2. 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
3. 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
4. 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
5. Insufficient evidence of safety from clinical trials
Animal experiments
Phase 1 – 3 studies prior to marketing
authorization
Medicines are supposed to save lives!
6. 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
7. 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
8. 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
9. 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
10. 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.
11. 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)
12. 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
13. 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
14. 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
15. 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
16. 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
18. • 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
19. 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
20. 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
21. 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
22. Generic Substitution
Increased self medication
Increased use of herbal medicines outside
traditional culture of use
Biosimilars
Widespread Counterfeiting
Illegal sale on internet
