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Pharmacovigilance and Safety Monitoring for Herbal Medicinal Products Dr. Konstantin Keller Chair of the Herbal Medicin PowerPoint Presentation
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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.

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slide1

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

slide2

Pharmacovigilance

  • 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
slide3

Why Pharmacovigilance?

  • 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
slide4

Why Pharmacovigilance?

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

slide5

Why Pharmacovigilance?

  • “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
slide6

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
slide7

Herbal Medicinal Products in the EU

COMMISSION DIRECTIVE 2001/83/EC

(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.

“..vegetable pills have taken root in my nose. It was reddish before but now it is carotty” Morrison’s universal vegetable pills, 1834/1834

slide8

NON-CLINICAL TESTING OF HERBAL DRUG PREPARATIONS WITH LONG-TERM MARKETING EXPERIENCE

  • 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.
slide9

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

slide10

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 …

slide11

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.

slide12

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 …

slide13

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

slide14

Pharmacovigilance in the EU

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

slide15

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
slide16

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

slide17

Routine Work in Pharmacovigilance

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

slide19

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)
slide20

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 

Isphagula husk

Lithium / absorption 

Kava-Kava extract

Alprazolame / ADR 

St. Michael, Bamberg, 1614 a.d.

slide21

Pharmacovigilance Actions in Germany

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

slide22

Pharmacovigilance Actions in Germany

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

slide23

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 RegulatoryActivities Terminology)

WHO-ART (WHO-Adverse Reaction Terminology)

Electronic data transmission facilities

EMEA, WHO

Network on national level (if appropriate)

slide24

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

slide25

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
slide26

After the Decision

  • 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?
slide27

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 clearco-medication not specifiedinformation not complete / depending on primary assumption of the medical doctor
slide28

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

slide29

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”

slide30

Rates of Spontanous Reporting of Adverse Drug Reactions in France

Bégaud B, Martin K, Haramburu F, Moore NJAMA 288: 1588 (October 2, 2002)

Analysis of 3 studies in France

Conclusions

“ … No more than 5 % of serious Adverse Drug Reactions were reported …”

slide31

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
slide32

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)
slide33

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
slide34

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!
slide35

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