The need for

Pharmacovigilance

Mary R Couper and Shanthi Pal

Quality Assurance and Safety of Medicines

1| Technical Briefing Seminar 22- 26 September 2008

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 Risk
No medicinal product is entirely or
absolutely safe for all people, in all
places, at all times. We must always
live with some measure of uncertainty.

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 What is Pharmacovigilance?

WHO definition:

The science and activities relating to the

detection, assessment, understanding and
prevention of adverse effects or any other
drug-related problem.
This applies throughout the life cycle of a medicine equally to
the pre-approval stage as to the post-approval.

4| Technical Briefing Seminar 22- 26 September 2008

 Pharmaco - Vigilance

 Pharmaco = medicine
 Vigilare = to watch
– alert watchfulness
– forbearance of sleep; wakefulness
– watchfulness in respect of danger; care; caution;
circumspection
– the process of paying close and continuous attention

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What is the scope of pharmacovigilance?

 improve patient care and safety in relation to the use of medicines,

and all medical and paramedical interventions,

 improve public health and safety in relation to the use of medicines,

 contribute to the assessment of benefit, harm, effectiveness and risk

of medicines, encouraging their safe, rational and more effective
(including cost-effective) use, and

 promote understanding, education and clinical training in

pharmacovigilance and its effective communication to the public

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 Adverse event/experience
– WHO definition
Any untoward medical occurrence that may
present during treatment with a
pharmaceutical product but which does not
necessarily have a causal relationship with
this treatment

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Adverse Reaction to a medicine (ADR)
–WHO Definition
A reaction which is noxious and unintended,
and which occurs at doses normally used in
man for the prophylaxis, diagnosis or therapy
of disease, or for the modification of
physiological function

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Why do we need pharmacovigilance?

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 1959 / 61– Epidemia de focomelia por Talidomida (4.000 – 10.000 casos no
mundo, com 15% de mortos)

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 Why do we need pharmacovigilance?

Reason 1:

 Humanitarian concern –
– Insufficient evidence of safety from clinical trials
– Animal experiments
– Phase 1 – 3 studies prior to marketing authorization

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 Drug Development

Clinical development of medicines

Phase I Phase III

20 – 50 healthy volunteers
to gather preliminary data
Animal experiments for
acute toxicity, organ
damage, dose dependence,
metabolism, kinetics,
carcinogenicity,
mutagenicity/teratogenicity
250 – 4000 more varied
patient groups – to
determine short-term safety
and efficacy
Phase II
Phase IV
150 – 350 subjects with
Post-approval studies to
disease - to determine
determine specific safety issues
safety and dosage
recommendations

ion
strat
Preclinical
Phase IV Spontaneous
Animal Phase I Phase II Phase III

Regi
Experiments Post-approval Reporting

Development Post Registration

12 | Technical Briefing Seminar 22- 26 September 2008

 Limitations of phase 1 -3 clinical trials

 limited size: no more than 5000 and often as little

as 500 volunteers
 narrow population: age and sex specific
 narrow indications: only the specific disease
studied
 short duration: often no longer than a few weeks

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Examples of product recalls due to toxicity

 Medicine Year  Examples of serious and unexpected

adverse events leading to withdrawal
of medicine

 Thalidomide 1965  Phocomelia

 Practolol 1975  Sclerosing peritonitis

 Clioquinol 1970  Subacute nephropathy

 Benoxaprofen 1982  Nephrotoxicity, cholestatic jaundice

 Terfenadine 1997  Torsade de pointes

 Rofecoxib 2004  Cardiovascular effects

 Veralipride 2007  Anxiety, depression, movement

disorders

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 Why do we need pharmacovigilance?

Reason 2

• Medicines are supposed to save lives

Dying from a disease is sometimes unavoidable; dying

from a medicine is unacceptable. Lepakhin V. Geneva
2005

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 UK:
It has been suggested that ADRs may cause 5700 deaths per
year in UK.
Pirmohamed et al, 2004

 US:

ADRs were 4th-6th commonest cause of death in the US in 1994

Lazarou et al, 1998

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 Why do we need pharmacovigilance?

Reason 3: ADRs are expensive !!

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  6.5% of admissions are due to ADRs

 Seven 800-bed hospitals are occupied by ADR

patients

Cost £446 million per annum

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 Why do we need pharmacovigilance?

Reason 4:

Promoting rational use of

medicines and adherence

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 Prescription

Dr A. Who 31 December 2000

Re: Mr Joseph Bloggs

1) abacavir + lamivudine + zidovudine 1 BD
2) atenolol 100 mg/d
3) acetylsalicylic acid 150mg/d
4) cerivastatin 10 mg/d
5) gemfibrozil 200 mg/d
6) metformin 500 mg/d
7) fluoxetine 50 mg/d
8) Sildenafil

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Italian
Cohort
Main reasons of discontinuation
I C O of first HAART regimen within
N A 1st year: ICONA
Naive
Antiretroviral

Toxicity
Failure
Non-adherence
Other
Continued

Monforte et al. AIDS 1999

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 Why do we need pharmacovigilance?

Reason 5: Ensuring public confidence

If something can go wrong, it will –

Murphy's law

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 ALLEGATION:
Known about SSRI
prescribing at
unsafe doses for a
decade

Guardian Weekly
March 18-24 2004

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 Why do we need pharmacovigilance?

Reason 6: Ethics
To know of something that is harmful to another person
who does not know, and not telling, is unethical

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 Consequence

 Not reporting a serious unknown reaction is

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

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 Pharmacovigilance is Essential

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