Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Research Paper
Traditional herbal medicines worldwide, from reappraisal to assessment in Europe$ Emiel van Galen CBG-MEB Agency Botanicals & Novel Foods, Graadt van Roggenweg 500, PO Box 8275, 3503 RG Utrecht, The Netherlands
art ic l e i nf o
a b s t r a c t
Article history: Received 12 March 2014 Received in revised form 21 May 2014 Accepted 8 July 2014
Since 2004 the regulatory framework within the European Union has a specific assessment procedure for herbal medicinal products, with a medicinal use based on traditional practice. The main requirement concerning the traditional use is focussed on the period of time for medical use: at least 30 years, including 15 years in the EU. In addition to requirements for quality and safety, an evaluation of pharmacological effects or efficacy based on long-standing use, is a main objective. “Traditional Use” however encompasses European, and non-European traditional use. Outside the EU, the medicinal use of herbal substances, -preparations, and –combinations is well-known, with a long history, which is welldocumented in the different systems of medical practice. This has been addressed by WHO, but it has been acknowledged also by European Commission that herbal products from other systems of medicine, can be subject to the procedure for traditional herbal medicinal products. This paper will focus on the possibilities, restraints, and challenges of regulatory practice in the European Union regarding these category of medicinal products. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Traditional herbal medicinal products Committee on herbal medicinal products Community herbal monographs Ayurveda Traditional chinese medicine
1. Introduction Herbal medicinal products, including traditionally used herbal medicinal products are falling under the scope of the European Directive relating to medicinal products for human use (2001/83/ EC). With the amendment in 2004, a specific category of traditional herbal medicinal products was introduced, having regard the particular characteristics of these medicinal products, especially their long tradition (2004/24/EC). The simplified registration is considered to be acceptable only where the herbal medicinal product may rely on a sufficiently long medicinal use in the European Union. Medicinal use outside the European Union should be taken into account only if the medicinal product has been used within the EU for at least 15 years. Where there is limited evidence of use within the EU, it is necessary to assess carefully the validity and relevance of the use in other parts
Abbreviations used: ANVISA, Agência nacional de vigilância sanitária, Brazil; EMA, European medicines agency; EU, European union; HMPC, Committee on herbal medicinal products; HAS, Health science authority, Singapore; PDMA, Pharmaceutical and medical devices agency, Japan; TCM, Traditional chinese medicine; WHO, World health organization ☆ Legal disclaimer: The views expressed in this paper are my personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the Medicines Evaluation Board in the Netherlands, or of the European Medicines Agency or one of its committees or working parties. E-mail address: [email protected]
of the World, or within the framework of non-Western systems of traditional medicine. This paper will explore the legal provisions for traditional herbal medicinal products within the EU regulatory framework, when applied to herbal medicinal products based on medicinal use in “non-European” traditions (Table 1).
2. Traditional medicine worldwide Since 1978 World Health Organization is paying considerable attention to traditional medicine (WHO 1978), with the new WHO traditional medicine strategy 2014–2023 (WHO 2013), described by Zhang Qi in this issue, as most recent development. WHO's strategy makes a stronger emphasis on development of traditional medicine, instead of a focus on traditional medicinal products, as in the EU regulatory framework. “Traditional medicine” is defined by WHO as: “Traditional medicine has a long history. It is the sum total of the knowledge, skill, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness (WHO http://www.who.int/medicines/areas/tradi tional/definitions/en/). Although sometimes traditional knowledge, skills, and practices are far away from the principles of Western scientific medicine, the place of traditional medicine has not been ignored when the European framework for traditional
http://dx.doi.org/10.1016/j.jep.2014.07.013 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
E. van Galen / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Table 1 Examples of traditional medicine worldwide. Ayurvedic medicine Siddha medicine Unani medicine Arabic medicine Kampo medicine gSo-ba Rig-pa – Bhutanese medicine Australian bush medicine
Traditional Chinese Medicine (TCM) Tibetan, Mongolian, Uighur medicine Traditional African Medicine Traditional Korean Medicine Traditional Thai Medicine Traditional medicine of native Indians, in North and South America Rongoā – traditional Maori medicine
Use of medicinal plants in: Vietnam and Laos South Africa South Pacific Indonesia Guiana's: Guyana, Surinam, French Guiana Papua New Guinea
Table 2 Ways of interpretation of article 16a (1)e Directive 2001/83/EU. The data on the tradition of the medicinal use of the product are sufficient;
The justification of the tradition of the medicinal use of the active substance is sufficient; In particular the product proves not to be harmful in the specified conditions of use and In particular the traditional use and the long experience demonstrate that the product the pharmacological effects or efficacy are scientifically justified and are plausible. is not harmful and the pharmacological effects or efficacy are made plausible for the There is a long-standing use and tradition. specified active constituents and are in accordance with the principles of the specific medical tradition.
herbal medicinal products based upon long-standing use, was established in 2004. In this paper the focus will remain on “medicinal products”, subject to the regulatory system in the European Union. However, numerous products from nonEuropean traditions are on the markets of the EU Member States, without regulation on quality, safety, and the medicinal use.
3. European legislation and intentions In “Communication from the Commission to the Council and the European Parliament concerning….specific provisions applicable to traditional herbal medicinal products”, published in 2008 (COM 584), extensive clarification was given on the backgrounds for traditional medicines, used in other parts of the world than the European Union, as well as the considerations of the legislator. As main examples, Ayurveda and Traditional Chinese Medicine are mentioned, for both it is obvious that the European Commission is aware of the long tradition outside Europe (“have existed for centuries in other parts of the world” – COM 584), the concepts of healing of both, and to what extend the simplified procedure for traditional herbal medicinal products could be followed to get a registration in the EU. When speaking of a possible extension of the scope for medicinal products based on long-standing use and experience this is, for example related to “certain medicinal products from specific….nonEuropean medicine systems (such as..Ayurvedic, Chinese, Kampo, Korean, Mongolian, Thai, Tibetan, Unani, or Vietnamese medicine” – COM 584), but it is not clarified which medicinal products from non-European medicine systems already are eligible for the simplified registration procedure with a view to placing them on the market as traditional medicinal products. And those, which are not. The simplified registration for an herbal medicinal product is acceptable only where the product may rely on at least 30 years of medicinal use. Medicinal use outside the European Union can be taken into account only if the medicinal product has been used in the European Union for at least 15 years.
purposes or for prescription or monitoring of treatment; in accordance with a specified strength and posology; by oral, external and/or inhalation preparation; the medicinal product has been in use throughout period of at least 30 years preceding the date of application, including at least 15 years with the European Union. Especially in cases of doubt regarding the evaluation of the period of time, specific referral procedures have been established (NtA Vol.2A), in which the Herbal Medicinal Products Committee can draw up an opinion, if requested by a Member State. The core of the scientific assessment is expected to give an opinion whether the data of the traditional use of the medicinal product are sufficient; in particular the product proves not to be harmful under the specified conditions of use and the pharmacological effects or efficacy of the medicinal product are plausible on the basis of long-standing use and tradition. (art. 16a (1)e, 2001/83/ EC). Taking into account the limitation of the scope of this procedure, there is no doubt that this basis for assessment is applicable for medicinal products used in both a European tradition, and in a non-European tradition. For all traditional herbal medicinal products, the long-standing use and the tradition has to be assessed. Since the establishment of the specific provisions, very limited experience is gained in Member states for medicinal products from non-European traditions (Table 2). For applications for traditional herbal medicinal products, the competent authority lies at the Member States of the EU. During the last years only a very few applications have been assessed for medicinal products with a tradition outside the European Union. Only Diao Xin Xue Kang capsules were successfully registered in the Netherlands, but according to the public announcement and the published Public Assessment Report (CBG-PAR 2012- http://db. cbg-meb.nl/Pars/h102142.pdf), the assessment by the Dutch MEB does not give an opinion about the principles of TCM. Until now, no Referral procedures are initiated at the HMPC, for herbal medicinal products from non-European traditions as well. More national applications and an appropriate use of the Referral procedures for traditional herbal medicinal products could increase the regulatory experience on relevant issues.
4. Assessment of traditional herbal medicinal products Assessment following the specific provisions applicable to traditional herbal medicinal products (art. 16a (1), 2001/83/EC) is possible for a herbal medicinal product with indications used without the supervision of a medical practioner for diagnostic
5. Community herbal monographs and non-European traditions The Committee on Herbal Medicinal Products shall establish Community herbal monographs for herbal medicinal products
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
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with regard to bibliographical applications (art. 10a, 2001/83/EC) as well as traditional herbal medicinal products. Since 2004 a number of 125 Community herbal monographs have been published, and for some 15 other herbal substances Public Statements were established, giving reasons why at that time no Monograph could be established by the Committee. The current Herbal monographs are focusing on the use in Europe, but numerous herbal substances in these monographs are also used in nonEuropean herbal traditions: Curcuma rhizome (Curcuma longa) is used in TCM as Huang jiang 黄姜, in Ayurveda known as Haridra, in Pakistan as Haldi and in Indonesia as Temoe lawak; Arctii radix (Arctium lappa) as Niu bang zi 牛蒡子; Equiseti herba (Equisetum arvense) as Mu zei 木 贼; Zingiberis rhizome is known in Ayurveda as Ardhrakam or Viswasbhesaja and other preparations of Zingiber officinale are used in TCM as Sheng jiang 生姜 (rhizoma recens), Gan jiang 干姜 (rhizoma exsiccatum) and as Pao jiang 炮姜 (rhizoma preparatum), known in Pakistan as Adrak . HMPC established a Herbal monograph for Fraxini folii (Fraxinus excelsior), while Fraxini cortex is used in TCM (Qin pi 秦皮 ); Rhei radix (Rheum palmatum/Rheum officinale) as Da huang 大黄; Even well-known European herbal substances can be part of non-European traditions as well: Senna folium, Fan xie ye 番泻叶; Plantginis semen, Che qian zi 车前子 and Foeniculi fructus is known as Satuspuspa, and in Pakistan as Saunf . Cichori herba as Kasni in Ayurveda ( in Pakistan). Paulinia cupana (Guarana) is called Guisador or Azafran in South-America. The use of traditional herbal medicinal products outside Europe was noticed during assessment, but not established because of a lack of submitted bibliographical data. Public Statements published by the HMPC are referring to: Angelica sinensis (Dong quai, Dang gui 當歸), Adhatoda vasica (Vasaka), Andrographs paniculata (Bhunimba; Chuan xin lian 穿心 蓮 ) and Withania somnifera (Ashwagandha). These indicate a lack of proof that herbal medicinal products have been on the European market for at least 15 years. For reason that no Community monographs for traditional use could be established. Nevertheless, similar herbal substances and herbal preparations are in use elsewhere in the world, named in different languages, with a long historical use, and based on principles of therapy, which are still not really known in EU regulatory practice. To take into account the traditional use outside EU, a precise declaration (HMPC 2010) of corresponding herbal substances or – preparations is indispensable. For the comparison of names, e.g. in drafting Herbal monographs, the Latin and English names should be related to local names (for example in Chinese Pinyin), but also scientific translation from other systems of writing (see as examples Chinese sinograms, or in Urdu in Pakistan), will need specific linguistic expertise. Global harmonization of official Pharmacopoeias concerning herbal drugs, can play an important role. For the period 2012–2015 HMPC is committed to establish further regulatory guidance for applicants and interested parties, located outside the European Union. As a result, a new Questions & Answers document has been published (HMPC-QA 2014), clarifying all relevant aspects of the EU framework for (traditional) herbal medicinal products, including those from a non-European tradition. Discussions are ongoing to facilitate harmonization of assessment practice for herbal substances from non-European origin, at first instance related to the assessment of the submitted material in support of the establishment of Community monographs. Although in the Commission Communication (COM 584) it is acknowledged that many of these products are on the European market while differences still exist as regards classification between Member States, at the same time it is emphasized that the regulatory framework in the EU is based on a product-specific approach, and does not attempt to provide a framework for the
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regulation of different kinds of traditions of medical practice, or non-Western systems of medicine.
6. Global perspectives In 2012, Tai-Ping Fan eo., presented an extensive overview of different global regulations for Chinese herbal medicines, demonstrating that different global regulations applicable to traditional medicines in the European Union, China, Japan, South Korea, Taiwan, Russian Federation, Australia, Canada, United States and in Brazil can be divergent, have different approaches, and are following different classifications, which at first sight are difficult to harmonize. (Fan et al., 2012) Nevertheless a global approach towards regulation of traditional medicines and traditional systems of medicine seems to be the preferable way, not at least because these products already are used all over the world. In Chengdu, China, September 2013 at the 4th International Conference on the modernization of Traditional Chinese Medicine, not only the Chinese and European points of view were expressed, but also countries like Thailand, South Africa, Laos, Myanmar and Cambodia presented national policies concerning the quality and safety of traditional medicines. In Singapore, Health Sciences Authority (HSA) has specific guidelines for Chinese Proprietary Medicines, other traditional medicines and health supplements, including a decision tree for classification. Subsequently, in Bonn at the TradReg Symposium, October 2013, respective regulatory approaches in Brazil (ANVISA), Health Canada, Japan (PMDA), and US FDA could be mirrored with the European Union approach to traditional herbal medicinal products. It became obvious, that there is not one tradition on one national market. And in spite of several traditional systems of medicine, many products already are present at a global market.
7. Challenges for assessment within the European framework For the scientific assessment of traditional herbal medicinal products in the European regulatory framework, two major challenges have to be identified for non-European traditional products, both are not addressed specifically in the legislation: The perspective for assessment, and the indication which finally can be accepted. These key-issues are relevant for the assessment of submissions based on article 16a, at the Competent authorities of the EU Member States, as well as for establishing Community Herbal Monographs by the HMPC. 7.1. Perspectives for assessment Assessment of the data on the traditional use of the medicinal product conclude that the product proves not to be harmful under the specified conditions of use and the pharmaceutical effects or efficacy of the medicinal product are plausible on the basis of longstanding use and experience. (art. 16a (1)e, 2001/83/EC). First, the traditional use can be evaluated from a pharmacological perspective: The pharmacological activity of the herbal substance/-preparation has to be demonstrated, the role of possible active constituents can be identified. Information of the principles of the respective traditional medicine is not requested, only proof for the period of time (30/15 years) will be assessed and long-standing use is only supportive. Only Western indications can be accepted, and only in the labeling, the specific tradition can be mentioned. The current assessors of herbal medicinal products and members of HMPC have the expertise for this task.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
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Secondly, assessment from a traditional perspective: the plausibility of the pharmacological effects or efficacy can be justified based on the long-standing use and experience in a specific population (in- and outside EU), and the pharmacological effects of the herbal substance/-preparation are also related to the traditional medical practice. Information of the principles of the non-European tradition is part of the assessment. Indications following traditional understanding are allowed. Thirdly, assessment from a combined perspective (1 þ2): the plausibility of the pharmacological effects or efficacy of the herbal substance/-preparation is demonstrated, the role of possible active constituents are identified, but in the light of the principles and historical practice of the traditional system of medicine, which should be part of the data submitted. For this approach, combined expertise is needed. 7.2. Assessment of indications For a simplified registration procedure, based on traditionaluse, the first condition is that the products have indications exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practioner for diagnostic purposes or for prescription or monitoring of treatment. (article 16a (1)a, 2001/83/EC). In practice considered an “indication suitable for self-care”, “minor ailments”, or “indications for which no medical diagnosis is required in advance”. For traditional herbal medicinal products founded in a non-western system of medicine, two issues can be identified: In many non-western systems of medicine, medicinal products or traditional formulations are used on a personalized basis: the composition of the medicinal product is tailored for the individual patient, based on a traditional diagnosis. Consequently, traditional medicinal products from non-European traditions often start an application in the European framework standing on two feet: a Western indication for which registration is requested, but with a dossier justifying the traditional use in terms of, for example Traditional Chinese Medicine, or the principles of Ayurveda. During assessment, discussions arise how the traditional indication, can be “translated” into a western diagnosis. It seems that this is easier to establish from non-European point of view, than to accept in the European regulatory practice. First, the traditional-use indication is established from a pharmacological perspective: these are the indications for traditional herbal medicinal products which are established in Community herbal monographs: “Traditional herbal medicinal product for mild articular pain exclusively based upon long-standing use”. Secondly, the traditional-use indication is established from a traditional perspective: For example “Traditional Chinese herbal medicinal product used for treatment of deficiency of Kidney Yang and Spleen Qi, in its inability to transform, transport and evaporate fluids in the lower burner. The use is exclusively based on the principles of Traditional Chinese Medicine”. Thirdly, the traditional-use indication is established from a combined perspective: As a result of a national assessment, or as a result of establishing a Community herbal monograph by HMPC, a double indication is possible: A western indication suitable for self-care (taking into account the requirements in article 16a (1)a ), with the addition “equivalent to Vata Dosha imbalance, according to the principles for Ayurvedic medicine.” In the Commission Report (COM 584), this issue has been addressed by the legislator: “Medical traditions such as those mentioned above are based on a holistic approach, and the set of requirements for the simplified registration procedure under Directive 2004/24/EC is not appropriate for a global regulation of such medical practices. The regulation of such traditions would demand a different
approach from that introduced by Directive 2004/24/EC. Therefore, the Commission does not envisage extending the scope of the simplified registration procedure to cover traditional medical systems as such. Nevertheless, independently of this report, the suitability of a separate legal framework for products of certain traditions should be assessed”. Nevertheless it is questionably, whether a separate legal framework is necessary to cover traditional medical systems as such. In regulatory practice, the more relevant question is whether specific traditional indications based on long-standing use for at least 30 years outside the European Union, can be part of the outcome of the simplified registration procedure. 7.3. Community herbal monographs and non-European traditions: With a growing number of Community herbal monographs, more herbal substances in these monographs know a traditional use (also) in traditional medicine in other parts of the world. In several published assessment reports of HMPC, this is acknowledged. But in most cases, specific references are not unambiguous, or were simply not made available during the assessment by HMPC. One example is the Assessment Report (HMPC-AR 2008) and Overview of Comments (HMPC-OC 2008) of the Herbal monograph on Foeniculum vulgare Miller subsp. vulgare var. vulgare, fructus, in which the use of fennel in TCM has been considered; another example the Assessment report on Curcuma longa rhizoma (HMPC-AR 2010), in which the use outside the EU, in China (TCM), Japan and Korea, and in India (in Ayurveda, Unani and Siddha medicine), as well as inclusion in respective Pharmacopoeias is addressed. Extension the work on Community herbal monographs to non-European traditions is still under discussion.
8. Conclusions The ways, different kinds of “traditional medicinal use” worldwide are assessed, are not fully explored nor harmonized yet, considered from a regulatory point of view. The use of corresponding or even similar herbal products in different parts of the world can make scientific assessment based on principles of longstanding use, complicated. Since 2004, the EU regulatory framework for herbal medicinal products based on traditional use has developed to a more transparent system, both on the level of EU Member States, but also on European level with the publication of Community Herbal Monographs by the HMPC in London. At this moment the European approach has to respond to the growing interest of herbal medicinal products, having their basis in a nonEuropean tradition. Several of these products already are marketed as medicinal products all over the world, regulated by competent authorities with regulations equally aiming on good quality and safety, but also taking into account the traditional background of medicinal use. In the next years, the EU regulatory framework has to move forewards, but could benefit from the experiences of competent authorities in other parts of the world, in order to follow the long way from reappraisal to assessment of these medicinal products. References COM 584 - Communication from the European Commission to the Council and the European Parliament concerning the report on the experience acquired as a result of the applications of the provisions applicable to traditional herbal medicinal products, Brussels, 29-09-2008, COM(2008) 584 final. 〈http://eur-lex. europa.eu/LexUriServ/LexUriServ.do?uri=COM:2008:0584:FIN:en:PDF〉. CBG-PAR 2012 - College ter beoordeling van geneesmiddelen/Medicines Evaluation Board – Public Assessment Report Diao Xin Xue Kang capsules for oral use. 1403-2012, 〈http://db.cbg-meb.nl/Pars/h102142.pdf〉.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
E. van Galen / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 2001/83/EC - Directive of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to medicinal products for human use. Consolidated version, 16-11-2012, 〈http://ec.europa.eu/health/files/eudra lex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf〉. 2004/24/EC - Directive of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community Code relating to medicinal products for human use. (Official Journal L 136, 30-4-2004, p85-90), 〈http://ec.europa.eu/health/ files/eudralex/vol-1/dir_2004_24/dir_2004_24_en.pdf〉. Fan, TP., Deal, G., Koo, HL., Rees, D., Sun, H., Chen, S., Dou, JH., Makarov, VG., Pozharitskaya, ON., Shikov, AN., Kim, YS., Huang, YT., Chang, YS., Jia, W., Dias, A., Wong, VCW., Chan, K., 2012. Future development of global regulations of Chinese herbal products. Journal of Ethnopharmacology 140 (2012), 568–586. HMPC 2010 - Committee on Herbal Medicinal Products – Guideline on the Declaration of herbal substances and herbal preparations in herbal medicinal products/traditional herbal medicinal products. (EMA/HMPC/CHMP/CVMP/ 287539/2005 rev 1). Published april 2010, 〈http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2009/09/WC500003272.pdf〉. HMPC-AR 2008 - Committee on Herbal Medicinal Products – HMPC Assessement Report on Foeniculum vulgare Miller subsp, vulgare, var. vulgare, fructus (EMEA/HMPC/137426/2006), published 20-02-2008. 〈http://www.ema.europa. eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2009/ 12/WC500018463.pdf〉. HMPC-OC 2008 - Committee on Herbal Medicinal Products - Overview of comments reveived on the Community herbal monograph on HMPC
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Assessement Report on Foeniculum vulgare Miller subsp, vulgare, var. vulgare, fructus (EMEA/HMPC/200856/2007), published 20-02-2008. 〈http://www.ema. europa.eu/docs/en_GB/document_library/Herbal_-_Overview_of_comments_re ceived_during_consultation/2009/12/WC500018456.pdf〉. HMPC-AR 2010 - Committee on Herbal Medicinal Products – HMPC Assessement Report on Curcuma longa L., rhizoma (EMEA/HMPC/456848/2008), published 4-02-2010 〈http://www.ema.europa.eu/docs/en_GB/document_library/Her bal_-_HMPC_assessment_report/2010/02/WC500070700.pdf〉. HMPC-QA 2014 - Committee on Herbal Medicinal Products – Questions & Answers on the European framework for (traditional) herbal medicinal products, including those from a “non-European” tradition. (EMA/HMPC/402684/2013), 〈http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_ procedural_guideline/2014/05/WC500166358.pdf〉. NtA Vol.2A - European Commission - Notice to Applicants Volume 2A – Procedures for marketing authorisation, Chapter 3, Community Referral Procedures (Part B), Brussels ENTR/F2/SM D, September 2007. 〈http://ec.europa.eu/health/files/ eudralex/vol-2/a/vol2a_chap3_rev09-2007_en.pdf〉. WHO 1978 - World Health Organization – The promotion and development of traditional medicine, report of a WHO meeting, Geneva 1978, ISBN 9241206225, 〈http://apps.who.int/medicinedocs/documents/s7147e/s7147e. pdf〉. WHO 2013 - World Health Organization – WHO Traditional Medicine Strategy 2014-2023, Geneva 2013, ISBN 9789241506090. 〈http://apps.who.int/iris/bit stream/10665/92455/1/9789241506090_eng.pdf?ua=1〉.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
Contents lists available at ScienceDirect
Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Research Paper
Traditional herbal medicines worldwide, from reappraisal to assessment in Europe$ Emiel van Galen CBG-MEB Agency Botanicals & Novel Foods, Graadt van Roggenweg 500, PO Box 8275, 3503 RG Utrecht, The Netherlands
art ic l e i nf o
a b s t r a c t
Article history: Received 12 March 2014 Received in revised form 21 May 2014 Accepted 8 July 2014
Since 2004 the regulatory framework within the European Union has a specific assessment procedure for herbal medicinal products, with a medicinal use based on traditional practice. The main requirement concerning the traditional use is focussed on the period of time for medical use: at least 30 years, including 15 years in the EU. In addition to requirements for quality and safety, an evaluation of pharmacological effects or efficacy based on long-standing use, is a main objective. “Traditional Use” however encompasses European, and non-European traditional use. Outside the EU, the medicinal use of herbal substances, -preparations, and –combinations is well-known, with a long history, which is welldocumented in the different systems of medical practice. This has been addressed by WHO, but it has been acknowledged also by European Commission that herbal products from other systems of medicine, can be subject to the procedure for traditional herbal medicinal products. This paper will focus on the possibilities, restraints, and challenges of regulatory practice in the European Union regarding these category of medicinal products. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Traditional herbal medicinal products Committee on herbal medicinal products Community herbal monographs Ayurveda Traditional chinese medicine
1. Introduction Herbal medicinal products, including traditionally used herbal medicinal products are falling under the scope of the European Directive relating to medicinal products for human use (2001/83/ EC). With the amendment in 2004, a specific category of traditional herbal medicinal products was introduced, having regard the particular characteristics of these medicinal products, especially their long tradition (2004/24/EC). The simplified registration is considered to be acceptable only where the herbal medicinal product may rely on a sufficiently long medicinal use in the European Union. Medicinal use outside the European Union should be taken into account only if the medicinal product has been used within the EU for at least 15 years. Where there is limited evidence of use within the EU, it is necessary to assess carefully the validity and relevance of the use in other parts
Abbreviations used: ANVISA, Agência nacional de vigilância sanitária, Brazil; EMA, European medicines agency; EU, European union; HMPC, Committee on herbal medicinal products; HAS, Health science authority, Singapore; PDMA, Pharmaceutical and medical devices agency, Japan; TCM, Traditional chinese medicine; WHO, World health organization ☆ Legal disclaimer: The views expressed in this paper are my personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the Medicines Evaluation Board in the Netherlands, or of the European Medicines Agency or one of its committees or working parties. E-mail address: [email protected]
of the World, or within the framework of non-Western systems of traditional medicine. This paper will explore the legal provisions for traditional herbal medicinal products within the EU regulatory framework, when applied to herbal medicinal products based on medicinal use in “non-European” traditions (Table 1).
2. Traditional medicine worldwide Since 1978 World Health Organization is paying considerable attention to traditional medicine (WHO 1978), with the new WHO traditional medicine strategy 2014–2023 (WHO 2013), described by Zhang Qi in this issue, as most recent development. WHO's strategy makes a stronger emphasis on development of traditional medicine, instead of a focus on traditional medicinal products, as in the EU regulatory framework. “Traditional medicine” is defined by WHO as: “Traditional medicine has a long history. It is the sum total of the knowledge, skill, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness (WHO http://www.who.int/medicines/areas/tradi tional/definitions/en/). Although sometimes traditional knowledge, skills, and practices are far away from the principles of Western scientific medicine, the place of traditional medicine has not been ignored when the European framework for traditional
http://dx.doi.org/10.1016/j.jep.2014.07.013 0378-8741/& 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
E. van Galen / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
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Table 1 Examples of traditional medicine worldwide. Ayurvedic medicine Siddha medicine Unani medicine Arabic medicine Kampo medicine gSo-ba Rig-pa – Bhutanese medicine Australian bush medicine
Traditional Chinese Medicine (TCM) Tibetan, Mongolian, Uighur medicine Traditional African Medicine Traditional Korean Medicine Traditional Thai Medicine Traditional medicine of native Indians, in North and South America Rongoā – traditional Maori medicine
Use of medicinal plants in: Vietnam and Laos South Africa South Pacific Indonesia Guiana's: Guyana, Surinam, French Guiana Papua New Guinea
Table 2 Ways of interpretation of article 16a (1)e Directive 2001/83/EU. The data on the tradition of the medicinal use of the product are sufficient;
The justification of the tradition of the medicinal use of the active substance is sufficient; In particular the product proves not to be harmful in the specified conditions of use and In particular the traditional use and the long experience demonstrate that the product the pharmacological effects or efficacy are scientifically justified and are plausible. is not harmful and the pharmacological effects or efficacy are made plausible for the There is a long-standing use and tradition. specified active constituents and are in accordance with the principles of the specific medical tradition.
herbal medicinal products based upon long-standing use, was established in 2004. In this paper the focus will remain on “medicinal products”, subject to the regulatory system in the European Union. However, numerous products from nonEuropean traditions are on the markets of the EU Member States, without regulation on quality, safety, and the medicinal use.
3. European legislation and intentions In “Communication from the Commission to the Council and the European Parliament concerning….specific provisions applicable to traditional herbal medicinal products”, published in 2008 (COM 584), extensive clarification was given on the backgrounds for traditional medicines, used in other parts of the world than the European Union, as well as the considerations of the legislator. As main examples, Ayurveda and Traditional Chinese Medicine are mentioned, for both it is obvious that the European Commission is aware of the long tradition outside Europe (“have existed for centuries in other parts of the world” – COM 584), the concepts of healing of both, and to what extend the simplified procedure for traditional herbal medicinal products could be followed to get a registration in the EU. When speaking of a possible extension of the scope for medicinal products based on long-standing use and experience this is, for example related to “certain medicinal products from specific….nonEuropean medicine systems (such as..Ayurvedic, Chinese, Kampo, Korean, Mongolian, Thai, Tibetan, Unani, or Vietnamese medicine” – COM 584), but it is not clarified which medicinal products from non-European medicine systems already are eligible for the simplified registration procedure with a view to placing them on the market as traditional medicinal products. And those, which are not. The simplified registration for an herbal medicinal product is acceptable only where the product may rely on at least 30 years of medicinal use. Medicinal use outside the European Union can be taken into account only if the medicinal product has been used in the European Union for at least 15 years.
purposes or for prescription or monitoring of treatment; in accordance with a specified strength and posology; by oral, external and/or inhalation preparation; the medicinal product has been in use throughout period of at least 30 years preceding the date of application, including at least 15 years with the European Union. Especially in cases of doubt regarding the evaluation of the period of time, specific referral procedures have been established (NtA Vol.2A), in which the Herbal Medicinal Products Committee can draw up an opinion, if requested by a Member State. The core of the scientific assessment is expected to give an opinion whether the data of the traditional use of the medicinal product are sufficient; in particular the product proves not to be harmful under the specified conditions of use and the pharmacological effects or efficacy of the medicinal product are plausible on the basis of long-standing use and tradition. (art. 16a (1)e, 2001/83/ EC). Taking into account the limitation of the scope of this procedure, there is no doubt that this basis for assessment is applicable for medicinal products used in both a European tradition, and in a non-European tradition. For all traditional herbal medicinal products, the long-standing use and the tradition has to be assessed. Since the establishment of the specific provisions, very limited experience is gained in Member states for medicinal products from non-European traditions (Table 2). For applications for traditional herbal medicinal products, the competent authority lies at the Member States of the EU. During the last years only a very few applications have been assessed for medicinal products with a tradition outside the European Union. Only Diao Xin Xue Kang capsules were successfully registered in the Netherlands, but according to the public announcement and the published Public Assessment Report (CBG-PAR 2012- http://db. cbg-meb.nl/Pars/h102142.pdf), the assessment by the Dutch MEB does not give an opinion about the principles of TCM. Until now, no Referral procedures are initiated at the HMPC, for herbal medicinal products from non-European traditions as well. More national applications and an appropriate use of the Referral procedures for traditional herbal medicinal products could increase the regulatory experience on relevant issues.
4. Assessment of traditional herbal medicinal products Assessment following the specific provisions applicable to traditional herbal medicinal products (art. 16a (1), 2001/83/EC) is possible for a herbal medicinal product with indications used without the supervision of a medical practioner for diagnostic
5. Community herbal monographs and non-European traditions The Committee on Herbal Medicinal Products shall establish Community herbal monographs for herbal medicinal products
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with regard to bibliographical applications (art. 10a, 2001/83/EC) as well as traditional herbal medicinal products. Since 2004 a number of 125 Community herbal monographs have been published, and for some 15 other herbal substances Public Statements were established, giving reasons why at that time no Monograph could be established by the Committee. The current Herbal monographs are focusing on the use in Europe, but numerous herbal substances in these monographs are also used in nonEuropean herbal traditions: Curcuma rhizome (Curcuma longa) is used in TCM as Huang jiang 黄姜, in Ayurveda known as Haridra, in Pakistan as Haldi and in Indonesia as Temoe lawak; Arctii radix (Arctium lappa) as Niu bang zi 牛蒡子; Equiseti herba (Equisetum arvense) as Mu zei 木 贼; Zingiberis rhizome is known in Ayurveda as Ardhrakam or Viswasbhesaja and other preparations of Zingiber officinale are used in TCM as Sheng jiang 生姜 (rhizoma recens), Gan jiang 干姜 (rhizoma exsiccatum) and as Pao jiang 炮姜 (rhizoma preparatum), known in Pakistan as Adrak . HMPC established a Herbal monograph for Fraxini folii (Fraxinus excelsior), while Fraxini cortex is used in TCM (Qin pi 秦皮 ); Rhei radix (Rheum palmatum/Rheum officinale) as Da huang 大黄; Even well-known European herbal substances can be part of non-European traditions as well: Senna folium, Fan xie ye 番泻叶; Plantginis semen, Che qian zi 车前子 and Foeniculi fructus is known as Satuspuspa, and in Pakistan as Saunf . Cichori herba as Kasni in Ayurveda ( in Pakistan). Paulinia cupana (Guarana) is called Guisador or Azafran in South-America. The use of traditional herbal medicinal products outside Europe was noticed during assessment, but not established because of a lack of submitted bibliographical data. Public Statements published by the HMPC are referring to: Angelica sinensis (Dong quai, Dang gui 當歸), Adhatoda vasica (Vasaka), Andrographs paniculata (Bhunimba; Chuan xin lian 穿心 蓮 ) and Withania somnifera (Ashwagandha). These indicate a lack of proof that herbal medicinal products have been on the European market for at least 15 years. For reason that no Community monographs for traditional use could be established. Nevertheless, similar herbal substances and herbal preparations are in use elsewhere in the world, named in different languages, with a long historical use, and based on principles of therapy, which are still not really known in EU regulatory practice. To take into account the traditional use outside EU, a precise declaration (HMPC 2010) of corresponding herbal substances or – preparations is indispensable. For the comparison of names, e.g. in drafting Herbal monographs, the Latin and English names should be related to local names (for example in Chinese Pinyin), but also scientific translation from other systems of writing (see as examples Chinese sinograms, or in Urdu in Pakistan), will need specific linguistic expertise. Global harmonization of official Pharmacopoeias concerning herbal drugs, can play an important role. For the period 2012–2015 HMPC is committed to establish further regulatory guidance for applicants and interested parties, located outside the European Union. As a result, a new Questions & Answers document has been published (HMPC-QA 2014), clarifying all relevant aspects of the EU framework for (traditional) herbal medicinal products, including those from a non-European tradition. Discussions are ongoing to facilitate harmonization of assessment practice for herbal substances from non-European origin, at first instance related to the assessment of the submitted material in support of the establishment of Community monographs. Although in the Commission Communication (COM 584) it is acknowledged that many of these products are on the European market while differences still exist as regards classification between Member States, at the same time it is emphasized that the regulatory framework in the EU is based on a product-specific approach, and does not attempt to provide a framework for the
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regulation of different kinds of traditions of medical practice, or non-Western systems of medicine.
6. Global perspectives In 2012, Tai-Ping Fan eo., presented an extensive overview of different global regulations for Chinese herbal medicines, demonstrating that different global regulations applicable to traditional medicines in the European Union, China, Japan, South Korea, Taiwan, Russian Federation, Australia, Canada, United States and in Brazil can be divergent, have different approaches, and are following different classifications, which at first sight are difficult to harmonize. (Fan et al., 2012) Nevertheless a global approach towards regulation of traditional medicines and traditional systems of medicine seems to be the preferable way, not at least because these products already are used all over the world. In Chengdu, China, September 2013 at the 4th International Conference on the modernization of Traditional Chinese Medicine, not only the Chinese and European points of view were expressed, but also countries like Thailand, South Africa, Laos, Myanmar and Cambodia presented national policies concerning the quality and safety of traditional medicines. In Singapore, Health Sciences Authority (HSA) has specific guidelines for Chinese Proprietary Medicines, other traditional medicines and health supplements, including a decision tree for classification. Subsequently, in Bonn at the TradReg Symposium, October 2013, respective regulatory approaches in Brazil (ANVISA), Health Canada, Japan (PMDA), and US FDA could be mirrored with the European Union approach to traditional herbal medicinal products. It became obvious, that there is not one tradition on one national market. And in spite of several traditional systems of medicine, many products already are present at a global market.
7. Challenges for assessment within the European framework For the scientific assessment of traditional herbal medicinal products in the European regulatory framework, two major challenges have to be identified for non-European traditional products, both are not addressed specifically in the legislation: The perspective for assessment, and the indication which finally can be accepted. These key-issues are relevant for the assessment of submissions based on article 16a, at the Competent authorities of the EU Member States, as well as for establishing Community Herbal Monographs by the HMPC. 7.1. Perspectives for assessment Assessment of the data on the traditional use of the medicinal product conclude that the product proves not to be harmful under the specified conditions of use and the pharmaceutical effects or efficacy of the medicinal product are plausible on the basis of longstanding use and experience. (art. 16a (1)e, 2001/83/EC). First, the traditional use can be evaluated from a pharmacological perspective: The pharmacological activity of the herbal substance/-preparation has to be demonstrated, the role of possible active constituents can be identified. Information of the principles of the respective traditional medicine is not requested, only proof for the period of time (30/15 years) will be assessed and long-standing use is only supportive. Only Western indications can be accepted, and only in the labeling, the specific tradition can be mentioned. The current assessors of herbal medicinal products and members of HMPC have the expertise for this task.
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Secondly, assessment from a traditional perspective: the plausibility of the pharmacological effects or efficacy can be justified based on the long-standing use and experience in a specific population (in- and outside EU), and the pharmacological effects of the herbal substance/-preparation are also related to the traditional medical practice. Information of the principles of the non-European tradition is part of the assessment. Indications following traditional understanding are allowed. Thirdly, assessment from a combined perspective (1 þ2): the plausibility of the pharmacological effects or efficacy of the herbal substance/-preparation is demonstrated, the role of possible active constituents are identified, but in the light of the principles and historical practice of the traditional system of medicine, which should be part of the data submitted. For this approach, combined expertise is needed. 7.2. Assessment of indications For a simplified registration procedure, based on traditionaluse, the first condition is that the products have indications exclusively appropriate to traditional herbal medicinal products which, by virtue of their composition and purpose, are intended and designed for use without the supervision of a medical practioner for diagnostic purposes or for prescription or monitoring of treatment. (article 16a (1)a, 2001/83/EC). In practice considered an “indication suitable for self-care”, “minor ailments”, or “indications for which no medical diagnosis is required in advance”. For traditional herbal medicinal products founded in a non-western system of medicine, two issues can be identified: In many non-western systems of medicine, medicinal products or traditional formulations are used on a personalized basis: the composition of the medicinal product is tailored for the individual patient, based on a traditional diagnosis. Consequently, traditional medicinal products from non-European traditions often start an application in the European framework standing on two feet: a Western indication for which registration is requested, but with a dossier justifying the traditional use in terms of, for example Traditional Chinese Medicine, or the principles of Ayurveda. During assessment, discussions arise how the traditional indication, can be “translated” into a western diagnosis. It seems that this is easier to establish from non-European point of view, than to accept in the European regulatory practice. First, the traditional-use indication is established from a pharmacological perspective: these are the indications for traditional herbal medicinal products which are established in Community herbal monographs: “Traditional herbal medicinal product for mild articular pain exclusively based upon long-standing use”. Secondly, the traditional-use indication is established from a traditional perspective: For example “Traditional Chinese herbal medicinal product used for treatment of deficiency of Kidney Yang and Spleen Qi, in its inability to transform, transport and evaporate fluids in the lower burner. The use is exclusively based on the principles of Traditional Chinese Medicine”. Thirdly, the traditional-use indication is established from a combined perspective: As a result of a national assessment, or as a result of establishing a Community herbal monograph by HMPC, a double indication is possible: A western indication suitable for self-care (taking into account the requirements in article 16a (1)a ), with the addition “equivalent to Vata Dosha imbalance, according to the principles for Ayurvedic medicine.” In the Commission Report (COM 584), this issue has been addressed by the legislator: “Medical traditions such as those mentioned above are based on a holistic approach, and the set of requirements for the simplified registration procedure under Directive 2004/24/EC is not appropriate for a global regulation of such medical practices. The regulation of such traditions would demand a different
approach from that introduced by Directive 2004/24/EC. Therefore, the Commission does not envisage extending the scope of the simplified registration procedure to cover traditional medical systems as such. Nevertheless, independently of this report, the suitability of a separate legal framework for products of certain traditions should be assessed”. Nevertheless it is questionably, whether a separate legal framework is necessary to cover traditional medical systems as such. In regulatory practice, the more relevant question is whether specific traditional indications based on long-standing use for at least 30 years outside the European Union, can be part of the outcome of the simplified registration procedure. 7.3. Community herbal monographs and non-European traditions: With a growing number of Community herbal monographs, more herbal substances in these monographs know a traditional use (also) in traditional medicine in other parts of the world. In several published assessment reports of HMPC, this is acknowledged. But in most cases, specific references are not unambiguous, or were simply not made available during the assessment by HMPC. One example is the Assessment Report (HMPC-AR 2008) and Overview of Comments (HMPC-OC 2008) of the Herbal monograph on Foeniculum vulgare Miller subsp. vulgare var. vulgare, fructus, in which the use of fennel in TCM has been considered; another example the Assessment report on Curcuma longa rhizoma (HMPC-AR 2010), in which the use outside the EU, in China (TCM), Japan and Korea, and in India (in Ayurveda, Unani and Siddha medicine), as well as inclusion in respective Pharmacopoeias is addressed. Extension the work on Community herbal monographs to non-European traditions is still under discussion.
8. Conclusions The ways, different kinds of “traditional medicinal use” worldwide are assessed, are not fully explored nor harmonized yet, considered from a regulatory point of view. The use of corresponding or even similar herbal products in different parts of the world can make scientific assessment based on principles of longstanding use, complicated. Since 2004, the EU regulatory framework for herbal medicinal products based on traditional use has developed to a more transparent system, both on the level of EU Member States, but also on European level with the publication of Community Herbal Monographs by the HMPC in London. At this moment the European approach has to respond to the growing interest of herbal medicinal products, having their basis in a nonEuropean tradition. Several of these products already are marketed as medicinal products all over the world, regulated by competent authorities with regulations equally aiming on good quality and safety, but also taking into account the traditional background of medicinal use. In the next years, the EU regulatory framework has to move forewards, but could benefit from the experiences of competent authorities in other parts of the world, in order to follow the long way from reappraisal to assessment of these medicinal products. References COM 584 - Communication from the European Commission to the Council and the European Parliament concerning the report on the experience acquired as a result of the applications of the provisions applicable to traditional herbal medicinal products, Brussels, 29-09-2008, COM(2008) 584 final. 〈http://eur-lex. europa.eu/LexUriServ/LexUriServ.do?uri=COM:2008:0584:FIN:en:PDF〉. CBG-PAR 2012 - College ter beoordeling van geneesmiddelen/Medicines Evaluation Board – Public Assessment Report Diao Xin Xue Kang capsules for oral use. 1403-2012, 〈http://db.cbg-meb.nl/Pars/h102142.pdf〉.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
E. van Galen / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 2001/83/EC - Directive of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to medicinal products for human use. Consolidated version, 16-11-2012, 〈http://ec.europa.eu/health/files/eudra lex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf〉. 2004/24/EC - Directive of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community Code relating to medicinal products for human use. (Official Journal L 136, 30-4-2004, p85-90), 〈http://ec.europa.eu/health/ files/eudralex/vol-1/dir_2004_24/dir_2004_24_en.pdf〉. Fan, TP., Deal, G., Koo, HL., Rees, D., Sun, H., Chen, S., Dou, JH., Makarov, VG., Pozharitskaya, ON., Shikov, AN., Kim, YS., Huang, YT., Chang, YS., Jia, W., Dias, A., Wong, VCW., Chan, K., 2012. Future development of global regulations of Chinese herbal products. Journal of Ethnopharmacology 140 (2012), 568–586. HMPC 2010 - Committee on Herbal Medicinal Products – Guideline on the Declaration of herbal substances and herbal preparations in herbal medicinal products/traditional herbal medicinal products. (EMA/HMPC/CHMP/CVMP/ 287539/2005 rev 1). Published april 2010, 〈http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2009/09/WC500003272.pdf〉. HMPC-AR 2008 - Committee on Herbal Medicinal Products – HMPC Assessement Report on Foeniculum vulgare Miller subsp, vulgare, var. vulgare, fructus (EMEA/HMPC/137426/2006), published 20-02-2008. 〈http://www.ema.europa. eu/docs/en_GB/document_library/Herbal_-_HMPC_assessment_report/2009/ 12/WC500018463.pdf〉. HMPC-OC 2008 - Committee on Herbal Medicinal Products - Overview of comments reveived on the Community herbal monograph on HMPC
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Assessement Report on Foeniculum vulgare Miller subsp, vulgare, var. vulgare, fructus (EMEA/HMPC/200856/2007), published 20-02-2008. 〈http://www.ema. europa.eu/docs/en_GB/document_library/Herbal_-_Overview_of_comments_re ceived_during_consultation/2009/12/WC500018456.pdf〉. HMPC-AR 2010 - Committee on Herbal Medicinal Products – HMPC Assessement Report on Curcuma longa L., rhizoma (EMEA/HMPC/456848/2008), published 4-02-2010 〈http://www.ema.europa.eu/docs/en_GB/document_library/Her bal_-_HMPC_assessment_report/2010/02/WC500070700.pdf〉. HMPC-QA 2014 - Committee on Herbal Medicinal Products – Questions & Answers on the European framework for (traditional) herbal medicinal products, including those from a “non-European” tradition. (EMA/HMPC/402684/2013), 〈http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_ procedural_guideline/2014/05/WC500166358.pdf〉. NtA Vol.2A - European Commission - Notice to Applicants Volume 2A – Procedures for marketing authorisation, Chapter 3, Community Referral Procedures (Part B), Brussels ENTR/F2/SM D, September 2007. 〈http://ec.europa.eu/health/files/ eudralex/vol-2/a/vol2a_chap3_rev09-2007_en.pdf〉. WHO 1978 - World Health Organization – The promotion and development of traditional medicine, report of a WHO meeting, Geneva 1978, ISBN 9241206225, 〈http://apps.who.int/medicinedocs/documents/s7147e/s7147e. pdf〉. WHO 2013 - World Health Organization – WHO Traditional Medicine Strategy 2014-2023, Geneva 2013, ISBN 9789241506090. 〈http://apps.who.int/iris/bit stream/10665/92455/1/9789241506090_eng.pdf?ua=1〉.
Please cite this article as: van Galen, E., Traditional herbal medicines worldwide, from reappraisal to assessment in Europe. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.07.013i
