region
Notification/registration
Argentina Association of South East Asian Nations Australia Brazil Canada Chile China Colombia United States Japan Mexico Russia European Union
Registration Notification or registration Notification/listing Notification Registration Notification Both Registration Notification or none None Notification Registration Notification or none
paradigm. For most of these countries, some form of a notification- or registration-based system (or a combination of both) is required to bring new products to the market (Table 3.1). This approach is in contrast to the premarket approval approach required for drugs in most countries, and appropriately fits the category of foods, because these pose inherently low safety risks relative to drugs. China and Brazil are examples of two large markets that have revised regulations regarding market entry. In the case of Brazil, an entirely new regulatory framework governing supplements and functional foods was published as a series of six consultations in mid-2018.1 Regarding market entry, the Agência Nacional de Vigilância Sanitária (National Sanitary Surveillance Agency, ANVISA), which oversees supplements in Brazil, has exempted food supplements (with the exception of enzymes and probiotics) from the traditional registration process.2 The formal establishment of a legal and regulatory category for supplements in Brazil should have a positive effect on the market for responsible companies and should benefit consumers as well. A notification-based system will allow ANVISA to be aware of products entering the marketplace in Brazil, but it will reduce greatly the resources needed from both the agency and the industry to bring products to the market. Before Brazil, China’s Food and Drug Administration (CFDA) in 2016 relaxed its regulations allowing for the notification of vitamin and mineral-containing health foods (previously subject to burdensome registration requirements).3 Although some viewed this move as insufficiently progressive, this represents a significant step for a market with historically rigid requirements for health foods. The Chinese government has since undergone a substantial reorganization, resulting in the renaming of 1 http://portal.anvisa.gov.br/noticias?p_p_id=101_INSTANCE_FXrpx9qY7FbU&p_p_col_id=column-2&p_p_col_
count=2&_101_INSTANCE_FXrpx9qY7FbU_groupId=219201&_101_INSTANCE_FXrpx9qY7FbU_urlTitle=anvisaquer-regulacao-especifica-para-suplementos-alimentares&_101_INSTANCE_FXrpx9qY7FbU_struts_action=%2Fasset_ publisher%2Fview_content&_101_INSTANCE_FXrpx9qY7FbU_type=content. 2Resolution of the Board of Directors - RDC Nº 243, July 26, 2018. Brazilian Ministry of Health, National Health Surveillance Agency. 3China Food and Drug Administration. Detailed Rules on Health Food Registration Review and Approval Process 2016.
3.2 Market entry requirements
39
agencies and reallocation of resources. This includes the CFDA, which no longer exists. The State Administration for Market Regulation, a new government entity, will oversee health foods. What impact, if any, this government reorganization will have on the health food category in China remains to be seen.
3.2.1 Positive and negative ingredient lists The safety and acceptability of new products in the marketplace starts first with the ingredients. In most regions of the world, the safety and acceptability of excipients used in a given formula are governed via established food additive requirements. In the United States [1] (including Generally Recognized as Safe [GRAS] [2]) and the EU [3] there are well-established food additive regulations, and for countries that lack their own established approaches, many rely on standards set by the Codex Alimentarius [4]. Therefore, when evaluating the entry of new products into the marketplace, most regulators focus attention on the safety and acceptability of the active or driver ingredients. In many countries, regulators rely on established formal positive and/or negative ingredient lists or their derivations to guide evaluations. As their name implies, these lists indicate which ingredients are considered acceptable for use in foods and/or supplements and which are not allowed. Some countries will rely on only a positive list, and others only a negative list; some countries rely on both and some do not rely on a list but employ a broader approach. The basis for how ingredients are added to these lists varies widely around the world, and the formal role the lists have varies as well. An ingredient may be added to a negative (not allowed in foods) list based on well-established safety issues (e.g., a botanical with well-known toxic effects), or an ingredient may be added to the list based on the perception (often ill-conceived) or speculation about adverse effects. Ingredients known to be inherently safe, such as vitamins and minerals, will appear on most positive lists, or owing to their inherent safety, they may not appear on a list at all. Most regulatory agencies keep separate lists for botanicals allowable for use in foods and supplements. New botanicals or other novel ingredients may also be allowed and added to positive lists on a case-by-case basis after their formal evaluation. Whether an ingredient is considered new or novel depends on the specific policies and regulations of the given country or region. In Australia, the Therapeutic Goods Administration (TGA) regulates supplements under a Complementary Medicines category and maintains a positive list of allowable ingredients, including excipients and actives [5]. This list includes vitamins, minerals, and botanicals. China [6] is an example of a country that uses both a positive and negative list. China’s positive list includes ingredients that can be added to foods, drugs, and health foods, as well as a list of banned ingredients. Canada employs a unique monograph system: ingredients that comply with already established monographs have an easier path to market as Natural Health Products (NHPs), whereas those that have not yet been the subject of a monograph must go through a more formal approval process [7]. In the EU, the European Commission published a list of vitamin and mineral ingredients allowable in foods and food supplements [8]. Ingredients that have not been used for human consumption to a significant degree before May, 1997 are considered novel foods, requiring the marketer to apply for authorization [9]. There is an online catalog that uses a traffic light system to highlight whether the ingredient is novel, not novel, or can only be used in food supplements, or whether it is not yet certain [10]. For other physiologic substances, including botanicals, regulations in the EU for acceptable ingredients have not yet been harmonized. As a result, different positive lists have been developed by some individual member states. For example, Italy [11], Denmark [12], and the Czech Republic [13]
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Chapter 3 Global market entry regulations
Table 3.2 Countries/regions employing positive and/or negative ingredient lists. Market/region Argentina Australia Brazil Canada Chile China Colombia Mexico Paraguay Russia United States Uruguay Venezuela European Union Italy Denmark Czech republic Association of South East Asian Nations
Positive list
Negative list
Other
✓ ✓ Monograph system ✓
✓
✓ ✓ Generally Recognized as Safe, new/old dietary ingredients ✓ ✓ ✓ ✓ ✓
✓ Novel food
Restricted list
established their own versions of positive lists of substances that can be added to foods and/or supplements. Russia is an example of a non–member state with a positive list [14]. In the United States, the US Federal Food and Drug Administration (FDA) maintains a list of ingredients that are GRAS for use in foods [2]. In many cases, these ingredients are acceptable for use in dietary supplements as well, although the agency does not maintain a specific positive list of ingredients for supplements. Regarding ingredients not allowed for use in supplements, the FDA has published several rulings [15,16] and/or warning letters [17–19] indicating that certain ingredients are not acceptable for inclusion in dietary supplements or are unsafe for the public [20]. In the United States, the FDA must be notified of New Dietary Ingredients (NDI), whereas “old” dietary ingredients, or grandfathered ingredients (ingredients marketed before Oct., 1994) need not be notified. However, no formal list of grandfathered ingredients exists in the United States. In South America, the situation varies from country to country, with some not relying on a list (e.g., Argentina, Chile, Colombia), others a positive list (e.g., Brazil), and others both (e.g., Venezuela). Brazil updated its positive list to include acceptable forms of vitamins, minerals, and bioactive substances.4 The list excludes botanicals and probiotics. In the ASEAN, the region aims to establish a restricted list of substances allowed in traditional medicines and health supplements [21]. A brief summary of the different types of lists used in different countries or regions is summarized in Table 3.2. 4Normative
Instruction 28/2018. Lists of constituents, limits of use, claims and supplementary labeling of food supplements. July 27, 2018. Brazilian Ministry of Health, National Health Surveillance Agency.
3.2 Market entry requirements
41
3.2.2 Botanicals Botanicals can present unique regulatory, quality, and safety challenges and thus tend to be more restricted in many markets. Lack of understanding on the part of regulators, lack of transparency in the supply chain, and a less robust evidence base relative to vitamins and minerals serve to undermine the confidence of regulators in this category of ingredients. Thus, the appearance of botanical ingredients on positive lists is limited in many countries. In Brazil ANVISA, only water or ethanol-extracted botanicals are allowed in foods, and each product is evaluated on a case-by-case basis [22]. In Mexico, the Federal Commission for the Protection against Sanitary Risk maintains a positive and negative list for botanicals allowed in foods [23]. The agency proposed adding certain botanical ingredients with a long history of safe use to a negative list, including inulin and aloe [24], based on the belief that these have documented therapeutic uses (and thus are medicines, not acceptable for use in foods). In the EU, the European Food Safety Authority published a botanicals compendium [25] that includes a list of botanicals reported to contain toxic, addictive, psychotropic, or other substances of concern. Although this document does not have official regulatory standing, it could be interpreted as a form of negative list for the EU. However, other EU member states published and continue to update their own positive and negative botanical lists. Italy maintains a list of permitted botanicals with related health benefits [26] and one of nonpermitted botanicals [26]. Belgium has one list including permitted and nonpermitted botanicals and mushrooms with related maximum allowable levels for some botanicals [27]. Germany maintains a list that has been used by regulators as a guidance document to assess botanicals [28]. In these countries, whether a botanical appears on a positive or negative list for foods depends largely on whether it is perceived as medicinal. A plant may be judged medicinal if scientific data show an influence on physiological functions. When applicable, an assessment of the minimum dosage for such activity is determined. Therefore, traditional use has become an important resource for determining whether certain plants, plant parts, and preparations may be added to positive lists. One challenge that has arisen is the lack of consensus on what constitutes traditional use. Individually, experts seem to agree on its meaning, but this has not been codified in a globally recognized resource. Criteria that could be considered include widespread use (e.g., by large or multiple populations), long duration of use (e.g., over generations), and documented (e.g., in compendia) conditions of use (e.g., plant, plant part, preparation, dosage, indication, etc.). These are all aspects that would support a safe and efficacious history of use, which is the basis of many positive lists. Another check is whether the ingredient is novel, in which case the EU novel food catalog is consulted as a reference. Finally, the botanical may be checked against conformity with other approvals (e.g., additives) and whether the product would be considered as safe. If formal lists are to be in place, the preference should be for a negative list (i.e., limiting ingredients that are not allowed), which tends to be much shorter and easier to maintain and allows consumers access to a greater variety of products. If allowable ingredients are restricted to a positive list, this would limit the industry’s ability to bring novel products to market. Because of the inherent safety of most food and supplement ingredients, a negative list most appropriately balances consumer access with risk.
3.2.3 Notification versus registration Although there are some differences among countries, a notification-based system usually represents a means of informing the regulatory authorities of a product’s introduction to the marketplace or the intent to introduce a new product. Notifications tend to be composed of information about the manufacturer, product form, formulation, and label; these tend to be subjected to minimal review by regulators.
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Product ingredients must be derived from a positive list (if one exists), and the entry of the product into the marketplace does not signify or constitute an approval or authorization from regulators, but they have the authority to question or object to a notification. The notification results in the addition of the new product to a list that regulators maintain for enforcement purposes. The notification approach tends to be most efficient for getting new products to the market, for both industry and regulators, because minimal premarket resources are necessary. This approach also allows regulators to focus resources on enforcing critical postmarket activities, such as good manufacturing practices, and collecting, handling, and reporting adverse events. Notification is thus a proportionate approach to the low level of risk posed by these categories of food products. Registration-based approaches differ from notification-based ones in that they require more detailed information in the form of a registration dossier, intense review by regulators, and a lengthier and more resource intensive review process. A typical registration dossier requires much more detailed information than is found in a notification, including details about the specifications of the finished product, evidence supporting the safety and efficacy of the ingredients, a certificate of analysis, stability testing (to support shelf-life dating), the product label, a certificate of free sale, and a good manufacturing practice (GMP) certification or compliance statement. Although this approach allows regulators to scrutinize new products closely, in most countries that require registration, it is a slow and extremely resource-intensive process ranging from months to years. Lengthy registration time tends to result from a lack of resources and expertise, along with the obligation of regulators to approve or authorize product dossiers. A drawback of this approach is the length of time to market for products regardless of the risk they may pose, and even fewer resources for enforcement in other, potentially more critical areas. A comparison of notification versus registration appears in Table 3.3. Table 3.3 Notification versus registration submissions for foods, supplements, and nutraceuticals. Ingredients in accordance with applicable positive and negative lists Applicable good manufacturing practices Label according to regulation Detailed product specifications Certificate of analysis Claim substantiationa Shelf-life substantiation Certificate of free sale Implications Helps authority to process high volume of products Immediate access to market N/A, not applicable. aIn countries where claims are allowed.
Notification
Registration
Required
Required
Manufacturer expected to adhere to
Official certification or statement required with dossier Required Required Required Required Required
Required N/A N/A Manufacturer expected to have on file N/A or manufacturer expected to have on file N/A Surveillance and control regime Requires high government resources Slow access to market
Required Reduces postsurveillance and control regime
3.2 Market entry requirements
43
Table 3.4 Current health supplement market entry requirements for various Association of South East Asian Nations member countries. Premarketing registration Time line for evaluation <2 months 2–3 months 6 months 6–12 months
Brunei
Cambodia
Indonesia
Malaysia
Philippines
Singapore
Thailand
Vietnam
No
Yes
Yes
Yes
Yes
No
Yes
Yes
✓ ✓
✓ ✓
✓ ✓
The EU is an example of a region that uses the notification approach [29]. Although specific requirements differ among countries, of the 27 member states, 23 have opted to incorporate a notificationbased approach for new product entry. Austria, Holland, Sweden, and the United Kingdom are among those for which notification for new products is optional. In the ASEAN, the 10-member country region is in the process of finalizing harmonized regulations for traditional medicines and health supplements [30]. Currently, both registration and notificationbased procedures are used, depending on the country (Table 3.4). As with other regions, the specific requirements in each country vary [31]. For market entry of health supplements, the region will require a comprehensive product dossier as part of a registration-based process, with the emphasis on quality, safety, and efficacy. The United States represents a unique situation in which no product notification is required unless the product contains NDI [32]. If a new product does not contain NDI, no notification is required. If a new product contains NDI, notification to the FDA is required 75 days before the product enters the market. The basis of the notification is substantiation that the manufacturer or marketer believes the NDI are safe in the product under its intended conditions of use [33]. In Latin America, market entry requirements for foods and supplements vary. Notification-based approaches are employed in Mexico and Chile, whereas registration-based approaches are followed in Colombia, Brazil, and Argentina. In countries such as Brazil (ANVISA [34]), China (China State Food and Drug Administration [6]), and Taiwan (Taiwan Food and Drug Administration [35]), regulators require animal and/or human clinical studies for product registration for some, but not all, products. This requirement tends to be limited to products for which efficacy claims are intended. In Australia and Canada, supplements and nutraceuticals are regulated more closely to a drug than food category. The TGA in Australia regulates supplements under a Complementary Medicines category [36]. Premarket approval requirements for this category are comparable to registration requirements for foods and supplements in other countries [37], although other requirements such as GMPs tend to be more drug-like than food-like. In Canada, Health Canada (HC) regulates supplements under an NHP category [38]. Because of the allowance of medicinal or therapeutic claims for NHPs, HC takes a more rigorous approach to new product entry. The licensing process in Canada for NHPs is riskbased, with products posing the highest risk requiring the greatest premarket review by the agency.
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Although a variety of individual systems exists in various countries and regions worldwide, the approach to bringing new foods, supplements, or nutraceutical products to the market has begun to converge toward notification-based systems. The notification-based approach most optimally balances premarket resources, consumer access, and consumer safety. However, a key aspect to ensuring product safety and quality in the marketplace, regardless of premarket requirements, is robust postmarket surveillance.
References [1] FDA. Food additives. 2012. Retrieved from: http://www.fda.gov/Food/FoodIngredientsPackaging/ FoodAdditives/default.htm. [2] FDA. Generally recognized as safe (GRAS). 2012. Retrieved from: http://www.fda.gov/Food/ FoodIngredientsPackaging/GenerallyRecognizedasSafeGRAS/default.htm. [3] European Commission. Food additives and flavourings. January 15, 2013. Retrieved from: http://ec.europa. eu/food/fs/sfp/flav_index_en.html. [4] JECFA. About Codex. Codex Alimentarius. 2013. Retrieved from: http://www.codexalimentarius.org/ scientific-basis-for-codex/jecfa/en/. [5] Therapeutic Goods Administration. Substances that may be used in Listed medicines in Australia. 2007. Retrieved from: http://www.tga.gov.au/pdf/cm-listed-substances.pdf. [6] SFDA. Regulations on supervision of functional foods (draft for approval). 2009. Retrieved from: January 15, 2013. [7] Natural Health Products Directorate. Compendium of monographs. Drugs and health products. 2009. Retrieved from: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/index-eng.php. [8] European Commission. Commission Regulation (EC) No 1170/2009 of 30 November 2009 amending Directive 2002/46/EC of the European Parliament and of Council and Regulation (EC) No 1925/2006 of the European Parliament and of the Council as regards the lists of vitamin and minerals and their forms that can be added to foods, including food supplements. Off J Eur Union 2009. L314/36. [9] European Commission. Novel foods and novel food ingredients. Food and Feed Safety 2012. Retrieved from: http://ec.europa.eu/food/food/biotechnology/novelfood/index_en.htm. [10] European Commission. Novel Food catalogue–Search. Food and Feed Safety January 15, 2013. Retrieved from: http://ec.europa.eu/food/food/biotechnology/novelfood/nfnetweb/mod_search/index.cfm. [11] della Salute M. Altri nutrienti e altre sostanze ad effetto nutritivo o fisiologico. January 15, 2013. Retrieved from: http://www.salute.gov.it/imgs/C_17_pagineAree_1268_listaFile_itemName_4_file.pdf. [12] Ministerialtidende. Bekendtgørelse om tilsætning af visse andre stoffer end vitaminer og mineraler til fødevarer. 2012. Retrieved from: https://www.retsinformation.dk/Forms/R0710.aspx?id=137299. [13] Sbírka Zákonů. Kterou se stanoví požadavky na doplňky stravy a na obohacování potravin. 2008. [14] Customs Union Commission. Uniform sanitary and epidemiological and hygienic requirements for products subject to sanitary and epidemiological supervision (control). 2010. [15] FDA. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Fed Regist 2004;69(28):6788–854. [16] CFSAN, FDA. CFSAN office of food additive safety. FDA response to OVOS natural health homotaurine petition. Washington, DC: Department of Health and Human Services; 2011. [17] FDA. FDA advises dietary supplement manufacturers to remove comfrey products from the market. 2001. [18] FDA. February 28, 2003 warning letter to powerhouse supplements. 2003. [19] FDA. Letter to Health Professionals regarding safety concerns related to the use of botanical products containing aristolochic acid. 2001.
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[20] FDA. Consumer advisory: kava-containing dietary supplements may be associated with severe liver injury. 2002. [21] ASEAN. Guiding principles for inclusion of active substances into the restricted list for traditional medicines and health supplements. TMHS; 2010. [22] ANVISA. Novos ingredientes aprovados. 2009. Retrieved from: http://portal.anvisa.gov.br/wps/content/ Anvisa+Portal/Anvisa/Inicio/Alimentos/Assuntos+de+Interesse/Novos+Alimentos+e+Novos+Ingredientes/ 29bd7700401adec6b403b654e035b7cb. [23] COFEPRIS. What is the COFEPRIS?. 2011. Retrieved from: http://www.cofepris.gob.mx/Paginas/Idiomas/ Ingles.aspx. [24] Asociacion Nacional de la Industria de los Suplementos Alimenticios. ANAISA noticias. 2013. Retrieved from: http://www.anaisa.mx/. [25] European Food Safety Authority. Compendium of botanicals reported to contain naturally occurring substances of possible concern for human health when used in food and food supplements. EFSA J 2012;10. [26] della Salute M. Disciplina dell’impiego negli integratori alimentari di sostanze e preparati vegetali (G.U. 21-7-2012 serie generale n. 169). 2012. [27] Belgian Health. F. C. S. E. Food supplements – enriched foodstuffs. 2012. Retrieved from: http://www. health.belgium.be/eportal/foodsafety/foodstuffs/foodsupplements/index.htm?fodnlang=en#Plants. [28] The Federal Office of Consumer Protection and Food Safety (BVL). Entwurf einer Liste für die Kategorie “Pflanzen und Pflanzenteile”. 2010. Retrieved from: http://www.bvl.bund.de/SharedDocs/Downloads/01_ Lebensmittel/stoffliste/stoffliste_pflanzen_pflanzenteile.html?nn=1406620. [29] European Commission. Directive 2002/46/EC of the european parliament and of the council. 2002. [30] ASEAN. Harmonization of standards and technical requirements in ASEAN. 2012. Retrieved from: http:// www.asean.org/news/item/harmonization-of-standards-and-technical-requirements-in-asean. [31] ASEAN. Profile of definition, terminology, and technical requirement of traditional medicines and health supplements among ASEAN member countries. 2006. [32] FDA. Draft guidance for industry: dietary supplements: new dietary ingredient notifications and related issues. 2011. Retrieved from: http://www.fda.gov/food/guidancecomplianceregulatoryinformation/guidancedocuments/dietarysupplements/ucm257563.htm. [33] FDA. New dietary ingredients in dietary supplements–background for industry. 2012. Retrieved from: http:// www.fda.gov/Food/DietarySupplements/ucm109764.htm. [34] ANVISA. Registration of Products: manual covering procedures for registration and exemption from registration of imported products. 2000. Retrieved from: http://www.anvisa.gov.br/eng/food/registration.htm. [35] TFDA. Food and drug administration, department of health. 2012. Retrieved from: http://www.taiwan.gov. tw/ct.asp?xItem=25613&ctNode=1957&mp=999. [36] TGA. The regulation of complementary medicines in Australia–an overview: pre-market assessment. 2012. Retrieved from: http://www.tga.gov.au/industry/cm-basics-regulation-overview.htm#pre. [37] TGA. Australian guidelines for complementary medicines (ARGCM) Part II: listed complementary medicines. 2011. [38] Health Canada. Natural health products. 2012. Retrieved from: http://www.hc-sc.gc.ca/dhp-mps/prodnatur/ index-eng.php.