Herbal Remedies - Natural Medicine

term “herbal remedies” includes Because herbal remedies can rely on long-term use and experience, bibliographic data Herbal remedies with “tradition …

Drug Information Journal, Vol 30, pp 933948, 1996 Printed in the USA All rights reserved

0092-8615/96 Copyright 1996 Drug Information Association Inc

HERBAL MEDICINAL PRODUCTS IN GERMANY AND EUROPE: EXPERIENCES WITH NATIONAL AND EUROPEAN ASSESSMENT
KONSTANTIN KELLER, PHD
Director and Professor, Federal Institute for Drugs and Medical Devices, Berlin, Germany

The German Medicines Act AMG and the Council Directive 65/65 European Economic Community EEC apply fully to herbal medicinal products This was confirmed by the European Court of Justice in 1992 A marketing authorization according to Article 4 of Council Directive 65/65 EEC granted by the competent authority is obligatory if herbal remedies are sold as finished medicinal products The applicant must document quality, safety, and efficacy of its product The term herbal remedies includes medicinal products containing exclusively plant material or vegetable drug preparations as active ingredients Homoeopathic preparations or
isolated constituents such as Menthol or Digitoxin are not considered herbal remedies Herbal drugs are included in the German Pharmacopoeia DAB 96 and in the European Pharmacopoeia Specific aspects of quality control of herbal remedies are described in the EEC Note for Guidance Quality of Herbal Remedies and, on a national level, in the Guidelines for the Testing of Drugs following Article 26 AMG The criteria for the evaluation of safety and efficacy apply to herbal remedies in the same way as they apply to other medicinal products with comparable indications The complex composition of herbal active ingredients, however, must be taken into account Because herbal remedies can rely on long-term use and experience, bibliographic data can be used in the assessment according to Article 4 No 8 a, ii of Council Directive 65/ 65 EEC On a national level a definition of bibliographic data is set out in Article 22 3 AMG and in the 5th section of the Guidelines for the Testing of Drugs following
Art 26 AMG The review of old medicinal products on the German market has resulted in monographs on active ingredients of herbal origin providing a positive or a negative assessment of the safety and efficacy of these compounds Herbal remedies with traditionally used labeling do not comply with the European Union EU criteria For this reason they are only acceptable on national markets and with strictly limited indications and special labeling Key Words: Herbal medicinal products; Safety; Efficacy

INTRODUCTION THE DISCUSSION ON HERBAL remedies has a long history in Germany and within
Presented at the 8th Dia Euromeeting, May 58, 1996, Copenhagen, Denmark, and the DIA Annual Meeting, June 913, 1996, San Diego, California Reprint address: Dr Konstantin Keller, Director and Professor, Federal Institute for Drugs and Medical Devices, Seestrasse 10, D-13353 Berlin, Germany

the EEC Commission In Germany, the Parliament decided to include specific regulations in its 1976 Medicines Act One
result was to establish the so-called Commission E and to prepare monographs for herbal remedies At the European level a working group for medicinal products of plant origin was established in March 1978 The result of 10 years of discussion was the Note for Guidance Quality of Herbal Remedies of No-

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Konstantin Keller TABLE 1 European Court of Justice Judgment of October 28, 1992 1 a product recommended or described as having prophylactic or therapeutic properties is a medicinal product within the meaning of the first subparagraph of Article 1 2 of CD 65/65 EEC even if it is generally regarded as a foodstuff and in the current state of scientific knowledge has no known therapeutic effect; 2 a product whose therapeutic properties are described only in documentation such as a brochure sent on demand after sale, or by the manufacturer, or the supplier of the product, or by a third party may, where in the latter case the third party is not acting totally
independently of the manufacturer or supplier, may be described as a medicinal product

vember 1988 A consensus on medical questions was far from being reached at that time In October 1990, the European Scientific Cooperative on Phytotherapy ESCOP presented the first series of draft core summary of product characteristics SPC on herbal remedies This activity stimulated a constructive discussion of the question The Committee for Proprietary Medicinal Products CPMP adopted final core SPCs for four laxatives in May 1994 No final agreement was achieved on core SPCs for Matricariae flos and Valerianae radix, though a relatively advanced state has been reached so that they may be useful in the context of national applications in some Member States There has been no concrete progress from 1994 until March 1996 when the industry presented a new series of proposals for core SPC guidelines It should be noted that these texts were prepared with substantial financial support by the commission
It is questionable, however, if these ESCOP proposals will be discussed in the same framework as the previous one Today, there is a new situation in the EU: there are new procedures for marketing authorizations, there is a new agency to coordinate activities, and there are three new Member States with different experiences which have not participated in previous discussions on herbal remedies The function of CPMP and CPMP working parties have changed and CPMP and European Medicines Evaluation Agency EMEA decided not to continue work within the field of herbal and over-the-counter OTC remedies Thus, results of future discussions are difficult to predict THE LEGAL STATUS OF HERBAL REMEDIES The legal requirements and the definition of terms related to the problem, however, are clear and beyond any doubt It is clear that herbal remedies are medicinal products as defined in Article 1 of Council Directive CD 65/65 EEC Table 1 They are neither foods–most of them have no nutritional value or
pleasant taste, nor cosmetics Decisions of the European Court of Justice sup-

port this interpretation 1,2 Divergent legislation in some Member States has been changed meanwhile Member States which may have believed that they had no herbal problem have discovered that herbal medicinal products are on their markets; others found out that the number of products had been underestimated Questions of assessment of herbal remedies and OTC products have become increasingly important, especially with the decentralized procedure and the mutual recognition of marketing authorizations within Europe This is why the EU Council declared on December 6, 1995 that the wider and growing use of medicinal plants in the EU has to be considered 3 It expressed possible concern that the heterogeneity of the commercial presentation of herbal remedies could have a negative impact on public health and on the free movement of goods The EU Commission was called on to study the situation One thing is clear: if the
criteria for herbal remedies should be less stringent, namely in the sense of traditionally used products with no proven or plausible efficacy, the definition of medicinal products in CD 65/65 is to be discussed anew and maybe even changed Such a change would have a substantial impact on many other medicinal products cov-

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ered by EU directives until now An exclusion of herbal remedies would lead to the paradoxical situation that homeopathic remedies would be included, while herbal remedies would be excluded Such a substancerelated exclusion would lead to a revival of the so-called exclusion products, whereas it has been the political will and the commissions goal to overcome the problem of exclusion products by the inclusion directives of 1991/1992 A substance-orientated exclusion could not eliminate all herbal remedies and the curious situation would appear that Belladonna or Senna leafs would have to be declared as herbal
nonherbals Therefore, such an approach is in the Federal Institute for Drugs and Medical Devices view neither reasonable nor acceptable THE EEC MARKET FOR HERBAL REMEDIES Herbal remedies are indeed a relevant factor in EU harmonization efforts They are not just a German problem that would originate from the lingering influences of 19th century romanticism 4 An investigation conducted in the Member States in 1991 revealed the impressive number of about 1,400 herbal drugs used in the EEC When the study focused on those drugs that were used in half of the responding Member States five out of a possible 10, there are still 145 herbal drugs Table 2 6,7 Even if this number is a rather broad brush, due to problems with defining a given drug, this shows that herbal drugs are indeed a major problem for harmonization in the EU The commission, on the call of the EU Council, decided to repeat this inquiry and it can be expected that the number of relevant herbal drugs will continue to increase
Herbal remedies are a relevant economic factor as well Sales of herbal remedies in the EU were reported in 1994 to amount to a value of six billion dollars United States Table 3 Increases until 1998 are estimated to be 8 per year In the sector of herbal OTCs, Germany holds the biggest share with 25 billion followed by France with 16

billion and Italy with 600 million Every citizen of the EU spends 174 per year for herbal remedies 8,9,10 Because of their legal status as medicinal products, finished drugs of herbal origin must be authorized according to Article 4 of CD 65/65 EEC Applicants must document quality, safety, and efficacy of their products in compliance with CD 75/318 EEC At a European level, the definitive result of the assessment process of a medicinal product is the summary of product characteristics SPC While SPCs for new chemical entities are no real problem in centralized procedures, consensus on SPCs for generic applications will pose a major problem, especially in
cases of well-known old medicinal products, maybe with a long tradition as OTC products In these cases not only the individual application is to be checked, but former decisions on similar products are to be discussed to overcome differences among Member States Harmonization of old products at the EU level may result in a deharmonization of national markets with many problems for the industry and national authorities Finally, consumers will be confronted with very similar or identical products but different medical information depending on the origin and type of authorization This will be particularly relevant for those countries where herbal remedies had a food-like status in the past This situation may explain why there are only four officially accepted core SPCs on herbal laxatives The underlying problem, however, is not a specifically herbal one there is only one core SPC on chemically defined OTCs, ie, bisacodyl, on the contrary, the legal framework and the scientific requirements
for herbal remedies are clearly set out

PROBLEMS AND EXPERIENCES WITH HERBAL REMEDIES Identifying the Market The term herbal remedies applies to medicinal products whose active ingredients consist exclusively of plant material or vegetable drug preparations, for example, powdered vegeta-

936 TABLE 2 Most Relevant Herbal Drugs Achillea millefolium Acorus calamus Aesculus hippocastanum Agar Agrimonia eupatoria Agrimonia procera Agropyron repens Alchemilla vulgaris Allium cepa Allium sativum Aloe species barbadensis, capensis, ferox Alpinia officinarum Althaea officinalis Althaea officinalis Althaea officinalis Anethum graveolens Angelica archangelica Arctium lappa Arctostaphylos uva-ursi Armoracia rusticana Arnica montana Artemisia absinthium Atropa bella-donna Barosma betulina Betula pendula Calendula officinalis Capsella bursa-pastoris Capsicum annuum Carum carvi Cassia angustifolia Cassia senna Centaurium erythraea Cephaelis ipecacuanha Chamomilla recutica Chondrus crispus
Cimicifuga racemosa Cinnamomum aromaticum Citrus limon Cnicus benedictus Cola nitida Commiphora molmol Coriandrum sativum Crataegus laevigata Crocus sativus Curcuma longa Cynara scolymus Drosera rotundifolia Equisetum arvense Eucalyptus species Ferula asa-foetida Ficus carica Filipendula ulmaria Foeniculum vulgare var vulgare Foeniculum vulgare var vulgare Herba Rhizoma Semen Herba Herba Rhizoma Herba Bulbus Bulbus Succus sicc Rhizoma Flores Folium Radix Fructus Radix Radix Folium Radix Flores Herba Folium Folium Folium Flores Herba Fructus Fructus Folium Folium, Fructus Herba Radix Flores Thallus Rhizoma Cortex Aetheroleum Herba Semen Gum-Resin Fructus Folium Stigma Rhizoma Folium Herba Herba Aetheroleum Gum-Resin Fructus Flores, Herba Aetheroleum Fructus Fraxinus excelsior Fraxinus excelsior Fucus vesiculosus Fumaria officinalis Geranium robertianum Glycyrrhiza glabra Hamamelis virginiana Harpagophytum procumbens Hedera helix Humulus lupulus Humulus lupulus Hydrastis canadensis
Hypericum perforatum Hyssopus officinalis Illicium verum Inula helenium Juniperus communis Krameria triandra Lamium album Laurus nobilis Lavandula angustifolia Levisticum officinale Linum usitatissimum Lobelia inflata Malva sylvestris Malva sylvestris Marrubium vulgare Marrubium vulgare Melaleuca species Melissa officinalis Mentha piperita Mentha piperita Menyanthes trifoliata Myristica fragrans Myroxylon balsamum var pereirae Olea europaea Olea europaea Origanum vulgare Panax ginseng Papaver rhoeas Passiflora incarnata Peumus boldus Pimpinella anisum Pimpinella anisum Pinus species Plantago ovata Podophyllum peltatum Polygonum aviculare Potentilla erecta Primula veris Prunus cerasus ssp acida Prunus spinosa Quercus robur Quillaja saponaria

Konstantin Keller

Cortex Folium Thallus Herba Herba Radix Folium Radix Folium Glandula Strobuli Rhizoma Herba Herba Fructus Rhizoma Fructus Radix Flores Folium Flores Radix Semen Herba Flores Folium Flores Herba Atheroleum Folium Aetheroleum
Folium Folium Semen, Arillus Balsamum Folium Oleum Herba Radix Flores Planta tota Folium Fructus Fructus, Aetheroleum Aetheroleum Terpentin Semen Rhizoma, Resina Herba Rhizoma Radix Stipites Flores Cortex Cortex

Herbal Medicinal Products in Germany and Europe TABLE 2 Continued Rhamnus frangula Rhamnus purshianus Rheum officinale Rosa canina Rosa centifolia Rosmarinus officinalis Rubus fruticosus Rubus idaeus Salvia officinalis Sambucus nigra Silybum marianum Silybum marianum Solidago virgaurea Tamarindus indica Taraxacum officinale Thymus serpyllum Cortex Cortex Radix Fructus Flores Folium Folium Folium Folium Flores Fructus Herba Herba Fructus Radix Herba Thymus vulgaris Tilia cordata Trigonella foenum-graecum Urtica dioica Vaccinium myrtillus Valeriana officinalis Verbascum phlomoides Verbascum thapsus Verbena officinalis Viburnum prunifolium Viola odorata Viola tricolor Viola tricolor Vitis vinifera Zea mays Zingiber officinale Herba Flores Semen Radix Folium Radix Flores Flores
Herba Cortex Flores Flores Herba Folium Stipites Rhizoma

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ble drugs, vegetable secretions, essential oils, or extracts Homeopathic preparations are excluded as are chemically defined substances such as menthol, thymol, or eugenol This notion of herbal remedies has a broad international basis since the world Health Organization WHO defined the term herbal remedies in the same way 11 Even if herbal drugs are widely used for self-medication, the term herbal remedies is not automatically linked to an OTC status In Germany and France, a relevant portion of medical prescriptions is made up by herbal remedies 10,12 Table 4 Some herbal remedies, for example, Belladonna leaves, are prescription-only medicines

Regulating the Market In dealing with the scientific assessment of herbal remedies, agencies are regularly confronted with two types of problems: 1 The huge number of products on the market, and 2 The criteria which have to be applied to these drugs Since 1978 when the German
Medicines Act came into force, every finished drug has been liable to registration by the Federal Institute for Drugs and Medical Devices formerly the Federal Health Office Even products produced in individual pharmacies or health food stores and sold outside these places on a regional market have been covered by this regulation Owing to this situation and to the fact that different dosage forms were counted separately, the office was confronted with about 148,000 registered finished drugs in 1978 Of these drugs, 126,000 were still registered in 1989 The impressive number of about 67,000 of 126,000 registered finished drugs contained herbal constituents Forty thousand of these products were herbs used for tea infusions and these products were typically sold outside pharmacies All these herbal medicines were produced on the basis of about 1,100 different botanical drugs

TABLE 3 EU Sales of Herbal Remedies IMS 1994 Million US Germany France Italy United Kingdom Spain Netherlands
Belgium Others Total 2,500 1,600 600 300 230 100 40 130 5,500 p capita US 370 280 105 50 60 65 40 45 174

938 TABLE 4 Drug Sales in Germany in 1994 Prescription only Value Billion US 208 5 Nonprescription Prescribed by physician Self-medication Value Billion US 54 56

Konstantin Keller

Packages 652 Million

Packages 369 Million 723 Million

Herbal Remedies West Germany 1994 Prescribed by physician Self-medication Value Billion US 14 6 11 0

Total US 25 Billion 23 of nonprescription market

Being confronted with a market of 148,000 medicinal products will present a problem to any administration The institutes strategy to overcome this problem was to follow two lines: the introduction of standardized marketing authorization, and the review of old drugs, in addition to the individual marketing authorization Standardized Marketing Authorization Medicines or groups of medicines which do not pose a direct or indirect risk to the health of man or animal could be exempted from the
requirement for an individual marketing authorization according to Article 36 of the Medicines Act To assure quality, safety, and efficacy of such products each medicinal product referring to this procedure must comply exactly with a monograph of a standardized marketing authorization published by the Federal Ministry of Health The monographs include analytical test requirements and also the texts for labels and package leaflets Two hundred seventy nine monographs of standardized marketing authorizations have been published mainly for such herbal remedies as herbal teas If an applicant refers to such a monograph it does not need not to present any documentation to the Federal

Institute for Drugs and Medical Devices Compliance with the requirements of the monograph is controlled by the local inspection authority If the drug will be sold in pharmacies only, the producer will only have to inform the institute that it refers to the monograph Review of Active Principles The review of
existing products started in 1978 and was stopped by an amendment to the Medicines Act in August 1994 The review was focused on active ingredients and not on individual products, because of the large number of products on the market The concept of the procedure was to establish clear, a priori criteria for active ingredients and to make it transparent to industry which products would have a chance to be authorized The institute thinks that these two approaches have been a success: The number of products covered by a standardized marketing authorization is estimated to be 25,000 The number of finished medicinal products of herbal origin, which are going to be checked individually, has decreased to 5,381 Three hundred and thirty monographs prepared by Commission E cover more than

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80 of the herbal medicinal products on the German market CRITERIA FOR THE ASSESSMENT OF HERBAL REMEDIES Points of conflict in the assessment of quality,
safety, and efficacy of herbal remedies are the criteria to be applied, especially in the case of safety and efficacy Quality Herbal remedies represent complex biological mixtures, and achieving a reproducible pharmaceutical quality could appear to be a problem The EU Council asked the commission to study any tests required to ensure the quality of raw materials and medicinal plant preparations The EEC Note for Guidance Quality of Herbal Remedies, however, already provides a well-defined framework for quality testing 13 Table 5 It is without question that consistent quality of products of vegetable origin can only be assured if the starting materials are defined rigorously and in great detail An exact definition and the control of all steps of the manufacturing process are necessary to assure consistent quality of a herbal medicinal product Member States refer to these regulations in granting marketing authorizations to herbal products The Note for Guidance can guarantee a reproducible
quality of a specific herbal product If a European harmonization of multisource products is wanted, uniform definitions of vegetable drugs in all Member States are needed The European PharmacoTABLE 5 QUALITY: Note for Guidance Quality of Herbal Remedies, November 1988 A–Qualitative and Quantitative Particulars of the Constituents B–Method of Preparation C–Control of Starting Materials D–Tests Carried out at an Intermediate State E–Tests on the Finished Product F–Stability

poeia reflects the high standard of phytotherapy in Europe and provides a worldwide unique collection of official, high-standard monographs on herbal drugs One advantage of this pharmacopoeia is that it is published in all languages of the EU, and the Spanish, Portuguese, and French editions, beside the English texts, are relevant for many countries outside Europe Quality requirements are, therefore, transparent for any third country producing herbal raw materials for export to EU Member States Group 13 of the
European Pharmacopoeia Commission, responsible for the monographs on herbal drugs, agreed to adopt the CPMP list of the most important herbal drugs in its priority ratings for future work There are 60 monographs already included in the European Pharmacopoeia Forty five draft monographs have been published in Pharmeuropa for comments This cooperative approach will greatly facilitate harmonization of herbal remedies Quality assessment of herbal remedies does not pose fundamental problems in practice, because of the high standards and long scientific tradition phytochemistry and pharmacognosy have in the Member States More controversy is found when safety and efficacy of herbal remedies are addressed Reasons for the divergent opinions are the different traditions in administrative practice some Member States have considered herbal remedies as food-like products, problems associated with the acceptance of bibliographic data, difficulties in the assessment of typical OTC products with minor
indications, and, maybe, reservations toward everything that comes from traditional, nonmodern, and nonmainstream academic medicine National agencies, however, not only must provide service to the industry but their primary task is consumers and public health protection The topics agencies must deal with are partly determined by consumers who wish to have access to safe and effective herbal and other OTC medicines There are at least two types of herbal remedies or OTC consumers: 1 Consumers who use herbal remedies for self-medication because they are recom-

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Konstantin Keller

mended by their doctors or by pharmacists, even for the treatment of more serious indications, and even though they are not or no longer reimbursed by health insurance, and 2 Consumers who prefer to use herbal remedies because they are representatives of an alternative lifestyle who fully trust in their grandmothers or herbal books advice and who, therefore, prefer natural products Both types of consumer
must be informed, even if the latter may pretend that they, rather than the health professionals, are the competent authority In a situation such as this scientific fundamentalism will be seen by many of the industrys compatriots as an administrative attack against holistic medicine, it will block any dialogue and, finally, will put consumers who have access to the product, at least to botanical drugs, at risk This is why the German Parliament repeatedly stated that especially in the sector of herbal and OTC medicines the long-term therapeutic experience and the particularities of therapy with complex natural mixtures must be respected in administrative decisions and that at the same time, consumers must be protected from fraudulent and dangerous medicinal products The European Parliament and parliaments from other Member States came to identical or essentially similar conclusions Council directives provide a framework for the assessment of safety and efficacy of well-known herbal and
OTC products if they are applied with the aim of protecting public health, and not in just a formalistic way Proof of safety and efficacy is not only provided by new pharmacological and toxicological studies or recent double blind randomized clinical trials According to Art 4 No 8a ii of CD 65/65 EEC, published literature must be considered in the case of wellknown medicinal products, a category which herbal remedies usually belong to As long as publications give sufficient evidence that the product in question has a well-established medicinal use with recognized efficacy and

an acceptable level of safety it is not necessary to repeat all the tests and trials The situation of herbal remedies is in this aspect identical to that of other known drugs occasionally used for minor indications The terms well-established medicinal use, recognized efficacy, and acceptable level of safety are open for interpretation by assessors in agencies; they include the obligation for a case-by-case
assessment Evidently, such an individual judgment will pose problems to EU harmonization and mutual recognition, because well-established criteria are lacking in this area Maybe this is the reason why the Scotia-decision of the European Court of Justice ECJ received so much attention 14 In his judgment of October 5, 1995 the ECJ had to answer the question: can a marketing authorization be granted by the competent authority if the application under Article 4 8 a ii of CD 65/65 does not contain a detailed reference to published scientific literature and if expert reports complying with the CD 75/319 EEC are absent? The Court stated that the abridged procedure in no way relaxes the requirements of safety and efficacy which must be met by medicinal products If an applicant wants to use the abridged procedure, it must demonstrate by scientific literature that the requirements set out by CD 75/318 are met The competent authority is not allowed to decide to which extent an applicant must
satisfy these criteria The institute does not believe that this decision contrasts with the possibility to accept bibliographic data and documented well-established use for herbal and OTC products under the conditions of Article 4 No 8 a ii It should be noted, however, that all items in the annex of CD 75/318 EEC must be addressed in the expert report and in the documentation Relevant aspects which cannot be covered by scientific literature must be covered by appropriate new studies, especially if it is a question of safety For example, it is not reasonable to require animal studies on the acute toxicity of Peppermint tea, but the problem of Peppermint-tea

Herbal Medicinal Products in Germany and Europe

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toxicity must be discussed by the experts on the basis of its widespread use and experience Safety Concern about the safety of herbal remedies is growing worldwide, with the main concern focusing on appropriate quality control and proper labeling of ingredients 15,16,21 This
aspect is of particular importance for those countries which, until now, have not had full control of their markets with herbal remedies; most of the cases of intoxication or of problems come from such countries Many herbal remedies can rely on long-term use documented in the literature and the question arises as to whether an acceptable level of safety can be based on widespread and well-established use, despite the fact that, from a formal point of view, nonclinical tests are incomplete or not in accordance with todays state of the art This question was addressed by the CPMP in the context of mutual recognition of marketing authorizations Development of criteria for safety assessments of well-known medicinal products with a broad use on national markets is ongoing and a draft paper was published in April 1996 Nonclinical testing of old substances should be directed toward the study of effects that are difficult or even impossible to detect clinically Such effects are reproductive
toxicity, genotoxicity, and carcinogenicity These criteria and the discussion of the underlying problem come one step closer to a more precise definition of the type and contents of bibliographic safety data presented in abridged or bibliographic applications They come one step closer to a more realistic approach to the existing markets with products which are neither new chemical entities nor high tech products After more than 18 years of experience with the review and medical assessment of herbal medicines in Germany, it can be said that products devoid of any risks are rare Clear definitions of herbal drugs and their preparation is fundamental to safe use For

each preparation it must be assured that it really has a well-established use It is difficult, for example, to find a link between an herbal tea or a tincture and an extract prepared by supercritical carbondioxide Because of the high standards of analytical phytochemistry, there are examples where data are available on
unwanted ingredients or negative markers In these cases, reasonable suspicion can result from the pharmacognostic characterization of an herbal drug, and more toxicological data may be necessary before researchers can agree on the safety assessment of an herbal medicinal product Examples are the content of emodin in Senna, or cytotoxic valepotriates in Valerian root or estragole in fennel oil 17 In contrast to many chemically defined products indicators can be found for a traditional reproductive toxicology: herbal drugs are described in textbooks to have abortive properties and they may be used for birth-control in ethnomedicine Such data may serve as negative markers as well In these cases, there are reasonable grounds to ask for more detailed studies It should be noted that more than 4,000 herbal medicinal products on the German market have been subject to pharmacovigilance actions since 1978 and that many of them had to be withdrawn from the market or their use had to be restricted
Table 6 At the European level, one important result of the discussions on safety aspects in the former CPMP was a list of herbal drugs that pose more severe risks but have no proven benefit, so that at the present state of knowledge they do not qualify for authorization Table 7 6 Examples are drugs with pyrrolizidinic alkaloids, Secale cornutum, or Teucrium chamaedris Drugs with a particularly high risk require a more detailed discussion concerning the benefit to risk ratio, among them comfrey preparations for external use, and herbal drugs with cardiac glycosides and with alkaloids, for example, Atropa belladonna or Cephaelis ipecacuanha This list demonstrates that discussion of drug risks is hardly possible without the pres-

942 TABLE 6 Pharmacovigilance Problems Year 1981 1985 1987 1988 1990 1990 1991 1991 1992 1992 1992 1992 1993 1994 1995 of Products 336 11 59 1 2 2,817 14 95 1,427 1,427 159 7 2 44 1 Reason Aristolochic acid Sugar in teas for children Vinca minor Echinacin
parenteral Dionaea muscipula Pyrrolizidinic alkaloids Ginkgo biloba parenteral Rauvolfia/Aflatoxins Anthranoids Step I Anthranoids Step II Rubia tictorum Teucrium chamaedris Ginkgo biloba iv infusion Sassafras albidum Safrole

Konstantin Keller

ence of plausible benefits Therefore, a systematic risk evaluation must include the plausible proof of efficacy A traditionally used label will only defer the problem of assessment to the consumer, who is probably the least capable of well-founded decision making Efficacy A medicinal product is essentially characterized by its indications In some Member States herbal remedies are generally labeled traditionally used products whereas other Member States use a so-called regular indication CDs do not, however contain such a category as traditional efficacy; on the contrary, they apply to herbal remedies in the same way as to any other medicinal product A traditional use label is not acceptable on the basis of EC directives but it might be used for
products limited to national markets On a free European market, however, such strictly national products are a pure illusion After all, it is not clear what the basis of a traditionally used label should be: marketing authorizations granted though efficacy that cannot be demonstrated from bibliographic

data do not comply with CD 65/65 EEC If a well-established medicinal use can be taken from published data, the label traditional could be seen as discrediting, especially as this term is not used in chemically defined substances with comparable conditions Considering that herbal remedies are often used by way of self-medication, comprehensive patient information is crucial This includes unambiguous information on indications and adverse reactions, contraindications, interactions as well as details of the route of administration and dosage The CPMP debate on toxicological requirements for old substances opened up the discussion for a more realistic view of the existing market of old
medicinal products that have been reviewed in national procedures Such discussions are also needed in the field of efficacy assessment Indeed, it is a problem for herbal remedies that there are many active constituents accepted in the literature to be safe and effective although there are no new clinical studies complying with current criteria But this is a problem for many other well-established OTC drugs as well In the regulations under Article 26 of the German Medicines Act 19 the term bibliographic data mentioned in the EEC directive is stated more precisely as: Controlled clinical trials, Other clinical trials, Field studies, A collection of single cases, allowing a scientific evaluation, or Scientifically documented medical experience, for example, scientific literature and expertise of scientific medical associations The data presented must be such that an assessment of safety and efficacy of the product is possible They are required to correlate with the severity of
indications claimed for the product and the risks of the active constituents In the years from 19781994 a pluridisciplinary expert group for herbal remedies, the so-called Commission E, made a review of herbal drugs on the German market Table 8 In 1984, it proposed the following additional criteria for the evaluation of long-

TABLE 7 Herbal Drugs with Serious Risks without any Accepted Benefit Not acceptable for revision
Claviceps purpurea FR TULASNE parts: Secale cornutum Sclerotium reason: contains toxic ergot-alkaloids benefit/risk negative Convolvulus scammonia L parts: resin reason: drastic laxative with irritant properties Croton tiglium L parts: seed, fatty oil from seed reason: drastic laxative, contains tumor-promoting phorbol diesters Cynoglossum officinale L parts: herb reason: contains pyrrolizidine-alkaloids with genotoxic, carcinogenic and hepatotoxic properties

Aconitum all species parts: all parts reason: contains aconitine and other toxic alkaloids, benefit not
proven

Angelica archangelica L parts: fruit, herb reason: contains phototoxic furanocumarins, benefit not proven Aristolochia all species parts: all parts reason: contains aristolochic acids, strong carcinogen, genotoxicity, benefit not proven

Artemisia cina BERG WILLKOMM parts: flower-bud reason: contains the toxic lactone santonin, benefit/risk negative

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Berberis vulgaris L parts: bark, root bark, root reason: contains the alkaloid berberine

Borago officinalis parts: herb, flowers reason: contains pyrrolizidine-alkaloids with genotoxic, carcinogenic and hepatotoxic properties

Dryopteris filix mas L SCHOTT parts: rhizome reason: the constituents drug are highly toxic, severe intoxications may occur when absorption is increased, benefit/risk is negative Exogonium purga WEND BENTH parts: root, resin reason: drastic laxative with irritant action Juglans regia L parts: Fruit-shell reason: may contain the naphtoquinone juglone which is mutagenic and possibly carcinogenic no
benefit proven Juniperus sabina L parts: herb reason: toxic herb, no benefit proven Ledum palstre L parts: herb reason: contains essential oil which is a potent irritant of the GI-tract, kidneys and urinary tract no benefit proven continued

Bryonia all species parts: root reason: cytotoxic cucurbitacines, drastic laxative and emetic Chenopodium ambrosioides L var anthelminthicum L AGRAY parts: essential oil reason: contains the toxic principle ascaridole, benefit/risk negative

Chrysanthemum vulgare L BERNH parts: flower, herb reason: may contain essential oil with the neurotoxic thujone Citrullus colocynthis L SCHRAD parts: fruit reason: contains cytotoxic cucurbitacines, drastic laxative

TABLE 7 Continued
Senecio all species parts: herb, root reason: contains pyrrolizidine-alkaloids with genotoxic, carcinogenic and hepatotoxic properties Strychnos nux-vomica L parts: seed reason: contains alkaloids, especially strychnine benefit/risk negative Symphytum all species, internal use
parts: herb, leaf, root reason: contains pyrrolizidine-alkaloids with genotoxic, carcinogenic and hepatotoxic properties no benefit proven Teucrium chamaedris L parts: herb reason: hepatotoxicity Tussilago farfara L parts: flower, root reason: contains pyrrolizidine-alkaloids with genotoxic, carcinogenic and hepatotoxic properties no benefit proven Vinca minor L parts: herb, leaf reason: hematological changes leucocytopenia, lymphocytopenia, reduced globuline levels have been observed in rabbits no benefit proven Drugs with Toxic Principles, where a More Detailed Discussion Concerning the Benefit/Risk Ratio is Necessary: 1 Drugs with pyrrolizidine-alkaloids where a use is accepted under special precautions/labeling: Symphytum officinale L, external use parts: leafs, herb, root restric- use only on unbroken, intact skin, use during pregnancy requires medical tions: advice, use no longer than 6 weeks per year, temporarily tolerable dose TTD 100 g PA/day

Mallotus phillipinensis LAM
MULLER-ARG parts: gland and trichomes Kamala reason: drastic laxative which may cause severe gastroenteritis, diarrhea and vomiting when taken in higher dosages; benefit/risk negative

Ocimum basilicum L parts: essential oil reason: contains high amounts of estragole which is genotoxic and a carcinogen in rodents no benefit proven

Petasites hybridus L GAERT MEYER et SCHREB parts: leaf reason: contains pyrrolizidine-alkaloids with genotoxic, carcinogenic and hepatotoxic properties

Petroselinum crispum MILL Nym ex A W HILL parts: fruit reason: contains significant amounts of essential oil with toxic apiole Apiole and the fruits are used for self-induced abortions

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Pulsatilla vulgaris MILLER parts: herb reason: higher doses may irritate the kidneys and urinary tract and pregnancy is an absolute contraindication no benefit proven

Ruta graveolens L parts: herb, leafs reason: causes phototoxic reactions, genotoxic, used for self induced abortions, resulted in fatal intoxications no
benefit proven

Rubia tinctorum L parts: root reason: contains lucidin with genotoxic and probably carcinogenic activity no benefit proven

Sassafras albidum NUTT NEES parts: wood, root reason: contains essential oil with carcinogenic and genotoxic safrole no benefit proven

Tussilago farfara L parts: leaf contraindicated during pregnancy and lactation, use no longer than 6 restric- weeks per year, temporarily tolerable dose TTD 1 g herbal tea 10 g tion: PA/day Digitalis species Nerium oleander L Urginea maritima L BAKER Strophanthus species For these drugs a detailed benefit/risk assessment is necessary

Petasites parts: restriction:

hybridus L GAERT MEYER et SCREB rhizome contraindicated during pregnancy and lactation, use not longer than 6 weeks per year, temporarily tolerable dose TTD 1 g PA/day

For these drugs a limitation of the toxic principle and a strict definition of the conditions of use is necessary

A similar approach is necessary for herbal drugs with small amounts of
toxic constituents and accepted uses, for example, estragole in sweet fennel

3 Drugs with alkaloids for example: Atropa belladonna L Cephaelis ipecacuanha KARSTEN Datura stramonium L Ephedra sinica STAPF Hyoscymaus niger Pausinystalia yohimbe K SCHUM PIERRE Rauwolfia serpentina L BENTHAM ex KURZ For these drugs a detailed benefit/risk assessment is necessary

2 Drugs with cardiac glycosides for example: Adonis vernalis L Convallaria maialis L

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946 TABLE 8 Commission E Articles 25 5 and 25 7 Medicines Act: Experts with special theoretical knowledge and practical experience with herbal remedies 12 Members 12 Substitute Members: Pharmacy 1 Pharmacology/Toxicology 1 Clinical Pharmacology 1 Medical Statistics 1 Medical Practice 8 Physicians, Pharmacists, nonmedical Practitioners

Konstantin Keller

term experience with herbal drugs: without new controlled clinical trials, evidence of safety and efficacy is accepted as plausible if: An herbal drug is mentioned in the standard
literature or well-documented review articles, There are clinical trials which are not conclusive alone but are supported by supplementary experimental data, or There is well-documented knowledge on traditional use that is supported by significant experimental studies Traditional use without supplementary data or experimental data alone cannot be accepted as sufficient evidence of efficacy An example of this approach is the drug Manna which consists mainly of mannitole Mannitole is not fully absorbed in the gut and, therefore, it can be used as an osmotic laxative In this case, the traditional use has a pharmacologically plausible basis The situation is different with the fruits of Ficus carica, mainly consisting of saccharose, which have no laxative effect The amount of fiber is quite low, so it is not a bulk forming laxative A laxative action of this drug, at least at therapeutic dosages, is not plausible even if the traditional use is documented in the literature 20 The assessment
of other gums which are highly 70 fermentable, for example, Pectin, Gum arabic, or Tragacanth, could be done on a similar basis 18 Maybe this approach could be a starting

point for developing guidance to the interpretation of the terms of Article 4 No 8 a, ii for herbal remedies A consensus is needed if arbitration in decentralized procedures is to be avoided One key to the solution of these problems could be core SPC guidelines on active principles or even groups of substances As the time for the mutual recognition procedures is very strict, it will not be possible to discuss all problems related to an application Problems can be expected especially in those cases where divergence is great, for example, herbal remedies and many other OTC remedies Biological products such as herbal remedies pose specific problems in assessment and need special experience and expertise for evaluation due to their complex composition One herbal preparation is considered one active constituent even if it
is composed of many different chemically defined substances In some cases, where the active ingredients of herbal preparations are well known, a reproducible therapeutic activity can be assured by a standardization of these active ingredients, an example of which is sennosides in Senna In most cases it is not possible to clearly associate one active ingredient with the therapeutic effect Even in those cases where an active ingredient is known, the therapeutic activity may be inf luenced by other constituents of the herbal preparation, for example, tannins, flavonoids, or saponins, which may enhance, prevent, or prolong absorption or modify metabolism As a consequence, every assessment of efficacy must be based on the individual herbal drug preparation This may result in one assessment for a number of similar preparations covered by one monograph of the European Pharmacopoeia In cases where bibliographic data are presented, posology and therapeutic effect must be correlated to the
particular preparation This is why an assessment of such preparations requires a pluridisciplinary approach of pharmacists, toxicologists, and medical assessors It is hardly imaginable that a consensus can be reached without prior discussions and experience Concern of individual Member States about the decision will lead to time-

Herbal Medicinal Products in Germany and Europe

947

consuming arbitration procedures It was an important step against arbitration when the CPMP decided to accept existing core SPC guidelines and to focus discussion on indications, posology, contra-indications/special warnings, and shelf-life Unfortunately, such guidelines are practically absent for most OTC and herbal products After all that is known about the situation, it does not seem reasonable to postpone all these open questions to arbitration A platform is needed to discuss these problems and to exchange experiences with the assessment of herbal drugs Identical problems in the EMEA and the CPMP have
already led to the creation of a special group, the Mutual Recognition Facilitating Group The group will try to answer open questions with single applications or harmonization of SPCs These activities demonstrate that decisions on efficacy that are based on bibliographic data and the consequences derived from this approach are not a specific herbal problem There could be a forum to discuss such questions Fixed Combinations One additional, mainly efficacy-related, problem with the scientific acceptance of herbal remedies is the fear of completely chaotic fixed combinations and the revival of ancient Theriak Table 9 The problem of OTCfixed combinations on the market was addressed in discussions on the new EU Note for Guidance on fixed combinations as well Clear criteria for well-known fixed combinaTABLE 9 Theriak Andromachi Antidotum Mithridaticum 64 consituents with Opium, Vipers, Squill, Rhubarb, Ruta, Saffron, Valerian, Myrrh, Angelica, Asphalt, Vitriol, Blood of Ducks It really
works?
Andromachos 1st century AD Mithridates Eupator 120163 BC

tions are still lacking It is right to say that the use of fixed combinations is one characteristic aspect of phytotherapy, yet in the institutes experience irrational combinations are not found more frequently in phytotherapy than in any other segment of the market, especially in the OTC market It is possible to apply strict and consistent criteria in the assessment of well-known herbal medicines Theriaks approach of it really works will not be acceptable As in the case of any other product, benefits and risks of herbal combinations must be balanced and compared to those of single ingredients There must be a clear indication for the combination and each constituent must contribute to this indication Dosage and function of each constituent are to be justified by the applicant The result of review in Germany demonstrates that the number of constituents will decrease and most of the products will be accessible to a
scientific evaluation once criteria are set out clearly SUMMARY In summary, the following points should be stressed The legal and terminological framework for herbal remedies in the EU is clear Proper labeling and a consistent quality of herbal remedies is a prerequisite in public health protection Quality criteria are set out in the European Pharmacopoeia and in the EEC Note for Guidance The problem lies in the interpretation of open terms such as wellestablished use and acceptable safety and the apparent lack of guidance in interpreting these open terms for widespread OTC and herbal products The unease of some Member States with this situation is expressed by discussions on toxicological requirements and criteria for fixed combinations of this part of the pharmaceutics market, but EMEAs and CPMPs resources are mainly focused on a limited number of products with new active principles and high-tech products It is well known that there is a great difference in the assessment of these
products in the Member States and that the share of these products of the pharmaceutics market is relevant Sit

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Konstantin Keller
10 Grunwald J, Buttel K Der europaische Markt fur Phytotherapeutica, Pharm Industrie 1996;58:209 214 11 WHO Sixth International Conference of Drug Regulatory Authorities–Report of the conference proceedings held in Ottawa, Canada from 7 to 11 October 1991, Genf 1993:7380 12 Schwabe U, Paffrath D Ed ArzneiverordnungsReport 95 Stuttgart: G Fischer; 1995 13 Commission of the European Communities: The Rules Governing Medicinal Products in the European Community, Volume III: Note for Guidance: Quality of Herbal Remedies November 1988 14 ECJ judgment of 5 October 1995, case C-440/93 15 Perharic L, Shaw D, Murray V Toxic effects of herbal medicines and food supplements Lancet 1993;342:180181 16 De Smet PAGM Toxicological Outlook on the Quality Assurance of Herbal Remedies In De Smet PAGM, Keller K, Hansel R, Chandler RF ed Ad verse Effects of Herbal
Drugs Vol 1 Berlin, Heidelberg, New York: Springer Verlag; 1992;172 17 Keller K Foeniculum vulgare In De Smet PAGM, Keller K, Hansel R, Chandler RF ed Adverse Effects of Herbal Drugs Vol 1 Berlin, Heidelberg, New York: Springer Verlag; 1992;135142 18 Leng-Peschlow E Pharmacological Aspects of Fiber In Csomos G, Kusche J, Meryn S Ed Fibers Berlin, Heidelberg, New York: Springer Verlag; 1993;6988 19 Bekanntmachung der Neufassung der Allgemeinen Verwaltungsvorschrift zur Anwendung der Arzneimittel Prufrichtlinien vom 5 Mai 1995 Bundesan zeiger Vol 47 No 96a of May, 20 1995 20 Ministere des Affaires Sociales et de la Solidarite Me dicaments a Base de Plantes; Avis aux fabricants concernant les demandes dautorisation de mise sur le marche Bulletin Officiel 1990: No 90/22 bis 21 De Smet PAGM Health Risks of Herbal Remedies, Drug Safety 1995;13:8193

and wait does not seem to be a reasonable approach to determine results that are a substantial response to the industrys and consumers
demands Scientific fundamentalism will do more harm than benefit to consumers health Herbal remedies have a well-defined position in the market of medicinal products; it is possible to assess quality, safety, and efficacy on the basis of the existing directives if bibliographic data are accepted in an unbiased way The best way to protect public health from risks associated with botanical drugs is to make well-tested and adequately labeled herbal medicinal products available

REFERENCES
1 Official J No C 310/2, 27111992 2 Decision of January 14, 1993; case C-177/91 ref in: Pharma Recht 1993;15:215216 3 Council resolution 12213/95 on medicinal plant preparations of 6 December 1995 4 Payer L Medicine and Culture Notions of health and sickness in Britain, the US, France and West Germany London: Victor Gollancz; 1990 6 Keller K Phytotherapy at a European Level ESCOP: European Phytotelegram Sixth Issue 1994:4047 7 Keller K Therapeutic Use of Herbal Drugs and their Potential Toxicity Problems
and Results of the Revision of Herbal Remedies in the EEC Proceedings of the 3rd International Conference on Pharmacopoeias and Quality Control of Drugs, Rome, November 1992 1993:243250 8 Informations Medicales et Statistiques 1994 in 10 9 The Herbal Medicinal Database in 10

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