Why do we need Pharmacovigilance?

2. Why do we need Pharmacovigilance? Samira Saleh Prof. of Pharmacology Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University Egypt 5thGlobal Pharmacovigilance Summit, 8-29 April 2016, Dubai, UAE

3. ? Outline Theme Ensure safer drugs to the healthcare community Adverse Drug Reactions • Why is detection & assessment of ADRs inadequate in clinical trials? Pharmacovigilance • Why do we need pharmacovigilance

4. The study of ADRs is the concern of the field of pharmacovigilance

5. Adverse drug reactions • ADR is defined as any harm associated with the use of given drugs at a normal dosage during normal use. • ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. • The meaning of ADR differs from the meaning of "side effect ", as this last expression might also imply that the effects can be beneficial.

7. Types of ADRs • Type A: Augmented pharmacologic effects (dose-dependent and predictable) • Type B: Bizarre effects (dose independent & unpredictable) • Type C: Chronic effects • Type D: Delayed effects • Type E: End-of-treatment effects • Type F: Failure of therapy • Type G: Genetic reactions

8. Possible causes of ADRS • Intrinsic Idiosyncrasy Mutagenicity Carcinogenicity Teratogenicity • Extrinsic Adulterations, contamination • Underlying medical conditions • Interactions • Wrong use

9. Serious and severe Serious (FDA): when it meets one of the following criteria: • Results in death • Life-threatening • Requires inpatient hospitalization or prolongation of hospitalization • Results in disability - or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life • Results in congenital abnormalities • Requires intervention to prevent permanent damage Severity: intensity of the adverse effect

10. Economic impact of ADRs • The cost to the country of ADRs may exceed the cost of the medications themselves • 30-60 % of ADRs may be preventable

11. Before drugs become available to the patients, they are subjected to rigorous clinical studies. Post-marketing Surveillance in real life patients Pre-clinical Research However, some adverse drug reactions (ADRs) are often detected ONLY after marketing.

12. Limitations of clinical trials • Number of patients is limited: ~ 5000 • Narrowpopulation: Specific age and sex • Narrow indications: only those having the specific disease studied • Short duration: often no longer than a few weeks

13. Why is detection & assessment of ADRs inadequate in clinical trials? Discovering ADR depends on: • Frequency of occurrence • Number of patients exposed to the drug Clinical trials are usually short-term studies conducted in a few hundred patients before marketing a drug. Therefore, further investigation on ADRs must be pursued in the post-marketing phase.

15. Pharmaco - Vigilance Pharmaco (Greek): drug Vigilance (Latin): • to keep awake or alert • to keep watch • the process of paying close and continuousattention

16. Definition of Pharmacovigilance PV is the science and activities dealing with the detection, assessment, understanding and prevention of adverse effects of drugs. It has been widened to include biological products, herbals, traditional and complementary medicines.

17. Why do we need pharmacovigilance? Reason 1: Insufficient evidence of safety • Animal experiments • Clinical trials prior to marketing Reason 2: Dying from a disease may be inevitable, dying from a medicine is unacceptable (WHO,2005) Reason 3: ADR are expensive

18. Aims of pharmacovigilance • Identify previously unrecognized adverse effects or changes in the patterns of adverse effects • Assess the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use • Provide information to healthcare professionals and patients to optimize safe and effective use of medicines

19. Thus, the ultimate purpose of ADR reporting and monitoring is to reduce risks associated with drug prescribing and administration • Improve patient care and patient safety • Communication with international institutions working in pharmacovigilance

20. A lesson from history 1959 – 1961 thalidomide 4,000 - 10, 000 cases of phocomelia (congenital limb defects) This lead to withdrawal of the drug from the market

21. Pharmacovigilance is gaining importance as the number of stories of drug recalls increases

23. Examples of licensed drugs withdrawn after marketing for drug safety reasons • Thalidomide (1965) Phocomelia • Practolol (1975) Sclerosing peritonitis • Phenformin (1982) Lactic acidosis • Rofecoxib (2004) Cardiovascular effects • Veralipride (2007) Anxiety, depression, movement disorders • Troglitazone(Rezulin) (2000) Hepatitis • Rosiglitazone (2010 (Increased risk of MI and death from CV causes

24. Pharmacovigilance cycle

25. Actions taken from the PV findings include • Restriction in use • Changes in the specified dose of the medicine • Introduction of specific warnings in the product information • Changing the legal status of a medicine, e.g., from over-the-counter to prescription only • Product recall: In rare cases, removal of the medicine from the market, if the risks of a medicine are found to outweigh the benefits

26. International collaborationin the field of pharmacovigilance • WHO runs the Uppsala Monitoring Centre (started in 1968, moved to Uppsala Sweden in 1978) • European Union runs the European Medicines Evaluation Agency (EMEA) • United States, the FDA is responsible for monitoring post-marketing studies. • Egyptian PV center

28. Growth of membership of International Drug Monitoring Programme since 1968

29. WHO drug monitoring programme, March 2006 As for August 2011: 106 members and 33 awaiting for full membership

30. Cumulative number of reports

32. Establishment of the Egyptian Pharmacovigilance Center (EPVC) The Egyptian Pharmacovigilance Center (EPVC) December 2009 مركز اليقظة الدوائية المصري ديسمبر 2009 http://epvc.gov.eg Personnel training is ongoing in order achieve the highest level of competency

33. Middle East Members • Morocco 1992 • Tunisia 1993 • Oman 1995 • Iran 1998 • Egypt 2001 • Jordan 2002 • Sudan 2008 • Saudi Arabia 2009 • Iraq 2010 • United Arab Emirates

34. The First Eastern Mediterranean Region (EMR)/Arab Countries Meeting of pharmacovigilance was held in Rabat Morocco, from 22 to 26 September 2014. Drugs - Real World Outcomes (2015)

35. HarmonizedArab PVdefinitions and terms

36. Why is it important for countries to support their own PV programs? • Citizens may have unique traditions and diets influencing reactions to medications • ADRs may be associated with traditional or herbal remedies unique to each country • In some cases, ADRs to certain drugs may only occur in particular ethnic groups • Alternate brands of therapy may be imported or manufactured & differ in ingredients or production processes

37. How to report?Yellow Card Scheme • The Yellow Card Scheme is the UK system for collecting information on suspected ADRs. • The Scheme was founded in 1964 after the thalidomide disaster.

39. Essential information included on the yellow card • Patient details • Suspected drug • Suspected reaction • Reporter details

40. What should be reported? • All suspected reactions including minor ones • All serious, unexpected, unusual ADRs • Change in frequency of a given reaction • All suspected drug-drug, drug-food, drug food supplements interactions • ADRs associated with drug withdrawal • ADRs due to medication errors • ADRs due to lack of efficacy or suspected pharmaceutical defect

41. Why is the yellow card scheme important? • The scheme acts as an early warning system for the identification of previously unrecognized reactions • It enables to identify risk factors, outcomes of the ADR and other factors that may affect clinical management

42. Who can report? ► Patients, patients relatives or patients carers ► Health care professionals (physicians, dentists, pharmacists, nurses) ► Manufacturers ► Authorities

43. Report to whom? ► Regulatory Authority ► Industry, manufacturers ► Health professionals ► Patient organizations ► General public ► Social security

44. Cumulative reports as of April 2004

45. Causality assessment How likely is this medication the cause of this problem in this particular patient?

46. The Naranjo algorithm This is a questionnairefor determining the likelihood of whether an ADR is actually due to the drug  rather than the result of other factors. Probability is assigned by a score(definite, probable, possible or doubtful). Naranjo CA, Busto U, Sellers EM, et al. (1981). A method for estimating the probability of adverse drug reactions Clin. Pharmacol. Ther.30 (2): 239–45.

47. Naranjo scoring system

48. Factors to be considered (Questionnaire) • Are there previous conclusive reports on this reaction? • Did the adverse event appear after the suspected drug was given? • Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given? • Did the adverse reaction appear when the drug was readministered? • Are there alternative causes that could have caused the reaction?

49. Questionnaire (cont) 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in any body fluid in toxic concentrations? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?

50. Categories of causality (Scoring) Definite ADR > 9 Probable ADR 5-8 Possible ADR 1-4 Doubtful ADR 0