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1 Introduction

Traditional Chinese medicine (TCM) is undergoing rapid growth and development in China and worldwide. Risks and benefits associated with Chinese herbal products, that are consumed as functional foods or nutraceuticals, requires further understanding before entering new markets including Canada. A recent market report indicates that China exports 240,000 tonnes of Chinese medicine annually, of which 200,000 tonnes are raw herbs that accounts for 20 % of the country’s annual harvest [1]. The growth in demand of Chinese herbs can be attributed to the rise in use of complementary and alternative medicine in the U.S., which has increased from 36 % of population in 2002 to 38.3 % in 2007 [2]. Nutritional Business Journal’s Supplement Report for 2012 shows that herbs (botanicals) represented 17 % of dietary supplement sales in 2011 and the industry grew by 7 % in the U.S in the same time period [3]. While many Chinese herbal remedies have been used for more than 5000 years [4], their efficacy and safety needs to be evaluated using evidence-based approaches including double-blinded randomized clinical trials and toxicological studies. Another important issue is the lack of uniform regulations for herbal remedies (other terms are herbal supplements, herbal substances, botanicals, and others) which vary significantly between jurisdictions [5].

2 Regulation of Dietary Use of Herbal Remedies in Canada, USA and European Union

2.1 Natural Health Product Regulation in Canada

In Canada, herbal remedies and traditional Chinese medicine products (TCM) are regulated as Natural Health Products (NHP). In 2013, NHP market includes more than 50,000 products authorized for sale by Health Canada [6] including 2000 TCM [7]. According to Ipsos Reid 2010 report, 73 % of Canadians regularly take natural health products. While vitamin, minerals and essential fatty acids represent the most widely consumed NHP (71 %), herbal products are typically used as a tea (11 %), herbal remedies (10 %) and Echinacea (7 %) [8]. There is no distinction between dietary and non-dietary (i.e. medicinal) herbs in Canadian Regulations even though the earlier version of NHP regulation was intended to distinguish between dietary and medicinal herbs [9]. The consumption pattern of NHP in Canada and other countries does not account for the ethic and cultural specifics which influence the choice and type of NHP consumed. The study conducted with Canadians of Chinese and white backgrounds revealed that the responders of Chinese descent were more inclined to use herbal medicine compared to their white counterparts. Furthermore, their motivation to use herbal products was different. Thus, for Chinese responders the main factor to choose herbal medicine was the presence of chronic disease while for white responders it was perceived higher safety of herbal products compared to pharmaceuticals [10]. This indicates the substantial gaps in consumers’ knowledge and provides the opportunities for nutritionists and other health care practitioners to translate the available scientific data and promote at least those products with proven safety and clinical efficacy.

While the main purpose of NHP is to: prevent, treat, mitigate a disease, disorders or abnormal physical state or its symptoms, or restore, correct or modify organic functions and overall maintain and promote human health [9], the Food and Drug Act prohibits to advertise and label any food, drug, cosmetic or device as a treatment preventative or cure for any of the diseases listed in Schedule A [11]. This list includes the following conditions: 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, haematologic bleeding disorders, hepatitis, hypertension, nausea and vomiting of pregnancy, obesity, rheumatic fever, septicemia, sexually transmitted diseases, strangulated hernia, thrombotic and embolic disorders, thyroid disease, and ulcer of the gastro-intestinal tract. In 2007, NHP were exempted from preventative claim prohibition in respect to Schedule A listed diseases, while the previous conditions regarding the treatment and mitigation remain in force [12]. Considering that in Canada TCM are regulated as NHP, these regulations pertain to Chinese herbs as well. In order to better understand the issues related to TCM including traditional and novel TCM products, their sale, importation and use in Canada, the Advisory Council on Traditional Chinese Medicines represented by stakeholder groups including industry, consumers and patients, health care professionals and academics was established by Health Canada in 2011.

2.2 Botanical Products and Their Regulation in the U.S. and European Union

In the U.S., herbal products are regulated under the Federal Food, Drug, and Cosmetic Act either as foods, botanical drugs or dietary supplements. While the herbs consumed as foods primarily due to their taste, aroma or nutritive value are regulated as foods, dietary supplements are regulated under the Dietary Supplement Health and Education Act (DSHEA) of 1994 and may not claim to: diagnose, mitigate, treat, cure, or prevent a specific diseases. Instead, dietary supplements may claim a benefit related to a classical nutrient deficiency disease, describe the benefits for structure or function of human body and the mechanisms of thereof. If a botanical product is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans, such product is regulated as a drug. Both botanical drug products and herbal dietary supplements can be manufactured in the form of herbal tea and non-food forms such as concentrates, powder, tablet, capsule, elixir and other forms. Another type of products that are not regulated as drugs and do not require prescription are called medical foods intended to meet specific nutritional requirements of a disease or condition and must be used under medical supervision. The regulation of botanical products and medical foods in the U.S. is enforced by U.S. Food and Drug Administration [13].

In the European Union, the use of herbal products is regulated under the Directive 2004/24/EC of the European Parliament and of the Council enacted in 2004. Article 31 of the Directive defines herbal substances as mainly: whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried, form, but sometimes fresh. This definition also includes certain exudates that have not been subjected to a specific treatment. Article 32 defines herbal preparations as preparations obtained by subjecting herbal substances to treatments such as: extraction, distillation, expression, fractionation, purification, concentration or fermentation. These include: comminuted or powdered herbal substances, tinctures, extracts, essential oils, expressed juices and processed exudates [14]. According to the Directive, each Member State has to set up a simplified registration for herbal medicines that have been traditionally used for at least 30 years including 15 years within the EU. In 2004, the Committee on Herbal Medicinal Products (HMPC) was established and aimed to assist the harmonisation of procedures and provisions concerning herbal medicinal products laid down in EU Member States, and further integrating herbal medicinal products in the European regulatory framework. HMPC serves as a scientific body and provides its opinion on herbal medicinal products to EU Member States, establishes ‘Community list of herbal substances, preparations and combinations thereof for use in traditional herbal medicinal products’, and Community herbal monographs [15]. In respect to botanicals intended for use in food applications, European Food Safety Authority (EFSA) has issued the “Compendium of botanicals reported to contain naturally occurring substances of possible concern for human health when used in food and food supplements”. The Compendium covers about 900 botanicals, their scientific name, common synonyms and safety concerns [16].

3 Randomized Clinical Trials Using Dietary Herbs and/or Active Ingredients and Their Limitations

Dietary Chinese herbs have long been used in Traditional Chinese Medicine (TCM) for disease prevention, treatment and to enhance the overall wellbeing of human beings. However in the recent years, an increased focus on clinical and pharmacological-evidence based investigation on the efficacy of herbs and their active ingredients can be noticed. Based on a study published in the Chinese Medical Journal, the four major health categories where the application of Chinese medicine and natural products were more pronounced included: cancer, cardiovascular, oral & gastrointestinal as well as inflammatory/immune disorders [17]. Other categories consisted of neurological disorders, stroke, skin diseases, metabolic disorders, reproductive health, mental health and metabolic or endocrine disorders [17].

A wide range of disparity exists in the use of Chinese herbs for therapeutic purposes in modern medical practice. Traditional Chinese medicine practitioners use herbal combinations rather than single herbs in which each herb plays a specific role in addressing the patterns of symptoms. The inclusion of one herb may enhance the activity of the other or reduce the risk of short-term or long-term side effects of another herb [18, 19]. When herbal combinations/decoctions are subjected to preliminary studies, characterization of the principal component and/or adjuvant phytochemical constituents responsible for the curative action becomes impossible [20]. This is extremely essential when studies are to be applied to human subjects in various clinical trials. However, such an approach is not compatible with the basic theories of TCM including ‘treating the patient as a whole’ where the interaction of forces and energies both within and outside the individual is given importance [21].

Conducting randomized, controlled clinical trials in human subjects using dietary herbs becomes difficult due to: various factors including herb quality issues, improper processing and manufacturing practices, variations in active herbal components and interactions between herbs as well as with administered drugs [22]. The chemical composition of TCM and natural products are mostly governed by growing conditions such as rainfall, length of cultivation, soil nutrients and geography. A change in any one of these factors inevitably affects the content of chemical constituents present in herbal products. Even though the products are standardized for content of their known active ingredients, there could be differences in the content of other components. Such variations can pose problems while conducting preclinical, pharmacological and clinical assessment of herbal formulations/products. Studies by Fitzloff et al. [23] showed that 26 % of the ginseng products marketed in North America did not meet the label claims of ginsenoside content of Panax ginseng and Panax quinquefolius products. An extensive study by Gilroy et al. [24] reported the reduced contents of active ingredients echinacoside or cichoric acid in Echinacea products marketed in the United States. Lack of quality control/quality assurance requirements for the dietary ingredient suppliers have been indicated as the cause of adulteration, substitution or low quality of materials being incorporated in the dietary herbal supplements [25]. In addition to this, various herb-herb interactions (incompatibilities and counteracting abilities) have been documented [26]. Also, interactions of herbal medicines with drugs such as warfarin, aspirin, midazolam, digoxin and irinotecan have been reported [27, 28]. Hence, understanding these pitfalls and taking remedial measures are crucial while integrating herbal medicine into evidence-based clinical practice. Preclinical and pharmacological assessment of herbal medicines conducted using animal model systems might sometimes not prove useful in humans as biological responses may not be species transferable. It is possible to have a positive effect of a drug/active ingredient in animals whereas it may be completely inactive in humans. Testing the toxicity levels and manifestations of a certain drug in animal models is particularly useful while assessing drug safety issues. Moreover, testing the presence of heavy metals such as arsenic, lead, copper and mercury in herbal ingredients is necessary to avoid possible adverse effects while conducting trials in humans [22]. The Consolidated Standards of Reporting Trials (CONSORT) checklist developed by the CONSORT group (www.consort-statement.org) provides a solid basis for conducting and reporting randomized controlled trials (RCT). This includes documentation of various aspects of RCT’s including randomization, blinding and analysis along with detailed descriptions on patient eligibility criteria, experimental objectives and hypotheses, sample size calculation, implementation of the study and statistical methods used [29, 30]. However at times, implementing herbal medicinal trials pose problems due to their distinguishable organoleptic properties compared to placebo which could have a confounding effect on the efficacy of the treatment. In such cases, strategies adopted to control this possible bias should be well documented so as to facilitate replication of treatments by other investigators.

Although it is uncommon among the TCM practitioners to use single herbs, some specific herbs have gained attention and have been investigated for their potential to be used in the development of treatments or as therapeutic interventions. A large number of trials on herbs and their active ingredients can be retrieved from The Cochrane Central Register for Controlled Trials (www.cochranelibrary.com) and PubMed. Few examples of randomized, single/double blinded, placebo-controlled clinical trials of Chinese herbs and active ingredients for various diseases/disorders are shown in Table 2.1.

Table 2.1 List of few randomized, single/double blinded, placebo-controlled clinical trials of Chinese herbs and active ingredients for various diseases/disorders
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Some clinical trials on herbs provide promising results, where as some do not show any significant difference between the treatment and the placebo. In such cases, investigators are led to conclude that more randomized controlled trials are recommended to understand the benefits. However, extensive research reviews on the scientific validity of clinical trials of TCM are available, which points out the various drawbacks of the studies and also provide recommendations for proper future trials [31]. Publication bias resulting from selective outcome reporting has been projected as one of the drawbacks that could diminish the strength of evidence while making informed decisions about a treatment [31]. In order to increase the transparency of randomized clinical trials and to improve the quality of trials, registration of prospective trials in international clinical trials registry such as ClincalTrials.gov and International Clinical Trial Registry Platform (ICTRP) (http://www.who.int/ictrp/en/) established by World Health Organization has been highly warranted.

4 Market Trends in the Functional Foods and Natural Health Products Industry

The functional foods and natural health products industry is expanding with major financial implications on the world stage and shows growth in all areas including firms, sales and new product development. In 2004, the World Bank estimated the functional foods and natural health products industry to be worth 30–60 billion US dollars with estimates of it reaching $130 billion US dollars by 2015, which corresponds to 1–3 % of the total food market [32]. Three leading markets dominate this industry, the U.S, Japan and Europe, with over 90 % of the total sales for functional foods and natural health products [33]. The expansion of these markets is expected to continue over the next few years with markets also growing in China, India, and the Asia-Pacific countries [32].

An overview of the leading markets reveal that in the United States, the retail value of the functional foods and natural health products industry was $59 billion in 2007 with the natural health product segment accounting for 26.4 % of the total US health food sales [32]. The number of products on the market is increasing steadily, with new introductions increasing from 200 to 800 between 2006 and 2008 [34]. Several factors contribute to the growth of this industry including the increased awareness between health and diet, an aging population, the increasing cost of health care, increasing competition in the food industry for novel products, and the challenges consumers face while trying to meet their nutritional needs using conventional foods [32, 34]. The estimated value for functional foods and natural health products in Japan was estimated to be 16.4 billion US dollars in 2007 [32]. In Europe, the market was estimated at 8 billion US dollars, with the natural health product segment accounting for 6 billion US dollars [32]. The European Union is also the largest importer of medical plants with an estimated 100,000 tonnes of plant material being imported in 2000 [32].

Canada has a small portion of the global functional food and natural health product market which constitutes only about 1 % of the total global market. Although Canada’s market share is small, it is increasing with further demands for novel products from Canadian consumers. Within Canada, the functional food and natural health product industry generates $3.7 billion in revenue with $1.7 billion coming from firms producing only natural health products [35]. The Canadian functional foods and natural health product industry has also expanded from 389 food and natural health product companies to over 680 companies between 2005 and 2007 producing over 22,062 product lines [32, 35]. Canadian firms who specialize in natural health products are targeting four main health areas: vascular health, weight control, energy and general nutrition. There is also a focus on the health of the immune system, the eyes, the bones, the urinary tract, the prostrate and the gut as well as diabetes, cancer, arthritis, menopause, anxiety and other mental health issues and sexual health and performance [32, 35].

4.1 Patents with Herbs

Patents granted by world governments are used in the food industry to protect the exclusive rights of the inventors or applicants of a novel product for a limited amount of time. According to the 2007 results from the Functional Foods and Natural Health Products Survey, there was a total of 999 existing patents worldwide for functional food and natural health products with another 1005 pending approval [35]. As with the overall industry, the number of patents in this sector is also expanding. For example, in the European Union functional foods and natural health patents grew from 3.2 to 7.7 % between 1994 and 2000 [32]. The United States and Canada, are also experiencing an increase in functional foods and natural health products patents. In the United States, the growth in patent applications is driven by the regulatory approval of many health claims [32]. Patents are granted by the United States Patent and Trademark Office in United States and by the Canadian Intellectual Property Office in Canada. An inventor in the United States must demonstrate that the invention is useful and new within the patent application whereas in Canada the invention must not only be first in the world or show “novelty” but also be functional and operative or have “utility” and show “ingenuity” in order for the application to be successful [32]. Patent regulation within Japan is based on the similar concept of novelty as in Canada. Between 1994 and 2001, Japan held over 22 % of the global patent applications with a major focus on dairy-based functional foods [32, 36, 37].

The majority of successful functional foods and natural health patents have been in the area of extraction and purification techniques of plants and plant parts [32]. For example, one patent provides a method of β-carotene extraction from the genus Momordica and yields an oil rich in β-carotene [38]. The patented process is done without the use of organic solvents and provides a stable source of β-carotene that can be used in products as a nutritional supplement for human and animal consumption as well as for pharmaceuticals and cosmetics [38]. Another process patent describes a low-temperature extraction process for several species of plants including Zingiber officinale (ginger), Curcuma longa (turmeric), Cinnamomum cassia (Chinese cinnamon), and Mentha (Mint) species for producing heat stable flavorings used in bakery applications [39]. An emulsion of edible oil, water and an emulsifier is created with the plant material and than separated to produce the liquid flavorings fraction. This fraction is then encapsulated and dried into a heat-stable powder [39]. Patents have also been obtained for the production technique used for enhancing the physico-chemical properties of beverages. Mennett et al. [40] described a method for enhancing the foam properties of a number of beverages including fermented malt beverages, beer, cappuccino, flavored coffee, tea, hot chocolate, and carbonated soft drinks by incorporating foam-enhancing formulations comprising plant materials from the mint family either to the finished beverage or into a step in the beverage manufacturing process.

4.2 Food Products with Added Herbs

Patents dealing with actual food products are less common but still exist. Morazzoni et al. [41], holds a patent for a medicament or a dietary supplement with gingko derived from the plant Ginkgo biloba, complexed with phosphatidylserine for the enhancement of cognitive function and to alleviate mental fatigue. The authors state that the product is “to improve the speed of memory and memory quality, to increase accuracy and attention in activities in normal healthy subjects, to prevent deterioration of the speed and quality of memory in people with decreased cognitive functions and to counteract cognitive fatigue, having also an influence on the mood, particularly in healthy children, young adults, middle-aged and/or old people” [41]. A dietary supplement comprised of fibre, whey and plant parts from plants of the genus Capsicum and Mentha and aimed for regulating appetite was patented [42]. It induces satiety by occupying the stomach and sending satiety signals to the brain and involve some other metabolic mechanisms. The herb Angelica sinensis is patented in the use of a fermented herbal drink which is effective in treating the symptoms of menopause [43]. The herb is extracted with yeast and water which allows the yeast to ferment the crushed herb. This fermentation process is carried out over seven days at 10–20 °C and is than filtered [43]. One more example of successful application of patents using herbs as part of the food product is described by Adachi et al. [44] as a flavor deterioration inhibitor for foods, drinks and/or oral care products. This product is made by extracting Angelica keiskei , avocado, Cassia tora , Plantago asiatica, hawthorn, fermented tea leaves with water, an organic polar solvent, and a deterioration smell inhibitor. The addition of the flavor deterioration inhibitor to foods will improve storage life by maintaining the product’s flavor [44].

4.3 Natural Health Products Based on Herbal Remedies: What Is on the Market?

Health Canada with its Natural Health Product Database provides consumers with a means to search for licensed natural health products available in Canada, including vitamin and mineral supplements, herb and plant-based remedies, traditional Chinese and Indian medicines, omega 3 and essential fatty acids, probiotics, homeopathic medicines and many oral and personal hygiene products. These licensed products have been assessed by Health Canada and have been found to be of high quality, effective, and safe under the recommended usage of the products. Consumers can find information such as product name, product licence holder, Natural Product Number (NPN) or Homeopathic Medicine Number (DIN-HM), product’s medicinal ingredients, product’s non-medicinal ingredients, product’s dosage, product’s recommended use, and cautions, warnings, contra-indications and known adverse reactions with the product’s use (Health Canada, 2013) [45]. Several examples of natural health products in Canada using selected Chinese herbs are given in Table 2.2.

Table 2.2 Examples of natural health products in Canada using selected Chinese herbs
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5 Conclusion

Growing market for dietary and medicinal herbs including TCM requires the harmonization of food and supplement regulations between jurisdictions. The new unified standards for herbal products and their clinical efficacy and safety evaluations need to be implemented in order to provide both healthcare providers and consumers with transparent and explicit information. The creation of a global database using the existing platforms (e.g., WHO, FAO, Codex Alimentarius, etc.) may provide a unique opportunity to consolidate all available information on herbal products and their nomenclature, efficacy, toxicity, applications, origin, territorial regulation and approval status.