Regulation of dietary supplements and functional foods in Canada

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Regulation of dietary supplements and functional foods in Canada

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Jon-Paul Powers, Matthew Farrell, Colleen McMullin, Lewis Retik, Jessica White Gowling WLG (Canada) LLP, Ottawa, ON, Canada

17.1 Introduction Products typically regarded as functional foods, dietary supplements, and complementary medicines within jurisdictions around the world fall into one of three main regulatory categories in Canada: cosmetics, as regulated by the Cosmetic Regulations [1]; and foods and/or drugs, as regulated by the Food and Drug Regulations [2]. These main regulatory categories are further divided into subcategories which include conventional foods, infant formulas, foods for special dietary use, meal replacements and nutritional supplements, and supplemented foods on the food side, as well as natural health products (NHPs) and over-­the-­counter (OTC) and prescription drugs on the drug side. The entire Canadian regulatory framework for dietary supplements and functional foods is expansive. A discussion of the regulatory parameters affecting cosmetics, specific food categories (e.g., meal replacements), OTC and prescription drugs, as well as products intended for animal use (veterinary drugs and veterinary health products) is beyond the scope of this chapter. For practical reasons, this chapter will focus on the Canadian regulation of foods, supplemented foods, and NHPs because these regulatory categories capture most products typically regarded as dietary supplements and functional foods intended for human use throughout the world. The classification of a product as a food, supplemented food, or NHP depends on a variety of factors including, but not limited to, product composition and format, product representation (including health claims), consumer perception, place of sale, and history of use. For a variety of products, particularly those at the periphery of the classification spectrum, categorization is clear. For example, pharmaceutical-­type formats such as tablets and capsules, are consistently viewed as NHPs whereas formats such as bars and yogurts are consistently viewed as foods. For products in the middle of the spectrum, categorization is sometimes ambiguous because classification criteria do not depend entirely on format. Products falling into this gray area commonly include powdered beverage mixes, ready-­to-­drink liquid beverages, gummies, and gums, all of which could exist in any of the regulatory categories described previously. We will discuss the associated regulatory implications of each category separately.

Nutraceutical and Functional Food Regulations in the United States and around the World. https://doi.org/10.1016/B978-­0-­12-­816467-­9.00017-­4 Copyright © 2019 Elsevier Inc. All rights reserved.

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17.2 Foods The Canadian government defines a food as any item that is made, sold, or represented as a food, drink, or chewing gum, or any ingredient that can be mixed with food [3]. This broad definition encompasses a range of products. Common examples include whole fruits and vegetables, pasta, coffee beans, approved food additives, prepackaged water, and alcoholic beverages [2]. Food sale in Canada is primarily governed by the Food and Drugs Act [3] and the Food and Drug Regulations [2], which are established by Health Canada’s Food Directorate and the Canadian Food Inspection Agency (CFIA). In addition, the Safe Food for Canadians Act [4] and Safe Food for Canadians Regulations [5] reinforce various aspects of the Food and Drugs Act [3] and Food and Drug Regulations [2] and contain measures designed to improve food traceability, establish licensing and preventative control plan requirements, and provide the CFIA with powers to address noncompliance and unsafe food practices. In addition to basic requirements for safety and quality, the Food and Drugs Act contains the following requirements pertaining to health claims and advertising, which are relevant to this chapter because they relate to functional foods [3]:   1. they may not be labeled, sold, or advertised as a treatment, prevention, or cure for a disease, disorder, or abnormal physical state; and 2. they may not be labeled, packaged, treated, processed, sold, or advertised in a way that is false, misleading, or deceptive.   With the exception of novel foods (foods produced through new processes, which do not have a history of safe use as a food, or which have been modified by genetic manipulation), new food additives, and foods making certain health claims, most foods in Canada do not require premarket approval. Thus, most food products rely on surveillance of the Canadian marketplace to identify products that contravene the Food and Drug Regulations and the Food and Drugs Act. This surveillance, and associated compliance and enforcement activities, are the responsibility of the CFIA. Because there is no premarket approval process, it is the responsibility of the marketer to ensure compliance with the Food and Drug Regulations and Food and Drugs Act and that products are safe and meet the appropriate standards (where a standard is defined).

17.2.1 Food health claims As discussed, it is the responsibility of the industry to ensure that food is marketed in a manner that is neither false nor misleading. With this in mind, marketers must ensure that all health claims on foods are stringently reviewed to ensure they are neither false nor misleading and are supported by adequate and proper substantiation. The CFIA has published guidance with respect to the variety of claims that may be made on foods and the conditions that must be met to support these claims [6]. Although a discussion of the various conditions is beyond the scope of this chapter, owing to the complexity of the variety of food types, we will highlight the approved claims because they are likely interesting to parties that market dietary supplements and functional foods. The approved claims may be categorized as disease risk reduction claims and function claims (which include probiotic claims). These health claims serve to inform consumers about beneficial health qualities provided by a specific food product.

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17.2.2 Disease risk reduction and therapeutic claims Disease risk reduction claims are statements that relate a food or food constituent to the reduced occurrence of a diet-­originating health condition. The CFIA has established a list of acceptable disease risk reduction and therapeutic claims [7]. Claims of this nature are also permitted for Schedule A conditions (Table 17.5); however, these claims need to undergo a premarket assessment by the Food Directorate of Health Canada because a regulatory amendment is required to allow their use. Because disease risk reduction claims generally speak to the diet as a whole, rather than supplementation, a discussion of these claims is not warranted as part of this chapter. For more information, CFIA guidance may be consulted [7].

17.2.3 Function claims Function claims speak to direct beneficial effects resulting from ingesting a food product or constituent. Acceptable function claims are those that state a specific scientifically supported, physiological effect associated with good health or performance. The CFIA has established a list of acceptable function claims which are included here as Table 17.1 [8]. Function claims are not made for the food itself but rather for the specific component of the food that supports the function. For example, a food cannot state “Product A contributes to normal muscle function.” An acceptable claim would be structured as: “Product A contains magnesium, which contributes to normal muscle function”.

17.2.4 Probiotic claims Species-­specific probiotic claims are accepted for use in foods provided that a serving of a stated size of the food product contains a minimum level of 1 billion colony-­forming units of one or more of the eligible microorganisms specified by the CFIA [9]. These claims have been worded as function claims and speak to the premise that the specified species naturally form part of the human gut flora (Table 17.2).

17.2.5 Supplemented foods Under the Food and Drug Regulations, there is a limited set of foods for which fortification with vitamins, minerals nutrients, and amino acids is mandatory or permitted. For example, it is mandatory to fortify flour with thiamine, riboflavin, niacin, folic acid, and iron. Similarly, milk must be fortified with vitamin D. Breakfast cereals are permitted to be fortified with thiamine, niacin, vitamin B6, folic acid, pantothenic acid, magnesium, iron, and zinc. Unless a food is included in the specific table found in Section D.03.002 of the Food and Drug Regulations [2], there is a general prohibition against adding vitamins, mineral nutrients, or amino acids to any foods sold in Canada. The fortification rules better align with the eating habits of Canadians during the final decades of the 20th century, because that was when the bulk of the fortifications rules were drafted. With the diversification of food choices, a rise in plant-­based eating, as well as many dietary intolerances, there has been a growing push to expand available options for consumers to obtain fortified foods. Similarly, with innovations in food science and an increasingly globalized world, the industry has advocated for regulatory change to permit the introduction of new fortified products into the Canadian market.

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Table 17.1  Function claims for food products. Food or food constituent

Acceptable claima

Coarse wheat bran Psyllium Green tea (unfermented leaves and/or bud from Camellia sinensis) Protein

Various regularity and laxation claims Various regularity and laxation claims Various antioxidant claims

Fat DHA ARA Carbohydrates Vitamin A

Vitamin D

Vitamin E Vitamin C

Thiamine (Vitamin B1) Riboflavin (Vitamin B2) Niacin

Helps build and repair body tissues Helps build antibodies Helps build strong muscles Supplies energy Aids in absorption of fat-­soluble vitamins DHA, an ω-­3 fatty acid, supports normal physical development of brain, eyes, and nerves primarily in children aged under 2 years ARA, an ω-­6 fatty acid, supports normal physical development of brain, eyes, and nerves primarily in children aged under 2 years Supplies energy Assists in use of fats Aids normal bone and tooth development Aids in development and maintenance of night vision Aids in maintaining health of skin and membranes Contributes to normal function of immune system Contributes to maintenance of normal vision Helps build strong bones and teeth Supports night vision Supports healthy skin Factor in formation and maintenance of bones and teeth Enhances calcium and phosphorus absorption and use Helps build strong bones and teeth Builds and maintains strong bones and teeth Improves calcium absorption Improves calcium and phosphorus absorption A dietary antioxidant A dietary antioxidant that protects fat in body tissues from oxidation Factor in development and maintenance of bones, cartilage, teeth, and gums Dietary antioxidant Dietary antioxidant that significantly decreases adverse effects of free radicals on normal physiological functions Dietary antioxidant that helps to reduce free radicals and lipid oxidation in body tissues Factor in energy metabolism Helps build teeth, bones, cartilage, and gums Protects against free radicals Protects against damage of free radicals Protects against oxidative effects of free radicals Releases energy from carbohydrates Aids normal growth Factor in energy metabolism and tissue formation Aids in normal growth and development Factor in energy metabolism and tissue formation

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Table 17.1  Function claims for food products.—cont’d Food or food constituent

Acceptable claima

Vitamin B6 Folacin or folate

Factor in energy metabolism and tissue formation Aids in red blood cell formation Factor in normal early fetal development Factor in normal early development of fetal brain and spinal cord Contributes to normal amino acid synthesis Aids in red blood cell formation Factor in energy metabolism Factor in energy metabolism Contributes to maintenance of bones Factor in energy metabolism and tissue formation Aids in formation and maintenance of bones and teeth Factor in energy metabolism Factor in formation and maintenance of bones and teeth Contributes to normal muscle function Factor in energy metabolism, tissue formation, and bone development Factor in red blood cell formation Helps build red blood cells Contributes to maintenance of normal skin Contributes to normal function of immune system Factor in energy metabolism and tissue formation Factor in normal function of thyroid gland Dietary antioxidant involved in formation of protein that defends against oxidative stress Dietary antioxidant Helps protect against oxidative stress Contributes to normal glucose metabolism Contributes to maintenance of normal connective tissue Contributes to formation and maintenance of bones Factor in energy metabolism

Vitamin B12 Biotin Vitamin K Pantothenic acid Calcium Phosphorus Magnesium Iron Zinc

Iodine Selenium

Chromium Copper Manganese

ARA, arachidonic acid; DHA, docosahexaenoic acid. aRefer to source links for associated conditions for use requirements. Source: Canadian Food Inspection Agency (2019). Adapted with the permission of the Canadian Food Inspection Agency [2019].   

To address these changing demands, Health Canada has permitted certain fortified foods to access the Canadian market through the use of Temporary Marketing Authorization Letters (“TMALs”). A TMAL is essentially a letter of permission from Health Canada’s Food Directorate to sell a food that does not comply with the requirements of the Food and Drug Regulations. Health Canada describes these products as supplemented foods. Health Canada broadly defines a supplemented food as “a prepackaged product that is manufactured, sold, or represented as a food, which contains added vitamins, minerals, amino acids, herbal, or bioactive ingredients. These ingredients may perform a physiological role beyond the provision of nutritive requirements” [10]. Although the definition of supplemented foods is sufficiently broad to include foods that are fortified in accordance with the Food and Drug Regulations, for the purposes of this chapter, any reference to supplemented foods will refer only to foods that do not meet the requirements of the Food and Drug Regulations.

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Table 17.2  Acceptable non–strain specific claims for probiotics in food products. Eligible bacterial species Latin name (acceptable nomenclature) and synonym where applicable Bifidobacterium adolescentis Bifidobacterium animalis subsp. Animalis B. animalis subsp. lactis (synonym: B. lactis) Bifidobacterium bifidum Bifidobacterium breve B. longum subsp. infantis Bifidobacterium longum subsp. longum Lactobacillus acidophilus Lactobacillus casei Lactobacillus fermentum Lactobacillus gasseri Lactobacillus johnsonii Lactobacillus paracasei Lactobacillus plantarum Lactobacillus rhamnosus Lactobacillus salivarius

Acceptable non–strain specific probiotic claims Probiotic that naturally forms part of gut/digestive tract flora Provides live microorganisms that naturally form part of gut/digestive tract flora Probiotic that contributes to healthy gut/digestive tract flora Provides live microorganisms that contribute to healthy gut/digestive tract flora

Source: Canadian Food Inspection Agency (2019). Adapted with the permission of the Canadian Food Inspection Agency [2019].   

To obtain a TMAL, manufacturers or distributors must submit a Temporary Marketing Authorization Application (TMAA) to the Food Directorate. The TMAA requires full disclosure of the product’s formula, information regarding the proposed quantity of food to be sold, information regarding the proposed claims, specific variations required from the Food and Drug Regulations, as well as adequate safety data. To assist the industry with preparing TMAAs, Health Canada released a general guidance document on TMALs [11], a guidance document for caffeinated energy drinks [12] and a guidance document for other supplemented foods [10]. If a TMAA is approved, Health Canada issues a TMAL, which consists of a letter of agreement (setting out conditions of the grant) and an appendix listing ingredients relevant to the TMAL. The TMAL is generally granted with the condition of a number of items. This may include the mandatory addition of cautionary statements to the product’s labeling, a commitment that the holder of the TMAL will collect information regarding sales data, demographics of users (if available), and marketing activities (if available), with this information submitted to Health Canada annually. Depending on the nature of the product, the TMAL may even be premised on an obligation to collect data on consumption incidents in Canada, and to submit consumption incident reports to Health Canada annually, or an obligation to conduct market studies (with a protocol having a content and methodology satisfactory to Health Canada). For smaller industry players, the latter requirement can generally be achieved through the use of trade groups, provided the food fits within a product category for which an applicable trade group exists. As is evident by the name of the grant itself, a TMAL is a temporary measure generally offered for 5 years. Health Canada has indicated that the long-­term plan is to facilitate market access for supplemented foods under the same regulatory system that applies to most other categories of food [10]. The purpose of TMALs is to allow supplemented foods to be sold temporarily while information is gathered to address gaps in knowledge needed to develop amendments to modernize the food regulatory framework.

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There are many limitations and difficulties with the TMAL process. Unfortunately for the industry, it has not offered a seamless way to introduce products formulated for other markets into Canada. There are two major regulatory hurdles that a TMAL cannot overcome. First, a product containing food additives that are not used in compliance with Health Canada’s Lists of Permitted Food Additives [13] cannot obtain a TMAL. Supplemented foods must be fully compliant with the Lists of Permitted Food Additives before the Food Directorate will issue a TMAL. If the lists do not allow for a particular use of a food additive, the food containing the additive may not be sold. To highlight this point, at the time of writing, because monk fruit extract is permitted only in tabletop sweeteners in Canada, monk fruit extract cannot be used in a supplemented food that is, for example, a carbonated beverage. Manufacturers wishing to use an unapproved additive, or an approved additive for an unapproved use or at an unapproved level of use, must first file a food additive submission in accordance with Section B.16.002 of the Food and Drug Regulations [2]. The second major limitation of a TMAL is that with limited exceptions (detailed subsequently), it cannot be used to sell a supplemented food that contains novel food ingredients. Health Canada’s position is that all novel foods must go through the mandatory premarket assessment process set out in Division 28 of the Food and Drug Regulations before it is authorized for sale in Canada [2]. A novel food assessment requires applicants to submit detailed scientific data for review by Health Canada’s Food Directorate [14]. In the category Specific Guidance for Temporary Marketing Authorization: Supplemented Food [10], Health Canada makes some allowances for certain novel food ingredients for which Health Canada’s Food Directorate has conducted a hazard screen. With respect to these exempted novel food ingredients, Health Canada determined that there is no immediate risk or that product labeling can provide sufficient risk information for products that cannot be consumed safely ad libitum by the general population. As such, Health Canada decided to regulate these exempted novel food ingredients on an interim basis. For the period of a TMAL, Health Canada allows them to be eligible for exemption from the novel food requirements (Division 28) of the Food and Drug Regulations [2]. The list of ingredients that are eligible is included in Appendix 2 of the Supplemented Food Guidance [10]. The list includes, but is not limited to, green tea extract, Panax ginseng, quercetin, and glucosamine sulfate. This list is not duplicated in this chapter because it is our understanding that it will be modified over time. To be eligible for this exemption, the ingredient must not be included in the product for a conventional food purpose, specifically, nutrition, hydration, flavor, or a technical effect (i.e., a food additive) in the food. Including an ingredient in Appendix 2 does not mean that it is a blanket authorization for its inclusion in a supplemented food. Health Canada will still assess these ingredients for safety on a case-­by-­ case basis. Furthermore, it is Health Canada’s official policy that including these ingredients precludes a TMAA from being reviewed within the regular performance targets. As such, these ingredients should still be viewed with caution. Although the TMAL option was initially regarded as presenting exciting new opportunities for food manufacturers, the reality has proven to be largely disappointing. The Food Directorate’s review process is extremely onerous. As more and more food manufacturers are submitting applications, delays continue to grow. Furthermore, the Food Directorate’s questioning is not related solely to ingredients for which an exemption is requested from the Food and Drug Regulations. Manufacturers wishing to pursue this route should expect detailed questions about even traditional food ingredients for which no exemption is required. Moreover, because the Food Directorate’s review entails the submission passing through

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many different bureaus, the process can be “death by 1000 cuts” in that similar questions can be posed about the same ingredient multiple times, sometimes even months apart. When products are not sold in an obvious food format (such as is the case with teas and powders), it is generally advisable to position the product as an NHP. The regulation of this product category is detailed in the next section.

17.2.6 Natural health products (NHPs) While some products commonly regarded as dietary supplements and functional foods in other jurisdictions fall into the food category, the vast majority are regulated as NHPs in Canada. NHPs are categorized as a subset of drugs and are regulated by Health Canada in accordance with the Natural Health Products Regulations (“NHP Regulations”) [5], which came into force on January 1, 2004, and are promulgated under the Food and Drugs Act [3]. An NHP is defined as a substance, or combination of substances that are manufactured, sold or represented for use in Ref. [5]:   1. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans; 2. restoring or correcting organic functions in humans; or 3. modifying organic functions in humans, such as modifying those functions in a manner that maintains or promotes health.   In addition to the above definition of an NHP, Schedule one of the NHP Regulations provides additional criteria outlining the substances that may be included in an NHP (Table 17.3): For completeness, Schedule 2 of the NHP Regulations provides additional criteria outlining substances that may not be included in an NHP (Table 17.4).

17.2.7 Premarket approval process To sell or import an NHP legally, a product license must be issued by Health Canada. To obtain a product license, referred to as a Natural Product Number, applicants must submit a product license application to Health Canada’s Natural and Nonprescription Health Products Directorate (NNHPD). This application consists of a variety of evidentiary documents intended to support the safety, efficacy (health claims), and quality of the product. In contrast to other jurisdictions, all NHPs must have an associated health claim (i.e., one cannot justify a lack of demonstrable efficacy by stating that the product does not make a health claim). Although a health claim is required for each NHP, there are a number of diseases, disorders, or abnormal physical states for which NHPs (or any food, drug, cosmetic, or device) may not make claims with respect to the treatment, prevention, or cure for the general public. These conditions are specified in Schedule A of the Food and Drugs Act and are included here for clarity (Table 17.5). It is permissible to make claims pertaining to the treatment, prevention, or cure of symptoms pertaining to these conditions, provided acceptable evidence exists. Because NHPs are classified as a subset of drugs, their composition is further distinguished as medicinal or, when present, nonmedicinal ingredients. Medicinal ingredients are components of a formula that contribute to the efficacy of the product and are subject to more stringent requirements than their nonmedicinal counterparts. For application purposes, medicinal ingredients must be identified by their proper name, common name, quantity per dosage unit (e.g., milligrams per capsule), potency (e.g., extract ratio and/or standardized component), source material, and an indication of whether the

Table 17.3  Included natural health product substances. Item

Substances

1 2

A plant or a plant material, an alga, a bacterium, a fungus, or a nonhuman animal material An extract or isolate of a substance described in Item 1, the primary molecular structure of which is identical to that which it had before its extraction or isolation Any of the following vitamins: Biotin Folate Niacin Pantothenic acid Riboflavin Thiamine Vitamin A Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin E Vitamin K1 Vitamin K2 An amino acid An essential fatty acid A synthetic duplicate of a substance described in any of Items 2–5 A mineral A probiotic

3

4 5 6 7 8

Source: © All rights reserved. Natural Health Products Regulations. Health Canada. Adapted and reproduced with permission from the Minister of Health, 2019.   

Table 17.4  Excluded natural health product substances. Item

Substances

1 2

A substance set out in Schedule C to the Food and Drugs Act (i.e., radiopharmaceuticals) A substance set out in Schedule D to the Food and Drugs Act (i.e., biologics), except for: (1) A drug that is prepared from any of the following microorganisms, namely, an alga, a bacterium, or a fungus; and (2) any substance set out on Schedule D when it is prepared in accordance with the practices of homeopathic pharmacy A substance set out in any of Schedules I–V of the Controlled Drugs and Substances Act A substance that is administered by puncturing the dermis An antibiotic prepared from an alga, a bacterium, or a fungus or a synthetic duplicate of that antibiotic Cannabis as defined in Subsection 2(1) of the Cannabis Act, except for a derivative or a product made from a derivative that is exempt from application of the Cannabis Act under the Industrial Hemp Regulations and that does not contain an isolated or concentrated phytocannabinoid or a synthetic duplicate of that phytocannabinoid Anything referred to in Schedule 2 to the Cannabis Act that contains more than 10 μg/g tetrahydrocannabinol, an isolated or concentrated phytocannabinoid, or a synthetic duplicate of that phytocannabinoid

3 4 5 6

7

Source: © All rights reserved. Natural Health Products Regulations. Health Canada. Adapted and reproduced with permission from the Minister of Health, 2019.   

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Table 17.5  Diseases, disorders, or abnormal physical states for which advertisements to the general public regarding treatment, prevention, or cure may not be made. Disease, disorder, or abnormal physical state Acute alcoholism Acute anxiety state Acute infectious respiratory syndromes Acute, inflammatory, and debilitating arthritis Acute psychotic conditions Addiction (except nicotine addiction) Appendicitis Arteriosclerosis Asthma Cancer Congestive heart failure Convulsions Dementia Depression Diabetes Gangrene Glaucoma Hematologic bleeding disorders Hepatitis Hypertension Nausea and vomiting of pregnancy Obesity Rheumatic fever Septicemia Sexually transmitted diseases Strangulated hernia Thrombotic and embolic disorders Thyroid disease Ulcer of gastrointestinal tract Source: © All rights reserved. Food and Drugs Act. Health Canada. Adapted and reproduced with permission from the Minister of Health, 2019.   

ingredient is naturally or synthetically produced. Although it may seem counterintuitive that synthetic ingredients may be present in a natural health product, as per Item 6 of Table 17.3, synthetic duplicates of naturally occurring substances are permitted. With these requirements in mind, a typical medicinal ingredient representation would be, using green tea extract as an example: 100 mg green tea 10:1 extract (Camelia sinensis leaf) standardized to 50% polyphenols. Nonmedicinal ingredients are ingredients added to a formula to aid in manufacturing or to serve a nonactive role in the finished product. Examples include magnesium stearate, which acts as a flow agent, or hypromellose or gelatin, which may form a capsule shell. As per NNHPD guidance, nonmedicinal ingredients should be safe; should not exhibit pharmacological effects or adversely affect the bioavailability, pharmacological activity, or safety of the medicinal ingredients; should not have a contradictory effect to the product’s recommended purpose; and should be used at the minimum concentration required for the formulation. For ease of application, the NNHPD maintains the Natural Health

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Products Ingredients Database, which, among other things, contains common nonmedicinal ingredients and associated purposes [16]. When preparing a product license application, applicants must provide a qualitative list of nonmedicinal ingredients within the product and indicate the purpose of each according to the database. In situations where required information is not present within this database, applicants may request revisions to the database itself. Upon receipt of a product license application, the NNHPD triages the package and assigns it to one of three possible assessment streams, the classification of which is based on the type of evidence contained in the application. These assessment streams dictate the nature and duration of the assessment itself, as specified subsequently.

17.2.8 Class I application With respect to both safety and efficacy, Health Canada developed a number of monographs [17] that applicants may reference in support of product licensing. These monographs contain detailed information on permissible health claims, doses, dosage forms, subpopulations, and required use and risk information. Class I applications are those for which the safety and efficacy of the product is fully supported by a single NNHPD monograph. This means that the dose, quantities of ingredients, subpopulations, claims, risk information, duration of use, and directions for use must be entirely consistent with the information specified in the referenced monograph. Class I applications are assessed by the NNHPD for administrative completeness to ensure the application is consistent with the referenced monograph (i.e., there should be no scientific re-­ review of the actual safety and efficacy evidence). At the time of writing, the target assessment time for Class I product license applications is 60 days (increased from the previous 10-­day target time). Class I applications are not issued correspondence from the NNHPD other than a product license or refusal.

17.2.9 Class II application Class II applications are those for which the safety and efficacy of the product are supported by a combination of NNHPD monographs. These applications may also contain medicinal ingredients that are fruits or vegetables as listed in the Canadian Nutrient File [18]. Products that are identical to an existing listed product (provided a letter of access is provided from the license holder), as well as traditional Chinese medicine (TCM) products that match a pharmacopeia formulation, may be included as class II applications. These types of applications are assessed by the NNHPD for administrative completeness, to ensure the application is consistent with the referenced monographs. Class II applications may also be assessed for safety and efficacy concerns resulting from the combination of monographed ingredients; however, a complete assessment of all medicinal ingredients is not performed. At the time of writing, the target assessment time for Class II product license applications is 90 days (increased from the previous 30-­day target time). Class II applications are issued an acknowledgment letter for confirmation of receipt and may also be issued information request notices (IRN) if the NNHPD requires additional information or requests revisions to the application.

17.2.10 Class III application Class III product license applications are those that deviate from monographs (e.g., different subpopulations, routes of administration, methods of preparations, dosing regimens, potencies, cautionary

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statements) and/or rely on sources of evidence other than NNHPD monographs to support the safety and efficacy of the product. Additional sources of evidence commonly include clinical studies and other scientific literature, master files (discussed subsequently), and opinions/conclusions of other reputable and comparable regulatory bodies. Although NNHPD monographs are a useful tool to facilitate licensing of a product, applicants are not limited to information specified in the monographs. Indeed, product licenses may be sought for different claims, doses, dosage forms, subpopulations, etc., if acceptable evidence supporting these deviations is submitted (which makes the application Class III). At the time of writing, the target assessment time for class III product license applications is 210 days (composed of a 30-­day administrative screening and a 180-­day assessment of the entire application). As with the Class II application stream, Class III applications are issued an acknowledgment letter to confirm receipt and may also be issued IRNs. Contrary to Class I applications, for which a 60-­day disposition is specified in the NHP Regulations, target assessment times indicated for Class II and III applications are merely NNHPD targets and are not guaranteed. At the time of writing, there are no government-­ mandated cost-­recovery fees for NHP licensing; however, these are expected to be implemented at some time in the future.

17.2.11 Evidentiary requirements for products making traditional health claims Traditional NHPs are formulated according to healing paradigms present before the application of modern science. Evidence must establish that the ingredient has been traditionally used within a given medicine system for at least two generations [19]. Common traditional medicine systems include Ayurveda, TCM, and herbalism. Typically, evidence supporting the safety and efficacy of traditional use products consists of traditional pharmacopeias and/or other highly regarded documentation associated with these healing paradigms (e.g., the Ayurvedic Pharmacopoeia of India). Three important factors are considered with respect to traditional-­use NHPs. First, the ingredient(s) contained in the product must be prepared in accordance with traditional evidence. For example, a peony extract prepared by supercritical extraction and standardized to a particular constituent would not be supported by TCM evidence from which the ingredient is prepared by decoction. Second, the health claim must be phrased in a fashion consistent with the traditional paradigm itself. This is accomplished by prefacing the health claim with a qualifying statement indicating the paradigm in which the ingredient and/or product is used. For example, a product containing astragalus root could be licensed with the associated health claim “Astragalus is used in TCM to tonify the lungs and is used for frequent colds.” Third, the final product must be regarded as equivalent to that used in the traditional preparation. In this instance, a product containing licorice root, which traditionally has been used to help relieve inflammatory conditions of the gastrointestinal tract, combined with l-­glutamine, which is also indicated for digestive system health, would not be regarded as traditional because l-­glutamine was not used in a traditional paradigm. For this combination product, evidence of traditional use could be used to support the safety and efficacy of the licorice component and modern evidence could be used to support the safety and efficacy of the l-­glutamine component. The product itself would be regarded as nontraditional because of the l-­glutamine component, and could be licensed with both modern and traditional claims provided the traditional claim is specifically linked to the licorice component as: “helps support digestive system health after periods of physical stress, and licorice is used in herbal medicine to help relieve inflammatory conditions of the gastrointestinal tract.” For a more exhaustive

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discussion of traditional health claims and associated standards of evidence, we recommend consulting the Health Canada Guidance document Pathway for Licensing Natural Health Products Used as Traditional Medicines [19].

17.2.12 Evidentiary requirements for products making modern health claims Whereas the NNHPD reviews the totality of evidence in support of the safety and efficacy of a product or ingredient, our experience is that only clinical evidence is considered in the assessment process. With few exceptions, all health claims must be supported by statistically significant results derived from placebo-­controlled studies. The studies do not necessarily need to be product-­specific. Instead, they may support the safety and efficacy of a single ingredient in the product formulation, provided the evidence package supports the safety in humans of all medicinal ingredients, and that efficacy is supported for at least one ingredient (because each NHP must have an associated health claim). Health claims are assessed based on risk and evidentiary requirements corresponding to the type and associated risk of the health claim itself. When referring to health claims, “risk” is typically regarded as the risk for failed efficacy and associated health outcomes (i.e., deleterious health effects if the product does not work). General claims pertaining to health maintenance, support, and promotion (e.g., “helps in energy production”) are considered to have a relatively low risk profile with a low therapeutic impact, whereas treatment claims for major or serious diseases or conditions (e.g., “for the treatment of depressive disorders”) are considered to have a high risk profile and would need to be supported by a more robust or detailed level of evidence owing to the potential seriousness of therapeutic failure. For a more exhaustive discussion of health claim categories and associated standards of evidence, we recommend consulting the Health Canada Guidance document Pathway for Licensing Natural Health Products Making Modern Health Claims [20]. In addition to monographs and traditional and scientific evidence, applicants may also reference licensed NHPs or NHP master files in support of new product license applications. In terms of referencing NHPs, one can freely reference one’s own licensed products to support the safety, efficacy, and/or quality of a specific ingredient, or a specific combination of ingredients. Moreover, applicants may also reference other licensed NHPs in support of new applications provided a letter of access is obtained from the license holder that permits such access. Master files are useful tools for ingredient suppliers and serve as a convenient source of safety, efficacy, and quality information that product license applicants may reference. A master file is a collection of documentation intended to support the safety, efficacy, and/or quality of a particular ingredient. Master files are a convenient means to facilitate the confidential flow of information direct from the ingredient supplier to the NNHPD, because the owner of the master file does not have to disclose confidential information to a party wishing to cite material in support of the application. For example, if Company A produces a proprietary probiotic strain, it may provide proprietary evidence such as clinical trials, ingredient-­specific quality information, chemistry and manufacturing data, recommended health claims, etc., directly to the NNHPD in the form of a master file. Company A would then provide Company B with a letter of access to the master file so that the NNHPD could proceed to assess the relevant information during the review of Company B’s product license application. This would allow Company B to include this particular probiotic organism into its products without Company A having to disclose lengthy and/or proprietary information to Company B. This practice ensures proprietary information remains confidential while reducing the administrative burden on the master file holder’s customers.

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17.2.13 Quality In addition to safety and efficacy, applicants must also support the quality of the product by demonstrating compliance with Good Manufacturing Practices (GMP) [21]. As per Section 44 of the NHP regulations, every NHP available for sale must comply with finished product specifications submitted as part of the product license application [15]. In addition to complying with approved specifications, all products must be manufactured, packaged, and labeled in accordance with GMPs. To support GMP requirements for these activities, product license applications may include reference to Health Canada–issued site licenses (provided for domestic parties) as evidence of compliance [22]. In instances in which a product is manufactured, packaged, and/or labeled outside Canada, the Health Canada–issued site license for the domestic importer may be specified on the product license application form. This has implications with respect to the importer’s site license, which are described subsequently (under Site Licensing). Although a product license application may be submitted before identifying a manufacturer, packager, labeler, or importer, site information demonstrating GMP compliance of each NHP must be provided to Health Canada before commencing sales [15].

17.2.14 Site licensing As per Part 2 of the NHP regulations, no person may manufacture, package, label, or import an NHP for sale unless that person holds a valid site license for the respective activity [15]. Similar to NHP licensing, to obtain a site license, applicants must submit a site license application to the NNHPD. This site license package consists of a variety of documentation, typically a quality assurance report (QAR) and supporting documentation (e.g., standard operating procedures, records) for the particular facility, which are intended to support the GMP compliance of activities being conducted on-­site. At the time this chapter was written, the site licensing process was paper-­based and did not involve on-­site audits. A discussion of documentation required in support of GMP compliance is beyond the scope of this chapter. Interested parties should consult Part 3 of the NHP regulations [15], the NNHPD Site Licensing Guidance document [22], or the associated GMP Guidance document [21] for detailed information. Considering the global supply chain, the NNHPD issues site licenses only to domestic facilities. For NHPs manufactured, packaged, and/or labeled outside Canada, GMP compliance of each activity must be demonstrated and is accomplished by adding each foreign facility onto the Canadian importer’s site license. This is achieved in one of the following ways:   • The foreign entity provides a detailed QAR and supporting documentation directly to the Canadian importer. The importer then submits a site license application (if a site license has not already been issued) or a site license amendment (if a valid site license is held) containing the QAR and associated documentation to the NNHPD. • The foreign entity provides one of the following pieces of precleared evidence in support of GMP compliance directly to the Canadian importer: a Health Canada–issued Drug Establishment License or a GMP certificate from a qualified authority (a country where Health Canada has a mutual recognition agreement regarding GMP for drug products, or an authority member of the Pharmaceutical Inspection Cooperation Scheme). The importer then submits a site license application or a site license amendment containing the specified certificate to the NNHPD. • The foreign entity obtains a Foreign Site Reference Number (FSRN) from Health Canada by submitting an FSRN application. This application may consist of any of the GMP evidence

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described previously (i.e., QAR and supporting documentation, reputable third-­party GMP certification, drug establishment license), which is submitted directly to the NNHPD by the foreign entity. Once an FSRN is issued, the foreign entity simply provides this number via an FSRN Authorization (FSRNA) form to each importer that is importing a product handled at the foreign site. The importer then submits a site license application or a site license amendment containing only the FSRNA form to the NNHPD.

All methods may be used to demonstrate GMP compliance, but the FSRN option is typically preferred by foreign entities because it allows them to communicate directly with Health Canada and reduce administrative burden on their customers (because the foreign entity provides only the FSRNA form to the importer).

17.2.15 Post-­license changes The NHP regulations set out the types of changes permitted for an NHP after a product license has been issued. These changes are categorized into notifications, amendments, and fundamental changes. Notifications are general changes to an NHP that do not have a significant impact on the safety, efficacy, or quality of the product. Notifications can be made to an existing product license and can be instituted on product labels as soon as the notification has been filed, because an approval from the NNHPD is not required. The NNHPD will issue a No Objection Letter to confirm receipt of the post-­license change. Notifications include [15]   1. any change to the name, address, and telephone number of the license holder, manufacturer, packager, labeler, or importer; 2. the addition or substitution of a nonmedicinal ingredient (which does not affect the product’s safety or efficacy); 3. the sale of the licensed product under a different brand name; 4. a change in the common or proper name of any medicinal ingredients; or 5. the addition of risk information.   Amendments are typically changes to an NHP that may affect the safety, efficacy, or quality of that product. Amendments often involve submissions of new evidence or rationalization of why the proposed changes do not affect these parameters. Amendments occur to existing product licenses and can be issued IRNs requesting additional information, or objection letters resulting in a refusal of the amendment itself. If the amendment has been found to be to in accordance with the NHP regulations, the NNHPD will issue a No Objection Letter and a revised version of the product license. Amendments include changes to [15]:   1. the recommended dose; 2. the duration of use; 3. the recommended use or purpose; 4. the deletion or modification of risk information shown on any of the product’s labels; 5. the source material of any medicinal ingredients; 6. any medicinal ingredient to or from being synthetically manufactured; 7. the potency of any medicinal ingredients; or 8. specifications, including but not limited to, the removal of a test method.  

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Fundamental changes include revisions to the quantity of a medicinal ingredient, addition or substitution of a medicinal ingredient, changes to the dosage form (e.g., from a capsule to a powder), and changes in the recommended route of administration [15]. Fundamental changes require the applicant to submit a new product license application (i.e., to obtain a new product license) because they cannot be applied to an existing product license.

17.2.16 Future considerations Health Canada is working to overhaul how self-­care products are regulated in Canada. Self-­care products in Canada refers to products currently regulated as cosmetics, NHPs, and OTC drugs. Effectively, these are personal care and health products that consumers can purchase and use without a prescription from a health care practitioner. Health Canada currently refers to this project as the Self-­Care Framework. Health Canada’s rationale for this project is that it should regulate products with comparable risks to the consumer in a comparative manner. In other words, the oversight and requirements should be proportional to the risk associated with the product. Currently, this is not necessarily the case. A product is a cosmetic based on the existence of a cosmetic claim without the presence of a drug-­like claim. A product is an NHP based on a combination of its ingredients and indications for use. An OTC is determined based on similar parameters. It is technically possible for an OTC to have a risk comparable to that of certain NHPs and cosmetics, yet such OTCs must comply with more onerous regulatory requirements. It is also possible that for product types, depending on the exact formula and indication for use, to exist in any one of these three categories based on formulation and claim distinctions that have limited or no impact on risk. One example of this phenomenon is sunscreen. A lipstick with sun protectant ingredients can be a cosmetic, NHP, or OTC, depending on whether a sun protectant claim is made with respect to the ingredient and whether the sun protectant ingredient exists in nature. As part of moving this matter forward, Health Canada has held a series of public and stakeholder consultations in an attempt to inform and obtain feedback from Canadians about the proposed Self-­ Care Framework. Health Canada is proposing a phased approach to implementing the Self-­Care Framework. It proposes that the first phase will include what it describes as improved labeling for NHPs, otherwise known as plain language labeling. At the time this chapter was written, Health Canada expected to be consulted on draft regulatory language for plain language labeling by spring, 2019. We expect plain language labeling to have similarities to the current requirements for OTCs in Canada and the supplement facts box on dietary supplements in the United States. However, Health Canada continues to work on specific details as it considers this matter with respect to NHPs in Canada. Health Canada currently proposes that the second phase will focus on targeted amendments to the Food and Drug Regulations to address risk-­based regulatory oversight. Finally, it proposes that the third and final phase will focus on regulatory amendments to address evidence standards, additional matters relating to regulatory oversight, and Health Canada powers as they relate to enforcement. There has been a varied and evolving consumer and industry response to the proposed Self-­Care Framework to date. Some concerns include:   • consumers concerned about product safety; • consumers concerned about loss of products from the marketplace; • industry members concerned that certain low-­risk products are regulated in the same manner as higher-­risk products;

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• industry members concerned that the Self-­Care Framework will unnecessarily lead to a more restrictive regulatory environment for certain NHPs; • industry members concerned that NHPs will be subject to more onerous conditions for licensing, manufacturing, or importation, preventing certain NHPs currently on the market from continuing; • industry members concerned that legislative and regulatory changes will require a number of significant investments from industry; the NHP industry is particularly concerned because of the NHP regulations that came into force Jan. 1, 2004; and • industry members concerned that the phased approach will result in multiple investments and costs over time (for example, a requirement to update labeling in the first phase and then an additional label change owing to product class changes in either the second or the third phase).   At the time this chapter was written, Health Canada’s proposal divided products into three classes; however, a number of key details continue to be developed. Without limitation, they include:   1. specific quality assurance requirements that will exist for each product class; 2. whether products currently regulated as NHPs will have to comply with what are currently considered drug quality assurance requirements; and 3. whether the industry will have to change indications for use on any NHPs currently on the market, to maintain comparable regulatory requirements.   Other details that we expect Health Canada to develop further, these should better inform these industry regarding the true impact of the Self-­Care Framework.

References [1] Government of Canada. Cosmetic Regulations (C.R.C., c. 869). 2007. https://laws-­lois.justice.gc.ca/eng/ regulations/C.R.C.,_c._869/. [2] Government of Canada. Food and Drug Regulations (C.R.C., c. 870). 2018. http://laws.justice.gc.ca/eng/ regulations/c.r.c.,_c._870/. [3] Government of Canada. Food and Drugs Act (R.S.C., 1985, c. F-­27). 2018. http://laws-­lois.justice.gc.ca/eng/ acts/f-­27/. [4] Government of Canada. Safe Food for Canadians Act. 2014. https://laws-­lois.justice.gc.ca/eng/acts/S-­1.1/ index.html. [5] Government of Canada. Safe Food for Canadians Regulations. 2018. https://laws-­lois.justice.gc.ca/eng/ regulations/SOR-­2018-­108/index.html. [6] Government of Canada. Food labelling: health claims. 2016. https://www.canada.ca/en/health-­canada/services/ food-­nutrition/food-­labelling/health-­claims.html. [7] Government of Canada. Acceptable disease risk reduction claims and therapeutic claims. 2018. http://www. inspection.gc.ca/food/labelling/food-­labelling-­for-­industry/health-­claims/eng/1392834838383/1392834887 794?chap=7. [8] Government of Canada. Function claims. 2018. http://www.inspection.gc.ca/food/labelling/food-­labelling-­ for-­industry/health-­claims/eng/1392834838383/1392834887794?chap=8. [9] Government of Canada. Probiotic claims. 2018. http://inspection.gc.ca/food/labelling/food-­labelling-­for­industry/health-­claims/eng/1392834838383/1392834887794?chap=10. [10] Government of Canada. Category specific guidance for temporary marketing authorization: supplemented food. 2016. https://www.canada.ca/en/health-­canada/services/food-­nutrition/legislation-­guidelines/guidance-­ documents/category-­specific-­guidance-­temporary-­marketing-­authorization-­supplemented-­food.html.

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[11] Government of Canada. General guidance document for temporary marketing authorization for foods. 2013.https:// www.canada.ca/en/health-­canada/services/food-­nutrition/legislation-­guidelines/guidance-­documents/ general-­guidance-­document-­temporary-­marketing-­authorization-­foods-­2012.html. [12] Government of Canada. Category specific guidance for temporary marketing authorization -­caffeinated energy drinks. 2013. https://www.canada.ca/en/health-­canada/services/food-­nutrition/legislation-­guidelines/ guidance-­documents/category-­specific-­guidance-­temporary-­marketing-­authorization-­caffeinated-­energy-­ drinks.html. [13] Government of Canada. Lists of permitted food additives. 2017. https://www.canada.ca/en/health-­canada/ services/food-­nutrition/food-­safety/food-­additives/lists-­permitted.html. [14] Government of Canada. Novel foods. 2010. https://www.canada.ca/en/health-­canada/services/food-­nutrition/ genetically-­modified-­foods-­other-­novel-­foods/factsheets-­frequently-­asked-­questions/novel-­foods.html. [15] Government of Canada. Natural Health products Regulations (SOR/2003-­196). 2018. https://laws-­lois.justice.gc.ca/eng/regulations/sor-­2003-­196/. [16] Health Canada. Natural health products ingredients database. 2018. http://webprod.hc-­sc.gc.ca/nhpid-­bdipsn/ search-­rechercheReq.do. [17]  Health Canada. Listing of monographs. 2018. http://webprod.hc-­sc.gc.ca/nhpid-­bdipsn/monosReq. do?lang=eng. [18] Government of Canada. Canadian nutrient file (CNF). 2018. https://food-­nutrition.canada.ca/cnf-­fce/index-­ eng.jsp. [19] Government of Canada. Pathway for licensing natural health products used as traditional medicines. 2012. https://www.canada.ca/en/health-­canada/services/drugs-­health-­products/natural-­non-­prescription/legislation­guidelines/guidance-­documents/pathway-­licensing-­traditional-­medicines.html. [20] Government of Canada. Pathway for licensing natural health products making modern health claims. 2012. https://www.canada.ca/en/health-­canada/services/drugs-­health-­products/natural-­non-­prescription/legislation-­ guidelines/guidance-­documents/pathway-­licensing-­making-­modern-­health-­claims.html. [21] Government of Canada. Good manufacturing practices guidance document. 2015. https://www.canada.ca/ en/health-­canada/services/drugs-­health-­products/natural-­non-­prescription/legislation-­guidelines/guidance-­ documents/good-­manufacturing-­practices.html. [22] Government of Canada. Site licensing guidance document. 2015. https://www.canada.ca/en/health-­canada/ services/drugs-­health-­products/natural-­non-­prescription/legislation-­guidelines/guidance-­documents/site-­ licensing-­guidance-­document.html.