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

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

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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. 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

  3. 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

  4. 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

  5. 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

  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 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

  8. 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.

  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 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

  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. 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

  18. 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  Isphagula husk Lithium / absorption  Kava-Kava extract Alprazolame / ADR  St. Michael, Bamberg, 1614 a.d.

  21. 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

  22. 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

  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 RegulatoryActivities 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. 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?

  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 clearco-medication not specifiedinformation 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 NJAMA 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

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