Pharmakon = drug Vigilare = to keep watch
 Development of science and regulation in drug safety.
 Safety of drugs under the practical conditions of clinical use
 Identifying new information about hazards associated with
medicines, preventing harm to patients
Pharmacovigilance: science and activities relating to the
detection, assessment, understanding and prevention of
adverse drug reactions

 Thalidomide tragedy (1961-62): The
greatest of all drug disasters.
 Thalidomide: introduced and welcomed as
a safe and effective drug for the treatment
of nausea and vomiting in early pregnancy.
 Tragically the drug proved to be a potent
human teratogen that caused major birth
defects in an estimated 10,000 children
 Phocomelia was a characteristic feature

 improve patient care and safety
 improve public health and safety
 contribute to the assessment of
benefit, harm, effectiveness and risk of medicines
 promote understanding, education and clinical training

 Insufficient evidence of safety from clinical trials
 Animal experiments
 Phase 1 – 3 studies prior to marketing
authorization
Medicines are supposed to save lives!

Phase IV
Post-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
Preclinical
Animal
Experiments
Phase I Phase II
Development Post Registration
Phase III
Phase IV
Post-approval
Spontaneous
ReportingRegistration
Phase I
20 – 50 healthy volunteers
to gather preliminary data
Phase II
150 – 350 subjects with
disease - to determine
safety and dosage
recommendations
Phase III
250 – 4000 more varied
patient groups – to
determine short-term safety
and efficacy

 Standard conditions
 limited group of selected patients
 narrow population: age and sex specific
 narrow indications: only the specific disease studied
 short duration: often no longer than a few weeks

AE: 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
ADR: A noxious and
unintended response to
a drug at normal doses
for prophylaxis,
diagnosis or therapy of
disease
ADEs
ADRs
Diseases
Genetics
Other Drugs
Environment
Diet
Other
factors

 Type A Effects (“Augmented”): common, dose dependent &
predictable
 Type B Effects (“Bizzare”): rare, dose independent &
unpredictable
 Type C Effects (“Chronic”): after long term therapy, no time
relationship
 Type D Effects (“Delayed”): may be presented years after
 Type E Effects (“End of treatment”): Absence of drug after
withdrawal

ADRs that is either:
• life-threatening,
• fatal,
• cause of prolong hospital admission,
• cause persistent disability
ADR, the nature or severity of which is not
consistent with market authorization, or expected
from the characteristics of the drug.

Association in timeLikelihood of a causal relationship
between drug exposure and adverse events
It is necessary to evaluate
 Temporal relationship between drug use and event
 Dechallenge and rechallenge information
 Pharmacology (including current knowledge of nature and
frequency of adverse reactions)
 Medical or pharmacological plausibility (signs and
symptoms, tests, pathological findings, mechanism)

Few assessment scales for causality evaluation include:
 WHO probability scale
 Naranjo scale
 Karch and Lasagna scale
 Jones scale
WHO probability scale:
Certain: positve dechallenge & positve rechallenge
Probable: positve dechallenge & negative rechallenge
Possible: temporal relationship
Unlikely: disease or drug provide plausible explanations
Unclassified: more data needed (under assessment)
Unclassifiable: data cannot be verified

NARANJO's ALGORITHM
question Yes No Don't know
Are there previous conclusion reports on this reaction? +1 0 0
Did the adverse event appear after the suspect drug was administered? +2 -1 0
Did theARimprove when the drug was discontinued or a specific
antagonist was administered?
+1 0 0
Did theARreappear when drug was readministered? +2 -1 0
Are there alternate causes [other than the drug] that could solely have
caused the reaction?
-1 +2 0
Did the reaction reappear when a placebo was given? -1 +1 0
Was the drug detected in the blood [or other fluids] in a concentration
known to be toxic?
+1 0 0
Was the reaction more severe when the dose was increased, or less
severe when the dose was decreased?
+1 0 0
Did the patient have a similar reaction to the same or similar drugs in any
previous exposure?
+1 0 0
Was the adverse event confirmed by objective evidence? +1 0 0
> 9 = definite ADR
5-8 = probable ADR
1-4 = possible ADR
0 = doubtful ADR

Signal: reported information on a possible relationship
between an adverse event and a drug, unknown or
incompletely documented previously
Usually more than a single report is required to generate
a signal
Data mining pharmacovigilance databases - become
increasingly popular with the availability of extensive
data sources and inexpensive computing resources

New drug: Any drug product that has not
been marketed for more than five years
PSUR: A report containing information collected
by marketing authorisation holders through
pharmacovigilance activities.
It is usually required by regulatory authorities
for drugs that have not been marketed for more
than five years

 Spontaneous reporting: healthcare professionals
(and in some countries consumers)
 Aggregate Reporting: compilation of safety data of
drug over a prolonged period of time - PSUR
 Expedited Reporting: serious and unlabelled event
Within clinical trials such a cases is referred to as a
SUSAR (a Suspected Unexpected Serious Adverse
Reaction)
 Clinical Trial Reporting: safety information from
clinical studies

Patient-HW
Suspicion of
ADR
PV Unit/
Coordinator
hand
delivery
Reporting
ADR
PV Unit/MoH
HQ
fax - mail
courier
Analyze ADR
& submit to
WHO/UMC
database
Analyze global
ADRs
Web
upload
Sharing the
findings

• India – Central Drugs Standard Control Organization (CDSCO)
• UK – Medicines and Healthcare Products Regulatory Agency
(MHRA)
• USA – Food and Drug Administration (US FDA)
• Europe - The European Medicines Agency (EMEA)
• Japan - Ministry of Health, Labor and Welfare (MHLW)
• Australia – Therapeutic Goods Administration
• Canada – Heath Canada
• Switzerland - Swiss Agency for Therapeutic Products

 EudraVigilence – data processing network for reporting
and evaluating suspected ADRs in European Economic
Area
 WHO- Uppsala Monitoring Centre (WHO-UMC) in Sweden
– Established in 1978
– Coordination of the WHO programme for International
Drug Monitoring
– Collection, processing of data, Education, Research

 Increased awareness and interest amongst doctors and
pharmacists to report ADRs
 More hospitals and companies using on-line reporting
system – less hassle than submitting hard copy reports
 Increasing involvement by hospital pharmacists in
pharmacovigilance – during clinical ward rounds and
when counseling patients

 Increasing number of clinical trials being
conducted especially in Singapore, Thailand and
Malaysia
 GCP training for investigators served to increase
awareness of SAE and ADR reporting amongst
health care professionals and the industry

 Generic Substitution
 Increased self medication
 Increased use of herbal medicines outside
traditional culture of use
 Biosimilars
 Widespread Counterfeiting
 Illegal sale on internet