Herbal medicinal products in the European Union

Herbal medicinalproducts in theEuropean Union

Study carried out on behalf of the European Commission

Association Européenne des Spécialités Pharmaceutiques Grand PublicThe Association of the European Self-Medication Industry

Europäischer Fachverband der Arzneimittel-Hersteller

Avenue de Tervuren, 7 – B-1040 Brussels – BelgiumTel: +32 2 735 51 30 – Fax: +32 2 735 5222

E-mail: [email protected] – Internet: http://www.aegsp.be

This paper does not express the Commission’s official views.Neither the Commission nor the authors accept liability for the consequences of actions taken on

the basis of the information contained herein.

iii

TABLE OF CONTENTS

TABLE OF CONTENTS ......................................................................................................... III

I. EXECUTIVE SUMMARY ........................................................................................... 1

II. INTRODUCTION........................................................................................................ 4

III. BACKGROUND AND OBJECTIVES OF THE STUDY RELATING TO HERBALMEDICINAL PRODUCTS........................................................................................... 4

IV. CURRENT LEGAL SITUATION OF HERBAL MEDICINAL PRODUCTS IN THEEUROPEAN UNION .................................................................................................. 5

IV.1 DEFINITION OF MEDICINAL PRODUCTS................................................................... 5IV.2 HERBAL PRODUCTS NOT REGARDED AS MEDICINAL PRODUCTS ............................ 5IV.3 REQUIREMENTS FOR MARKETING AUTHORISATION .............................................. 5IV.4 EUROPEAN PHARMACOPOEIA.................................................................................. 6IV.5 BIBLIOGRAPHIC APPLICATIONS.............................................................................. 6IV.6 THE “SCOTIA” CASE ................................................................................................ 6

V. ATTEMPTS TO HARMONISE SCIENTIFIC AND REGULATORY CRITERIA ............... 8V.1 THE NORDIC COUNCIL ON MEDICINES ................................................................... 8V.2 THE AD HOC WORKING GROUP ON HERBAL MEDICINAL PRODUCTS .................... 8V.3 THE ROLE OF SCIENTIFIC MONOGRAPHS................................................................ 9

VI. WORKING PROGRAMME TO STUDY THE SITUATION OF HERBAL MEDICINALPRODUCTS IN THE EUROPEAN UNION................................................................... 10

VII. COMPARISON OF THE LEGAL REQUIREMENTS AND THE ASSESSMENT OFHERBAL MEDICINAL PRODUCTS IN THE MEMBER STATES OF THE EUROPEANUNION ...................................................................................................................... 10

VII.1 GENERAL ITEMS ...................................................................................................... 10VII.1.1 Implementation of EC Directives ............................................................ 10VII.1.2 Definition of Herbal Medicinal Products ............................................... 13VII.1.3 Classification of Herbal Preparations ..................................................... 18VII.1.4 Medicinal Products without Claims Containing Herbal Preparations... 26VII.1.5 Combinations of Herbs and Combinations with Other Groups of

Substances................................................................................................. 28VII.2 REQUIREMENTS FOR MARKETING AUTHORISATION .............................................. 31

VII.2.1 Application of Council Directive 65/65/EEC to Herbal MedicinalProducts..................................................................................................... 31

VII.2.2 Documentation of Quality, Efficacy and Safety: “Full” Application....... 32VII.2.3 Bibliographic Applications ....................................................................... 37VII.2.4 The “Scotia” Case...................................................................................... 43VII.2.5 ESCOP and WHO Monographs and WHO Guidelines........................... 46VII.2.6 Existence of a Category for Well-Known Plants ..................................... 47VII.2.7 Simplified Proof of Efficacy..................................................................... 48VII.2.8 Indication Claim of the Category with Simplified Proof of Efficacy....... 57VII.2.9 Further Developed Products: Requirements for Proof of Efficacy and

Safety......................................................................................................... 58VII.2.10 Comparison of the Requirements for Proof of Efficacy in the Member

States ......................................................................................................... 61VII.3 SPECIFIC QUESTIONS ON MARKETING AUTHORISATION ........................................ 63

VII.3.1 Marketing Authorisation for Combination Products............................... 63VII.3.2 Individual Supply by Practitioners .......................................................... 66VII.3.3 Intermediate Products............................................................................... 68VII.3.4 Products from Foreign Countries............................................................. 70VII.3.5 Important Products.................................................................................... 73

VII.4 GOOD MANUFACTURING PRACTICE AND QUALITY CONTROL .................................... 78VII.4.1 Manufacturing Requirements of Council Directive 75/319/EEC............. 78VII.4.2 EC GMP Requirements............................................................................. 78VII.4.3 Use of European Pharmacopoeia Monographs ......................................... 79VII.4.4 GMP Inspections....................................................................................... 79

i v

VII.5 POST MARKETING SURVEILLANCE........................................................................... 81VII.5.1 Monitoring of Herbal Medicinal Products............................................... 81VII.5.2 Withdrawal of Herbal Medicinal Products Due to Safety Reasons......... 83VII.5.3 Consumer Reports ..................................................................................... 84

VII.6 LABELLING AND ADVERTISING OF HERBAL MEDICINAL PRODUCTS...................... 87VII.6.1 Implementation of Council Directive 92/27/EEC into National Law....... 87VII.6.2 Application of Council Directive 92/27/EEC to Herbal Medicinal

Products..................................................................................................... 89VII.6.3 Implementation of Council Directive 92/28/EEC into National Law....... 92VII.6.4 Application of Council Directive 92/28/EEC to Herbal Medicinal

Products..................................................................................................... 94VII.7 DISTRIBUTION AND RETAIL SALE OF HERBAL MEDICINAL PRODUCTS................... 97

VII.7.1 Good Distribution Practice........................................................................ 97VII.7.2 Retail Sale of Herbal Medicinal Products................................................ 98VII.7.3 Distance Selling and Teleshopping.......................................................... 101

VIII. CONCLUSIONS AND RECOMMENDATIONS ............................................................ 103

IX. LEGAL REQUIREMENTS AND THE ASSESSMENT OF HERBAL MEDICINALPRODUCTS IN NORTH AND CENTRAL AMERICA .................................................... 104

IX.1 CANADA .................................................................................................................... 104IX.1.1 Classification of herbal medicinal products ........................................... 104IX.1.2 Application of the Food & Drugs Act to herbal medicinal products ......... 106IX.1.3 Application of Good Manufacturing Practices to herbal medicinal

products...................................................................................................... 109IX.1.4 Post-marketing surveillance.................................................................... 110IX.1.5 Labelling and advertising of herbal medicinal products........................ 110IX.1.6 Distributions and retail sale of herbal medicinal products..................... 111

IX.2 MEXICO .................................................................................................................... 111IX.2.1 Classification of herbal products .............................................................. 111IX.2.2 Application of the General Health Law to herbal medicinal products..... 113IX.2.3 Application of Good Manufacturing Practices to herbal medicinal

products...................................................................................................... 116IX.2.4 Post-marketing surveillance.................................................................... 116IX.2.5 Labelling and advertising of herbal medicinal products........................ 117IX.2.6 Distributions and retail sale of herbal medicinal products..................... 117

IX.3 UNITED STATES OF AMERICA................................................................................... 118IX.3.1 Classification of herbal products .............................................................. 118IX.3.2 Application of the Federal Food, Drug and Cosmetic Act as amended by

the Dietary Supplement Health and Education Act of 1994 (DSHEA) ...... 120IX.3.3 Application of Good Manufacturing Practices to dietary supplements.... 125IX.3.4 Post-marketing surveillance and “vigilance” of dietary supplements... 126IX.3.5 Labelling and advertising of herbal products.......................................... 128IX.3.6 Distribution and retail sale of herbal products......................................... 129

X. ACKNOWLEDGEMENTS .......................................................................................... 131

XI. REFERENCES .......................................................................................................... 135

XII. ANNEXES ................................................................................................................. 142XII.1 LIST OF ACRONYMS .................................................................................................. 142XII.2 LIST OF TABLES ....................................................................................................... 144XII.3 TRANSLATION OF “HERBAL MEDICINAL PRODUCTS” IN THE OFFICIAL

LANGUAGES OF THE EUROPEAN COMMUNITY........................................................... 145

1

I. EXECUTIVE SUMMARYHerbal medicinal products exist in all Member States of the European Union (EU), althoughtheir importance varies considerably from one country to another. They do not represent ahomogeneous group. Generally speaking, there are either fully licensed medicinal productswith efficacy proven by clinical studies or by bibliography (in accordance with Article 4.8 a(ii) of Council Directive 65/65/EEC) or products with a more or less simplified proof ofefficacy according to their national use. Although these two categories exist in manyMember States, there are major discrepancies between the Member States in theclassification of individual herbal drug preparations and products into one of thesecategories as well as in the requirements for obtaining a marketing authorisation.

Definition of herbal medicinal products

According to Council Directive 65/65/EEC, which has been implemented into national law i nall Member States, medicinal products require prior marketing approval before gainingaccess to the market. In almost all Member States, herbal medicinal products are consideredas medicinal products. As such they are in principle subject to the general regulations formedicines as laid down in the various national medicines laws. A specific definition ofherbal medicinal products is available in many cases. This definition is in line with the EUGuideline "Quality of Herbal Remedies" (now replaced by "Quality of Herbal MedicinalProducts"). It includes plants, parts of plants and their preparations, mostly presented withtherapeutic or prophylactic claims. Different categories of medicinal products containingplant preparations exist or are in the process of being created. For instance, draft legislationin Spain includes the definitions “herbal medicinal products” and “phytotraditionalproducts”. The latter are however not considered as “pharmaceutical specialties” and aretherefore not classified as herbal medicinal products.

Classification of herbal products

In general, herbal products are classified as medicinal products if they claim therapeutic orprophylactic indications, and are not considered as medicinal products insofar as they donot make these claims. Products not classified as medicinal products belong in most cases tothe food or cosmetic area, even though they sometimes contain plants which havepharmacological properties. For example, senna pods can be marketed as food in Belgium.Furthermore, there are specific categories of non-medicinal products, e.g. the so-called“therapeutic supplement products” in Austria. Such products are specifically regulated bynational law and sometimes require notification to the competent national authority.

In Ireland, Spain and the United Kingdom there exist preparations defined as medicinalproducts which are under specific conditions exempt from licensing requirements.

Combination products

Combinations of herbal ingredients are widely used in Europe and their assessment is oftenperformed according to specific guidelines. Combinations of herbal and homeopathicingredients exist in a few countries. Their assessment follows rather strict criteria, usuallythose of a “full” application procedure. Combinations of herbal ingredients and vitamins areavailable in many countries. In some cases these combinations are regarded as food or foodsupplements, in other cases a “full” application dossier as a medicinal product is required.

Documentation of quality, safety and efficacy

A marketing authorisation as a herbal medicinal product is in principle granted based on a“full” dossier in terms of proof of quality, safety and efficacy in all Member States, with theexception of Denmark and Finland. In these countries it is only possible to use bibliographicapplications for herbal medicinal products. Luxembourg in practice only grants marketingauthorisations based on the assessment of other countries. The option of bibliographicapplications according to Article 4.8 (a) (ii) of Council Directive 65/65/EEC is in principleavailable in all Member States. However, it is sometimes only available through assessmenton a case-by-case basis or not used in practice. An exception is Austria, which permits thistype of application for safety documentation only.

The opinions obtained from national health authorities about the possible implications of theScotia Judgement are not uniform. Obviously there is no problem in the implementation ofthis judgement.

2

ESCOP and WHO monographs

ESCOP as well as WHO monographs may be used in many Member States as a summary ofbibliographic data. Further clarification concerning the efficacy and safety documentation,e.g., from the EMEA Ad Hoc Working Group on Herbal Medicinal Products, is regarded asdesirable by many regulatory authorities.

Simplified proof of efficacy

Beside the category of fully licensed herbal medicinal products, a range ofnational/traditional herbal medicinal products exists in many Member States. For theseproducts, national authorities usually verify the safety and ensure a sufficient level ofquality. For proof of efficacy, the level of requirements is sometimes adjusted to take intoaccount the long-term experience and in a certain sense simplified. A specific simplifiedprocedure exists in Austria, Belgium, France and Germany, and is proposed in Spain. Theindications often refer to the traditional use of the product, and a specific statement“traditionally used in ...” is at present added to the indication claims in France andGermany.

Further developed products

For herbal medicinal products which are further developed from their traditional use, e.g.,further processed extracts and/or products with “high-level” indications, a full licence i srequired in most cases, and efficacy has to be proven by clinical studies. In severalcountries such products do not exist.

Different requirements for proof of efficacy

It has been demonstrated that different requirements exist for herbal medicinal products i nterms of proof of efficacy:

1. The option exists to provide simplified proof of efficacy in Austria, Belgium, Germany,France and (is proposed) in Spain.

2. The option exists to provide bibliographic proof of efficacy in almost all countries,although it is in practice sometimes unknown or difficult to provide, or can be onlysupportive of clinical data in Austria.

3. The option exists to provide full clinical proof in all countries except Denmark andFinland (which allow only bibliographic applications) and Luxembourg (unknown i npractice).

Individual supply

In many cases, herbal medicinal products (like other medicinal products) are made upand/or supplied to individual patients following a one-to-one consultation between patientand practitioner.

A number of herbal medicinal products are magisterial formulas, which are prepared by thepharmacist. For magisterial formulas, a marketing authorisation is not needed according toArticle 2.4 of Council Directive 65/65/EEC. A specific situation exists in the United Kingdom,where a practitioner – according to Section 12(1) of the Medicines Act – may supply productswithout a licence to a customer.

Intermediate products

Intermediate products of herbal origin intended for further processing by an authorisedmanufacturer or for the preparation of a magisterial or officinal formula do not fall underthe definition of a medicinal product according to Council Directive 65/65/EEC, and aretherefore not subject to marketing authorisation as such. Intermediate products of herbalorigin are mostly handled like any other raw material used for the production of medicinalproducts, and are therefore regulated according to the applicable EC rules, e.g. on GoodManufacturing Practice.

3

Products from foreign countries

The quality of imported medicinal plants and their preparations is assessed differently.Finished products are often treated as new chemical entities with full proof of quality, safetyand efficacy being required. There are however in several cases no specific regulationsconcerning the control of raw materials or crude drugs, particularly not for those productsthat enter the market as foodstuffs or other products not controlled in the same way asmedicinal products.

Good Manufacturing Practice and quality control

All Member States also apply the manufacturing requirements of Council Directive75/319/EEC to herbal medicinal products. Starting materials of herbal medicinal productsare in principle controlled in accordance with the European Pharmacopoeia in all MemberStates. Inspections concerning GMP are carried out in practically all Member States.Inspections in third countries are performed as well, but not by all Member States.

Post marketing surveillance

The adverse reaction reporting systems of the Member States also monitor herbal medicinalproducts insofar as they are authorised medicinal products. The effectiveness of existingpharmacovigilance systems can be demonstrated by several withdrawals of marketingauthorisations for herbal medicinal products due to safety concerns in connection withcertain plants. Consumer reports could give an improved picture of the spectrum of adversereactions to herbal medicinal products. The degree of acceptance of reports obtained fromconsumers in the national pharmacovigilance systems varies from one country to another.

Labelling

Council Directive 92/27/EEC on labelling and leaflets has been implemented by all MemberStates. In principle, the national requirements on labelling also apply to herbal medicinalproducts insofar as they are authorised medicinal products. No specific problems seem tooccur except in cases where there is no prior control of labels or where promotional materialis included in the label.

Advertising

All Member States have implemented Council Directive 92/28/EEC on advertising intonational law. This directive also covers herbal products as far as they are authorised asmedicinal products. The specific problems encountered are particularly due to healthproducts not licensed as medicines claiming “indications” which they are not allowed toclaim.

Distribution and retail sale

Council Directive 92/25/EEC on the wholesale of medicinal products in principle applies toall medicinal products and therefore also to all authorised herbal medicinal products.

The retail sale of herbal medicinal products is restricted to pharmacies in Belgium, France,Greece, Ireland, Italy, Luxembourg, Portugal and Spain. It is permitted in other outlets – atleast for certain herbal medicinal products – in Austria, Denmark, Finland, Germany, theNetherlands, Sweden and the United Kingdom.

Distance selling and teleshopping

Both distance selling and teleshopping are not permitted for herbal medicinal products i nmost countries. In several cases they are allowed under certain conditions.

Herbal medicinal products in the single market

Herbal medicinal products are regarded as medicinal products in more or less all MemberStates and therefore have – at least in theory – the option to obtain a marketing authorisationin the same way as all other medicinal products. There are however large differences in thelegal systems of the Member States, in particular concerning: the classification of herbalproducts, the possibility to receive a marketing authorisation based on a full application,bibliographic application or simplified proof of efficacy; and retail distribution. Furthermorethere are different traditions regarding the therapeutic use of medicinal plant preparations.

4

For instance, Garlic (Allium sativum) is used for cough and cold in the United Kingdom andfor the prevention of arteriosclerosis in Germany. Such differences, particularly i nclassification, marketing authorisation procedures and therapeutic use, make it often moredifficult for herbal medicinal products than for chemical substances to use the decentralisedprocedure successfully. That might explain that up to now only few companies have appliedfor marketing authorisation using the decentralised procedure, and only three applicationshave been successful so far: two for products containing Ispaghula husk (Plantago ovata),and one for a product containing Valerian (Valeriana officinalis).

Conclusions and Recommendations

Chapter VIII contains the conclusions and recommendations of this report on the situation ofherbal medicinal products in Europe. It is recommended that the work of the Ad hocWorking Group on Herbal Medicinal Products is further supported, eventually leading to theestablishment of a permanent Committee on Herbal Medicinal Products (CHMP) within theEMEA. It is also considered necessary that further clarification of the existing regulatoryframework for herbal medicinal products be provided in order to facilitate the application ofthese provisions in the EU Member States.

II. INTRODUCTIONMedicinal plants and their preparations have been used since the earliest history ofhumanity and have formed one of the foundations for healthcare in cultures throughout theworld. In various countries, different names are used to refer to botanicals, such as “herbalmedicines”, “herbal remedies”, and “traditional medicines”. In this study, the name “herbalmedicinal products” is chosen, in accordance with the terminology used by the Ad HocWorking Group on Herbal Medicinal Products, established by the European Agency for theEvaluation of Medicinal Products (EMEA) at the beginning of 1997.

Although herbal medicinal products have a long tradition as medicinal products,recognition of their clinical, pharmaceutical and economic value and the public’s interest i nthem are still growing. The European market for herbal medicinal products was estimatedto be worth USD 5,600 million at public price level in 1995 [1].

In 1987, the European Parliament acknowledged in a resolution “that there do exist a largenumber of well-known medicinal plants, traditionally used by the population and fullydescribed in scientific literature whose very slight pharmacological effect allows theirauthorisation on the basis of a list to ensure correct identification of the species, variety,conservation, labelling and specified dosage and application; this group would not require thesame kind of monitoring as proprietary medicinal products.” Furthermore, the EuropeanParliament called on the European Commission “to help to ensure that, profiting by theresults of research work to date, a scientific approach to phytopharmaceuticals is developed,which will not only incorporate centuries of practical experience but will also respect theindispensable requirement of scientific precision.” [2].

III. BACKGROUND AND OBJECTIVES OF THE STUDYRELATING TO HERBAL MEDICINAL PRODUCTS

On 20 December 1995, the Council of Ministers called on the European Commission toexamine the current situation of herbal medicinal products in the European Union [3]. TheCouncil’s priority objectives were to safeguard public health, facilitate the development ofindustry and foster the free movement of medicinal products within the European Union. On23 April 1996, the Council of Ministers adopted another resolution asking the Commission towork with the Member States to review the situation of manufacturers of non-prescriptionherbal products [4]. In a resolution of 16 April 1996, the European Parliament requested thatthe Commission propose improvements in the marketing of herbal and homeopathicmedicinal products and create a specific agency for the evaluation of traditional medicinalproducts [5]. Furthermore, the mutual recognition procedure under Council Directive75/319/EEC was to become compulsory on 1 January 1998 and needed clarification withrespect to herbal medicinal products. Based on these resolutions and the need for

5

clarification, the European Commission issued a call for tender for a study on herbalmedicinal products in the pharmaceutical sector [6].

The main objectives of the study were described as follows:

• to clarify the current legal situation for herbal medicinal products in each MemberState with respect to the implementation of the requirements of Council Directives65/65/EEC, 75/318/EEC and 75/319/EEC;

• to compare actual practices in the assessment of quality, safety and efficacy of herbalmedicinal products in the Member States, with particular emphasis on the applicationof the derogation in Article 4.8 (a) (ii) of Council Directive 65/65/EEC;

• for the purpose of mutual recognition under Council Directive 75/319/EEC, to evaluatethe consequences of possible divergence in either the legal position or the assessmentof herbal medicinal products; and

• to make recommendations on how to best safeguard public health while allowing thefree movement of herbal medicinal products throughout the European Union.

AESGP was selected to carry out the study and started work on 1 January 1998. Inaccordance with the contract for the study, an Interim Report was provided on 29 May 1998and the Draft Final Report was submitted on 30 September 1998.

IV. CURRENT LEGAL SITUATION OF HERBAL MEDICINALPRODUCTS IN THE EUROPEAN UNION

IV.1 Definition of Medicinal ProductsAccording to Council Directive 65/65/EEC of 26 January 19651, a medicinal product i sdefined as “any substance or combination of substances presented for treating or preventingdisease in human beings or animals”. This Directive further states that “any substance o rcombination of substances which may be administered to human beings or animals with a viewto making a medical diagnosis or to restoring, correcting or modifying physiological functionsin human beings or in animals is likewise considered a medicinal product”. Article 3 clarifiesthat no medicinal product may be marketed in a Member State unless an authorisation hasbeen issued by the competent authority of that Member State.

IV.2 Herbal Products Not Regarded as Medicinal ProductsApplying the definition of a medicinal product laid down in Council Directive 65/65/EEC toherbal preparations, has led to the conclusion that these preparations are not considered asmedicinal products if they are intended to be used as food, cosmetics, etc. and are notintended or presented for treating, preventing or diagnosing diseases or restoring,correcting or modifying physiological functions. Herbal preparations that are not medicinalproducts do not require a marketing authorisation from the competent authority.Homeopathic preparations, covered by Council Directive 92/73/EEC of 22 September 19922, arelikewise not considered as herbal medicinal products.

Although Council Directive 65/65/EEC defines the basic criteria for a medicinal product, it i sin many cases not so easy to draw the line distinguishing medicinal products from non-medicinal products. This dilemma is illustrated in the disparate definitions of herbalmedicinal products used by each Member State.

IV.3 Requirements for Marketing AuthorisationCouncil Directive 65/65/EEC establishes that proof of quality, safety and efficacy is a pre-condition for delivering a marketing authorisation for a medicinal product. The specificrequirements for documentation and expert reports on quality, safety and efficacy are 1 Council Directive 65/65/EEC of 26 January 1965 on the approximation of provis ions laid down b y

law, regulation or administrative action relating to medicinal products (OJ 22 of 9.2.1965, p. 369).2 Council Directive 92/73/EEC of 22 September 1992, widening the scope of Directives 65/65/EEC and

75/319/EEC on the approximation of provisions laid down by law, regulation or administrativeaction relating to medicinal products and laying down additional provisions on homeopathicmedicinal products (OJ L 297 of 13.10.1992, p. 8).

6

delineated in Council Directive 75/318/EEC3 as amended. However, the Member States havetaken a variety of approaches to meeting these requirements, and in several cases the optionexists to supply simplified proof of efficacy in addition to or instead of the proof required fora “full application” (i.e., including a bibliographic or clinical dossier). In this study,particular emphasis is placed on the apparent divergence in the description of the respectiveapplication procedures.

IV.4 European PharmacopoeiaSince its creation in 1964, the European Pharmacopoeia has dedicated part of its work to theestablishment of monographs on herbal drugs which are used either in their natural stateafter desiccation or concentration or for the isolation of natural active ingredients. 83monographs have either been published in the European Pharmacopoeia or adopted by theEuropean Pharmacopoeia Commission for publication. An additional 82 monographs arecurrently in progress, and recently 56 new monographs were authorised by the Commissionfor elaboration. Most of the existing national pharmacopoeias use the methods of theEuropean Pharmacopoeia in drafting national monographs. Since national authorities alsoapply the criteria laid down by the European Pharmacopoeia Commission in theestablishment of national monographs (e.g. Technical Guide), the possibility exists totransfer such national monographs to the European Pharmacopoeia.

IV.5 Bibliographic ApplicationsAccording to Article 4.8 (a) (ii) of Council Directive 65/65/EEC, “the applicant shall not berequired to provide the results of pharmacological and toxicological tests or the results ofclinical trials if he can demonstrate ... by detailed references to published scientificliterature presented in accordance with the second paragraph of Article 1 of Directive75/318/EEC that the constituent or the constituents of the medicinal product have a wellestablished medicinal use, with recognised efficacy and an acceptable level of safety.”Therefore, in principle, data from published literature may be used to substantiate safety andefficacy in expert reports and dossiers. Other exemptions from the requirement to submitresults of pharmacological and toxicological tests and clinical trials are provided in Article4.8 (a) (i) (“informed consent”) and Article 4.8 (a) (iii) (“generic applications”) of CouncilDirective 65/65/EEC, and in Council Directive 92/73/EEC for homeopathic medicinalproducts.

IV.6 The “Scotia” CaseThe European Court of Justice, in its Judgement of 5 October 1995 in case C-440/93 (TheQueen v (1) Licensing Authority of the Department of Health and (2) Norgine Limited, exparte Scotia Pharmaceuticals Limited), clearly stated that, in terms of the utilisation ofbibliographic data according to Article 4.8 (a) (ii) of Council Directive 65/65/EEC, the testsreferred to in the data should actually have been carried out previously and that expertreports must be provided in accordance with Council Directive 75/318/EEC. In detail, theCourt stated in point 17 of the judgement that:

"The abridged procedure in no way relaxes the requirements of safety and efficacy whichmust be met by medicinal products but is merely intended to shorten the period for preparingan application for authorisation by freeing the applicant from the obligation to carry out thetests specified in point (8) of the second paragraph of Article 4. However, that obligation isreplaced by the obligation to demonstrate by detailed references to published scientificliterature that the tests listed in the Annex to Directive 75/318 were carried out previously andshowed that the constituent or constituents of the medicinal product satisfied the criteriareferred to in Article 4."

Furthermore, the Court provided the following clarification in point 18:

"Nor does recourse to the abridged procedure relax the obligations with which experts mustcomply by virtue of Articles 1 and 2 of Directive 75/319. Although that procedure substitutes forthe requirement to carry out tests the requirement to present, in the form of publishedreferences, all the results of the tests performed by other experts, point (b) of the first

3 Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States

relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of thetesting of medicinal products (OJ L 147 of 9.6.1975, p. 1).

7

paragraph of Article 2 of the directive still requires the analyst, pharmacologist and clinician toprovide reports containing the information specified by that provision."

An examination of the impact of the interpretation of Article 4.8 (a) (ii) of Council Directive65/65/EEC by the European Court of Justice on the assessment of marketing authorisationapplications for herbal medicinal products in the Member States will be performed i nChapter VI.2.4 below.

8

V. ATTEMPTS TO HARMONISE SCIENTIFIC ANDREGULATORY CRITERIA

V.1 The Nordic Council on MedicinesThe Nordic Council on Medicines (NLN) is a body jointly set up by the Nordic countriesDenmark, Finland, Iceland, Norway and Sweden. It acts on behalf of all citizens byworking for a high-quality, harmonised medicines market and a rational use of medicines.

The NLN has taken limited steps in the field of herbal medicinal products. In 1996, itpublished “Quality Assessment of Natural Remedies”, No 40, NLN Regulatory Seminars1995 reflecting the outcome of a regulatory seminar held in Nådendal/Naantali, Finland i nAugust 1995. It lays down a common Nordic approach to the quality assessment of herbalremedies. The outcome of the discussions is not binding and must be seen only as an effortto facilitate co-operation among the Nordic countries and with the neighbouring regions. Nofurther regulatory seminars relating to herbal remedies are planned for the moment.

The quality assessment requirements in the Nordic countries are based on CouncilDirectives 65/65/EEC, 75/318/EEC, 75/319/EEC4 and 92/27/EEC5 and EC Guidelines “Qualityof Herbal Remedies”6 and “Manufacture of Herbal Medicinal Products”7. However, certaindifferences may be found in the various Nordic countries in this respect (see specificallyDenmark, Finland and Sweden).

V.2 The Ad Hoc Working Group on Herbal MedicinalProducts

In early 1997, the Ad Hoc Working Group on Herbal Medicinal Products was established bythe European Commission, the EMEA Executive Director, and the EMEA ManagementBoard. This Working Group is made up of representatives from the Member States(primarily health authorities) and representatives from the European Parliament, theEuropean Commission and the European Pharmacopoeia. The Working Group met fivetimes in 1997 and 1998.

The Working Group has reviewed the criteria for the demonstration of quality, pre-clinicalsafety and clinical efficacy in marketing authorisation applications for herbal medicinalproducts as set out in the Council Directives. In particular, it has completely revised theguidance provided in “Quality of Herbal Remedies” (now called “Quality of HerbalMedicinal Products”), taking into consideration that herbal medicinal products and theirraw materials are complex mixtures. The Working Group has also proposed requirementsfor non-clinical testing of herbal drug preparations based on a draft EC Guideline for oldsubstances with long market histories. Furthermore, the Working Group has discussed theappropriate role of scientific monographs prepared by the World Health Organisation(WHO) and the European Scientific Co-operative on Phytotherapy (ESCOP). In addition, apaper on fixed combination products has been developed.

The initiatives of the Working Group are highly appreciated by all parties involved in theassessment and development of herbal medicinal products, and it is hoped that the Groupwill provide further guidance for the evaluation of quality, safety and efficacy of herbalmedicinal products.

• Good Manufacturing Practice (GMP): Comments and proposals for revision

• Proposals for revision of note for guidance “Quality of herbal remedies” (November1988)

• Proposal for new guidance “Non-clinical testing of herbal drug preparations withlong-term marketing experience” Guidance to facilitate mutual recognition and useof bibliographic data

• Note to Applicants Volume 2A and Volume 2B Parts IB1, IC2 and III – Comments and

4 Council Directive 75/319/EEC of 20 May 1975 on the approximation of provisions laid down by l a w ,

regulation or administrative action relating to medicinal products (OJ L 147 of 9.6.1975, p. 13).5 Council Directive 92/27/EEC of 31 March 1992 on the labelling of medicinal products for human use

and on package leaflets (OJ L 113 of 30.4.1992, p. 8).6 The Rules Governing Medicinal Products in the European Community, Volume 3A.7 The Rules Governing Medicinal Products in the European Community, Volume 4.

9

proposals for revision

• Comments on Part 4 of Annex to Council Directive 75/318/EEC if 20 May 1975“Clinical documentation”

• Proposal for a core-SPC for Valerianae radix (7 July 1998)

These six documents were released for consultation by the EMEA in January 1998.

The deadline for comments was April 1998.

The release of final proposals took place on 17 September 1998, under the numberEMEA/adhocHMPWG/114/98

• Proposal for new guidance “Fixed combinations of herbal medicinal products withlong term marketing experience” – Guidance to facilitate mutual recognition anduse of bibliographic data

• Comments and proposals for revision of the Notice to Applicants Volume 2B PartsIC1 and II, including a proposal for tabular formats specific to herbal medicinalproducts

These two documents were released for consultation by the EMEA in September 1998.

The deadline for comment is December 1998.

Table 1: Documents Prepared by the ad hoc Working Group on Herbal MedicinalProducts

V.3 The Role of Scientific MonographsIn 1989, ESCOP was founded by the national scientific associations of phytotherapy andgiven the mission to provide scientifically based assistance for a harmonised assessment ofherbal medicinal products. The main objectives of this European umbrella organisationhave been as follows:

• to establish harmonised criteria for the assessment of herbal medicinal products;

• to provide support for scientific research; and

• to contribute to the acceptance of phytotherapy at the European level.

ESCOP also writes monographs for individual plant drugs, primarily focusing on thoseplant drugs for which European or national pharmacopoeia monographs exist. To be in linewith the requirements of EC Guidelines, the format of a Summary of Product Characteristics(SPC) was chosen for these texts. Clinical aspects and details of the pharmacologicalproperties are particularly highlighted. To date, ESCOP has published 50 monographs andsubmitted them to the Ad Hoc Working Group on Herbal Medicinal Products. Thesemonographs represent an overview of the current scientific data on each medicinal plant,but they are not intended to eliminate the need for an expert report or documentation.

Based on its “Guidelines for the Assessment of Herbal Medicines”, (Geneva, 1991), whichdefined basic criteria for the evaluation of quality, safety and efficacy of herbal medicinalproducts, the WHO’s Traditional Medicine Programme (TRM) has prepared a technicaldocument entitled “Model Monographs of Widely Used Medicinal Plants”. Thesemonographs include summaries of botanical characteristics, quality control and majoractive chemical constituents as well as clinical applications, pharmacology, posology,contra-indications and adverse reactions. Publication of these monographs is scheduled forthe near future.

In November 1997, the Ad Hoc Working Group on Herbal Medicinal Products concluded thatdrafting “core-SPCs” would be the most appropriate way of developing general criteria forassessing the efficacy data provided in the bibliographic documentation. General agreementhad already been reached during discussions about a core-SPC for Valerianae radix that hadbeen based on a proposal submitted by ESCOP. The Working Group had further proposed anamendment to the Notice to Applicants (The Rules Governing Medicinal Products in theEuropean Union), stating that scientific monographs (e.g., those drafted by ESCOP andWHO) “offer a valuable and updated overview on published scientific literature, whichtogether may be used in support of the proof of safety and efficacy of a medicinal product in abibliographic application in accordance with Article 4.8 (a) (ii). These monographs mayavoid duplication of work and bring about gradual harmonisation in the evaluation ofmedicinal products, e.g. herbal medicinal products. Therefore the European Commission

10

and Member States recommend that both applicants and competent authorities should makeuse of these monographs.”

VI. WORKING PROGRAMME TO STUDY THE SITUATIONOF HERBAL MEDICINAL PRODUCTS IN THEEUROPEAN UNION

In order to gather the most detailed and reliable information possible, the Association of theEuropean Self-Medication Industry (AESGP) prepared a questionnaire based on theobjectives described in the Technical Annex of the Call for Tenders for the EuropeanCommission’s study. Using this questionnaire, all available information from AESGP andits European member organisations was compiled in close co-operation with nationalexperts. These completed questionnaires were then sent to the national health authorities forreview, in particular to persons responsible for herbal medicinal products. All informationavailable by the end of May 1998 was included in the Interim Report, which was submitted tothe European Commission on 29 May 1998. This report was regarded purely as a descriptionwith as much detail as possible on the current legal situation of herbal products and herbalmedicinal products in the Member States. The focus was specifically placed on theimplementation of Council Directives 65/65/EEC, 75/318/EEC and 75/319/EEC, the legalrequirements and the authorities’ actual practice of assessing herbal medicinal products. Ofparticular importance was the possibility to use bibliographic data in accordance with Article4.8 (a) (ii) of Council Directive 65/65/EEC. This study demonstrates that in several MemberStates a more or less simplified proof of efficacy is permitted without submittingbibliographic data, provided that reference is made to a positive list of plants and/orindications and a specific introductory term such as “traditionally used …” is included i nthe indication. The data obtained reveal that significant differences exist among theMember States, particularly with regard to standards for proof of efficacy.

In the following step, interviews with representatives of the national health authorities wereconducted in order to obtain more detailed information on specific items, and particularlyon problems that might arise in Member States with regard to the implementation of the ECDirectives. Information from interviews was evaluated, together with data from literatureresearch and the Interim Report. In this (the final) report, these results are presented item byitem rather than country by country in order to facilitate comparison of the situation in eachMember State with respect to the implementation of the requirements of Council Directives65/65/EEC, 75/318/EEC and 75/319/EEC. In addition, detailed descriptions of the regulatorysituation of herbal medicinal products in Canada, Mexico and the United States of Americaare included for further comparison.

By comparing actual practices in the assessment of quality, safety and efficacy of herbalmedicinal products in the Member States, particular emphasis is placed on the application ofthe derogation provided for in 4.8 (a) (ii) of Council Directive 65/65/EEC. The consequencesof possible divergence in either the legal position or the assessment of herbal medicinalproducts is evaluated and assessed, leading to recommendations on how to best safeguardpublic health while allowing the free movement of herbal medicinal products throughout theEuropean Union.

VII. COMPARISON OF THE LEGAL REQUIREMENTS ANDTHE ASSESSMENT OF HERBAL MEDICINALPRODUCTS IN THE MEMBER STATES OF THEEUROPEAN UNION

VII.1 General items

VII.1.1 Implementation of EC DirectivesThe European Union has developed a comprehensive legislative network in order tofacilitate the free movement of goods, capital, services and persons in the Community.According to Council Directive 65/65/EEC, medicinal products require pre-marketingapproval before gaining access to the market. Requirements for the documentation of

11

quality, safety and efficacy, the dossier and the expert reports are laid down in CouncilDirective 75/318/EEC, as amended by Council Directive 91/507/EEC. Article 39 paragraph 2 ofCouncil Directive 75/319/EEC obliged the Member States to check all products on the marketwithin a deadline of fifteen years to determine whether they meet the requirements of the ECDirectives. The Member States have taken a variety of approaches in assessing whetherherbal medicinal products fulfil the requirements of the EC Directives.

The following table includes an overview of how Council Directive 65/65/EEC has beenimplemented into national law in the Member States.

12

Country National legislationAustria *1) 2

nd Amendment to Medicines Law 1994

Belgium *2) Royal Decree of 3 July 1969Denmark Medicines Law of July 1975Finland *3) Medicines Act No. 395 of 10 April 1987France Public Health CodeGermany Medicines Law of 1976Greece *4) Medicines Law of 1985Ireland *5) Medical Preparations (Licensing and Sale) RegulationsItaly *6) Legislative Decree of 29 May 1991Luxembourg Not availableThe Netherlands Medicines LawPortugal Law-decree No. 353/93Spain *7) Medicines Law of 1990Sweden *8) Medicinal Products Act (SFS 1992: 859)United Kingdom *9) Medicines Act 1968

Table 2: Implementation of Council Directive 65/65/EEC

Notes:

1) Austria:The Third Amendment to the Medicines Law (“Arzneimittelgesetz” or “AMG”) incorporatingthe EC Directives on the new marketing authorisation system into Austrian law came intoeffect on 1 August 1996. Registration of medicinal products had already been brought intoline with Community requirements by means of the Second Amendment to the MedicinesLaw, which took effect on 16 February 1994.

2) Belgium:The procedures laid down in the Community legislation concerning the registration ofmedicinal products are described in the Royal Decree (“Arrêté Royal”) of 3 July 1969, whichhas been amended several times. The Ministerial Circular (“Circulaire ministérielle”) of 30November 1994 [B 2] also refers to the framework established by Council Directive 65/65/EEC.It replaces the previous Circular published in 1989 [B 3] and was subsequently modified bythe Ministerial Circular of 12 December 1997 (Federal Gazette of 25 December 1997 [B 4]). Itproposes an abridged registration procedure for herbal medicinal products based on plantsincluded in a positive list.

3) Finland:For herbal preparations, administrative regulation 9/93 [FIN 1] takes into account theprovisions of Council Directive 65/65/EEC, particularly Article 4.8 (a) (ii) as amended.Requirements for proof of efficacy and safety are simplified.

4) Greece:Council Directive 65/65/EEC was implemented by the Greek Medicines Law of 1985, whichhas been amended several times [GR 2]. Council Directive 93/39/EEC8 was implemented asof September 1995 by Ministerial Decree Y6a/3221 [GR 3].

5) Ireland:The Medical Preparations (Licensing and Sale) Regulations, latest version of 1998 [IRL 3],provide a statutory licensing system for all medicinal products, both proprietary and non-proprietary medicinal products, taking into account the respective Council Directives65/65/EEC, 75/318/EEC and 75/319/EEC.

6) Italy:With regard to those products that claim to have therapeutic indications, the EC’spharmaceutical framework as laid down in Council Directive 65/65/EEC and CouncilDirective 75/318/EEC has been implemented into Italian law through Legislative Decree(“Decreto Legislativo”) of 29 May 1991, No. 178 [I 6] modified by Legislative Decree of 8 Council Directive 93/39/EEC of 14 June 1993 amending Directives 65/65/EEC, 75/318/EEC and

75/319/EEC in respect of medicinal products (OJ L 214 of 24.8.1993, p. 22).

13

18 February 1997, No.44 [I 7] and through a Ministerial Decree (“Decreto Ministeriale”) of10 March 1998 [I 8].

7) Spain:Council Directive 65/65/EEC was implemented into Spanish legislation in 1990 by theMedicines Law (“Ley del Medicamento”) [SP 2].

8) Sweden:The basis for marketing authorisations is the Medicinal Products Act (SFS 1992:859).

9) United Kingdom:Council Directives 65/65/EEC, 75/318/EEC and 75/319/EEC have been implemented by SI1994/3144, the Medicines for Human Use (Marketing Authorisations etc.) Regulations.

VII.1.2 Definition of Herbal Medicinal ProductsAccording to Council Directive 65/65/EEC, a medicinal product is defined as “any substanceor combination of substances presented for treating or preventing disease in human beingsor animals.” The Directive further states that “any substance or combination of substanceswhich may be administered to human beings or animals with a view to making a medicaldiagnosis or to restoring, correcting or modifying physiological functions in human beingsor in animals is likewise considered a medicinal product.” In this study, Member Stateswere asked whether herbal medicinal products are considered as medicinal products andhow herbal medicinal products are defined in their country. In several cases, differentcategories of herbal medicinal products exist and are listed below.

a) Herbal Medicinal Products Considered As Medicinal Products

In all Member States, herbal medicinal products are considered as medicinal products,except in Portugal where (with a few exceptions of fully authorised products) herbal productsin general have not yet entered the legislative framework on medicinal products. At present,these products are covered by the 1993 Portuguese legislation on health products coveringcosmetics, medicinal plants, dietetic products with therapeutic use and homeopathics [P 1].

The following additional information is available:

Austria

The Austrian Medicines Law [AT 1] does not distinguish between medicinal products madefrom chemical substances and those made from plants or natural substances. Herbalmedicinal products are regulated by the same rules as all other medicinal products.Registration requirements are the same concerning production, over-the-counter (OTC) andprescription-only status, labelling, advertising and selling for both chemical and herbalmedicinal products. According to the Austrian Medicines Law, both herbal and homeopathicmedicinal products belong to the category of medicinal products.

France

Article L.511 of the Public Health Code (“Code de la Santé Publique”), which definesmedicinal products, does not distinguish between medicinal products made from chemicalsubstances and those made from plants or natural substances. Herbal medicinal productsfall under the definition of Article L.511 of the Public Health Code and are thus subject to thegeneral regulations for medicinal products.

Germany

Herbal medicinal products are fully considered as medicinal products. There is nodistinction between medicinal products made from chemical substances and those madefrom plants or natural substances.

Spain

Article 42 of the Spanish Medicines Law [SP 2] states that “the plants and the mixtures thereofas well as the preparations obtained from plants in the form of extracts, lyophilised, distilled,

14

tinctures, coctions or any other galenic preparation that may be presented with therapeutic,diagnostic or preventive utility, will follow the system of magisterial formulae, officinalpreparations or pharmaceutical specialties, as it may be appropriate and with the specificationsthat may be established by regulation.”

Note:

According to Article 3 of Council Directive 65/65/EEC, medicinal products need priormarketing authorisation. Magisterial formulas (prepared in a pharmacy upon prescriptionfor an individual patient) and officinal formulas (prepared according to a pharmacopoeiaand intended to be supplied directly to patients) according to Article 1.4 and 1.5, respectively,do not fall under the definition of a medicinal product according to Article 1.2 of CouncilDirective 65/65/EEC.

United Kingdom

A herbal medicinal product which is industrially produced is included within the definitionof “relevant medicinal product” given in the Statutory Instrument 1994 No. 3144, TheMedicines for Human Use (Marketing Authorisations, etc.) Regulations 1994 [UK 2]: “Amedicinal product for human use to which Chapters II to V of Council Directive 65/65/EECapply, and accordingly includes the industrially produced medicinal products mentioned inArticle 2.2 of that Directive”. There is no distinction between medicinal products made fromchemical substances and those made from plants or natural substances.

b ) Definition of Herbal Medicinal Products

Austria

There is no legal definition of herbal medicinal products.

Belgium

Herbal medicinal products are products consisting entirely of plant substances.

Denmark

Under the Danish Ministry of Health Order No. 790 of 21 September 1992 [DK 1], naturalremedies covered by the authorisation system are defined as follows:

• Natural remedies shall be understood to mean medicinal products in which the activesubstance (content) exclusively comprises naturally occurring substances i nconcentrations that are not substantially greater than those in which they are found i nnature.

• The order applies to natural remedies intended for oral use or application on skin ormucous membranes. It does not apply to natural remedies containing prescription-onlymedicinal products or to homeopathic medicinal products.

An absolute requirement is that all active substances originate from nature and that they donot contain any synthetic or chemical substances. However, the latter can be included in theproduct as inactive substances. The Order does not distinguish between natural remedies ofdifferent (animal, mineral or plant) origin. The view is that all three can theoretically befound in nature. It is supposed, however, that most products covered by the Order are plants.

Indications for the use of natural remedies shall only include minor illnesses, i.e. ailmentsfor which it is not usual to seek a doctor’s advice. It is not possible to lay down all possibleindications that can be approved for authorising natural remedies.

Finland

Herbal medicinal products are defined as follows in Section 21 of the Medicines Law:“Natural remedies” are products traditionally used for medicinal purposes in which theactive principle or principles is or are derived from the vegetable or animal kingdom,bacteria or minerals.

According to the definition in the legislation, the term “for medicinal purposes” in thiscontext means “to cure, alleviate or prevent disease or symptoms of disease and to restore,correct or modify physiological functions”. This is also the criterion for the classification of

15

a product as a medicinal product, both by function and by presentation. The term “medicinalpurposes” is applied on a case-by-case basis taking into account all properties of a certainherbal medicinal product.

In this context, the term “traditionally” means traditionally used in the proposed indicationin Europe or in countries that are close to Europe with regard to their healthcare traditions.Use for 20 years can be regarded as traditional use. A shorter period cannot be acceptable i nthe case of herbal medicinal products.

The administrative regulation 9/93 [FIN 1] of the National Agency for Medicines(“Lääkelaitos” or “NAM”) regulates the status of herbal medicinal products in Finland.According to this regulation, herbal products contain plants or parts of plants that aretraditionally used (in Europe or similar countries with the same therapeutic culture), i ndried form, extracts or tinctures prepared from them, or traditionally used essential or fattyoils.

France

There is no legal definition of herbal medicinal products. In the Agency Instructions No. 3(“Cahiers de l’Agence N° 3”) [F 4], the French Medicines Agency (“Agence du Médicament” or“AdM”) considers that herbal medicinal products are medicinal products containing asactive ingredients exclusively herbal drugs and/or herbal drug preparations. Herbal drugsare substances used for medicinal purposes and derived from either fresh or dried plants.Herbal drugs can be the whole plant, plant parts (cut or whole) or unprocessed plant exudates(e.g., gums, latex, etc.). Active ingredients are herbal drugs or herbal drug preparationswhether or not the active constituents are known. Isolated chemical constituents extractedfrom a herbal drug are not considered herbal products. The list of poisonous substances andnarcotic substances (which is fixed by Decrees published in the Official Journal of theFrench Republic) indicates some materials of plant origin (e.g. belladonna) which are forprescription-only use.

Germany

Herbal medicinal products are medicinal products containing as active ingredients onlyplants, parts of plants or plant materials, or combinations thereof, whether in crude orprocessed form. Chemically defined, isolated constituents of herbal origin (such as menthol,cineol, or digitoxin) are not classified as herbal medicinal products. Most herbal medicinalproducts are available for self-medication without a prescription.

Greece

According to a Ministerial Decree on herbal medicinal products of 1 April 1994 [GR 1],herbal medicinal products are medicinal products that contain as active ingredients onlyplants or preparations of plants. The regulation is not applicable to plant products that areused as food supplements, beverages or for other purposes which are regulated as food.

Ireland


Italy

For the definition of medicinal products, the Community definition applies, according toCouncil Directive 65/65/EEC. There is also a proposal for a definition of herbal products[I 18]. Therefore, those herbal products that make therapeutic claims or have a particularpharmaceutical activity are considered as herbal medicinal products.

There is no specific framework for isolated chemical compounds or highly purified extractsof herbal drugs. They can be included in medicinal or non-medicinal products. They shouldnot be considered as herbal medicinal products but rather constituents of regular medicinalproducts, in agreement with the definition of the Ad Hoc Working Group on HerbalMedicinal Products. Table III of the Italian pharmacopoeia (“FU”): “Substances registered i nthe FU to be kept in locked cabinet” (which is commonly considered as a table of poisonoussubstances registered in the FU) and the list of narcotic substances include some materialsof plant origin (e.g. belladonna) for prescription-only use.

16

There is for the time being no specific framework for products containing medicinal plants[I 18].

Luxembourg

There is no legal definition of herbal medicinal products. Fruits, vegetables or their partswhich are used by humans are not considered as medicinal products. In this country, thereis only one registered manufacturer of herbal medicinal products who produces herbal teas.

The Netherlands

Herbal products are defined according to the EC Guideline “Quality of Herbal Remedies”(“Quality of Herbal Medicinal Products”); i.e., they are products containing as activeingredients plants, parts of plants, extracts, gums, juices, etc.

Portugal


Spain

The definition of herbal medicinal products can be found in Article 42 paragraph 1 of theSpanish Medicines Law [SP 2] which states that plants and their preparations such asextracts, tinctures, etc., making therapeutic, diagnostic or preventive claims will follow thesystem of magisterial formulae, officinal preparations or pharmaceutical specialties.

The definition according to the Ministerial Order of 1973 [SP 5] is the following:“Preparations consisting solely of one or more medicinal plants or parts of plants in a cut orpowdered state are medicinal products included in the Special register (“Registro Especial”).Exempted from this are medicinal products from plants included in the Annex (withoutindications) and those considered pharmaceutical specialties (with indications).”

According to a draft Royal Decree published in 1997 [SP 1], phytopharmaceuticals(“medicamentos de las plantas medicinales”) are plant-based medicinal products preparedsolely from medicinal plants or their preparations. They may be either herbal medicinalproducts (“especialidades farmacéuticas a base de plantas”) or phytotraditional medicinalproducts (“productos fitotradicionales”).

Sweden

Herbal medicinal products are included in the term “natural remedy.”

According to the Medical Products Agency’s (MPA), guidelines on authorisation to placenatural remedies on the market (LVFS 1995:18) [S 1], a natural remedy is defined as follows:

• Medicinal products are products that are intended for administration to human beingsor animals in order to prevent, detect, palliate, or cure disease or symptoms of disease(medicinal products definition).

• A natural remedy denotes a medicinal product in which the active ingredient oringredients are derived from natural sources such as plants or animals, or consist ofa bacterial culture, minerals, salts or salt solutions. The active ingredients, however,must not be processed too highly. For example, constituents may not be chemicallymodified, produced by biotechnological methods or be in a chemically defined isolatedform.

A natural remedy must be suitable and intended for self-medication in accordance withtested national traditions or traditions of countries close to Sweden in respect of medicineuse. Products for injection and homeopathic preparations are not covered by the definition.

United Kingdom

Section 132 of the Medicines Act 1968 [UK 1] defines a herbal remedy as: “A medicinalproduct consisting of a substance produced by subjecting a plant or plants to drying, crushing o rany other process, or of a mixture whose sole ingredients are two or more substances soproduced, or of a mixture whose sole ingredients are one or more substances so produced andwater or some other inert substance.”

17

c ) Different Categories of Herbal Medicinal Products

The Netherlands

There are two categories of herbal products in the Netherlands:

• herbal medicinal products, which are fully registered as medicinal products accordingto Council Directive 65/65/EEC, including those which are admitted to the market(“licensed”) and still have to be reviewed; and

• unlicensed and unregistered products, which are classified as food supplements orfoodstuffs (see point VII.1.3.b) below).

A further category of products may exist without any information to be provided to theMedicines Evaluation Board (MEB) and therefore without registration or control. They mayhave indications but cannot be prosecuted by the MEB because no authorisation orregistration is required.

Spain

The classification according to the Ministerial Order of 1973 [SP 5] is the following:

Preparations consisting solely of one or more medicinal plants or parts of plants in a cut orpowdered state are medicinal products included in the Official Register (“RegistroEspecial”). Exempted from this are medicinal products from plants included in the Annex(without indications) and those considered as pharmaceutical specialties (with indications).

According to the draft Royal Decree of 1997 [SP 1], phytopharmaceuticals (“medicamentos delas plantas medicinales”) may be either:

• herbal medicinal products (“especialidades farmacéuticas a base de plantas”) or

• phytotraditional medicinal products (“productos fitotradicionales”).

According to this draft, herbal medicinal products are authorised to claim indications.Phytotraditional medicinal products are also medicinal products, but they may not claimtherapeutic indications. They may be plants that are traditionally used, or preparationspresented with defined dosage and composition. Both of these categories are regarded asmedicinal products which must fulfil all the requirements of the Spanish Medicines Law[SP 2].

18

Medicinal products(“Medicamentos”)

Plant-based medicinal products(“Fitofarmacos”)

↓ ↓Pharmaceutical specialties(“Especialidades farmacéuticas”)

Medicinal products which are notpharmaceutical specialties

Herbal medicinal products(“Especialidades farmacéuticas a base deplantas”)

Phytotraditional medicinal products(“Productos fitotradicionales”)

Indication No indication

Authorisation Notification (except combinations)

Table 3: Categories of plant-based medicinal products in Spain

According to Article 8.6 of the draft Royal Decree, a pharmaceutical specialty (“especialidadfarmacéutica”) is a “medicinal product with defined composition and information, ofdetermined pharmaceutical form and dosage, prepared for immediate medicinal use, readyand packaged for dispatching to the public, with uniform name, packing, packaging andlabelling, which has been granted a health authorisation by the State’s Administration andregistered in the Pharmaceutical Specialties Register.”

Note:Medicinal products which are not pharmaceutical specialties can be prefabricated medicinalproducts (Article 8.7), magisterial formulas (Article 8.9) or officinal preparations orformulas (Article 8.10).

d ) Summary: Definition of Herbal Medicinal Products

In almost all Member States, herbal medicinal products are considered as medicinalproducts. As such, they are in principle subject to the general regulations for medicinalproducts as laid down in national Medicines Law. A specific definition of herbal medicinalproducts which is in line with the EC Guideline “Quality of Herbal Remedies” (“Quality ofHerbal Medicinal Products”) and which includes plants, parts of plants and theirpreparations, mostly presented with therapeutic or prophylactic claims is available in manycases. Different categories of products containing plant preparations are described e.g. i nSpain according to a legislative draft as “herbal medicinal products” and “phytotraditionalproducts”. The latter are however not regarded as pharmaceutical specialties and aretherefore not herbal medicinal products.

VII.1.3 Classification of Herbal PreparationsAs indicated above, Council Directive 65/65/EEC defines the basic criteria for a medicinalproduct. Herbal preparations are not considered medicinal products if they are intended to beused as food, cosmetics, etc. and are not intended or presented for treating, preventing ordiagnosing diseases or restoring, correcting or modifying physiological functions.However, the line distinguishing medicinal from non-medicinal products, in many casessuch as in the case of herbal products, is not easy to draw. For this reason, in this studynational authorities were asked: (a) which criteria for classification as a medicinal product(e.g., by function or presentation or both) are used; and (b) which products containing plantsare not classified as medicinal products. Herbal preparations that are not medicinalproducts do not require a marketing authorisation from the competent authority. In somecases, however, a notification has to be performed. Several examples of products are giventhat might fit into both these areas (c). Furthermore, in several Member States medicinalproducts exist which are exempted from licensing (d).

19

a) Classification Criteria

Austria

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC

Belgium

Herbal products can be classified as medicinal products available without a prescription oras foodstuffs. Currently, there is a proposal to amend the definition of a medicinal productunder the Belgian Medicines Law in order to bring it in line with the definition in CouncilDirective 65/65/EEC. For the moment, the Belgian definition classifies a product as amedicinal product according to its “presentation” (or “destination”). This means that theauthorities will assess whether a product is presented (or intended to be used) as amedicinal product. If medicinal claims are made for a herbal product, it will be classifiedas a medicinal product.

Denmark

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC

Finland

To enable classification of plant products either as herbal medicinal products or as foodsupplements, Finland has a national list of examples of herbs that are traditionally used formedicinal purposes. The list includes herbs for medicinal use. If a certain herb is notincluded, this indicates that the herb is to be considered as a foodstuff provided that nomedicinal claims are made. It must be noted, however, that the list is only considered to beindicative. The list, which has existed for around thirty years, is not closed and more herbscan be added.

France

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC Medicinal plants (“Plantes médicinales”) are defined in the French pharmacopoeia(Monograph “Plantes médicinales,” March 1991) as plants that have at least one part withmedicinal properties. Medicinal plants can only be sold by pharmacists (Article L512-5° ofthe Public Health Code) and qualified herbalists (see point VII.6.2. below). As an exception, aDecree issued in June 1979 authorised the direct retail sale to the public of 34 plants andseven combinations of plants [F 2]. In this case, it is legally possible that a plant i ssimultaneously marketed as a medicinal product for prophylactic or therapeutic use and as arefreshing beverage, depending on the claims.

Germany

Article 2 of the German Medicines Law defines which products are medicinal products.According to Section 1 of the Law on Foodstuffs and Consumer Goods (“Lebensmittel- undBedarfgegen-ständegesetz” or “LMBG”), certain products are not generally considered asmedicinal products (e.g., foodstuffs). In cases where the differentiation is unclear, thefollowing criteria must be taken into account. The main criterion for the legaldifferentiation between medicinal products and foodstuffs is the objective determination ofthe product’s predominant purpose according to the common opinion and interpretation of thetrade. Criteria that may be used by the trade for this determination include composition,posology and claims. (Claims related to a disease often lead to consideration of a product asa medicinal product.) Additional less important criteria might include dosage form(particularly for vitamins and minerals), labelling, retail outlets or price.

20

Greece

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC. They will therefore have to fulfil the requirements of the Ministerial Decree of1994 [GR 1]. If medicinal indications are claimed, the regulations of the Medicines Law[GR 2] will apply.

Note:Since 1 January 1998, the general requirements of the mutual recognition procedures havebeen applied. Since that moment, the Greek Health Authority (EOF) has not applied theMinisterial Decree of 1994 [GR 1], although it is still valid. Only European legislation isapplied so as not to create additional standards on the national level.

Ireland

To assist the classification of medicinal products, a memorandum was issued by theDepartment of Health in 1988 [IRL 1], explaining the position of certain products on theborderline between food and medicinal products. This was of particular importance forproducts on the Irish market which were not registered as medicinal products and whichmade preventative, curative or remedial claims. According to this memorandum, productscontaining herbal ingredients were considered to be medical preparations under theregulations in force when the labelling or accompanying or associated literature makes anypreventative, curative or remedial claim, or any of the herbal ingredients present i srecognised as having medicinal properties. An illustrative list of such herbs is included asan annex and lists about one hundred herbs with these properties.

In December 1993, the Food Safety Advisory Committee prepared a Report on FoodSupplements and Health Foods for the Minister for Health and the Minister for Agriculture,Food and Forestry [IRL 2]. The report addressed the question of an appropriate policy for thecontrol of products which are on the borderline between foods and medicinal products,including natural materials whose compositions and status may not have been established(such as herbal extracts, herbal teas, essential oils, etc.). These products should be subject toauthorisation by the Irish Medicines Board (IMB) prior to marketing. Reference was made tothe above-mentioned memorandum of the Department of Health on “borderline” products[IRL 1].

With respect to herbal teas, it was recommended that a regulatory framework is necessary toensure that no potentially toxic plants are marketed as herbal teas, that all the plantmaterials comply with stringent quality standards, and that problems on environmentalcontamination of herbal materials (i.e. the need for statutory controls on levels of pesticides,heavy metals and radio nuclides in teas) are taken into account. In case of medicinalbenefits or even imaginative labelling which suggests medicinal benefit for herbal teas,they should be regarded as medicinal products and are therefore regulated by the NationalDrugs Advisory Board (replaced by the Irish Medicines Board in 1996). The materials foruse as herbal teas should not be permitted by the IMB unless they have GRAS (GenerallyRecognised As Safe) status, are recommended as acceptable for inclusion in food by theCouncil of Europe or have been approved for food use by another authoritative body. Qualitycontrol should be guaranteed in accordance with the European Pharmacopoeia.

With respect to essential oils it is recommended that they should not be permitted unless theyhave been approved for use as flavouring substances and natural sources of flavourings bythe Council of Europe, or that they have been granted GRAS status or have been accepted forfood use by other authorities. Furthermore, it was recommended that the IMB should draw upa list of herbal substances which are toxic under normal conditions of use. The Food SafetyAdvisory Committee’s Report on Food Supplements and Health Foods has not yet beenformally implemented in terms of national legislation.

New prescription control regulations were introduced in 1996 [IRL 5], restricting a number ofmaterials of plant origin to prescription-only supply. These included Broom, Comfrey (itcould be sold over the counter from pharmacies for external use), Ginkgo biloba, Mistletoeand Pook Root. In 1996 Ephedra Herb (including Ma-Huang) and Melatonin were alsoclassified as prescription-only substances. Once a substance is classified as prescription-only or pharmacy-only in Ireland, any product containing that substance is automaticallydeemed to be a medicinal product and may only be sold with a valid product authorisation.

21

Italy

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC.

For the time being, there is only the Circular (“Circolare”) No. 1 of 8 January 1981 of theMinistry of Health [I 1]. This document is not binding. The document classifies a smallnumber of plants into two indicatory lists: List A for those plants that should only be sold i npharmacies and List B for those plants that can also be sold outside pharmacies. A singleherb belonging to List A which has pharmaceutical activity but does not claim therapeuticindications may be freely sold in pharmacy if it is not considered as a poison or is not in thelist of narcotic substances. Herbs belonging to Lists A or B claiming therapeutic activitymust be registered as medicinal products and may only be sold in pharmacy like anymedicinal product.

Luxembourg

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC.

The Netherlands

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC. The definition of a medicinal product according to the Dutch Medicines Law isas follows: “Any substance or combination of substances that is intended to be used or that i sin any way indicated or recommended as being suitable for:

1. healing, treating or preventing any infection, disease, symptom, pain, wound orillness in human beings;

2. restoring, correcting or modifying the function of bodily organs in human beings;

3. making a medical diagnosis by its administration to or use upon human beings.”

The main criterion for classification as a medicinal product is the claim made for theproduct (“aandieningscriterium”). If a medicinal claim is used in the marketing of a product,the product is classified as a medicinal product and must consequently be registered orlicensed.

Portugal

Medicinal products normally have an indication claim that food and cosmetics do not have.

Spain

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC. The criteria for the definition of a medicinal product are laid down in Article 8.1of the Spanish Medicines Law [SP 2]:

“Any medicinal substance and the associations or combinations thereof, intended for use i npersons or in animals, with properties to prevent, diagnose, treat, alleviate or cure illnessesor ailments, or to affect functions of the body or the state of mind. Also considered asmedicinal products will be those medicinal substances or combinations thereof which can beadministered to persons or animals with any of such purposes, although they may be offeredwithout explicit reference thereto.”

Sweden

Herbal products that make therapeutic claims or have a particular pharmaceutical activityare considered as medicinal products in accordance with Article 1 of Council Directive65/65/EEC. The general rule is to determine the intention from the marketing presentation.The overall presentation is considered including the content, the text on the label and i n

22

advertisements and the form (tablets, capsules, etc.). The marketing presentation will bedecisive when assessing a certain product.

United Kingdom

In December 1995 a guideline “A Guide to What is a Medicinal Product” (MAL 8) waspublished by the Medicines Control Agency (MCA). In accordance with Council Directive65/65/EEC, it gives examples for clarification where the borderline is between medicinalproducts and e.g. cosmetics and foodstuffs, taking into consideration e.g. the claims of theproduct, the properties of the ingredients, the labelling, promotional literature, product formand whether there are similar licensed products on the market. Criteria include function aswell as presentation. This guideline does not affect the status of products legally sold withouta licence, nor does it affect the current exemptions for certain herbal remedies sold i nspecific circumstances [UK 3].

There is no list or procedure to determine which plants are considered as medicinal productsby function. MCA considers certain herbs to be medicinal by function if they have apharmacological effect at the dose supplied and have no recognised usage other thanmedicinal.

For example, Echinacea, Boldo and Hypericum are considered by MCA as medicinalproducts by function as they have no recognised usage other than as a medicinal product andall have pharmacological effects. These will always be classified as medicinal productsalthough they can avoid the need for a marketing authorisation if they are not industriallyproduced and make no claims (i.e. “exempt herbal remedies”, see point VII.1.4. below).

b ) Products Falling Outside the Area of Medicinal Products

Austria

Herbal products which are not considered as medicinal products, can be:

1. foodstuffs

2. cosmetics

3. “Therapie-Ergänzungsmittel” (therapeutic supplement products).

1. Specific kinds of food are food supplements, which can be:a) So-called consumable products (“Verzehrprodukte”) which are defined by law as

neither food nor medicinal products and are intended to be chewed andswallowed; “not preponderantly serving nutritional or delight reasons”. Forexample, garlic can be marketed as a spice, as a consumable product in capsules(both without medicinal claims) or as a standardised preparation with medicinalclaims if authorised as a medicinal product.

b) Dietetic products, e.g., bulk-forming diets enriched with vitamins, nutrients forchildren, and isotonic beverages for sportsmen.

Products belonging to 1(a) and 1(b) have to be notified to the Federal Ministry of Labour,Health and Social Affairs. Marketing can be prohibited within three months fromnotification. Health claims are allowed.

A growing number of products that are not registered as medicinal products (e.g., dieteticfoodstuffs and food supplements) are sold on the market with medicinal claims. It is possiblethat during notification the Ministry decides that when a new medicinal claim occurs, thismay result in a switch from food supplement or dietetic foodstuff status to medicinal productstatus (e.g., Black Caraway seed oil).

2. CosmeticsThe substances which are allowed to be used in cosmetics are included in the CosmeticsRegulation of 1996, amended in 1997 (“Kosmetik-Verordnung”) [AT 6, 7]. Annex 2 of theRegulation contains several herbal preparations such as sage extract, hamamelis extract,horse chestnut extract or lavender oil.

3. Therapeutic supplement products (“Therapie-Ergänzungsmittel”)According to the Austrian Medicines Law and to the general understanding of the trade,these products are not medicinal products. For example, spagyrica, anthroposophicmedicinal products, Bach flowers or other esoteric medicinal products belong to thiscategory. They are defined by Section 1 Paragraph 3 Number 9 of the Austrian Medicines

23

Law [AT 1] as substances or preparations thereof exclusively intended to be used according tomethods of complementary medicine. Therapeutic supplement products are not medicinalproducts as long as they do not serve or are not intended to serve purposes characteristic ofmedicinal products (as defined in Section 1), except those preparations which are producedaccording to homeopathic principles. The Ministry of Health and Consumer protection mustbe notified about the marketing of these products according to Section 11c of the AustrianMedicines Law, and documents on quality and safety have to be submitted. Claims are notallowed.

Belgium

Products outside the area of medicinal products are classified as food. In November 1997, achange in the Belgian Medicines Law [B 1] introduced an extensive number of well-knownplants that may be sold as food and/or herbal medicinal products under certain conditions.

Three lists were defined (they are not exhaustive and changes may be proposed before eachmeeting of the Group on herbal medicinal products):

• List 1: Dangerous plants, which cannot be used as/within foodstuff.

• List 2: Non-toxic mushrooms (cultivated and uncultivated).

• List 3: Plants to be notified if sold in a pre-dosed form. The law requires that theMinistry of Public Health be notified about food products containing herbs that are onthis list. The same applies to mushrooms in List 2.

Herbal medicinal products can be made from plants on List 1 (if they are not poisonoussubstances). Medicinal claims are possible if they are justified. A marketing authorisationis required.

Pre-dosed forms of plants from List 3 are not considered as herbal medicinal products if nomedicinal claims are made. Pre-dosed forms of plants from List 3, however, are consideredas herbal medicinal products if medicinal claims are made. They cannot simply be notifiedand require a marketing authorisation. Pre-dosed forms include – among others – all typesof capsules, tablets, powder, sachets, ampoules, etc.

It is forbidden to produce or to put on the market foodstuffs containing plants not listed i nList 3 in a pre-dosed form without submitting a notification.

It is envisaged that a guideline will clarify the labelling of all notified foodstuffs.

Denmark

Products outside the area of medicinal products are classified as food.

Finland

There are many products on the market that contain plants but that are not classified asmedicinal products. They are sold without any medicinal claims as so-called specialpreparations or food supplements (or health products) under the Food Act.

Some products containing herbs may be sold under the Food Act without any medicinalclaims. However, they may not be called herbal medicinal products. Instead, they are calledherbal products, special preparations, food supplements or health products. They may be soldin ordinary shops. As is the case in many European countries, some difficulties haveoccurred with regard to claims. The National Agency for Medicines (NAM) collaborates i nthis respect with the National Agency for Food.

France

As no definition of medicinal plants is given in the Public Health Code (CSP), Circular 346(“Circulaire”) of 2 July 1979 published in September 1979 [F 3] defined the limits of theapplication of Article L.512-5° (non-inclusion in the pharmaceutical sector of plants largelyused in the food sector). No list exists of herbal products that can be classified as cosmetics.

The French pharmaceutical industry has publicly denounced the sale of “pseudo-medicinalproducts”, which are alleged to endanger public health and constitute unfair competition formedicinal products sold in pharmacies. Moreover, Decree No. 95-284 of 14 March 1995, whichcontains a Code of Conduct for pharmacists, stipulates that the pharmacist shall contribute to

24

the fight against charlatans, in particular by refusing to manufacture, distribute or sell anyobject or product having these characteristics.

Germany

Herbal products not considered as medicinal products belong to the food or cosmetic area.Examples of health claims in the food area can be “... helps maintain intestinal flora andsupports resistance of the body” or “helps to control cholesterol”.

Greece

Herbal products in the food supplement sector do not have indication claims. Like all foodsupplements, they require prior marketing authorisation from the Greek Health Authority(EOF).

Ireland

Herbal products not considered as medicinal products belong to the food area.

Italy

For herbal products not considered as medicinal products, a specific legal framework iscurrently being discussed in the Italian Parliament. The law is expected to govern themanufacture and retail sale of plant-based products. Particular attention is being given to adifferentiation of the distribution of these products to either inside or outside pharmacy. Saleoutside pharmacy takes place in outlets such as herbal shops.

Health claims are allowed for health products unless they refer to therapeutic qualities.There is no list of health claims and no list of claims distinguishing between health claimsand medicinal claims (e.g. fibres).

There is a specific category of (non-medicinal) herbal products without therapeutic claim.They serve nutritional purposes and are not allowed to claim therapeutic indications. Theyare classified as dietetic products.

Council Directive 89/398/EEC9 was transposed into Italian national legislation through theDecree No. 111 of 27 January 1992, published in the Official Gazette of 17 February 1992 [I 2].This type of herbal product includes plants traditionally used as food or flavouring. Theyserve nutritional purposes and are not allowed to claim therapeutic indications. Some ofthese products are classified as dietetic products (replacements for meals with dieteticindications) and are subject to approval by the Ministry of Health’s Department of Food,Nutrition and Animal Health Care (“Ministero della Sanità, Dipartimento degli Alimenti,Nutrizione e Sanità Pubblica Veterinaria”). Other products with limits linked to RDA areconsidered as food supplements; for those products, the labelling must be notified to theMinistry of Health, e.g. in the case of fibres. There is no specific guideline for suchlabelling.

The manufacturers of all other non-medicinal herbal products do not have to notify thelabelling of their products. The Ministry of Health can only be informed of infringementsor misleading labelling when a complaint is brought to its attention.

A single herb belonging to the (non-binding) List A which has pharmaceutical activity butdoes not claim therapeutic indications may be freely sold in pharmacy (if it is notconsidered a poison or is not on the list of narcotic substances). It is however not a medicinalproduct.

Luxembourg

The Ministry of Health has issued a list of medicinal plants that are not to be considered asmedicinal products if they are presented as herbal teas without any therapeutic claim [L 1].These products may be sold by persons other than pharmacists (even in combination) butshould always be pre-packaged (e.g., in boxes or tea bags). The Division of Pharmacy and

9 Council Directive 89/398/EEC on the approximation of the laws, regulations and administrative

provisions of the Member States relating to foodstuffs intended for particular nutritional uses (OJ L186 of 30.6.1989, p. 27).

25

Medicinal Products is not directly informed about the labelling of non-medicinal herbalproducts.

The Netherlands

Herbal products that do not carry a medicinal or therapeutic claim are sold on the market asfoodstuffs. For products classified as food supplements or foodstuffs, the law does not allowmedicinal claims.

Portugal

Herbal products are not covered by the legislation on medicinal products. At present they areconsidered as health products (“productos sanitários”). According to Article 3 of the relevantlaw (Decreto-Lei n° 353/93 [P 1], these include cosmetics, medicinal plants, dietetic productswith therapeutic use and homeopathics. They may carry health or maintenance claims.

Health products are controlled by the National Institute of Pharmacy and Medicines(Infarmed), an authority responsible to the Ministry of Health. A special division ofInfarmed is entitled to develop rules for the marketing, quality and safety of this group ofproducts [P 1].

Sweden

There are a few cases where products containing plants do not carry medicinal claims andare not classified as herbal medicinal products or natural remedies:

— Products containing plants that are widely used as foodstuff such as teas containingcamomile or peppermint.

— Products that are specifically intended for athletes and contain ginseng. Otherproducts containing ginseng are usually regarded as herbal medicinal products.

— Garlic is considered a spice as long as it is in the form of the bulb, but it becomes aherbal medicinal product when processed and put into capsules.

United Kingdom

A number of products containing plants in combination with vitamins/minerals etc. havebeen introduced to the market as food supplements and are subject to food law provided theymake no medicinal claims and do not contain ingredients which the Medicines ControlAgency (MCA) considers as medicinal by function. They do not come within the definitionof a medicinal product.

c ) Examples of Products That Can Fit into Both Areas

France

A plant can simultaneously be marketed for prophylactic or therapeutic use as a medicinalproduct and as a refreshing beverage, depending on claims.

Germany

Examples of substances that could fall into either category depending on the classificationcriteria mentioned under point VII.1.3.a include vitamins, minerals and herbal products.For example, peppermint tea can be marketed for prophylactic or therapeutic use as amedicinal product or as a refreshing beverage, depending on claims.

Italy

In the current system, a plant such as camomile may be simultaneously marketed forprophylactic or therapeutic use as a medicinal product and as a refreshing beverage,depending on claims. Some herbal (non-medicinal) products may also be classified ascosmetics (e.g., calendula cream).

There is no list of essential oils. They may either be classified as medicinal products or ascosmetics, depending on claims.

26

United Kingdom

Peppermint and camomile are examples of borderline products that are only medicinalproducts if presented with medicinal claims.

d ) Summary: Classification of Herbal Products

In general, herbal products are classified as medicinal products if they make therapeutic orprophylactic claims. Products not classified as medicinal products belong in most cases tothe food or cosmetic area although they sometimes contain plants with undisputedpharmacological properties. For example, Senna pods can be marketed as food in Belgium.Furthermore, specific categories of non-medicinal products exist, e.g. “therapeuticsupplement products” in Austria. These products are specifically regulated by national law,either with or without notification of the competent authority. Several examples exist ofproducts that can fit into more than one area.

VII.1.4 Medicinal Products without Claims Containing Herbal PreparationsIn many countries, various types of preparations of herbal origin exist. For example,homeopathics are also medicinal products without claims but will not be examined herebecause there are specific EC and national regulations on homeopathics. In Ireland, Spainand the United Kingdom, specific groups of medicinal products exist which containpreparations of medicinal plants but which are exempt from licensing because they do notmake medicinal claims. Medicinal products exempt from licensing are described below.

Ireland

Preparations consisting of dried, crushed or comminuted herbs labelled in a manner whichspecifies the herb and the process of production are excluded from the scope of the regulationprovided no other name is given to the preparation and no recommendation to use as amedicinal preparation is made. Examples of such exempted products include Senna leaves,Senna pods and Carrageen moss [IRL 1].

These products (e.g., Senna pods in an unprocessed state) which have pharmacologicalproperties are considered as medicinal products but are exempt from licensing as long as nomedicinal claim is made and they are not presented as a medicinal product.

Spain

According to the Ministerial Order of 3 October 1973 [SP 5], preparations consisting of one ormore medicinal plants in a cut or powdered state have to be included in the Official Register(“Registro Especial”) as medicinal products (Group 1). Exempt from that obligation aremedicinal plants and their preparations (as single species) without an indication claim(Group 2a). They are included in a particular list in the Annex containing about 100 plants.Inclusion in this group means that there is no need to register and that no indication claimmay be made; however, they are nevertheless considered as medicinal products.

According to the draft Royal Decree [SP 1], phytotraditional products (“productosfitotradicionales”) are considered as medicinal products according to Article 8.1 of theSpanish Medicines Law. However, they are not considered as herbal medicinal productsaccording to Article 8.6 of the same law because they do not have any therapeutic, diagnosticor prophylactic indication. Phytotraditional products do not require prior marketingauthorisation with the exception of blends. The plants that may be sold as phytotraditionalproducts are listed in Annex I of the draft Royal Decree. The Ministry of Health must benotified when these products are placed on the market and documents on their quality andsafety should be provided in accordance with Annex VIII of the draft Royal Decree. Amaximum of three excipients representing up to 15 % of the total weight are allowed.

According to Article 15.3 of the draft Royal Decree however, manufacturers producingcombinations of the plant species listed in Annex I and/or their preparations must apply forauthorisation as specified in Articles 5.1 and 5.2 of the draft. The application must contain adossier justifying the traditional use of the combination and its safety.

The new Royal Decree is intended to offer a much better control of products sold outsidepharmacy which up to now were not obliged to demonstrate their quality. Except for theproduction of teas used as food and plants used as spices, companies producing

27

phytotraditional products have to follow Royal Decree 1564/1992 [SP 6] in terms of production.They are controlled by the local authorities.

A problem which has arisen during discussion on the draft Royal Decree is that i fphytotraditional products are regarded as medicinal products, it might be appropriate to sellthem only under the supervision of a pharmacist. Therefore it is still an open questionwhether it would not be better to categorise these products as non-medicinal products whichcan be sold outside pharmacy by herbal shops.

United Kingdom

A herbal product which is not “industrially produced” does not fall within the definition of a“relevant medicinal product” unless it makes claims on the label or in advertising.

Note:A “relevant medicinal products” means any medicinal product which needs a marketingauthorisation. “Industrially produced” medicinal products are always “relevant medicinalproducts”. Non-“industrially produced” herbal remedies are only “relevant medicinalproducts” if they make claims. If they do not make claims, they are not “relevant medicinalproducts” but “exempt herbal remedies”.

Thus a herbal remedy which is only dried, crushed or comminuted and sold withoutindications is exempt from the specific requirement to obtain a marketing authorisation. Inall other respects (labelling, advertising etc.), the product is regulated as a medicinalproduct. These products are known as “exempt herbal remedies” under Section 12 of theMedicines Act [UK 1].

Dried, crushed or comminuted herbal remedies not subjected to industrial processing andsold without claims are exempt from licensing under Section 12 of the Medicines Act. Thereare two distinct and separate parts to Section 12. There is an exemption for products made upon the premises of a “practitioner” (Section 12(1)) and one for products supplied by amanufacturer. The latter can be supplied over the counter through any retail premises(Section 12(2)).

The definition of a “relevant medicinal product” is given in United Kingdom StatutoryInstrument 1994 No. 3144, The Medicines for Human Use (Marketing Authorisations etc.)Regulations 1994 [UK 2] as described in Section 1.1. The same Statutory Instrument states thefollowing:

“For the purposes of the definition of “relevant medicinal product” … a medicinal productwhich is a herbal remedy is not industrially produced if:

(a) it is, or is to be, sold or supplied in circumstances to which either 12(1) of the Act orArticle 2 of the Medicines (Exemptions from Licences) (Special and TransitionalCases) Order 1971 (k) [UK 4] relate and has been manufactured or assembled only forsale or supply in those circumstances; or

(b) the process to which the plant or plants are subjected in producing the product consistsonly of drying, crushing or comminuting, and the product is, or is to be, sold orsupplied only as provided by Section 12(2) of the Act.”

The Act referred to is the Medicines Act 1968, Sections 12(1) and 12(2), which have thefollowing wording:

12(1) The restrictions imposed by Sections 7 and 8 of this Act do not apply to the sale, supply,manufacture or assembly of any herbal remedy in the course of a business where(a) the remedy is manufactured or assembled on premises of which the person

carrying on the business is the occupier and which is able to close so as toexclude the public, and

(b) the person carrying on the business sells or supplies the remedy foradministration to a particular person after being requested by or on behalf of thatperson and in that person’s presence to use his own judgement as to the treatmentrequired.

28

12(2) Those restrictions also do not apply to the sale, supply, manufacture or assembly of anyherbal remedy where the process to which the plant or plants are subjected in producingthe remedy consists only of drying, crushing or comminuting, and the remedy is, oris to be, sold or supplied.(a) under a designation which only specifies the plant or plants and the process and

does not apply any other name to the remedy, and

(b) without any written recommendation (whether by means of a labelled containeror package or a leaflet or in any other way) as to the use of the remedy.

Sections 7 and 8 of the Medicines Act relate to the requirement to hold licences for the sale,supply and manufacture of, and wholesale dealing in, medicinal products. The MedicinesOrder 1971 [UK 4], as amended, sets out exclusions from some of the requirements ofSection 7 of the Medicines Act where:

( i ) the product is sold or supplied to, among others, a person, in the course of whosebusiness herbal remedies are sold, where that medicinal product being a herbalremedy is to be sold or supplied in circumstances to which Section 12(1)(b) of the Actrelates,

Provided that

(i i ) no advertisement is made for it, and sale or supply is in response to an unsolicitedorder;

(ii i) manufacture/assembly is under the supervision of staff qualified to ensure the productis of the character/specification required by the person at (i);

(iv) written records to manufacture and sale are kept;

(v) a manufacturers licence is held.

The categories of products above are medicinal products but exempt from marketingauthorisation if they fulfil the requirements above. The two exemptions are specificallyintended to allow herbalists to continue to make up tailored herbal remedies and forsuppliers of basic unprocessed herbal products through any retail outlet to continue to do so.

Summary

In Ireland, Spain and the United Kingdom, there are preparations defined asmedicinal products which are exempt from licensing under specific conditions.

VII.1.5 Combinations of Herbs and Combinations with Other Groups ofSubstances

Questions were asked as to whether there are “combination products” on the marketincluding combinations of herbal ingredients with homeopathics and food supplements suchas vitamins, etc. Inquiries were also made as to how authorities assess these products. Forthe assessment of criteria for combinations of herbs, see point VII.3.1.

29

Country Combinations ofherbal

ingredients in themarket

Combinations of herbalingredients with

homeopathics in themarket

Assessment ofcombinations with

homeopathics

Austria Yes Yes Full application,Section 13

Belgium Yes No Not allowedDenmark Yes - -Finland Yes Yes Homeopathic product

as non-activeingredient

France Yes No Not allowedGermany Yes Yes These are “old”

products (a newapplication would berefused)

Greece Yes No Not allowedIreland Yes Yes Full applicationItaly Yes No Not allowed *1)Luxembourg - No -The Netherlands Yes Yes Normal procedure

*2)Portugal Yes - -Spain Yes - -Sweden Yes - -United Kingdom Yes - -

Table 4: Combinations of herbal ingredients and combinations of herbal andhomeopathic ingredients

Notes:

1) Italy:The Italian legislation on homeopathy began with Legislative Decree (“Decreto legislativo”)17 March 1995 No. 185 (G.U. 117 of 22 May 1995) [I 9] and was modified by Law (“Legge”) 8October 1997 No. 347 (G.U. No. 241 of 15 October 1997) [I 10]. It reproduces the exact terms ofCouncil Directive 92/73/EEC and does not consider this type of combination.

2) The Netherlands:There are various combination products on the market. They fall into the category offoodstuffs and are therefore not assessed by any authority as long as they do not makemedicinal claims. There are, however, several products on the market which do not yetfulfil the requirements of a full marketing authorisation while they are in the reviewprocess.

Combinations with homeopathics seem to pose a major problem. With the implementation ofCouncil Directive 92/73/EEC by the Homeopathic Act, any medicinal product containinghomoeopathically prepared substances falls under this Homeopathic Act and may notcontain any substance that is not manufactured according to a homeopathic pharmacopoeia.Therefore, combinations with homeopathic ingredients must be approved prior to marketing.There are “old” products on the market that are neither fully registered nor purely herbalmedicinal products but that are partly old homeopathic preparations or mixtures.

Country Combination with vitaminsin the market

Assessment

Austria Yes Full application, Section 13Belgium Yes *1)Denmark Yes Pharmaceutical specialtiesFinland Yes *2) Vitamin as non-active ingredientFrance Yes *3) -Germany Yes *4) Justification neededGreece - -

30

Ireland Yes Normal procedureItaly Yes Food supplementsLuxembourg - -The Netherlands Yes FoodPortugal - -Spain Yes Dietary supplementSweden Yes *5) As Herbal Medicinal ProductsUnited Kingdom Yes As Food or following CPMP

Guidelines

Table 5: Combination of herbal ingredients with vitamins and foodsupplements

Notes:

1) Belgium:In general, the Ministry of Public Health does not easily accept combinations of plants andfoods. However, prior to the publication of the Royal Decree (“Arrêté Royal”) of 29 August1997 [B 1], it was not unusual for the Ministry of Public Health to designate products as“food” if they contained plants as the applicant seeking to put such products on the marketwas often looking for some type of legal recognition. This situation was acknowledged i nthe Royal Decree by the double classification of “food/plant”.

2) Finland:There are herbal medicinal products on the market that are combinations of herbs andvitamins, and herbs and homeopathics, but not combinations of herbs and amino acids.Vitamins and homeopathics in these products are classified as non-active ingredients, andthe amount of vitamin in the daily dose must be less than the Recommended DailyAllowance (RDA) level of the vitamin in question. Quality assessment of these combinationproduct vitamins is performed according to the same guidelines as active ingredients. Somecombination products are sold without any medicinal claims under the Food Act.

3) France:There are no registered combinations of herbals and homeopathics. The current legalframework for abridged procedures does not permit the registration of combinations ofmedicinal plants (either homeopathic or not), vitamins and oligo elements. Suchcombinations (some exist in the market e.g. “aspirin, caffeine and meadowsweet”) require acompletely new registration. Normally speaking Community legislation would apply but thecurrent legal framework for abridged procedures in France does not permit the registrationof such combinations.

4) Germany:For these products, the Federal Institute for Drugs and Medical Devices (BfArM) requires ajustification of the combination according to Section 22 paragraph 3a (see Point VII.2.7.).This requirement might prevent some products from receiving a positive decision on theirapplication for registration renewal. Combinations of products with different legal status(e.g., medicinal products combined with foodstuffs or cosmetics) are not allowed.

5) Sweden:There are combination products containing herbs plus vitamins and mineral substances onthe market. The assessment procedures for combinations are the same as those applied toherbal medicinal products. For herbs, there is an efficacy and safety requirement. Forvitamins and minerals, there is only a safety evaluation (and they must not be alleged tohave any efficacy). With regard to combination substances that are not herbs, there is arequirement that these substances must not be active substances. No specific guidelines existwith regard to “combination products”.

Summary

Combinations of herbal ingredients are widely used in Europe. Their specificassessment criteria will be treated in a separate chapter (point VII.3.1.).Combinations of herbal and homeopathic ingredients are only available in a fewcountries (Austria, Finland, Germany, Ireland and the Netherlands), and thesecombinations are mostly assessed by rather strict criteria, i.e. those of a “ ful l”application procedure. Combinations of herbal ingredients and vitamins are

31

available in many countries, in some cases these combinations are regarded asfood or food supplements, in other cases a “full” application procedure isrequired.

VII.2 Requirements for Marketing AuthorisationVII.2.1 Application of Council Directive 65/65/EEC to Herbal Medicinal

ProductsCouncil Directive 65/65/EEC lays down that proof of quality, safety and efficacy is a pre-condition for marketing authorisation of medicinal products. Article 39 Paragraph 2 ofCouncil Directive 75/319/EEC requires the Member States to progressively apply theprovisions of the Directive to all medicinal products placed on the market within fifteenyears. Member States have taken a variety of approaches to meeting these requirements. Forthis reason, they were asked whether Council Directive 65/65/EEC is also applied tomedicinal products containing herbal ingredients. The results are shown in the followingtable:

32

Country AppliedAustria YesBelgium YesDenmark *1)Finland YesFrance YesGermany YesGreece YesIreland YesItaly YesLuxembourg YesThe Netherlands YesPortugal *2)Spain *3)Sweden YesUnited Kingdom Yes

Table 6: Application of Council Directive 65/65/EEC to herbal medicinalproducts

Notes:

1) Denmark:Council Directive 65/65/EEC is only partly applied. Expert reports are currently not required(this will change when the new legislation enters into force, see below). Only generallyaccepted North American and European literature is allowed for safety and efficacy. Thereis a simplification of requirements as compared to other medicinal products. Unpublishedreports of non-clinical and clinical studies are not accepted. The Danish Executive Order onHerbals and corresponding guidelines are for the moment being discussed. It is expectedthat a new piece of legislation, corresponding more precisely to Council Directive 65/65/EEC,will be completed during the autumn of 1998.

2) Portugal:Council Directive 65/65/EEC is applied if the relevant product is regarded as a medicinalproduct. This is however only rarely the case as herbal products are mostly classified as“health products”.

3) Spain:Article 42 of the Spanish Medicines Law [SP 2] states that “the plants and the mixturesthereof as well as the preparations obtained from plants in the form of extracts, lyophilised,distilled, tinctures, coctions or any other galenic preparation that may be presented withtherapeutic, diagnostic or preventive utility, will follow the system of magisterial formulae,officinal preparations or pharmaceutical specialties, as it may be appropriate and with thespecifications that may be established by regulation. The Ministry of Health will set forth alist of plants whose sale to the public shall be restricted or prohibited on account of theirtoxicity. The plants traditionally considered as medicinal plants offered without reference totherapeutic, diagnostic or preventive properties, may be freely sold to the public, but theambulant sale thereof is prohibited.” A two-year transition period was laid down to adaptcommercial activities to the provisions in Article 42. As this section needed furtherregulatory action, the draft Royal Decree of 1997 was produced.

VII.2.2 Documentation of Quality, Efficacy and Safety: “Full” ApplicationCouncil Directive 65/65/EEC lays down that proof of quality, safety and efficacy is a pre-condition for marketing authorisation of medicinal products. The specific requirements fordocumentation and expert reports on quality, efficacy and safety were delineated in CouncilDirective 75/318/EEC. However, the Member States have taken a variety of approaches whichare described below.

Austria

The registration procedure for herbal medicinal products is, in principle, the same as for al lmedicinal products. The requirements for an application are specified in the Notice toApplicants (The Rules Governing Medicinal Products in the European Union). According to

33

Section 11 Paragraph 1 of the Austrian Medicines Law [AT 1], a prior marketingauthorisation is mandatory. Section 15 contains a list of all the documents that have to besubmitted.

The Regulation on Healing Specialties (“Arzneispezialitätenverordnung”) of 1985 providedan option for herbal medicinal products to be assessed differently than chemical drugs(Section 3 Paragraph 3 and Section 35 Paragraph 5) [AT 5]. According to these provisions, theFederal Ministry of Labour, Health and Social Affairs could require further documentationand justification of why particular data were not submitted. This Regulation was howeverrepealed on 9 July 1998 because all requirements applicable to the submission of the dossierhad already been included in the Medicines Law of 1996 [AT 1].

The Austrian Medicines Law distinguishes between the procedures for full marketingauthorisation (according to Section 13) and simplified registration (according to Section17a). In order to obtain a full marketing authorisation, all pharmacological, toxicologicaland clinical studies must be performed on the actual preparation that is to be authorised oran equivalent one (i.e., identical plant, manufacturing procedure and standardisation).Clinical data may be supported by experience reports or cited monographs. However, a fullmarketing authorisation (according to Section 13) based solely on this material is notpermitted. If a portion of the required data cannot be provided, an explanation must be givenand substantiated, and literature may be used for this purpose. At least one clinical study onthe actual product must be performed in order to qualify for full marketing authorisation. Inthe case of both these options for marketing authorisation, renewal should be obtained afterfive years to continue marketing. The Federal Ministry currently intends to call forsubmission of the relevant documents according to indication groups.

Belgium

A full application is always possible although there is no specific requirement for herbalmedicinal products. Assessment of the application is carried out according to the “normal”procedure (as can be the case for a new indication). Pure and chemically definedsubstances, isolated from herbal drugs or combinations of such, cannot be registered throughan abridged procedure.

The Ministry of Public Health has a flexible approach with regard to unpublished reports ofnon-clinical and clinical studies; the scientific value being determined on a case-by-casebasis.

It is forbidden to put on the market pre-dosed forms of plants or preparations of plants withoutpackaging (e.g., capsules not packed in a blister or a bottle).

Denmark

The requirements for registration are given in Section 5 of the Danish Ministry of HealthOrder No. 790 of 21 September 1992 [DK 1] and Registration of Natural Remedies – Guide forApplicants issued by the Danish National Board of Health on 30 September 1992 [DK 2]. Afull application is possible, at least in theory. The only practical way, however, is the optionof a bibliographic application (see point VII.2.3.).

Finland

In practice, the approach to use bibliographic data as proof of efficacy and safety (see pointVII.2.3.) is the only way for applications for herbal medicinal products to be accepted. Theonly herb that could perhaps qualify under a full application today is Senna.

France

The registration procedure for herbal medicinal products is, in principle, the same as thatfor other medicinal products. According to Article L.601 of the Public Health Code (CSP), anymedicinal product manufactured by a pharmaceutical company must be given a marketingauthorisation before being marketed or distributed free of charge. The marketingauthorisation is granted based on a dossier as described in articles R.5128-5136 of the CSP.

However, for herbal medicinal products of traditional use, the marketing authorisationapplication may be made on the basis of an abridged dossier without all or part of thepharmacological, toxicological and clinical studies (see point VII.2.7.).

34

Germany

In 1994, the Federal Institute for Drugs and Medical Devices (BfArM) replaced the formerFederal Health Authority (“Bundesgesundheitsamt” or “BGA”). The BfArM is responsible forthe assessment of medicinal products and the verification of submitted dossiers with respectto quality, safety and efficacy. Criteria for registration are set out by EC Directives andGuidelines (such as “Quality of Herbal Remedies” and the European Pharmacopoeia) and bynational guidelines and directives (such as the guidelines for testing of drugs(“Arzneimittel-Prüfrichtlinien”) of 5 May 1995 [D 3] based on Section 26 of the Medicines Law.These guidelines implement Council Directive 91/507/EEC into German legislation.

Requirements with regard to proof of quality, efficacy and safety are, in principle, the samefor all medicinal products, including chemical medicinal products. For well-knownsubstances such as herbal medicinal products, bibliographic data and, for example,Commission-E monographs (see point VII.2.3.) are acceptable to demonstrate efficacy andsafety. The quality dossier is checked for each individual case.

Whether efficacy is proven by clinical studies, bibliographic data or reference to amonograph (see paragraph on “bibliographic applications”), “normal” indications withoutany additional term may be claimed.

In order to facilitate and speed up the review process, the 5th amendment of the MedicinesLaw further provided (in Section 105 Paragraph 5c) a possibility for old products to remainon the market until 31 December 2004 provided that the application was withdrawn by 31December 1995. This deadline was extended to 31 December 1999 by the 6th amendment of theMedicines Law. For these products, the dossiers are no longer checked by the BfArM butremain the full responsibility of the applicant (also under criminal law). Furthermore, theymay be controlled and – in cases of risk – withdrawn from the market by the localauthorities.

Exceptional case:

According to Section 36 of the Medicines Law, medicinal products or groups of medicinalproducts that do not pose a direct or indirect risk to the health of humans or animals may beexempted from the requirement to obtain an individual marketing authorisation. To assurethe quality, safety and efficacy of such products, each medicinal product referring to thisprocedure must comply exactly with a monograph of a standardised marketing authorisation(“Standardzulassung”) published by the Ministry of Health. The monographs includeanalytical testing requirements as well as the allowable texts for label and package leaflet.Preparations marketed with a standardised marketing authorisation have “normal”indications without any amendment. Data on safety or efficacy are often based on literatureor on Commission-E monographs.

This regulation is not specific to herbal medicinal products but also covers many chemicalsubstances. In the area of herbal medicinal products, a large number of monographs forstandardised marketing authorisation have been published, mainly for herbal teas. If anapplication refers to such a monograph, there is no need to present further documentation tothe BfArM

Greece

The Greek Health Authority (EOF) is the competent authority for granting marketingauthorisations for medicinal products. EOF procedures on medicinal products followCommunity legislation.

Until 1 January 1998, Ministerial Decree Y6a/14290/93 [GR 1] was being used. According tothis decree, a registration dossier needs to be submitted for herbal medicinal products.Article 3 contains a detailed description of the dossier requirements which comply i nprinciple with EC legislation. The dossier should be submitted to EOF, which grants orrejects the registration. Section 7 provides detailed instructions for the contents of thepackage leaflet and the labelling in accordance with the (former) EC Guideline “Quality ofHerbal Remedies.

Ireland

According to the Medical Preparations (Licensing and Sale) Regulations 1998 [IRL 3], anauthorisation is in general required in order that a medicinal product may be imported or

35

placed on the market. The Irish Medicines Board (IMB), which replaced the NDAB on1 January 1996, is responsible for the licensing of medicinal products.

In August 1985, guidelines for the application for a product authorisation of herbal productswere issued by the then NDAB [IRL 4] giving information about the requirements to allowassessment of herbal products. These guidelines contain detailed requirements for the plantraw material as well as for the finished product. The herbal product guidelines issued i n1985 have however largely been superseded by the EC Guideline, particularly in relation tothe quality of herbal medicinal products. In relation to safety and efficacy requirements,these are largely consistent with those required for conventional pharmaceutical productshitherto. According to the 1985 NDAB Guidelines, experimental animal studies have to beundertaken to delineate the effects of the contained substances and of the medicinal product.Where possible, comparative studies should be provided with a pure drug substance having asimilar effect. The tests should generally include examinations in rodents as well as i nhumans. In the case of a drug substance which is likely to be used in association with otherdrugs, account should be taken of the potential for interaction in terms of therapeutic effects,side effects and toxicity of each drug substance concerned. Each active ingredient shouldmake a relevant and reasonable contribution to the overall therapy, and the quantity of eachactive ingredient must be effective, safe and appropriate to the recommended use and rangeof dosage. Detailed requirements for the tests of acute and chronic toxicity have to befulfilled, e.g. a test for acute toxicity in at least three mammalian species and a detailed listof requirements for the tests of chronic toxicity [IRL 4].

From the viewpoint of the IMB, the requirements in the Notice to Applicants (The RulesGoverning Medicinal Products in the European Union) would likely be followed.

Italy

Herbal medicinal products may be registered with a full or an abridged application based onbibliographic data. The application dossier must contain technical and analyticaldocumentation according to Council Directive 75/318/EEC and the Notice to Applicants (TheRules Governing Medicinal Products in the European Union) [I 8]. With respect to thepharmacological, toxicological and clinical documentation, a bibliographic application i naccordance with the Council Directive 65/65/EEC is possible.

Reports of non-clinical or clinical studies that have not been published might be accepted,based on a case-by-case evaluation.

It is not envisaged to have a particular commission or group of experts dealing with herbalmedicinal products, as in Germany.

Luxembourg

Luxembourg uses mutual recognition of marketing authorisations granted in other MemberStates. In practice, Luxembourg does not grant a “first” marketing authorisation butrecognises marketing authorisations from other Member States.

The Netherlands

Herbal medicinal products are assessed using the same procedure and criteria as “regular”(chemical) medicinal products.

Portugal

In general, the national marketing authorisation procedure for medicinal products is laiddown in the Statute of Medicines of 1991 [P 2]. The measures concerning the Communitymarketing authorisation system (Council Regulation (EEC) No. 2309/93 of 22.7.1993 andCouncil Directive 93/39/EEC) were incorporated into Portuguese law by a Decree law of 1995[P 3].

As specific rules on herbal medicinal products are not part of the Portuguese medicines law,herbal medicinal products are subject to the same registration requirements as syntheticmedicinal products. Some herbal products have been registered as medicinal products.

According to the health authorities, any future developments will depend on the results of theEMEA Ad hoc Working Group on Herbal Medicinal Products.

36

Spain

Registration requirements are in accordance with EU legislation and are laid down i nRoyal Decree 767/1993 of 2 July 1993 on the registration and evaluation of medicinal products[SP 3]. A subsequent Royal Decree 2000/1995 of 7 December 1995 [SP 4] amended the 1993Royal Decree and implemented Council Directive 93/39/EC.

Present situation:

In order to establish effective control, a specific registration procedure for medicinal plantswas implemented by Ministerial Order of 3 October 1973 [SP 5]. According to this Order,preparations (Group 1) consisting of one or more medicinal plants in a cut or powdered statehad to be included in an Official Register (“Registro Especial”) as medicinal products.Exempt from that obligation are the following (Group 2):

(a) Medicinal plants and their preparations (as single species) included in a particularlist from the Annex containing about one hundred plants. Inclusion in this groupmeans that there is no obligation to register and that no indication claim may bemade. They are nevertheless regarded as medicinal products and can be sold outsidepharmacy.

(b) Extracts, tinctures and further galenical preparations, with indications and registeredas pharmaceutical specialties with analytical and pharmacological documentation.

For Groups 1 and 2a, no specific conditions exist for labelling, manufacture, distributionand sale. They nevertheless fall under the inspection of the Directorate-General forPharmacy and Sanitary Products (“Dirección General de Sanidad”).

The plants used in Groups 1 and 2b are the same.

According to the present legislation, the applicant should submit analytical andpharmacological documentation only for a preparation with medicinal indications, which istherefore registered as a pharmaceutical specialty.

New draft legislation:

In 1996, the Ministry of Health drafted a Royal Decree [SP 1] according to which priormarketing authorisation is required for herbal medicinal products. In this respect, quality,safety and efficacy must be proven and documented. Bibliographic data on the safety andefficacy of herbal medicinal products may be submitted if the constituents are well knownand are on a certain list. In case indications are claimed which are not included in the list,efficacy and safety have to be demonstrated by relevant data.

Sweden

The Medicinal Products Act (SFS 1992:859) [S 2], which entered into force on 1 July 1993, alsoapplies to natural remedies. An authorisation given by the Medical Products Agency (MPA)is valid for five years and may be renewed. The general requirements in the MedicinalProducts Act are also applicable to natural remedies. They must have a complete declarationof the contents, an acceptable name, and a clear label. Their manufacture has to follow GoodManufacturing Practices (GMP).

Specific rules apply to natural remedies that were on the market before 1 July 1993. If themanufacturer/importer submitted a notification to the MPA before that date, they received atemporary marketing authorisation (MPA’s transitional ordinance for natural remedies,LVFS 1993:6). The transitional permissions are in force while the MPA is consideringwhether the products can be approved as medicinal products or herbal medicinal products.The revision in relation to the indications of the natural remedies is still ongoing. It i sexpected that this revision will be completed in the year 2000. Certain differences apply to theauthorisation. Natural remedies in accordance with the previous system were onlycontrolled as far as safety was concerned. No other checks were done.

The MPA’s guidelines on marketing authorisation for natural remedies (LVFS 1995:18)contain detailed requirements for the application dossier. The documentation should be i naccordance with the Notice to Applicants (The Rules Governing Medicinal Products in theEuropean Union). The requirements for quality documentation take into consideration thatnatural remedies have special characteristics. For this reason, guidelines for documentationof quality have been compiled as an annex to the guidelines. According to the current

37

system, documentation is required safeguarding the quality (both manufacturing andproduct quality) at the same level as is required for chemically manufactured medicinalproducts. Complete documentation of quality is to be submitted. It includes chemical,microbiological and pharmaco-technical data, and its purpose is to describe and ensuresatisfactory product quality. In order to achieve this, the raw materials need to be of a highand uniform quality. Furthermore, the documentation should adequately describe that themanufacturing process is conducted in compliance with the EC Guidelines on GoodManufacturing Practice (GMP). Control of these factors helps to ensure that the product hasreproducible composition and other characteristics which in turn means that the finalconsumer receives a product of uniform quality. With regard to safety and efficacy,bibliographic applications are in principle possible (see point VII.2.3.).

United Kingdom

The requirements of the marketing authorisation system are set out principally in theMarketing Authorisations Regulations [UK 2]. No distinction is made betweenmanufactured medicinal products based on plant ingredients or other ingredients. However,exemptions from licensing for certain herbal remedies are contained in Section 12 of theMedicines Act [UK 1]. There is no simplified procedure and the only alternative would be afull application.

Summary

A “normal” registration procedure for herbal medicinal products with full proofof safety and efficacy is possible in all Member States except Denmark, Finlandand Luxembourg. In Denmark and Finland, only bibliographic applications areused. Luxembourg grants marketing authorisations based on the assessment o fother countries.

VII.2.3 Bibliographic ApplicationsAccording to Article 4.8 (a) (ii) of Council Directive 65/65/EEC, “the applicant shall not berequired to provide the results of pharmacological and toxicological tests or the results ofclinical trials if he can demonstrate … by detailed references to published scientificliterature presented in accordance with the second paragraph of Article 1 of CouncilDirective 75/318/EEC that the constituent or the constituents of the medicinal product have awell established medicinal use, with recognised efficacy and an acceptable level of safety.”Therefore, in principle, data from published literature may be used to substantiate safety andefficacy in expert reports and dossiers. In this study Member States were asked whether theyaccept applications which make use of Article 4.8 (a) (ii) of Council Directive 65/65/EEC toprove or support the safety and efficacy of herbal medicinal products.

Austria

A full marketing authorisation (according to Section 13 of the Austrian Medicines Law[AT 1]) solely based on bibliographic material in terms of the clinical documentation is notpermitted. According to Section 15 Paragraph 13 of the same law, however, scientificknowledge or practical experience can be used for safety documentation instead of therelevant studies.

According to Section 17a, submission of studies on efficacy and safety is not required if theapplication is in line with this regulation.

Belgium

There have been no examples of bibliographic applications in Belgium.

The Ministry of Public Health does not consider that all extracts of a similar plant areequivalent. However, they support the idea of having monographs of families of plants i norder to introduce three or four different extracts on such a scale that they become a Europeanstandard, in order to protect those companies that conducted the clinical research.

The Ministerial Circular (“Circulaire ministérielle”) of 30 November 1994 [B 2] lays down thatpharmaco-toxicological data may be replaced with references to published literature. Thisprovision is not specific to herbal medicinal products but also applies to other medicinalproducts when the active principle(s) already exist(s) on the market.

38

Denmark

Bibliographic applications are accepted. According to Section 5 of the Danish Ministry ofHealth Order No. 790 of 21 September 1992 [DK 1] and Registration of Natural Remedies –Guide for Applicants issued by the Danish National Board of Health of 30 September 1992[DK 2], complete pharmaceutical/chemical documentation is required. In accordance withArticle 4.8 (a) (ii) of Council Directive 65/65/EEC, the applicant does not need to presentresults of pharmacological or toxicological tests or clinical studies if it is shown byreference to published scientific literature that the ingredient in the preparation has beenused traditionally with a recognised effect or an acceptable level of safety. Applicationscannot be supported by unpublished non-clinical or clinical study reports but require a fullapplication in accordance with the Medicines Act. As a basis for evaluation, relevantliterature must be submitted consisting of a concluding evaluation of generally available(European and North-American) bibliographic documentation of the ingredient(s). Long-term use of a natural remedy must be certified by reference to recognised literature.

Active herbal ingredients will only be approved if they are in a concentration that i sequivalent to or not considerably higher than the concentration that can be found in nature.A higher concentration is approved only if the manufacturer can document the need for sucha concentration as well as that the higher concentration and its use are not hazardous.

Previously, when there was no control of herbal products, the Medicines Agency acceptedonly extracting methods using water and ethanol. Today other methods are also accepted aslong as documentation is provided that they are not hazardous.

The following requirements for a marketing authorisation are laid down in Section 5 ofOrder No. 790/92 [DK 1]:

1) The herbal medicinal product must be manufactured by an entity that has thenecessary knowledge and whose premises can be considered to ensure the safemanufacturing of herbal medicinal products.

Note:

The natural remedy must be manufactured in accordance with the rules in Order No.968 of 31 December 1993 on Good Manufacturing and Distribution Practice.

2) The products must be of satisfactory quality.Note:

With regard to quality, the rules in Order No. 49 of 8 January 1987 [DK 3] applytogether with standards defined in the Danish Pharmaceutical Standards (“DanskLægemiddelstandarder” or “ DLS”), which are the relevant Danish monographs. Thedocumentation must be comprised of chemical, microbiological or pharmacologicaltechnical data in order to ensure satisfactory quality as well as variations betweenbatches. Documentation regarding the chemical, microbiological or pharmacologicalpart must be in accordance with the requirements laid down in Notice for Applicantsfor Marketing Authorisations for Medicinal Products for Human Use in the MemberStates of the EC, Volume II, Annex I, Part II.

3) The products must not be hazardous during normal use.

4) It must be documented that the product can be put on the market with the indicationsaccompanying the application.

Notes on 3 and 4:

The evaluation is carried out based on an abridged application. The requirementsconcerning the quality documentation of a natural remedy are equivalent to those ofother registered medicinal products, whereas the requirements concerning thedocumentation on safety and efficacy are less comprehensive.

The applicant must thus explain:

1) the manufacturing process;

2) the concentration used;

3) the given dosages;

4) all active ingredients and their combinations.

39

The descriptions of the analytical data must be so detailed that it is possible for the DanishMedicines Agency to perform controls. Methods of analysis that do not come fromrecognised pharmacopoeias must be validated, i.e. it must be shown that the method issuitable for the purpose.

Modifications to the composition of a herbal medicinal product must be done in accordancewith Order No. 49 of 1987 on the quality of medicinal products. Such changes could concernspecifications for a medicinal product or a raw material which is not or only partly coveredby a monograph included in a valid pharmacopoeia. Modifications must be approved by theDanish Medicines Agency.

Finland

Finland accepts applications which make use of Article 4.8 (a) (ii) of Council Directive65/65/EEC as almost the only way to prove or support the safety and efficacy of herbalmedicinal products.

The requirements for the marketing authorisation of herbal medicinal products are asfollows:— compliance with the definition of herbal medicinal products as laid down in the

Medicines Law (see point VII.1.1.);

— quality and manufacturing in accordance with the requirements for normalmedicinal products, taking into account the special characteristics of herbal medicinalproducts;

— safety and efficacy in accordance with bibliographic data;

— adequate expert reports; and

— adequate labelling with the term “herbal remedy.”

In accordance with Council Directive 75/319/EEC, an expert report together with appendicesin tabular form and an optional written summary should be submitted on thepharmaceutical and chemical particulars. With regard to pharmacological and toxicologicalparticulars, a summary should be submitted based on the application material and brieflydescribing the main indications of the products as well as other facts that the manufacturerconsiders to be of significance in the evaluation of the application. A critical evaluation ofthe pharmacological and toxicological data should be included in the summary.

The documentation on pharmaceutical and chemical particulars should be presented i naccordance with Council Directive 75/318/EEC, which is applicable to all medicinal products.The particulars on the quality and manufacturing of herbal medicinal products shouldfurther take into account the EC Guideline “Quality of Herbal Remedies”. The rawmaterials must meet the requirements of the pharmacopoeia or, in the absence of suchspecifications, detailed quality requirements should be drafted in accordance with the modelmonographs of the European Pharmacopoeia. Quality requirements and analytical methodsfor intermediate and finished products must be presented. Analytical methods must bevalidated. If the product contains more than one herbal drug or herbal drug preparation,these should be identified (e.g., by the thin layer chromatography fingerprint method). Thefinished products should meet the requirements of the European Pharmacopoeia and theFinnish and Swedish Standards for Medicinal Products. Shelf-life should be indicated forthe finished product based on appropriate stability tests. The tests should be conducted i nspecified circumstances in the package intended for sale.

If the herbal medicinal product or its active ingredient has been used for a long time i nEurope or in countries close to Europe with regard to healthcare traditions, the safety andproposed indication of the product can normally be explained by information available i nthe scientific literature. The application should also contain a bibliography listing of thecitations for the data that are appended or otherwise referred to in the application.

The proposals for the labelling and package leaflet as well as the summary of productcharacteristics should be submitted to the National Agency for Medicines (NAM) togetherwith the application. The label of a herbal medicinal product must clearly state that it is aherbal medicinal product [FIN 1].

Renewals of marketing authorisation can be granted for a period of five years at a time. Theapplication for renewal of a marketing authorisation with its appendices should be submittedto the NAM at least three months before the expiry of the marketing authorisation, i naccordance with Administrative Regulation 4/93.

40

Products referred to in Section 68, Paragraphs 1 and 3 of the Medicines Act (1987/395) which,upon the entry into force of the Administrative Regulation 9/93 have an authorisationreferred to in Section 69, Paragraph 1 of the Medicines Law or a license for sale or otherconsumption granted under Section 10 (f) of the Pharmaceutical Preparations Law or whichhave been granted a license for a semi-medicinal purpose under the Decree on licenses forlabelling the purpose of a semi-medicinal product (1993/1046), should, under the transitionalprovisions of the law amending the Medicines Law (1993/1046), have been taken to theregister as herbal remedies with a marketing authorisation upon the entry into force of thelatter Act. Registration as herbal remedies also applies to homeopathic and anthroposophicalproducts which, upon the entry into force of the Administrative Regulation 9/93, have alicense referred to above and which do not meet the requirements of registration laid downin Section 21a, Paragraphs 1 and 2 of the Medicines Law (1993/1046). The labelling of thesepreparations should have been made to comply with the above provisions and those containedin the Administrative Regulation 5/93 of NAM not later than 31 December 1995.

Holders of the marketing authorisations should submit their applications for renewal of themarketing authorisations in accordance with the following groupings:

Corresponding licenceor approval granted in

Authorisation should be (have been)submitted by

1983 – 1985 31 December 19951986 – 1987 31 December 19961988 – 1989 31 December 19971990 – 1991 31 December 19981992 – 1993 31 December 1999

Table 7: Renewal of marketing authorisations in Finland

The applications for renewal need to comply with the existing rules for applications formarketing authorisations.

France

Bibliographic applications are accepted. However, none of them has up to now led to amarketing authorisation as the dossiers were insufficient.

Germany

According to Section 5 of the Guidelines for Medicines Testing (“Arzneimittel-Prüfrichtlinien”) [D 3], bibliographic data may be used as a reference for well-knownsubstances. Acceptable data include pharmacological, toxicological and clinical studies,observational field studies, scientifically evaluated case reports and scientificallydocumented medical experience.

During the review process between 1978 and 1994, monographs on active ingredients were asa first step compiled by Expert Commissions according to Section 25 Paragraph 7 of theGerman Medicines Law. The objective of the procedure was to establish clear, a prioricriteria for active ingredients and to make it clear to industry which products had a chanceof being authorised. The review of herbal remedies was conducted by a multidisciplinarycommission of experts, the so-called Commission E, consisting of pharmacists,pharmacologists, toxicologists, clinical pharmacologists, biostatisticians, medical doctorsfrom hospitals and general medical practitioners [D 2]. This Commission was responsiblefor the evaluation of more than 300 medicinal plants, and the results (i.e., the monographs)have been published in the Federal Gazette (“Bundesanzeiger”), beginning in 1984. Thesemonographs cover most of the ingredients of industrially prepared herbal medicinalproducts on the market.

The work of all review commissions, including Commission E, regarding the evaluation ofbibliographic data and the preparation of monographs was ended with the publication of the5th Amendment of the Medicines Law in August 1994. The main reason was that the mostrelevant active principles were covered by monographs and the remaining products could bemore economically assessed on a case-by-case basis. The commissions now serve asadvisory boards to the Federal Institute for Drugs and Medical Devices (BfArM) in makingdecisions on the registration of new medicines and in the individual assessment of oldmedicinal products, as the second step of the review process.

41

Although no further monographs can be published due to the absence of a legal basis, theexisting texts remain valid unless they are superseded by new scientific knowledgeresulting, for example, from clinical studies. It is therefore in principle still possible for anapplicant to refer to a monograph regarding efficacy and safety of a medicinal plant (andits preparations) and submit only a complete quality dossier. For this reason, monographs orbibliographic data may, to a large extent, replace pharmacological, toxicological andclinical documentation. However, earlier monographs often require an updated literaturereview.

Greece

According to information from the Greek Health Authority (EOF), reference to bibliographicdata is possible in accordance with Article 4.8 (a) (ii) of Council Directive 65/65/EEC. Underthe Ministerial Decree of 1994 [GR 1] (which is no longer used), the applicant was not obligedto perform new pharmacological, toxicological and clinical studies if the active ingredientsof the herbal medicinal products were commonly used in medical practice and if they hadestablished efficacy and an acceptable level of safety. Safety and efficacy had to bedemonstrated by scientific literature, which had to be submitted together with the application.If a herbal medicinal product was used traditionally and it could be demonstrated that it hadno side effects, the submission of a specific toxicological part was not necessary. A nexception was made in case new circumstances required a revision of the benefit-risk ratio.If toxic effects were reported or a long-term traditional use could not be demonstrated or therewere doubts concerning a product’s safety, submission of toxicological expert reports wasrequired.

Ireland

Until the end of 1995 it was not possible to identify a simplified procedure for dealing withassessment of such products based upon the waiving of any requirement for efficacy and/orsafety. The Irish Medicines Board (IBM) has not yet made any decision in this regard. Atpresent it is awaiting the outcome of the deliberations of the Ad Hoc Working Group onHerbal Medicinal Products.

The option whether bibliographic references can be used seems to depend on the indicationclaim and is assessed case by case. In cases of medicinal plants with a well-established use,e.g. Valerian, it seems possible to use Article 4.8 (a) (ii) of Council Directive 65/65/EEC.

Italy

For well-known products, the pharmacological, toxicological and clinical documentationmay be based on scientific literature. Indications may be claimed if they are supported bydocumentation in the marketing authorisation. Recently, the Ministry of Health issued aguideline regarding definition, classification and patient leaflets of self-medicationmedicinal products but without any particular reference to herbal medicinal products [I 3].

In case of abridged applications, the Ministry of Health will not outright reject literaturefrom non-occidental (i.e. non-North American or non-European) sources but will considerthem on a case-by-case basis.

Marketing authorisations for laxative products containing sennosides and cascarosideshave usually been based on bibliographic applications.

Luxembourg

If a medicinal product (herbal or synthetic) has been granted a marketing authorisation i nanother Member State based on a bibliographic application, this will normally be recognisedby the Division of Pharmacy and Medicinal Products.

The Netherlands

In principle it is possible to use Article 4.8 (a) (ii) of Council Directive 65/65/EEC, providedthe quality of the referenced studies is acceptable to the Medicines Evaluation Board (MEB).For example, scientific journals are accepted. However, the MEB notes that Article 1 ofCouncil Directive 75/318/EEC requires that published literature be referenced in accordancewith the Annex to this Directive. In the MEB’s experience, it is very difficult to compile a

42

bibliographic registration dossier for a herbal medicinal product that meets the requirementsof Article 1 of Council Directive 75/318/EEC.

For bibliographic documentation on clinical efficacy of an extract, the MEB is of the opinionthat all extracts are not equivalent. Therefore there must be similarity between the extractdescribed in the supporting literature and the herbal medicinal product in the application.

Portugal

Reference to literature is in principle accepted.

Spain

According to Royal Decree 767/1993 [SP 3], pharmacological, toxicological and clinicalstudies may in principle for non-prescription medicinal products be replaced bybibliographic documentation. According to information from the Directorate General ofPharmacy and Sanitary Products, it is sufficient in case of herbal medicinal products tomake reference to a monograph.

Sweden

According to the MPA’s Guidelines on marketing authorisation for natural remedies (LVFS1995:18) [S 1], regarding safety consideration should primarily be given to experience withthe use of the product or its constituents, and it should be demonstrated that no harmfuleffects have been reported or are being suspected. If satisfactory proof of safety is notprovided, this should be established by means of clinical trials and/or pharmacological andtoxicological studies. Even if the experience of long-term use of a natural remedy does notindicate that it has any harmful effects, this cannot always be assumed to be proof of theremedy’s safe use.

By definition, natural remedies may only be marketed with indications for diseases orsymptoms of diseases which are temporary or mild in nature, i.e. for diseases or conditionsthat are suitable for self-medication. The fields that may be approved for natural remedies ata later date depend on the supporting documentation provided in the application.

For well-documented ingredients or products for which there is adequate experience, reliablebibliographic data may be sufficient to support statements about a natural remedy’s efficacy.However, the precondition is that the product’s formulation, use and dosage, etc. do notdeviate from those traditionally described. In cases where the product’s properties deviatefrom the traditional description, the application is to be supplemented by specific product-related documentation in accordance with the MPA’s Guidelines on the documentation ofnatural remedies, Part IV, efficacy documentation.

A specific statement on traditional use should be included in the label.

United Kingdom

In principle, the MCA accepts bibliographic proof of efficacy under 4.8 (a) (ii) for all herbalmedicinal products, but this has to satisfy all the requirements of Council Directives75/318/EEC and 75/319/EEC. For products well-established in the United Kingdom, theapplicant has to submit the actual documentation (i.e. provide the MCA with copies of thedocuments, not only refer to it). Documents have to be in English, otherwise they have to betranslated. The full package should be provided, and there must be an expert report. Forproducts not already licensed in the United Kingdom, the application is treated as a NewChemical Entity (NCE).

The problem of the bibliographic proof of efficacy under Article 4.8 (a) (ii) of CouncilDirective 65/65/EEC is the concept of essential similarity.

Summary

The option of bibliographic application is available in the following Member States:

Country Option of bibliographic applicationAustria Yes - only for safety documentationBelgium Yes - in principle

43

Denmark Yes - as the only way in practiceFinland Yes - as the only way in practiceFrance Yes - in principleGermany YesGreece YesIreland Yes - on a case-by-case basisItaly YesLuxembourg YesThe Netherlands Yes - in principlePortugal Yes - in principleSpain Yes - in principleSweden YesUnited Kingdom Yes

Table 8: Option of bibliographic application

It can be demonstrated that the option of bibliographic application is available i nall Member States except in Austria, where it is only accepted for the safetydocumentation. The option of bibliographic application is however sometimesonly available through assessment on a case-by-case basis, or in several cases it i snot used in practice.VII.2.4 The “Scotia” CaseThe European Court of Justice, in its Judgement of 5 October 1995 in case C-440/93 (TheQueen v (1) Licensing Authority of the Department of Health and (2) Norgine Limited, exparte Scotia Pharmaceuticals Limited), stated that in terms of the utilisation of bibliographicdata according to Article 4.8 (a) (ii) of Council Directive 65/65/EEC, the tests referred to i nthe data should actually have been carried out previously and that expert reports must beprovided in accordance with Council Directive 75/318/EEC.

National authorities have been asked about the implications of this interpretation by theEuropean Court of Justice in the assessment of applications for marketing authorisation ofherbal medicinal products. The replies from the national health authorities are given below.

Austria

The Federal Ministry of Labour, Health and Social Affairs considers that this is a generalquestion concerning acknowledgement of bibliographic material. If the preparation isalready authorised according to European law, bibliographic material is accepted for apreparation containing the same active ingredient. The expert has to decide in his criticalevaluation whether it is the “same” active ingredient, e.g., if it contains the samecharacteristic compounds.

Belgium

There have not been any examples of a similar case. The Ministry of Public Healthconsiders that this has to be discussed at the European level in order to avoid further cases.

Denmark

According to the Danish Medicines Agency, there are no implications of the “Scotia” case forherbal medicinal products. Expert reports are currently not required (the new legislationwill include this requirement). The Danish Medicines Agency considers that, according tothe “Scotia” case, this is in conflict with the interpretation of Article 4.8 (a) (ii) of CouncilDirective 65/65/EEC made by the European Court of Justice.

Finland

According to National Agency for Medicines (NAM), there are no implications of the“Scotia” case for herbal medicinal products.

44

France

According to the French Medicines Agency (AdM), there are no implications of the “Scotia”case for herbal medicinal products.

Germany

According to the Federal Institute for Drugs and Medical Devices (BfArM), there are noimplications of the “Scotia” case for herbal medicinal products.

Greece

According to the Greek Health Authority (EOF), implications for herbal medicinal productsare likely, although there has been no example of a similar case.

Ireland

According to the Irish Medicines Board (IMB), it is not yet clear but theoretically there areimplications for herbal medicinal products.

Italy

The Ministry of Health considers that there are implications for herbal medicinal products,as there are for other medicinal products. The Ministry is waiting for further clarificationat the European level. It is for the moment considering that studies have to be performed withidentical preparations.

Luxembourg

The Division of Pharmacy and Medicinal Products considers that mutual recognition is i nprinciple possible, depending on the decision of the Member State.

The Netherlands

The Medicines Evaluation Board (MEB) considers that the most important implication isthat, for bibliographic applications, the provisions of Council Directive 75/318/EEC mustapply in a like manner. That means that all the requested material has to be submitted.

Portugal

No specific implications.

Spain

The Directorate General of Pharmacy and Sanitary Products has no fixed opinion. Itconsiders that that Article 4.8 (a) (ii) of Council Directive 65/65/EEC is strictly applied in thecountry.

Sweden

According to the Medicinal Products Agency (MPA), there are no implications of the“Scotia” case for herbal medicinal products.

United Kingdom

According to the Medicines Control Agency (MCA), there are implications for herbalmedicinal products, specifically when a product is within its ten-year period of exclusivity.

SummaryInformation obtained from national health authorities shows that the opinionsabout possible implications of the “Scotia” case are not uniform. According to the

45

answers received, there is obviously no practical experience yet on how to handlethis problem.

46

VII.2.5 ESCOP and WHO Monographs and WHO GuidelinesThe utilisation of monographs can be useful for the assessment and review of herbalmedicinal products as stated by the Ad Hoc Working Group on Herbal Medicinal Productsin November 1997. National authorities were therefore asked whether the monographs ofESCOP (European Scientific Co-operative on Phytotherapy) and/or WHO (World HealthOrganisation) as well as the “WHO Guidelines on the Assessment of Herbal Medicines” arealready used or intended to be used.

Austria

ESCOP and WHO monographs may only be used as a source for bibliographic data. It seemsdifficult for the Federal Ministry of Labour, Health and Social Affairs to use them as a basisfor marketing authorisation because they often contain bibliographic data themselves andnot original data from studies.

Experts from the Federal Ministry are not required to follow the monographs. However, itseems possible that a European core-SPC could be used, if available.

Belgium

ESCOP and WHO monographs may be used, but references are not limited to thesemonographs.

Denmark

ESCOP monographs may be used as part of the bibliographic documentation but are notaccepted automatically. WHO monographs are not used as they cannot be considered to keepup with the required standards. Other references may be used but will have a supportive role.

The Danish Medicines Agency will follow the recommendations of the EMEA Ad hocWorking Group on Herbal Medicinal Products.

Finland

ESCOP monographs and the “WHO Guidelines on the Assessment of Herbal Medicines”may be used.

Other sources of literature may be used with a supportive purpose. The National Agency forMedicines (NAM) intends to follow most of the recommendations of the Ad Hoc Workinggroup on Herbal Medicinal Products as they consider it lacks a lot of the expertise andcompetence that is available in this Working Group.

France

The French Medicines Agency (AdM) uses ESCOP and WHO monographs as a summary ofthe current literature. WHO Guidelines are not used.

Germany

The Federal Institute for Drugs and Medical Devices (BfArM) considers that ESCOPmonographs offer a valuable overview of the published literature. They are used, togetherwith the bibliography, in the assessment of dossiers. The WHO monographs are not yetfinally published; however, the drafts are used in the same way as ESCOP monographs.

Greece

ESCOP and WHO monographs and WHO Guidelines are taken into account although theyhave no official status. The Greek Health Authority (EOF) is waiting for the outcome of theassessment by the Ad Hoc Working Group before officially accepting the ESCOP and W H Omonographs.

47

Ireland

The Irish Medicines Board (IMB) considers that ESCOP and WHO monographs and W H OGuidelines have a supporting role.

Italy

The Ministry of Health has so far not considered ESCOP and WHO monographs and W H OGuidelines as reference tools for medicinal products. It is awaiting the results of the Ad HocWorking Group on Herbal Medicinal Products. It would not oppose the development ofEuropean core-SPCs.

Luxembourg

ESCOP and WHO monographs would in theory be acceptable as references, but at presentthere is no assessment specific to herbal medicinal products.

The Netherlands

Monographs on indications or clinical use are at present not used.

Portugal

All this material is regarded as useful, but has not yet had any impact on the currentassessment process.

Spain

ESCOP and WHO monographs are used as bibliographic references.

Sweden

ESCOP monographs may be used along with other documents, but are not alone accepted assufficient support for approval (i.e., they cannot be the sole source). WHO monographs areaccepted as contributing support in the assessment process, but so far there has been noexperience with these monographs. The monographs are considered as not being completeenough. The “WHO Guidelines on the Assessment of Herbal Medicines” have been partiallyimplemented.

United Kingdom

ESCOP and WHO monographs are regarded as a useful summary, but the originalreferences are needed.

SummaryESCOP as well as WHO monographs are regarded as useful summaries of bibliographicdata in many countries. Other sources such as European Core-SPCs as well as further resultsof the EMEA Ad hoc Working Group on Herbal Medicinal Products are considered desirableby many health authorities for the assessment of herbal medicinal products.

VII.2.6 Existence of a Category for Well-Known PlantsThe authorities were asked whether there is a specific category in which herbal medicinalproducts containing well-known plants can be classified.

In the following countries, well-known plants can be included in the following categories:

Country CategoriesAustria List according to Section 17a of the Medicines Law [AT 2,3]Belgium Lists of the Ministerial Circular (“Circulaire ministérielle”) [B 2]France Agency Instructions (“Cahiers de l’Agence No.3”) [F 4]

48

Germany • Commission E monographs,

• List according to Section 109a of the Medicines Law, or

• “Standardzulassung”

Spain • Herbal medicinal products, or

• Phytotraditional products

Table 9: Existence of a category for well-known plants

In the following countries, there is no specific category for herbal medicinal productscontaining well-known plants:

DenmarkFinland *1)GreeceIrelandItalyLuxembourgPortugal *2)SwedenThe NetherlandsUnited Kingdom *3)

Table 10: Countries without a specific category for well-known plants

Notes:

1) Finland:There is no special category for herbal medicinal products containing well-known plants.Herbal medicinal products only contain well-known plants because, according to thedefinition, herbal medicinal products only contain traditionally used plants. Traditionallyused herbal medicinal products that are marketed for the treatment of certain illnesses orproducts marketed with medicinal claims or indications fall within the scope of herbalmedicinal products as defined in Section 21 of the Medicines Law. As such, they need amarketing authorisation granted by NAM.

2) Portugal:An expert group consisting of pharmacognosists has been founded by Infarmed [P 8]. Itswork has however been suspended since the Ad hoc Working Group on Herbal MedicinalProducts started its activities.

3) United Kingdom:In the United Kingdom in the early 1970s, all medicinal products were given licences ofright. These were gradually reviewed in order to grant the product licence seen today. Al lproducts were required to provide sufficient data to satisfy all licensing requirements. Insummary, a herbal product can only be on the market as:

• A product with a reviewed licence of right now given a full marketing authorisation

• A product with a full marketing authorisation as a New Chemical Entity (NCE) orunder Article 4.8 a (i), (ii) or (iii) of Council Directive 65/65/EEC.

• An exempt unprocessed herbal remedy without claims

• A food, if the herb has a recognised food use and makes no medicinal claims

VII.2.7 Simplified Proof of EfficacyIn several Member States, the requirements for the proof of efficacy are simplified, e.g. i nthe case of certain substances or indications or if the indications refer to the traditional useof the product. The option of obtaining a marketing authorisation with simplified proof ofefficacy in the different Member States is described below. In this context, particularconsideration has been given to the requirements for proof of efficacy as well as for qualitydocumentation and, if required, for proof of safety.

49

Austria

According to Section 17a of the Medicines Law, for a simplified registration procedureneither efficacy nor safety must be demonstrated in detail. Documents on safety andefficacy do not need to be submitted if the active ingredient(s) is/are included in a specificlist. These active ingredients are non-prescription-bound substances whose quality andsafety are regarded to be proven without any detailed assessment for marketingauthorisation. The list of active substances and their permitted indications qualifying forthe abridged procedure was published in 1989 [AT 2] and last amended in 1992 [AT 3]. Ifquality complies with the specifications in the list, e.g. Flos Arnicae ÖAB (AustrianPharmacopoeia), no individual specification needs to be submitted. This procedure is appliedexclusively to medicines and indications included in the specific list (see above).

The list includes approximately five hundred substances, medicinal plants, parts of plants,essential oils, etc. for which a simplified registration procedure can be used. According toSection 17a of the Medicines Law, this procedure applies not only to herbal medicinalproducts but more generally to those substances that are considered by the Federal Ministryof Labour, Health and Social Affairs to be suitable, well known and safe. The followingexamples of plant drugs are included in the table:

50

Flos ArnicaeFlos CalendulaeFolium BetulaeFolium Crataegi cum floreHerba EquisetiHerba UrticaeRadix CurcumaeRadix GentianaeRadix ValerianaeSemen Plantaginis ovatae

Table 11: Examples of plant preparations included in the Austrian “Section 17a”list

The list has been compiled by an expert committee consisting of pharmacognosists,pharmacologists, pharmaceutical chemists, etc. Proposals from industry for substances to beincluded in the list are taken into consideration as long as the requirements for quality andsafety are fulfilled.

Belgium

A simplification of requirements as compared to other medicinal products is laid down i nthe Ministerial Circular (“Circulaire ministérielle”) of 30 November 1994 (“Moniteur Belge” of10 February 1995) [B 2]). According to this Circular, herbal medicinal products may beregistered following an abridged procedure. The 1994 Circular replaced the previous onepublished in 1989 [B 3]. The 1994 procedure was subsequently modified by the MinisterialCircular of 12 May 1997 (Federal Gazette of 25 December 1997 [B 4]). Because the 1997Circular contained an updated list of plants, it is sometimes difficult to tell whichframework has been used in applications for product registration.

The abridged registration procedure for herbal medicinal products can be used if referenceis made to the plants listed in the Annex to the Circular. There are twenty-three lists. A listof indications for which the various groups of plants are traditionally used is also available;however, a list of indications only appears in Circular No. 367 of 22 September 1989 [B 3] andwas no longer included as they were not mentioned in the Circular of 30 November 1994[B 2].

There is no standard in the abridged procedure for the quality documentation that has to besubmitted. Reference is usually made to official monographs, e.g., those of the EuropeanPharmacopoeia. The Ministry of Public Health can however demand further documents suchas certificates of analysis, stability tests, etc.

Valeriana officinalisMatricaria chamomilla

Cassia sennaGinkgo biloba

Plantago (ovata)

Table 12: Examples of plants included in the Belgian list with the option ofsimplified proof of efficacy

Denmark

There is no specific category for particular herbal medicinal products. The herbal productswhich may be registered as natural remedies must have a well-established use, which issubstantiated by relevant references to generally recognised European or North Americanliterature. The Danish Medicines Agency may disregard this requirement in the case oftraditional natural remedies, which are generally known and have been used for a longtime in Denmark. An example of this is Ginkgo biloba, which has been used since the early1980s and which was authorised for the first time in 1995. There is no general definition ofwhat could constitute “well-established use”.

In practice, only a few traditional indications have been accepted. The Danish MedicinesAgency nevertheless asks for generally recognised literature in accordance with Article 4.8

51

(a) (ii) of Council Directive 65/65/EEC. No simplified proof of efficacy exists other than theoption of bibliographic applications.

Finland

The requirements for proof of efficacy have already been eased because these products fallwithin the scope of “herbal medicinal products”. According to the existing legislation, theefficacy (i.e., the proposed indication of the product) can be explained or proved byinformation available in the scientific literature (bibliographic data). The requirements forproof of efficacy cannot be simplified further, even when the manufacturer refers in theindication to the “traditional use” of the herbal medicinal product.

France

The French Medicines Agency (AdM) grants marketing authorisations based on abridgeddossiers by making reference to traditional use. The shortened procedure requires limited orno pharmacological, toxicological and clinical tests and is detailed in the AgencyInstructions No. 3 (“Cahiers de l’Agence No. 3”) [F 4]. The list of drugs with acceptedtraditional uses was first published in 1985 by the Ministry of Health in a Notice toApplicants (“Avis aux fabricants”). This list has been revised several times since 1985 i norder to incorporate Community requirements and new scientific developments. The AgencyInstructions No. 3 include the most recent list. Traditional use has been recognised forminor indications of approximately 200 herbal drugs as well as most of the preparationsderived from these drugs. Except for plant-based laxatives, indications are introduced by thestatement “Traditionally used in …” (“ Traditionellement utilisé dans … ”).

The abridged registration procedure may be used for herbal medicinal products if the herbaldrug or herbal drug preparation is included in the positive list of almost 200 herbal drugsrecognised by the AdM [F 4]. This list was compiled on the basis of available literature,historical proof of widespread traditional use, safety, an optimum benefit-risk ratio,chemical composition and well-established use in self-medication. The list may be updatedas new scientific data become available. It does not describe the preparations in detail.Therefore, some flexibility concerning what constitutes innovation is left to the marketingauthorisation applicant. Generally, the AdM recommends that applicants justify the use ofany unusual preparation.

If the drugs and the indications claimed are on the positive list, the requirements forpharmacological, toxicological and clinical data may be reduced or waived entirely.

When establishing the positive list, the AdM recognised that the available bibliographic datado not meet the pharmaco-toxicological and clinical criteria required for a marketingauthorisation as defined in the EC Directives.

The Agency Instructions No. 3 also include a detailed description of the required contents ofthe dossier, a list of toxicological recommendations by preparation and rules for labellingand packaging of herbal medicinal products (with special recommendations for laxatives).

Chemical and pharmaceutical dossiers must be submitted in all cases.

The need for toxicological evaluation of a herbal drug or preparation depends on itstraditional use, pharmaceutical form and the presence of undesirable constituents in thedrug. With regard to the toxicological dossier, two cases are envisaged:

— Category 1: No study is required for most of the herbal drugs and herbal drugpreparations. This is the case in particular for herbal teas and laxative herbal drugs

— Category 2: A reduced toxicological study may be required for some herbal drugpreparations. This is the case in particular for most powdered drugs.

In certain cases, additional toxicological studies may be requested. This is particularlylikely for topical forms and for combinations of two plants included in the positive listwhose combination was not on the list.

With regard to clinical dossiers:

— Clinical data are not necessary if drugs and claimed indications are on the positivelist.

— Acceptability and/or bioavailability studies are generally not required.

52

According to the Agency Instructions No. 3, there should be only two possibilities:

— The drug is included in the positive list. An abridged application may be submittedwith the therapeutic indication “Traditionally used in …”. However, there is anexemption for laxatives, for which the laxative nature of the medicinal product and itsindication, i.e. constipation, must be clearly stated. Indications such as “purgative” or“for slimming purposes” etc. are not accepted.

— The drug is not included in the positive list. There is no simplification in therequirements for proof of efficacy (and therefore no option to use an abridgedprocedure).

Traditional therapeutic indications for herbal drugs reported in Annex II to AgencyInstructions No. 3 have been selected based on a careful review of all available literature,including chemical composition and pharmacological, toxicological and clinical data. Thenumber of therapeutic indications allowed for a herbal medicinal product has usually beenlimited to two; they are chosen by the applicant from the list of indications for the activeprinciple. When two indications are chosen for a combination of several active principles,they should belong to the same therapeutic category.

53

Medicinal plant Information for the medical profession * Information for the public *Valerianaofficinalis

Traditionally used in the symptomatictreatment of neurotonic conditions ofadults and children, notably in cases ofmild sleeping disorders (95).

Traditionally used to reduce nervousnessin adults and children, notably in caseof sleeping disorders (95).

Matricariachamomilla

Traditionally used topically as a soothingand antipruriginous application fordermatological ailments and as aprotective treatment for cracks, grazes,chapped skin and insect bites (30).

Traditional used topically as a soothingapplication and to calm the itching ofskin ailments and in cases of cracks,grazes, chapped skin and insect bites(30).

Traditionally used in the symptomatictreatment of digestive upsets such as:epigastric distension, slow digestion,eructation and flatulence (41).

Traditionally used to promote digestion(41).

Traditionally used to stimulate appetite(81).

Traditionally used to stimulate appetite(81).

Traditionally used in cases of eyeirritation or discomfort due to variouscauses (smoky atmospheres, sustainedvisual effort, swimming in the sea orswimming baths etc.) (102).

Traditionally used in cases of eyeirritation or discomfort due to variouscauses (smoky atmospheres, sustainedvisual effort, swimming in the sea orswimming baths etc.) (Precaution: useonly for mild conditions. If the symptomsincrease or persist for more than twodays, consult a doctor) (102).

Traditionally used locally (mouth andthroat washes, lozenges) as an analgesicin conditions of the oral cavity and/orlarynx (142).

Traditionally used for the temporaryrelief of sore throat and/or transienthoarseness (142).

Cassia senna Short-term treatment of occasionalconstipation (L1).

This medicinal product is a stimulantlaxative; it stimulates bowel evacuation.It is intended for the short-termtreatment of occasional constipation(L1).

Hyper i cumperforatum


Traditional used topically as a soothingapplication and to calm the itching ofskin ailments and in cases of cracks,grazes, chapped skin and insect bites(Precaution: Do not use before exposureto the sun) (30).

Traditionally used for sunburn,superficial burns of small area andnappy rash (32).

Traditionally used for sunburn,superficial burns of small area andnappy rash (Precaution: Do not usebefore exposure to the sun) (32).

Traditionally used locally (mouth andthroat washes, lozenges) as an analgesicin conditions of the oral cavity and/orlarynx (142).

Traditionally used for the temporaryrelief of sore throat and/or transienthoarseness (142).

Plantago majorL.


Traditional used topically as a soothingapplication and to calm the itching ofskin ailments and in cases of cracks,grazes, chapped skin and insect bites(Precaution: Do not use before exposureto the sun) (30).

Traditionally used in cases of eyeirritation or discomfort due to variouscauses (smoky atmospheres, sustainedvisual effort, swimming in the sea orswimming baths etc.) (102).

Traditionally used in cases of eyeirritation or discomfort due to variouscauses (smoky atmospheres, sustainedvisual effort, swimming in the sea orswimming baths etc.) (Precaution: useonly for mild conditions. If the symptomsincrease or persist for more than twodays, consult a doctor) (102).

Table 13: Examples of plants and indications from the French AgencyInstructions No. 3 (“Cahiers de l’Agence No. 3”)

Note:The numbers in brackets indicate the group of indications from the Agency InstructionsNo.3.

Germany

The 5th Amendment of the German Medicines Law (which became effective on 17 August1994) provided a new procedure for old products with respect to proof of quality and efficacy.The new Section 109a simplifies the requirements for products already on the market since

54

1978. The regulation is not specific to herbal medicinal products. A description of traditionaluse instead of proof of efficacy is accepted for these products, which are mostly sold outsidepharmacies. The Federal Institute for Drugs and Medical Devices (BfArM) does not checkthe documentation on quality. All of these products must be labelled as “traditionally used”and have a mild indication claim (e.g., for supporting various functions or as a tonic).

In accordance with Section 109a of the Medicines Law, the BfArM has compiled lists for oldproducts stating which preparations are allowed to refer to this regulation and whichtraditional uses can be claimed. Publication of these lists started with the 25th promulgation,and so far more than 800 positions consisting of substances, combinations and indicationsare covered [D 4]. The applicant may decide if his old product should go through thistraditional procedure. If this option is chosen, the applicant must refer to a position on the listand does not need to submit proof of efficacy and safety. Permission for inclusion on the listmust have been previously applied for.

A specific Expert Commission, the so-called Commission according to Section 109a, decidesabout inclusion of preparations and indications in the list. Submitted material (e.g., proof oftradition, plausible documents to support the indications) is thoroughly evaluated by theCommission’s members who are pharmacognosists, pharmacologists, practitioners withclinical experience, etc.

This system of “traditionally used” products may offer a legal alternative for a largenumber of old preparations which lack the scientific documentation needed to prove efficacyand which may thus receive a positive decision in the re-registration procedure.

In contrast to regular herbal medicinal products, the quality dossier of the “traditional”products is not checked by the BfArM. However, the applicant is legally responsible for itsappropriateness (“Eidesstattliche Versicherung”). Furthermore, the quality dossier does notneed to comply with the current Guidelines for Medicines Testing (corresponding to CouncilDirective 91/507/EEC amending Council Directive 75/318/EEC) [D 3] but rather with theprevious version of 14 December 1989 [D 5].

55

Examples of preparations from the “traditional” list according to Section 109a of the GermanMedicines Law are given below:

Active ingredients Dosage form Indication: “Traditionally used ...”Ginseng root (liquidextract prepared withwine)

Liquid for oraladministration

for improvement of the general condition.This statement is exclusively based ontradition and long-term experience.

St. John’s Wort (aqueousliquid extract)

Liquid for oraladministration

for improvement of the condition in caseof nervous stress. This statement isexclusively based on tradition and long-term experience.

Garlic + Mistle herb +Hawthorn flowering tops

Sugar-coated tablets for support of the cardiovascular function.This statement is exclusively based ontradition and long-term experience.

Garlic oil Gastro-resistantcapsules

for the prevention of generalatherosclerosis. This statement isexclusively based on tradition and long-term experience.

Hamamelis leaf (aqueousliquid extract)

Cream for support of the skin function

Ginger + Juniper berries Tablets for support of the digestive functionOnion (oily viscousextract)

Capsules for the prevention of generalatherosclerosis. This statement isexclusively based on tradition and long-term experience.

Melissa leaf Sugar-coated tablets for improvement of the condition in caseof nervous stress, for support of thestomach function. This statement isexclusively based on tradition and long-term experience.

Dandelion root(aqueous solid extract)

Capsules for support of the excretory function of thekidney. This statement is exclusivelybased on tradition and long-termexperience.

Table 14: Examples of plants and indications from the German “traditional” list

Luxembourg

According to the Division of Pharmacy and Medicinal Products, simplified proof of efficacyis handled on a case-by-case basis, depending on the Member State granting the firstmarketing authorisation. Cases of simplified proof of efficacy in the sense of a “traditionalcategory” are also handled on a case-by-case basis.

The Netherlands

There is no simplified procedure.

Portugal

At present, no simplified procedure exists. New legislation is planned. The basic assumptionis that simplified proof of efficacy should cover a specific group of products regarded asmedicinal products. There is however no further information available.

Spain

According to the draft Royal Decree [SP 1], a simplified registration procedure for herbalmedicinal products is possible along the lines of the provisions of Royal Decree 767/93 [SP 3].The applicant is obliged to submit the pharmaceutical documentation detailed in Annex VII,which is in principle in line with the EC Guideline “Quality of Herbal Remedies”. In termsof safety and efficacy documentation, reference can be made to a positive list. Annex II ofthe draft Royal Decree lists the therapeutic, diagnostic and prophylactic indications and themedicinal plant species for which the simplified registration procedure can be used. Thefollowing plants and their permitted indications might serve as examples:

56

Indication PlantsMedicinal plants for symptomatictreatment of digestive disorders

Yarrow, Aneth, Caraway, Fennel,Peppermint, Thyme, etc.

Medicinal plants for symptomatictreatment of slight diarrhoea

Black tea, Strawberry, Tormentill, Blueberry,etc.

Medicinal plants for improvement of renalelimination function

Birch, Dandelion, Fennel, etc.

Table 15: Examples of medicinal plants and their indications from Annex II ofthe Spanish draft Royal Decree

Phytotraditional products (“productos fitotradicionales”) are medicinal products exemptedfrom licensing. For this reason, they are dealt with under point VII.1.4.

Sweden

There is no further simplification other than bibliographic application.

United Kingdom

There is no simplified procedure.

SummaryThe following Member States have not established a simplified procedure toprovide proof of efficacy during the marketing authorisation procedures:

57

DenmarkFinlandGreeceIrelandI t a l yLuxembourgThe NetherlandsPortugalSwedenUnited Kingdom

Table 16: Countries without the option to provide simplified proof of efficacy

Austria, Belgium, France, Germany and Spain have established a simplified proof ofefficacy in their marketing authorisation procedures. The following requirements exist forquality documentation, proof of safety and proof of efficacy:

Country Quality Safety Efficacy

Austria Specified in list Considered as proven Reference to listBelgium Specified in list (Ph.Eur.) Reference to list Reference to listFrance Dossier to be submitted Cat. 1: no studies

Cat. 2: reducedtoxicity required

Reference to list

Germany Dossier to be submitted,but only checked on arandom basis

Considered as proven Reference to list

Spain Dossier to be submitted Considered as proven Reference to list

Table 17: Requirements for quality documentation, proof of safety and proof ofefficacy in Member States

VII.2.8 Indication Claim of the Category with Simplified Proof of EfficacyMember States were asked if a specific indication claim (introductory term) exists forpreparations included in the above-mentioned category – as far as this category exists –which is authorised by a simplified marketing authorisation procedure.

Country No specific statement Specific statement

Austria xBelgium xFrance “Traditionally used in ...” (except laxatives)Germany “Traditionally used in ...”Spain x

Table 18: Specific indication claims for the simplified proof of efficacy

Notes:

1) Belgium:The phrase “Traditionally used in…” was used up to 1994.

Other countries use a “traditional” term for specific groups of products whose marketingauthorisation procedure is different from the simplified proof of efficacy described in thischapter:

2) Finland:According to the legal definition, “herbal remedies” are products traditionally used formedicinal purposes in which the active principle or principles is or are derived from the

58

vegetable or animal kingdom, bacteria or minerals. They are, however, not authorised by asimplified procedure with a simplified proof of efficacy but with a bibliographic applicationprovided for in Article 4.8 (a) (ii) of Council Directive 65/65/EEC.

3) Sweden:The Guidelines on authorisation to place natural remedies on the market (LVFS 1995:18)state that the indications of natural remedies must contain the wording: “traditionally used...” or, when applicable, be labelled with other wording prescribed by the Medical ProductsAgency. However, this does not refer to a simplified procedure as described in thisparagraph.

4) United Kingdom:The Medicines Control Agency reviews herbal medicinal products in the same way in whichit reviews any other medicinal product. When herbal medicinal products were reviewedoriginally, some were required to incorporate “a traditional herbal remedy for” in theindication. This was granted provided the product was of satisfactory quality and there wereno safety concerns. Medical claims were limited to those for minor self-limiting conditions.This requirement is maintained for these products at renewal and therefore still exists i nmost licensed products, but is not incorporated into new applications. Thus, there arerelatively few products with this statement in the indications.

VII.2.9 Further Developed Products: Requirements for Proof of Efficacy andSafety

In many countries “modern” herbal medicinal products are on the market that have beenfurther developed from their traditional use, e.g., highly processed or special extracts but notisolated substances. They have “modern” indications. The requirements for the proof ofefficacy and safety are described below. In the absence of harmonised traditional use, aMember State may consider a product as “modern” while another one may consider it as“traditional”.

Austria

For example, Ginseng and Hypericum have been authorised with a full marketingauthorisation according to Section 13 of the Medicines Law. Ginkgo biloba has also beenauthorised but as a prescription-only preparation.

Belgium

The following products have been registered with indication(s) which do not refer to theirtraditional use(s):

• Carduus (Silybum) marianus, intended for improving the function of the liver in somewell-defined ailments of the hepatic cell

• Serenoa repens, which is prescription only and used as an adjuvant for urinationtroubles associated with mild (benign) prostatic hyperplasia.

However, this is not the general trend.

DenmarkThe indications for some herbal medicinal products (e.g., Ginkgo biloba) are based onmodern bibliographic literature and not only on traditional use. The products consist ofmodern extracts rather than traditional forms such as teas, infusions, etc.

Finland

There are modern herbal medicinal products on the market that have been further developedfrom their traditional use. New pharmaceutical forms of traditionally used products can beaccepted. The indications of the herbal medicinal products must be traditional; newindications are not acceptable. Highly processed products were approved prior to 1994 but areno longer allowed. It has been difficult to fit some highly processed products into the new

59

legislation (e.g., betasitosterol and phytoestrogens). With regard to sitosterol, the finalsolution is still pending. Until now, such products have been considered as foodstuffsintended for particular nutritional uses.

France

Since the implementation of Council Directive 75/318/EEC, there have been very fewmarketing authorisations delivered to plant-based medicinal products based on a fullapplication. Among the notable exceptions are medicinal products containing specific plantextracts: Gingko biloba (Tanakan™); Pygeum africanum (Tadenan™); and Serenoa repens(Permixon™). An abridged procedure was not possible because these plants are not includedin the positive list established by the French Medicines Agency (AdM) (see point VII.2.7).

Marketing authorisations of almost all other plant-based medicinal products have beengranted or validated following an abridged procedure for herbal medicinal productsintended for traditional use (see point VII.2.7.).

Germany

There are many modern products on the market containing extracts and claimingindications that have mostly been proven by clinical studies, as shown in the followingtable.

60

Preparations from Indications

St. John's Wort (herb) Slight transient depressive disordersSaw palmetto (fruit) Micturition disorders in benign prostate hyperplasia stages I

and IINettle (root) Micturition disorders in benign prostate hyperplasia stages I

and IIHawthorn (flowering tops) Decreasing cardiac function (NYHA* stage II)Kava Kava (rhizome) Nervous tension, anxiety and restlessnessGinkgo biloba (leaf) Symptomatic treatment of disturbed performance in organic

brain syndrome...* Classification according to New York Heart Association

Table 19: “Modern” herbal medicinal products in the German market

Greece

There are no “modern” products as such on the market.

Ireland

There are no “modern” products as such on the market.

Italy

There are highly processed extracts on the market which are standardised by their activeprinciples and are considered by the Ministry of Health as “modern”. Examples arebilberry, silymarin, and laxatives (i.e., sennosides and cascarosides).

Marketing authorisations for such products have usually been based on bibliographicapplications. However, in the absence of a specific legal framework for plant-basedmedicinal products, it is not appropriate to ask whether such products should be considered asherbal or regular medicinal products. The Ministry of Health will follow any guidancefrom the European Commission or the EMEA Ad hoc Working Group on Herbal MedicinalProducts that might bring some clarification.

Luxembourg

In light of the systematic mutual recognition of other Member States’ marketingauthorisations in Luxembourg, it is supposed that such products exist on the market.

The Netherlands

For example, products from Cassia (Senna), Rhamnus frangula, Valeriana officinalis, Plantagoovata, Hamamelis virginiana, Ginkgo biloba, some of them also as combinations, were fullyregistered in 1996. A product containing Crataegus and a combination of Hamamelisvirginiana and Aesculus hippocastanum are for the moment “licensed”, that means not (yet)fully registered.

For example, Hypericum and garlic products were not registered as medicinal products evenafter assessment, and therefore these products tend not to be developed from their traditionaluse status. An application for Hypericum has not yet been submitted.

One Ginkgo biloba extract was registered in 1996 after a full assessment. Several Valerianae,Senna and Psyllium products had been registered earlier as medicinal products.

Portugal

In cases of “modern” herbal medicinal products, full proof of quality, safety and efficacy isrequired like for any other medicinal product.

61

Spain

For new indications and new dosage forms, a new application is required (whether or not itis a herbal medicinal product). In case of old products which are being further developedfrom their traditional use, the dossiers will be checked by the authorities.

Sweden

If any of the parameters (e.g., indication or content) do not have a long tradition, theindication may not contain the wording “Traditionally used for …”. If the herbal medicinalproducts are too highly processed (e.g., pure substances isolated from plant material), theyare not classified as herbal medicinal products but rather as ordinary medicinal products.In that case, of course, the indication does not begin with the wording mentioned above.There is no general rule concerning the time-limit when “traditionally” is discussed. TheMPA has been reluctant to set any specific time-limit. Instead, this has to be decided for eachproduct on a case-by-case basis.

United Kingdom

— Hypericum: “depression” would be a new clinical indication. No product has beenlicensed yet. There are food supplements supplied with indications of anti-depressiveeffects but MCA is trying to stop this.

— Gingko biloba: there have been some applications but the MCA has not agreed ondelivering a marketing authorisation. This would be an NCE (New Chemical Entity)which would require a full application and would be assessed in the same way as asynthetic drug.

— Crataegus: this would be an NCE.

— Valerian: the United Kingdom was the Reference Member State in a MutualRecognition Procedure for a Valerian-containing medicinal product.

— Garlic: There are licensed garlic products for colds, flu, etc. There is no garlic productlicensed for, e.g., cardiovascular usage. Numerous unlicensed food supplements claimcholesterol and heart benefits. A licence application would be considered as anabridged application.

The problem with “new” indications is that they usually fail to satisfy requirements onefficacy. However, some valuable examples of the contrary are:— Isphagula husk, which is a bulk forming laxative but now has an indication for

lowering cholesterol. It is available OTC

— Evening primrose oil, which is widely sold as a food supplement but is also licensedfor eczema and breast pain.

— Peppermint oil, which is sold OTC for irritable bowel syndrome.

SummaryFor herbal medicinal products which are further developed from their traditionaluse, e.g. further processed extracts and/or products with “high level” indications,a full licence is required in most cases, and efficacy has to be proven by clinicalstudies. In several countries however, such products do not exist.

VII.2.10 Comparison of the Requirements for Proof of Efficacy in the MemberStates

Country Simplified Proof Bibliographic proof Full clinical proofAustria Yes Only supportive YesBelgium Yes (Yes) YesDenmark N o Yes N oFinland N o Yes N oFrance Yes (Yes) YesGermany Yes Yes Yes

62

Greece N o Yes YesIreland N o (Yes) YesItaly N o Yes YesLuxembourg N o (Yes) (Yes)The Netherlands N o (Yes) YesPortugal N o (Yes) YesSpain Yes Yes YesSweden N o Yes YesUnited Kingdom N o Yes Yes

(Yes) = In principle existing, but in practice unknown or difficult

Table 20: Comparison of the requirements for proof of efficacy

SummaryThe table shows which requirements exist for herbal medicinal products in termsof proof of efficacy in the Member States:1. The option of simplified proof of efficacy exists in Austria, Belgium,

Germany, France and (in future) Spain.

2. The option of bibliographic proof exists in almost all countries, although itis sometimes in practice unknown or difficult, or only supportive forclinical data in Austria), and

3. The option of full clinical proof exists in all countries except Denmark andFinland (only bibliographic applications) and Luxembourg (unknown i npractice).

63

VII.3 Specific Questions on Marketing AuthorisationVII.3.1 Marketing Authorisation for Combination ProductsAt the EU level, guidance on combinations of active ingredients is provided in the“Guideline on fixed combination products” issued by the Committee for ProprietaryMedicinal Products (CPMP)10. Moreover, the EMEA Ad hoc Working Group on HerbalMedicinal Products in 1998 finalised a proposal for new guidance on “Fixed combinations ofherbal medicinal products with long term marketing experience” – Guidance to facilitatemutual recognition and use of bibliographic data (see Table 1). In the case of marketingauthorisations for combinations of several herbal ingredients, the following requirementscurrently exist in the Member States.

Austria

Combinations of several herbal ingredients are authorised either according to Section 13(full marketing authorisation) or Section 17a (abridged procedure) of the Medicines Law.The latter procedure permits a maximum of three active ingredients only.

Belgium

In general, the Ministry of Public Health (and the Medicines Commission) have a criticallook upon combination products unless a scientific rationale can be provided. Combinationproducts are not normally accepted if they contain more than three plants from one list or i fthe plants belong to different lists [B 2], although there might be some flexibility in thisrequirement if the usefulness of the combination is demonstrated. Up to six plants areaccepted in teas (but only three for taste and aspect).

Denmark

Combination products are accepted. If the product consists of several herbal ingredients,bibliographic documentation for the actual combination will be necessary.

All declared herbal active substances must be safe and all must contribute to the overalleffect of the product. Herbal active substances in medicinal tea mixtures should normallyconstitute at least 70% (by weight). It must be endeavoured to limit the total number of activesubstances in medicinal tea mixtures to a maximum of seven, and the number of aromaticsubstances, appearance-enhancing components and flavouring ingredients to a maximumof three. For tablets, capsules and tinctures, the Danish Medicines Agency normally acceptsup to five active ingredients. Tablets with up to nineteen herbal active substances have beenapproved, but this must be seen as an exception.

Finland

For a marketing authorisation for combinations of several herbal ingredients, Section 21 ofthe Finnish Medicines Law must be followed. Each compound of the combination mustcontribute to the effect (i.e., the proposed indication) of the product. There are no limits to thenumber of herbal ingredients allowed, as long as they all contribute to the effect of theproduct.

France

For new combination products containing known ingredients that have not been previouslyused together for therapeutic purposes, pharmacological, toxicological and clinical tests onthe combination must be conducted. It is not necessary to provide documentation for eachindividual component (Article R. 5133 of the Public Health Code (CSP)).

For some medicinal products based on plants with traditional uses, up to five drugs orpreparations may be combined, if justified (Agency Instructions No. 3) [F 4]. Combinationsof herbal drugs (or their preparations) with similar uses are permissible. Combinations ofherbal drugs (or their preparations) with complementary uses are acceptable if the formula

10 Guideline on Fixed-Combination Medicinal Products (III/5773/94, CPMP/EWP/240/95 ). The Rules

Governing Medicinal Products in the European Community, Volume 3C.

64

is justified. Certain combinations defined in the Agency Instructions No. 3 do not need to beexamined on a case-by-case basis.

Some herbal drugs may be added in order to improve the taste or other aspects. Forcombinations of plants intended for use as herbal teas, the Agency allows a maximum of tendifferent plants (and a maximum of five herbal drugs as active principles).

Germany

For medicinal products containing more than one active ingredient, Section 22 Paragraph3a of the German Medicines Law must be respected. According to this legislation, it must bejustified that each active ingredient contributes to the positive assessment of the medicinalproduct. In this context Paragraph 5 of the Guidelines for Medicines Testing(“Arzneimittelprüfrichtlinien”) describes the documents that must be submitted anddifferentiates between new and well-known combinations. For a combination of new activeingredients, pharmacological-toxicological as well as clinical data are required. The sameprinciple applies to new combinations of well-known ingredients. However, well-knowncombinations of well-known substances (assumed to make up the largest proportion of herbalcombination products) are assessed using bibliographic data.

The specific characteristics of the medicinal products in question must be evaluated using agraduated risk assessment. Preparations with a low risk, including many herbal medicinalproducts, might benefit from this approach if the requirements for the justification of thecombination are lower.

The Federal Institute for Drugs and Medical Devices (BfArM) has published a CommissionE working document “Assessment Criteria for Fixed Combinations” which is based on theidea that the single ingredients contribute to a positive assessment of the preparation bycontributing to safety or efficacy. The dosage of the single ingredients must be appropriatewith regard to efficacy. Fixed combinations may be assessed positively if the ingredientshave an additive or potentiating effect, if side-effects can be reduced or if a simplification oftherapy or an improvement of therapeutic safety is provided by the combination.

Greece

For combination herbal medicinal products that have not previously been usedtherapeutically in this particular combination, the results of studies on the actualcombination must be submitted. Studies on each single herbal ingredient are not required.

Ireland

With regard to combination medicinal products in general, guidelines published by theNational Drugs Advisory Board (NDAB) in 1984 [IRL 6] stated that evidence was required i nsupport of the following criteria for assessment:

1. Each active ingredient should make a relevant and reasonable contribution to thetherapy.

2. The quantity of each active ingredient must be effective, safe and appropriate to therecommended use and range of dosage.

3. Adverse interactions should not occur between the active ingredients at theconcentrations to be used. Such interaction would include diminished efficacy,reduced biological availability and altered excretion.

4. Each of the active ingredients should have an appropriate duration of action relative tothe other constituents.

5. The active ingredients should not have widely different therapeutic benefit-risk ratios.

6. The fixed combination product should not be recommended for use in the treatment ofdisease in which careful individual adjustment of dosage is required.

Insofar as herbal medicinal products are treated in the same way as other medicinalproducts, it would appear likely that the NDAB guidelines on fixed product combinationswould be applied to the licensing of combinations of several herbal ingredients. There are noguidelines dealing specifically with combinations of herbal products

65

Italy

In general, combination products are regarded critically by the Italian MedicinesCommittee (“Commissione Unica del Farmaco” or CUF). However, the conditions are almostidentical to those covered by Council Directive 65/65/EEC on combinations of several activeprinciples.

The National Formulary of the Italian pharmacopoeia, 9th edition (“Formulario Nazionaledella Farmacopea Ufficiale IX Edizione”) contains some preparations for herbal teas [I 16]and for certain defined products such as ipecacuana syrup, “Senna composta” oral powder,etc. [I 20]. Any new application for a herbal tea deviating from these preparations should beassessed on a case-by-case basis.

Luxembourg

This is handled on a case-by-case basis, depending on the Member State granting the firstmarketing authorisation.

The Netherlands

Combination products are assessed according to the Guideline on fixed combination productsissued by the EU’s Committee for Proprietary Medicinal Products (CPMP).

Portugal

No specific requirements exist for combination products.

Spain

Combinations must always be justified, and more than two or three active ingredients arenot allowed per combination. According to Chapter II Article 4 of the draft Royal Decree of1997 [SP 1], combinations of fixed amounts of herbal drugs or their preparations are allowed,provided they claim similar or complementary therapeutic indications and have advantagesover the single ingredient. According to Annex V of the draft Royal Decree, combinationsmust not contain more than three species as excipients, and the total amount of the excipientsmust not exceed 15% (m/m).

Several combination products exist with an old registration. They will be subject to revision.In these cases, the use of bibliographic references such as monographs on single herbsprepared by ESCOP, WHO, the German Commission E or the French Agency InstructionsNo. 3 seems possible to demonstrate safety and efficacy instead of a detailed expert reports.

Sweden

Combination products containing several active ingredients need a special explanatorystatement in the application. A fundamental precondition for the approval of combinationproducts is that each active ingredient contributes to the overall effect of the indicationsubmitted in the application. This may be increasingly difficult to prove if the product i nquestion has several herbal ingredients. However, no restriction has been placed on thenumber of herbal drugs included in a remedy, provided that the documentation issatisfactory with respect to quality, safety and efficacy. The MPA keeps strictly to its rulesin this respect, and the outcome may be that combinations of several herbal ingredients mayfind it more difficult to obtain a marketing authorisation compared with other countries.

United Kingdom

In general, combinations are licensed on proof of efficacy:

1. Combinations already on the market or identical products do not need additionalefficacy or safety data unless existing products are less than ten years old.

2. New combinations: full clinical data required.

3. Combinations of unprocessed exempt herbal remedies are allowed without claims andwill remain exempt.

66

The MCA would follow the CPMP Guideline on combinations.

Summary

Combinations of two or more herbal ingredients in a medicinal product are i nmost cases assessed according to the relevant EC Directives and Guidelines. Inseveral cases, specific assessment criteria are available such as the French AgencyInstructions No. 3 or the German Commission E monograph on fixedcombinations. In case of new combinations, full clinical proof of efficacy isusually required.

VII.3.2 Individual Supply by PractitionersIn many cases, herbal medicinal products (like other medicinal products) are made upand/or supplied to individual patients following a one-to-one consultation between patientand practitioner. The following data are available on how Member States treat suchmedicinal products, taking into consideration Article 2.4 of Council Directive 65/65/EECwhich states that “a Member State may, in accordance with legislation in force and to fulfilspecial needs, exclude from Chapters II to V medicinal products supplied in response to abona fide unsolicited order, formulated in accordance with the specifications of anauthorised health care professional and for use by his individual patients on his directpersonal responsibility”.

Austria

Individual supply: Doctors are not permitted to dispense medicinal products directly topatients except in cases of urgent need or first aid, unless they obtain a special dispensingpermission (“Hausapotheken-Berechtigung”). In 1997 there were 965 self-dispensing doctorsin Austria.

Magisterial and officinal preparations: Magisterial formulas must be prepared bypharmacists. According to Section 11 Paragraph 2 of the Medicines Law [AT 1], they do notneed a marketing authorisation.

Belgium

Individual supply: The Ministry of Public Health does not encourage this practice andconsiders the pharmacist to be the appropriate intermediary between patient and practitioner.

Magisterial and officinal preparations: A specific framework for magisterial preparations iscurrently under evaluation. There is legislation on raw materials for medicinal products,but there is no regulation on foodstuffs yet. As an example, a medical doctor can prescribe aChinese plant introduced in Belgium. The medical doctor is the responsible person. Thepharmacist can make a magisterial preparation. The pharmacist is the person responsiblefor quality and identification.

Denmark

Individual supply: There are no specific rules for products manufactured and sold bypractitioners to individual patients since this tradition does not exist in Denmark.

Magisterial and officinal preparations: All products that are on the market as medicinalproducts must have a marketing authorisation.

Finland

Individual supply: Section 21 of the Finnish Medicines Law applies to herbal medicinalproducts made up for and/or supplied to individual patients following a one-to-oneconsultation between patient and practitioner.

France

Individual supply: The manufacture and marketing of all medicinal products are thedomain of the pharmaceutical industry.

67

Magisterial and officinal preparations: Article 2.4 of Council Directive 65/65/EEC may beapplied to magisterial preparations. Article L.511-1-1° of the CSP states that a magisterialpreparation is any medicinal product prepared on the spot in a pharmacy according to aprescription for a specific patient. Medical doctors are free to prescribe as they see fit.However, the French Pharmacopoeia contains a list of medicinal plants with traditional usein magisterial preparations for which the risk-benefit ratio is negative (i.e., the potentialside effects are greater than the intended therapeutic benefit) (French Pharmacopoeia,Chapter IV.7.B).

Germany

Magisterial and officinal preparations: Magisterial and officinal preparations: According toSection 21 Paragraph 1 together with Section 4 Paragraph 1 of the AMG or Medicines Law, aherbal medicinal product (like all medicinal products) may be prepared in a pharmacywithout registration by the Federal Institute for Drugs and Medical Devices (BfArM) if it i sprepared for an individual patient upon prescription by a doctor or (only in the case of non-prescription-bound substances) by a practitioner (“Heilpraktiker”).

According to Section 21 Paragraph 2 Point 1, a herbal medicinal product may be prepared i na pharmacy without registration by the Federal Institute for Drugs and Medical Devices(BfArM) if it is intended to be supplied directly to patients or customers by frequentprescription. Under these circumstances, products may be prepared in batches of not morethan 100 packages per day in the usual pharmacy business.

Medicinal products include magisterial and officinal formulas. Both these groups do notrequire prior marketing authorisation because they are not regarded as proprietarymedicinal products / specialties (“Arzneispezialitäten”) under the German Medicines Law.

Greece

The requirements are the same as for all medicinal products in accordance with CouncilDirective 65/65/EEC.

Ireland

Individual supply: There are no specific legal provisions governing the supply ormanufacture of herbal medicinal products following a one-to-one consultation between thepatient and the practitioner.

Italy

Magisterial and officinal preparations: Medical doctors are allowed to give a prescription to apatient and, based on that prescription, the pharmacist is allowed to make the preparation forthat patient in the pharmacy (Article 1(4) of D.L.vo 178/91 [I 6], modified by D.L.vo 44/97 [I 7]).

Luxembourg

Magisterial and officinal preparations: A medical doctor is allowed to give a prescription tothe patient for a medicinal product to be prepared by a pharmacist. These magisterialpreparations are, however, not controlled by the Division of Pharmacy and MedicinalProducts.

The Netherlands

Magisterial and officinal preparations: As long as these products are prescribed by a medicaldoctor and are prepared in a pharmacy according to this prescription, it is permissible tosupply these products to an individual patient.

Portugal

Magisterial and officinal preparations are practically unknown.

68

Spain

Magisterial and officinal preparations: Magisterial formulas are defined in Article 8.9 of theSpanish Medicines Law.

Sweden

Individual supply: Herbal medicinal products are not prepared on a one-to-one basis. Theyare industrially prepared and sold as finished products in health food stores or pharmacies.There is, however, one exception. There is a small clinic for anthroposophy in Järna thathas received an exemption to prepare and supply a limited range of anthroposophicmedicinal products, including some herbals, to individual patients.

Magisterial and officinal preparations: Medical doctors may prescribe a specific medicinalproduct for a certain individual patient. The product is then prepared by a pharmacist in apharmacy.

United Kingdom

Individual supply: In the case of unlicensed herbal remedies (see point VII.1.4.) made up by apractitioner on his own premises, these may be supplied under Section 12(1) of the MedicinesAct to the customer for which the product is tailored. A practitioner is anyone who givesadvice on herbal remedies and makes up products. There is no legally imposed ethicalstandard.

Some herbs are considered insufficiently safe to be supplied OTC or by a practitioner (e.g.Strophanthus). These are listed in the Medicines (Retail Sale or Supply of Herbal Remedies)Order 1977 (SI No. 2130). In theory, these herbs could be supplied by a doctor or dentist but thisis uncommon.

Magisterial and officinal preparations: In the same way as for any unlicensed medicine,unlicensed herbal medicinal products may be supplied upon the order of a doctor or dentistfor an individual patient on his personal responsibility, subject to certain conditions.

Summary

A number of herbal medicinal products are magisterial formulas, which areprepared by the pharmacist. For these magisterial formulas, a marketingauthorisation is not needed according to Article 2.4 of Council Directive65/65/EEC. A specific situation exists in the United Kingdom, where apractitioner, according to Section 12(1) of the Medicines Law may supplyproducts without licence to the customer.

VII.3.3 Intermediate ProductsIntermediate products of herbal origin intended for further processing by an authorisedmanufacturer or for the preparation of a magisterial or officinal formula do not fall underthe definition of a medicinal product according to Council Directive 65/65/EEC and aretherefore not subject to marketing authorisation as such. Nevertheless, in order to guaranteetheir constant quality, these intermediate products have to be controlled. The regulations i nMember States are described as follows:

Austria

These materials are handled like all other raw materials intended for medicinal products.Good Manufacturing Practices (GMP) rules must be followed. Specific storage conditionsmust be maintained according to the nature and origin of the material (e.g., propertemperature, well-ventilated area, dry, regular control for animals and insects, etc.).

Belgium

There is legislation for raw materials for medicinal products but not for foodstuff.Production is subject to authorisation and to inspection (by Pharmacy Inspectors, even if theherbal products are not regarded as medicinal products). They are regulated as rawmaterial under a Royal Decree (“Arrêté Royal”).

69

Legislation on starting materials for magisterial and officinal preparations was publishedin 1997 and was implemented in July 1998. Herbal medicinal products are not treateddifferently than other starting materials. Since the beginning of 1998, an authorisation hasbeen required for starting materials. This authorisation is based on analytical and not onpharmaco-toxicological criteria.

Denmark

Intermediates are handled in accordance with the Notice to Applicants (The Rules GoverningMedicinal Products in the European Union). Herbal active substance preparations are thustreated as raw materials under part 2C in accordance with the rules governing productionand control of starting materials laid down in the Notice to Applicants. In this case,documentation is required on both the herbal active substance and the herbal activesubstance preparation.

Finland

Herbal medicinal preparations (e.g., herbal tinctures) are not classified as intermediateproducts but rather as raw materials and are regulated as such in accordance with CouncilDirective 65/65/EEC. According to the regulations governing pharmacies, the quality of rawmaterials must be analysed before they may be used for preparing a magisterial or officinalformula.

France

The sale of the medicinal plants that are included in the French Pharmacopoeia is restrictedto the pharmaceutical industry. However, extracts or other preparations that are consideredas active ingredients for medicinal products may be manufactured in a non-pharmaceuticalplant.

Both the manufacture of proprietary medicinal products containing such substances and thepreparation by a pharmacist (following a doctor’s prescription) are controlled by thepharmaceutical legislation.

There is no definition of “intermediate products” for products of herbal origin and this has tobe studied on a case-by-case basis. An extract is usually recognised as an active principle.Manufacturers of herbal medicinal products generally buy their raw materials from dealerswho can provide them with documents that certify the pharmaceutical grade. They maythemselves perform further tests and/or assays. The same principle applies to pharmacists,who have no advantage in buying raw materials outside the pharmaceutical circuit.

Germany

There are no specific regulations for herbal drug preparations, except EC Guidelines onGMP and the quality of herbal medicinal products.

Greece

Quality proof of intermediate products is part of the registration/marketing authorisationprocedure.

Ireland

The problem has not been encountered but, as a general rule, GMP would apply.

Italy

There is no definition of “intermediate products” for products of herbal origin. For thepreparation of herbal medicinal products, including officinal and magisterial formulae ( inthe pharmacy), the GMP rules commonly applied to intermediates for medicinal productsshould be followed. Particular reference is made to the EC Guidelines. Moreover, anyproduction is always subject to authorisation.

70

Luxembourg

The Division of Pharmacy and Medicinal Products asks for certificates of analysis for anymaterial bought by the manufacturer. The term “intermediate products” has not beendefined.

The Netherlands

Intermediate products are not specifically regulated.

Portugal

These products are not specifically regulated except material for narcotic and psychotropicproducts.

Spain

A decree is under development for preparation of products according to magisterial formulasand officinal formulas contained in the National Formulary (“Formulario Nacional”)(Articles 35, 55.5).

Sweden

Intermediate products of herbal origin that are intended for further processing are regardedand treated as any other raw material intended for the production of medicinal products.Their production is subject to authorisation and inspections if the end product is a herbalmedicinal product.

United Kingdom

Intermediate products are considered as active ingredients. At present, there is norequirement for the manufacturer of active ingredients to be authorised or inspected.However, inspections of the licensed manufacturers of medicinal products ensurecompliance with GMP. This requires, amongst other things, that starting materials arechecked for quality and identity, are in accordance with the relevant product licence and arehandled, processed and released by the authorised manufacturer in an appropriate mannerin accordance with a documented quality system.

Summary

Intermediate products of herbal origin are mostly handled like any other rawmaterials used in the production of medicinal products and therefore regulated i naccordance with the relevant EC Directives (e.g., GMP).

VII.3.4 Products from Foreign CountriesPlants which are not native to Europe might present a problem in the European market eitherbecause they have not been subject to extensive scientific research according to EC Directivesor the research data are not readily available. They fall under the regulations of theircountry of origin (e.g., China or South America). The authorities were asked how MemberStates assess the quality, safety and efficacy of these plants.

Austria

If plants non-native to Europe are to be used as medicinal products, their quality, safety andefficacy must be demonstrated by a full marketing authorisation procedure (according toSection 13 of the Medicines Law). No abbreviated or simplified procedure is permitted. If thesame plant is intended for use in food or cosmetics, its safety must be proven on areasonable basis. For food, cosmetics and the so-called consumable products(“Verzehrprodukte”), simplified registration is possible in a three-month procedure as longas the same plant or plant preparation is used in the country of origin in the same mannerand it is considered to be safe in that country.

71

Belgium

Plants not native to Europe such as ginseng are regulated. There is no specific regulationfor less common plants, and they are considered on a case-by-case basis. The Ministry ofPublic Health is very cautious with these herbs. However, many products are marketed i nhealth stores.

There have been problems with non-occidental products (e.g., imported Chinese herbs) thatwere analysed according to the Chinese Pharmacopoeia and declared to be conform. Now thepharmacopoeia referred to must have modern scientific value. In addition, there have beenproblems with Chinese plants whose microscopy and macroscopy were described for thewhole plant while the imported plants were in powder form, making performance of therequired tests impossible.

Denmark

Plants that do not have a well-established use cannot normally be authorised as naturalremedies. There is no definition of “well-established”, but it is understood that the use mustbe within Western Europe. The supporting bibliographic material must be based uponpublished scientific studies.

Finland

According to the definition of herbal medicinal products, products containing Chinese orSouth-American herbs with or without medicinal indication cannot be classified as herbalmedicinal products because they have no medicinal tradition in Europe (or countries likeEurope).

Products containing plants that are not native to Europe (e.g., some Chinese or South-American herbs), herbs used in Traditional Chinese Medicine (TCM) and plants that haveno European healthcare tradition are not classified as herbal medicinal products. Instead,they are treated as normal medicinal products under Council Directive 65/65/EEC if they aremarketed with medicinal claims. A full application becomes necessary.

There is a problem with products on the market containing Chinese herbs which are soldwithout medicinal claims. At the moment, most of these are sold as health products or foodsupplements under the Food Act.

France

The assessment of products based on plants non-native to Europe must comply with theCommunity legislation. The quality of the plant should be controlled according to thestandards of the French or the European Pharmacopoeias.

With regard to medicinal products, a full dossier is required for any plant that would not beon the positive list (see point VII.2.7). With regard to magisterial preparations, it is possibleto obtain preparations containing non-native herbs with a medical prescription. In this case,and the pharmacist is responsible for the pharmaceutical quality of the raw material used i nthe preparation.

Germany

If preparations of plants non-native to Europe are marketed as finished products, they areregarded as “new entities” and must fulfil the complete requirements concerning quality,safety and efficacy, particularly in terms of toxicological data and clinical documentation.There is no specific regulation for crude herbal drugs that are not finished products.

Greece

Full proof of quality, safety and efficacy is required for plants non-native to Europe, i naccordance with Council Directive 65/65/EEC.

72

Ireland

The case has not been encountered but, in order to get a marketing authorisation, amedicinal product based on a plant non native to Europe would require a dossier asprescribed in the Notice to Applicants (The Rules Governing Medicinal Products in theEuropean Union).

Italy

Regarding the registration of herbal medicinal products, it is necessary to submit anapplication with a full dossier (including Parts III and IV). Therefore, results ofpharmacological, toxicological and clinical studies (in accordance with the general rulesfor medicinal products) should be included.

For herbal (non-medicinal) products (i.e. health products without therapeutic indications), theresponsibility for marketing authorisation lies with the importer and/or the manufacturer.At the time of importation of a pre-finished product or its herbal ingredient(s), the Ministryof Health requests documents that certify the absence of chemical contaminant residues(e.g., heavy metals, pesticides and mycotoxins) and microbiological and biologicalcontaminants. As far as Central and East European countries are involved, the Ministryalso requests a document certifying the absence of radioactivity. If it appears that theproducts or materials are contaminated, the product may be refused or destroyed at theexpense of the importer and/or manufacturer.

Luxembourg

The case of plants non-native to Europe is handled on a case-by-case basis.

The Netherlands

The situation would depend on how herbal products based on plants non-native to Europeenter the market. If they do so as a foodstuff without medicinal claims, safety and efficacyare not assessed. If an application for marketing authorisation as a medicinal product i ssubmitted, then safety and efficacy are assessed in accordance with Council Directives65/65/EEC, 75/318/EEC and 75/319/EEC.

Oriental herbs (e.g., from India) present a problem of control. The Medicines EvaluationBoard (MEB) intends to establish a list of herbs with forbidden substances.

Portugal

There is no defined policy as the health authority does for the moment not think theseproducts are of major relevance. Currently there is a debate on regulating productsoriginating in Macão.

Spain

Plants that are not known to Spain or Europe must be registered as with a full dossier. Afterfive years on the market and once safety has been proven, they can be switched to non-prescription status. It is supposed that in the future they will become phytotraditional productsif they are added to the Annex to the draft Royal Decree of 1997 [SP 1] described in pointVII.1.2.b above.

Sweden

Either full or abridged applications may be used for plants traditionally used in the occident.For plants traditionally used in other parts of the world, the requirements are the same asfor ordinary medicinal products (i.e., full application needed). This does not preventGinseng from being sold in Sweden based on extensive use in Europe. However, productscontaining Ginseng have not yet been revised under the 1993 Medicinal Products Act.

United Kingdom

Plants non-native to Europe are considered as new chemical entities.

73

Summary

The quality of imported medicinal plants and their preparations is assesseddifferently in the various Member States. Finished products are often treated asNew Chemical Entities (NCEs) requiring full proof of quality, safety and efficacy.In several countries there are however no specific regulations on the control o fraw materials or crude drugs. This is particularly the case for products entering themarket as foodstuffs or other products not controlled in the same way as herbalmedicinal products.

VII.3.5 Important ProductsThe number of herbal medicinal products authorised in each country together with theirmajor ingredients and indications are listed below insofar as the information is available.

Austria

Approximately 700 herbal medicinal products have been officially approved, around 400 ofwhich according to the normal registration procedure (Section 13 of the Medicines Law) andapproximately 300 under an abbreviated procedure (Section 17a). Herbal medicinal productsare usually combinations of herbal drugs, although some combinations with allopathicchemical ingredients exist (e.g., “old approvals” without a modern marketingauthorisation). In addition, there are approximately six hundred homeopathics with herbalingredients approved or registered. In principle, any indication may be applied for if it i ssupported by studies or bibliographic data. Lists of major ingredients are not available.

Belgium

Some herbal medicinal products sold on the market were notified in 1964. The validationprocess for these products was supposed to be completed in 1990. However, for many of theherbal medicinal products that are sold in traditional forms (e.g., herbal teas), thevalidation process continues.

Apart from these products, a small number of herbal medicinal products (approximately 20)are marketed according to the procedure implemented in 1995. Other registrationapplications are pending. The indications accepted in the registration of these herbalmedicinal products are strictly scrutinised by the Ministry of Public Health.

Denmark

By 12 June 1998, 159 natural medicinal products were authorised [DK 4]. The list is notexclusively made up of natural remedies with an active herbal ingredient.

Finland

There are 131 herbal medicinal products with a valid marketing authorisation.Additionally, 140 anthroposophic products (with the indication: “to be used as anthroposophicproduct”) and one homeopathic product (with the indication: “to be used as homeopathicproduct”) have been approved as herbal medicinal products. Herbal medicinal productscontain more than 1/10 000 of the anthroposophic/homeopathic parent solution, so they cannotbe accepted in the registration procedure for anthroposophic/homeopathic products.

Below are lists of the main indications for and the main ingredients used in herbalmedicinal products in Finland.

• Mild symptoms due to common cold, headache, temporary cough

• Maintenance of vitamin A and vitamin D levels

• Mild stimulating effect on blood circulation in limbs

• Food additive containing ubidecarenone

• Favourable effect on the function of the bladder

74

• Mild diuretic effect

• Mild relaxing effect, sleep aid, temporary insomnia

• Mild cardiac troubles

• Intestinal flora stabiliser

Table 21: Main indications for herbal medicinal products in Finland

Echinacea purpurea , E. pallida, E. angustifolia (14)

Ginkgo biloba (11)

Crataegus oxycantha (9)

Jecoris aselli oleum (8)

Sabal serrulata (6)

Melissae folium (5)

Valerianae radix (4)

Equiseti herba (4)

Ginseng radix (4)

Solidaginis herba (4)

Strobuli lupuli (4)

Taraxaci radix (4)

Violae tricoloris herba (4)

Anisi fructus (3)

Betulae folium (3)

Chrysanthemum parthenium (3)

Equisethum arvense (3)

Hyperici herba (3)

Passiflorae herba (3)Ubidecarenonum (10)Natural bicarbonate (3)Magnesium hydroxide (2)

Table 22: Main ingredients for herbal medicinal products in Finland (number ofproducts)

75

France

There are approximately 530 proprietary medicinal products containing only plant-basedpreparations. The major indications are: diet aids, laxatives, improving blood circulationand light sedatives. The major ingredients are Fucus, Orthosiphon, Plantago ovata, Senna,Aesculus hippocastanum, Vitis vinifera, Valeriana, Crataegus, Passiflora and others. Someolder products that contain a combination of active chemicals and plant extracts are still onthe market (e.g., cough syrup containing pholcodine and drosera extract).

Germany

About 800 herbal medicinal products have successfully completed review or been granted anew marketing authorisation. The most important preparations contain Crataegus sp.,Hypericum perforatum, Ginkgo biloba, Valeriana officinalis, Senna, Matricaria chamomilla,Urtica dioica, Echinacea purpurea, Allium sativum, etc. About 3 700 old herbal medicinalproducts are still under review. The exact number of herbal medicinal products covered bystandard marketing authorisations is not known as products that can be distributed outsidepharmacy are not reported to the Federal Institute for Drugs and Medical Devices (BfArM).

Greece

44 herbal medicinal products were authorised as of May 1998. These products were approvedunder the EC Directives as well as the specific regulation in the Ministerial Decree of 1994[GR 1]. Examples include Senna and Ginseng products.

Ireland

No information available.

Italy

The estimation is that there are about 100 products on the market with about 180 marketingauthorisations granted. See also the data from the Institute for Medical Statistics (IMS) 1996[I 4-5]. Main indications are laxatives, sedatives, digestive products and cough and coldproducts.

Most herbal products on the market are not registered as medicinal products.

Luxembourg

There is no information available from the Division of Pharmacy and Medicinal Productsabout the number of herbal medicinal products that have been authorised. In total, there areabout 11 000 medicinal products on the market.

The Netherlands

The following examples were given by the Medicines Evaluation Board (MEB). ExceptCrataegutt and Hametum, these products are registered according to Council Directive65/65/EEC. They all have indication claims.

76

Product Active ingredient

Bekunis Senna Cassia sennaRichter’s kruidenthee Rhamnus frangula, Cassia sennaValdispert Valeriana sp (extractum siccum)Sanox Valeriana mexicana (extractum oleosum)Tendo-Valeriaantinctuur Valeriana sp (tinctura)Metamucil Plantago ovataHoestelixer Weleda Althaea officinalis, malt extractum, Marrubium vulgare,

Pulsatilla pratensis, Thymus vulgaris, Pimpinella anisi.Hamamelis zalf Voorhoeve Hamamelis virginianaNormacol Sterculia urens, Rhamnus frangulaSennocol Cassia senna (extractum)Agiolax Plantago ovata, Cassia senna (fructus)Hamameliszalf A. Vogel Echinacea sp., Hamamelis virginiana, Ricini oleumNervex Valeriana mexicanaVolvolon Plantago ovataHerbesan Rhamnus frangula, Cassia sennaMucofalk Plantago ovataRegucol Plantago ovataPsyllium-Searle Plantago ovataAlosan Forte Cassia senna (fructus extractum)Fiberform Tritici testaValeriaan 45 Pharbita Valeriana sp (extractum spissum)Valeriaan 45 PCH Valeriana sp (extractum spissum)Valeriaandragees Valeriana sp (extractum siccum/spissum)Valeriaanextract Valeriana sp (extractum siccum/spissum)Crataegutt Crataegus (extractum)Hametum Hamamelis (cortex), Aesculus hippocastanumBekunis Plantaardig Lax Cassia senna (fructus extractum)Konsyl Plantago ovataPsylliumvezels Plantago ovataTavonin Ginkgo biloba (extractum)

Table 23: Main ingredients of herbal medicinal products in the Netherlands

Portugal

There are products containing Ginseng, Ginkgo biloba, or Valerian in the market. Thenumber of products is, according to the health authority, unknown due to the limitations ofits information technology system.

Spain

In the Official Register (“Registro Especial”) (Ministerial Order of 3 October 1973), 1 028products are listed, whereas about 1 600 are authorised as “pharmaceutical specialties” (July1998).

Sweden

40 herbal medicinal products have been approved in Sweden. 280 natural remedies that wereon the market before 1 July 1993 have received a transitional permission.

The following list shows herbal medicinal products authorised on the Swedish market:

Product name Ingredient(s)

Andrews Antacid, tablets Calcium carbonate, magnesium carbonateAnjo GB & Ginkgo, oral liquid Ginkgo Biloba

Anjo GB & Ginkgo, tablets Ginkgo Biloba

77

Baldrian Radiotron, capsules Valeriana officinalis

Bio-Strath Salix, oral drops Salix purpurea, Primula elatior

Biostrath Valeriana, drops Valeriana officinalis, Passiflora incarnata

Calmigen, tablets Hypericum perforatum

Cedelax, single-dose powders wine acid, natriumbicarbonate, natriumcaliumtartratCurbicin, tablets Serenoa repens, Cucurbita pepo

Dormesan, drops Valeriana officinalis, Humulus lupulus

Echinagard, drops Echinacea purpurea

Echinagard, tablets Echinacea purpurea

EFI Ginkgo Biloba, capsules Ginkgo Biloba

Esbericum, capsules Hypericum perforatum

Gink-Yo, tablets Ginkgo Biloba

Herbalax, tablets Cassia senna, Cassia angustifolia

Hyperiforce, drops Hypericum perforatum, Melissa officinalis, Humulus lupulus

Kira, tablets Hypericum perforatum

Lugn och Ro, tablets Valeriana officinalis, Humulus lupulus, Melissa officinalis,Hypericum perforatum, passiflora incarnata

Lupilon, tablets Valeriana officinalis, Humulus lupulus

Movina, tablets Hypericum perforatum

Neval, capsules Valeriana officinalis

Nocturne, oral liquid Valeriana officinalis

Nosweat, capsules Salvia officinalis

Relaxin Dag, tablets Valeriana officinalis, Melissa officinalis

Relaxin Natt, tablets Valeriana officinalis, Passiflora incarnata, Melissaofficinalis

Salus Migränte, tea Ilex paraguariensis, Salix alba spp, Valeriana officinalis,Cola nitida, Juniperus communis

Samarin, single-dose powder Natriumbicarbonate, wine acid, lemon acid,natriumcarbonate, natriumcaliumtartrate

Samarin, oral powder ibid .Samarin, effervescent tablets ibid .Samarin Antacid Apelsin,chewable tablets

Magnesium hydroxide, calcium carbonate, magnesiumcarbonate

Samarin Antacid Mint,chewable tablets

ibid .

Sandolor, tablets Salix alba, S. purpurea, S. fragilis, S. daphnoides, S.pentandra

Songha Natt, tablets Valeriana officinalis, Melissa officinalis

Soval, tablets Valeriana officinalis, Melissa officinalis

Uva-E, tablets Taraxacum officinalis, Arctostaphylos uva-ursi, Menthapiperita

Valeriana Bioforce, drops Valeriana officinalis

Valerina Forte, drops Valeriana officinalis

Valerina Natt, tablets Valeriana officinalis, Melissa officinalis, Humulus lupulus

Valerina Dag, tablets Valeriana officinalis, Melissa officinalis

Table 24: Authorised herbal medicinal products in the Swedish market

United Kingdom

There are 548 marketing authorisations currently granted for herbal products, although thisfigure changes frequently. The most commonly licensed plants in the United Kingdom areValerian, Passiflora, Garlic, Senna, Capsicum, Echinacea, Skullcap, Dandelion, Hops andBuchu.

The most commonly associated indications for these plants are:

Valerian – irritability, sleeplessness

Passiflora – irritability, sleeplessness

Garlic – catarrh, cold, cough

78

Senna – constipation

Capsicum - muscle pain, muscle stiffness, rheumatic pain, lumbago

Echinacea – cold, skin infection, catarrh

Skullcap – nervous tension, restlessness

Dandelion – constipation, slimming

Lupulus – irritability, nervous tension, sleeplessness

Buchu – bladder pain, water retention.

Table 25: Ingredients and indications of licensed herbal medicinal products inthe United Kingdom market

The most common licensed indications for herbal medicinal products in general use arerheumatic pain, constipation, catarrh, cold, lumbago, muscle pain, muscle stiffness, cough,backache, and fibrositis.

VII.4 Good Manufacturing Practice and Quality ControlVII.4.1 Manufacturing Requirements of Council Directive 75/319/EECIt can be demonstrated that all Member States apply manufacturing requirements of CouncilDirective 75/319/EEC also to herbal medicinal products. Specific information on this issuewas obtained from the following countries:

Belgium

The GMP requirements of Council Directive 75/319/EEC are applied to registered herbalmedicinal products, but registered products represent a minority of the herbal products on themarket. There is a risk that the implementation of the recent legislation on herbal-basedfoodstuffs may to lead to a transfer of some products to food status, where Council Directive75/319/EEC will not apply.

Finland

Administrative Regulation 3/93 of the National Agency for Medicines (NAM) applies to al lmanufacturing. The manufacturing stages should be described from raw material to finalproduct. As far as possible, the manufacturing should be validated.

Germany

The manufacturing requirements laid down in Council Directive 75/319/EEC have beentransposed into the German Medicines Law. Concerning manufacturing (e.g., licence,responsible persons), there is no difference between herbal medicinal products and othermedicinal products. In general, it is not allowed to market products that are lower in qualitybecause of the manufacturing process not being in accordance with pharmaceutical rules(Section 8 Paragraph 1 Point 1 of the Medicines Law).

The Netherlands

The requirements of Council Directive75/319/EEC also apply to herbal medicinal products. Ifa product is marketed as a food-supplement, the provisions of this Directive do not apply.

VII.4.2 EC GMP RequirementsEC Guidelines on good manufacturing practice and quality for herbal medicinal productsare applied in all Member States. The EC Good Manufacturing Practice Guidelines, whichcontain an annex covering herbal products, are considered as an interpretation of theGerman “Pharmabetriebsverordnung” or “PharmBetrVO”. In the United Kingdom, GMPrules are not applied to products covered by Section 12 of the Medicines Act. The followingdetailed information on Spain is available.

79

Spain

According to Chapter III Article 9 of the draft Royal Decree of 1997 [SP 1], laboratories andcompanies manufacturing and marketing herbal medicinal products are classified aspharmaceutical laboratories. As such, they are covered by Royal Decree 1564/1992 [SP 6],which regulates the authorisation of pharmaceutical laboratories and importers of medicinalproducts as well as the quality assurance of their industrial manufacturing processes.

According to the draft Royal Decree of 1997 [SP 1], providers of raw materials must keep thedocumentation on the raw materials and the quality certificates until the materials’ expirydate.

The Directorate General of Pharmacy and Sanitary Products should check, through regularinspections, that manufacture and control of herbal medicinal products are in line with theGMP regulations. Annex VI of the draft Royal Decree of 1997 [SP 1] includes additionalGMP regulations for medicinal products.

Manufacturers producing or marketing “phytotraditional products” are also subject to theregulations of Royal Decree 1564/1992 [SP 6]. However, products are exempt if they onlycontain herbal teas or soluble extracts of plant species listed in Royal Decree 3176/1983 [SP 7]regulating the manufacture and marketing of herbal teas used as food. Companies thatmarket spices are regulated by Royal Decree No. 2244/1984 [SP 8] and are exempt from therequirements of the other decrees. Teas derived from the botanical genus “Thea” are coveredby Royal Decree 1354/1983 [SP 11].

Any companies providing raw material for “phytotraditional products” or preparing,packing or marketing these products must guarantee the quality and purity of the plants andtheir preparations. These businesses are also subject to inspections.

VII.4.3 Use of European Pharmacopoeia MonographsThe European Pharmacopoeia provides many monographs on quality requirements formedicinal plant starting materials. Thus, starting materials of herbal medicinal productsare in principle controlled in accordance with the European Pharmacopoeia in all MemberStates.

Detailed information is available from Finland and Spain, where the following regulationsare applied.

Finland

In assessing and reviewing the herbal medicinal products, the National Agency forMedicines (NAM) makes use of the monographs of the European Pharmacopoeia. CouncilDirective 75/318/EEC also applies to starting (raw) materials of herbal medicinal products.Quality of herbal medicines, Volume 3A of The Rules Governing Medicinal Products in theEuropean Union must also be followed. The raw materials of a herbal remedy should meetthe requirements of the pharmacopoeia in force as well as the requirements of the Finnishand Swedish Standards for Medicinal Products. If no valid monographs exist for the rawmaterials, detailed quality requirements for them should be drafted in accordance with themodel of the monographs of the European Pharmacopoeia.

Monographs of herbal remedies should indicate the scientific name of the herb together withthe name of the author, the origin, the producer(s) as well as, where possible, the time ofharvesting, the growth stage of the plant at harvesting, its handling during growth, anddrying and storage conditions.

Where possible, the concentrations of the active ingredients of the herbs should bedetermined and their limits indicated. Normally, herbs should be analysed formicrobiological purity, heavy metal and pesticide residues and radioactive impurities. Anysubstances and methods used to decrease and prevent the growth of microbes should beexplained. The packaging material and its quality should also be documented.

VII.4.4 GMP InspectionsIt has been examined whether GMP inspections are carried out in the Member State and i nthird countries exporting herbal medicinal products or raw materials to the European Union.

80

Almost all countries perform GMP inspections, with the following restrictions orexplanations.

Austria

Inspections are carried out in Austria but not in third countries (due to lack of funds).Herbal drugs are controlled voluntarily by manufacturers and/or wholesalers before beingsold or processed.

Belgium

Plants are considered as raw material but extracts might sometimes also be considered asraw material. In Belgium, GMP inspections are only carried out in case the legislation onthe manufacture of registered medicinal products or on starting materials applies. Withregard to third countries, the Ministry of Public Health takes into account the inspectionreports drafted by the competent national authorities.

Denmark

The Danish Medicines Agency carries out GMP inspections in Denmark. A manufacturingauthorisation is required from foreign manufacturers. The authorisation must not be morethan one year old.

Finland

Good Manufacturing Practices, Volume 4 of The Rules Governing Medicinal Products in theEuropean Union, Annex 7, Manufacture of Herbal Medicinal Products, must be applied toGMP inspections. In addition, Quality of Herbal Medicines, Volume 3 of The RulesGoverning Medicinal Products in the European Union must be followed.

Germany

GMP inspections are the responsibility of the German local state health authorities.Inspections are also carried out in third countries.

Luxembourg

The Division of Pharmacy and Medicinal Products requires certificates.

Portugal

There are about 40 manufacturing sites, of which about 10 are larger ones. All are inspected.

Spain

Inspections are carried out on domestic companies. So far, very few herbal medicinalproducts are imported from third countries.

United Kingdom

The Medicines Control Agency (MCA) routinely inspects for compliance with GMP alllicensed UK manufacturers of medicinal products and those manufacturers in thirdcountries (i.e., not in the UK or other EU/EEA Member States) which supply licensedmedicinal products to the United Kingdom where there is no mutual recognition agreementwith respect to inspection and GMP.

Summary

Inspections according to GMP are carried out in almost all Member States.Inspections are also carried out in third countries, but not by all Member States.

81

VII.5 Post Marketing SurveillanceVII.5.1 Monitoring of Herbal Medicinal ProductsThe adverse reaction reporting systems of Member States are based on CommissionDirective 91/356/EEC11. They also monitor herbal medicinal products in most cases, as i sshown in the following answers from the national health authorities.

Austria

Reports of adverse reactions to herbal medicinal products must be submitted just like for anyother medicinal products.

Belgium

The legislation on pharmacovigilance also applies to herbal medicinal products. The holderof a marketing authorisation for a herbal medicinal product should nominate a responsibleperson for pharmacovigilance, just like any other marketing authorisation holder. Themajority of the adverse events described so far have involved non-registered products whicheither contained plants or were presented as if they contained plants. In fact, it has appearedthat some of these non-registered products contained pharmacologically active ingredientsthat could also be found in medicinal products.

Denmark

The reporting requirements for ordinary medicinal products also apply to herbal medicinalproducts. At present, periodic safety updates are not required but they will become compulsorywhen the new draft legislation enters into force (see point VII.2.4.).

Finland

The adverse reaction reporting systems monitor normal as well as herbal medicinalproducts. Safety Update Reports are required. In practice there have however been only a fewreports on herbal medicinal products.

France

Herbal products with a marketing authorisation (herbal medicinal products) are wellintegrated in the national network of pharmacovigilance, just like other medicinal products.Adverse effects are reported to the 31 regional centres and are collected in thepharmacovigilance data bank, thus allowing an efficient and active surveillance.

Adverse reactions are rarely reported in the Summary of Product Characteristics (SPC) (andtherefore the leaflet) of herbal medicinal products.

Germany

The adverse reaction reporting systems monitor herbal medicinal products as well as allother medicinal products.

Greece

The pharmacovigilance system also monitors herbal medicinal products.

Ireland

Authorised products, including herbals, are subject to the normal pharmacovigilancerequirements.

11 Commission Directive 91/356/EEC of 13 June 1991 laying down the principles and guidelines of good

manufacturing practice for medicinal products for human use (OJ L 193 of 17.7.1991, p. 30)

82

Italy

In the pharmacovigilance system, all medicinal products are monitored. If a herbal remedyis classified as a medicinal product, it is also monitored.

Luxembourg

The reporting system also monitors herbal medicinal products.

The Netherlands

There are no differences between the post-marketing surveillance obligations for herbal andother medicinal products.

Portugal

At present, the reporting system does not monitor herbal medicinal products. No report onadverse reactions has been received so far by National Institute of Pharmacy and Medicines(Infarmed).

Spain

The pharmacovigilance system records all matters that refer to medicinal products.

Sweden

The system for adverse-reaction reporting is the same for herbal and ordinary medicinalproducts. Periodic Safety Update Reports are required. As is the case for chemically producedmedicinal products, manufacturers and importers of herbal medicinal products are requiredto report side effects without any delay. The same rules apply to hospitals and comparableinstitutions.

United Kingdom

The pharmacovigilance system also monitors herbal medicinal products.

Summary

With regard to post-marketing surveillance, national monitoring systems alsocover herbal products insofar as they are authorised as medicinal products.

83

VII.5.2 Withdrawal of Herbal Medicinal Products Due to Safety ReasonsIn the following cases, reports on adverse reactions have led to withdrawal of herbalmedicinal products from the market.

Belgium

Based on experimental studies, some plants and their derivatives have been forbidden in thecomposition of medicinal products (e.g., Royal Decree (“Arrêté Royal”) on plants containingpyrrolizidine alkaloids). However, the same plants are still used in non-registered productson the Belgian market.

Finland

There have been no reports of adverse reactions that have lead to withdrawal of herbalmedicinal products from the market. Products containing Aristolochia sp., Teucriumchamaedris, Rubia tinctorum or Vinca minor are not allowed as herbal medicinal products,nor are products containing toxic pyrrolozidine alkaloids (e.g., Senecio sp., Symphytum sp.,Borago officinalis, Petasites hybridus, and Tussilago farfara).

France

Some adverse reactions have been reported for herbal medicinal products. As an example, i n1992, reports on 26 cases of acute cytolitic hepatitis after administration of herbal tea capsulescontaining Teucrium chamaedrys (“Common Germander”) led to the withdrawal of the siximplicated medicinal products from the French market. Those medicinal products hadpreviously obtained a marketing authorisation following an abridged procedure.

Germany

A significant number of herbal medicinal products have been the subject ofpharmacovigilance actions (e.g., certain medicinal products containing 1.2- unsaturatedpyrrolizidine alkaloids). Safety measures have been undertaken for anthranoid laxatives i nterms of risk information and restriction of pack sizes. For other products, the compositionhad to be changed and harmful constituents eliminated.

Pharmacovigilance actions are in line with a list issued in 1992 by the EU’s Committee forProprietary Medicinal Products (CPMP) containing several herbal drugs with more seriousrisks.

Luxembourg

Some herbal medicinal products have been withdrawn from the market when they werewithdrawn in other Member States.

The Netherlands

According to the Medicines Evaluation Board (MEB), cases of withdrawal are not knownbecause dangerous products are not registered.

Spain

According to the Directorate General of Pharmacy and Sanitary Products, very few reportshave been connected to herbal medicinal products and in no case has it been necessary towithdraw products from the market. More details may be obtained from the National ADRCentre.

United Kingdom

Manufacturers are required to notify the Medicines Control Agency (MCA) of any complaintthat might lead to a recall, in accordance with Article 13 of Commission Directive91/356/EEC. MCA monitors and may direct the recall of any batch of medicinal product

84

because of defective quality. There have been recalls of batches of herbal medicinal products.Such recalls by United Kingdom manufacturers are notified to the regulatory authorities i nother Member States.

Note:

National authorities were also asked if there are cases of herbal medicinal products thathave been withdrawn from the market in one Member State and have continued to beallowed to be sold after this withdrawal in their own country. As far as cases are brought tothe attention of national health authorities, they are reported below, together with anyadditional information.

Austria

When a product is withdrawn from the market in another Member State, the FederalMinistry of Labour, Health and Social Affairs carefully considers the case and decides onthe matter independently.

France

Decisions for such withdrawals are made at the national level and communicated to theother Member States. However, certain plant-based products are sold in health shops or bymail order. These products have no marketing authorisation and their trade is illegal.Monitoring of adverse effects after administration of these products is possible with apharmacovigilance system but is more difficult because patients rarely inform medicaldoctors about the use of these products.

Summary

The effectiveness of existing pharmacovigilance systems can be demonstrated byseveral withdrawals of marketing authorisations for herbal medicinal productsdue to safety concerns related to certain plants.

VII.5.3 Consumer ReportsReports from consumers could give an improved picture of the spectrum of adverse reactionsto herbal medicinal products. Opinions on whether these reports should be accepted are asfollows:

Austria

Adverse drug reaction (ADR) reports from consumers are accepted by the Federal Ministryof Labour, Health and Social Affairs. Consumers are moreover invited to report them to theirpharmacists and doctors.

Belgium

For the time being, only those reports that are issued by health professionals (pharmacists,medical doctors, etc.) are taken into account. The Ministry of Public Health only acceptsreports from consumers if they are corroborated by a health professional.

Denmark

Reports from consumers are handled in the same way for herbal medicinal products as forother medicinal products. Reporting is done by medical doctors or pharmacies. There are nospecific problems in this respect. Package leaflets do not contain any information about thereporting of adverse reactions.

Finland

The National Agency for Medicines (NAM) considers that reports from consumers shouldnot be accepted. Package leaflets for herbal medicinal products do not contain anyinformation on adverse reactions.

85

France

Package leaflets include information about the reporting of adverse reactions to the medicaldoctor or the pharmacist. The surveillance system for adverse reactions is based onvoluntary reporting by health specialists. Reports from consumers are not taken intoaccount. However, depending on their relevance, severity and newness, reports receiveddirectly from consumers may be accepted in exceptional circumstances.

Germany

From the viewpoint of the Federal Institute for Drugs and Medical Devices (BfArM),consumer reports should be accepted. The use of such reports requires criteria for adequatedocumentation of adverse effects and for control by health professionals. Consumer reportsof high quality may improve knowledge on the safety of herbal drugs.

Greece

From the viewpoint of the Greek Health Authority (EOF), consumer reports should beaccepted.

Ireland

The policy of the Irish Medicines Board (IMB) is to require ADRs to be validated by ahealthcare professional using the Yellow Card scheme.

Italy

Package leaflets of medicinal products include information about the reporting of adversereactions. The Ministry of Health is in favour of the consideration of reports fromconsumers.

Luxembourg

From the viewpoint of the Division of Pharmacy and Medicinal Products, consumer reportsshould be accepted.

The Netherlands

Reports from consumers on adverse drug reactions are relevant for all medicinal products,including herbal medicinal products. However, because herbal medicinal products aremainly sold as non-prescription products, the relevance of consumer reporting becomes evenmore significant. According to the Medicines Evaluation Board (MEB), current legislationdoes not provide for consideration of reports from consumers. Consumer reports are onlyaccepted when corroborated by a medical doctor.

Portugal

Consumer reports should be accepted.

Spain

The Directorate General of Pharmacy and Sanitary Products is of the opinion that onlyhealth professionals should report ADRs.

Sweden

Consumers can report either to the company responsible for the product or to the MedicalProducts Agency (MPA). The package leaflet does not include information about thereporting of adverse reactions. Reports from consumers are assessed differently than reportsfrom the medical profession.

86

United Kingdom

In early 1997, the Medicines Control Agency (MCA) extended their Adverse Drug Reactionmonitoring scheme to include herbal remedies. The Medical Toxicology Unit of Guy’s andSt. Thomas’ Hospital Trust also completed a 5-year project investigating adverse healtheffects arising from use of traditional remedies and dietary supplements around this time.MAFF (the Ministry of Agriculture, Fisheries and Food) reported that “overall the findingswere reassuring and do not indicate any significant health problems associated with mosttypes of traditional remedies and dietary supplements”. Chinese herbs and remedies fromthe Indian Sub-Continent were identified as main areas of concern.

UK companies generally record and investigate consumer reports of ADRs. Productinformation includes a referral to a doctor or pharmacist where untoward/unwanted effectsare experienced and this allows for verification and an “official” report to be made.

Reporters to the United Kingdom Yellow Card Scheme are doctors, dentists, coroners andhospital pharmacists, all of whom are able to provide details of the patient’s relevant medicalhistory. This is essential for effective assessment of suspected adverse reaction reports. Also,at present the United Kingdom is operating a Pilot Scheme for adverse reaction reporting bycommunity pharmacists.

87

Summary

The acceptance of consumer reports is summarised in the following table:

Country Accepted Remarks

Austria YesBelgium (Yes) Only if supported by a health professionalDenmark YesFinland NoFrance (No) Only in exceptional casesGermany YesGreece YesIreland NoItaly YesLuxembourg YesThe Netherlands (Yes) At present only if supported by a medical doctorPortugal Should be accepted but at present no reports are availableSpain NoSweden (Yes) Assessed differently than reports from the medical

professionUnited Kingdom Yes

Table 26: Acceptance of consumer reports

The degree of acceptance of reports obtained from consumers in the nationalpharmacovigilance systems varies from one country to another.

VII.6 Labelling and Advertising of Herbal MedicinalProducts

VII.6.1 Implementation of Council Directive 92/27/EEC into National LawCouncil Directive 92/27/EEC lays down the requirements for the label and the packageleaflet of medicinal products for human use. It has been implemented into national law byall EU Member States, and the details are summarised below.

88

Country National legislation Remarks

Austria 2nd amendment to the Medicines Law 1994 *1)Belgium Royal Decree of 31 December 1992 *2)Denmark Ministry of Health Order No. 314 of 18 May 1993Finland Administered Regulation 5/93France Decree 94-19 of 5 January 1994Germany 5th amendment to the Medicines LawGreece Ministerial Decree Y6a/776 [GR 4]Ireland Medical Preparations (Labelling and Package Leaflets)

Regulations 1993 (S.T. No. 71 of 1993)Italy Decreto legislativo No. 540 [I 11]Luxembourg *3)The Netherlands Decree on labels/leaflet *4)Portugal Decree No. 101/94 of 19 April 1994 *5)Spain Royal Decree of 2236/1993 of 17 December 1993

[SP 9]Sweden Medical Products Agency’s Provisions and Guidelines

on the Packaging and Labelling of Medicinal Products(LVFS 1995:11) [S 3]

United Kingdom The Medicines Labelling (Amendment) Regulations1992 (SI 1992/3273) [UK 6]; Medicines Leaflets(Amendment) Regulations 1992 (SI 1992/3274) [UK 7]

Table 27: Implementation of Council Directive 92/27/EEC

Notes:

1) Austria:Additional general statements concerning a product’s medical surroundings (“medizinischesUmfeld”) do not require special permission (“nicht genehmigungspflichtig”).

2) Belgium:The package leaflet must be written in the three national languages (Dutch, French andGerman). It must also be consumer-friendly in accordance with the Royal Decree of 7 April1995 on the information and advertising of medicinal products.

3) Luxembourg:The Division of Pharmacy and Medicinal Products mutually recognises the label and theleaflet of the original product. The language should be German or French. It is notmandatory to use both languages, but if both language versions are included, they should bestrictly similar in content.

4) The Netherlands:Before the decree took effect, package leaflets were only compulsory if the medicinal productwas marketed with an outer packaging. Otherwise, the compulsory details had to be includedon the container label. According to current Dutch labelling rules, manufacturers areobliged to mention all approved indications in the leaflet. However, in advertising to thegeneral public only indications suitable for self-medication may be mentioned. Inaccordance with the Directive, label and leaflet information must be drafted in consumer-friendly language. Pictograms may be used on labels and leaflets. All information must bein Dutch. Additional languages are allowed as long as the same information is given in al llanguages.

5) Portugal:The information required on the outer packaging, on the label of the primary packaging andin the patient information leaflet should be written in Portuguese, using language that i sclearly and easily understood. The information may also be provided, in parallel, in otherlanguages. The outer packaging may include symbols or pictures to help explain certainparts of the required information. The information must be in accordance with the summaryof product characteristics and should contribute to health education. Labelling and packageleaflets should not include any information of a promotional nature.

89

SummaryIt can be demonstrated that Council Directive 92/27/EEC on the labelling has beenimplemented by all Member States.

VII.6.2 Application of Council Directive 92/27/EEC to Herbal MedicinalProducts

National authorities were asked if Council Directive 92/27/EEC also applies to herbalmedicinal products. Their replies are summarised below.

Austria

The Medicines Law also applies to herbal medicinal products.

Belgium

As under the terms of the abridged licensing procedure the indication should be introducedby the statement “This herbal medicinal product is indicated in ….”, the medicinal productis always identified as a herbal medicinal product. Under the full application procedure,there is no specific requirement for herbal medicinal products. The labelling of herbal (non-medicinal) products should be reported to the Ministry of Public Health.

Denmark

The national legislation implementing Council Directive 92/27/EEC also applies to naturalremedies [DK 3]. Natural medicinal products must have the supplementary labelling“Natural Medicinal Product”. The labelling of natural remedies does not have to be reportedto the Danish Medicines Agency.

No specific rules apply to laxatives with plant ingredients apart from the fact that they mustbe labelled with a statement that they should not be used for more than one week.

Finland

Administrative Regulation 5/93 entered into force on 1 January 1994, as part of the EuropeanEconomic Area (EEA) harmonisation process. Applications for marketing authorisationssubmitted after that date had to include proposals for label and package leaflet texts. Thepackage leaflet should be in Finnish and Swedish. It should be written using clear languagethat is understandable to the consumer. Its information should be based on the approvedsummary of product characteristics. The outer package of a medicinal product must bear theindication(s) and normal dosage as well as any other necessary information. If themedicinal product is indicated for children, the dosage for children should also be shown.Products that have not been approved for use by children should be marked “Not forchildren”.

Regarding “old” herbal medicinal products, the implications of Council Directive 92/27/EECwill be taken into consideration at the time of renewal of the marketing authorisation. Thisprocess started in 1995 and is scheduled to be finished by 1999.

The text “Rohdosvalmiste - Naturmedel” (“natural remedy”) must always be included i nlabelling for herbal medicinal products.

There are no specific labelling requirements for certain products such as laxatives.

France

The package leaflet mentions the therapeutic class of the product. Herbal medicinal productsmention the herbal origin of the products or the fact that they belong to phytotherapy, althoughthis is not mandatory.

Germany

Council Directive 92/27/EC is applicable to all medicinal products, including herbalmedicinal products. Patient information leaflets are compulsory for newly registered

90

products. So-called “old” medicinal products must include a package leaflet one year afterre-registration. However, in practice, nearly all “old” medicinal products are alreadymarketed with leaflets and conform to the labelling requirements. If a medicinal product i smarketed without outer packaging, the leaflet may be omitted provided the requiredinformation is displayed on the label.

Greece

Ministerial Decree Y6a/776 [GR 4] is applicable to all medicinal products. Both inner andouter packaging (where they exist) should bear all information required by the relevant ECDirective. The information must be printed clearly and legibly in Greek, using languagethat is easily understood. For non-prescription medicinal products, the instructions for usemust appear on the outer and inner packaging. Special rules are included for smallpackages. The patient information may be printed in more than one language provided theyall convey the same information.

A patient leaflet is mandatory. The outer packaging and the leaflet may include symbols orpictures to explain certain parts of the required information in accordance with theSummary of Product Characteristics. This information should contribute to health educationand should not be of a promotional nature.

Ireland

As there are no specific guidelines on the labelling of herbal medicinal products, they wouldhave to be labelled in accordance with the regulations of the Medical Preparations(Labelling and Package Leaflets) Regulations, 1993 (S.I. No. 71 of 1993), and contain theappropriate patient information leaflet.

Italy

In case a herbal product is considered as a medicinal product according to Council Directive65/65/EEC and is registered as such, a leaflet which provides information on the indicationclaims, risks, dosage, etc. must be provided as laid down in Legislative Decree No. 540/92[I 11].

The Ministry of Health stresses the importance of developing package leaflets that uselanguage that is easily understood by patients and avoids the use of scientific terms(Circular of 8 April 1993). This requirement is valid for all medicinal products except thosedispensed by a hospital or directly by a specialist (Articles 9 and 10 of Legislative Decree of30 December 1992, No. 539 [I 12], implementing Council Directive 92/26/EEC).

Herbal medicinal products are presented in the leaflet as products of herbal origin. There i sno specific recommendation for the labelling of herbal medicinal products.

Luxembourg

As the Division of Pharmacy and Medicinal Products recognises marketing authorisationsissued by other Member States, the presentations on the market are those marketed in thecountry of origin. It is not compulsory to have specific labelling for herbal medicinalproducts such as “herbal medicinal product”, “natural medicinal product” or “naturalremedy”.

The Netherlands

The requirements are only applicable to authorised herbal medicinal products.

Portugal

The requirements are only applicable to authorised herbal medicinal products.

Spain

According to Royal Decree 2236/1993 of 17 December [SP 9] , which regulates the labellingand patient information for human medicinal products, it is not necessary for non-

91

prescription medicinal products to carry a patient information leaflet if all the compulsoryinformation is mentioned on the label. Royal Decree 1416/1994 of 25 June 1994 [SP 10] onpharmaceutical advertising lays down that non-prescription medicinal products containingactive ingredients included in a positive list established by the Directorate General ofPharmacy and Sanitary Products can be advertised to the general public. The labels of theseso-called Especialidades Farmacéuticas Publicitarias or EFP products should – after thenational code – include the main therapeutic indication, the statement “without prescription”and the word “EFP”.

Herbal medicinal products must comply with the legal requirements of Royal Decree2236/1993 [SP 9]. Specific labelling requirements for laxatives are given in Annex IV of thedraft Royal Decree [SP 1].

Phytotraditional products must include the following information: “phytotraditional product”(“producto fitotraditional”), qualitative and quantitative composition including excipients,method of application, name of the company responsible for marketing the product, batchnumber and expiry date. In addition, brand name, dosage form and content, warnings andrisks, dosage, oral or external use, maximum time of use, instructions for correct use, price,and country of origin must be mentioned. Information about the traditional use may beincluded if it has been authorised beforehand.

Sweden

The requirements for labelling are given in the Medical Products Agency (MPA)Provisions and guidelines on the packaging and labelling of medicinal products (LVFS1995:11) [S 3]. Proposals for the wording should be submitted to the MPA in conjunction withthe application for approval.

Pursuant to Section 4 Paragraph 2 of the Medical Products Act, a medicinal product mustgive a complete declaration of its composition, have an acceptable and distinguishable nameand be clearly labelled. According to Section 4 of the Medicines Ordinance (SFS 1992:1752)[S 4] the MPA may grant exemptions from the requirement to completely declare a product’scomposition.

Furthermore, the labelling must make it clear that the preparation has been approved forsale as a natural remedy with the wording “Natural remedy” on the pack. The indicationsstated for natural remedies must contain the following wording: “Traditionally used …” or,when applicable, be labelled with other wording prescribed by the MPA. Specific rules applyto laxatives regarding dosage limits and warning texts.

Detailed information for users (cf. the current consumer FASS, the Swedish list of approvedmedicinal products, entry for medicinal products) is to be enclosed with medicinal productsin the form of a separate package leaflet or, if there is room, as text on the package label. Inthe latter case, however, the text must not obscure the legibility of the other information on thepack.

These requirements are laid down in the MPA Provisions and guidelines on the packagingand labelling of medicinal products (LVFS 1995:11).

United Kingdom

The labelling requirements according to Council Directive 92/27/EEC are applicable to al lherbal medicinal products including those exempted from licensing.

Specific problems

In the following cases, specific problems with regard to herbal medicinal products havearisen. No information was available from any of the other national authorities.

Finland

Certain problems with regard to labelling have been encountered. For example, claims aremainly controlled by the Food Agency and some bad labels may slip through. There is noprior control of labels and only few infringements are detected.

92

United Kingdom

The major problem with the labelling of these products relates to the large amount ofpromotional material which companies attempt to introduce as “strap-lines” on the labelling.Council Directive 92/27/EEC prohibits the inclusion of extra-statutory information of apromotional nature.

Summary

In principle the national requirements on labelling (according to CouncilDirective 92/27/EEC) also apply to herbal medicinal products insofar as they havebeen authorised. No specific problems seem to occur except in cases where thereis no prior control of the labelling or where the manufacturer includespromotional material in the label.

VII.6.3 Implementation of Council Directive 92/28/EEC into National LawCouncil Directive 92/28/EEC regulates the advertising of medicinal products in the EuropeanUnion. It has been implemented into national law by the following regulations.

Austria

Council Directive 92/28/EEC has been implemented by the Second Amendment to theMedicines Law, which came into effect on 16 February 1994.

Belgium

Council Directive 92/28/EEC has been implemented by the Royal Decree (“Arrêté Royal”) of 7April 1995 on information and advertising of medicinal products for human use (“MoniteurBelge” of 12 May 1995) and by the Royal Decree of 11 January 1993 on product samples formedical doctors (“Moniteur Belge” of 30 January 1993).

The Royal Decree of 7 April 1995, which also regulates advertising to health professionals,came into force on 1 October 1995. The Advertising Control Commission, which operatesunder the auspices of the Ministry of Public Health, issues the visas that authorisebroadcasting of radio and television advertising spots. The visas are valid for two years.

Denmark

The Directive has been implemented by the Danish Ministry of Health Order No. 736 of 7August 1996 [DK 4].

Finland

The National Agency for Medicines (NAM) Administrative Regulation No. 3/97 regulatesthe advertising of medicinal products for human use. It also covers herbal medicinalproducts.

France

Council Directive 92/28/EEC has been implemented by Law No. 94-43 of 18 January 1994published on 19 January 1994 and by Decree No. 96-531 of 14 June 1996 (Journal Official de laRépublique française 16 June 1996), modifying Articles R 5045 to 5055-4 of the Public HealthCode (“Code de la Santé Publique”).

Germany

Council Directive 92/28/EEC has been implemented by the Fifth Amendment to theMedicines Law (AMG) published in the Federal Gazette of 16 August 1994, which entered intoforce on 17 August 1994.

93

Greece

Council Directive 92/28/EEC has been implemented by Ministerial Decree Y6a/776 [GR 4]which took effect in July 1993.

Ireland

Council Directive 92/28/EEC has been implemented via the Medical Preparations(Advertising) Regulations, 1993 (S.I. No 76 of 1993) and the Medical Preparations(Advertising) (Amendment) Regulations, 1996 (S.I. No. 308 of 1996). The Department ofHealth and the Irish Medicines Board (IMB) are in discussions on matters related toregulation and enforcement.

Italy

Council Directive 92/28/EEC has been implemented by the Law of 30 December 1992(Legislative Decree No. 541 [I 13], published in the Official Gazette of 11 January 1993). Itentered into force on 12 March 1993.

Luxembourg


The Netherlands

Council Directive 92/28/EEC has been implemented by the Decision of 31 October 1994 on therules concerning the advertising of medicinal products (Staatsblad 1994 787 of 15 November1994). The Decision officially took effect on 16 November 1994. Article 30 of the DutchMedicines Law will be amended to incorporate the self-regulatory system of advertisingcontrol.

Portugal

Council Directive 92/28/EEC has been implemented by Decree Law No. 100/94 of 19 April1994. It takes into account the dispositions of the Advertising Code approved by Decree LawNo. 330/90 of 23 October 1990, as amended by Decree Law No. 6/95 of 17 January 1995. OTCadvertising is allowed in all media.

Spain

According to Royal Decree 1416/1994 of 25 June 1994 [SP 10] on pharmaceutical advertising,only products containing active ingredients included in a positive list established by theDirectorate General of Pharmacy and Sanitary Products (the so-called EFP products) may beadvertised to the general public. EFP advertising is allowed in all media.

Sweden

Council Directive 92/28/EC has not been implemented in detail in Sweden, but it i sconsidered that its provisions are covered by the Marketing Act [S 5] and the MedicinalProducts Act [S 2].

United Kingdom

The Medicines (Advertising) Regulations 1994 (SI 1994/1932) [UK 8] together with theMedicines (Monitoring of Advertising) Regulation 1994 (SI 1994/1933) [UK 9] and theMedicines (Advertising) Amendment Regulations 1996 (SI 1996/1552) [UK 10] implementedCouncil Directive 92/28/EEC into UK law.

Summary

Council Directive 92/28/EEC on advertising has been implemented into nationallaw in all Member States.

94

VII.6.4 Application of Council Directive 92/28/EEC to Herbal MedicinalProducts

National authorities were asked whether Council Directive 92/28/EEC also applies to herbalmedicinal products. Their replies are summarised below.

Austria

The Medicines Law which also regulates pharmaceutical advertising is applied to herbalmedicinal products.

Belgium

The Royal Decree of 7 April 1995 explicitly forbids advertising that links the efficacy orsafety of a medicinal product to the fact that it is a natural substance. It is important to stressthat this limitation only pertains to medicinal products. Foodstuffs that are in accordancewith the Royal Decree (“Arrêté Royal”) of 29 August 1997 are not covered and are onlysubject to the general rules of consumer protection.

Denmark

The Danish Ministry of Health Order No. 736 implementing Council Directive 92/28/EECalso applies to natural remedies.

Finland

NAM’s Administrative Regulation 3/97 implementing Council Directive 92/28/EEC alsoapplies to herbal medicinal products.

France

The French pharmaceutical advertising regulations also apply to herbal medicinal products.Advertising of medicinal products to the general public is allowed in all media after a visahas been obtained from the French Medicines Agency (AdM). Reimbursable medicinalproducts, regardless of their legal status (non-prescription or prescription only), may not beadvertised to the general public. Herbal medicinal products are usually not reimbursed,although a few are.

Germany

Council Directive 92/28/EEC is applicable to all medicinal products, including herbalmedicinal products. OTC advertising to the general public is allowed for all non-prescription medicinal products (including reimbursed medicinal products) in all media.However, certain indications may not be advertised to the general public.

Greece

OTCs and herbal remedies may be advertised; however, the Greek Health Authority (EOF)has the right to ban the advertising of reimbursable products (Law 1965 Section 17). All publicadvertising must be submitted to EOF prior to publication. A post-publication monitoringsystem has already been established by EOF and an industry pre-vetting system is also i nforce. Advertising through the mass media should comply with the SPC or the patient leafletregarding safety, quality and efficacy. No medical information should be provided throughadvertising. According to the regulation of April 1994 [GR 1], the advertising of herbalmedicinal products is only allowed for non-prescription products using a text that has beenauthorised by the EOF. Advertising statements must be restricted to the summary of productcharacteristics that has been authorised by the EOF.

95

Ireland


Italy

The Ministry of Health in a Decree dated 16 April 1998 [I 17] has approved a Guideline on theadvertising of laxative products (i.e., herbal and non-herbal medicinal products). There is arequirement that explicitly forbids any advertising that would link the efficacy or safety of aherbal-based laxative medicinal product to the fact that it is a “natural” substance.

Luxembourg

Council Directive 92/28/EEC is applied to herbal medicinal products.

The Netherlands


Portugal

The Directive is only applicable to authorised herbal medicinal products.

Spain

The draft Royal Decree of 1997 [SP 1] also regulates the advertising of herbal medicinalproducts.

Sweden

The Marketing Act and the Medicines Act, which cover the advertising of all medicinalproducts, consequently also cover the advertising of natural remedies.

United Kingdom

The provisions of Council Directive 92/28/EEC are applied to herbal medicinal productsgranted marketing authorisation.

Specific problems:

The following specific conditions apply concerning the advertising of herbal medicinalproducts.

Austria

Health claims are permitted for “health products” after a licence has been granted by theFederal Ministry of Labour, Health and Social Affairs.

Finland

Food supplements or health products are not allowed to make medical or medicinal claims.Such advertising is regulated by the Food Act and controlled by the National FoodAdministration. Controlling illegal medicinal advertising of food supplements is a bigproblem for both the National Food Administration and National Agency for Medicines(NAM). Most of these products contain herbs but are not classified as herbal medicinalproducts because officially they are sold without medicinal claims. Most of them, however,are marketed illegally with medicinal claims.

96

Germany

According to Section 18 Article 1 Point 1 of the Law on Foodstuffs and Consumer Goods(LMBG), these products may not carry medical claims. There is therefore no category of“health products” in Germany. Furthermore, it is not permissible to use misleadingadvertising (Section 17 Paragraph 1 Point 5a (exaggerated claims) and 5c (foodstuffs beingpresented as medicinal products) of the LMBG).

Italy

The sale of so-called “miracle products” (i.e., products not registered as medicinal productsmaking medicinal claims) is not allowed. In the absence of a specific legal framework andthe existence of a control body, the Ministry of Health has no way of controlling theadvertising of such products. Control is delegated to local authorities and it is in practice upto competitors to denounce this kind of advertising on the basis of unfair competition.

The Netherlands

The Dutch medicinal products manufacturers’ associations Neprofarm, Nehoma, NPN andNefarma, in close co-operation, have drafted a general Code of Conduct based on the ECDirective. This code covers advertising to the public as well as to health professionals. Thesection on advertising to the general public, which stands alone (Code on Public Advertisingof Medicines), became effective on 1 January 1995.

OTC advertising (including advertising for reimbursed medicinal products) is allowed i nall media. However, only those indications suitable for self-medication can be mentioned i npublic advertising. A list of these indications is annexed to the Code on Public Advertisingof Medicines.

A reference to indications and contra-indications must be included in all mediaadvertising. In radio and television commercials, a recommendation to “read the outerpackage label before purchase” can replace the requirement to mention contra-indications.An invitation to read the leaflet before taking the product has to be included in all media.However, in cases where the outer packaging bears all instructions for use and aninvitation to read the leaflet before using the product, this obligation is fulfilled in thecommercial by the sentence “Read the outer packaging before purchase.”

The Code of Advertising for Health Products complementing the Code on Public Advertisingof Medicines (see above) also became effective on 1 January 1995. It clarified that medicinalclaims will only be allowed for medicinal products. An extensive list of claimsdistinguishing between health claims and medicinal claims is annexed to the code.

Sweden

As the system for using an approved SPC for a herbal medicinal product is rather new andthe text in the approved SPC, based on the documentation presented by the applicant, i susually short and concise, there have been some initial problems with the advertising ofapproved products.

United Kingdom

The United Kingdom does not have any particular problem with herbal medicinal productssubject to the advertising legislation in force. Section 12 of the Medicines Act sets out specificprovisions in relation to unlicensed herbal remedies.

Summary

Council Directive 92/28/EEC applies to herbal products as far as they areauthorised as medicinal products. Specific problems occur which are particularlydue to health products not licensed as medicinal products claiming “indications”which they are not allowed to claim.

97

VII.7 Distribution and Retail Sale of Herbal MedicinalProducts

VII.7.1 Good Distribution PracticeCouncil Directive 92/25/EEC and the Guideline on Good Distribution Practice (GDP)(Official Journal of the European Communities No. C 63 of 1 March 1994) lay down theprovisions for the wholesale distribution of medicinal products. These provisions are appliedto the distribution of herbal medicinal products in the Member States, as set out below.

Austria

The provisions apply to herbal medicinal products as well.

Belgium

Herbal medicinal products are distributed just like conventional medicinal products. Thereis no regulation for borderline products.

Denmark

Council Directive 92/25/EEC and the Guidelines on GDP apply to herbal medicinal products.A wholesale permission is required both for importing and stocking herbal medicinalproducts.

Finland

A wholesale permission is required for importing or stocking herbal medicinal products.

France

Herbal medicinal products are distributed like all other medicinal products.

Germany

The German system for wholesale distribution of medicinal products has been in line withCouncil Directive 92/25/EEC for years. Therefore, the adoption of the Community rules didnot introduce any problems concerning the distribution of medicinal products. Thedistribution system does not distinguish between herbal medicinal products and other, e.g.chemical-based, medicinal products.

Greece

Wholesale distribution is governed by Council Directive 92/25/EEC, which was implementedby Presidential Decree 194 in June 1995 [GR 5]. Distribution of herbal medicinal productsfollows the Directive.

Ireland

Council Directive 92/25/EEC is applicable to herbal medicinal products. However, the largeamount of unregulated activity might be a problem.

Italy

Council Directive 92/25/EEC was incorporated into Italian law with Legislative decree 30December 1992 No. 538 [I 14], published in G.U. of 11 January 1993. This legislative decreealso applies to herbal medicinal products, as they are not differentiated from othermedicinal products. With regard to GDP, a decree is in the pipeline. It should bring thisprinciple in line with Article 12 of Legislative Decree (“Decreto legislativo”) 538/92 [I 14].

98

Luxembourg

Council Directive 92/25/EEC is applied and has been implemented by the law governing thewholesale distribution of medicinal products of 6 January 1995 (“Loi du 06.01.1995 relative àla distribution en gros des médicaments”).

The Netherlands

Council Directive 92/25/EEC and the EC Guideline are applied uniformly to all of thevarious groups of medicinal products, including herbal medicinal products, regularmedicinal products and homeopathic medicinal products.

Portugal

The distribution of medicinal products is regulated by Decree Law No. 135/95 of 9 June 1995,which implements Council Directive 92/25/EEC but only applies to medicinal products forhuman use.

Spain

Council Directive 92/25/EEC is applied uniformly for all medicinal products.

Sweden

Wholesale permission is required for importing or stocking herbal medicinal products i nSweden.

United Kingdom

Council Directive 92/25/EEC has been implemented by SI 1971/972 Schedule 3(implementation) and SI 1993/833 and 1994/103. The Directive and the EC Guideline areapplied to all relevant medicinal products, including herbal medicinal products. Wholesaledistributors are required to hold Wholesale Dealer Licences and are inspected forcompliance with GDP.

Summary

Council Directive 92/25/EEC on the wholesale of medicinal products in principleapplies to all medicinal products and therefore also to all authorised herbalmedicinal products.

VII.7.2 Retail Sale of Herbal Medicinal ProductsAccording to information obtained from the national authorities, the retail sale of herbalmedicinal products is arranged as described below.

Austria

In principle, medicinal products, including herbal medicinal products, may only be sold i npharmacy. However, an exemption is given in Section 59 Paragraph 3 of the AustrianMedicines Law, which states that certain products that do not present any risk (e.g., teas)may also be sold in other outlets (e.g., drugstores) under a special licence. A list of theseproducts, many of which are medicinal plants, has been officially published in the so-called“Abgrenzungsverordnung” which contains descriptions of the medicinal plants, plant parts,wording for the indications and dosage recommendations [AT 4]. Self-service is notpermitted for medicinal products that are sold in pharmacies or in drugstores (“Drogerien,”“Gesundheitsläden”). No specific problems were reported.

Belgium

Herbal medicinal products, like all registered medicinal products, may only be sold i npharmacy. Self-service is not allowed. Parapharmaceutical products may also be sold i n

99

supermarkets and health shops and by mail-order companies. Foodstuffs may be soldanywhere.

Denmark

The retail sale of natural remedies is not limited to pharmacies. Retail sale does not requireauthorisation.

Finland

Distribution of herbal medicinal products can be restricted in the marketing authorisation topharmacies only. If there is no restriction recorded in the marketing authorisation, herbalmedicinal products may also be sold in ordinary shops. In the case of a pharmacy onlyrestriction, this is controlled by local food authorities in Finland. The efficacy of theseinspections is, however, a bit doubtful.

France

All medicinal products are sold exclusively in pharmacy.

Herbal medicinal products are normally sold in pharmacies. Certain qualified herbalists(“herboristes diplômés”) (Article L.659 of the CSP) are also allowed to sell medicinal plants.However, the last herbalist diploma was granted in 1941 and only a few qualified herbalistsare still practising. Herbalists may not hold or sell medicinal plants that are on the list ofpoisonous substances and pharmacists may only dispense these plants on prescription.Herbalists are not authorised to sell combinations prepared in advance except thoseauthorised by the Decree of 7 April 1943 and modified by the Ministerial Decree (“Arrêtéministériel”) of 27 January 1959 [F 1].

Germany

Herbal medicinal products are distributed in pharmacies as well as in certain other retailoutlets. The Medicines Law provides as a general rule that medicinal products are sold i npharmacies. Exceptions are made for medicinal products that:

1. are marketed exclusively for purposes other than curing or alleviating illness,injuries, aches or pains (Section 44 Paragraph 1) and

2. contain specific substances without risk (Section 44 Paragraph 2 and specificOrdinance according to Section 45 of the Medicines Law).

In retail outlets other than pharmacies, a qualified member of the staff must be presentduring sale.

Except for a few preparations, herbal medicinal products are not prescription-bound. Inprinciple, herbal medicinal products are reimbursable by the health insurance systemunless general criteria for exemption are applicable. These criteria include specifiedindications (e.g., common cold or laxatives) or substances (e.g., those with a negativeassessment by Commission E).

Greece

Distribution of all medicinal products (prescription or non-prescription) is only permitted i npharmacy [GR 6]. The sale of herbal medicinal products and food supplements is alsorestricted to pharmacy. In remote areas, local doctors or Health Centres may distributemedicinal products after obtaining special permission from the Greek Health Authority(EOF).

Ireland

Non-prescription medicinal products can be sold in pharmacies and a limited number ofproducts (e.g., aspirin, vitamins, paracetamol and simple cough bottles) can be sold in non-pharmacy outlets. Herbal products not registered as medicinal products can be soldanywhere (e.g., in pharmacies, drugstores, department stores and health food shops).

100

Italy

The sale of medicinal products, including herbal medicinal products, is restricted topharmacy. Pharmacies are subject to control from the Ministry of Health. Self-service is notpermitted.

Dietetic products and food supplements can be sold outside pharmacies, although theynormally use pharmacy distribution. Those (non-medicinal) herbal products classified asfood are allowed to be sold outside pharmacies, in so-called herbal shops (“erboristerie”). Theherbalist (“erborista”) is the responsible person for the herbal shop (“erboristeria”) and maygive recommendations on the use of herbal products. The herbalist is not allowed torecommend herbal products for a therapeutic use or to present them with a therapeutic claim.The herbalist may sell herbal products that are not pharmacy-bound. However, thesemixtures must be prepared at the client’s request and may not be made up in advance. Auniversity course leading to a diploma in techniques in the medicinal herbs sector (“Corsodi diploma in techniche erboristiche”) was introduced in 1995 [I 19]. These technical coursesare held in a few Italian universities and are usually split between the Faculty of Pharmacyand the Faculty of Agriculture. Prior to this date, the only title that existed since the 1930swas the diploma of herbalist.

Herbal products making therapeutic claims, having a particular pharmaceutical activity orthat might be toxic are considered as medicinal products and are only allowed to be soldthrough pharmacies.

Mixtures of herbs with therapeutic indications (e.g., herbal teas or similar preparations)must be registered as medicinal products. They can only be sold by a pharmacist in apharmacy. The herbalist is not allowed to sell medicinal plants for therapeutic purposes,whereas the pharmacist is allowed to prepare and sell mixtures of medicinal plants to thepublic. Such mixtures may be prepared before the sale if they are reported in the ItalianPharmacopoeia, or they can be prepared for a patient on the spot according to a prescriptionfrom a medical doctor.

Luxembourg

All medicinal products are to be sold to the public in pharmacies.

The Netherlands

Non-prescription medicinal products (herbals and others) can be sold through pharmaciesand druggists. Prescription-only medicinal products may only be sold through pharmacieson a prescription from a medical doctor. Herbal products that are not registered asmedicinal products may be sold in pharmacies, drugstores, department stores, health shops,etc.

Portugal

The sale of medicinal products is restricted to pharmacies. Herbal products may be sold i nsupermarkets and herbal stores. Authorised herbal medicinal products however are sold i npharmacies only.

Spain

Medicinal products (including herbal medicinal products) may only be sold in pharmacy.Article 42.3 of the Spanish Medicines Law [SP 2] states that plants traditionally consideredas medicinal plants, offered without reference to therapeutic, diagnostic or preventiveproperties, may be freely sold to the public; however, door-to-door sale is not permitted.

According to the draft Royal Decree of 1997 [SP 1], phytotraditional products may be soldoutside pharmacy under the following conditions:

— the plants must be included in Annex I;

— they must be solely marketed with information related to their traditional use in theEuropean Union and bear the term “phytotraditional product” (“productofitotraditional”);

— they are used solely for oral or topical application;

101

— there is no need for particular measures to guarantee the safety of use, except thoserelated to their handling, manufacture or packaging.

Sweden

The retail sale of herbal medicinal products is unrestricted; there are no regulations in thisarea.

United Kingdom

Herbal products are supplied by retail, both inside and outside pharmacies, in accordancewith the usual rules for supplying medicinal products to the public. Under Council Directive92/26/EEC and the Medicines Act 1968 [UK 1], medicinal products are classified as GeneralSale List (GSL), Pharmacy (P) or Prescription Only Medicines (POM). POM and Pmedicinal products can be sold or supplied only from pharmacies, by or under thesupervision of a pharmacist and, in the case of POMs, against a prescription. GSLmedicinal products can be supplied outside pharmacies as long as they are in amanufacturer’s sealed pack and supplied from lockable premises. In practice, GSL productsare sold mainly from grocery outlets, drug stores and health food shops.

In addition, under the Medicines Act 1968 and the Retail Sale or Supply of Herbal RemediesOrder [UK 5], unprocessed exempt herbal remedies without claims can be sold outsidepharmacies from lockable premises without being supplied in a sealed manufacturer’s pack.Medicinal plants listed in Part I of the Schedule to the Order can only be supplied through apharmacy. Medicinal plants listed in Part II and Part III of the Schedule may be supplied bypractitioners for administration to a particular person following a personal consultation,and otherwise only through a pharmacy.

Summary

The following table shows the possibilities for retail sale of non-prescriptionbound herbal medicinal products in the Member States.

Country Pharmacies Otheroutlets

Remarks

Austria Yes Yes See “Abgrenzungsverordnung”Belgium Yes NoDenmark Yes YesFinland Yes YesFrance Yes NoGermany Yes Yes See Sections 44, 45 of the Medicines

LawGreece Yes NoIreland Yes NoItaly Yes NoLuxembourg Yes NoThe Netherlands Yes YesPortugal Yes NoSpain Yes NoSweden Yes YesUnited Kingdom Yes Yes See: General Sales List

Table 28: Retail sale of herbal medicinal products

VII.7.3 Distance Selling and TeleshoppingIn many Member States, distance selling and teleshopping are forbidden in the supply ofherbal medicinal products. However, in several cases it is allowed under certain conditions:

102

Country Status of distance selling Status of teleshopping

Austria Not permitted Not permittedBelgium Not permitted Not permittedDenmark Allowed AllowedFinland Allowed for pharmacies Not permittedFrance Not permitted Not permittedGermany Allowed for non-pharmacy-

bound productsNot permitted

Greece Not permitted Not permittedIreland Not permitted Not permittedItaly Not permitted Not permittedLuxembourg Not used Not usedThe Netherlands Allowed *1) Not used *1)Portugal Not permitted Not permittedSpain Not permitted Not permittedSweden Allowed AllowedUnited Kingdom *2) *2)

Table 29: Distance selling and teleshopping

Notes:

1) The Netherlands:Some health insurers in the Netherlands have begun dispatching prescribed medication bymail. This has led to concern in pharmacy circles. One company (James Telesuper) sellsOTCs by mail catalogue. This practice is legal because OTCs can officially be supplied by adruggist. Druggists are currently requesting the right to dispense prescribed OTCs.Teleshopping of non-prescription medicinal products is not found in the Netherlands.

2) United Kingdom:The Medicines Control Agency (MCA) is not aware of evidence of supply by teleshopping. Itis aware of some supply of herbal medicinal products by mail order and is consideringwhether there is a need to clarify the legal position.

Summary

It can be concluded that both distance selling and teleshopping are not permittedfor herbal medicinal products in most countries; in several cases however they areallowed under certain conditions.

103

VIII. CONCLUSIONS AND RECOMMENDATIONSCouncil Directive 65/65/EEC defines the basic criteria for medicinal products. Herbalpreparations are considered as medicinal products if they meet the definition of thisDirective. Herbal medicinal products can be found in all Member States of the EuropeanUnion although the relative size of their markets varies considerably. According to CouncilDirective 65/65/EEC, herbal medicinal products – like all other medicinal products – need toobtain a marketing authorisation before they can be placed on the market. This guarantees ahigh level of consumer protection through the fact that proof of quality, safety and efficacyhas to be provided.

The Ad hoc Working Group on Herbal Medicinal Products established in 1997 at theEuropean Agency for the Evaluation of Medicinal Products (EMEA) has carried out acomprehensive review of existing guidelines and updated/adapted them to the particularneeds of herbal medicinal products. This work is highly appreciated by all parties involvedbecause it helps to provide specific guidance in the assessment of the quality, safety andefficacy of herbal medicinal products. It is therefore recommended to strengthen the Ad hocWorking Group. This should help to further develop and update guidelines to clarify thesituation for herbal medicinal products, with the final objective of allowing their freecirculation throughout the European Union. This work should also include the verification ofmonographs proposed by the European Scientific Co-operative on Phytotherapy (ESCOP) andthe World Health Organisation (WHO) in order to come to generally accepted EuropeanSummaries of Product Characteristics for widely used medicinal plants. To carry out thiswork, it would seem appropriate to endow the Ad hoc Working Group on Herbal MedicinalProducts with an enlarged budget and an improved infrastructure. Consideration shouldalso be given to turning the Ad Hoc Working Group into a committee with a permanentstructure, and eventually into a Committee on Herbal Medicinal Products (CHMP) whichwould co-ordinate the assessment of herbal medicinal products within the EMEA andconsequently for the European Union.

Although herbal medicinal products are covered by the requirements of Council Directive65/65/EEC, several EU Member States seem to face problems in applying identical rules toall medicinal products in a uniform manner. It is therefore recommended that someclarification of Council Directive 75/318/EEC be incorporated into the existing EC legislationon pharmaceuticals for those herbal medicinal products which are safe, of appropriatequality and whose indications are exclusively based on adequate proof of efficacy throughdocumented traditional use. This might include the incorporation of a statement relating tothis traditional use in the approved indication, e.g. in the form of a prefix. In this way,communication on such medicines would become identifiable, e.g. through the label/leafletand through advertising.

104

IX. LEGAL REQUIREMENTS AND THE ASSESSMENT OFHERBAL MEDICINAL PRODUCTS IN NORTH ANDCENTRAL AMERICA

It was regarded as useful for this study also to collect information for the countries of theNorth American Free Trade Agreement (NAFTA). In light of the efforts to establish aTransatlantic Market Place and a Transatlantic Partnership there have been debates on thefree movement of herbal medicinal products on both sides of the Atlantic. The informationon Canada, Mexico and the United States of America therefore seems to be useful in thecontext of this study.

IX.1 CanadaNote:

These answers are based on the regulatory environment in Canada as of August 1998. Itshould however be noted that the Standing Committee on Health, a parliamentary committee,has been studying the regulatory situation of natural health products in Canada sinceDecember 1997. This Committee is scheduled to report its recommendations, including a newregulatory framework for these products, by the autumn of 1998. It is expected that significantchanges to the current regime will occur as a result. Some of the issues being consideredinclude a definition for natural health products, implementation of a post-marketnotification system for low-risk products (involving attestation to monographs or standards),labelling requirements including permitted health claims (structure/function, riskreduction and treatment claims), as well as quality, safety and efficacy issues.

IX.1.1 Classification of herbal medicinal products

a) How are herbal medicinal products defined in your country and whichproducts containing plants are not classified as medicinal products? What are thecriteria for classification as a medicine (e.g., by function or presentation or both)?

Currently there is no definition for herbal medicinal products in Canada. (This is one of theissues being reviewed by the Standing Committee on Health.)

Under existing regulations, a plant product is classified as either a food or a drug dependingon whether or not it makes a therapeutic claim. According to the Food and Drugs Act, a“drug” includes any substance or mixture of substances manufactured, sold or representedfor use in the:

(a) diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormalphysical state, or its symptoms, in human beings or animals;

(b) restoring, correcting or modifying organic function in human beings or animals; or

(c) disinfecting of premises in which food is manufactured, prepared or kept.

According to this Act, a “food” is defined as any article manufactured, sold or representedfor use as a food or drink for human beings, chewing gum, and any ingredient that may bemixed with food for any purpose. In general, if a plant product does not make a therapeuticclaim according to the drug definition, it is classified as a food and subject to foodregulations. If it does make a therapeutic claim, however, it is classified as a drug productand subject to drug regulations.

The herbal ingredient which is appropriate as a food (e.g., certain herbal teas and candies)can be consumed more or less as desired because of the absence of pharmacologicalproperties which might produce side effects. When a herbal ingredient possessespharmacological activity which leads to its use as a remedy – and, in fact, makes its use asa remedy more appropriate than as simply another article in the diet – then it is regulated asa drug product in exactly the same way as non-herbal ingredients would be treated undersimilar circumstances. For example, proper labelling is required so that the consumer mayselect and use the product wisely.

In addition, a plant product may also be classified as a narcotic or controlled substanceunder the Controlled Drugs and Substances Act and would not be available to consumersexcept under special circumstances. Plants or plant materials that are scheduled under theAct are: Cannabis (marijuana), Opium poppy (opium), Catha edulis (Khat) and Psilocybin

105

(magic mushrooms). Also, legislation is currently in place to control the import and exportof ephedrine and pseudoephedrine.

Although there is no actual definition for herbal medicinal products to date, the TherapeuticProducts Programme (TPP) [CAN 1] has determined that “natural health products” willinclude the following: homeopathic drugs; vitamins and minerals which meet therequirements of a class monograph; drugs that contain a plant, mineral or animalsubstance for which therapeutic activity or disease prevention activity is claimed, includingtraditional herbal medicinal products, traditional Chinese medicinal products, ayurvedic(East Indian) medicinal products and traditional aboriginal (North American) medicinalproducts where the medical use is based solely on historical and ethnological evidence fromreferences to a medical system other than conventional scientific standards.

b ) Is there a specific category for herbal medicinal products that have notherapeutic claim?

At present, there is no specific category for herbal medicinal products without therapeuticclaim. These products are simply classified as foods.

c ) Is there a specific category for herbal medicinal products containing well-known plants?

There is no specific category for herbal medicinal products containing well-known plants.Again, these products would either be classified as drugs or as foods, depending on whether atherapeutic claim was made.

d) Is there a specific category for traditionally used herbal medicinal products(e.g., in the treatment of certain indications)?

Within the drug category, there is a separate Directorate Guideline and Policy Issues forTraditional Herbal Medicines (THM) [CAN 2, CAN 3]. According to these documents, a“Traditional Herbal Medicine” refers to finished drug products intended for self-medicationthat contain, as active principles, herbal ingredients that have received relatively littleattention in world scientific literature, but for which traditional or folkloric use is well-documented in herbal references. THMs may contain chemically-defined or herbal-basedexcipients in addition to the active ingredients. These products must be identified on thelabel as a Traditional Herbal Medicine and usually include the statement “traditionalherbal medicine used for …”.

e ) Are there “combination products” on the market, including combinations withhomeopathics, food supplements, vitamins, amino acids, etc.? How do theauthorities assess these products?

Yes, there are “combination products” on the market in Canada. There are a number ofdifferent ways in which “combination products” are assessed:

(a) Combinations with food (i.e., non-medicinal) ingredients are accepted, provided thatthe product is not represented in a misleading manner. Combination products whichdo not make therapeutic claims are assessed as foods and are subject to the appropriatefood regulations.

(b) Traditional herbal combination products with therapeutic claims are assessed as drugsunder the guideline for traditional herbal medicinal products [CAN 2]. Under theseguidelines, combination products are permitted although illogical combinations ofherbs — that is, combinations that would be expected to exert several effects (e.g., thoseof diuretics and laxatives) or contradictory effects (e.g., laxatives and astringents) —are questionable. Herbal combination products which do not meet the criteria set out i nthis guideline are considered to be “new drugs” and subject to the requirements ofDivision 8 of the Food and Drug Regulations, as are pharmaceutical drugs.

(c) Combinations of herbs with vitamins or minerals are not prohibited. However,sponsors of such submissions are required to provide an appropriate rationale to justifythe combination of ingredients in terms of the indications for use, dosage anddirections for use. (For example, laxative herbal ingredients could prevent theabsorption of vitamins and/or minerals present in the product, and while vitamins

106

and minerals may be recommended for daily use, laxatives should only berecommended for occasional use.) No such combinations with herbs and vitamins orminerals have been authorised for sale so far.

(d) Very few amino acids have been accepted for use as medicinal ingredients.Tryptophan and arginine are restricted to prescription only and a few others requiresubmission of a New Drug Application to establish safety and efficacy.

(e) Homeopathic ingredients in homeopathic dilutions are not acceptable in combinationwith other types of products, such as herbals, vitamins, minerals, etc. Suchcombinations are not compatible with the principles applicable to homeopathicpreparations.

A separate guideline exists for homeopathic preparations [CAN 4]. According to thisguideline, the term homeopathic preparation applies to any drug that is composed only of oneor more ingredients for which a homeopathic monograph is defined in the current edition ofthe Homeopathic Pharmacopoeia of the United States (HPUS), the Pharmacopée française(Ph.F.) or the Homöopathische Arzneibuch (HAB) (the German HomeopathicPharmacopoeia). Furthermore, the homeopathic preparation must be prepared in accordancewith the procedures prescribed by and offered for sale in a dosage form defined in one ofthese compendia. The labelling of homeopathic products must make reference only to theclassification of the product as a homeopathic preparation. In addition, a statement that theproduct is “to be used as directed by a physician” or “to be used as directed by a homeopathicpractitioner” must be included on the label.

A manufacturer may submit a homeopathic application in one of two ways:

1. They may submit an application under the Labelling Standard for HomeopathicPreparations, which does not permit any therapeutic claims, explicit or implied.

2. They may submit an application under the Policy Issues: Indications for Use - Multi-ingredient Low Dilution Homeopathic Preparations [CAN 5, CAN 6]. This policypermits therapeutic claims based on traditional homeopathic references. Thehomeopathic preparation must have at least two ingredients and the concentration maynot be more dilute than 8CH.

As with traditional herbal medicinal products, homeopathic preparations that do not meet thecriteria defined in the guideline are considered as “new drugs” and are subject to therequirements of Division 8 of the Food and Drug Regulations.

f ) Are there modern herbal medicinal products on the market that have beenfurther developed from their traditional use (e.g., highly processed, new indications,new pharmaceutical form, etc.)? Are there herbal medicinal products approvedand sold as OTC drugs?

Yes, there are modern herbal products on the market that have been further developed fromtheir traditional use. Examples of such plant-based prescription drugs include Taxol,vincristine and estrogens from plant sources.

There are also herbal products approved and sold as OTC drugs in Canada. In fact, sincetraditional herbal medicinal products are considered to be drugs and can only be sold forself-medication purposes, many herbal medicinal products are sold as OTC drugs i nCanada. In addition, products such as senna and sennosides, which are listed i nconventional pharmacopoeias (e.g., USP and BP), are sold as OTC drugs.

With the exception of Taxol and a product called Ginsana (trade name), which containsstandardised ginsennosides to assist in recuperation from long periods of inactivityfollowing an illness and to help hand/eye co-ordination when inhibited in the elderly, thereare no recent new uses of herbal substances.

IX.1.2 Application of the Food & Drugs Act to herbal medicinal products

a) What is the legal basis for marketing authorisation of medicinal products, andis this legislation also applicable to herbal medicinal products?

There are a number of laws governing medicinal products. One of the most significant i sthe Food and Drugs Act. The Act prohibits the sale of any food or drug that has beenadulterated or represented in a manner that is false, misleading or deceptive. The scope of

107

the Act is focused on safe and nutritious foods and the safety and effectiveness of drugs andmedical devices. The resulting Food and Drugs Regulations contain detailed requirements,standards and rules relating to the pre-market review and approval of drugs and medicaldevices as well as requirements for post-market surveillance.

This legislation applies to herbal medicinal products as well. The definition of the term“drug” in the Act brings herbal products intended for therapeutic purposes under the generalrequirements of the legislation, including the requirement to obtain marketingauthorisation.

b ) What are the requirements for marketing authorisation of herbal medicinalproducts in your country? (Or, if they are not authorised prior to marketing: How ismarketing of herbal medicinal products regulated in your country?)

Herbal medicinal products offered for sale to treat, prevent, mitigate or cure diseases orconditions, or marketed for their pharmacological activity, are regulated as drugs under theFood and Drugs Act and Regulations. All drug products intended to be sold in Canada arerequired by regulation to undergo a pre-market assessment. This assessment focuses on theefficacy, safety, quality and labelling of the product.

In order to obtain approval to market a product, manufacturers and/or distributors mustobtain a product license or Drug Identification Number (DIN) to provide assurances of safetyand efficacy. Application for a DIN includes: submission of a draft of the proposed Canadianproduct labelling (this includes inner and outer labels, package inserts and prescribinginformation when applicable); a list of references supporting any claims or indicationsmade on the label (or reference to a standardised drug monograph, if available); a list ofreferences supporting the safety of the product; etc. Once approval has been granted, themanufacturer must notify the Therapeutic Products Programme within 30 days of the date aproduct is first sold in Canada. Manufacturers must also verify annually the market statusof all drugs for which they hold Drug Identification Numbers.

All drug products, including herbal medicinal products, must be manufactured according toGood Manufacturing Practice (GMP) guidelines to provide assurance of quality.Furthermore, all manufacturers of drug products are required to hold an establishmentlicence indicating that manufacturing is conducted in compliance with GMP regulations.(Manufacturers of natural health products are currently exempt from holding establishmentlicences while the Standing Committee on Health reviews the regulatory situation of theseproducts in Canada.)

c ) Does your country have any specific provisions for the regulation of well-known herbal medicinal products?

No, Canada does not have any specific provisions for the regulation of well-known herbalmedicinal products.

d) What are the scientific standards required for safety and efficacy of herbalmedicinal products? Are manufacturers required to refer to published scientificliterature and/or expert reports in their applications for marketing authorisationfor their herbal medicinal products?

Herbal medicinal products sold as drugs must meet the same scientific standards as othernon-prescription drugs. The requirements depend on the amount of information availablefor the product ingredients. When an ingredient is well known for a specific non-prescription use, the pre-market assessment is limited to a sponsor’s attestation to apublished monograph standard. Known ingredients without monograph standards areassessed based on published data (including traditional references). A well-knowningredient for a new use will require a new clinical data package, and possibly new orexpanded safety data. A new ingredient will require a full clinical, safety, and formulationquality data package.

A manufacturer who wishes to submit an application for a traditional herbal medicinalproduct, must submit traditional references that support the indications for use as well as thedosages, provided there is no recent evidence of toxicity. Scientific studies will not beaccepted as references for traditional herbal medicinal products. If a sponsor wishes to

108

submit clinical studies and other scientific data, the application must be filed as a New DrugSubmission, as per Division 8 of the Food and Drug Regulations.

e ) Does your country relax the requirements for proof of efficacy for certainindications, or where the indications refer to the “traditional use” of the product?

For traditional herbal medicinal products, special guidelines have been established. Ingeneral, references must still be submitted supporting the claims and indications made bythe product as well as the safety of the product; however, there is flexibility in the types ofsupporting references acceptable to the Health Protection Branch for market authorisation.THM products undergoing a drug product assessment must include photocopies of at leasttwo traditional herbal references for each herbal ingredient and the herbal monographindicating the reputed pharmacological action(s)/therapeutic use(s) for the part of the plantused and the dosage for the part of the plant used, the form and its indication for use.

f ) When assessing and reviewing herbal medicinal products, does your countrynow use any of the following references? Does your country intend to use any o fthese references?

• the monographs of the European Pharmacopoeia• the monographs of the European Scientific Co-operative for Phytotherapy

(ESCOP)• the WHO Model Monographs• the “WHO Guidelines on the Assessment of Herbal Medicines”

All of these references are acceptable for use in assessing and reviewing herbal medicinalproducts in Canada. In addition, the British Pharmacopoeia as well as the United StatesPharmacopoeia are acceptable as references. An Expert Advisory Committee onComplementary Medicine is currently reviewing a number of different pharmacopoeias onherbal medicinal products as well as developing monographs specific to Canada.

Although the references listed are not necessarily documents that would provide support forindications or that would be restricted to indications appropriate for self-medication, theymay be used for other purposes. For example, the WHO Guidelines on the Assessment ofHerbal Medicines have been used as a model for a GMP document for herbal preparations.

g) What are the requirements for marketing authorisation of combinations o fseveral herbal ingredients?

The requirements for combinations of several herbal ingredients are similar to those forsingle herbal ingredients. Two traditional references supporting the indication/therapeuticuse, part of the plant used, dosage for the part of the plant used, the dosage form and the dailyand single dose must be supplied.

There are no special requirements for combinations of several herbal ingredients; eachherbal ingredient and dosage is assessed independently. Like acting herbs are considered tohave an additive effect. The intended use of each ingredient must support a logical use of thecombination in question. Illogical combinations of herbs (e.g., combinations that containone ingredient used as a diuretic and a second ingredient used as a laxative) would bequestionable.

h) How does your country treat herbal medicinal products that are made upand/or supplied to individual patients following a one-to-one consultation betweenthe patient and the practitioner?

The legislation applies to products offered for general sale, not for extemporaneouscompounding and dispensing.

109

i) How does your country regulate intermediate products of herbal origin thatare intended for further processing by an authorised manufacturer or for thepreparation of a magisterial or an officinal formula?

See answer to point IX.1.3 b) below.

j ) How does your country assess the safety and efficacy of plants which are notnative to North America or Europe and have not been subjected to extensive oraccessible scientific research (e.g. some of the Chinese or South American herbs)?

Traditional herbal references must be submitted that support the indication/therapeutic use,part of the plant used, dosage for the part of the plant used, the dosage form and the daily andsingle dose. Illogical combinations of herbs (e.g., combinations that contain one ingredientused as a diuretic and a second ingredient used as a laxative) would be questionable.

k ) How many herbal medicinal products are authorised in your country? Whatare the major ingredients and indications?

The Therapeutic Products Programme (TPP) has been issued Drug Identification Numbersfor numerous herbal products for several years. The products are for OTC self-medicating,self-limiting conditions.

IX.1.3 Application of Good Manufacturing Practices to herbal medicinalproducts

a) Does your country apply Good Manufacturing Practices requirements toherbal medicinal products?

Herbal products making no therapeutic claims are classified as foods and are thereforesubject to voluntary food guidelines for good manufacturing practices. Herbal productsmaking therapeutic claims are considered as drugs and are subject to the same goodmanufacturing practices as other drug products. For the latter, the requirements areprescribed by Division 2, Part C of the Regulations to the Food and Drugs Act. SupplementaryGuidelines for the Manufacture of Herbal Medicinal Products [CAN 7], based on W H Oguidelines, have also been developed which provide further guidance appropriate for theseproducts.

b ) How does your country’s control of the starting (raw) material of herbalmedicinal products compare with the standards of the European Pharmacopoeia?

The regulation of herbal medicinal products as drug products is in its infancy in Canadaand regulations are still being developed for these products. Currently, there is onlycertification by the manufacturer that the raw materials have been tested and meet theappropriate GMP standards. Drug manufacturers must ensure that raw materials meetappropriate standards. GMP standards for Active Pharmaceutical Ingredients, based oninternational standards, are under consideration but may require regulatory changes.

c ) Are GMP inspections carried out in your country and in third countries thatare exporting herbal medicinal products or raw material to Canada?

GMP inspections can be carried out in third countries but this is not a common practice.Foreign sites must demonstrate GMP compliance. The importer is required to demonstratethat the site meets GMP standards equivalent to Canada’s. This can be demonstrated bycorporate audits or inspections conducted by the foreign regulatory authority.

Although manufacturers of natural health products are currently exempt from establishmentlicences, they are required to have a GMP inspection prior to obtaining a Drug IdentificationNumber.

110

IX.1.4 Post-marketing surveillance

a) Do the adverse reaction reporting systems in your country also monitor herbalmedicinal products? Have there been reports of adverse reactions that have led towithdrawal of herbal medicinal products from the market? Are you aware of casesof herbal medicinal products that have been withdrawn from the market in aEuropean Union Member State and have continued to be sold, after thewithdrawal, in Canada?

The adverse drug reaction (ADR) reporting systems in Canada also monitor herbalmedicinal products. Although the current ADR system was initially intended to monitor newactive substances (prescription drugs), potentially all drug ADRs can be reported to thesystem. At this time, the system has little information on herbal products, which areprimarily used without the knowledge of practitioners who actively participate in the ADRsystem.

Withdrawal of herbal products from the Canadian market has occurred as a result ofadverse reactions reported in other countries. Examples include chaparral, germander,Stephania tetrandra, Magnolia officinalis, Acorus calamus and comfrey as well as plantscontaining echimidine.

As a result of adverse reactions reported in the United States, the product ephedra was notwithdrawn from the market but regulatory requirements continue to apply, dosage andindications are restricted and labelling cautions are required.

b ) Should reports from consumers be accepted in order to more completelyrepresent the spectrum of adverse reactions to herbal medicinal products?

Consumer reports on products should be critically assessed and compiled as an adverse drugreaction (ADR) only if they appear to be truly product-related. The ADR system is part of alarger Continuing Assessment/Post-Market Surveillance program that is currently underdevelopment. Consumer reporting on non-prescription drug products is one of the topics beingconsidered.

IX.1.5 Labelling and advertising of herbal medicinal products

a) How are labelling and package leaflets of herbal medicinal productsregulated in your country? Do you have any specific problems with regard to thelabelling and package leaflets of herbal medicinal products?

Herbal products classified as foods may make no therapeutic claim. Likewise, promotionalliterature provided by the manufacture may not make or infer a therapeutic claim.

Herbal products classified as drugs must submit a draft of the proposed Canadian productlabelling (this includes inner and outer labels, package inserts and prescribinginformation when applicable) for pre-market approval at the time of application for a DIN.Strict guidelines apply but in general, as with all drugs, the product may not include on itslabel or packaging any reference to an unapproved therapeutic claim.

Yes, there are problems with the labelling and package leaflets of herbal products,particularly for food products where there is currently no pre-market approval. There areproducts currently on the market with labels and/or package inserts that list or inferunapproved therapeutic claims. Also, although manufacturers are not permitted to provideliterature on their products for unapproved therapeutic claims, these often appear on displaysor leaflets.

b ) How is the advertising of herbal medicinal products regulated in yourcountry? Do you have any specific problems with regard to the advertising o fherbal medicinal products?

The Food & Drugs Act (the Act) regulates the advertising of food and drug products. The Actprohibits misleading advertising and advertising to the general public of those productsintended for diseases listed in Schedule A (these are considered to be disease states whichrequire practitioner intervention).

111

Herbal medicinal products regulated as drugs are subject to voluntary pre-clearance by athird party. Advertising is not permitted for unapproved claims or claims that are not in thelabelling standard. Herbal medicinal products that are regulated as foods are also subject tovoluntary guidelines for advertising of these products.

IX.1.6 Distributions and retail sale of herbal medicinal products

a) How is the wholesale distribution of herbal medicinal products regulated inyour country? What kinds of problems arise in this respect?

Importers, fabricators, packagers, distributors (name on label), testers and wholesalers(name not on label) must all obtain an establishment licence to conduct these drug relatedactivities in Canada. Maintenance of a license is subject to compliance with the GMP andother drug regulations. Wholesale distributors are subject only to limited GMP requirementssuch as the maintenance of a recall system. At the present time, however, since theregulation of herbal medicinal products is currently under review in Canada,establishments dealing in these products are not subject to these licensing requirements,pending the outcome of the review process. They are, however, still subject to the appropriateGMP requirements.

There have been compliance problems such as distributing products with unapproved claimsor the importation and/or distribution of drug products without the appropriate marketingauthorisation.

b ) How is the retail sale of herbal medicinal products arranged in your country?Does your country have additional mechanisms to control the retail sale of herbalmedicinal products?

Retailers, like manufacturers and distributors, must meet the requirements set forth by theFood and Drugs Act insofar as they must only sell products that comply with the legislation.

Currently there are no restrictions on where herbal products may be sold, as herbalmedicinal products have not yet been scheduled. These products will, however, need to bescheduled at some point and this may lead to restrictions, such as in-pharmacy sale only, orthey may remain in general distribution. These further restrictions on place of sale fallunder provincial jurisdiction.

c ) Are distance selling and teleshopping used in your country for the supply o fherbal medicinal products?

Yes, distance selling and teleshopping are currently used in Canada for the supply of herbalmedicinal products. There is a provision in place that allows the importation of drugproducts into Canada for personal use. Otherwise, these agents are also subject to therequirements set forth by the Food and Drugs Act.

Of significant concern to Canadian industry and regulatory officials is the marketing ofproducts directly to Canadian consumers by foreign (primarily US) companies when someof these products may not currently be approved for sale in Canada. Although Canadiansmay import small amounts of such products for personal use (not intended for furtherdistribution), the consumer cannot be assured that the foreign products they are purchasingmeet appropriate standards or that the health claims are valid.

IX.2 MexicoIX.2.1 Classification of herbal products

a) How are herbal medicinal products defined in your country and whichproducts containing plants are not classified as medicinal products? What are thecriteria for classification as a medicinal product (e.g., by function or b ypresentation or both)?

In accordance with the Bylaws of the General Health Law put in force on 4 February 1998[MEX 1], herbal products may be defined either as herbal medicinal products or herbalremedies. Herbal medicinal products refer to those products manufactured with vegetal

112

materials that have well recognised rehabilitating, preventive or curing properties. Herbalremedies are defined as those products manufactured with a single part of a medicinalplant, or a combination of its parts that have been used for the relief of certain symptomsbased on popular or traditional knowledge. Herbal products in either category should not becombined with narcotics, psychotropics, chemical active ingredients, allopathic products,human or animal hormones or products that have an anti-hormonal or hormonal activity.Injectable presentations shall not be classified as herbal medicinal products.

Herbal tea products, such as camomile, are not classified as medicinal products. Inaddition, there are vegetal extracts such as Cnidoscolos chayamansa, Sabila, Cuachalalate,etc., which are presented in a pharmaceutical form and are not registered as herbalmedicinal products but are still considered as food supplements. This situation is mainlyexplained by the fact that it was not until 1995 that the Ministry of Health strengthened itsclassification criteria and started requesting herbal medicinal product manufacturers toregister their products as medicinal products. Before 1995, all of these products could beregistered as food supplements.

In accordance with the General Health Law, medicinal products are firstly defined byfunction and secondly by presentation. That means that a medicinal product should haverehabilitating, preventive or curing properties and be presented in a pharmaceutical form.

b ) Is there a specific category for herbal medicinal products that have notherapeutic claim?

All products legally registered as herbal medicinal products may make claims i naccordance with the authorisation issued by the Ministry of Health. Herbal remedies maymake symptomatic claims noting that such effects are based on their traditional use. Asmentioned above, there are also some products containing herbal extracts that are stillmaking unauthorised claims.

c ) Is there a specific category for herbal medicinal products containing well-known plants?

Yes, the herbal medicinal category.

d) Is there a specific category for traditionally used herbal medicinal products(e.g., in the treatment of certain indications)?

Yes, the herbal remedies category.


Currently, there are products that combine herbals, vitamins and minerals only. Theseproducts may be considered food supplements provided that none of their vitamin or mineralconcentrations exceed the lower limits established for non-prescription vitamins orminerals. Ministry of Health assesses these products as any other medicinal combinationproducts, looking at each component’s therapeutic activity and the possibility for it to causesynergistic, antagonistic or adding effects.

f ) Are there modern herbal medicinal products on the market that have beenfurther developed from their traditional use (e.g., highly processed, new indications,new pharmaceutical form, etc.)? Are there herbal medicinal products approvedand sold as OTC drugs?

There is one product made out of camomile that is presented in ointment and solution. Itsname is Camilosan and it is manufactured by a national pharmaceutical company.

Another product is made out of Garcinia cambogia and classified as a prescription for weightreduction.

113

All other herbal medicinal products registered as medicinal products have been classified asOTCs. In addition, there are prescription products, classified as allopathic medicinalproducts, which combine chemical ingredients and herbal extracts.

IX.2.2 Application of the General Health Law to herbal medicinal products

a) What is the legal basis for marketing authorisation of medicinal products, andis this legislation also applicable to herbal medicinal products?

The General Health Law and its Bylaws regulate all pharmaceutical activities in Mexico,including registration and selling of medicinal products. The Bylaws of the General HealthLaw have specific sections that refer to herbal medicinal products and herbal remedies.

b ) What are the requirements for marketing authorisation of herbal medicinalproducts in your country? (Or, if they are not authorised prior to marketing: How ismarketing of herbal medicinal products regulated in your country?)

Herbal medicinal products should submit the following documents in order to be registeredand authorised for selling and advertising:

a) Technical and scientific information that demonstrate the identity and purity of eachplant element in accordance with specific pharmacopoeias or international scientificsources;

b) Certificate of analysis of raw materials;

c ) Method of identification of the active ingredients;

d) Stability tests performed in accordance with the Mexican established norm;

e) Certificate of the taxonomic identification of the plant;

f ) Bibliographic references that support therapeutic indications, warnings andcontraindications;

g ) Description of formula;

h) Labelling and package insert drafts;

i ) Description of the manufacturing process;

j ) Certificate of analysis of the finished product;

k ) Description of the packaging materials;

i ) For imported herbal medicinal products it is also necessary to provide:

• Free sale certificate;

• Certificate of analysis issued by the foreign manufacturing company. The healthauthority of the country of origin should endorse this certificate;

• Letter of representation of the manufacturer, only when such manufacturer is nota subsidiary of the head office of the importing company.

c ) Does your country have any specific provisions for the regulation of well-known herbal medicinal products?

The Bylaws of the General Health Law have a specific set of articles that regulate herbalmedicinal products and herbal remedies.

d) What are the scientific standards required for safety and efficacy of herbalmedicinal products? Are manufacturers required to refer to published scientificliterature and/or expert reports in their applications for marketing authorisationfor their herbal medicinal products?

Microbiological tests are used as a means to assess safety. Efficacy should be supported bybibliographic references from well-known sources.

114

The Department of Herbal Medicinal Products of the Mexican Ministry of Health mainlyuses Codex, Atlas of Medicinal Plants and the German and British pharmacopoeias asreferences when assessing medicinal plants. Other references that are used by theaforementioned Department are the monographs of the European Pharmacopoeia, the W H OModel Monographs and the WHO Guidelines on the Assessment of Herbal Medicines.

e ) Does your country relax the requirements for proof of efficacy for certainindications, or where the indications refer to the “traditional use” of the product?

No, all herbal medicinal products should meet the requirements mentioned in point IX.2.2.b.In the case of herbal remedies, these products should comply with a set of specificrequirements including identification of their different components along with theirscientific and plain denomination, Certificate of Good Manufacturing Practices andMicrobiological Analysis, description of the manufacturing process, etc. As in the case ofherbal medicinal products, imported herbal remedies should submit a Free Sale Certificate,Certificate of Analysis issued by the foreign manufacturing company and endorsed by thehealth authority of the country of origin and a letter of representation when the foreignmanufacturer is not a subsidiary of the head office of the importing company.

f ) When assessing and reviewing herbal medicinal products, does your countrynow use any of the following references? Does your country intend to use any o fthese references?

• the monographs of the European Pharmacopoeia

• the monographs of the European Scientific Co-operative for Phytotherapy(ESCOP)

• the WHO Model Monographs

• the “WHO Guidelines on the Assessment of Herbal Medicines”As mentioned in point IX.2.4 below, the Department of Herbal Medicines of the MexicanMinistry of Health have stated that they use all of these references with the exception of theESCOP monographs.

g) What are the requirements for marketing authorisation of combinations o fseveral herbal ingredients?

As in any other medicinal products, combinations of herbal products should demonstrate thatnone of the herbal ingredients included in the formula have synergistic, antagonistic oradding effects.

h) How does your country treat herbal medicinal products that are made upand/or supplied to individual patients following a one-to-one consultation betweenthe patient and the practitioner?

There is no control over these kinds of preparations.

i) How does your country regulate intermediate products of herbal origin thatare intended for further processing by an authorised manufacturer or for thepreparation of a magisterial or an officinal formula?

There is no specific regulation for these kinds of products. However, all materials includedin any herbal medicinal product should have their Certificate of Analysis along withbibliographic references that support their identity and purity.

j ) How does your country assess the safety and efficacy of plants which are notnative to North America or Europe and have not been subjected to extensive oraccessible scientific research (e.g. some of the Chinese or South American herbs)?

In these cases, manufacturers have to provide bibliographic references which are evaluatedby the Mexican Ministry of Health.

115

k ) How many herbal medicinal products are authorised in your country? Whatare the major ingredients and indications?

There are 14 herbal medicinal products authorised in Mexico. Their ingredients andindications are as follows:

116

Ingredients Indications

Senna fruits Laxative

Garlic (Allium sativum) Cholesterol reductionValeriana officinalis Mild hypnotic/sedativeValeriana officinalis & Melissaofficinalis

Mild hypnotic/sedative

Valeriana extract & Lupulin Mild hypnotic/sedativePiper methysticum Mild sedativeSerenoa repens Micturition disordersAdonis vernalis & Convallaria majalis& Nerlum oleander & Scilla maritima &Rutin & Escin

Varicose veins

Passiflora & Crataegus oxyacantha &White Willow dry extract

Mild sedative

Ginkgo biloba Memory disordersSenna powder & Cassia fistula &Tamarindus indica & Coriander dryextract & Orozuz

Laxative

Psyllium plantago LaxativeChamomile Topical anti-inflammatoryGarcinia cambogia By Prescription: Weight reduction

Table 30: Herbal medicinal products authorised in Mexico

IX.2.3 Application of Good Manufacturing Practices to herbal medicinalproducts

a) Does your country apply Good Manufacturing Practices requirements toherbal medicinal products?

Yes.

b ) How does your country’s control of the starting (raw) material of herbalmedicinal products compare with the standards of the European Pharmacopoeia?

The Mexican Ministry of Health is not aware of the aforementioned standards.

c ) Are GMP inspections carried out in your country and in third countries thatare exporting herbal medicinal products or raw material to Mexico?

GMP inspections are only carried out in Mexico by the Ministry of Health.

IX.2.4 Post-marketing surveillance

a) Do the adverse reaction reporting systems in your country also monitor herbalmedicinal products? Have there been reports of adverse reactions that have led towithdrawal of herbal medicinal products from the market? Are you aware of casesof herbal medicinal products that have been withdrawn from the market in aEuropean Union Member State and have continued to be sold, after thewithdrawal, in Mexico?

The adverse reaction reporting system in Mexico, which is not in force yet, covers all typesof medicinal products. Tepezcohuite (Mimosa tenuiflora) is the only herbal product that hasbeen withdrawn from the market. It was withdrawn based on several reports that showed thisproduct may cause serious central nervous system side effects. There are no references ofherbal medicinal products that are continued to be sold in Mexico after they have beenwithdrawn in a European Union Member State.

117

b ) Should reports from consumers be accepted in order to more completelyrepresent the spectrum of adverse reactions to herbal medicinal products?

There have been no reports of this type from Mexican consumers.

IX.2.5 Labelling and advertising of herbal medicinal products

a) How are labelling and package leaflets of herbal medicinal productsregulated in your country? Do you have any specific problems with regard to thelabelling and package leaflets of herbal medicinal products?

All medicinal products, including authorised medicinal herbal products, have to complywith the labelling norm [MEX 2] that sets out the specific requirements that these productsshould have. These requirements include information on:

a) Indications

b) Dosage

c ) Administration form

d) Usage during pregnancy and lactation

e) Paediatric usage

f ) Contraindication

g ) Warnings

h) Side effects

i ) Interactions

j ) Overdose indications.

Those products not authorised by the Ministry of Health as medicinal herbal products do notcomply with the above mentioned requirements. The labels on these products do not providecomplete information and in most cases they bear false or exaggerated claims.

b ) How is the advertising of herbal medicinal products regulated in yourcountry? Do you have any specific problems with regard to the advertising o fherbal medicinal products?

Authorised herbal medicinal products are subject, as any other non-prescription medicinalproducts, to advertising pre-approval from the Ministry of Health. Some herbal products thatare still registered as food supplements have developed inappropriate advertisingcampaigns.

IX.2.6 Distributions and retail sale of herbal medicinal products

a) How is the wholesale distribution of herbal medicinal products regulated inyour country? What kinds of problems arise in this respect?

Authorised medicinal products are distributed in Mexico through wholesalers andpharmacies. Both wholesalers and pharmacies should have a specific authorisation issued bythe Ministry of Health. As long as many “traditional herbals” that are sold as rawmaterials in several places, and even on the streets, are not controlled by the Ministry ofHealth, consumers will be exposed to contaminating effects or toxic materials.

b ) How is the retail sale of herbal medicinal products arranged in your country?Does your country have additional mechanisms to control the retail sale of herbalmedicinal products?

In accordance with the Bylaws of the General Health Law, all medicinal products, includingauthorised herbal medicinal products and herbal remedies, should be sold in authorisedoutlets. As long as these products are classified in Mexico as non-prescription medicinalproducts, they can be sold in pharmacies, supermarkets or small grocery stores. There areno specific mechanisms to control the retail sale of herbal products.

118

c ) Are distance selling and teleshopping used in your country for the supply o fherbal medicinal products?

The sale of herbal products not authorised by the Ministry of Health usually take advantageof these methods.

IX.3 United States of AmericaIX.3.1 Classification of herbal products

a) How are herbal products defined in your country and which productscontaining plants are not classified as medicinal products? What are the criteriafor classification as a medicinal product (e.g., by function or by presentation orboth)?

Herbal products may be defined as foods (e.g., fruits, vegetables, teas, spices or flavourings),dietary supplements (a subcategory of food), drugs or cosmetics, depending upon theirintended use. Dietary supplement and over-the-counter (OTC) drug status and are the mostrelevant to this study on “herbal medicinal products” and are discussed further.

Dietary Supplement StatusDietary supplement status (which is legally in the classification of “food”) is by far the mostcommon choice made by manufacturers for their herbal products to date, since no pre-marketapproval is required. The definition of the term “dietary supplement” was established i nSection 3 of the Dietary Supplement Health and Education Act of 1994 (DSHEA) [USA 1]which amended Section 201 of the Federal Food, Drug and Cosmetic Act (FDC Act) with 21U.S.C. 321 (ff). Dietary supplements include products that are intended to supplement the dietand contain: a vitamin; a mineral; a herb or other botanical; an amino acid; a dietarysubstance for human use to supplement the diet by increasing the total dietary intake; or aconcentrate, metabolite, constituent, extract, or combination of any of these ingredients.Dietary supplements must be labelled as such and do not include tobacco, food products thatare marketed as conventional foods, and products that are represented as the sole item of ameal or the diet. Note, however, that a dietary supplement may be sold in conventional foodform. Thus, a herbal tea can be either a conventional food or a dietary supplement,depending upon the intended use of the product.

DSHEA expressly excludes a dietary ingredient intended for use in a dietary supplementfrom the definition of “food additive”. This means that Section 409 of the FDC Act is notapplicable to such ingredients. The term “food additive” is defined in Section 201(s) (21U.S.C. 321(s)).

Under DSHEA, articles that have been approved as new drugs, certified antibiotics andlicensed biologics are excluded from the definition of dietary supplement. Also excluded arearticles authorised for investigation as new drugs, antibiotics and licensed biologics forwhich substantial clinical investigations have become publicly known. These exclusionsapply if the article was not marketed as a dietary supplement or food prior to such approvalor authorisation (and clinical investigation). The interpretation of this DSHEA provision isthe basis for a current legal case which is further described in point IX.3.1.f below.

In the Federal Register dated 22 April 1996, the Food and Drug Administration (FDA)clarified that under the existing statute dietary supplements are for use by man andtherefore DSHEA does not apply to products intended for animal (non-human) use. Thiscontrasts with drugs which can be for human or animal use.

OTC Drug StatusOTC drug status requires that products be generally recognised as safe and effective(GRASE) in accordance with federal regulations [USA 2]. Safety can be established based onpublished studies in some cases, but acute and long-term animal toxicological studies mayalso be required. Proof of efficacy generally demands double-blinded, placebo-controlledhuman clinical trials to meet the requirement of adequate and well-controlled studies[USA 3].

When it was enacted in 1938, the Food, Drug and Cosmetic Act (FDC Act) required proof ofsafety and submission of a new drug application (NDA) for new drugs. In 1962, the FDC Act

119

was amended to also require proof of efficacy for new drugs. The Food and DrugAdministration (FDA) then undertook a review of all drugs, including 400 over-the-counter(OTC) drugs, that had been approved for marketing between 1938 and 1962 on the basis ofsafety data alone. In 1972, FDA established the OTC drug monograph review system [USA 4]and began reviewing the safety and efficacy of all OTC drugs that either were not covered byan NDA or were approved prior to 1962 on the basis of safety data alone. Since 1972, OTCmonographs have been published by drug classes, categorised by therapeutic effect, therebyestablishing doses of active ingredients considered generally safe and effective.

Herbal products that were not grandfathered in through the OTC review process and areintended for therapeutic use require FDA approval through a new drug application (NDA). Asubstance is not considered a new drug if it is GRASE and also has been marketed to a“material extent” and “material time” (Section 201(p) (21 U.S.C. 321 (p)). Currently FDAbases material extent and material time on marketing experience in the United States,although consideration of foreign marketing experience is under discussion (see pointIX.3.2.a).

Since substantial research is required in order to obtain OTC status, this question alsoraises the issue of patent protection. Because herbal products generally tend to be natural orgeneric products without substantial human innovation involved, obtaining patents for themis difficult. Without patent protection, manufacturers have lacked a market incentive toconduct extensive research on their herbal products because the results would also beavailable to their competitors and because herbal products can be marketed as dietarysupplements without such investments in research.

Homeopathic Product StatusUnder the FDC Act, articles listed in the Homeopathic Pharmacopeia of the United States arelegally defined as “drugs”. However, drugs listed in the Homeopathic Pharmacopeia of theUnited States are exempt from pre-market FDA review of safety and efficacy. When the FDCAct was enacted in 1938, such articles were essentially grandfathered into the definition ofdrug. Some manufacturers have begun to market herbal products as homeopathic drugs forminor, self-limiting conditions. Products that are sold as homeopathic remedies mustcomply with the specifications set out in the Homeopathic Pharmacopeia of the United Statesand relevant regulations.

Functional FoodsSo-called “functional foods” are not legally defined and may be sold either as foods ordietary supplements, depending upon the intended use of the product.

b ) Is there a specific category for herbal products that have no therapeuticclaim?

The category for herbal medicinal products with no authorised therapeutic claims is dietarysupplements, which are legally classified as “food”. Disease claims, express or implied, arenot permitted for dietary supplements. Under the FDC Act, a product intended to diagnose,treat, cure, mitigate or prevent any disease is considered a drug. DSHEA does allowstatements of nutritional support in the labelling of dietary supplements that describegeneral well-being or the intended effect on the structure or function of the human body.These statements are commonly known as “structure/function claims”. In the FederalRegister dated 29 April 1998, FDA issued proposed rules further distinguishing“structure/function claims” from “disease claims”. These proposed rules subsequentlyentered a 120-day comment period.

c ) Is there a specific category for herbal products containing well-known plants?

There is no specific category for herbal products containing well-known plants.

d) Is there a specific category for traditionally used herbal products (e.g., in thetreatment of certain indications)?

There is no specific category for traditionally used herbal products.

120


There are many combination products on the market. Under DSHEA, combination productsare regulated as dietary supplements if they bear or contain a vitamin, mineral, herb,botanical, amino acid, or a concentrate, metabolite, constituent, extract, or combination ofany of these ingredients and are otherwise labelled and marketed in accordance with therelevant provisions of the FDC Act. However, a homeopathic drug product may not containany non-homeopathic active ingredients and therefore is rarely included in combinationdietary supplements.

f ) Are there modern herbal products on the market that have been furtherdeveloped from their traditional use (e.g., highly processed, new indications, newpharmaceutical form, etc.)? Are there herbal products that are approved and soldas OTC drugs?

There are many herbal products that have been further developed from their traditional use.For example, some products are selectively concentrated to exclude some components and/orto standardise others. The mere concentration of a herbal product does not alter its legalstatus as a dietary supplement (i.e., food).

Of the botanical ingredients that were included in the OTC review (see point IX.3.1.), sixwere listed as safe and effective for their intended uses (e.g., Cascara bark, Senna leaf andPsyllium seed as laxatives) and over 150 were eliminated from the review process [USA 5] orwere found to be unsafe, ineffective or lacking sufficient evidence for evaluation. Some ofthe six herbal products that were previously approved as safe and effective for their intendedOTC uses have since been moved to the “more data needed” category (e.g., Cascara, Sennaand Aloe).

Herbal products that were not grandfathered in through the OTC review and are intended fortherapeutic use require FDA approval under a new drug application (NDA). To date no newherbal products have been approved as OTC drugs through the new drug application process,although several applications are in progress.

One current legal suit centres on the interpretation of DSHEA with regard to marketing of aherbal product (Cholestin) which contains a naturally occurring compound (mevinolin).FDA asserts that mevinolin is chemically indistinguishable from lovastatin. Lovastatinwas approved by FDA as a new drug (Mevacor) in 1987. Under DSHEA, articles that havebeen approved as new drugs are excluded from the definition of dietary supplement if thearticle was not marketed as a dietary supplement or food prior to such approval. The suit i sstill in progress, but one key to the interpretation of DSHEA in this case has been whether ornot the fact that the compound lovastatin is present in the herbal product may be used in themarketing and labelling of the herbal product. This case raises complex legal issues and,more specifically, goes to what is the relevant “article” for purposes of Section 201(ff)(3)(B)(i)of DSHEA.

IX.3.2 Application of the Federal Food, Drug and Cosmetic Act as amendedby the Dietary Supplement Health and Education Act of 1994(DSHEA)

a) What is the legal basis for marketing authorisation of medicinal products, andis this legislation also applicable for herbal products?

The Federal Food, Drug and Cosmetic Act of 1938 (FDC Act) as subsequently amendedgoverns the marketing and sale of food, drugs and cosmetics in interstate commerce in theUnited States. The Food and Drug Administration (FDA) is primarily responsible forinterpreting and enforcing the FDC Act. Herbal products that will be marketed with diseaseclaims are considered drugs and are currently subject to the drug provisions of the FDC Act.

In 1992, the European-American Phytomedicines Coalition (EAPC) submitted two citizenpetitions for herbal products (valerian as a sleep aid and ginger as an antiemetic or forrelief of symptoms of motion sickness). In their petitions they requested that FDA amend itspolicy with regard to evaluation of substances for inclusion in the OTC drug monographsystem by permitting use of foreign data. In response to the EAPC petitions and seven otherpetitions on this issue, FDA published an Advance Notice of Proposed Rulemaking

121

(ANPRM) on 3 October 1996, clarifying their position on the use of foreign data andmarketing experience and inviting public comment. FDA’s final decision on the EAPCpetitions and the related issues is pending.

The Dietary Supplement Health and Education Act of 1994 (DSHEA) mandated theestablishment of a Commission on Dietary Supplement Labels in the executive branch (thePresident’s Commission) to “evaluate how best to provide truthful, scientifically valid, andnot misleading information to consumers so that such consumers may make informed andappropriate health care choices for themselves and their families.” In November 1997 thereport of the President’s Commission commented that there are particular herbal productswith therapeutic or preventive uses that are recognised in other industrialised nations andthat in the United States these products are currently labelled with indirect statements abouttheir uses. The President’s Commission indicated that consumers would be better served i fthese herbal products were marketed as OTC drugs so that they could be labelled with clearstatements regarding therapeutic claims. The President’s Commission stronglyrecommended that “FDA promptly establish a review panel for OTC claims for botanicalproducts that are proposed by manufacturers for drug uses” and stated that “FDA needs togive special attention to the feasibility of approving botanical remedies for OTC uses i ncases in which sufficient evidence is available.” The President’s Commission also advisedthat “more study is needed regarding the establishment of some alternative system forregulating botanical products that are used for purposes other than to supplement the diet butthat cannot meet OTC drug requirements.” They further noted the need for a comprehensivereview of the approaches taken by other nations to regulating herbal medicinal products.

In the Federal Register of 29 April 1998, FDA responded to these suggestions from theCommission and made reference to their 3 October 1996 advance notice of proposedrulemaking (ANPRM) as follows (quoted at length because of its marked significance to theUS regulatory situation).

“Although the agency agrees that a much more comprehensive evaluation would behelpful, .… because resources have not been allocated, … FDA is unable to act on its own toimplement the Commission’s suggestion at this time. …”.“In the Federal Register of October 1996, FDA issued an advance notice of proposedrulemaking (ANPRM) seeking comment on eligibility requirements and, among othermatters, whether OTC marketing experience abroad could be used to establish ‘materialtime’ and ‘material extent’ requirements (61 FR 51625, October 3, 1996). For manybotanical products, the history of use is based on marketing experience outside the UnitedStates.Based on the comments received in response to the October1996 ANPRM, the agencyexpects to issue a proposed rule setting forth criteria for eligibility in the OTC drugmonograph system, including definitions of the terms ‘material extent’ and ‘materialtime.’ Unless and until regulations are in place that would allow FDA to accept foreignmarketing experience, it may be difficult for many botanical products to qualify forinclusion in the existing OTC monograph system. Consequently, establishing an OTCadvisory panel to evaluate therapeutic and preventive drug claims for botanical products,as the Commission recommends, would be premature at this time. The agency, however,intends to work expeditiously on rulemaking for this issue.In the interim, if there were a situation in which the scientific evidence and marketingexperience submitted to the agency are sufficient to allow a botanical ingredient to beconsidered under the existing framework, then the agency would work expeditiously toassess whether the submitted data and experience supports marketing under an OTC drugmonograph.In addition, recognizing the need for guidance for manufacturers seeking to developbotanicals as either OTC or prescription drug products, and recognizing the unique natureof botanical products, the agency currently is developing a draft guidance for industry thatdiscusses the kinds of data necessary to satisfy drug regulatory requirements based onexisting statutes and regulations. The draft guidance will be made available for publiccomment before a final guidance is issued.”

b ) How is marketing of herbal products regulated in your country?

Dietary supplement products are required to be prepared, packaged, and stored in accordancewith current Good Manufacturing Practices applicable to food products. All ingredients mustbe truthfully and accurately listed on the label and the product may not be adulterated withother substances.

122

Section 4 of the Dietary Supplement Health and Education Act of 1994 (DSHEA) establishedthat the burden of proof for safety lies with the Federal Food and Drug Administration(FDA). The President’s Commission on Dietary Supplement Labels indicated that “FDA andappropriate agencies in some States may need additional resources to develop the necessaryevidence … to meet this important responsibility …” [USA 5]. FDA may remove a dietarysupplement from the market if they can demonstrate that the product presents a significantor unreasonable risk of injury or illness when it is used as recommended on the label or, i fit is not labelled, under conditions of ordinary use. FDA may also oppose marketing of adietary supplement product if the label violates the regulations governing structure/functionclaims.

Dietary supplement ingredients that were first marketed in the United States after 15 October1994 are defined by Section 8 of DSHEA as new dietary ingredients. A dietary supplementproduct that contains a new dietary ingredient is deemed adulterated unless it meets one oftwo conditions. Either it must be an ingredient that has previously been in the food supply i nthe same chemical form. Or the manufacturer must submit evidence for the conclusion thatthere is a reasonable expectation that the new dietary ingredient will be safe when it is usedunder the conditions recommended on the label. The supporting information may include ahistory of use or other evidence. Scientific publications used as evidence must be fully cited.DSHEA requires the manufacturer to submit all evidence at least 75 days before the productenters interstate commerce. FDA may prohibit marketing if they are not satisfied with theevidence, but pre-market authorisation is not required. Ninety days after receipt, FDA mustplace the non-proprietary information provided by the manufacturer on public display.

c ) Does your country have any specific provisions for the regulation of well-known herbal products?

Dietary supplement ingredients that were marketed before 15 October 1994 are considered tobe safe unless FDA demonstrates otherwise. For new dietary ingredients marketed after 15October 1994, published scientific studies, a history of use, previous presence in the foodsupply, or other evidence that establishes the safety of the herbal product must be submitted 75days before marketing. Pre-market authorisation is not required.

FDA’s list of botanical ingredients that are generally recognised as safe (GRAS) includesessential oils, extracts, spices and flavourings for use in foods, and natural flavouringagents for use in foods and beverages.

d) What are the scientific standards required for herbal products? Aremanufacturers required to refer to published scientific literature and/or expertreports when substantiating structure/function claims for their herbal products?

Issues relating to scientific standards, the effectiveness of products and the dissemination ofinformation regarding health related benefits of dietary supplements have posedconsiderable regulatory challenges for industry, FDA and state regulatory agencies.

Section 485C of DSHEA mandated the establishment of an Office of Dietary Supplementswithin the National Institutes of Health. Under DSHEA, this office was mandated to:

1) conduct and co-ordinate scientific research;

2) collect and compile results of scientific research; and

3) serve as the principal advisor to other government agencies on issues relating todietary supplements.

However, in practice this office has received limited funding and FDA has continued to playthe primary role in regulating dietary supplements. The President’s Commission on DietarySupplement Labels recommended that the Office of Dietary Supplements be funded at thelevel authorised by DSHEA and place greater emphasis on its advisory role. TheCommission also suggested that the supplement industry establish an expert advisorycommittee to guide them on technical issues, particularly related to labelling.

In the Federal Register of 23 September 1997, FDA issued a final rule clarifying therequirements for notifications regarding structure/function claims. The concurrence orpermission of FDA is not required for structure/function claims. However, the manufacturermust notify FDA about the structure/function claim within the first 30 days of marketingtheir product. The structure/function claim must be truthful, not misleading, and based onscientific evidence contained in the manufacturer’s substantiation file at the time the claim

123

is made. Because of the lack of patent protection and consequent lack of proprietary researchon herbal products (see point IX.3.1.), structure/function claims tend to be based on researchthat is publicly available, conducted in other countries, or on a history of use. Under DSHEA,manufacturers’ substantiation files are not required to be accessible to FDA. DSHEA doesnot define how claims of nutritional support are to be substantiated. Without proposing thatthe rulemaking be reopened, the President’s Commission on Dietary Supplement Labelssuggested that manufacturers’ substantiation files include the following items:

• a copy of the notification letter;

• the ingredients in the dietary supplement (including quantities and active principlesif known);

• evidence to substantiate the statements of nutritional support;

• evidence to substantiate safety;

• Good Manufacturing Practices followed; and

• qualifications of the individuals who reviewed the evidence.

FDA agreed with this guidance but has no plans for rule revisions at this time.

e ) Does your country relax the requirements for health claims orstructure/function claims with respect to certain indications, or where theindications refer to the “traditional use” of the product?

“Indications” is a term applied to drugs and not to dietary supplements. Proof of efficacy isnot required for dietary supplements.Health claims that have been approved by FDA in accordance with the Nutrition Labelingand Education Act of 1990 (NLEA) are limited to a short list12 based on extensive scientificdata (on substances that would generally not be considered the active constituent i nbotanicals).

Regarding label claims, the President’s Commission on Dietary Supplement Labelssuggested that statements of nutritional support (i.e., structure/function claims) should bebacked by scientifically valid evidence. The Commission indicated that claims ofnutritional support based only on historical use should be “carefully qualified to preventmisleading consumers.”

A history of safe use is considered valid evidence for purposes of establishing the safety ofnew dietary ingredients.

f ) When assessing and reviewing herbal products, does your country now use anyof the following references? Does your country intend to use any of thesereferences?

• the monographs of the European Pharmacopoeia

• the monographs of the European Scientific Co-operative for Phytotherapy (ESCOP)

• the WHO Model Monographs

• the “WHO Guidelines on the Assessment of Herbal Medicines”

These references may be used to evaluate or substantiate structure/function claims fordietary supplements. However, data from sources outside the United States may not be used toestablish OTC drug status.

g) How is the marketing of combination products containing several herbalingredients regulated in your country?

Combination products containing several herbal ingredients are governed by the sameregulations as all other dietary supplement products. As mentioned above under question 1.5,

12 Approved health claims for dietary supplements and conventional foods: Calcium and osteoporosis;

folate and neural tube defects; soluble fiber from whole oats and coronary heart disease; solublefiber from psyllium husks and coronary heart disease; and sugar alcohols and dental caries

124

homeopathic products are regulated as drugs and may not contain any non-homeopathicactive ingredients.

h) How does your country treat herbal products that are made up and/orsupplied to individual patients following a one-to-one consultation between thepatient and the practitioner?

DSHEA governs the marketing and sale of all dietary supplements that are in interstatecommerce, including those dispensed by a practitioner. Each state is responsible for locallyproduced and marketed herbal products that do not enter interstate commerce.

i) How does your country regulate intermediate products of herbal origin thatare intended for further processing by a manufacturer?

DSHEA regulations apply both to dietary supplements and to ingredients intended for use i na dietary supplement. The current Good Manufacturing Practices for dietary supplementsthat were proposed in 1997 (see point IX.3.3.a below) also cover intermediate products or“dietary ingredients” intended for use in the manufacture of dietary supplement finishedproducts.

j ) How does your country assess the safety of and claims for plants which are notnative to the United States or Europe and have not been subjected to extensive oraccessible scientific research (e.g. some of the Chinese or South American herbs)?

There are no laws specific to the origin of the botanical.

If the dietary ingredient was marketed before 15 October 1994, then it is considered to be safeunless proven otherwise by FDA. If it was marketed after 15 October 1994, then it is regulatedas a new dietary ingredient and evidence of historical use may be provided to establishsafety. This information must be provided to FDA at least 75 days prior to marketing. Pre-market approval is not required, but FDA may choose to prohibit marketing. It remains to beseen whether or not in practice historical use data alone will be sufficient to conclude that aproduct can “reasonably be expected to be safe” as required by DSHEA.

Structure/function label claims for poorly studied botanicals would need to be madecautiously. These statements generally require the backing of scientifically valid evidenceso as not to mislead consumers.

k ) [How many herbal medicinal products are authorised in your country? Whatare the major ingredients and indications?] What are the top selling herbalproducts in your country?

Dietary supplements are not authorised per se. Total retail sales of herbal products in theUnited States during 1997 are estimated at USD 3.24 billion [USA 6]. Mass market sales for1997 were estimated at USD 400 million [USA 7]. The twenty top selling botanicals in naturalfood stores in the United States are listed in the table below.

125

1997 Rank Herb % of 1997 Sales % of 1996 Sales 1996 Rank

1 Echinacea 11.93% 9.6% 12 Garlic 8.52% 7.2% 23 Ginkgo biloba 6.80% 5.1% 44 Goldenseal 5.95% 4.7% 55 Saw palmetto 4.87% 3.1% 96 Aloe 4.76% 2.4% 126 Ginseng 4.76% 6.4% 38 Cat’s claw 3.49% 2.1% 149 Astragalus 3.07% 1.3% 2710 Cayenne 2.83% 2.5% 1111 Siberian ginseng 2.70% 3.5% 712 Bilberry 2.61% 1.6% 2313 Cranberry 2.47% 1.7% 1814 Dong quai 2.13% 1.8% 1715 Grape seed extract 2.07% 2.0% 1516 Cascara sagrada 1.92% 2.8% 1017 St. John’s wort 1.87% n/a n /a18 Valerian 1.73% 2.2% 1319 Ginger 1.69% 1.7% 1820 Feverfew 1.59% 1.6% 23

Table 31: Herbal supplements sales in natural food stores in USA [USA 8]

IX.3.3 Application of Good Manufacturing Practices to dietary supplements

a) Does your country apply Good Manufacturing Practice requirements to herbalproducts?

In November 1994, Section 9 of DSHEA extended the application of existing GoodManufacturing Practice (GMP) regulations [USA 9] to include dietary supplements. Section 9also gave the option to develop GMP regulations specifically for dietary supplements,modelled after current good manufacturing practice regulations (CGMP) for food and notimposing standards for which there is no current and generally available analyticalmethodology.

In November 1995, draft CGMP regulations were submitted to FDA by representatives of thedietary supplement industry. The industry draft was modelled after GMP regulations forfoods, with additional provisions specific to dietary supplements as needed. In particular,“there was no desire or intent to impose on dietary supplements the type of documentationand validation currently required in the manufacture of pharmaceutical products.” FDAreviewed the draft and issued it as proposed rules in the Federal Register of 6 February 1997,opening a comment period to address specific questions. Among the issues raised by FDAwere the following:

• whether or not regulations are needed, and, if they are needed, whether they should bemandatory or voluntary;

• the appropriateness of applying defect action levels for foods (i.e., spices andflavourings) to dietary supplements given the differences in consumer exposurelevels; procedures for positive identification of botanical dietary ingredients;

• the need for documentation of day-to-day quality control procedures for dietarysupplements (these would be beyond the requirements for foods);

• the involvement of competent medical authorities (in addition to quality controlpersonnel) in the evaluation of adverse event reports;

• the need to specify procedures for evaluating the seriousness of adverse event reports;

• the need for evaluation and documentation of safety of dietary supplements; and

• quality control of computer software programs and equipment used in GMPprocedures.

mcmc

126

Finally, FDA suggested that the principles of Hazard Analysis and Critical Control Points(HACCP) might be more appropriate and less burdensome than the regulatory approachsubmitted by industry. (In a HACCP system food processors assess the hazards specific totheir products, use routine controls to prevent or minimise those hazards, monitor theperformance of the controls, and maintain regular records.) The inspection procedure nowused evaluates the conditions at the time of inspection but does not assess the adequacy ofongoing food safety assurance programs within a company. To make their inspections morepreventive of (rather than reactive to) food safety problems, FDA has proposed to incorporateHACCP into the food inspection regulations.

The public comment period on these issues ended on 6 June 1997. FDA is now evaluating thecomments and their final decision on CGMP regulations specifically for dietarysupplements is pending.

b ) How does your country’s control of the starting (raw) material of herbalproducts compare with the standards of the European Pharmacopoeia?

The existing CGMP regulations for food, which also apply to dietary supplements, allowcertification from the supplier of the raw material in lieu of direct testing by themanufacturer of the finished product. In the Federal Register of 6 February 1997, FDArequested comments on the adequacy of such certification for dietary supplements,particularly for lesser-known ingredients. FDA’s final rule on this issue is pending.

c ) Are GMP inspections carried out in your country and in third countries thatare exporting herbal products or raw material to the United States?

FDA is mandated to ensure the safety of the nation's food supply by the Federal Food, Drug,and Cosmetic Act and the Public Health Service Act (42 U.S.C. 264). As part of that mandate,FDA conducts GMP inspections in the United States and its territories. In practice,inspections in foreign countries are conducted infrequently. However, issues regardingimported dietary supplements and dietary ingredients remain on the agenda for GMPdiscussions.

IX.3.4 Post-marketing surveillance and “vigilance” of dietary supplements

a) Do the adverse reaction reporting systems in your country also monitor herbalproducts? Have there been reports of adverse reactions that have led to withdrawalof herbal products from the market? Are you aware of cases of herbal products thathave been withdrawn from the market in a European Union Member State andhave continued to be sold, after the withdrawal, in the United States?

There are several large-scale, passive surveillance systems that monitor adverse reactionsto all foods, including dietary supplements. Reporting to any of these systems is voluntarywith no legal obligations. The Association of Poison Control Centers monitors all adversereactions reported to the national network of Poison Control Centers. The United StatesPharmacopoeia maintains a Practitioners’ Reporting Network for clinicians. FDA entersall reports of adverse events related to dietary supplements that they receive into the Centerfor Food Safety and Applied Nutrition’s (CFSAN) Special Nutritionals Adverse EventMonitoring System for further evaluation and monitoring. Serious adverse events that areassociated with dietary supplements (and other FDA-regulated products) and voluntarilyreported by health professionals or consumers are tracked by FDA using their MedWatchsystem.

FDA also receives passive surveillance data on adverse events associated with foods anddietary supplements through CFSAN’s Adverse Event Monitoring Systems, the Drug QualityReporting System and the Office of Regulatory Affairs Consumer Complaint System. ThePresident’s Commission on Dietary Supplement Labels recommended that FDA, industry,scientists, and consumer groups co-operate in the establishment of a post-marketingsurveillance system specifically for dietary supplements. In the Federal Register of 29 April1998, FDA stated that it will be initiating a process to further such co-operation. An internalworking group of FDA’s Foods Advisory Committee (comprised of outside experts) has beenasked to address the question of post-market surveillance.

The Dietary Supplement Health and Education Act of 1994 only requires FDA to demonstratethat a herbal product presents a significant or unreasonable risk of illness or injury. A n

127

actual injury or illness need not have occurred before FDA takes regulatory action. ThePresident’s Commission on Dietary Supplement Labels strongly suggested to manufacturersthat they include appropriate warnings in product information and the FDA Foods AdvisoryCommittee, together with industry, is developing guidance on this matter.

Regarding market withdrawals, on 12 June 1997, FDA issued a statement warning that somedietary supplement products labelled as containing “plantain” might be contaminated withDigitalis lanata Ehrh. The warning was issued after a 23-year-old woman was admitted tohospital following ingestion of a herbal “cleansing” program comprised of five dietarysupplement products. She presented with nausea, vomiting, dizziness, irregular heart ratewith heart block and toxic levels of digoxin. The implicated product contained fourteenbotanicals. FDA identified Plantago lanceolata L. (supplied from Germany) as theingredient adulterated with Digitalis lanata Ehrh (also supplied from Germany). At the timethe contamination was confirmed, 7 million tablets had been ready to ship and wererecalled. FDA’s trace back to suppliers involved approximately 6 000 pounds of adulteratedplantain that had been distributed over a period of 2_ years. Fifteen companies, includingseveral hundred establishments and individuals, received recall actions. No known deathsresulted from this incident.

Another recent example where adverse event reports led to regulatory action is herbalproducts containing ephedrine alkaloids (commonly known as Ma huang, ephedra, Chineseephedra, and epitonin, primarily from the species Ephedra sinica Stapf, E. equistestina Bunge,E. intermedia var. tibetica Stapf and E. distachya L.). In the Federal Register dated 4 June1997, after weighing its regulatory options and the limitations of the available data, FDAconcluded that without pre-market review authority they could not ban these products from themarket. However, FDA did propose to restrict levels of ephedrine alkaloids and conditionsfor their use. These restrictions were based on FDA’s authority under DSHEA to limit theconcentrations of constituents in and conditions for use of a dietary supplement that FDAcan prove may present a significant or unreasonable risk of illness or injury when used asdirected on the label or, in the absence of labelling, under conditions of ordinary use.

The comment period for these proposed rules closed on 2 December 1997 and final action ispending. Meanwhile, the Federal Trade Commission has taken regulatory action on allegedmisrepresentations in the advertising of the herbal product called “Herbal Ecstasy,” whichcontains ephedrine alkaloids. Also, legislation on ephedra has been proposed independentlyin several states (e.g., Texas, California, Indiana, Virginia, Vermont, Illinois, Hawaii,Iowa, New York, New Hampshire, Montana, Pennsylvania, and Massachusetts), rangingfrom complete bans on ephedra (Texas, rejected) to exemptions for dietary supplements onrestrictions of over-the-counter sales of ephedrine products (Montana, passed).

Comfrey (Symphytum officinale L.) is an example of a herbal product that has been at leastpartially banned from the market in a European Union Member State but remains on themarket in the United States. Comfrey contains pyrrolizidine alkaloids that have been linkedto veno-occlusive disease and liver tumors in humans [USA 10]. In Germany, the use ofcomfrey has been restricted to the external use of the root, with a limitation of thepyrrolizidine alkaloids. In the US, comfrey remains available in some health food stores,although it is sold less widely than previously. In July 1996 the American Herbal ProductsAssociation, a trade organisation representing the dietary supplement industry, beganrecommending that manufacturers include the following warning on products containingcomfrey: “For external use only. Do not apply to broken or abraded skin. Do not take whilenursing.” Many manufacturers do voluntarily include such warnings or have removedcomfrey from their products.

b ) Should reports from consumers be accepted in order to more completelyrepresent the spectrum of adverse reactions to herbal products?

Consumer reports of adverse events associated with herbal products are currently accepted byPoison Control Centers and FDA. Nearly half of all Americans use dietary supplements[USA 11] and about one-third of the adult U.S. population uses botanical medicinal products[USA 12]. The President’s Commission identified a need for healthcare professionals tobecome more knowledgeable about herbal products. Because of the high prevalence of self-medication with herbal products and the limited knowledge and involvement of clinicians,reports from consumers should be accepted in post-market surveillance systems.

128

IX.3.5 Labelling and advertising of herbal products

a) How are labelling and package leaflets of herbal products regulated in yourcountry? Do you have any specific problems with regard to the labelling andpackage leaflets of herbal products?

Issues regarding labelling and package leaflets were left unresolved during congressionaldebates on DSHEA. In order to address these technical questions, the Commission on DietarySupplement Labels (“the President’s Commission”) was mandated by DSHEA, appointed bythe President of the United States in November 1995 and issued their final report i nNovember 1997. Labelling of dietary supplements, particularly herbal products, has been acomplex and contentious issue that cannot be fully detailed within the scope of this report.However, the aspects that are most relevant to this study are summarised below, includingcomments from the President’s Commission, FDA’s response to those comments and FDA’ssubsequent rulemaking on labelling.

Structure/Function ClaimsDSHEA restricts nutritional support claims made on dietary supplement labels todescriptions of the intended effect of the dietary ingredient on the structure or function of thehuman body. Nutritional support claims, preferably called structure/function claims, mustnot suggest disease prevention or treatment either explicitly or implicitly and must beaccompanied by the following disclaimer: “This statement has not been evaluated by theFood and Drug Administration. This product is not intended to diagnose, treat, cure, orprevent any disease.” Prior to DSHEA, making a structure/function claim on a label wouldhave rendered that product a drug. Consequently, since DSHEA was enacted there has beensome regulatory ambiguity in the distinction between “disease claims” and“structure/function claims”. To address this need for clarification, the specific languagethat constitutes a disease claim versus a structure/function claim was published by FDA i nthe Federal Register as a proposed rule on 29 April 1998. This issue continues to be debated.

Health ClaimsThe Nutrition Labeling and Education Act of 1990 (NLEA) [USA 13] established theprocedures for approving health claims for foods. Unlike structure/function claims, healthclaims do require pre-market FDA approval. NLEA requires “significant scientificagreement” before a health claim is permitted on a food label. The Dietary SupplementsHealth and Education Act of 1994 left the standard for dietary supplement health claims up toFDA’s discretion, and FDA applied the NLEA standard. The President’s Commission onDietary Supplement Labels in 1997 supported the position that the standard for health claimsfor both dietary supplements and foods be “significant scientific agreement”. However, theCommission clarified that “agreement” should not be interpreted to mean unanimous ornear unanimous support, and should include the opinions of experts outside FDA. The healthclaim provisions of the Federal Food, Drug and Cosmetic Act were further amended in theFood and Drug Administration Modernization Act of 1997 [USA 14]. So far these provisionsare most applicable to non-botanical dietary supplements or those used primarily as foods(e.g., whole oats, psyllium husks). The President’s Commission suggested that NLEA healthclaims be expanded to include appropriate health claims for herbal products.

Exempt PublicationsUnder Section 5 of DSHEA, a publication or other reference may be used in connection withthe sale of dietary supplements and is exempt from labelling restrictions if it meets thefollowing requirements:

• it is not false or misleading;

• it does not promote a particular manufacturer or brand of a dietary supplement;

• it is displayed or presented so as to convey a balanced view of the available scientificinformation on a dietary supplement;

• if displayed in an establishment, it is displayed physically separate from the dietarysupplements; and

• it does not have appended to it any additional information by sticker or any othermethod.

The President’s Commission noted the difficulties in applying this provision of DSHEA andsuggested FDA proactively monitor this aspect.

129

Nutrition Labelling RequirementsFDA’s final rule on labelling of dietary supplements was issued in the Federal Register of 23September 1997. All dietary supplement labels must be in compliance with theserequirements by 23 March 1999. The label requirements for dietary supplements werederived from the requirements for food labels with a few modifications. For example, underthe new regulations dietary supplement labels must list total calories, calories from fat, totalfat, saturated fat, cholesterol, sodium, total carbohydrate, dietary fibre, sugars, protein,vitamin A, vitamin C, calcium and iron if the substance is present in the product aboveminimum threshold levels. (For foods these substances must be listed whether or not they arepresent in the product.) For botanical ingredients, the common name may be used if it i slisted in the book Herbs of Commerce [USA 15]. Otherwise, the Latin binomial (includingauthor) must be used. All ingredients must be listed including those used solely forformulation. Extract solvents, ratios to starting material, plant part, and whether thestarting material was fresh or dried must also be declared on the label. Certain aspects of thesolvent declaration requirements were subsequently modified by FDA in their final rule of 5June 1998 in response to petitions from industry representatives.

Alcohol ContentOne final labelling issue that has arisen recently concerns the alcohol content in somedietary supplement products. The Bureau of Alcohol, Tobacco, and Firearms (ATF) in theDepartment of Treasury regulates products that contain more than 0.5% alcohol and are fitfor beverage use. The Food and Drug Administration (FDA) has authority over otherproducts that contain alcohol. In response to reports of misuse of alcohol-containing ginsengextracts in New York State, ATF has taken regulatory action to bring all ginseng productsinto compliance with federal labelling requirements with regard to declaring alcoholcontent.

b ) How is the advertising of herbal products regulated in your country? Do youhave any specific problems with regard to the advertising of herbal products?

Advertising of herbal products in all media is governed by the Federal Trade CommissionAct [USA 16] and the Federal Trade Commission’s criteria for support of food advertisingclaims [USA 17 and USA 18]. Recent Federal Trade Commission actions involvingmanufacturers of dietary supplement products have alleged violations in the form ofdeceptive acts or practices or unfair methods of competition through advertising ontelevision, e-mail and the Internet. In advertisements, representations (express or implied)about efficacy, performance, safety or benefits must be substantiated by competent andreliable scientific evidence. An advertisement may not present an individual’s testimonialas a typical user’s experience without substantiation. Representations for dietarysupplements must comply with the labelling regulations contained in the Nutrition Labelingand Education Act of 1990.

IX.3.6 Distribution and retail sale of herbal products

a) How is the wholesale distribution of herbal products regulated in yourcountry? What kinds of problems arise in this respect?

Wholesale distribution of herbal products is governed by DSHEA. The confirmedadulteration of Plantago lanceolata L. with Digitalis lanata Ehrh. which was described abovehighlights some of the problems that have arisen with respect to wholesale distribution ofherbal products. In particular, that incident raised concern about the adequacy of existingsystems with regard to proper identification and vouchering of botanicals, use of commonnames, record keeping, inaccurate certificates of analysis, economic adulteration and post-market surveillance.

b ) How is the retail sale of herbal products arranged in your country? Does yourcountry have additional mechanisms to control the retail sale of herbal products?

Herbal products are primarily sold in health food stores. A few of the top-selling herbalproducts are being sold increasingly in pharmacies, mass retail chain stores andsupermarkets. Many herbal products may be purchased in the offices of alternative healthcare practitioners. There are also specialty shops in some locations that exclusively sellherbal products, raw plant material and related books and magazines.

130

As mentioned under question 5.1, the retail sale of herbal products that contain more than0.5% alcohol and are fit for use as a beverage may be controlled by the Bureau of Alcohol,Tobacco, and Firearms.

DSHEA governs dietary supplements that are involved in interstate commerce. Each state i sresponsible for locally produced and marketed products that do not enter interstatecommerce.

c ) Are distance selling and teleshopping used in your country for the supply o fherbal products?

A wide variety of herbal products are available by mail order. Some of these products aregrown and manufactured in the United States, others are imported. Several States haveexpressed concern to the President’s Commission on Dietary Supplement Labels about theuncontrolled information on herbal products that is available on the Internet.

131

X. ACKNOWLEDGEMENTSThe following persons have kindly supported this study by contributing to the countryreports:

AustriaDr Alexander JentzschFederal Ministry of Health and Consumer Protection, Vienna

Dr Johann KönigSanova Pharma, Vienna

BelgiumDr Pascale PoukensNational Commission for Medicinal products, Brussels

Prof. Arnold G. VlietinckDepartment of Pharmaceutical Sciences, University of Antwerp

Mr Yvan DierckxsensDolisos, Brussels

DenmarkMr Steffen BagerDanish Medicines Agency, Brønshøj

Mr Finn Møllgaard, Ferrosanon behalf of The Danish Association of the Pharmaceutical Industry (LIF), Copenhagen

FinlandMs Anna-Liisa EnkovaaraNational Agency for Medicines, Helsinki

Ms Elvi MetsärantaThe Finnish Pharmaceutical Industry Federation, Helsinki

FranceMs Kareen BenmaorFrench Agency for Medicines, Saint-Denis

Mr Pierre ChaumelleVilleneuve de Tolosane

132

GermanyDr Konstantin KellerFederal Institute for Drugs and Medical Devices, Berlin

Staff of the German Medicines Manufacturers’ Association, Bonn

GreeceDr Catherine KarahaliouNational Drug Organization, Athens

Prof. N.H. ChoulisDepartment of Pharmacy, University of Athens

IrelandDr John G. KellyIrish Medicines Board, Dublin

Ms Leonie ClarkeIrish Pharmaceutical Healthcare Association, Dublin

ItalyDr Marisa DelbòMinistry of Health, Rome

Prof. Franco F. VincieriDepartment of Pharmaceutical Sciences, University of Florence

Dr Antonella RivaIndena, Milan

LuxembourgMs Jacqueline Genoux-HamesDivision of Pharmacy and Medicinal Products, Luxembourg

The NetherlandsDr André BroekmansMedicines Evaluation Board, The Hague

Dr Emiel van GalenMedicines Evaluation Board, The Hague

Dr Carla RutgersMinistry of Health, Welfare and Sport, The Hague

Mr Lucas W. von HebelNehoma, Zwolle

Dr Rommert WijnsmaNeprofarm, Utrecht

PortugalDr Isabel AbreuInfarmed, Lisbon

133

SpainDr Gonzalo Saiz FernandezMinistry of Health and Consumption, Madrid

Ms Maite López-GilSpanish Medicines Manufacturers’ Association, Madrid

SwedenMs Maria SzirmaiMedical Products Agency, Uppsala

Ms Anna-Maria Nilsson-ÅslundMedical Products Agency, Uppsala

Ms Eva RämmeThe Swedish Association of the Pharmaceutical Industry (LIF), Stockholm

Ms Anna DahlinNordic Council on Medicines

United KingdomDr Linda AndersonMedicines Control Agency, London

Mr Richard WoodfieldMedicines Control Agency, London

Mr Paul BrittainMedicines Control Agency, London

Mr Michael BakerThe Proprietary Association of Great Britain, London

Ms Erica SmithThe Proprietary Association of Great Britain, London

CanadaMs Grace ChavesNon-prescription Drug Manufacturers’ Association of Canada, Ottawa

Mr David SkinnerNon-prescription Drug Manufacturers’ Association of Canada, Ottawa

Staff of theTherapeutic Products Directorate of Canada, Ottawa

Dr Frank ChandlerDalhousie University, Halifax (retired)

MexicoMr Héctor A. BolañosMexican Medicines Manufacturers’ Association (AFAMELA), Mexico City

Dr Magdalena Sanchez-BedollaMinistry of Health, Mexico City

United States of AmericaMs Rowena K. Richter

134

Yale University, New Haven, Connecticut

Dr Marilyn BarrettPharmacognosy Consulting Services, Redwood City, California

The following people from AESGP have contributed to this study:Dr Hubertus Cranz, BrusselsMr Jean-François Dechamp, BrusselsMr Johan Lindberg, BrusselsMs Rowena K. Richter, Brussels and New HavenDr Barbara Steinhoff, BonnMs Mary Coronel, Brussels

135

XI. REFERENCES

[1] Quaeyhaegens W., Size and structure of the European Market of HerbalMedicinal Products. Presentation at the AESGP Annual Meeting, Athens, 21-23May 1998.

[2] Official Journal of the European Communities No. C 305 of 16 October 1987.

[3] Official Journal of the European Communities No. C 350 of 30 December 1995.

[4] Official Journal of the European Communities No. C 136 of 8 May 1996.

[5] Official Journal of the European Communities No. C 141/64 of 13 May 1996.

[6] Official Journal of the European Communities No. C 335/07 of 9 November 1996.

[AT 1] Arzneimittelgesetz/Österreich in der Fassung vom 31. Juli 1996 (VO 379/96).

[AT 2] 541. Verordnung des Bundesministers für Gesundheit und öffentlicher Dienstvom 16. Oktober 1989 betreffend Erleichterungen bei der Zulassung bestimmterArzneispezialitäten. Bundesgesetzblatt für die Republik Österreich 1989:3641-3666.

[AT 3] 727. Verordnung des Bundesministers für Gesundheit, Sport undKonsumentenschutz, mit die der Verordnung betreffend Erleichterungen bei derZulassung bestimmter Arzneispezialitäten geändert wird. Bundesgesetzblatt fürdie Republik Österreich 1992:3912-3915.

[AT 4] Abgrenzungsverordnung vom 25. August 1995 (VO 568/95). Bundesgesetzblatt fürdie Republik Österreich 1995:7005-7046.

[AT 5] Arzneispezialitätenverordnung vom 28. Februar 1985 (AspV, VO 82/85),withdrawn by: 220. Verordnung der Bundesministerin für Arbeit, Gesundheitund Soziales über die Zulassung von Arzneispezialitäten, Bundesgesetzblatt fürdie Republik Österreich 1998:1115.

[AT 6] Kosmetikverordnung vom 12. April 1996 (VO 166/96). Bundesgesetzblatt für dieRepublik Österreich 1996:833-862.

[AT 7] Kosmetikverordnung vom 13. August 1997 (VO 22/97). Bundesgesetzblatt für dieRepublik Österreich 1997:1115-1124.

[B 1] Ministère des Affaires Sociales, de la Santé Publique et de l’Environnement.Arrêté royal du 29 août 1997 relatif à la fabrication et au commerce de denréesalimentaires composées ou contenant des plantes ou préparations de plantes.Moniteur belge (21 novembre 1997) 97-2706.

[B 2] Ministère des Affaires Sociales, de la Santé Publique et de l’Environnement.Circulaire ministérielle du 30 novembre 1994. Directives à la constitution dudossier d’enregistrement des médicaments à base de plantes. Moniteur belge3103-9 (10 février 1995).

[B 3] Ministère des Affaires Sociales, de la Santé Publique et de l’Environnement.Circulaire ministérielle No. 367 du 22 septembre 1989. Directives à laconstitution du dossier d’enregistrement des médicaments à base de plantes.

[B 4] Ministère des Affaires Sociales, de la Santé Publique et de l’Environnement.Circulaire ministérielle du 12 mai 1997 modifiant les listes en annexe à laCirculaire du 30 novembre 1994. Directives à la constitution du dossierd’enregistrement des médicaments à base de plantes. Moniteur belge 3103-9 (10février 1995).

[DK 1] Bekendtgørelse om naturlaegemidler. Sundhedsministeriet nr. 790 af 21.september 1992.

[DK 2] Sundhedsstyrelsens vejledning af 30. september 1992 vedrørende registrering afnaturlaegemidler.

136

[DK 3] Bekendtgørelse om mærkning af og indlaegssedler til lægemidler optaget iSundhedsstyrelsens specialitetsregister. Sundhedsstyrelsens bekendtgørelse nr.314 af 18. maj 1993.

[DK 4] Bekendtgørelse om reklame for lægemidler. Sundhedsministeriet nr. 736 af 7.august 1996.

[FIN 1] Marketing Authorisation for a Herbal Remedy. Administrative Regulation 9/93.National Agency for Medicines. 30 November 1993. Medicines Law, 10 April1987/395 with all amendments.

[F 1] Mélanges de plantes autorisés à être vendus par les herboristes. Arrêté du 7 avril1943 (Journal Officiel de la République Française (J.O.R.F.) du 4 mai 1943)modifié par Arrêté du 27 janvier 1959 (J.O.R.F. du 15 février 1959).

[F 2] Vente des plantes servant à la composition de boissons hygiéniques. Loi du 21juin 1941 (J.O.R.F. du 24 juin 1941). Vente au public de plantes médicinalesinscrites à la Pharmacopée. Décret 79-480 du 15 juin 1979 (J.O.R.F. du 22 juin1979).

[F 3] Circulaire 346 du 2 juillet 1979 (Bulletin Officiel du Ministère de la Santé(B.O.M.S.) du 12 septembre 1979, 79/32) du Ministre de la Santé et de la Famille.

[F 4] Médicaments à base de plantes: Les Cahiers de l’Agence No.3. Agence duMédicament (Note: this document replaces the previous “Avis aux fabricant”published in the Bulletin officiel No. 90/22 of 1990).

[D 1] Naturheilmittel und Besondere Therapierichtungen. Bundesgesundheitsblatt33:297-301.

[D 2] Keller K. Pflanzliche Arzneimittel - rechtlicher Status und offeneForschungsfragen. Forschungsmagazin der Johannes Gutenberg UniversitätMainz, Sonderausgabe Naturheilkunde 1992;59-68.

[D 3] Bekanntmachung der Neufassung der Allgemeinen Verwaltungsvorschrift zurAnwendung der Arzneimittel Prüfrichtlinien vom 5. Mai 1995. Bundesanzeiger1995;47 No. 96a vom 20. Mai 1995.

[D 4] 25. Bekanntmachung über die Verlängerung der Zulassungen nach § 105 desArzneimittelgesetzes (AMG) (Anwendungsgebiete für traditionelle Arzneimittelnach § 109a AMG) vom 11. Juli 1995. Bundesanzeiger Nr. 141 vom 29. Juli 1995,8306-8309.

[D 5] Allgemeine Verwaltungsvorschriften zur Anwendung derArzneimittelprüfrichtlinien vom 14. Dezember 1989. Bundesanzeiger 1989;41 No.243a vom 29. Dezember 1989.

[GR 1] Minister of Health, Providence & Social Insurance. Ministerial DecreeY6a/14290/93 Government’s Gazette Nr.217 of 1 April 1994.

[GR 2] Medicines Law 1985, last amended by Ministerial Order Nr. 9392/93.

[GR 3] Ministerial Decree Y6a/3221, Government Gazette’s No. 782 of 12 September 1995.

[GR 4] Ministerial Decree Y6a/776, Government’s Gazette No. 536.

[GR 5] Presidential Decree 194, Government’s Gazette No. 102, June 1995.

[GR 6] Law 1963/91, Government’s Gazette No. 138.

[GR 7] Ministerial Decree Y6/10170 of 19 October 1995.

[IRL 1] Medical Preparations (Licensing, Advertisement and Sale) Regulations, 1984(S.I. No. 210 of 1984). Borderline Products. Department of Health, Dublin, April1988.

137

[IRL 2] Food Supplements & Health Foods. Report to the Minister of Health and theMinister for Agriculture, Food and Forestry. Food Safety Advisory CommitteeReport No. 16. December 1993.

[IRL 3] Medical Preparations (Licensing, Advertisement and Sale) Regulations, 1998(S.I. No. 142 of 1998).

[IRL 4] Guidelines for Application for Product Authorisation of Herbal Products.National Drugs Advisory Board. Dublin: August 1985.

[IRL 5] Medicinal Products (Prescription and Control of Supply) Regulations, 1996 (S.I.No. 256 of 1996).

[IRL 6] “Fixed Product Combinations”. National Drugs Advisory Board. Annual Report1984.

[I 1] Prodotti a base di piante medicinali. Circolare No. 1 (No. 800.7.AG.8/254).Direzione Generale del Servizio Farmaceutico Divisione VII, 08/01/1981.

[I 2] D.L.vo n. 111 del 27 January 1992 (pubblicato sulla G.U. No. 39 – 17 febbraio 1992)sulla attuazione della Direttiva 89/398/CEE concernente i prodotti alimentaridestinati ad un’alimentazione particolare.

[I 3] Circolare n. 13 del 16 October 1997 (pubblicata sulla G.U. No. 269 del 18 novembre1997) sui medicinali di automedicazione: definizione, classificazione e modellodi foglio illustrativo.

[I 4] IMS: 1996 data on extracts or active principles of vegetal origin (internaldocument).

[I 5] Table dated 18 February 1998 (document from Indena, Milan, Italy).

[I 6] D.L.vo 178/91 (pubblicato sulla G.U. No. 139 del 15 giugno 1991): Recepimentodelle Direttive della Comunità economica europea in materia di specialitàmedicinali.

[I 7] D.L.vo 44/97 (pubblicato sul S.O. alla G.U. No. 54 del 18 febbraio 1997): Attuazionedella Direttiva 93/39/CEE, che modifica le Direttive 65/65/CEE, 75/318/CEE e75/319/CEE relative ai medicinali.

[I 8] D.M. 10 marzo 1998 (pubblicato sulla G.U. No. 83 del 9 aprile 1998): Disposizionisulla documentazione da presentare a corredo delle domande di autorizzazioneall’immissione in commercio dei medicinali per uso umano e di modificadell’autorizzazione.

[I 9] D.L.vo. 185/95 (pubblicato sulla G.U. No. 117 del 22 maggio 1995): Attuazionedella Direttiva 92/73/CEE in materia di medicinali omeopatici.

[I 10] L. 347/97 (pubblicata sulla G.U. No. 241 del 15 ottobre 1997): Disposizioni i nmateria di commercializzazione di medicinali omeopatici.

[I 11] D.L.vo 540/92 (pubblicato sul S.O. alla G.U. No. 7 del 11 gennaio 1993): Attuazionedella Direttiva 92/27/CEE concernente l’etichettatura ed il foglietto illustrativodei medicinali per uso umano.

[I 12] D.L.vo 539/92 (pubblicato sul S.O. alla G.U. No. 7 del 11 gennaio 1993): Attuazionedella Direttiva 92/26/CEE riguardante la classificazione nella fornitura deimedicinali per uso umano.

[I 13] D.L.vo 541/92 (pubblicato sul S.O. alla G.U. No. 7 del 11 gennaio 1993): Attuazionedella Direttiva 92/28/CEE concernente la pubblicità dei medicinali per usoumano.

[I 14] D.L.vo 538/92 (pubblicato sul S.O. alla G.U. No. 7 del 11 gennaio 1993): Attuazionedella Direttiva 92/25/CEE riguardante la distribuzione all’ingrosso deimedicinali per uso umano.

[I 15] Lista dei fitoterapici riportati sul Formulario Nazionale della FarmacopeaUfficiale IX Edizione (internal document).

[I 16] Formulario Nazionale della Farmacopea Ufficiale IX Edizione: Galenicitradizionali – Miscele per tisane (as indicated in [I 15]).

138

[I 17] D.M. 16 aprile 1998 "Approvazione di linee-guida in materia di pubblicità deilassativi"(pubblicato sulla G.U. n. 92 del 21 aprile 1998).

[I 18] XII Commissione Affari Sociali: Testo unificato delle proposte di legge 94.558.639“Regolamentazione del settore erboristico”.

[I 19] Corso di diploma universitario in tecniche erboristiche (Tabella XXVIIIpubblicata sulla G.U. n. 41 del 19 febbraio 1996).

[I 20] Formulario Nazionale della Farmacopea Ufficiale IX Edizione: Galenicitradizionali.

[L 1] Table of medicinal plants and/or parts of medicinal plants intended for use asherbal teas which might be delivered to the public by persons other thanpharmacists on the condition that the labelling and presentation do not refer toany therapeutic property or favourable effect on the health (Ministry of Health).

[NL 1] Wet van 28 juli 1958, Staatsblad 408, houdende nieuwe regeling nopens degeneesmiddelenvoorziening en de uitoefening der artsenijbereidkunst (Wet opde Geneesmiddelenvoorziening).

[P 1] Ministério da Saude. Decreto-Lei n.° 353/93 de 7 de Outubro. Diário da RepúblicaI série A No. 235,5623-5631 (1993).

[P 2] Decreto-Lei n.° 72/91 de 8 Fevereiro 1991.

[P 3] Decreto-Lei n.° 272/95 de 23 Outubro 1995.

[P 4] Decreto-Lei n.° 101/94 de 19 Avril 1994.

[P 5] Decreto-Lei n.° 100/94 de 19 Avril 1994.

[P 6] Decreto-Lei n.° 330/90 de 23 Outubro 1990, com a nova redacção dada pelo Decreto-Lei n.° 6/95 de 17 Janeiro 1995.

[P 7] Decreto-Lei n.° 135/95 de 9 Junho 1995.

[P 8] Instituto Nacional da Farmácia e do Medicamento. Deliberação No. 166/97.Diário da República II série No. 180 de 6 Augustu 1997.

[SP 1] Borrador de Real Decreto, por el que se regulan las plantas, las mezclas, losproductos y medicamentos a base de plantas medicinales, del 4 de avril de 1998.Draft of a Royal Decree on medicinal products based on plants.

[SP 2] Ley 25/1990, de 20 de diciembre 1990, del Medicamento (Boletín Oficial del Estado(B.O.E.) de 22 de diciembre de 1990). (Medicines Law.)

[SP 3] Real Decreto 767/1993, de 21 de mayo, por el que se regula la evaluación,autórización, registro y condiciones de dispensación de especialidadesfarmacéuticas y otros medicamentos de uso humano fabricados industrialmente(B.O.E. de 2 de julio de 1993). (Royal Decree on the evaluation, authorisation, andsale of medicinal products and other drugs for human use to be manufactured onan industrial basis.)

[SP 4] Real Decreto 2000/1995, de 7 de diciembre 1995, por el que se modifica el RealDecreto 767/1993, de 21 de mayo, que regula la evaluación, autórización, registroy condiciones de dispensación de especialidades farmacéuticas y otrosmedicamentos de uso humano fabricados industrialmente (B.O.E. de 12 de enero1996). (Royal Decree modifying Royal Decree 767/1993.)

[SP 5] Orden de 3 de octubre de 1973 por la que se establece el registro especial parapreparados a base de especies vegetables medicinales (B.O.E. de 15 de octubre de1973). (Instruction on registration of herbal remedies.)

[SP 6] Real Decreto 1564/1992, de 18 de diciembre 1992, pro el que se desarrola y regulael régimen de autorización de los laboratorios farmacéuticos e importadores demedicamentos y la garantía de calidad en su fabricación (B.O.E. de 2 de febrerode 1993). (Royal Decree on pharmaceutical companies.)

139

[SP 7] Real Decreto 3176/1983, de 16 de septiembre 1983, por el que se aprueba laReglamentación Tecnico-Sanitaria para la elaboración, circulación y comerciode especias vegetales para infusiones de uso en alimentación (B.O.E. de 28 dediciembre de 1983). (Technical and sanitary regulation on herbal teas.)

[SP 8] Real Decreto 2244/1984, de 26 de septiembre 1983, por el que se aprueba laReglamentación Tecnico-Sanitaria para la elaboración, circulación y comerciode condimentos y especias (B.O.E. de 22 de diciembre de 1984). (Technical andsanitary regulation on food additives.)

[SP 9] Real Decreto 2236/1993, de 17 de diciembre 1993, por el que se regula el etiquetadoy el prospecto de los medicamentos de uso humano (B.O.E. de 18 de febrero de1994). (Royal Decree on labelling of medicines.)

[SP 10] Real Decreto 1416/1994, de 25 de junio 1994, por el que se regula la publicidad delos medicamentos de uso humano (B.O.E. de 29 de julio de1994). (Royal Decreeon advertising of medicinal products for human use.)

[SP 11] Real Decreto 1354/1983, de 27 de abril 1983, por el que se regula laReglamentación Tecnico-Sanitaria para la elaboración, circulación y comerciodel té y derivados (B.O.E. de 27 de mayo de 1983). (Technical and sanitaryregulation on herbal teas.)

[S 1] Läkemedelsverkets allmänna råd om godkännande av naturläkemedel förförsäljning (LVFS 1995:18).

[S 2] Läkemedelslag (SFS 1992:859).

[S 3] Läkemedelsverkets föreskrifter och allmänna råd (LVFS 1995:11) omläkemedelsförpackningar och märkning av läkemedel.

[S 4] Läkemedelsförordning (SFS 1992:1752).

[S 5] Marknadsföringslag (SFS 1995:450).

[UK 1] The Medicines Act 1968. London: HMSO, 1968.

[UK 2] UK Statutory Instrument 1994 No. 3144, The Medicines for Human Use(Marketing Authorisations Etc.) Regulations 1994.

[UK 3] Medicines Control Agency. A Guide to what is a medicinal product. MedicinesLaw Leaflet MAL 8. London: December 1995.

[UK 4] The Medicines (Exemptions from Licences) (Special and Transitional Cases)Order 1971 (k).

[UK 5] The Medicines (Retail Sale or Supply of Herbal Remedies) Order 1977. London:HMSO, 1977 (Statutory Instrument (SI) 1977/2130).

[UK 6] The Medicines Labelling (Amendment) Regulations 1992 (SI 1992/3273).

[UK 7] The Medicines Leaflets (Amendment) Regulations 1992 (SI 1992/3274).

[UK 8] The Medicines (Advertising) Regulations 1994 (SI 1994/1932).

[UK 9] The Medicines (Monitoring of Advertising) Regulation 1994 (SI 1994/1993).

[UK 10] The Medicines (Advertising) Amendment Regulations 1996 (SI 1996/1552).

[CAN 1] TPP Background Information for the Standing Committee on Health, Producedby the Therapeutic Products Programme, Health Canada, November 1997.

[CAN 2] Traditional Herbal Medicines, Drugs Directorate Guideline, Health ProtectionBranch, Canada, 1990.

[CAN 3] Policy Issues: Medicinal Herbs in Traditional Herbal Medicines, Bureau ofNonprescription Drugs, The Drugs Directorate, Canada, October 1995.

[CAN 4] Homeopathic Preparations: Application for Drug Identification Numbers, DrugsDirectorate Guideline, Health Protection Branch, Canada, 1990.

140

[CAN 5] Policy Issues: Indications for Use – Multi-ingredient Low Dilution HomeopathicPreparations, Bureau of Pharmaceutical Assessment, Therapeutic ProductsProgramme, March 1997.

[CAN 6] Guideline for Low Dilution Multi-ingredient – Homeopathic Products withIndications for Use, Bureau of Pharmaceutical Assessment, Therapeutic ProductsProgramme, March 1997.

[CAN 7] Good Manufacturing Practices, Supplementary Guidelines for the Manufactureof Herbal Medicinal Products, Final Version, Drugs Directorate, Canada, 1996.(1998 version to be available in the near future.)

[CAN 8] Policy Issues: Herbs Used as Non-medicinal Ingredients in NonprescriptionDrugs for Human Use, Bureau of Nonprescription Drugs, The Drugs Directorate,Health Canada, September 1995.

[MEX 1] Bylaws of the General Health Law, 4 February 1998.

[MEX 2] Labeling Norm for Medicinal Products.

[USA 1] Dietary Supplement Health and Education Act. 1994. Public Law 103-417.

[USA 2] Office the Federal Register. 1997. Code of Federal Regulations. Procedures forclassifying OTC drugs as generally recognized as safe and effective and notmisbranded, and for establishing monographs. Title 21: Food and drugs, part330.10 rev. Washington, DC: U.S. Government Printing Office.

[USA 3] Office of the Federal Register. 1997. Code of Federal Regulations. Adequate andwell-controlled studies. Title 21: Food and drugs, part 314.126 rev. Washington,DC: U.S. Government Printing Office.

[USA 4] Federal Register. May 11, 1972. 37:9464.

[USA 5] Commission on Dietary Supplement Labels. 1997. Report on the Commission onDietary Supplement Labels.

[USA 6] Quote from Prevention Magazine survey. 1997. In: HerbalGram 40.

[USA 7] Tom Simone citing data from Information Resources Inc., Chicago. In:Drugstores largest mass-market channel for supplement sales, Natural Business,March 1998.

[USA 8] Richman, A. and J.P. Witkowski. 1997. Whole Foods, October. In: Herbalgram41:53.

[USA 9] Office of the Federal Register. 1997. Code of Federal Regulations. Current goodmanufacturing practice in manufacturing, packing or holding human food. Title21: Food and drugs, part 110 rev. Washington, DC: U.S. Government PrintingOffice.

[USA 10] Keller, K. 1992. Results of the revision of herbal drugs in the Federal Republic ofGermany with a special focus on risk aspects. Zeitschrift für Phytotherapie116:118.

[USA 11] Henry A. Waxman in Hearing of the Subcommittee on Health andEnvironment, Committee on Energy and Commerce, House of Representatives,29 July 1993.

[USA 12] Tyler, Varro. 1997. When will there come a savior? HerbalGram 41:27-28.

[USA 13] Nutrition Labeling and Education Act. 1990. Public Law 101-535.

[USA 14] Food and Drug Administration Modernization Act of 1997. Public Law 105-115.

[USA 15] Foster, S. ed. 1992. Herbs of Commerce. American Herbal Products Association,Bethesda, MD.

[USA 16] Federal Trade Commission Act, 5 U.S.C. 45.

[USA 17] Federal Trade Commission. 1994. Enforcement policy statement on foodadvertising. Federal Register 59:28388-28396.

141

[USA 18] Federal Trade Commission. 1983. Advertising substantiation program; requestfor comment. Policy statement regarding advertising substantiation. FederalRegister 48:10471-10475.

142

XII. ANNEXES

XII.1 List of AcronymsAdM French Medicines Agency (“Agence du Médicament”) FranceADR Adverse Drug Reaction GeneralAESGP Association of the European Self-Medication Industry GeneralAMG Medicines Law (“Arzneimittelgesetz”) Austria & GermanyANPRM Advanced Notice of Proposed Rule Making USAAspV Regulation on Curing Specialties (“Arzneispezialitätenverordnung”) AustriaATF Bureau of Alcohol, Tobbaco and Firearms USABfArM Federal Institute for Drugs and Medical Devices (“Bundesinstitut für Arzneimittel

und Medizinprodukte”) GermanyBGA Federal Health Authority (“Bundesgesundheitsamt”) GermanyBP British Pharmacopoeia United KingdomCFSAN Center for Food Safety and Applied Nutrition USACGMP Current Good Manufacturing Practice USACPMP Committee for Proprietary Medicinal Products GeneralCSP Public Health Law (“Code de la Santé Publique”) FranceCUF Italian Medicines Committee (“Commissione Unica del Farmaco”) ItalyD.L.vo Legislative Decree (“Decreto legislativo”) ItalyDIN Drug Identification Number CanadaDLS Danish Pharmaceutical Standards (“Dansk Lægemiddelstandarder”) DenmarkDSHEA Dietary Supplement Health and Education Act USAEAPC European-American Phytomedicines Coalition USAEEA European Economic Area GeneralEEC European Economic Community GeneralEFP Products containing active ingredients included in the positive list established

by the Ministry of Health SpainEMEA European Agency for the Evaluation of Medicinal Products GeneralEOF Greek Health Authority GreeceESCOP European Scientific Cooperative on Phytotherapy GeneralEU European Union GeneralFU Italian Pharmacopoeia (“Farmacopea Ufficiale”) ItalyFASS List of approved medicinal products SwedenFDA Federal Food and Drug Administration USAFDCA Federal Food, Drug and Cosmetic Act USAGDP Good Distribution Practice GeneralGMP Good Manufacturing Practices GeneralGRAS Generally Recognised As Safe GeneralGSL General Sale List United KingdomGU Official Journal (“Gazzetta Ufficiale”) ItalyHAB Homeopathic Pharmacopoeia (“Homöopathisches Arzneibuch”) GermanyHACCP Hazard Analysis and Critical Control Points USAHPUS Homeopathic Pharmacopoeia of the United States USAIMB Irish Medicines Board IrelandInfarmed National Institute of Pharmacy and Medicines (“Instituto Nacional da Farmácia

e do Medicamento”) PortugalIPHA Irish Pharmaceutical Healthcare Association IrelandJORF Official Journal of the Republic of France (“Journal Officiel de la République

française”) FranceLIF The Association of the Pharmaceutical Industry Sweden & DenmarkLMBG Law on Foodstuffs and Consumer Goods (“Lebensmittel- und Bedarfsgegen-

ständegesetz”) Germany

143

LVFS Ordinance issued by the Medical Products Agency (“Läkemedelsverketsföreskrifter”) Sweden

MAFF Ministry of Agriculture, Fisheries and Food United KingdomMAL Medicines Act Leaflet United KingdomMCA Medicines Control Agency United KingdomMEB Medicines Evaluation Board The NetherlandsMPA Medical Products Agency (“Läkemedelsverket”) SwedenNAFTA North American Free Trade Agreement North & Central AmericaNAM National Agency for Medicines (“Lääkelaitos”) FinlandNCE New Chemical Entity GeneralNDA New Drug Application USANDAB National Drugs Advisory Board IrelandNLEA Nutrition Labeling and Education Act USANLN Nordic Council on Medicines GeneralNYHA New York Heart Association GeneralÖAB Austrian Pharmacopoeia (“Österreichisches Arzneibuch”) AustriaOJ Official Journal of the European Communities EUOTC Over-the-counter GeneralP Pharmacy-only United KingdomPh.Eur. European Pharmacopoeia GeneralPh.F. French Pharmacopoeia (“Pharmacopée française”) FrancePOM Prescription-Only Medicine United KingdomRDA Recommended Daily Allowance FinlandSFS Act issued by the Swedish Parliament (“Svensk Författningssamling”) SwedenSPC Summary of Product Characteristics GeneralTCM Traditional Chinese Medicine GeneralTHM Traditional Herbal Medicine CanadaTLC Thin Layer Chromatography GeneralTPP Therapeutic Products Programme CanadaTRM WHO Traditional Medicine Programme GeneralUSP United States Pharmacopoeia United StatesW H O World Health Organisation General

144

XII.2 List of Tables

Table 1: Documents Prepared by the ad hoc Working Group on Herbal MedicinalProducts.......................................................................................................... 10

Table 2: Implementation of Council Directive 65/65/EEC........................................... 13Table 3: Categories of plant-based medicinal products in Spain ................................ 20Table 4: Combinations of herbal ingredients and combinations of herbal and

homeopathic ingredients................................................................................ 33Table 5: Combination of herbal ingredients with vitamins and food supplements.... 34Table 6: Application of Council Directive 65/65/EEC to herbal medicinal products... 36Table 7: Renewal of marketing authorisations in Finland ....................................... 46Table 8: Option of bibliographic application................................................................ 49Table 9: Existence of a category for well-known plants.............................................. 54Table 10: Countries without a specific category for well-known plants........................ 54Table 11: Examples of plant preparations included in the Austrian “Section 17a”

list................................................................................................................... 56Table 12: Examples of plants included in the Belgian list with the option of

simplified proof of efficacy............................................................................ 56Table 13: Examples of plants and indications from the French Agency Instructions

No. 3 (“Cahiers de l’Agence No. 3”) ................................................................ 59Table 14: Examples of plants and indications from the German “traditional” list .... 61Table 15: Examples of medicinal plants and their indications from Annex II of the

Spanish draft Royal Decree ........................................................................... 62Table 16: Countries without the option to provide simplified proof of efficacy.............. 63Table 17: Requirements for quality documentation, proof of safety and proof of

efficacy in Member States.............................................................................. 63Table 18: Specific indication claims for the simplified proof of efficacy..................... 63Table 19: “Modern” herbal medicinal products in the German market ...................... 66Table 20: Comparison of the requirements for proof of efficacy................................... 68Table 21: Main indications for herbal medicinal products in Finland....................... 82Table 22: Main ingredients for herbal medicinal products in Finland (number of

products) ......................................................................................................... 82Table 23: Main ingredients of herbal medicinal products in the Netherlands............ 84Table 24: Authorised herbal medicinal products in the Swedish market..................... 85Table 25: Ingredients and indications of licensed herbal medicinal products in the

United Kingdom market................................................................................ 86Table 26: Acceptance of consumer reports..................................................................... 96Table 27: Implementation of Council Directive 92/27/EEC........................................... 97Table 28: Retail sale of herbal medicinal products....................................................... 113Table 29: Distance selling and teleshopping................................................................. 113Table 30: Herbal medicinal products authorised in Mexico......................................... 129Table 31: Herbal supplements sales in natural food stores in USA [USA 8] ................ 140

145

XII.3 Translation of “Herbal Medicinal Products” in theOfficial Languages of the European Community

LanguageTranslation

Danish Naturlægemidler (term used today)Plantelægemidler (herbal medicinal products)

Dutch Kruidengeneesmiddel (NL)Plantaardige medicinale producten (B)

Finnish Rohdosvalmiste (term used today)Käsvirohdoslääke (herbal medicinal products)

French Médicament à base de plantesGerman Pflanzliches ArzneimittelGreek º˘ÙÈk· Ê·ÚÌ·kÂ˘ÙÈk· ÚÔÈÔÓÙ·Italian Fitoterapici

orMedicinali a base di piante

Portuguese Produto medicinal à base de plantasorMedicamento à base de plantas

Spanish Medicamento a base de plantasSwedish Naturmedel (term used today in Finland)

Naturläkemedel (term used today in Sweden)Växtbaserade Läkemedel (plant-based medicinalproducts)

Herbal medicinal products in the European Union

Documents

Transcript of Herbal medicinal products in the European Union