1. Pharmacovigilance WHO definition
The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem

2. Why pharmacovigilance?
Humanitarian concerns
Hippocrates’ admonition
“at least do not harm”
Economical concerns

3. Why pharmacovigilance?
Drug monitoring
Drug surveillance
Pharmacovigilance
check if drugs on the market fulfil their intended role in society i.e. if resources spent on drugs produce optimal results in terms of
alleviating human suffering
reduce disease related economical loss

4. How knowledge about safety problems is created
animal experiments
clinical trials
epidemiological methods
spontaneous reporting
case reports
case series
Post-Marketing Surveillance (PMS)
prescription event monitoring
cohort studies
intensive hospital monitoring
case - control studies
record - linkage
meta-analysis

5. Animal Tests acute toxicity organ damage dose dependence metabolism
kinetics
carcinogenicity
mutagenicity
teratogenicity
species specificity

6. Statistical considerations
Incidence of Spontaneous Minimum number
ADR to be background of patients to be
detected incidence exposed
1 in
1 in
1 in
1 in
1 in
1 in
1 in
1 in
Incidence of Spontaneous Minimum number
ADR to be background of patients to be
detected incidence exposed
1 in
1 in
1 in
1 in
1 in
1 in
1 in
1 in

7. Limitations of clinical trials
limited size
narrow population
narrow indications
short duration

8. Topics to be studied after approval
fine tuning of dosage recommendations
reappraisal of indications
extension or restriction

9. Topics to be studied after approval - continued
assessment of side effects
detection of unexpected adverse effects and interactions
identification of risk factors
quantitative measurement of (un)safety
long term safety/toxicity
study of potential risk groups (children/elderly, pregnant women etc)
detection of unexpected beneficial effects

10. Topics to be studied after approval - continued
characteristics of drug use and drug users
inappropriate drug use
e.g. addiction, non-compliance, medication error, intoxication
quality of life and utility assessment
cost assessment

11. Topics to be studied after approval - continued
pharmaceutical defects and counterfeiting
further kinetic, pharmacological and mechanistic studies
assessment of long-term efficacy
e.g. when surrogate endpoints used for approval

12. Need for information Health authority to monitor:
Medicines of adequate quality
Medicines suitable for intended purpose
benefit/risk balance
3. Medicines used rationally
science and experience

13. Need for information (2)
Health practitioner
Each patient a therapeutic challenge
1. Knowledge
2. Therapeutic tools
diet
surgery
medicines
etc
3. Knowledge and tools changing
need for up-dating
Rational therapy

14. Drug info/ADR reporting
Patient
Health professional
Drug info/ADR reporting
Centre
Experience
report
Drug
experience
Information
Drug Authority

15. Spontaneous ADR reporting
Principle
The alert health professional connects an undesirable medical event with drug exposure
SUSPICION
Reports suspicion to information collecting centre

16. Spontaneous ADR reporting advantages
large population
all medicines
hospital and out-patient care
long perspective
patient analyses possible
non-interventional
low cost

17. Spontaneous ADR reporting disadvantages
under-reporting
difficult to detect
delayed reactions
reactions with high background
incidence
number of exposed unknown
bias

18. Reporting varies with severity of reaction
time from market introduction
reaction known to reporter
promotion of reporting system
publicity of specific association

19. International differences Quantitative and Qualitative
Disease prevalence
Genetic
Social
Cultural
Health care systems
Health practices
Indication for and use of medicines
Pharmaceutical formulations
Drug monitoring practices

20. International differences
 Examples
metamizole blood cells
nitrofurantoin respiratory
neurological
mianserin blood cells disorders
flucloxacillin liver
Apparent or Real?

21. Size and severity of the ADR problem Meta-analysis
39 prospective studies from US hospitals
Overall incidence of serious ADRs = 6.7%
Overall incidence of fatal ADRs = 0.32%
( individuals)
4th - 6th leading cause of death
Lazarou et al JAMA 1998;279:

22. ADRs in hospital patiens
Wiffen P et al. Bandolier Extra 2002; June:

23. Size and severity of the problem
25 studies
Hospital admissions due to ADRs
% with a median of 5.8%
Pharmacoepidem & Drug Safety 6; suppl 3: s71-s77 (1997)

24. US estimate for 2000 Cost of drug-related morbidity and mortality
>177.4 billion US$
Ref. Ernst & Grizzle J Am Pharm Assoc. 41: 192(2001)

25. Direct costs of ADRs 13 studies 1980-95
Median length of stay in hospital = 8.7 days
Total estimated cost of ADRs in Germany =
588 million $/year
30.7% of admissions estimated to be preventable
Pharmacoepidemiol & Drug Safety 6; suppl 3: S79-S90 (1997)

26. Burden of ADRs England 6.5% of hospital admissions
4% of hospital bed capacity
0.15% fatality
70% avoidable
Cost to NHS £466 million/year
Pirmohamed M. et al. Br Med J 329:15-19 (2004)

27. Ethics in pharmacovigilance
To know of something that is harmful to another person, who does not know, and not telling, is unethical
Modifiers
knowledge - suspicion
if other person should have known
seriousness
distance

28. Consequence Not reporting a serious unknown reaction is unethical
valid for everyone
patient
health professional
manufacturer
authorities

29. Type A adverse reactions could be prevented if
doctors and pharmacists had a sufficient basic education in pharmacotherapy
doctors and pharmacists had a sufficient continuing education
doctors had time & facilities to adjust drug therapy to the individual
all doctors prescribed according to principles of science and established experience
laymen knew how to use drugs rationally
drugs always were of best possible quality

30. Pharmacovigilance Major Aims
early detection of unknown safety problems
detection of increases in frequency
identification of risk factors
quantifying risks
preventing patients from being affected unnecessarily
Rational and Safe use of Medicines