Why Presentation

The need for Pharmacovigilance Mary R Couper and Shanthi Pal Quality Assurance and Safety of Medicines

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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

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Medicine Safety  To undergo treatment you have to be very healthy, because apart from your sickness you have to withstand the medicine. Molière

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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.

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Techn ical Brie fing Semi na r 22 - 26 Septemb er 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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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

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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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

W?hy do we need pharmacovigilance

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

1959 / 61– Epidemia de focomelia por Tal id omi da (4.000 – 10.000 casos no mundo, com 15% de mortos)

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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

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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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

Drug Development Clinical development of medicines Phase I 20 – 50 healthy volunteers to gather preliminary data

Phase I

Phase II

Phase II

Development

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Phase IV

150 – 350 subjects with disease - to determine safety and dosage recommendations

Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

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Post-approval studies to determine specific safety issues

trat io

Preclinical Animal Experiments

250 – 4000 more varied patient groups – to determine short-term safety and efficacy

Reg is

Animal experiments for acute toxicity, organ damage, dose dependence, metabolism, kinetics, carcinogenicity, mutagenicity/teratogenicity

Phase III

Phase III

Phase IV

Spontaneous Post-approval Reporting

Post Registration

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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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

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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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

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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Techn ical Brie fing Semi na r 22 - 26 Septemb er 2008

 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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 125 Patients  24 Patients experienced ADRs (19%)

(59%) were avoidable

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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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Cost of ADRs in the US?  Cost of drug related morbidity and mortality exceeded $177.4 billion in 2000 (Ernst FR & Grizzle AJ, 2001: J American Pharm. Assoc)  ADR related cost to the country exceeds the cost of the medications themselves

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Why do we need pharmacovigilance? Reason 4:

Promoting rational use of medicines and adherence

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Pre script ion Dr A. Wh o

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

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gemfibrozil 200 mg/d

6)

metformin 500 mg/d

7) 12) 23 |

fluoxetine 50 mg/d Sildenafil

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Italian Cohort I

C O N A

Naive Antiretroviral

Main reasons of discontinuation of first HAART regimen within 1st year: ICONA

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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ALLEGAT ION:

! r e t disas !

Known a bo ut S SRI prescri bi ng a t unsafe do ses fo r a deca de Gu ardi an W eekl y March 18- 24 2004

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Safety concerns now high on the agenda of ALL countries  Developed countries

 Developing countries

Need for Pharmacovigilance

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Freetown, Sierra Leone 19 Aug.th 2008 Techn ical Brie fing Semi na r 22 - 26 PV Septemb er Countries, 2008 in Emerging CPT2008 29 July 2008 th

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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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