Pharmacovigilance WHO definition

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

Why pharmacovigilance?

• Humanitarian concerns– Hippocrates’ admonition

“at least do not harm”

• Economical concerns

• 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

Why pharmacovigilance?

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

Animal Tests• acute toxicity• organ damage• dose

dependence• metabolism• kinetics

• carcinogenicity• mutagenicity• teratogenicity• species specificity

Statistical considerationsIncidence of Spontaneous Minimum numberADR to be background of patients to bedetected incidence exposed

1 in 100 0 3601 in 10 000

5201 in 1 000 7301 in 100 2 000

1 in 500 0 1 8001 in 10 000 3

2001 in 1 000 6 7001 in 100 35 900

Incidence of Spontaneous Minimum numberADR to be background of patients to bedetected incidence exposed

1 in 1 000 0 3 6001 in 10 000 7 3001 in 1 000 20 3001 in 100 136 400

1 in 5 000 0 18 2001 in 10 000 67

4001 in 1 000 363 0001 in 100 3 255 000

Limitations of clinical trials

• limited size• narrow population• narrow indications• short duration

Topics to be studied after approval

• fine tuning of dosage recommendations

• reappraisal of indications– extension or restriction

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

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

Topics to be studied after approval - continued

• pharmaceutical defects andcounterfeiting

• further kinetic, pharmacological and mechanistic studies

• assessment of long-term efficacy– e.g. when surrogate endpoints used for

approval

Need for information

Health authority to monitor:1. Medicines of adequate quality2. Medicines suitable for intended

purposebenefit/risk balance

3. Medicines used rationally science and experience

Need for information (2)Health practitioner

– Each patient a therapeutic challenge1. Knowledge2. Therapeutic tools

– diet– surgery– medicines– etc

3. Knowledge and tools changing– need for up-dating

Rational therapy

Experiencereport

Drugexperiencereport

DrugInformation

DrugInformation

Patient

Health professional

Drug info/ADR reportingCentre

Drug Authority

Spontaneous ADR reportingPrinciple

The alert health professional connects an undesirable medical event with drug exposure

SUSPICION

Reports suspicion to information collecting centre

International differencesQuantitative and Qualitative

• Disease prevalence• Genetic• Social• Cultural• Health care systems• Health practices• Indication for and use of medicines• Pharmaceutical formulations• Drug monitoring practices

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%

(106 000 individuals)• 4th - 6th leading cause of deathLazarou et al JAMA 1998;279: 1200 - 1205

ADRs in hospital patiens

Wiffen P et al. Bandolier Extra 2002; June: 1 - 16

Size and severity of the problem

25 studies 1970-75

• Hospital admissions due to ADRs– 4.2 - 6.0% with a median of 5.8%

Pharmacoepidem & Drug Safety 6; suppl 3: s71-s77 (1997)

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)

Direct costs of ADRs13 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)

Burden of ADRsEngland

• 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)

Ethics in pharmacovigilance

• To know of something that is harmful to another person, who does not know, and not telling, is unethicalModifiers– knowledge - suspicion– if other person should have known– seriousness– distance

Consequence

• Not reporting a serious unknown reaction is unethical

valid for everyone• patient• health professional• manufacturer• authorities

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