Pharmacovigilance

Mohanad AlBayati

Mohanad AbdulSattar Al-Bayati, BVM&S, MS, PhD

Assistant Professor of Pharmacology and Toxicology
Department of Physiology and Pharmacology
College of Veterinary Medicine
University of Baghdad
Al Ameria, Baghdad
Phone: 0964 7802120391
E. Mail: aumnmumu@covm.uobaghdad.edu.iq
aumnmumu@yahoo.com
 Objectives

• To discuss the need for

pharmacovigilance

• To present WHO’s role in

promoting pharmacovigilance

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World Health Organization
 Medicine Safety
• To undergo
treatment you
have to be very
healthy, because
apart from your
sickness you
have to stand
the medicine.
Molière
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World Health Organization
 Pharmacovigilance

What IS this?

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World Health Organization
 Vigilance
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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World Health Organization
 Pharmacovigilance
• The science and activities relating
to the detection, evaluation,
understanding and prevention of
adverse drug reactions or any other
drug-related problems

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World Health Organization
 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

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World Health Organization
 Why Pharmacovigilance?

• Pre-marketing safety data

Animal Experiments : Relevant?
Clinical Trials: Complete?

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World Health Organization
 Why Pharmacovigilance?
• Post-marketing Topics
Unexpected adverse reactions
Interactions
Dependence
Long-term efficacy, Resistance
Risk factors
Quality (Counterfeit)
Cost assessment
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 Why Pharmacovigilance?

• Adverse Drug Reactions are the

4th to 6th largest cause of mortality
in the USA
(Lazarou J. et al., 1998)

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World Health Organization
 WHO Programme for International
Drug Monitoring

WHO
WHO
Collaborating
HQ Centre, Uppsala

National
Centres

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 Outline
Theme
Ensure safer drugs to the healthcare community

Adverse Drug Reactions

 Why is detection & assessment of ADRs
inadequate in clinical trials?

Pharmacovigilance
 Why do we need pharmacovigilance
The study of ADRs is the
concern of the field of
pharmacovigilance
 Adverse drug reactions

• ADR is defined as any harm associated with the

use of given drugs at a normal dosage during
normal use.

• ADRs may occur following a single dose or

prolonged administration of a drug or result
from the combination of two or more drugs.

• The meaning of ADR differs from the meaning of

"side effect ", as this last expression might also
imply that the effects can be beneficial.
 Types of ADRs
1. Type A: Augmented pharmacologic
effects (dose-dependent and
predictable)
2. Type B: Bizarre effects (dose independent
& unpredictable)
3. Type C: Chronic effects
4. Type D: Delayed effects
5. Type E: End-of-treatment effects
6. Type F: Failure of therapy
7. Type G: Genetic reactions
 Possible causes of ADRS
1. Intrinsic
Idiosyncrasy Mutagenicity
Carcinogenicity Teratogenicity
2. Extrinsic
Adulterations, contamination
3. Underlying medical conditions
4. Interactions
5. Wrong use
 Serious and severe
Serious (FDA): when it meets one of the following
criteria:
1. Results in death
2. Life-threatening
3. Requires inpatient hospitalization or prolongation of
hospitalization
4. Results in disability - or permanent change, impairment,
damage or disruption in the patient's body
function/structure, physical activities or quality of life
5. Results in congenital abnormalities
6. Requires intervention to prevent permanent damage

Severity: intensity of the adverse effect

Economic impact of ADRs
• The cost to the country of ADRs
may exceed the cost of the
medications themselves

• 30-60 % of ADRs may be

preventable
Before drugs become available to the
patients, they are subjected to rigorous
clinical studies.
Post-
Pre- marketing
clinical Surveillance
Research in real life
patients

However, some adverse drug reactions

(ADRs) are often detected ONLY after
marketing.
 Limitations of clinical trials

1. Number of patients is limited: ~ 5000

2. Narrow population: Specific age and
sex
3. Narrow indications: only those having
the specific disease studied
4. Short duration: often no longer than a
few weeks
Why is detection & assessment of ADRs
inadequate in clinical trials?

Discovering ADR depends on:

Frequency of occurrence

Number of patients exposed to the drug

Clinical trials are usually short-term studies

conducted in a few hundred patients before
marketing a drug. Therefore, further investigation on
ADRs must be pursued in the post-marketing phase.
 Pharmaco - Vigilance
Pharmaco (Greek): drug

Vigilance (Latin):
– to keep awake or alert
– to keep watch
– the process of paying close and
continuous attention
Definition of Pharmacovigilance

PV is the science and activities dealing

with the detection, assessment,
understanding and prevention of
adverse effects of drugs.
It has been widened to include biological
products, herbals, traditional and
complementary medicines.
 Why do we need
pharmacovigilance?
Reason 1: Insufficient evidence of safety
– Animal experiments
– Clinical trials prior to marketing

Reason 2: Dying from a disease may be

inevitable, dying from a medicine is
unacceptable (WHO,2005)

Reason 3: ADR are expensive

 Aims of pharmacovigilance
1. Identify previously unrecognized adverse
effects or changes in the patterns of adverse
effects

2. Assess the risks and benefits of medicines in

order to determine what action, if any, is
necessary to improve their safe use

3. Provide information to healthcare

professionals and patients to optimize safe
and effective use of medicines
– Thus, the ultimate purpose of ADR
reporting and monitoring is to reduce risks
associated with drug prescribing and
administration

– Improve patient care and patient safety

– Communication with international

institutions working in pharmacovigilance
 A lesson from history
1959 – 1961 thalidomide 4,000 - 10, 000 cases of
phocomelia (congenital limb defects)

This lead to withdrawal of the drug from the market

Pharmacovigilance is
gaining importance as
the number of stories
of drug recalls
increases
Examples of licensed drugs withdrawn
after marketing for drug safety reasons
1. Thalidomide (1965) Phocomelia
2. Practolol (1975) Sclerosing
peritonitis
3. Phenformin (1982) Lactic acidosis
4. Rofecoxib (2004) Cardiovascular
effects
5. Veralipride (2007) Anxiety,
depression,
movement disorders
6. Troglitazone (Rezulin) (2000) Hepatitis
7. Rosiglitazone (2010( Increased risk of
MI and death
from CV causes
Pharmacovigilance cycle
Collection &
Management of data

Analysis &
Evaluation of data

Acting to protect
public health
Actions taken from the PV findings
include

1. Restriction in use
2. Changes in the specified dose of the medicine
3. Introduction of specific warnings in the
product information
4. Changing the legal status of a medicine, e.g.,
from over-the-counter to prescription only
5. Product recall: In rare cases, removal of the
medicine from the market, if the risks of a
medicine are found to outweigh the benefits
 International collaboration
in the field of pharmacovigilance
• WHO runs the Uppsala Monitoring
Centre( started in 1968, moved to
Uppsala Sweden in 1978)
• European Union runs the European
Medicines Evaluation Agency (EMEA)
• United States, the FDA is responsible
for monitoring post-marketing studies.
• Egyptian PV center
 Pharmacovigilance

‫مركز اليقظة الدوائية‬

Personnel training is ongoing in order achieve the

highest level of competency
 Middle East Members
1. Morocco 1992
2. Tunisia 1993
3. Oman 1995
4. Iran 1998
5. Egypt 2001
6. Jordan 2002
7. Sudan 2008
8. Saudi Arabia 2009
9. Iraq 2010
10. United Arab Emirates
 The First Eastern Mediterranean Region (EMR)/Arab Countries Meeting of
pharmacovigilance was held in Rabat Morocco, from 22 to 26 September 2014.
Drugs - Real World Outcomes (2015)
Harmonized
Arab PV
definitions
and
terms
 Why is it important for countries to
support their own PV programs?

1. Citizens may have unique traditions and diets

influencing reactions to medications
2. ADRs may be associated with traditional or
herbal remedies unique to each country
3. In some cases, ADRs to certain drugs may
only occur in particular ethnic groups
4. Alternate brands of therapy may be imported
or manufactured & differ in ingredients or
production processes
 How to report?
Yellow Card Scheme
• The Yellow Card Scheme is the UK
system for collecting information on
suspected ADRs .

• The Scheme was founded in 1964 after

the thalidomide disaster .
Essential information included
on the yellow card

1. Patient details

2. Suspected drug

3. Suspected reaction

4. Reporter details
 What should be reported?
1. All suspected reactions including minor
ones
2. All serious, unexpected, unusual ADRs
3. Change in frequency of a given reaction
4. All suspected drug-drug, drug-food, drug
food supplements interactions
5. ADRs associated with drug withdrawal
6. ADRs due to medication errors
7. ADRs due to lack of efficacy or suspected
pharmaceutical defect
 Why is the yellow card scheme
important?
1. The scheme acts as an early warning
system for the identification of
previously unrecognized reactions

1. It enables to identify risk factors,

outcomes of the ADR and other
factors that may affect clinical
management
 Who can report?
► Patients, patients relatives or patients
carers
► Health care professionals (physicians,
dentists, pharmacists, nurses)
► Manufacturers
► Authorities
 Report to whom?
► Regulatory Authority
► Industry, manufacturers
► Health professionals
► Patient organizations
► General public
► Social security
 Causality assessment
How likely is this medication the cause
of this problem in this particular
patient?
 The Naranjo algorithm
This is a questionnaire for determining the
likelihood of whether an ADR is actually due
to the drug rather than the result of other
factors.
Probability is assigned by a score (definite,
probable, possible or doubtful).

Naranjo CA, Busto U, Sellers EM, et al. (1981).

A method for estimating the probability of adverse drug reactions
Clin. Pharmacol. Ther. 30 (2): 239–45.
Naranjo scoring system
 Factors to be considered (Questionnaire)
1. Are there previous conclusive reports on this
reaction?
2. Did the adverse event appear after the
suspected drug was given?
3. Did the adverse reaction improve when the
drug was discontinued or a specific
antagonist was given?
4. Did the adverse reaction appear when the
drug was readministered?
5. Are there alternative causes that could have
caused the reaction?
 Questionnaire (cont)
6. Did the reaction reappear when a placebo was
given?
7. Was the drug detected in any body fluid in
toxic concentrations?
8. Was the reaction more severe when the dose
was increased, or less severe when the dose
was decreased?
9. Did the patient have a similar reaction to the
same or similar drugs in any previous
exposure?
10. Was the adverse event confirmed by any
objective evidence?
Categories of causality (Scoring)

Definite ADR >9

Probable ADR 5-8

Possible ADR 1-4

Doubtful ADR 0
 Take home message
• Pharmacovigilance is a dynamic clinical
and scientific discipline
• ADR reporting is the cornerstone
pharmacovigilance activity
• The majority of global information related
to ADRs arises from Western countries
• Countries have to support their own
national pharmacovigilance.
• Each country should support its own PV
program
 A successfully implemented
pharmacovigilance centre can
minimize, prevent and improve the use
of drugs by discovering ADRs at the
level of general public use.

Ensure Safer Drugs to the Healthcare

Community
 The goal of pharmacovigilance:

 Systematic surveillance of all authorised veterinary medicinal

products

 Ensure safe and effective products on the market

 Fast and proportional action on signals from data analysis

 Active crisis management with good and open communication

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EU-Pharmacovigilance scope

 Animal safety
• serious and non-serious adverse reactions
 Lack of expected efficacy
 Off-label use / misuse
 Humans reacting after exposure
 Violations of residue levels
 Potential environmental problems

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 Minimal requirements of an AE report

• Identifiable reporter
• Animal (species)
• Suspected product
• Adverse event

 However, many more details are desired and possible

to fill in to the database/reporting form

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Thank you for patient