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The New Attitude of the European Regulatory Authorities about Herbal Medicinal
Products
Paolo M. Biffignandi and Lorella Carletto
Drug Information Journal 2000 34: 801
DOI: 10.1177/009286150003400316
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D ~ I nRf o m f i o n Journal, Vol. 34, pp. 801-808. 2000

Printed in [he USA. All rights reserved.

0092-8615/2000

Copyright 0 2000 Drug Information Association Inc.

THE NEW ATTITUDE OF THE EUROPEAN

REGULATORY AUTHORITIES ABOUT
HERBAL MEDICINAL PRODUCTS
PAOLOM. BIFFIGNANDI,
MD, PHD
Societa Italiana Attivita Farmaceutiche, Torino, Italy

LORELLACARLETTO,
PHD
VI.REL Pharma, Vinovo (Torino), Italy

In 1997, an ad hoc Herbal Medicinal Products Working Group (HMPWG) was established
at the European Medicines Evaluation Agency in order to provide guidance for applicants
and prepare recommendations on the criteria for the assessment of quality, safety, and
efficacy of herbal medicinal products. The following topics were addressed in a detailed
document containing several notes for guidance, comments, or points to consider: Notice
to Applicants (presentation and content of the application dossier), quality guidance
(agricultural production, requirements of active herbal substances and herbal medicinal
products, and Type I and Type II variations), and preclinical and clinical assessment
(giving particular emphasis to taking the existing scientific literature into account in
order to avoid unnecessary animal tests and clinical trials in humans). Details and
implications of these documents are presented here.
Key Words: Herbal drugs; Europe; Regulatory affairs; European Medicines Evaluation
Agency; Summary of Product Characteristics

INTRODUCTION
BELIEF IN THE SUPERIORITY of natural
and organic remedies, which gained considerable impetus in industrialized countries in
recent decades, may be viewed as an outgrowth of the counterculture movement of
the 1960s. As a matter of fact, among consumers and health care providers, we still
find people who insist that Vitamin C from
natural sources is in some way different from
and superior to Vitamin C prepared synthetically from glucose.
On the other hand, it is well recognized
that the scientific advances on biodiversity

Reprint address: Paolo Biffignandi, Societa Italiana Attivita Farmaceutiche, Corso Re Umbeno I, 44,10128
Torino, Italy.

with the screening of biological extracts for

novel chemical compounds (not only herbal
in origin) can provide leads in the development of new medicines or in a better and
more responsible use of older, traditional
remedies. There are several issues, however,
involved in the licensing of herbal products;
these become all the more pressing as the
popularity of herbal products grows and the
dangers become more apparent (1).
Despite a number of definitions, the borderline between medicinal products, cosmetics, and food or dietary supplements is often
a gray area, sometimes making it difficult
to determine into which category a product
falls. This is partly because many herbal and
other natural remedies are currently marketed under differing regulatory labels, ranging from foods to over-the-counter products,

801
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Paolo M. BifJignandi and Lorella Carletto

802

largely depending on local marketing considerations and taking advantage of a substantial

lack of regulation (2).
This consumer-driven exponential pace of
nutritional and herbal excitement must not
overshadow the fact that many herbal remedies are founded on a sound and scientifically-proven basis and that this field has great
therapeutic expectations. The American Dietetic Association (ADA) recently stated that:
Growing scientific evidence supports the
role of phytochemicals and functional foods
in the prevention and treatment of at least
four of the leading causes of death in this
country (USA): cancer; diabetes, cardiovascular disease, and hypertension, and with the
prevention a n d o r treatment of other medical
ailments including neural tube defects, osteoporosis, abnormal bowel function, and arthritis (3).
From a marketing point of view, annual
sales growth rates of more than 100% for
popular herbs such as ginseng, St. Johns
Wort, and echinacea, or for oligosaccharides,
minerals, and Omega-3 fatty acids, have been
recorded everywhere. In Germany, for instance, the value of prescriptions for the antidepressant St. Johns Wort is twice that of
Prozac. Even more impressive is the nature
of the companies involved. No longer are
nutraceuticals being produced by niche manufacturers; some of the worlds leading pharmaceutical manufacturers have entered the
field. Analysts say that the impact of nutraceuticals on the health care market can only
increase (4). The aim of this paper is to discuss the new regulatory attitude of the European Medicines Evaluation Agency (EMEA)
toward herbal medicinal products.

THE CONTRIBUTION OF THE

EUROPEAN SCIENTIFIC
COOPERATIVE ON
PHYTOTHERAPY AND WORLD
HEALTH ORGANIZATION
MONOGRAPHS
In past years, a consultation of the World
Health Organization (WHO) drafted Guidelines for the Assessment of Herbal Medi-

cines with the aim of defining basic criteria

for the evaluation of quality, safety, and efficacy of herbal medicines. These documents
were intended to facilitate the work of regulatory authorities, scientific bodies, and industry. Based on these criteria, WHOS Traditional Medicine Programme (TRM) prepared
a technical document entitled Model Monographs of Widely Used Medicinal Plants,
including botanical, chemical, and pharmacological aspects. Twenty eight model monographs have been adopted and were presented at the 8 International conference of
Drug Regulatory Authorities (ICDRA) in
1996.
At the European level, the European Scientific Cooperative on Phytotherapy (ESCOP) was founded in 1989 by six national
scientific associations with the objective of
establishing a scientific umbrella organization to provide harmonized criteria for the
assessment of herbal medicinal products,
support scientific research, and contribute to
the acceptance of phytotherapy in Europe (5).
ESCOP is now comprised of 13 national associations across Europe (Austria, Belgium,
Denmark, France, Germany, Ireland, Italy,
the Netherlands, Norway, Portugal, Sweden,
Switzerland, and the United Kingdom) and
the American Botanical Council. The ESCOP Scientific Committee published 50
monographs for individual plant drugs following the European Summary of Product
Characteristics (SPC) format, some of which
have been officially adopted by the Committee for Proprietary Medicinal Products
(CPMP).

REGULATORY BACKGROUND
Until now, regulatory requirements for herbal
medicinal products were not harmonized in
the European Union (EU), and were based
upon different local attitudes. Such products,
however, when industrially prepared, fall
within the scope of Council Directive 65/65/
EEC. They haw access to the decentralized
marketing authorization procedure and the
current major differences in the assessment
of their quality, safety, and efficacy were felt

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803

European Herbal Medicinal Rules

to represent a risk to consumers or to hinder

their free circulation across the EU.
In order to prepare guidance intended for
mutual recognition of marketing authorizations (MA) in the field of herbal medicinal
products, an ad hoc Working Group (Herbal
Medicinal Products Working Group) was established at the EMEA in May 1997, under
the initiative of the European Parliament, the
European Commission, and the EMEA executive director. sumorted bv the EMEA Man-

inal products. Draft proposals and recommendations were presented in a report in

early 1999 (EMEA/HMPWG/25/99) to the
EMEA Management Board (A full copy of
the most recent draft and final proposals governing herbal medicinal products can be
found at the EMEA website: http://www.
eudra.org/emea.html.)

WORKING DEFINITIONS
According to the glossary adopted, the following terms are used:
Herbal drugs: plants (thallophytes, especially lichens, higher fungi, and algae, are
included as well) or part of plants in an
unprocessed state, which are used for a medicinal or pharmaceutical purpose (an
herbal drug is regarded as one active substance whether or not the constituents with
therapeutic activity are known),
Herbal drug preparations: comminuted or
powdered herbal drugs, extracts, tinctures,
fatty or essential oils, expressed juices, processed resins or gums, and so forth, prepared
from herbal drugs, and possibly including
solvents, dilutents, and preservatives,
Herbal medicinal products: medicinal
products containing as active substances
exclusively herbal drugs or herbal drug
preparations,
Constituents with known therapeutic activity: chemically defined substances or

groups of substances generally accepted to

contribute substantially to the therapeutic
activity of an herbal drug or of a preparation, and
Markers: chemically defined constituents
of an herbal drug which are of interest for
control purposes independent of whether
or not they have any therapeutic activity.

DETAILS OF THE REPORT

Regulatory Aspects
1. Final comments f o r revision of Notice to

Applicants Volume 2A Part 1.4.2. Bibliographic applications: these suggest including a paragraph on scientific monographs (eg, those drafted by ESCOP and
WHO for herbal drugs, as they offer a
valuable and updated overview on published scientific literature. These monographs may avoid duplication of work and
bring about gradual harmonization in the
evaluation of herbal medicinal products
(see Table 1 for an updated list of plants
included in ESCOP monographs),
2. Draft Comments on the Commission Regulation (EC) No. 541/95 of 10 March 1995
concerning the examinations of variations
to the terms of a marketing authorization
granted by a competent authority of a
Member State as amended by Commission
Regulation (EC) No. 1146/98: these comments amend Annex I and Annex I1 of the
above Commission Regulation to encompass herbal medicinal products (a final
version was issued in November 1999),
3. Drafi Comments on the European Commission Guideline on dossier requirements
f o r Type I variations: same as above (a
particular emphasis is put on manufacturing route, geographical source, and production of the herbal drug) (a final version
was issued in November 1999), and

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Paolo M.BifJignandi and Lorella Carletto

804

TABLE 1
List of Monographs on the Mediclnal Uses of
Plant Drugs Prepared by ESCOP (Updated: October 1999)
Wormwood
Garlic
0 Cape Aloes
0 Marshmallow Root
0 Aniseed
0 Arnica Flower
0 Birch Leaf
Bold0
0 Calendula Flower
0 Caraway
0 Centaury
Hawthorn Leaf and Flower
0 Pale Coneflower Root
0 Purple Coneflower Herb
0 Purple Coneflower Root
0 Eucalyptus Oil
0 Fennel
0 Frangula Bark
0 Gentian Root
0 Hamamelis Leaf

Devils Claw
Horse-chestnut Seed
0 St. Johns Wart
0 Juniper Berry
0 Iceland Moss
0 Linseed
0 Hop Strobile
0 Matricaria Flower
0 Melilotus
0 Melissa Leaf
0 Peppermint Oil
0 Peppermint Leaf
0 Myrrh
0 Restharrow Root
0 Java Tea
0 Passiflora
0 lspaghula
lspaghula Husk
0 Senega Root
0 Primula Root

Psyllium Seed
Cascara
0 Rhubarb
0 Blackcurrant Leaf
0 Rosemary
0 Willow Bark
0 Sage Leaf
0 Senna Leaf
0 Alexandrian Senna Pods
0 Tinnevelly Senna Pods
0 Golden Rod
0 Feverfew
0 Dandelion Leaf
0 Dandelion Root
0 Thyme
0 Nettle Leaf/Herb
0 Nettle Root
0 Bearberty Leaf
0 Valerian Root
0 Ginger

4. Comments on the Report Herbal medici-

nal products in the European Union following the study carried out by AESGP
on beharfof the European Commission: a
criticism was made on the labeling traditional use when no evidence of efficacy
is available, as this may be perceived by
the public as a positive enforcement of the
use, rather than to make the deficiency
evident.

Quality of Herbal Medicinal Products

1. Draft Comments on the draft directive on

the Good Manufacturing Practice (GMP)

guide f o r the starting materials of medicinal products and inspection of manufacturers: GMP, including Good Agricultural
Practice (GAP), should apply to herbal
starting materials. GAP guidelines were
prepared by the European Herbs Growers
and Producers Association (Europam) in
1998 and should become mandatory in
2003. They are intended to apply to the
growing and primary processing of all medicinal and aromatic plants traded and
used in the EU. A main goal is to ensure
that 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 reduce
microbiological load to a minimum, and
is produced with care, so that the negative
impacts affecting plants during cultivation,
processing, and storage can be limited.
Producers, traders, and processors of medicinal and aromatic plants should comply
with the GAP guidelines and document
this by a Way Bill (batch documentation),
2. Final Comments for revision of Good manufacturing Practice (GMP) provisions: a
need for a general monograph on herbal
drugs in the European Pharmacopoeia was
stressed because harmonized criteria for
limits for toxic metals and mycotoxins are
still lacking,
3. Final Comments f o r revision of Notice to
Applicants Volume 2B Part ICI Tabular
formuts specific to herbal medicinal products: a sample for tabular formats to be
included in the pharmaceutical Expert Report was given, containing some issues
specific to herbal medicinal products,
4. Final Comments for revision of Notice to
Applicants Volume 2B Part 11: detailed
amendments concerning chemical, phar-

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European Herbal Medicinal Rules

maceutical, and biological documentation

for vegetable medicinal products were
suggested, including the following: in the
case of an herbal drug preparation, a
monograph on the herbal drug must be
presented; if no such document exists, either in the European Pharmacopoeia or in
the pharmacopoeia of a Member State, a
comprehensive specification of the herbal
drug has to be filed, including parts of the
plant, definition of the herbal drugherbal
drug preparation, ratio of the herbal drug
to the preparation, extraction solvents,
constituents with known therapeutic activity or markers, and tests for adulterants
and for known toxic constituents (as far
as herbal drug preparations such as extracts are concerned, these latter are listed:
eg, ginkgolic acids, etc.). Data on stability
tests on active substances may not be required if justified by the applicant, provided that the finished product is manufactured immediately after production of the
active substance. For herbal medicinal
products, in the instance of herbal drug
preparations containing constituents with
known therapeutic activity, the limit
should be 5% of the initial assay value,
unless justified. In the case of constituents
withoutknown therapeutic activity, a limit
of 10% of the initial value can be accepted
if justified by the applicant. These criteria
apply to stability testing of active substances as well,
5 . Final Proposals for revision of the Note for
guidance on quality of herbal remedies:
Besides the fact that GMP must be strictly
followed, in the case of herbal drugs where
constituents of known therapeutic activity
are not known, assays of markers (with
test procedure) are required. The choice
of markers should also be justified. Analytical procedures not given in a pharmacopoeia should be validated in accordance
with the relevant International Conference
on Harmonization (ICH) guideline. If the
herbal medicinal product contains a preparation, the comprehensive specification on
both the drug and the preparation must be
supplied either as part of the Marketing

805

Authorization application or using the European Drug Master File procedure,

6. Draft Note for guidance on specications:
test procedures and acceptance criteria for
herbal drug preparations (herbal drug)
and herbal medicinal products: this is a
rather large guideline providing general
principles in the marketing approval process for a uniform set of specifications for
herbal drugs and their preparations and
herbal medicinal products, necessary to
ensure consistent production of such products. (A final version of this Note for guidance was issued in November 1999), and
7. Draft Comments on the CPMP Note for
guidance on stability testing for a Type II
variation to a marketing authorization: a
final version of the proposed changes was
issued in November 1999.

Safety of Herbal Medicinal Products

1. Final Comments on Notice to Applicants
Volume 2B Part IC2 Expert report on
toxico-pharmacological documentation
and Part III Toxico-pharmacological
documentation: These were found ade-

quate for herbal medicinal products,

2. Proposals for a Note for guidance on nonclinical testing of herbal drug preparations with long-term marketing experience-guidance
to facilitate mutual
recognition and use of bibliographic data:
It was recognized that published nonclinical trials for well-established herbal drug
preparations are often unsatisfactory compared with todays state of the art. Although the CPMP Safety Working Party
has not yet expressed its opinion, the
HMPWG stressed the need to avoid unnecessary tests in animals when clinical
and postmarketing experience gained by
widespread use in humans exists. Thus,
single and repeated dose toxicity, immunotoxicity, and local tolerance testing, as well
as pharmacological tests including safety
pharmacology and pharmacokinetics, are
not necessary for well-established herbal
drug preparations. New safety experience

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Puolo M. Biffignundi and Lorella Curletto

806

should be collected, however, on effects

difficult or even impossible to detect on
clinical grounds, such as toxicity to reproduction, genotoxicity, and carcinogenicity.
A major role of the Expert Report is recognized to critically discuss available evidence and to justify the lack of preclinical
safety studies, also taking into consideration related botanical species. Reproductive toxicological tests in animals are not
necessary if one of the following criteria
is fulfilled: results from epidemiological
data of adequate power or post-marketing
safety studies are available or results from
investigations in pregnant women and neonates are present.
As far as genotoxicity is concerned, it
was considered appropriate to initially perform a bacterial reverse mutation test using a test battery of different bacterial
strains and metabolic activation, according
to ICH guidelines. A cooperative approach
is encouraged to investigate herbal drug
preparations with the same specifications.
Carcinogenicity studies are not needed
when 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 Applicants
Volume 2 8 , Part I BI :Summary of Product Characteristics: No difference was
made between herbal medicinal products
and other medicinal products. Core SPCs
for Valeriana radix and Ispaghula husk,
based on those prepared by ESCOP are
attached to the set of guidelines,
2. Final Comments and proposals f o r revision of Part 4 of Annex to Council Directive 75/318/EEC of 20 May 1975 Clinical
documentation : as a general frame, documentation on experience in the form of
epidemiological studies can be taken into
account in bibliographic applications for
well-established medicinal products, provided that identity or essential similarity

between the product tested in published

clinical trials and the product intended for
marketing has been assessed. As with the
preclinical Expert Report, the Clinical Expert Report must pay particular attention
to available experience in humans, to the
differences between the product tested in
published papers and that to be submitted
for registration (this is often somewhat difficult for products such as extracts or other
herbal preparations), and to any missing
information in a bibliographical application for a well-established product. Since
the demonstration of the mode of action
of an herbal medicinal product often cannot be clarified, the documentation of efficacy should be a priority. On the other
hand, pharmacokinetic data will not be required unless there are grounds for safety
concerns, for example, a narrow therapeutic range of the active constituent. Postmarketing experience is of particular importance for herbal medicinal products.
The applicant is asked to put a special
emphasis on this issue for individual products and for all related products originating
from the same herbal drug,
3 . Final Note f o r guidance on fired combinations of herbal medicinal products with
long-term marketing experience-guidance to facilitate mutual recognition and
use of bibliographic data: It was recognized that fixed combinations of herbal
medicinal products are in widespread use
in phytotherapy and that there is a need to
guarantee the availability of such rational
combinations to consumers and physicians. Applicants will then be required to
justify the potential advantages of a fixed
combination (ie, a level of efficacy similar
to that achievable by each active substance
used alone at higher doses but associated
with a better safety profile, or a better level
of efficacy with an acceptable safety profile, or a simplification of therapy) and its
possible disadvantages. The Expert Report will address the question of the addition or potentiation of the phannacodynamic effects of the various herbal drugs/

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European Herbal Medicinal Rules

herbal drug preparations and of the pharmacokinetic parameters of each active

substance. Although bibliographic data
should be submitted for a fixed combination already in widespread use, for essentially new combinations (active substances
not usually combined, unusual quantitative
composition of usually combined substances, or one entirely new substance),
the data needed will be similar to a new
chemical entity,
4. Draft Points to consider on the evidence
of safety and eficacy required f o r wellestablished herbal medicinal products in
bibliographic applications: Many herbal
medicinal products have been used as medicinal products for several decades or
even hundreds of years, creating a comprehensive body of experience in published
medical literature. This evidence has to be
used to avoid or reduce animal experiments and clinical trials in humans. Also,
herbal medicinal products are often used
as over-the-counter drugs in the treatment
of minor illness and in some European
countries herbal preparations have a legal
status which is different from medicinal
products without being subject to a full
scientific assessment; although European
harmonization is the final aim of this body
of rules, it was recognized that older uses
in a less restricted environment may have
generated information on safety and efficacy of herbal medicinal products that
should be used in the current assessment.
In this regard, a detailed understanding
about the terms well-established use,
and recognized efficacy is crucial. In
order to label an herbal medicinal product
as having well-established use, the following conditions must be fulfilled:
0 In abridged applications, a well-established medicinal use can be accepted if
an herbal medicinal product is essentially similar to one authorized in the
EU for more than 6/10 years. Although
criteria for essential similarity are the
same as for conventional medicinal
products, complex biological mixtures,

807

such as herbal extracts produced by different manufacturers, are never identical; in using published literature to support an application, one should pay
attention to specifications and manufacturing process, the extraction solvents,
and the drug/extract ratio; appropriate
data on bioavailability may be required,
Well-established use also implies that a
sufficient number of patients were
treated by the concerned product or by
an essentially similar one, and
0 Inclusion of a given herbal drug preparation in official pharmacopoeias and scientific reference textbooks may finally
contribute to substantiating this label.
Recognized efficacy must emerge from
medical literature, taking into account the
type of documents to include and aspects
such as the number of patients, specific diagnosis, preparation used, dosage and duration
of treatment, criteria for evaluation, and applicable statistical analysis. Relevance and
credibility of published data must be judged
according to United States Food and Drug
Administration criteria (6). A review of the
literature should identify the level of evidence of the safe and effective use of an
herbal medicinal product. The definitions of
the types of evidence (ranging from Ia : Evidence obtained from meta-analysis of randomized controlled trials, to I V Evidence
obtained from expert committee reports or
opinions andor clinical experience of respected authorities) and the grading of recommendations (ranging from A to C, the latter indicating absence of directly applicable
studies of good quality) were based on the
United States Agency for Health Care Policy
and Research and WHO. and

5 . Final Proposal f o r a core-SPC f o r Valerianae radix andf o r Ispaghula husk: besides

these two finalized SPCs, others will be
issued based on scientific monographs
prepared by ESCOP and WHO, including
among others: Menthae piperitae folium,
Gentianae radix, Engiberis rhizoma, Boldo

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Paolo M. Biffignandi and Lorella Carletto

808

folium, Allii sativi hulbus, and Rosmarini

folium cum flore.

CONCLUSION
As stated by the director of the European
Pharmacopoeia Commission:
Medicinal plants and products made thereof have
a long history and tradition in Europe and were
described in many national pharmacopoeias; despite the predominance of synthetic substances,
natural products, especially from plants, play an
important role in modem medicine. This can also
be seen from market evaluations showing clearly
that phytornedicines are not to be considered any
longer as domestic medicines but as intemtionally applied and recognized medicines ( 7 ) .

The HMPWG set up at the EMEA in 1997

issued quality, safety, and efficacy guidelines
which attempted to be closer to herbal drug
pharmacology and pharmaceutics. It can be
expected that all these texts will be included
in the collection of European pharmaceutical
legislation and rules in the near future. (A
full copy of the most recent draft and final
proposals governing herbal medicinal products can be found at the EMEA website:
http://www.eudra.org/emea. html.) Anyone
preparing a registration dossier for such
products in Europe now has more specific
advice with an alternative to misleading traditional or structure-function claims, and

a framework for quality cultivation and production has been created. This will facilitate
the mutual recognition procedure for existing
herbal medicinal products and will harmonize local regulatory needs across the EU,
although new problems will arise for less
documented herbal medicines.
Core SPCs will constitute the basis of this
process; in our current global assessment environment, future work at the ICH level on
this topic could be highly desirable, although
no plans have been made to do this.

REFERENCES
1. Law J. Making sense of herbal medicines. Scrip Magazine. May 1999; 37-39.
2. Biffignandi P.Nutraceuticals and functional foods: a
consumerdriven regulatory issue. ESRA Rapporteur.
1999; 6(5): 24-27.
3.Bloch A, Thomson CA. Position of the American
Dietetic Association: Phytochemicals and functional
foods. 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 contribution of the European Scientific
Cooperative on Phytotherapy and World Health Organization monographs. Drug lnf J . 1999;33:17-22.
6 . FDA. Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products. Rockville, MD: Food and Drug Administration; May 1998.
7. Artiges A. Pharmacopoeial standards for herbal medicinal products in Europe. European Phytojournal.
1999. (u,ww.ex.ac.uWphvtoneYphytojournoV)

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