Transcript Slide 1

Dr. F. Qadan, PhD-Germany
University of Petra-Amman
REGULATORY ISSUES FOR THE
REGISTRATION PROCESS OF
HERBAL PHARMACEUTICAL
PRODUCTS IN EUROPE
Legal Provisions Relating to Efficacy and
Safety of Herbal Medicinal Products
1- Evidence of efficacy and safety required for
herbal medicinal products, including the well
established medicinal uses .
2- Attempts to harmonize the assessment criteria.
3- Special requirements for fixed combinations.
4- Marketing authorization of “traditionally used”
herbal medicinal products: the national ways and
future European options.
Evidence of Efficacy and Safety Required
for Herbal Medicinal Products
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For herbal medicinal products which are further
developed from a documented traditional use, e.g.
products containing highly processed extracts
and/or products with “ high level” or “modern”
indications, a “full” license is required.
Proper pharmacological and toxicological
examinations are requested. Furthermore, efficacy
and safety have to be proven by clinical studies.
In general, the toxicological and pharmacological
tests must show:
a. The potential toxicity of the product, in addition to
any dangerous or undesirable toxic effects that may
occur under the proposed conditions of use in
human beings. These should be evaluated in relation
to the pathological conditions concerned.
b. The pharmacological properties of the products,
both qualitative and quantitative, in relationship to
the proposed use in human beings.
Part 3. Toxicological and Pharmacological
Tests
- Toxicity (single dose toxicity and
repeated dose toxicity)
- Reproductive toxicity (Embryo/foetal
and perinatal toxicity)
- Mutagenic potential, Carcinogenic
potential
- Pharmacodynamics
- Pharmakakinetiks
- Local tolerance
Part 4. Clinical Documentation
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Conduct of trials
Presentation of results
Clinical pharmacology
Bioavailability/bioequivalence
Clinical safety and safety
Documentation for applications in
exceptional circumstances
Post marketing-experience
Examples on the Utilization of Bibliographic
Data in Member States of the EU
Germany
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According to Section 5 of the Guidelines for
Medicines Testing “ArzneimittelPruefrichtlinien”, bibliographic data may be used
as a reference for well-known substances.
Acceptable data include pharmacological,
toxicological and clinical studies, observational
field reports and scientifically documented
medicinal experience.
Germany
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Between 1978 and 1994, monographs
specific expert commission, on the
basis of Section 25 paragraph 7 of the
German Medicines Law, was
established to be the responsible body
for herbal medicinal products, the socalled Commission E. This
commission evaluated more than 300
medicinal plants. The results
(monographs) have been published in
the federal Gazette “bundesanzeiger”.
Germany
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However, by the 5th amendment of the
Medicines Law in August 1994, the work of all
review commissions, including Commission E,
regarding the evaluation of bibliographic data
and the preparation of monographs was
finished.
Although no further monographs can be
published due to the absence of a legal basis, the
existing texts remain valid unless they are
superseded by new scientific knowledge
resulting e.g. from clinical studies.
Germany
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For products with well-established medicinal
use, a complete quality dossier has to be
submitted (like in every case), as all the expert
reports and detailed documentation on efficacy
and safety. The latter is due to the 10th
amendment of the Medicines law in July 2000.
Finland
Applications using the option of bibliographic
applications are accepted as almost the only way
to prove or support the safety and efficacy of
herbal medicinal products, the following
requirements have to be fulfilled:
1- Compliance with the definition of herbal
medicinal products as laid down in the
Medicines law
Finland
2- Quality and manufacturing in accordance with
the requirements for normal medicinal
products, taking into account the special
characteristics of herbal medicinal products
3- Safety and efficacy in accordance with
bibliographic data
4- Experts’ reports
5- Labeling with the term “ herbal medicinal
products”
European Guidelines on Efficacy and Safety
Further clarification on a European level has been
achieved by two draft notes for guidance prepared by
the HMPWP:
1- Draft points to consider on the evidence of safety
and efficacy required for well-established herbal
medicinal products in bibliographic applications.
2- Proposal for new guidance “non-clinical testing of
herbal drug preparations with long term marketing
experience-Guidance to facilitate mutual
reorganization and use of bibliographic data”.
Evidence of Safety and Efficacy
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As a general principle, this draft guideline provides
that in case of well-established herbal medicinal
products, the requirements for the proof of efficacy
and the documentation required to support the
claims should depend on the nature and the level of
indications.
Bibliographic documents that may be taken into
consideration may comprise controlled clinical trials,
other clinical trials, case controlled studies, other
collections of single cases allowing a scientific
evaluation, scientific literature and expertise from
scientific associations.
The current level of evidence can be
identified by a review of the respective
literature. In accordance with
recommendations of the US Agency for
Health Care Policy and Research (AHCPR)
and the World Health Organization (WHO),
different levels and types of evidence are
proposed in the document.
Note for Guidance on Non-Clinical Testing
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This draft note for guidance refers to the general
principle that all aspects of safety must be
covered by appropriate bibliographic data and
the respective expert report.
However, certain tests do not have to be carried
out if sufficient experience is available in
humans.
New tests on single and repeated dose toxicity
and local tolerance are not required if there is
sufficient experience available in humans.
Note for Guidance on Non-Clinical Testing
Tests on reproductive toxicity are not necessary if
one of the following criteria is fulfilled:
a. Results from epidemiological or post-marketing
safety studies are available
b. Results from investigations in pregnant women
and neonates exist
c. The product is not intended to be used in women
during child-bearing age or during pregnancy and
lactation.
Attempts to Harmonize the Assessment
Criteria
In order to provide scientifically
based assistance for a
harmonized assessment of herbal
medicinal products, ESCOP, the
European Scientific Cooperative
on Phytotherapy, was founded in
1989 by six national scientific
associations, and during further
associations have joined ESCOP.
The main objectives for this European
scientific umbrella organization are:
1- To establish harmonized criteria for the
assessment of herbal medicinal products
2- To give support to scientific research
3- To contribute to the acceptance of
Phytotherapy on a European level.
ESCOP
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In October 1990, the first five monographs were
presented at a symposium in Brussels and were
officially handed over to representatives of the
European Community.
Since the end of 1992, the ESCOP Scientific
Committee has been working on monographs,
structured like SOCs (Summary of Product
Characteristic), for individual plant drugs, primarily
those for which European or national pharmacopoeial
monographs exist.
ESCOP
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An ESCOP monograph describing a medicinal plant and
its preparations refers to a Pharmacopeia monograph with
respect to quality, and the most important constituents,
which are possibly able to contribute to the claimed effect,
are listed.
The most relevant parts of the monographs (as for an
SPC) are: the therapeutic indications, the dosage and the
pharmacological properties. The latter paragraph gives
details as possible on phramcodynamic properties,
pharmacokinetic properties and preclinical safety data,
each statement supported by references.
ESCOP
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In the detailed reference list, all literature data and scientific
papers are listed which support the statement given in the
monograph.
Each ESCOP monograph takes into account the available
scientific literature as well as national viewpoints and the
advice of many authorities on the subject.
ESCOP monographs present an overview of the current
scientific data on a medicinal plant, but they cannot replace
either an expert report or a documentation. They can be used
as a “harmonized” scientific background for an application.
Sixty monographs have been published between 1996 and
1999.
Members of the ESCOP
Oestereichische Gesellschaft fuer Phytortherapie
Société Belge de Phytothérapi
Dansk Selskab for Fytoterapi
Gesellschaft fuer Phytotherapie
Irish Phytotherapy Association
British Herbal Medicine Association
Schweizerische Medizinische Gesellschaft fuer Phytotherapie
Norweigian Society for Phytotherapy
Norway
Nederlandse Vereniging voor Fytotherapie
Società Italiana di Fitochimica
Svenska Sällskapet för Fytoterapie
Association Francaise pour le Médicament de Phytothérapie
Turkish Society of Phytoterapy
Austria
Belgium
Denmark
Germany
Ireland
United Kingdom
Switzerland
Netherlands
Italy
Sweden
France
Turkey
Special Requirements for Fixed Combinations
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On a European level, guidance on combinations of active
ingredients is provided in the “Guideline on fixed
combination products” issued by the Committee for
Proprietary Medicinal Products (CPMP).
As a general principle, applicants are required to justify
the particular combination of active substances which is
proposed. The presence of each active substance should
make a contribution to the claimed effect, and the
potential advantages and disadvantages of the
combination have to be assessed.
Special Requirements for Fixed Combinations
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Moreover, the EMEA Herbal Medicinal Products Working
Party finished a proposal for new guidance on “fixed
combinations of herbal medicinal products with long term
marketing experience” in 1998. The principles are the same
as outlined in the above-mentioned general guideline.
Taking into consideration the specific characteristics of
herbal medicinal products, the quantitative composition of
“usually combined substances” can be adjusted to current
scientific knowledge. The combination itself is still
classified as well-known, thus, clinical data do not need to
be presented.
4- Marketing authorization of “traditionally
used” herbal medicinal products: the
national ways and future European options
4-1 Austria:
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According to Section 17a of the Austrian Medicines Law, neither efficacy
nor safety need be demonstrated in detail for a simplified registration
procedure.
Respective documents do not need to be submitted if the active
ingredient(s) is/are included in a specific list published in 1989 and
amended in 1992.
If quality complies with the specification needs to be submitted, e.g.
Flores Arnicae ÖAB (Austrian Pharmacopeia), no individual specification
needs to be submitted.
The list includes approximately five hundred substances, medicinal
plants, part of plants, essential oils etc., for which a simplified registration
procedure can be used, e.g. Arnicae flos, Crataegi folium cum flore,
Urticae herba, Gentainae radix or Valerianae radix.
4-2 France
The French health authority (Agence du Médicament) grants marketing
authorization based on abridged dossiers by marketing reference to traditional
use. The shortened procedure requires limited or no pharmacological,
toxicological and clinical tests in detailed in the Agency Instruction No. 3
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The traditional use has been recognized for minor indications of approximately
200 herbal drugs as well as most of the preparations derived from these drugs.
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Except for plant-based laxatives, indications are introduced by the statement
“Traditionally used in………………”
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This guideline includes a description of the required contents of the dossiers and
medicinal products (with special recommendations for laxatives).
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The need for toxicological evaluation (category 1 and 2) depends on its traditional
use, pharmaceutical form and the presence of undesirable constituents in the
drug:
a. Category 1: No study is required for most of herbal drugs and herbal drug
preparations, in particular for herbal teas and laxative herbal drugs.
b. Category 2: A reduced toxicological study may be required for some herbal drug
preparations, in particular powdered drugs.
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The guideline also contains specific requirements for combinations: the
number of therapeutic indications allowed for a herbal medicinal product
usually been limited to two: they are chosen by the applicant from the list of
indications are desired, they should belongs to the same therapeutic category.
Medicinal plant
Valeriana officinalis
Information for the
medicinal profession
Information for public
Traditionally used in the
symptomatic treatment
of neurotonic conditions
of adults and children,
notable in cases of mild
sleeping disorders.
Traditionally used to reduce
nervousness in adults and
children, notably in case of
sleeping disorders
5-3 Germany
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The 5th Amendment of the German Medicines Law
provided a new procedure for old products with respect to
proof of quality and efficacy.
Section 109a simplifies the requirements for products
already on the market since 1978. The regulations are not
specific to herbal medicinal products. A traditional use
instead of proof of efficacy is accepted for these products,
which are mostly sold outside pharmacies. All of these
products must be labeled as “traditionally used” and have a
mild indication claim (e.g. for supporting various functions
or as a tonic).
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In accordance with Section 109a of the Medicines Law,
the BfArM has complies lists for old products stating
which preparations are allowed to refer to this
regulations and traditional uses can be claimed.
Approximately 1000 positions consisting of substances
or their combinations and indications have been
covered. By the end of January 2001, the applicant had
to decide weather his product should go through this
traditional procedure or not. If this option was chosen,
the applicant had to refer to a position on the list and
did not need to submit proof on efficacy and safety.
Examples on the “Traditional List” According
to Section 109a of the German Law
Active ingredients
Dosage form
Indication:
“traditionally used…”
Hamamelis leaf
(aqueous liquid extract)
Cream
To support the skin
functions
Melissa leaf
Sugar coated tablets
To improve certain nervous
stress conditions and to
support the stomach
functions
Garlic oil
Gastro-resistant capsules
For the prevention of
general atherosclerosis. This
statement is exclusively
based on traditional and
long-term experience
Ginger + Juniper berries
Tablets
To support the digestive
functions
Examples on Some Plants and Their Indications
According to Annex II of the Spanish Draft Royal
Decree
Indication
Plants
Medicinal plants for symptomatic
treatment of digestive disorders
Peppermint, fennel, caraway, etc.
Medicinal plants for symptomatic
treatment of slight diarrhea
Black tea, strawberry, tormentil,
blueberry, etc.