2. Why do we need Pharmacovigilance?
Samira Saleh
Prof. of Pharmacology
Faculty of Pharmaceutical Sciences and Pharmaceutical Industries,
Future University
Egypt
5th Global 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
Narrow population: 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 continuous attention

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)
In 1961, it was determined that Thalidomide caused horrifying birth defects. It is estimated that between 10,000 to 20,000 people were affected in what is considered to be among the worst medical disasters in history.  
This lead to withdrawal of the drug from the market

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

22. the Food and Drug Administration (FDA) recorded 337 pharmaceutical recalls in 2014, a 7% increase over 2013 and up 16% from 2012.

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
Collection & Management of data
Analysis & Evaluation of data
Acting to protect public health
► Collection & management of data on the safety of medicines ►Analysis of the data to detect ‘signals’
►Evaluation of the data ►Decision making with regard to safety issues
►Acting to protect public health (including regulatory action)
►Communicating with stakeholders
►Auditing, both of the outcomes of action taken and of the key
Collection & management of data on the safety of medicines
►Analysis of the data to detect ‘signals’
►Evaluation of the data
►Decision making with regard to safety issues

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 collaboration in 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)
December 2009
مركز اليقظة الدوائية المصري
ديسمبر 2009
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
Jordan
Sudan
Saudi Arabia 2009
Iraq
United Arab Emirates
The Jordanian Food and Drug Agency (JFDA) was established in 2001, gained WHO membership in 2002, and had their PV guidelines approved in 2006.
The Tunisian National Centre for PV was created in 1984 and became a WHO CC for international drug monitoring in 1993.
The EPVC guidelines for healthcare professionals and marketing access holders were released in 2009.
Oman became a member of the UMC in 1995
The National Pharmacovigilance and Drug Safety Centre (NPC), created in association with the Saudi Food and Drug Agency (SFDA), was declared open in 2009 and became a member of the UMC in the same year.

34. Drugs - Real World Outcomes (2015)
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. Harmonized Arab PV definitions 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 questionnaire for 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

51. Take home message
Pharmacovigilance is a dynamic clinical and scientific discipline
ADR reporting is the cornerstone pharmacovigilance activity
The majority of global information related to ADRs arises from Western countries
Countries have to support their own national pharmacovigilance.
Each country should support its own PV program

52. Ensure Safer Drugs to the Healthcare Community
A successfully implemented pharmacovigilance centre can minimize, prevent and improve the use of drugs by discovering ADRs at the level of general public use.
Ensure Safer Drugs to the Healthcare Community

53. Thank you for your attention