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dr Barbara STEINHOFF

Co-Chair of the ESCOP Scientific Committee, Head of Department Herbal and HomoeopathicMedicinal Products, Bundesverband der Arzneimittel-Hersteller e.V.,

e-mail: steinhoff@bah-bonn.de

EUROPEAN HERBAL TRADITIONS AND MONOGRAPHS*Wyk³ad na temat europejskiej dyrektywy 2004/24/EC, zwalniaj¹cejproducentów tradycyjnych leków roœlinnych z obowi¹zku przeprowadzaniaprób klinicznych, za to nak³adaj¹cej obowi¹zek opracowania ich monografii

Traditional herbal medicinal products havebeen officially recognized in the European legi-slative framework for medicines since 2004,when the Directive on traditional herbal medici-nal products (2004/24/EC) was set into forcewhich became part of the general European le-gislation as laid down in Directive 2001/83/EC.The reasons of Directive 2004/24/EC explainthat the long tradition of a medicinal productmakes it possible to reduce the need for clinicaltrials, in so far as the efficacy of the medicinalproduct is plausible on the basis of long-stan-ding use and experience. Thus, besides theoption of a marketing authorisation (well-est-ablished medicinal use with recognised efficacyand an acceptable level of safety), herbal medi-cinal products can be registered with a docu-mented traditional use.

By end of 2015, altogether 1577 registrationswere granted by Member States of the Europe-an Union, most of them in the United Kingdom(344), Germany (263), Poland (197) and Austria(195). Out of a total of 768 marketing authorisa-tions, most of them were granted in Germany(278), followed by Austria (51), Poland (24) andthe Czech Republic (33) [1].

DOCUMENTS PREPARED BY THE HMPC

The Herbal Medicinal Products Committee(HMPC) was established as a permanent Com-mittee at the EMA, London, in 2004. It consistsof one delegate and one deputy member perEU Member State representing national healthauthorities as well as observers and maximumfive co-opted 5 additional experts. Besides thepreparation of guidance documents quality,efficacy and safety of herbal medicinal productsand traditional herbal medicinal products, oneof the main tasks of the Committee is the elabo-ration of European Union Herbal Monographsin the fields of the well-established medicinaluse (marketing authorisation) and the traditio-nal use (registration) of herbal medicinal pro-ducts in accordance with Directive 2001/83/EC.These monographs are published on the EMAwebsite and represent important and helpful to-ols for applications submitted to the nationalhealth authorities and for their assessmentprior to approval.

The minimum requirements for the „well-esta-blished medicinal use” are laid down in a res-pective HMPC guideline:

* This article is based on the presentation held at 16. Sejmik Zielarski – Herbal Jubilee Symposium, Stêszew, 17-18 June 2016.

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„In general, at least one controlled clinicalstudy (clinical trial, post-marketing study, epi-demiological study) of good quality is requiredto substantiate efficacy. In the absence of a con-trolled clinical trial a case-by-case assessmenttaking into account possible benefits, risks andtypes of disease may be acceptable, if clinicalexperience with the herbal medicinal product iswell documented and supportive, conclusive(human) pharmacological data of good qualityare available. Evidence of grade C/level IV sup-ported only by pre-clinical data are not suffi-cient to make the clinical efficacy of a productrecognised” [2].

As a consequence, available clinical studiesshould lead to allocation of the respective pre-parations to the „well-established medicinaluse”. However, in case these studies are not as-sessed as being „of good quality” (a criteriumthat might be open for individual interpreta-tion), and as far as the traditional use can beproven, a „traditional” indication is granted forthese preparations.

HMPC MONOGRAPHS AND TRADITIONAL USE

The following examples of recently publishedmonographs or drafts [3] shall illustrate whichindications have been adopted by the HMPC.

Draft monograph Silybum marianum(milk thistle, owoc ostropestu plamistego)This document describes both areas of use with

different indications, depending on the prepara-tion. A „well-established medicinal use” is pro-posed for a dry extract (DER 36-44:1), (extrac-tion solvent: ethyl acetate) standardised to conta-in 40-65% silymarin, calculated as silibinin withthe indication „herbal medicinal product for sup-portive treatment of alcoholic liver disease”. Fur-ther extracts are proposed to be suitable for a tra-ditional use „... for the symptomatic relief of di-gestive disorders with a sensation of fullness, blo-ating and flatulence”. As compared to existingpreparations in the European market, the propo-sed wording covers only part of their indications.Apparently the HMPC came to the conclusionthat the minimum criterium for the „well-establ-ished medicinal use” was not fulfilled, and that

the existing data do not justify indications otherthan the mentioned ones.

Monograph Serenoa repens (sabal – saw palmetto, owoc palmy sabal)This monograph as well contains both areas of

use, a „well-established medicinal use” for a softextract (DER 7-11:1, extraction solvent: hexa-ne) with the indication „herbal medicinal pro-duct for the symptomatic treatment of benignprostatic hyperplasia”; a „traditional use” forsoft extracts (DER 7.5-14.3:1, extraction sol-vent: ethanol 90% to 96% m/m) with the indica-tion „traditional herbal medicinal product forthe relief of lower urinary tract symptoms rela-ted to benign prostatic hyperplasia, after seriousconditions have been excluded by a doctor”.Also the posology is almost identical: „320 mgonce daily or 160 mg 2 times daily” as comparedto „320 mg once daily”. Although this mightsound strange at a first glance, the assessment isapparently based on a pure formalistic argu-ment with respect to the minimum criterium forthe „well-established medicinal use”, and exi-sting clinical data for the ethanolic extracts haveobviously not been considered sufficient.

Monograph Epilobium angustifolium,parviflorum (willow herb, zielewierzbówki kiprzycy)The same traditional indication like for sabal

fruit has been granted for a herbal tea from wil-low herb: „traditional herbal medicinal productfor the relief of lower urinary tract symptoms re-lated to benign prostatic hyperplasia after serio-us conditions have been excluded by a medicaldoctor”. Compared to the amount of clinicalstudies existing for the ethanolic extracts of sa-bal described above and the availabilitiy of onlypharmacological data for willow herb, thisexample shows the broad variety of evidence onwhich the traditional use can be based followingthe assessment within European Union herbalmonographs.

Monograph Rhodiola rosea (arctic root,k³¹cze ró¿eñca)For products from arctic root so far not regi-

stered as medicines, this monograph offersan interesting option. It describes a dry extract

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CZASOPISMO APTEKARSKIE Nr 8-9 (272-273) 20164 punkty naukowe Ministerstwa Nauki i Szkolnictwa Wy¿szego

(DER 1.5-5:1), extraction solvent ethanol 67--70% with the indication „Traditional herbalmedicinal product for temporary relief of symp-toms of stress, such as fatigue and sensation ofweakness”.

Draft monograph Sideritis (ironwort,ziele gojnika)Another new project is a monograph on a her-

bal tea originating from the Greek mountains.Two indications are proposed: „traditional her-bal medicinal product used for the relief of co-ugh associated with cold” and „traditional her-bal medicinal product used for the relief of mildgastrointestinal discomfort”.

Draft revision Harpagophyti radix(devil‘s claw root, korzeñ hakoroœli)This monograph which was open for com-

ments of interested parties by mid of May 2016,proposes to maintain the indications from theexisting monograph on the same herbal drug:„traditional herbal medicinal product for reliefof minor articular pain” and „traditional herbalmedicinal product used for the relief of mild di-gestive disorders such as bloating and flatulen-ce and where there is loss of appetite”. Like du-ring consultation on the original monograph,the herbal industry submitted comments on theassessment of the available clinical studieswhich, from the HMPC’s point of view, wherenot regarded sufficient to justify a „well-establ-ished medicinal use” in the area of rheumaticcomplaints.

Draft monograph Origanum majorana(majoram, ziele majeranku)Interestingly, for this herbal drug and its pre-

parations (herbal tea and semi-solid prepara-tions), respectively, the following traditional in-dications were proposed: „symptomatic relief ofmild spasmodic gastro-intestinal complaintssuch as bloating and flatulence” and „relief ofirritated skin around the nostrils”, the latter onerepresenting a traditional dosage form „majo-ram butter” and being recommended expressi-vely for children 1-11 years of age.

These examples demonstrate that traditionaluse as well as experience is represented in

HMPC monographs, in accordance with the as-sessment criteria laid down in the European le-gislation for medicinal products. In this context,a rather high indication level for traditionalherbal medicinal products is considered impor-tant in order to provide a distinction from foodsupplements for which to a certain extenthealth claims can be accepted if proven by spe-cific data.

THE EUROPEAN SCIENTIFIC COOPERATIVEON PHYTOTHERAPY (ESCOP)

ESCOP was founded in 1989 as a scientific or-ganization consisting of national societies onphytotherapy. Its main objective is to establishharmonized criteria for the assessment of effica-cy and safety of herbal medicinal products andto contribute to the acceptance of phytotherapyon a European level. As an important tool forEuropean harmonization, ESCOP started toelaborate monographs on the medicinal use ofplants and their preparations which was a uni-que task and a pioneer work at that time, longbefore the HMPC was founded in 2004.

Scientific societies from the following coun-tries are members of ESCOP:

• Austria• Denmark• Germany• France• Ireland• Italy• The Netherlands• Poland• Portugal• Romania• Switzerland• Spain• Turkey• United Kingdom

Currently, the ESCOP Board of Directorsconsists of the following persons:

• Liselotte Krenn (A) (Chair)• Simon Mills (GB) (Secretary)• Stephan Horsten (NL) (Treasurer) • Yves Barbin (F) • Anna Rita Bilia (I)

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DEBATY KONFERENCJE KONGRESYreferaty • sprawozdania • komentarze

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• Salvador Cañigueral Folcarà (E)• Marijke Frater (CH)• Martin Willoughby (GB)• Tankred Wegener (D)• Fritz H. Kemper (D) (Honorary President)• Barbara Steinhoff (D) (Sc Comm Represen-

tative)• Ann Kerridge (Administrator)

The preparation of monographs is performedin the Scientific Committee which works in twoparallel subcommittees. The project leaders areresponsible for performing literature searches,assessing the references for their relevance andscientific value, summarizing the relevant re-sults and elaborating the draft monographwhich is then presented to one of the subcom-mittees. In some cases, external experts are in-volved. During the discussions, the views,knowledge and experience are incorporatednot only of different nationalities, but also ofindividuals from different scientific and profes-sional backgrounds, such as medical doctors,pharmacists, practising phytotherapists, phar-macognosists, pharmacologists and regulatoryaffairs specialists.

The following scientists are members of theESCOP Scientific Committee:

Anna Rita Bilia, IJozef G. Corthout, BMaria do Céu Costa, PJürgen Drewe, CHFrans M. van den Dungen, NLSarah Edwards, UKMarijke Frater-Schröder, CH Lene Gudiksen, DKDidier Guédon, FIngrid Hook, IRLStephan Horsten, NL (Co-Chair)Roberta Hutchins, UKLiselotte Krenn, AFrédérique Lafforgue, FRadu Moldovan, ROAndrzej Ostrowicz, PLGeorg Seidel, DBarbara Steinhoff, D (Co-Chair)Sonja Sturm, A (Co-Secretary)Funda Nuray Yaln, TR (Co-Secretary)

After finalisation of the discussion in theScientific Committee, the drafts are circulatedto an independent Board of Supervising Editorsfor appraisal. These academic experts in phyto-therapy, pharmacology or medicinal plant rese-arch from all over Europe are invited to com-ment on and criticise each draft, and their com-ments are discussed and where appropriate in-corporated into the final version.

Each monograph text represents an up-to-date review of scientific information on the the-rapeutic uses of herbal medicinal products, inc-luding indications, dosage, contra-indications,interactions and undesirable effects, togetherwith detailed summaries of pharmacological,clinical and toxicological data, each statementbeing supported by literature references.

After publication of two books containing al-together 115 monographs (2003 and 2009), no-wadays ESCOP monographs are published onli-ne and can be obtained through the ESCOP we-bsite [4]. They are freely available for membersof the national societies of phytotherapy. The

Fig. 1. Example for ESCOP online monographs

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CZASOPISMO APTEKARSKIE Nr 8-9 (272-273) 20164 punkty naukowe Ministerstwa Nauki i Szkolnictwa Wy¿szego

first monograph published online has been theCimicifuga monograph (see Fig. 1)

Moreover, an extract of most important infor-mation from ESCOP monographs can be obta-ined through the ESCOP Herb ReferenceSmartphone and Tablet App (see Fig. 2). Theseare currently available in English and in Ger-man, further languages will follow.

Currently, revision of existing monographs ba-sed on new literature data represents an impor-tant task of ESCOP. E.g., recently an extensiverevision of Hyperici herba has been finalised,and further revision projects such as Allii sativibulbus, Solidaginis herba, Agni casti fructus,Echinaceae purpureae/pallidae root/herb andLini semen are ongoing. New monographs arebeing established e.g. on Equiseti herba or Rho-diolae roseae radix. ESCOP is aware of the factthat the HMPC monographs that appeared ap-proximately 15 years after ESCOP started itswork, have the advantage of „official” monogra-phs which are adopted by health authorities andwhich can serve as a basis for marketing autho-rization or registration procedures. ESCOP mo-nographs can be regarded as a scientific publica-tion which might in some cases come to conclu-sions different from an HMPC monograph.ESCOP’s aims for the future consist in the fur-ther preparation and updating of monographs,

predominantly on medicinal plants with rele-vance in the European market, and with theirfocus on the medicinal use of these plants. Mo-reover, exchange with the views of the HMPCcan take place by submission of comments onHMPC documents, e.g. monographs. With re-gard to building up a European network ofscientists interested in the utilization of medici-nal plants and the research in this field, anextension of the ESCOP website is plannedwhich will also include detailed informationfrom national societies.

■

References:

1. EMA. Uptake of the traditional use registration sche-me and implementation of the provisions of Directive2004/24/EC in EU Member States. Status: 31 Decem-ber 2015. http://www.ema.europa.eu/docs/en_GB/do-cument_library/Report/2011/05/WC500106706.pdf(checked 1 July 2016)

2. Guideline on the Assessment of Clinical Safety and Ef-ficacy in the Preparation of Community Herbal Mono-graphs for well-established and of Community HerbalMonographs / List Entries for Traditional Herbal Me-dicinal Products / Substances / Preparations (EMEA/HMPC/104613/2005). 7 September 2006. http://www.ema.europa.eu/docs/en_GB/document_library/Scienti-fic_guideline/2009/09/WC500003644.pdf (checked1 July 2016)

3. EMA. Herbal Medicines for Human Use.http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/herbal_search.jsp&mid=WC0b01ac058 001fa1d(checked 1 July 2016)

4. ESCOP. The European Scientific Coope-rative on Phytotherapy. http://escop.com/(checked 1 July 2016)

Fig. 2. ESCOP’s printed publications and Apps