Pharmacovigilance for Ayurvedic Products

Ayurveda, the knowledge of life, immortalized in the form of elegant Sanskrit stanzas in the samhitas describe diagnosis and therapy of disease as well as ways to maintain positive health. Although the technical term “Pharmacovigilance” does not feature in ayurvedic texts, the spirit of pharmacovigilance is vibrant and is emphasized repeatedly in all major texts. The major goals of pharmacovigilance, namely to improve patient care and safety in relation to drug use, and thus promote rational drug use are recurrent themes of ayurvedic pharmacology (dravyaguna vigyan) and therapeutics (chikitsa).

1. Safety Monitoring and Pharmacovigilance for Ayurvedic Products Prof. Vedanshu R. Malviya M.Pharm (Pharmaceutics) Dr. Rajendra Gode Institute of Pharmacy, Amravati

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. 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 ( Med ical D ictionary for R egulatory A ctivities Terminology) WHO-ART (WHO- A dverse R eaction T erminology)   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