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1. Pharmacovigilance and
Safety Monitoring for
Herbal Medicinal Products
Dr. Konstantin Keller
Chair of the Herbal Medicinal Products Working Party
European Medicines Evaluation Agency, London
Federal Institute for Drugs and Medical Devices, Bonn
Federal Institute for Drugs
and Medical Devices

2. Definition
All activities taken to ensure or to enhance the safety of a
therapy with
• authorized,
• registered or
• frequently individually prescribed
medicinal products.
“Post-approval” activities related to safety
Pharmacovigilance

3. Authorisation of new products
Pre-approval development and assessment
Positive benefit-to-risk ratio based on results from
• Clinical trials  efficacy, clinical safety
• Pharmacological / toxicological tests  safety
• Physical, biological and chemical testing  quality
Why Pharmacovigilance?

4. New Medicinal Products
Limited experiences at date of authorization:
 Small numbers of patients in clinical trials
 No detection of rare (< 1:1000) ADR
 Specific, artificial conditions in clinical trials
 Highly selected patients: no co-morbidity, no
children or elderly, no pregnant women etc.
 excellent monitoring of patients
Why Pharmacovigilance?

5. “Old” Medicinal Products
• Updating of the clinical safety profile
• Identification of new risks, not recognized empirically
(e.g. cancer, genotoxicity; toxicity on reproduction)
• Identification of rare ADR
• Updating of the benefit/risk ratio and comparison with
new options for treatment
• Updating information for consumers and health
professionals
Why Pharmacovigilance?

6. NON-CLINICAL TESTING OF
HERBAL DRUG PREPARATIONS
WITH LONG-TERM MARKETING EXPERIENCE
Guidance to facilitate mutual recognition
and use of bibliographic data
September 1998
Effects that are difficult, even impossible to detect clinically
- Toxicity to Reproduction
- Genotoxicity
- Carcinogenicity
Expert-Report points out the necessity or not of new studies

7. Herbal Medicinal Products in the EU
(e) Post-marketing experience
with other products containing
the same constituents is of
particular importance and
applicants should put a special
emphasis on this issue.
COMMISSION DIRECTIVE 2001/83/EC
“..vegetable pills have taken root in my nose. It
was reddish before but now it is carotty”
Morrison’s universal vegetable pills, 1834/1834

8. Tests not required, if sufficient experience in humans is available:
 single dose toxicity,
 repeated dose toxicity,
 immunotoxicity
 local tolerance testing
 pharmacological tests including safety
pharmacology,
 pharmacokinetic studies.
NON-CLINICAL TESTING OF
HERBAL DRUG PREPARATIONS
WITH LONG-TERM MARKETING EXPERIENCE

9. Directive 2001/83/EC
of the European Parliament and of the Council
of 6 November 2001
Community code relating to medicinal products for human use
Official Journal No. L 311 of 28 November 2001, p. 67
Title I
Definitions
Title IX
Pharmacovigilance

10. Directive 2001/83/EC
of the European Parliament and of the Council
Title I
Art. 1, Definitions
11. Adverse reaction:
A response to a medicinal product which is noxious and
unintended and which occurs at doses normally used in man for
the prophylaxis, diagnosis or therapy …

11. Directive 2001/83/EC
of the European Parliament and of the Council
Title I
Art. 1, Definitions
12. Serious adverse reaction:
An adverse reaction which results in death, is life-threatening,
requires inpatient hospitalization or prolongation of existing
hospitalization, results in persistent or significant disability or
incapacity, or is a congenital anomaly/birth defect.
13. Unexpected adverse reaction:
An adverse reaction, the nature, severity or outcome of which is not
consistent with the summary of product characteristics.

12. Directive 2001/83/EC
of the European Parliament and of the Council
Art. 101
Member States shall encourage doctors and health care
professionals to report suspected adverse drug reactions to the
competent authorities
Art. 102
Member States shall
… establish a pharmacovigilance system,
… collect information … with particular reference to adverse
reactions … and to evaluate such information scientifically.
… take into account … information on misuse and abuse of medicinal
products …

13. Directive 2001/83/EC
of the European Parliament and of the Council
Article 103
The marketing authorization holder (MAH) shall have permanently
and continuously at his disposal an appropriately qualified person
responsible for pharmacovigilance
Article 104
The MAH shall be required to … maintain detailed records of all
suspected adverse reactions …, to record and to report … adverse
reactions …
Unless other requirements have been laid down … records of all ADR
shall be submitted to the competent authorities in the form of a
periodic safety update report … The PSUR shall include a scientific
evaluation of the benefit and risks

14. Pharmacovigilance systems in each Member State
EMEA, European Medicines Evaluation Agency
CPMP, Committee for Proprietary Medicinal Products
(scientific evaluation board)
working parties: pharmacovigilance, efficacy,
safety, quality, biotechnology,
herbal, ad hoc working parties
European Commission
Pharmacovigilance in the EU

15. Which Medicinal Products are covered
by Pharmacovigilance Activities?
any medicinal products authorised in the EU i.e.
• centrally authorised
• authorised through mutual recognition procedure
• purely nationally authorised
• new medicinal products (NCE), old medicinal products
• biologicals: vaccines, blood products, others
• herbal medicinal products
• alternative and complementary medicinal products

16. Elements of Pharmacovigilance
Established sources of risk information
Health care professionals
(doctors, pharmacists, traditional practitioners)
Industry
Local health authorities
International organisations (WHO, EU, FDA)
Published literature (journals, handbooks, databases)
Registries / mortality statistics

17. National level: • collection of ADR reports and
other relevant safety information
in each member state
• evaluation and assessment
• running a data base
• regulatory actions
EU level: • running a data base
• exchange of information
• Pharmacovigilance Working
Party discussions
• Directives, guidelines, SOPs
• risk assessment, conclusions,
recommendations
Routine Work in Pharmacovigilance

18. 0
20000
40000
60000
80000
100000
120000
85 87 89 91 93 95 97 99 01
Spontaneous Reports recorded at the BfArM

19. Herbal Medicinal Products in the EU
Hepatotoxicity of Kava-Kava
• > 41 cases reported to BfArM
• exposure one week to two years,
• different extracts, dosages, co-medication
• Hepatitis, Enzymes ,
• Icterus, Liver necrosis
• Liver transplant (6 cases)
• Death (3 cases)

20. Interactions of herbal medicinal products
with other medication
Hypericum extract
Phenprocoumon 
Digoxin 
Ciclosporine 
Indinavir 
Theophylline 
OC 
Anti-epileptics 
Irinotecan 
Garlic
Aspirine / risk of bleeding 
Saquinavir AUC 
Ginkgo extract
Aspirine / risk of bleeding 
Kava-Kava extract
Alprazolame / ADR 
Isphagula husk
Lithium / absorption 
St. Michael, Bamberg, 1614 a.d.

21. Year Products Substance/Reason
1981 336 Aristolochic acid / carcinogen
1987 59 Vinca minor / immunotoxicity
1988 1 Echinacea (parenteral) / anaphylaxis
1990 2,817 Pyrrolizidinic alkaloids / carcinogen
1991 / 1993 14 Ginkgo biloba (parenteral) / anaphylaxis
1991 95 Rauvolfia / aflatoxins
1992 1,427 Anthranoids / chronic toxicity
1992 159 Rubia tinctorum / genotoxicity
Pharmacovigilance Actions in Germany

22. Year Products Substance/Reason
1992 7 Teucrium chamaedris / hepatotoxic
1994 44 Sassafras albidum / genotoxic carcinogen
1997 84 Cumarin (e.g. Melilotus) / hepatotoxic
1997 105 Ginkgo / Ginkgolic acid / allergic reactions
1999 180 Chelidonium / hepatotoxic reactions
1999 11 Royal Jelly / allergic reactions / asthma
2000 374 Hypericum / interactions)
2000 78 Kava-Kava / hepatotoxic reactions
2001 9 Tussilago farfara / Pyrrolizidinic alcaloids
Pharmacovigilance Actions in Germany

23. Elements of Pharmacovigilance
Data storage
Availability of an ADR data base
Equipement for rapid and easy retrievals
Use of an accepted medical terminology
MedDRA (Medical Dictionary for Regulatory
Activities Terminology)
WHO-ART (WHO-Adverse Reaction Terminology)
Electronic data transmission facilities
EMEA, WHO
Network on national level (if appropriate)

24. Elements of Pharmacovigilance
Continuous surveillance of drug safety profiles
Professional staff for single case assessment,
evaluation of studies and aggregated data
(periodic safety update reports)
Advisory board or external expert panel
Training of assessors

25. In Case of Safety Concerns
• Established and structured procedures for compiling
information
• Established and structured procedures for exchange of
information with external partners (industry, doctors,
pharmacists)
• Participation of concerned / interested parties
• Established and structured procedures for the decision
making process
• Catalogue of possible and appropriate actions

26. • Openness for information and communication
• Adequate information to the public / patients
• Transparency of the decision
Legal recourse (decision of the applicant)
Follow-up surveillance:
• Have the actions been successful in the way you
wanted?
After the Decision

27. Challenges and Problems
Huge amount of data to be recorded, assessed and exchanged
Pharmacovigilance requires sufficient technical and human
resources within the Agency
Spontaneous reporting:
underreporting
no information on frequency of AE
Quality of reports sometimes poor, e.g.
Product not clearly identified,
Outcome not clear
co-medication not specified
information not complete / depending on primary
assumption of the medical doctor

28. Trends in Alternative Medicine Use in the
US 1990-1997
Eisenberg et. al. JAMA 280:1569-1575 (1998)
Patients using herbal medicines / megavitamins
concurrently with prescription medicines estimated:
15 Million (18.4 % of all prescription users)
39.8% of alternative therapies were disclosed to physicians
46.0% of alternative therapies was done without any input
from a medical doctor or alternative practitioner

29. Different standards for reporting ADRs to
herbal remedies and conventional OTC
medicines: Interview with 515 users
Br. J. Clin Pharmacology 1998, Vol. 45: 496-500
Consumers’ Reaction to Adverse Drug Reactions
no for OTC yes for OTC
yes for herbal no for herbal
Consult GP (serious* ADR): 0,8% 26.0%
Consult GP (minor** ADR): 0.4% 14.6%
*serious = “worrying or alarming”
**minor = “some discomfort”

30. Rates of Spontanous Reporting of Adverse
Drug Reactions in France
Bégaud B, Martin K, Haramburu F, Moore N
JAMA 288: 1588 (October 2, 2002)
Analysis of 3 studies in France
Conclusions
“ … No more than 5 % of serious Adverse Drug
Reactions were reported …”

31. Elements for a Strategy
Herbal Medicinal Products
Identify the market:
• Which products
• Which constituent(s)
• New or well-established
• Industrially prepared
Identify Stakeholders:
• Industry
• Medical doctors
• Pharmacists
• Other health-care providers, e.g. trad. practioners, nurses

32. Elements for a Strategy
Herbal Medicinal Products
Create reporting lines and centers of competence
• Reference to established systems, e.g. WHO,
EU/MeDRA
• Trained assessors
• Advisory pannels
Identify areas of potential concern, e.g.
• Genotoxicity, Carcinogenicity
• Use in Children / pregnancy
• Interactions with modern medicinal products
• Symptoms of chronic toxicity interfering with symptoms
of diseases (hepatotoxicity)

33. Elements for a Strategy
Herbal Medicinal Products
Identify information gaps
• Systematic literature search on the medicinal plant,
related species
• Search for information on isolated constituents, e.g.
aristolochic acid, pyrrolizidinic alkaloids, phorbole-
esters, safrole etc.; concept of “negative markers”
• Search for information on “traditional misuse” e.g. as an
abortive agent

34. Elements for a Strategy
Herbal Medicinal Products
Take appropriate actions
• Discussion with stakeholders
• Explore possibilities of systematic studies, e.g. cohort-
studies, case-control-studies, observational studies
• Be aware of the publics’ acceptance of risks and notion
possible benefits of natural medicines
• Balanced information of the public on risks and benefits
of herbal medicines will increase publics’ confidence in
administrative actions
Overreacting will not solve, but add to the problem!

35. However
be prepared to be criticized having reacted
too late or too early and, especially, too weak or too strong
“Awful effects of Morrisons’ Vegetable Pills” 1834/1835