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

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

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 considerations Incidence of Spontaneous Minimum number ADR to be background of patients to be detected incidence exposed 1 in 100 0 360 1 in 10 000 520 1 in 1 000 730 1 in 100 2 000 1 in 500 0 1 800 1 in 10 000 3 200 1 in 1 000 6 700 1 in 100 35 900 Incidence of Spontaneous Minimum number ADR to be background of patients to be detected incidence exposed 1 in 1 000 0 3 600 1 in 10 000 7 300 1 in 1 000 20 300 1 in 100 136 400 1 in 5 000 0 18 200 1 in 10 000 67 400 1 in 1 000 363 000 1 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 and counterfeiting 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: Medicines of adequate quality Medicines suitable for intended purpose benefit/risk balance 3. Medicines used rationally science and experience

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

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

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

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

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

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

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

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

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 death Lazarou 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 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)

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)

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

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

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

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