Technical Briefing Seminar 22- 26 September 2008 1 |1 | The need for Pharmacovigilance Mary R Couper...

Technical Briefing Seminar 22- 26 September 20081 |

The need for Pharmacovigilance

Mary R Couper and Shanthi PalQuality Assurance and Safety of Medicines

The need for Pharmacovigilance

Mary R Couper and Shanthi PalQuality Assurance and Safety of Medicines


Medicine SafetyMedicine Safety

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

Molière


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.


What is Pharmacovigilance?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.


Pharmaco - VigilancePharmaco - Vigilance

Pharmaco = medicineVigilare = to watch

– alert watchfulness– forbearance of sleep; wakefulness– watchfulness in respect of danger; care; caution;

circumspection– the process of paying close and continuous attention


What is the scope of pharmacovigilance?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


Adverse event/experience – WHO definition

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


Adverse Reaction to a medicine (ADR) –WHO Definition

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


Why do we need pharmacovigilance?


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


Why do we need pharmacovigilance?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


Drug DevelopmentDrug Development

Phase IVPost-approval studies to

determine specific safety issues

Clinical development of medicines

Animal experiments for acute toxicity, organ

damage, dose dependence, metabolism, kinetics,

carcinogenicity, mutagenicity/teratogenicity

PreclinicalAnimal Experiments

Phase I Phase II

Development Post Registration

Phase III Phase IVPost-approval

SpontaneousReporting

Phase I

20 – 50 healthy volunteers to gather preliminary data

Phase II150 – 350 subjects with disease - to determine

safety and dosage recommendations

Phase III250 – 4000 more varied

patient groups – to determine short-term safety

and efficacy


Limitations of phase 1 -3 clinical trialsLimitations 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


Examples of product recalls due to toxicity Examples of product recalls due to toxicity

Medicine Year

Thalidomide 1965

Practolol 1975

Clioquinol 1970

Benoxaprofen 1982

Terfenadine 1997

Rofecoxib 2004

Veralipride 2007

Examples of serious and unexpected adverse events leading to withdrawal of medicine

Phocomelia

Sclerosing peritonitis

Subacute nephropathy

Nephrotoxicity, cholestatic jaundice

Torsade de pointes

Cardiovascular effects

Anxiety, depression, movement disorders



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


UK:

US:

ADRs were 4th-6th commonest cause of death in the US in 1994Lazarou et al, 1998

It has been suggested that ADRs may cause 5700 deaths per year in UK.

Pirmohamed et al, 2004


125 Patients

24 Patients experienced ADRs (19%)

(59%) were avoidable



Reason 3: ADRs are expensive !!


6.5% of admissions are due to ADRs

Seven 800-bed hospitals are occupied by ADR patients

Cost £446 million per annum


Cost of ADRs in the US?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



Reason 4:

Promoting rational use of medicines and adherence


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


Main reasons of discontinuation of first HAART regimen within

1st year: ICONA

Main reasons of discontinuation of first HAART regimen within

1st year: ICONAI C O

N A

ItalianCohort

NaiveAntiretroviral

Monforte et al. AIDS 1999

Toxicity

Failure

Non-adherence

Other

Continued



Reason 5: Ensuring public confidence

If something can go wrong, it will – Murphy's law


Guardian Weekly

March 18-24 2004

disaster!

!

ALLEGATION:

Known about SSRI prescribing at unsafe doses for a decade

Technical Briefing Seminar 22- 26 September 200829 |Need for Pharmacovigilance

Freetown, Sierra Leone 19th Aug. 200829

PV in Emerging Countries, CPT2008 29th July 200829

Safety concerns now high on the agenda of ALL countries

Safety concerns now high on the agenda of ALL countries

Developed countries Developing countries



Reason 6: Ethics

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


ConsequenceConsequence

Not reporting a serious unknown reaction is unethical

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


Pharmacovigilance is EssentialPharmacovigilance is Essential

Technical Briefing Seminar 22- 26 September 2008 1 |1 | The need for Pharmacovigilance Mary R Couper...

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