1. Technical Briefing Seminar 22- 26 September 2008 1 |1 | The need for Pharmacovigilance Mary R Couper and Shanthi Pal Quality Assurance and Safety of Medicines

2. Technical Briefing Seminar 22- 26 September 2008 2 |2 |

3. 3 |3 | Medicine Safety To undergo treatment you have to be very healthy, because apart from your sickness you have to withstand the medicine. Molière

4. Technical Briefing Seminar 22- 26 September 2008 4 |4 | Risk No medicinal product is entirely or absolutely safe for all people, in all places, at all times. We must always live with some measure of uncertainty.

5. Technical Briefing Seminar 22- 26 September 2008 5 |5 | What is Pharmacovigilance? WHO definition: The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. This applies throughout the life cycle of a medicine equally to the pre-approval stage as to the post-approval.

6. Technical Briefing Seminar 22- 26 September 2008 6 |6 | Pharmaco - Vigilance Pharmaco = medicine Vigilare = to watch –alert watchfulness –forbearance of sleep; wakefulness –watchfulness in respect of danger; care; caution; circumspection –the process of paying close and continuous attention

7. Technical Briefing Seminar 22- 26 September 2008 7 |7 | What is the scope of pharmacovigilance? improve patient care and safety in relation to the use of medicines, and all medical and paramedical interventions, improve public health and safety in relation to the use of medicines, contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use, and promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public

8. Technical Briefing Seminar 22- 26 September 2008 8 |8 | Adverse event/experience – WHO definition Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment

9. Technical Briefing Seminar 22- 26 September 2008 9 |9 | Adverse Reaction to a medicine (ADR) –WHO Definition A reaction which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function

10. Technical Briefing Seminar 22- 26 September 2008 10 | W hy do we need pharmacovigilance?

11. Technical Briefing Seminar 22- 26 September 2008 11 |  1959 / 61 – Epidemia de focomelia por Talidomida (4.000 – 10.000 casos no mundo, com 15% de mortos)

12. Technical Briefing Seminar 22- 26 September 2008 12 | Why do we need pharmacovigilance? Reason 1: Humanitarian concern – –Insufficient evidence of safety from clinical trials –Animal experiments –Phase 1 – 3 studies prior to marketing authorization

13. Technical Briefing Seminar 22- 26 September 2008 13 | Drug Development

14. Technical Briefing Seminar 22- 26 September 2008 14 | Limitations of phase 1 -3 clinical trials limited size: no more than 5000 and often as little as 500 volunteers narrow population: age and sex specific narrow indications: only the specific disease studied short duration: often no longer than a few weeks

15. Technical Briefing Seminar 22- 26 September 2008 15 | Examples of product recalls due to toxicity MedicineYear Thalidomide1965 Practolol1975 Clioquinol1970 Benoxaprofen1982 Terfenadine1997 Rofecoxib2004 Veralipride2007 Examples of serious and unexpected adverse events leading to withdrawal of medicine Phocomelia Sclerosing peritonitis Subacute nephropathy Nephrotoxicity, cholestatic jaundice Torsade de pointes Cardiovascular effects Anxiety, depression, movement disorders

16. Technical Briefing Seminar 22- 26 September 2008 16 | Why do we need pharmacovigilance? Reason 2 Medicines are supposed to save lives Dying from a disease is sometimes unavoidable; dying from a medicine is unacceptable. Lepakhin V. Geneva 2005

17. Technical Briefing Seminar 22- 26 September 2008 17 | UK: US: ADRs were 4 th -6 th commonest cause of death in the US in 1994 Lazarou et al, 1998 It has been suggested that ADRs may cause 5700 deaths per year in UK. Pirmohamed et al, 2004

18. Technical Briefing Seminar 22- 26 September 2008 18 | 125 Patients 24 Patients experienced ADRs (19%) (59%) were avoidable

19. Technical Briefing Seminar 22- 26 September 2008 19 | Why do we need pharmacovigilance? Reason 3: ADRs are expensive !!

20. Technical Briefing Seminar 22- 26 September 2008 20 | 6.5% of admissions are due to ADRs Seven 800-bed hospitals are occupied by ADR patients Cost £446 million per annum

21. Technical Briefing Seminar 22- 26 September 2008 21 | Cost of ADRs in the US? Cost of drug related morbidity and mortality exceeded $177.4 billion in 2000 (Ernst FR & Grizzle AJ, 2001: J American Pharm. Assoc) ADR related cost to the country exceeds the cost of the medications themselves

22. Technical Briefing Seminar 22- 26 September 2008 22 | Why do we need pharmacovigilance? Reason 4: Promoting rational use of medicines and adherence

23. Technical Briefing Seminar 22- 26 September 2008 23 | Prescription Dr A. Who 31 December 2000 Re: Mr Joseph Bloggs 1) abacavir + lamivudine + zidovudine 1 BD 2) atenolol 100 mg/d 3) acetylsalicylic acid 150mg/d 4) cerivastatin 10 mg/d 5) gemfibrozil 200 mg/d 6) metformin 500 mg/d 7) fluoxetine 50 mg/d 8) Sildenafil

24. Technical Briefing Seminar 22- 26 September 2008 24 | Main reasons of discontinuation of first HAART regimen within 1st year: ICONA ICO N A Italian Cohort Naive Antiretroviral Monforte et al. AIDS 1999

25. Technical Briefing Seminar 22- 26 September 2008 25 | Why do we need pharmacovigilance? Reason 5: Ensuring public confidence If something can go wrong, it will – Murphy's law

26. Technical Briefing Seminar 22- 26 September 2008 26 | Guardian Weekly March 18-24 2004 disaster !! ALLEGATION: Known about SSRI prescribing at unsafe doses for a decade

27. Technical Briefing Seminar 22- 26 September 2008 27 |

28. Technical Briefing Seminar 22- 26 September 2008 28 |

29. Technical Briefing Seminar 22- 26 September 2008 29 | Need for Pharmacovigilance Freetown, Sierra Leone 19 th Aug. 2008 29 PV in Emerging Countries, CPT2008 29 th July 2008 29 Safety concerns now high on the agenda of ALL countries Developed countries Developing countries

30. Technical Briefing Seminar 22- 26 September 2008 30 | Why do we need pharmacovigilance? Reason 6: Ethics To know of something that is harmful to another person who does not know, and not telling, is unethical

31. Technical Briefing Seminar 22- 26 September 2008 31 | Consequence Not reporting a serious unknown reaction is unethical valid for everyone patient health professional manufacturer authorities

32. Technical Briefing Seminar 22- 26 September 2008 32 | Pharmacovigilance is Essential