European Medicines Agency (EMA) assessment reports and conclusions

13.             The EMA framework specifies that the main regulatory pathways for bringing an herbal medicinal product to market in EU Member States are traditional use registration or well-established use marketing authorisation. For traditional use, herbal medicinal products can be registered under Article 16a of Directive 2001/83/EC if they have been in medicinal use for at least 30 years, including 15 years within the EU. Evidence of efficacy is based on bibliographic and historical data, demonstrating plausible efficacy and safety, without requiring clinical trials. These products are intended for minor conditions suitable for self-medication and must not be administered by injection. For well-established medicinal use, herbal medicinal products qualify under Article 10a of Directive 2001/83/EC when their active substances have been in well-established medicinal use within the EU for at least 10 years, supported by scientific literature showing recognised efficacy and acceptable safety.

14.             The EMA has published detailed assessment reports on three medicinally used species: E. purpurea (L.) Moench. (EMA, 2014), E. angustifolia DC, radix (EMA, 2012) and E. pallida (Nutt.) Nutt., radix (EMA, 2018). The EMA assessment reports include specifications for the herbal substances, such as active constituents and details on the herbal preparations themselves. In contrast, such specifications are not available for Echinacea-based foods and food supplements, making direct extrapolation from EMA conclusions challenging.

15.             According to the EMA assessment report on E. purpurea, the European Pharmacopoeia defines the herbal substance as the dried, whole or cut flowering aerial parts of E. purpurea with a minimum of 0.1% combined caftaric and cichoric acids content. It is also stated that US Pharmacopeia requires at least 1.0% cichoric acid and 0.01% dodecatetraenoic acid isobutylamides on a dry basis, detailed in the E. purpurea aerial parts pharmacopoeia monograph. Furthermore, the EMA report details that major constituents of E. purpurea include caffeic acid derivatives (cichoric acid 1–5%, caftaric acid, minor feruloyl-tartaric acid), alkylamides (notably dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamide), polysaccharides such as PS I (35 kDa) and PS II (450 kDa), and volatile oils (0.08 – 0.32%) including borneol, bornyl acetate, germacrene D, and caryophyllene (EMA, 2014). The herbal preparation for well-established use consists of expressed juice with drug extract ratio (DER) of 1.5 - 2.1:1 or the dried juice corresponding to expressed juice (EMA monograph, 2014).

16.             The EMA assessment report on E. angustifolia specifies that, according to the European Pharmacopoeia, Echinaceae angustifoliae radix consists of the whole or cut, dried underground parts of E. angustifolia DC and must contain not less than 0.5 % echinacoside. The EMA report details that major constituents of E. angustifolia root include caffeic acid derivatives (1.0 – 1.4%), cynarin (0.12 – 0.14%), chlorogenic acid and cichoric acid. Alkylamides are present at about 0.5%, mainly as isobutylamides and 2-methylbutylamides of straight-chain fatty-acids with olefinic and/or acetylenic bonds e.g. isomeric dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide. The root also contains polysaccharides and glycoproteins, including two polysaccharides (128 kDa and 4.5 kDa) and three glycoproteins (17–30 kDa), with the dominant sugars being arabinose (64–84%), galactose (2–5%), and glucosamine (6%). Volatile oils occur in small amounts (~0.1%) and include dodeca-2,4-diene-1-yl isovalerate and pentadeca-1,8Z-diene. Other constituents include phytomelanin and trace levels of saturated pyrrolizidine-type alkaloids (tussilagine and isotussilagine, approximately 0.006%) (EMA, 2012). The herbal preparation for traditional use consists of comminuted or powdered herbal substance, tincture (ratio of herbal substance to extraction solvent 1:5) or liquid extract (DER 1:1). Both tincture and liquid extract are obtained with 45% v/v ethanol extraction solvent (EMA monograph, 2012).

17.             The EMA assessment report on E. pallida states that, according to the European Pharmacopoeia, Echinaceae pallidae radix consists of the whole or cut, dried underground parts of E. pallida (Nutt.) Nutt and must contain not less than 0.2% echinacoside in the dried drug. Its major constituents are phenylpropanoids, particularly caffeic acid derivatives such as echinacoside (0.5–1.0%), chlorogenic acid, isochlorogenic acid, cynarin, and minor amounts of caftaric and cichoric acids. Unlike other species, alkylamides are essentially absent (approximately 0.001%). The root also contains phytomelanin, polysaccharides and glycoproteins, volatile oils (0.2–2.0%) including polyenes, polyacetylenes, ketoalkenes, and ketoalkenynes (EMA, 2018). The herbal preparation for traditional use consists of dry extract (DER 4-8:1) or tincture (ratio of herbal substance to extraction solvent 1:5), both obtained with 50% v/v ethanol extraction solvent (EMA monograph, 2018).

18.             Studies on reproductive toxicity, genotoxicity and carcinogenicity had not been performed for preparations of E. pallida (EMA, 2018) or E. angustifolia (EMA, 2012) at the time the EMA reports were written. In the absence of these data, the use of these species in pregnancy and lactation was not recommended by EMA. Due to the lack of genotoxicity data, the EMA did not recommend the addition of E. pallida (EMA, 2018) and E. angustifolia (EMA, 2012) to the Community list of herbal substances, herbal preparations and combinations thereof for traditional medicinal products. There were also insufficient clinical data to support the criteria for well-established medicinal use of E. angustifolia and E. pallida roots, in accordance with Directive 2001/83/EC. The traditional use of E. angustifolia and E. pallida root extracts for the relief of common cold symptoms was deemed as acceptably safe by EMA due to longstanding history of use without reports of serious adverse effects.

19.              E. purpurea is on the Community list of herbal substances, herbal preparations and combinations thereof for traditional medicinal products based on traditional topical use for the treatment of small superficial wounds (HMPC, 2007). The benefit-risk assessment, conducted by EMA, concluded that there was sufficient clinical evidence to support the well-established medicinal use, in accordance with Directive 2001/83/EC, of expressed juice preparations from E. purpurea fresh herb for the short-term prevention (maximum 10 days) and treatment of common cold in adults and children over the age of 12 (EMA, 2014).

20.              No genotoxic or mutagenic effects have been observed in bacterial reverse mutation tests, human lymphocyte assay and micronucleus assay with lyophilised E. purpurea (EMA, 2014). There were limited epidemiological data suggesting no adverse effects associated with oral E. purpurea use and pregnancy outcomes (EMA, 2014). However, the EMA did not recommend its use (both topical and oral) during pregnancy and lactation due to the lack of guideline-conforming preclinical data on reproductive and developmental toxicity.