Internationalization of Traditional/Complementary Medicine products: market entry as medicine

Chinese Medicine is considered a traditional medicine practice and a popular approach to health care adopted by many individuals throughout the world [1–4]. It refers to both traditional Chinese medical practices and traditional Chinese medicines (TCMs) [4]. In China, an ageing population, increased prevalence of chronic conditions, a rising GDP, and accommodating medical insurance programs are all considered drivers of the a growing TCMs market [5]. This has prompted the Chinese government to identify Chinese Medicine as a priority and they have issued supportive measures to support Chinese Medicine in a strategic attempt to provide universal health coverage. The State Council in the 13th Five-Year Plan (2016–2020) aim to ensure all citizens are covered with health care by 2020 and that Chinese Medicine will be an important element in achieving that goal and further supported with scientific research, education and cultural influences [6]. In 1996, China introduced the concept of “internationalization of TCMs” which had two main objectives: (1) to achieve the sustainable development of TCMs through fostering international trade and expanding TCMs in the global pharmaceutical market; and (2) to facilitate the development of appropriate regulatory systems that allows reasonable market entry under the protection of the local laws and regulations [7].

In the past 2 decades, advancements in research technologies has enabled a substantial body of research in TCMs to be conducted [8]. Research of TCMs supported with advancement in technology has better informed our understanding of TCMs, through the identification of active constituents and mechanisms of actions, and the identifying the forms and doses required to achieve positive therapeutic outcomes and minimize side effects and toxicity [9]. Despite this progress in developing the evidence base, the internationalization of TCMs has faced both intrinsic and extrinsic challenges. Take Chinese patent medicines (CPMs, referring to any TCMs formulated into a finished dosage form) as an example. Like any other types of TCMs, CPMs have uniquely complicated features [10]. They are used based on Chinese Medicine theory which cannot be fully explained or comprehended within the language or context of modern science. Maintaining a consistent constituent profile for many CPMs is difficult due to the lability of some constituents during the production process [8]. The quality control of CPMs is also difficult to sustain with challenges in accurate plant identification, cultivation, harvesting and the processing of herbal materials. Extrinsic factors including pesticide residues, and contamination with heavy metal and other unwanted chemical are regularly encountered during the production of CPMs. To deal with some of these challenges, the development of specifications for quality control of end products is under development. In contrast to pharmaceutical drugs, CPMs are inherently more complex to evaluate due to the complexity of multiple constituents and diverse therapeutic actions, and being less commonly the subject of large randomized controlled trials (RCTs).

One of the biggest extrinsic challenges facing the internationalization of TCMs is the registration/policy barriers [3, 5, 10–12]. Firstly, the terms used to refer TCMs varies from country to country. Depending on the culture, TCMs may be known as traditional medicines or complementary medicines (referred to the broad set of health care practices that are not part of the country’s own tradition or conventional medicine but used in additional to conventional medicine) [13]. More than 90 countries and regions have national polices, laws and regulations for the marketing approval of Traditional and Complementary Medicine (T&CM) products including TCMs [3]. However, depending on the national situation, the criteria for marketing T&CM products varies across the countries indicating that regulatory authorities have different standards and/or interpret evidence for quality, safety (risk) and efficacy, therefore the possible risk of using such products differently.

Some countries, as reported by the World Health Organization (WHO), have national policies on T&CM products and measures to ensure the quality, safety and efficacy of the T&CM products with a respect for the uniqueness of the traditional modality [4]. For some other countries, the regulatory authorities may include T&CM products into the scope of drug regulation, requiring that T&CM products meet the same set of stringent registration requirement as for other pharmaceutical products for marketing approval [14]. In some cases, authorities have additional regulations and guidelines to supplement the drug legislations to address issues related to the safe and appropriate use of T&CM products. There are also cases where T&CM products, when deprived of certain health claims, may be marketed as “non-medicine” entities. As a result, eligible T&CM products may be marketed as “medicine” only in some countries and areas depending on the regulations [3, 14].

With due respect to the therapeutic values of T&CM products (particularly TCMs), the identity of “medicine” in any regulatory systems is sought after during the course of internationalization. Currently, little research has been conducted to systemically analyze the regulation standards of T&CM products as a “medicine” entity across the countries. Therefore, the objective of this study was to compare the regulatory process for T&CM products using CPMs as products of interests among selected countries and regions. Specifically, the requirements for assessing quality, safety and efficacy for T&CM products classified as ‘medicine’ were analyzed. The findings of this study will be useful to inform a global perspective on the regulations of T&CM products, and specifically the internationalization strategies for TCMs.

Countries and regions including Macau-China, Hong Kong-China, Singapore, Australia, Canada, the European countries and the United States (US) were selected for this study based on the following considerations: (1) they have established regulatory practices that assess T&CM products as medicine; and (2) they represents a range of regulatory systems for T&CM products. A systematic qualitative analysis was conducted and included the review and interpretation of official legal documents related to the marketing of T&CM products. The publicly available documents were identified from the official website of the respective governing authorities of the selected countries and regions: Health Bureau, The Government of the Macau SAR (http://www.ssm.gov.mo) [15], Chinese Medicine Council, The Government of the Hong Kong SAR (http://www.cmchk.org.hk/) [16]; Chinese Medicine Division, Department of Health, The Government of the Hong Kong SAR (http://www.cmd.gov.hk/html/eng/index.html) [17], Health Sciences Authority of Singapore (http://www.hsa.gov.sg) [18], The Therapeutic Goods Administration of Australia (http://www.tga.gov.au) [19], Health Canada (https://www.canada.ca/en/health-canada/services/drugs-health-products/natural-non-prescription.html) [20], European Medicines Agency (http://www.ema.europa.eu/ema/) [21], Medicines and Healthcare Products Regulation Agency of the UK (https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency) [22], Medicines Evaluation Board of the Netherlands (https://english.cbg-meb.nl/) [23], and US Food and Drug Administration (https://www.fda.gov/AboutFDA/default.htm) [24]. The terminology used to describe the regulatory framework for marketing T&CM products and evidence requirements for demonstrating quality, safety and efficacy of the product in each regulatory system was extracted, interpreted and analyzed.

Macau is one of the two special administrative regions (SAR) of the People’s Republic of China, located on the western bank of the Pearl River Delta in the southern Guangdong Province. Macau had been a Portuguese colony since the mid-16th century until the handover to China in 1999 when it became a SAR. The city exercises a high degree of autonomy under the principle of “One country, two systems” and has a local regulatory system for TCMs which covers CPMs. Due to Macau’s deep-rooted connections with Portuguese-speaking countries, Macau is strategically placed for the facilitation of TCMs internationalization.

The regulation of CPMs and other TCMs is overseen by the Department of Pharmaceutical Affairs, Health Bureau [15]. At the moment, Macau does not have a registration system for CPMs. However, an alternative process is in place that takes reference of the regulatory decision made by the authority of the country of origin. Therefore a “sales pre-approval system” is adopted and supported and supplemented by a number of legislations, regulations and technical instructions. Decreta-Lei n 53/94/M, enacted in 1994, is the main legislation governing the licensing and operating conditions of companies involved in the import, export and wholesale of TCMs, as well as the TCMs pharmacies. Although it does not cover the sales pre-approval requirements of TCMs, it gives the legal definition of TCMs which refers to any medicines, plant or animal ingredients, or any materials extracted from these ingredients, used according to Chinese Medicine and Chinese pharmacology for the prevention or treatment of diseases, or the regulation of bodily functions.

In order to better inform the safety and efficacy of TCMs, a “List of Traditional Chinese Medicine Ingredients for consumption in Macao SAR” was developed by the Health Bureau, which consists of three sub-lists: (1) Part I—toxic traditional Chinese materials (30 types); (2) Part II—common therapeutic traditional Chinese materials (562 types); and (3) Part III—Chinese medicinal materials that are also used as food (112 types). According to Technical Instruction No 02/2005, CPMs refers to a product which has a definite pharmaceutical form and composes of (1) one or more ingredients from Part I and/or Part II; (2) one or more ingredients from Part III and carry claims about treating, alleviating or preventing a disease or symptoms on the product label; or (3) formulated with one or more natural medicinal ingredients from plants, animals, or minerals under the guidance of traditional Chinese Medicine theory, and are applied to the human body for the purpose of treating, alleviating, or preventing diseases or symptoms thereof. Sales of CPMs are exclusive to TCMs pharmacies. For products composing ingredients from Part III but without any claims of disease/symptom treatment, alleviation or prevention, they will not be considered as CPMs and not subject to sales restrictions.

The local manufacturing capacity of CPMs is very limited. Most of the CPMs available in the market are imported products. According to the “sales pre-approval system”, prior to importation of CPMs by licensed importers, certain documents must be submitted which includes a Drug Registration Certificate issued by the governing authority in the country of origin, certificates of analysis (including microbial and heavy metal contamination) for each batch of CPMs and the manufacturer’s license to demonstrate the minimal quality, safety and efficacy assurance. The adherence to GMP is recommended but not mandated. The maximum limits of heavy metal and toxic elements allowed in CPMs are specified in Despacho No. 10/SS/2013. Technical Instruction 01/2004 outlines the microbiological limits for different dosage forms of TCMs. When the CPMs originate from a country with a registration system in place, test reports of microbiological limits, heavy metals and toxic element content may be exempted. Labelling requirements stipulated in Technical Instruction 04/2005 apply to all TCMs.

Additional regulations and guidelines are in place for specific TCMs as a safeguard. For TCMs which contain high-risk Chinese medicinal materials, either a banning system or a restricted-use system is in place. For instance, Radix Aconiti Lateralis Preparata, which is an ingredient from Part II of the “List of Traditional Chinese Medicine Ingredients applied in the Macao SAR”, is recommended to be processed and used according to specific instructions with precautions due to the potential risks of toxicity as indicated in the official document “Instructions of using Radix Aconiti Lateralis Preparata”. Similar instructions are also in place for Rhaponticum uniflorum (L.) DC. Due to the high risk of toxicity, according to the Health Bureau Director Decision No. 6/SS/2004, utilization, manufacture, importation and sales of Caulis Aristolochiae Manshuriensis (Guanmutong), Radix Aristolochiae Fangchi (Guangfangji) and Radix Aristolochiae (Qingmuxiang) are prohibited in Macau. Additional document requirements are applicable to a special CPMs, Niuhuang Jiedu Tablets, as stipulated in the Chief Executive Decision No. 132/2001. In order to minimize the risks associated with bovine-derived drugs, additional production and importation requirements of bovine-derived drugs are listed in the Chief Executive Decision No. 120/2005 and Technical Instruction No. 02/2001.

As stated by the Macau SAR Government, the draft regulations for the registration scheme for TCMs have been prepared by the Health Bureau, and the relevant legislative processes are underway.

In Hong Kong, traditional Chinese Medicine is widely accepted as playing a substantial role in the public healthcare sector. To tighten the regulation of Chinese Medicine practice and Chinese herbal medicines, with a view to safeguarding the public, the Chinese Medicine Ordinance (Cap.549) was enacted in 1999, and officiated the legal status of TCMs. Accordingly, proprietary Chinese medicines (pCms) must be registered by the Chinese Medicines Board of the Chinese Medicine Council of Hong Kong (the Council) before they can be legally marketed [16]. The Council is a statutory body established under the Chinese Medicine Ordinance responsible for formulating and implementing regulatory measures of TCMs. The Council receives professional and administrative support from the Chinese Medicine Division of the Department of Health which is responsible for the enforcement of Chinese Medicine Ordinance [17].

By definition in the Chinese Medicine Ordinance [25], pCms refer to any proprietary product: (a) composed solely of the following as active ingredients: (i) any Chinese herbal medicines, (ii) any materials of herbal, animal or mineral origin customarily used by the Chinese; or (iii) any medicines and materials referred to in subparagraphs (i) and (ii) respectively; (b) formulated in a finished dosage form; and (c) known or claimed to be used for the diagnosis, treatment, prevention or alleviation of any disease or any symptom of a disease in human beings, or for the regulation of the functional states of the human body. For registration purposes [26], CPMs from China may fall into one of the three categories for pCms in Hong Kong: Established Medicines (pCms that are formulated according to an ancient prescription, a modified ancient prescription, a pharmacopoeia prescription or other prescriptions originated from the National Drug Standards of the People’s Republic of China), Non-established Medicines (pCms that are used for the purpose of regulating the functional states of the human body or Single Chinese medicine granules) and New Medicines (pCms that contain newly discovered Chinese herb or new ingredient, or have new indication, altered route of administration or altered dose form).

Any of these three categories may be subject to registration approval: Group I, Group II and Group III. Different registration groups mainly differ in the registration requirements and documents related to the safety and efficacy of the pCms. Group I and Group II registration groups have different documentary requirements for the mutagenicity, carcinogenicity and reproductive toxicity of the pCms. Group III registration requirements are the most stringent as they requirement full documentation to demonstrate safety and efficacy of the New Medicines.

The Health Science Authority (HSA) is responsible for the drug regulatory work, including the issuance of the licenses of the importers, wholesalers, manufactures and re-packers of Chinese proprietary medicines (Cpm) [18]. It is a statutory board of Singapore Ministry of Health that aims to protect and advance national health and safety. The Chinese Proprietary Medicines Unit is one of the divisions of HSA specifically responsible for the administration of regulatory control and approval of Cpm. Cpm that is intended to be imported and sold must be registered for product listing approval. In accordance with Medicines (Traditional Medicines, Homoeopathic Medicines and other Substances) (Exemption) Order in Medicine Act 1985 (CAP 176), Cpm refers to any medicinal product (a) which has been manufactured into a specific dosage form and contains one or more active substances derived wholly from any plant, animal and/or mineral using active substances that are listed in the current edition of “A Dictionary of Chinese Pharmacy” or “The Chinese Herbal Medicine Materia Medica”. Injectable products or medicinal products containing chemically-defined isolated constituent of any plant, animal or mineral, or any combination thereof are not considered Cpm. The number of the approved Cpm increased considerably from 2076 in 2011 to over 10,000 in 2013.

In Australia, Chinese medicine herbal products (equivalent to CPMs in this study), together with other herbal medicines, vitamin and mineral supplements, nutritional supplements, and other traditional remedies, fall into the category of complementary medicines (Therapeutic Goods Act 1989) [19, 27]. ‘Complementary medicines’ are regulated by the Therapeutic Goods Administration (TGA) and are defined as ‘therapeutic goods consisting wholly or principally of one or more designated active ingredients, each of which has a clearly established identity and (a) a traditional use or (b) any other use prescribed in the regulations’. The TGA has the responsibility for administering the federal Therapeutic Goods Act 1989, which provides the national framework for the regulation of therapeutic goods, including complementary medicines in Australia.

The regulatory framework for complementary medicines is based on a risk based system. The TGA currently takes a two-tiered approach based on risk: (1) Listed medicines or (2) Registered medicines. To be approved as a listed complementary medicine, the product is restricted to certain low risk ingredients in acceptable amounts that are permitted for use by the TGA and can only make indications for health maintenance and enhancement and/or for non-serious self-limiting conditions. Registered medicines can carry more specific therapeutic claims and/or contain a herb with a higher risk profile. In addition, registered medicines are independently assessed for quality, safety and efficacy. Registered CPMs on the Australian Register for Therapeutic Goods (ARTG) are currently outnumbered by listed CPMS. In 2016/2017, 1581 new complementary medicine products were listed on the ARTG as compared to 34 new registered complementary medicines. Listed medicines carry a unique AUST L number.

In Canada, T&CM products may be considered and regulated as Natural Health Products (NHPs) and are regulated by the Health Canada (HC) according to the Food and Drugs Act and the Natural Health Product Regulations [20]. Although there is no implication of “medicine” nature by the name, NHPs, by definition, refers to herbal or medicines of traditional medicine practices intended for use in the diagnosis, treatment, mitigation or prevention of a disease, disorder, or abnormal physical state or the symptoms thereof. According to the Natural and Non-prescription Health Products Directorate (NNHPD), NHPs are restricted to oral, topical, or sublingual routes of administration. The intended uses of NHPs encompass a wide range of claims ranging from maintaining or promoting health to diagnosis, treatment, prevention, and symptomatic relief of some diseases. Compared to the regulatory systems mentioned above, the health claims for NHPs in Canada are allowed to a greater extent and yet overlaps with mild claims of other non-medicine entities such as dietary supplements.

There are two subcategories to the NHPs claims: traditional health claims and modern health claims. TCMs, for instance, which contain multiple ingredients and are used based on a single cultural system of traditional medicine, Chinese Medicine, are considered NHPs with traditional health claims. For other T&CM products whereby the intended uses are not based on any one traditional medicine system, such claims are considered modern health claims. NHPs, when authorized for sale in Canada, are issued a product license and a Natural Product Number (NPN).

In European countries such as the UK and the Netherlands [22, 23, 30, 31], the marketing pathways of T&CM products can be either traditional herbal registration (THR) or marketing authorization (MA) via simplified registration for T&CM products as stipulated in the European Directive 2004/24/EC serving as an amendment of Directive 2001/83/EC. Either THR or MA mandates the marketing of T&CM products to be granted based on legislation applicable for all EU countries in the European Economic Area. However, the directive also sees slight variations when implemented in each country as an adaption to the country’s own law [32–35].

The UK use the term herbal medicine to describe T&CM products including CPMs. According to the Human Medicines Regulation (2012), a herbal medicine refers to a product if the active ingredients are herbal substances (reduced or powdered, a tincture, an extract, an essential oil, an expressed juice or a processed exudate) and/or herbal preparations. On the other hand, T&CM products can be referred to herbal medicinal products in the Netherlands. By definition, herbal medicinal products, also referred to as phyto-therapeutic products, are medicinal products whose active ingredients contain exclusively plants, parts of plants or plant materials or combinations thereof, in a crude or processed form. Herbal medicines in the UK are regulated by the Medicines & Healthcare products Regulatory Agency (MHRA) whereas traditional herbal medicinal products in the Netherlands are regulated by the Medicines Evaluation Board.

Unlike the strict centralized marketing authorization applications of the medicines from European Medicines Agency, the decentralized simplified registration procedure which was officially promulgated in 2004 offers a simplified application pathway especially for the T&CM products with a longstanding historical use (used for at least 30 years, including at least 15 years within the EU), and hence provides an opportunity for T&CM products to enter the EU market in an expedited manner. The UK introduced the THR system for T&CM products relatively recently based on the EU Directives. In the Netherlands, presently only two traditional herbal medicinal products from China have been successfully licensed via these simplified procedures and marketed (Diao Xin Xue Kang capsules from Di Ao Group in 2012 and Sichuan, and Danshen Capsules from Tasly Holding Group in 2016) [36, 37]. In UK, the Phynova Cold and Flu Relief Powder for Oral Solution was the first CPMs approved to be marketed in the UK market as a herbal medicine to treat colds.

In the US, there is no category established specifically for T&CM products. For products containing the same herbal ingredients, they may be regulated as drug, cosmetic or device depending on the route of administration, dosage form, formulation, evidence about the safety and the intended use. As a general rule, any product that contains plant materials, algae, macroscopic fungi, or combinations thereof, and is intended to be used as drug (to treat, prevent or mitigate a medical condition) is referred to botanical drug [24]. As far as structure functions claims are concerned, although these are allowed for drugs and dietary supplements, only drugs are allowed to have the structure function claims made specific to certain diseases or other medical conditions. According to the Dietary Supplement Health and Education Act (DSHEA), dietary supplements are not allowed to make any disease-related claims, neither explicitly not implicitly. Therefore, for the purpose of this study, DSHEA and other regulations bound to dietary supplements are not included for analysis.

T&CM products including TCMs containing herbal ingredients and carrying therapeutic claims are mostly considered as botanical drug product and may be marketed under either an over-the-counter drug monograph or an approved new drug application (NDA). For a botanical drug substance to be included in an OTC monograph, the safety and effectiveness must be well-established and supported with sufficient published data generated from adequate and well-controlled clinical studies. For T&CM products which do not have marketing history in the US or a foreign country, do not meet the criteria for inclusion in the OTC drug monograph based on available evidence of safety and effectiveness, nor carry a health claim appropriate for non-prescription use, the botanical drug product must undergo the NDA to obtain marketing approval from the FDA. NDA must be supported with substantial evidence of quality, safety and efficacy derived from adequate and well-controlled clinical studies. The recommendations on quality, nonclinical, clinical, and other unique aspects of botanical drug development are provided in the Guidance for Industry: Botanical Drug Development [38] and are summarized in the following.