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DOI: 10.1177/009286150003400316

2000 34: 801Drug Inform ation Journal Paolo M. Biffignandi and Lorella Carletto

ProductsThe New Attitude of the European Regulatory Authorities about Herbal Medicinal

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D ~ Rn f o m f i o n Journal, Vol. 34 pp. 801-808. 2000Printed in [he USA. All rights reserved

0092-8615/2000Copyright 2 rug Information Association Inc.

THE NEW ATTITUDE OF THE EUROPEANREGULATORY AUTHO RITIES ABO UT

HERBAL M EDICINAL PRODUC TS

PAOLO M. BIFFIGNANDI,D, PHD

LORELLAARLETTO, HDSocieta Italiana Attivita Farma ceutiche, Torino, Italy

VI.REL Pharm a, Vinovo Torino), Italy

In 1997, an ad hoc Herbal Medicinal Products Working Group HM PW G)was establishedat the European Medicines Evaluation Agency in order to provide guidance fo r applicantsand prepare recommendations on the criteria fo r the assessment of quality, safety, andefficacy of herbal medicinal products. T he following topics were addressed in a detaileddocument containing several notes fo r guidance, comments, or points to consider: Noticeto Applicants presentation and content of the application dossier), quality guidanceagricultural production, requirements of active herbal substances and herbal medicinal

products, and Type I and Type I I variations), and preclinical and clinical assessmentgiving particular emphasis to taking the existing scientific literature into account in

order to avoid unnecessary animal tests and clinical trials in humans). Details andimplications o these documents are presented here.

Key Words: Herbal drugs; Europe; Regulatory affairs; European Medicines EvaluationAgency; Summary of Product Characteristics

INTRODUCTION

BELIEF IN T HE SUPERIORITYof naturaland organic remedies, which gained consid-erable impetus in industrialized countries in

recent decades, may be viewed as an out-growth of the counterculture movement ofthe 1960s. As a matter of fact, among con-sumers and health care providers, we stillfind people who insist that Vitamin C fromnatural sources is in some way different fromand superior to Vitamin C prepared syntheti-cally from glucose.

On the other hand, it is well recognizedthat the scientific advances on biodiversity

Reprint address: Paolo Biffignandi, Societa ItalianaAt-tivita Farmaceutiche, Corso Re Umbeno I, 44 0128Torino, Italy.

with the screening of biological extracts fornovel chemical compounds (not only herbalin origin) can provide leads in the develop-ment of new medicines or in a better andmore responsible use of older, traditionalremedies. There are several issues, however,involved in the licensing of herbal products;these become all the more pressing as thepopularity of herbal products grows and thedangers become more apparent (1).

Despite a number of definitions, the bor-derline between medicinal products, cosmet-ics, and food or dietary supplements is oftena “gray area,” sometimes making it difficultto determine into which category a product

falls. This is partly because many herbal andother natural remedies are currently mar-keted under differing regulatory labels, rang-ing from foods to over-the-counter products,

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8 2 Paolo M ifJignandi and Lorella Carletto

largely depending on local marketing consid-erations and taking advantage of a substantiallack of regulation (2).

This consumer-driven exponential pace ofnutritional and herbal excitement must notovershadow the fact that many herbal reme-dies are founded on a sound and scientifi-cally-proven basis and that this field has greattherapeutic expectations. The American Di-etetic Association ADA) recently stated that:“Growing scientific evidence supports therole of phytochemicals and functional fo od sin the prevention and treatment of at leastfour of the leading causes of death in thiscountry USA): cancer; diab etes, cardiov as-cular diseas e, and hypertension, and with theprevention a n d o r treatment of other medicalailments including neural tube defe cts, osteo-porosis, abnormal bowel function, and ar-thritis” 3).

From a marketing point of view, annualsales growth rates of more than100 forpopular herbs such as ginseng, St. John’sWort, and echinacea, o r for oligosaccharides,

minerals, and Om ega-3 fatty acids, have beenrecorded everywhere. In Germany, for in-stance, the value of prescriptions fo r the anti-depressant St. John’s Wort is twice that ofProzac. Even more impressive is the natureof the companies involved. No longer arenutraceuticals being produced by niche man-ufacturers; som e of the world’s leading phar-maceutical manufacturers have entered thefield. Analysts say that the impact of nutra-ceuticals on the health care market can onlyincrease 4). The aim of this paper is to dis-cuss the new regulatory attitude of the Euro-pean Medicines Evaluation Agency EME A)toward herbal medicinal products.

THE CONTRIBUTION OF THEEUROPEAN SCIENTIFIC

COOPERATIVE ONPHYTOTHERAPY AND WO RLD

HEALTH ORGANIZATIONMONOGRAPHS

cines” with the aim of defining basic criteriafor the eva luation of q uality, safety, and effi-cacy of herbal medicines. These documents

were intended to facilitate the work of regula-tory authorities, scientific bodies, and indus-try Based o n these criteria, WH O’S Tradi-tional Medicine Programme(TRM) prepareda technical docum ent entitled “Model Mono-graphs of Widely Used Medicinal Plants,”including botanical, chemical, and pharma-cological aspects. Twenty eight model mono-graphs have been adopted and were pre-sented at the 8’ International conference ofDrug Regulatory Authorities ICDRA ) in1996.

At the European level, the European Sci-entific Cooperative on Phytotherapy ES-COP ) was founded in 1989 by six nationalscientific associations with the objective ofestablishing a scientific umbrella organiza-tion to provide harmonized criteria for theassessment of herbal medicinal products,support scientific research, and contribute tothe acceptance of phytotherapyin Europe (5).

ESCOP is now comp rised of 13 national as-sociations across Europe Austria, Belgium ,Denmark, France, Germany, Ireland, Italy,the Netherlands, Norway, Portugal, Sweden,Switzerland, and the United Kingdom) andthe American Botanical Council. The ES-COP Scientific Committee published 50monographs for individual plant drugs fol-lowing the European Summary of ProductCharacteristics SPC) format, some of whichhave been officially adopted by the Commit-tee for Proprietary Medicinal ProductsCPMP).

REGULATORY BACKGROUN D

Until now, regulatory requirements for herbalmedicinal products were not harmonized inthe European Union EU), and were basedupon d ifferent local attitudes. Such products,however, when industrially prepared, fall

within the scope of Council Directive 65/65/EEC. They haw access to the decentralizedIn past years, a consultation of the WorldHealth Organization WH O) drafted “Guide-lines for the Assessment of Herbal Medi-

marketing authorization procedure and thecu rrent major differences in the assessmentof their quality, safety, and efficacy were felt

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European Herbal Medicinal Rules 803

to represent a risk to consumers or to hindertheir free circulation across the EU.

In order to prepare guidance intended for

mutual recognition of marketing authoriza-tions MA) in the field of herbal medicinalproducts, an ad hoc Working Group HerbalMedicinal Products Working Grou p) was es-tablished at the EMEA in May 1997, underthe initiative of the European Parliament, the

groups of substances generally accepted tocontribute substantially to the therapeuticactivity of an herbal drug or of a prepara-

tion, andMarkers: chemically defined constituentsof an herbal drug which are of interest forcontrol purposes independent of whetheror not they have any therapeutic activity.

DETAILS OF THE REPORTuropean Commission, and the EMEA exec-utive director. su m ort ed bv the EMEA Man-

inal products. Draft proposals and recom-mendations were presented in a report inearly 1999 EMEA/HMPWG/25/99) to theEMEA M anagement Board A full copy ofthe most recent draft and final proposals gov-erning herbal medicinal products can befound at the EMEA website: http://www.eudra.org/emea.html.)

WORKING DEFINITIONS

According to the glossary adopted, the fol-lowing terms are used:

Herbal drugs: plants thallophytes, espe-cially lichens, higher fungi, and algae, areincluded as well) or part of plants in anunprocessed state, which are used fo r a me-dicinal or pharmaceutical purpose anherbal drug is regarded as one active sub-stance whether or not the constituents withtherapeutic activity are known),Herbal drug preparations: comminuted orpowdered herbal drugs, extracts, tinctures,fatty or essentialoils, expressed juices, pro-cessed resins or gums, andso forth, preparedfrom herbal drugs, and possibly includingsolvents, dilutents, and preservatives,Herbal medicinal products: medicinal

products containing as active substancesexclusively herbal drugs or herbal drugpreparations,Constituents wit h known therapeutic acti v-ity: chemically defined substances or

Regulatory Aspects

1. Final comments for revision of Notice toApplicants Volume 2A Part 1.4.2. Biblio-graphic applications: these suggest in-cluding a paragraph on scientific mono-graphs eg, those drafted by ESC OP and

WHO for herbal drugs, as they offer avaluable and updated overview on pub-lished scientific literature. These mono-graphs may avoid duplication of work andbring about gradual harmonization in theevaluation of herbal medicinal productssee Table 1 for an updated list of plants

included in ESCOP monographs),2. Draft Comments on the Commission Regu-

lation E C ) No. 541 95 of 10 March 1995concerning the examinations of variations

to the terms of a marketing authorizationgranted by a competent authority of aMember State a s amended by CommissionRegulation E C ) No. 1146/98: these com-ments amend Annex I and Annex I1 of theabove Commission Regulation to encom-pass herbal medicinal products a finalversion was issued in November 1999),

3. Drafi Comments on the European Com-mission Guidelineon dos sier requirementsfor Type I variations:

sameas

above aparticular emphasis is put on manufactur-ing route, geographical source, and pro-duction of the herbal drug ) a final versionwas issued in November 1999), and




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804 Paolo M ifJignandi and Lorella Carletto

TABLE 1List o Monographs on t he Medic lnal Uses of

Plant Drugs Prepared b y ESCOP Updated: October 1999)

Wormwood Devil’s Claw Psyllium SeedGarlic Horse chestnut Seed CascaraCape Aloes St. John’s Wart RhubarbMarshmallow Root Juniper Berry Blackcurrant LeafAniseed Iceland Moss RosemaryArnica Flower Linseed Willow BarkBirch Leaf Hop Strobile Sage LeafBold0 Matricaria Flower Senna LeafCalendula Flower Melilotus Alexandrian Senna PodsCaraway Melissa Leaf Tinnevelly Senna PodsCentaury Peppermint Oil Golden RodHawthorn Leaf and Flower Peppermint Leaf FeverfewPale Coneflower Root Myrrh Dandelion LeafPurple Coneflower Herb Restharrow Root Dandelion RootPurple Coneflower Root Java Tea ThymeEucalyptus Oil Passiflora Nettle Leaf/HerbFennel lspaghula Nettle RootFrangula Bark lspaghula Husk Bearberty LeafGentian Root Senega Root Valerian RootHamamelis Leaf Primula Root Ginger

4. Comments on the Report “Herbal medici-nal produ cts in the European Union ol -

lowing the study carried out by AESGPo beharfo f the European C omm ission: acriticism was made on the labeling “tradi-tional use” when no evidence of efficacyis available, as this may be perceived bythe public as a positive enforcement of theuse, rather than to make the deficiencyevident.

Quality of Herbal Medicinal Products

1. Draft Comments on the draft directive onthe Go od Manufacturing Practice G M P)guide f o r the starting materials of medici-nal products and inspection of manufac-turers: GMP, including Good AgriculturalPractice (GAP), should apply to herbalstarting materials. GAP guidelines wereprepared by the European Herbs Growersand Producers Association (Europam) in1998 and should become mandatory in

2003. They are intended to apply to thegrowing and primary processing of all me-dicinal and aromatic plants traded andused in the EU. A main goal is to ensurethat the plant raw material meets the de-

mands of the highest standards of quality.Crucial aspects are that this material: is

produced hygienically, in order to reducemicrobiological load to a minimum, andis produced with care, so that the negativeimpacts affecting plants during cultivation,processing, and storage can be limited.Producers, traders, and processors of me-dicinal and aromatic plants should complywith the GAP guidelines and documentthis by a Way Bill (batch documentation),

2 . Final Comm ents fo r revision of Good man-ufacturing Practice G M P ) provisions: aneed for a general monograph on herbaldrugs in the European Pharmacopoeia wasstressed because harmonized criteria forlimits for toxic metals and mycotoxins arestill lacking,

3. Final Comments for revision of Notice toApplicants Volume 2B Part ICI “Tabularform uts specific to herbal medicinal prod -uc ts” : a sample for tabular formats to beincluded in the pharmaceutical Expert Re-

port was given, containing some issuesspecific to herbal medicinal products,4. Final Com ments fo r revision of Notice to

Applicants Volume 2B Part 11: detailedamendments concerning chemical, phar-




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maceutical, and biological documentationfor vegetable medicinal products weresuggested, including the following: in the

case of an herbal drug preparation, amonograph on the herbal drug must bepresented; if no such document exists, ei-ther in the European Pharmacopoeia or inthe pharmacopoeia of a Member State, acomprehensive specification of the herbaldrug has to be filed, including parts of theplant, definition of the herbal drugherbaldrug preparation, ratio of the herbal drugto the preparation, extraction solvents,constituents with known therapeutic activ-ity or markers, and tests for adulterantsand for known toxic constituents (as faras herbal drug preparations such as ex-tracts are concerned, these latter are listed:eg, ginkgolic acids, etc.). Data on stabilitytests on active substances may not be re-quired if justified by the applicant, pro-vided that the finished product is manufac-tured immediately after production of theactive substance. For herbal medicinal

products, in the instance of herbal drugpreparations containing constituents withknown therapeutic activity, the limitshould be 5 of the initial assay value,unless justified. In the case of constituents‘without known therapeutic activity, a limitof 10 of the initial value can be acceptedif justified by the applicant. These criteriaapply to stability testing of active sub-stances as well,

5 . Final Prop osals fo r revision of the Note fo r

guidance on quality of herbal remedies:Besides the fact that GMP must be strictlyfollowed, in the case of herbal drugs whereconstituents of known therapeutic activityare not known, assays of markers (withtest procedure) are required. The choiceof markers should also be justified. Ana-lytical procedures not given in a pharma-copoeia should be validated in accordancewith the relevant International Conference

on Harmonization (ICH) guideline. If theherbal medicinal product contains a prepa-ration, the comprehensive specification onboth the drug and the preparation must besupplied either as part of the Marketing

Authorization application or using the Eu-ropean Drug Master File procedure,

6 Draft Note fo r gu idance on speci’cations:

test procedures and acceptance criteria f o rherbal drug preparations herbal dr ug )and herbal medicinal products: this is arather large guideline providing generalprinciples in the marketing approval pro-cess for a uniform set of specifications forherbal drugs and their preparations andherbal medicinal products, necessary toensure consistent production of such prod-ucts. (A final version of this Note for guid-ance was issued in November 1999), and

7 Draft Comments on the CPMP Note fo rguidance on stability testing fo r a Typevariation to a marketing authorization: afinal version of the proposed changes wasissued in November 1999.

Safety of Herbal Medicinal Products

1. Final Comments o Notice to Applicants

Volume 2B P art IC2 “Expert report ontoxico-pharmacological documentation”and Part “Toxico-pharm acologicaldocumentation”: These were found ade-quate for herbal medicinal products,

2. Proposals fo r a Note fo r guidance on non-clinical testing of herbal drug prepara-tions with long-term marketing experi-ence-guidance to facilita te mutualrecognition and use of bibliographic d ata:It was recognized that published nonclini-cal trials for well-established herbal drugpreparations are often unsatisfactory com-pared with today’s state of the art. Al-though the CPMP Safety Working Partyhas not yet expressed its opinion, theHMPWG stressed the need to avoid un-necessary tests in animals when clinicaland postmarketing experience gained bywidespread use in humans exists. Thus,single and repeated dose toxicity, immuno-

toxicity, and local tolerance testing, as wellas pharmacological tests including safetypharmacology and pharmacokinetics, arenot necessa ry for well-established herbaldrug preparations. New safety experience




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8 6 Puolo M iffignundi and Lorella Curletto

should be collected, however, on effectsdifficult or even impossible to detect onclinical grounds, such as toxicity to repro-

duction, genotoxicity, and carcinogenicity.A major role of the Expert Report is recog-nized to critically discuss available evi-dence and to justify the lack of preclinicalsafety studies, also taking into consider-ation related botanical species. Reproduc-tive toxicological tests in animals are notnecessary if one of the following criteriais fulfilled: results from epidemiologicaldata of adequate power or post-marketingsafety studies are available or results frominvestigations in pregnant women and ne-onates are present.

As far as genotoxicity is concerned, i twas considered appropriate to initially per-form a bacterial reverse mutation test us-ing a test battery of different bacterialstrains and metabolic activation, accordingto ICH guidelines. A cooperative approachis encouraged to investigate herbal drugpreparations with the same specifications.

Carcinogenicity studies are not neededwhen there is no suspicion of such a risk(this is in accordance to current CPMP/ICH pharmaceutical guidelines).

Efficacy of Herbal Medicinal Products

1. Final Comments on Notice to ApplicantsVolume 28 , Part I BI ummary of Prod-uct Characteristics: No difference wasmade between herbal medicinal productsand other medicinal products. Core SPCsfor Valeriana radix and Ispaghula husk,based on those prepared by ESCOP areattached to the set of guidelines,

2 . Final Comments and proposals f o r revi-sion of Part 4 of Annex to Council Dire c-tive 75/318/EECof 20 May 1975 “Clinicaldocumentation ” as a general frame, docu-mentation on experience in the form of

epidemiological studies can be taken intoaccount in bibliographic applications forwell-established medicinal products, pro-vided that identity or essential similarity

between the product tested in publishedclinical trials and the product intended formarketing has been assessed. As with the

preclinical Expert Report, the Clinical Ex-pert Report must pay particular attentionto available experience in humans, to thedifferences between the product tested inpublished papers and that to be submittedfor registration (this is often somewhat dif-ficult for products such as extracts or otherherbal preparations), and to any missinginformation in a bibliographical applica-tion for a well-established product. Sincethe demonstration of the mode of actionof an herbal medicinal product often can-not be clarified, the documentation of effi-cacy should be a priority. On the otherhand, pharmacokinetic data will not be re-quired unless there are grounds for safetyconcerns, for example, a narrow therapeu-tic range of the active constituent. Post-marketing experience is of particular im-portance for herbal medicinal products.The applicant is asked to put a special

emphasis on this issue for individual prod-ucts and for all related products originatingfrom the same herbal drug,

3 . Final Note fo r guidance on fir ed combina-tions of herbal medicinal products withlong-te rm marketing experi ence-g uid-ance to faci litat e m utual recognition anduse of bibliographic data: It was recog-nized that fixed combinations of herbalmedicinal products are in widespread usein phytotherapy and that there is a need toguarantee the availability of such rationalcombinations to consumers and physi-cians. Applicants will then be required tojustify the potential advantages of a fixedcombination (ie, a level of efficacy similarto that achievable by each active substanceused alone at higher doses but associatedwith a better safety profile, or a better levelof efficacy with an acceptable safety pro-file, or a simplification of therapy) and its

possible disadvantages. The Expert Re-port will address the question of the addi-tion or potentiation of the phannacody-namic effe cts of the various herbal drugs/




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herbal drug preparations and of the phar-macokinetic parameters of each activesubstance. Although bibliographic data

should be submitted for a fixed combina-tion already in widespread use, for essen-tially new combinations (active substancesnot usually combined, unusual quantitativecomposition of usually combined sub-stances, or one entirely new substance),the data needed will be similar to a newchemical entity,

4. Draft Points to consider on the evidenceof safety and eficacy required for well-established herbal medicinal products inbibliographic applications: Many herbalmedicinal products have been used as me-dicinal products for several decades oreven hundreds of years, creating a compre-hensive body of experience in publishedmedical literature. This evidence has to beused to avoid or reduce animal experi-ments and clinical trials in humans. Also,herbal medicinal products are often usedas over-the-counter drugs in the treatment

of minor illness and in some Europeancountries herbal preparations have a legalstatus which is different from medicinalproducts without being subject to a fullscientific assessment; although Europeanharmonization is the final aim of this bodyof rules, it was recognized that older usesin a less restricted environment may havegenerated information on safety and effi-cacy of herbal medicinal products thatshould be used in the current assessment.In this regard, a detailed understandingabout the terms “well-established use,”and “recognized efficacy” is crucial. Inorder to label an herbal medicinal productas having “well-established use,” the fol-lowing conditions must be fulfilled:

In abridged applications, a well-estab-lished medicinal use can be accepted ifan herbal medicinal product is essen-tially similar to one authorized in the

EU for more than 6/10 years. Althoughcriteria for essential similarity are thesame as for conventional medicinalproducts, complex biological mixtures,

such as herbal extracts produced by dif-ferent manufacturers, are never identi-cal; in using published literature to sup-

port an application, one should payattention to specifications and manufac-turing process, the extraction solvents,and the drug/extract ratio; appropriatedata on bioavailability may be required,Well-established use also implies that asufficient number of patients weretreated by the concerned product or byan essentially similar one, andInclusion of a given herbal drug prepara-tion in official pharmacopoeias and sci-entific reference textbooks may finallycontribute to substantiating this label.

“Recognized efficacy” must emerge frommedical literature, taking into account thetype of documents to include and aspectssuch as the number of patients, specific diag-nosis, preparation used, dosage and durationof treatment, criteria for evaluation, and ap-plicable statistical analysis. Relevance and

credibility of published data must be judgedaccording to United States Food and DrugAdministration criteria (6). A review of theliterature should identify the level of evi-dence of the safe and effective use of anherbal medicinal product. The definitions ofthe types of evidence (ranging from Ia Evi-dence obtained from meta-analysis of ran-domized controlled trials, to IV Evidenceobtained from expert committee reports oropinions andor clinical experience of re-spected authorities) and the grading of rec-ommendations (ranging from A to C, the lat-ter indicating absence of directly applicablestudies of good quality) were based on theUnited States Agency for Health Care Policyand Research and WHO. and

5 . Final Proposal fo r a core-SPC fo r Valeri-anae radix and o r Ispaghula husk: besidesthese two finalized SPCs, others will be

issued based on scientific monographsprepared by ESCOP and WHO, includingamong others: Menthae p iperitae folium,Gentianae r adix, Engiberis rhizoma, Boldo




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8 8 Paolo M iffignandi and Lorella Carletto

folium, Allii sativi hulbus and Rosmarinifol ium cum f lore .

CONCLUSION

As stated by the director of the EuropeanPharmacopoeia Commission:

“Medicinal plants and products m ade thereof havea long history and tradition in Europe and weredescribed in many national pharmacopo eias; de-spite the predominance of synthetic substances,natural p roducts, especially from plants, play animportant role in m od em medicine. This can also

be seen from market evaluations showing clea rlythat phytornedicines are not to be considered anylonger as ‘domestic medicines’ but as in te m ti on -ally applied and recognized medicines” 7 ) .

The HM PWG set up at the EMEA in1997issued quality, safety, and e fficacy guidelineswhich attempted to be closer to herbal drugpharmacology and pharmaceutics. It can beexpected that all these texts will be includedin the collection of European pharmaceu ticallegislation and rules in the near future. Afull copy of the most recent draft and finalproposals governing herbal medicinal prod-ucts can be found at the EMEA website:http://www.eudra.org/emea.html.) Anyonepreparing a registration dossier for suchproducts in Europe now has more specificadvice with an alternative to misleading “tra-ditional” or “structure-function’’ claims, and

a framework for quality cultivation and pro-duction has been created. This will facilitatethe mutual recognition procedure for existing

herbal medicinal products and will harmo-nize local regulatory needs across theEU,although new problems will arise for lessdocumented herbal medicines.

Core SPCs will constitute the basis of thisprocess; in our current global assessment en-vironment, future work at theICH level onthis topic could be highly desirable, althoughno plans have been made to do this.

REFERENCES

1. Law J. Mak ing sense of herbal medicines.Scrip Mag-azine. May 1999; 37-39.

2. Biffignandi P Nutraceuticals and functional foods: aconsumerdriven regulatory issue.ESRA Rapporteur.

3.Bloch A, Thomson CA. Position of the AmericanDietetic Association: Phytochemicals and functionalfoods. J Nutraceuricals, Functional Med Foods. 1991;1:33-45.

3 Dichek B. Enhancing the effects of nutraceuticals.

Scrip Magazine, May 1999, p. 35.5 . Steinhoff B. The contributionof the European ScientificCooperative on Phytotherapy and World Health Organi-zation monographs.Drug lnf J 1999;33:17-22.

6 . FDA. Guidance for Industry: Providing Clinical Evi-dence of Effectiveness for Hum an Drugs and Biologi-cal Produ cts. Rockville, MD:Food and Drug Adm in-istration; May 1998.

7. Artiges A. Pharmacopoeial standardsfor herbal me-dicinal products in Europe.European Phytojournal.1999. u,ww.ex.ac.uWphvtoneY‘phytojournoV)

1999; 6 ( 5 ) : 24-27.

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