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Pharmacovigilance

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
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
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
Cumulative number of reports
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

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