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Chinese herbal medicine in Europe: Are you legal?
Regulatory information TCM practitioners need to know
You-Ping Zhu
Legal/regulatory problems herbal practitioners face
Unexpected visitors from:
• Medicines agency
Food or medicine?
• Food safety authority
Contaminants?
Novel foods?
Herbs in “Negative list”?
• Customs/police officers
Tiger bones or Rhino horns?
Chinese herbal products are classified as medicines
by UK Licensing Authority
Even herbal drinks are classified as medicines
by UK Licensing Authority
Sales of unregistered CHM products are no longer allowed in UK
Chinese herbs no longer legally available ?
To: "CMC" <[email protected]>
Sent: Tuesday, May 03, 2011 1:50 PM
Subject: Herbs in stock
Dear sir,
Please advise if it is possible to know whether you have a list of the
products that you will stop having in stock due to new regulations. If
possible, we would like to know so we may stock on products or
forumlas you will no longer carry.
Best regards
José
Centro de Terapias Chinesas
Av. António Augusto de Aguiar, 56-1º
1050-017 Lisboa
Telef. 213161446
Fax: 213142034
Url: www.ctcportugal.com
What is a medicine? - The old definition
The first limb
“Medicine by presentation”
The second limb
“Medicine by function”
What is a medicine? - The new definition
What is a medicine? - Old legal case
Food or medicine? - New legal cases
Food or medicine? - New legal cases
The garlic powder capsule case
Garlic capsule was classified as medicine in Germany
Bundesgerichtshof (Federal Court of Justice, Germany) ruled on 19-01-1995 that a garlic capsule is a
medicinal product but not a food supplement for the following reasons:
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Garlic is known to contain constituents that can reduce blood pressure and cholesterol and thus
prevent arteriosclerosis.
Products in capsule form are usually medicinal products and only in exceptional cases food
supplements. Capsule is an unusual form for a garlic product intended for seasoning meals.
The use of blisters for packaging the dosage recommendation are further facts indicating the
product is a medicinal product.
Garlic capsules contain no nutrients that serve the development or preservation of the human
body, as opposed to, e.g. vitamins. Therefore, a nutritional purpose is missing and classification as
a foodstuff is impossible.
Customers would use the capsules not for nutritional or consumption purposes but to prevent
arteriosclerosis.
ECJ: Garlic powder capsule is not a
medicine by presentation
The capsule form is not exclusive to medicinal products.
ECJ: Garlic powder capsule is not a
medicine by function
Fishes have similar effects on physiological functions!
ECJ: Garlic powder capsule poses no more
risk than garlic taken as a food stuff
No harm to consumer health!
The red yeast rice capsule case
ECJ:
Red yeast rice capsules: Food or medicine?
• All aspects of the product needed to be taken into account when assessing
the product, including a consideration of whether or not the dose of any
active substance present would result in "appreciable effect" if the product was
used as the manufacturer intended.
• Absence of any medicinal claims in the product literature, the medicines
legislation should not apply unless it had been scientifically established the
product could exert a metabolic, pharmacological or immunological effect.
• No harm to consumer health
• ECJ dismissed the argument that food supplements tended to be taken in
higher doses than those recommended and equated this product with a lowdose vitamin preparation, despite evidence of the harmful side-effects.
Diabetruw®
had been a food supplement
was a medicinal product
is again a food supplement
in Germany
Cinnamon case: food–medicine–food
Court
District Court
in Bielefeld
Court of Appeals
in Hamm
Judgment
Reasons
Foodstuff
Show nutritive and not pharmacological
effects, based on the evaluation of several
university expert opinions and the evidence
before the court.
Medicinal product
Clinical studies undisputedly proven the
positive effect of cinnamon in reducing blood
glucose levels in diabetics.
No significant effect on metabolism;
Federal Court of
Justice
Foodstuff
Not health risks for the consumers
(harmlessness);
“Diabetruw” has a nutritive and not a
pharmacological effect.
UK still cites old case !
EU legislations applicable to herbal products
• Regulation 178/2002 on the general principles and
requirements of food law
• Regulation 852/2004 on the hygiene of foodstuffs
• Directive 2002/46 on food supplements
• Regulation 258/97 on novel foods and novel food
ingredients
• Regulation 1924/2006 on nutrition and health claims
• Directive 2004/24 on traditional herbal medicinal products
• Directive 2001/83 on medicinal products for human use
• Directive 93/42 concerning medical devices
• Directives 76/768 and 2003/15 on cosmetics
Regulatory categories of herbal products
• Medicines
• Foods/Food supplements
• Medical devices
• Cosmetics
Herbal products as medicines ?
Category
Requirements
New (botanical) drug
Marketing authorization with preclinical tests and
clinical trials results
Medicines with well
established use
Bibliographical application with reference to
published literature
Traditional herbal
medicinal products
Simplified (not simple!) registration with
traditional use evidence of safety for minor
indications
First FDA approved botanical drug: VeregenTM
Polyphenon®/Veregen™
A long journey from tea extract to prescription drug
1997
License
1999
One phase II trial
2004
Two phase III trials
2005
Submission of New Drug Application to the FDA
2006
In October 2006 the US FDA approved Veregen®.
2007
MA application in Germany, Spain, Austria
20092012
MA in Germany, Spain, Austria, ….., Switzerland
THMPD
Traditional Herbal Medicinal Products Directive
EU Traditional Herbal Medicinal Products Directive
Principal requirements
• Traditional use evidence
 30 years in EU or
 15 years in EU + 30 years elsewhere, e.g. China
• Pharmaceutical quality (GMP)
• Minor indications for self-medication
EU Traditional Herbal Medicinal Products Directive: “Simplified” registration
Pharmacovigilance
Consumer information, labeling, advertising
Clinical trials
Bibliographic
Traditional use
evidence
Animal tests
Clinical trials
Bibliographic
Expert report
Bibliographic
Post-marketing
surveillance
Efficacy
Safety
Quality Control
Good Manufacturing Practices
Good Agricultural and Collection Practices
New drug
Well-established use
Traditional
Quality
Keep evidence of traditional use !
Purchasing/sales invoices
Prescriptions/recipes
Syllables
EU Traditional Herbal Medicinal Products Directive
A great chance for CHM ?
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Give CHM products an identity
Improve quality and public confidence
Simplified registration
Common EU market for herbal products?
EU Traditional Herbal Medicinal Products Directive
Major problems for TCM products
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Complex composition
Traditional TCM indications
Traditional use evidence
Safety data
EU GMP
Registered traditional herbal medicinal products
1438 registrations by 31-12-2014
Registrations per country
Registered minor indications
Dioscorea nipponica in China and Netherlands
Commercial name
穿山龙
Chuan Shan Long
Legal status
Indications
Herb
Rheumatic arthritis, pain and
numbness in the lower back and legs,
hernia;
Dioscorea nipponica rhizome
9-15 g, >1.1% diosgenin
CN
Chronic bronchitis, cough and
wheezing
Prescription drug
地奥心血康
Di’ao Xinxuekang
Prevention and treatment of symptoms
of coronary artery disease, angina
pectoris
Dioscorea nipponica rhizome
Extract
100mg=35mg diosgenin/capsule
Diao Xin Xue Kang
NL
Dioscorea nipponica rhizome
Extract
100mg/capsule
Traditional
herbal
medicinal
product
Relieve of headaches, muscle pain and
muscle spasms in the neck, back and
legs
Danshen Capsules
A traditional herbal medicinal product to relieve mild menstrual pain
Herbal products as medicines
Category
Feasibility
New (botanical) drug
Costly and risky
Medicines with well
established use
Not applicable to CHM
products
Traditional herbal
medicinal products
Possible but ……
Herbal products as
Food supplements?
(+) Other substances: Amino acids, essential fatty acids, fiber,
plant and herb extracts.
= Positive list system
ECJ validated Food Supplements Directive
Positive list also for herbs etc. ?
Decision on other substances delayed indefinitely
Other substances: Amino acids, essential fatty acids, fiber, plant and herb extracts
Plant food supplements
National rules still apply
Different FS administrative systems in EU Member States
Country
Notification
Positive/Negative list
Country
Notification
Positive/Negative list
Austria
No
Both
Latvia
Yes
No. (medicinal plant list)
Belgium
Yes
Both
Lithuania
Yes
No
Bulgaria
Yes
Negative list
Luxemburg
Yes
No
Cyprus
Yes
No
Malta
Yes
Negative list
Czech Rep.
Yes
Negative list
Netherlands
No
Negative list
Denmark
Yes
Negative list
(Norway)
Yes
Both
Estonia
Yes
Negative list
Poland
Yes
Both
Finland
Yes
Negative list
Portugal
Yes
No
France
Yes
Positive list
Romania
Yes
Both
Germany
Yes
Both
Slovakia
Yes
No
Greece
Yes
No
Slovenia
Yes
Both
Hungary
Yes
Negative list
Spain
Yes
No
Ireland
Yes
No
Sweden
No
Negative list
Italy
Yes
Both
UK
No
No
Chinese herbs prohibited for use in food products in NL
“Negative list”
Herbs 中药名
Pharmaceutical Latin name 药材拉丁名
Plant Latin name 原植物拉丁名
Cao Wu
草 乌
Radix Aconiti Kusnezoffii
Aconitum kusnezoffii
Chuan Wu
川 乌
Radix Aconiti
Aconitum carmichaeli
Fu Zi
附 子
Radix Aconiti Preparata
Aconitum carmichaeli
Guan Mu Tong
关木通
Caulis Aristolochiae Manshuriensis
Aristolochia manshuriensis
Guang Fang Ji
广防己
Radix Aristolochiae Fangchi
Aristolochia fangchi
Huo Ma Ren
火麻仁
Fructus Cannabis
Cannabis sativa
Ma Dou Ling
马兜铃
Fructus Aristolochiae
Aristolochia contorta
Aristolochia debilis
Ma Huang
麻 黄
Herba Ephedrae
Ephedra spp.
Ma Qian Zi
马钱子
Semen Strychni
Strychnos nux-vomica
Qing Mu Xiang
青木香
Radix Aristolochiae
Aristolochia debilis
Tian Xian Teng
天仙藤
Herba Aristolochiae
Aristolochia debilis
Aristolochia contorta
Xi Xin
细 辛
Herba Asari
Asarum heterotropoides
Asarum sieboldii
Yang Jin Hua
洋金花
Flos Daturae
Datura metel
Ying Su Qiao
罂粟壳
Pericarpium Papaveris
Papaver somniferum
• Novel foods: No history of “significant” consumption in the
European Union prior to 15 May 1997.
• Any food or food ingredient that falls within this definition
must be authorized according to Regulation (EC) No 258/97.
• Two routes of authorization:
– Simplified application (only if substantially equivalent to an existing
food or food ingredient): Supercritical CO2 extract of Hou Po
(Magnolia officinalis) Bark
– Full application: Flavonoids from Gan Cao (Glycyrrhiza glabra)
Gou Qi Zi (Frucuts Lycii, Goji berry): A novel food candidate
Goji berry: Old enough not to be new !
Powdered Ling Zhi mushroom capsules classified as a novel food
Ling Zhi (Reishi, Ganoderma) is not a novel food!
Evidence of use
before May 1997 ?
Herbal products as
Medical devices ?
What is a medical device?
Classification and CE marking of medical devices
Classification
Risk
Notification
Class I
Low risk
Notification (self-certification)
Claas IIa
Medium-low risk
Notified body
Class IIb
Medium-high risk
Notified body
Class III
High risk
Notified body
Criteria for classification:
– Invasiveness
– Duration and contact
– Active or non-active
Type of CE
Notified bodies
• A notified body is an organization accredited by the
national competent authority of a member state to carry out
the conformity assessment procedures described in the
annexes of the medical devices directives.
• Applicant has a free choice of notified body.
• Each notified body has an identification number.
Notified bodies of medical devices
How to obtain a CE-Mark?
• Prepare a CE Marking Technical File that includes data
demonstrating compliance with the applicable directives.
• Establish and maintain a compliant Quality Management
System (typically by implementing ISO 13485) if your
medical device is class I provided sterile or has a measuring
function, or Class IIa, IIb, III devices.
• Obtain your CE certificates from a Notified Body, if
applicable, or self-certify your compliance with the MDD
(Class I non-sterile, non-measuring devices) or IVDD
(general/other IVDs).
Classification of medical devices
Technical documentation
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Intended use
Mode of action
Clinical and biological evaluation
Classification and conformity assessment
Declaration of conformity
Description of the raw material
Finished product
• Production process
• Composition
• Specification
• Packaging material
• CE mark, Package leaflet, instruction manual
Cranberry extract: A class IIa medical device
to prevent and treat urinary tract infection
Other (herbal) medical devices
Weight management
Liposinol™ contains Litramine®, a natural fibre complex derived
from dehydrated leaves of a cactus (Opuntia ficus-indica).
Liposinol™, with its ability to bind fats without any
pharmacological action, is certified as a Class IIa medical device.
Medical devices woth pharmacological action?
Yes, however:
Main action has to be achieved by physical means, but may be
assisted by pharmacological, immunological, or metabolic actions
Examples
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Bone cement with antibiotics
Catheter coated with heparin
Lens cleaner
Wound dressing with antibacterial substances
Herbal plaster a class I medical device !
Regulatory advantages of medical devices
• Less time- and cost-intensive than drug registration
• Less documentation
• Strong medical claims are possible
• With a CE-mark, the products can be distributed in all 30
EEA countries
• Medical devices with herbals are an interesting alternative
to herbal drug registration.
Herbal products as
Cosmetics ?
Key requirements
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Notification
Responsible person
Product information file
Cosmetic product safety report
No prohibited substances (Annex II: Aconitum, Rauwolfia serpentina, Atropa
belladonna, Strychnos, …)
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Substances subject to restrictions (Annex III)
Allowed colorants (Annex IV)
No animal testing unless no validated alternative methods
Labeling requirements
valid from 5 February 2015
Legal trade of CITES listed species
Appendix
Degree of protection
Permission for trade
I
Species threatened with extinction
Export permit +
Import permits
II
Species not necessarily threatened with extinction,
but in which trade must be controlled in order to
avoid utilization incompatible with their survival
Export permit +
(Import permits)
III
Species that are protected in at least one country,
which has asked other CITES Parties for assistance in
controlling the trade
Export permit
China asks
to protect turtles !
Chinese herbs derived from protected species
来源于受国际公约保护的濒危动植物的中药品种
Herbs中药名
Pharm. Latin 药材拉丁名
Source plant/animal 原动/植物
备 注 Note
Bai Ji
白及
Rhizoma Bletillae
Bletilla striata
Chen Xiang
沉香
Lignum Aquilariae Resinatum
Aquilaria sinensis
Gou Ji
狗脊
Rhizoma Cibotii
Cibotium barometz
(Hu Huang Lian)
(胡黄连)
Rhizoma Picrorhizae
Picrorhiza kurrooa
中国药典品种 Picrorhiza scrophulariiflora不受保护
(芦荟)
Aloe
Aloe ferox
库拉索芦荟 Aloe barbadensis (A. vera) 不受保护
Mu Xiang
木香
Radix Aucklandis
Aucklandia lappa
Synonym Saussurea lappa, Saussurea costus
(Ren Shen)
(人参)
Radix Ginseng
Panax ginseng
Only apply to the population of the Russian
Federation
Rou Cong Rong
肉苁蓉
Herba Cistanches
Cistanche deserticola
Shi Hu
石槲
Herba Dendrobii
Dendrobium cruentum
Tao Er Qi
桃耳七
Radix Podophylli
Podophyllum emodi
Tian Ma
天麻
Rhizoma Gastrodiae
Gastrodia elata
Xi Yang Shen
西洋参
Radix Panacis Quinquefolii
Panax quinquefolium
Chuan Shan Jia
穿山甲
Squma Manis
Manis pentadactyla
Gui Jia
龟甲
Carapax et Plastrum Testudinis Mauremys reevesii
动 Hai Ma
物
类 Hu Gu
海马
Hippocampus
Hippocampus spp.
虎骨
Os Tigris
Panthera tigris
Ling Yang Jiao
羚羊角
Cornu Antelopis
Saiga tatarica
She Xiang
麝香
Moschus
Moschus spp.
Xi Niu Jiao
犀牛角
Cornu Rhinocerotis
Rhinoceros spp.
Xiang Ya
象牙
Dens Elephantis
Elephas spp.
Xiong Dan
熊胆
Fel Ursi
Ursidae spp.
植
物 (Lu Hui)
类
PLANTS
Synonym Podophyllum hexandrum
Synonym Chinemys reevesii in Chinese
Pharmaceopoeia
ANIMALS
Herbal products in the EU
Legal category
Medicines
Requirements
Marketing authorization
Cost
Claims
High
Medical claims
Notification or no notification
Food supplements Positive list entry
Negative list restriction
Low
No medical claims
Maybe health claims
Medical devices
Notification and CE-marking
Medium
Medical claims
Cosmetics
Notification
Negative list restriction
Low
Cosmetic claims
Legal status of Chinese herbal products in the Netherlands
Foods
Medicines
Others
Legal status of Chinese herbal products in the Netherlands
Foods
Medicines
• Not in the negative list
• No medical claims
• Hygiene and contaminants
control
• Marketing authorization
• GMP compliance
• Post-marketing surveillance
Others
(medical devices, cosmetics)
• Notification
• Risk management
RESTRICTED