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 [32,33,34,35].
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.
Quality of the medicinal products is considered the most important element in the simplified procedures of the application process. The authority requires the submission of evidence of GMP and QC tests for evidence of quality. The quality of the herbal substances, herbal preparations and finished product are required for inspection. For the quality of herbal substance, the Guideline on Good Agricultural and Collection Practice for Starting Materials of Herbal Origin (EMEA/HMPC/24618/2005) must be followed to assure the quality of the herbal substances from the cultivation in the wild, harvest and collection, to primary processing. In particular, detailed descriptions of the plants from which the herbal substances originate are required: botanical characteristics, phytochemical characteristics, toxic constituents, biological/geographical variation, cultivation/harvesting/drying conditions, and pre/post-harvest chemical treatments. The manufacturing site and process must comply with the GMP standards. For the quality of finished products, the manufacturing process, in-process controls and linking specifications, water content, impurities, toxic (heavy) metals microbial limits, mycotoxins (aflatoxins, ochratoxin A), pesticide, fumigation agents will be carefully assessed. The test methods and parameters must be developed with reference to the European Pharmacopoeia or specific monographs. Assays for the contents of the constituents of known therapeutic activity or active markers of the herbal preparations should be determined. Quality tests specific to the dosage form are also applicable.
Unlike the full marketing authorization procedure, the simplified procedures do not require the submission of the full documentation on safety test and clinical trials to demonstrate safety and efficacy. Bibliographic data or toxicological tests to demonstrate safety may be acceptable. According to Article 16c (1) d of Directive 2001/83, safety should be justified by “a bibliographic review of safety data together with an expert report”. The prerequisite of longstanding use of the products has substantiated the safety of the traditional herbal medicinal products without the need of safety test. However, in case there are concerns about the safety of a traditional herbal medicinal product, the marketing authorization holder will have to provide comprehensive data upon the request from the authority.
To provide further guidance on safety assurance of the traditional herbal medicinal products, a number of scientific guidelines have been introduced such as EMEA/HMPC/138139/2005 (allergenicity issues of soya and peanut protein containing products). The establishment of Community herbal monographs or entries to the Community “List of herbal substances, preparations or combinations thereof for use in traditional herbal medicinal products” can be used to identify the new safety aspects of the listed plants, and it has been advised to consult other guidance documents which describe chemical, toxicological, pharmacological and pharmacokinetic properties of the medicinal substances, and provide usage instructions for special products such as herbal medicinal products containing concerning ingredients such as asarone, estragole, methyleugenol, Aristolochia species, etc. To continuously monitor the safety of herbal medicine in UK, a doctor-directed statistical survey is in place to collect post-marketing data about the herbal medicines. Actions of product recall will be triggered should there be high level of safety risk detected.
As defined in the Directive 2001/83/EC, traditional use is justified by bibliographical or expert evidence showing that the medicinal product in question, or a corresponding product has been in medicinal use throughout a period of at least 30 years preceding the date of the application, including at least 15 years within the European Union countries. With the justification of traditional use, the registration procedure can be simpler and less costly without requiring the clinical efficacy data. The documentation of traditional use, if deemed sufficient, will be used as the primary evidence for its safety in specific conditions and plausible efficacy and pharmacological effects. The European herbal handbooks, sales figures and documented use in the Netherlands, as well as France, Belgium and United Kingdom can be used as reference for indicated uses in EU. Moreover, due to inherent complexity of herbal active substance and lack of clinical data, indications for herbal medicines are restricted based on evidence of long standing use evidence in THR (Permitted indications under the Directive on Traditional Herbal Medicinal Products). More specifically, permitted claims of efficacy are only suitable for minor self-limit medical claim such as symptomatic relief cold, minor self-limiting bacterial infections, minor upper respiratory infections and other minor disease. The medical claims about treating more serious diseases such as cardiovascular disease that require proven medical treatments are restricted and require strong clinical data to support their safety and efficacy.