Transcript Major uses of causality assessment

CAUSALITY ASSESSMENT OF
SUSPECTED AEs
Dr. Retesh Kumar
Head, Global PhV Department
4/8/2016
What
causality
ssessment?
How
Whyiswe
causality
do Causality
assessment?
Assessment?
• Causality assessment is the evaluation of the
likelihood that a particular treatment is the cause of
an observed event.
• Decrease ambiguity of data, prevent erroneous
conclusions and aid data exchange – Structured
and harmonized system
• ~ 34 different methods: falling into 3 broad
approaches
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Major uses of causality assessment
An essential component of
Pharmacovigilance contributing to better:
• Risk benefit assessment
• Signal detection
• Evaluation of ADR reports
• Regulatory purposes
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Causality assessment
Three Key Questions
• Can the drug cause the adverse experience?
• Has the drug caused the adverse experience?
• Will the drug cause the adverse experience?
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Assigning Causality: Relevant
criteria
•
•
•
•
•
•
•
•
•
Temporal sequence
Previous experience/Drug info
Drug Level
Alternative aetiological candidates
Dechallenge/Rechallenge
Plausibility
Concomitant drugs
Objective evidence
Background epidemiological data
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Decision
based on the
information
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Quantitative Estimate
Confirmation: Experimental Study
 APPROVe Thrombotic Events
 Risk of thrombotic CV events
after 18 months of Tx
 Subgroup analyses: Age,
hypertension, diabetes,
hypercholesterolemia, aspirin use,
cigarette smoking, Increased CV risk
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Overall Perspective……
 Opinion of experts, clinical judgment or
global introspection
• Expert expresses
judgment: Considering
all available data
 Algorithm
or standardized
assessment
relevant to suspect ADR- Most widely used
method
• Advantages:
• Problem
specific
flowchart
/ decision table approach- Structured
• Similar
to clinical
diagnosis
 Probabilistic
or
Bayesian
approaches
and
approach
• standardized
Straight forward
Specific
findings
in a case to transform a prior into a posterior
• • Advantages:
• Easy to
use
probability
logical
• Quick and–Most
simple
to usemethod/ Gold standard
• Disadvantages:
• Advantages:
•• Higher
Inter & Intra rater reliability
Poor reproducibility
Open
ended
•• • High
degree
of consistency
and reproducibility
Inter
&
Intra
rater
disagreements
Highest
reproducibility
• Disadvantages:
• • No
standardized
evaluation
• Disadvantages:
• Lacks flexibility
Complex and
calculations
• • Inconsistent
useextensive
of terminology
• Unavailability of requisite epidemiological data
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WHO SCALE OF CAUSALITY ASSESSMENT
Certain
•Event or laboratory test abnormality, with plausible time relationship to drug intake
•Cannot be explained by disease or other drugs
•Response to withdrawal plausible (pharmacologically, pathologically)
•Event definitive pharmacologically or phenomenologically
•Rechallenge satisfactory, if necessary
Probable
/Likely
•Event or laboratory test abnormality, with reasonable time relationship to drug intake
•Unlikely to be attributed to disease or other drugs
•Response to withdrawal clinically reasonable
•Rechallenge not required
Possible
•Event or laboratory test abnormality, with reasonable time relationship to drug intake
•Could also be explained by disease or other drugs
•Information on drug withdrawal may be unclear or lacking
Unlikely
•Event or laboratory test abnormality, with a time to drug intake that makes a
relationship improbable (but not impossible)
•Disease or other drugs provide plausible explanations
Conditional /
Unclassified
•
•
•
Unassessable /
Unclassifiable
•Report suggesting an adverse reaction
•Cannot be judged because information is insufficient or contradictory
•Data cannot be supplemented or verified
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Event or laboratory test abnormality
More data for proper assessment needed
Additional data under examination
THE NARANJO ADR PROBABILITY SCALE
Questions
Yes
No
Don’t
Know
1) Are there previous conclusive reports on this
reaction?
+1
0
0
2) Did the ADR appear after the suspected drug was
administered?
+2
-1
0
3) Did the ADR improve when the drug was
discontinued?
+1
0
0
4) Did the ADR appear with re-challenge?
+2
-1
0
5) Are there alternative causes for the ADR?
-1
+2
0
6) Did the reaction appear when placebo was given?
-1
+1
0
7) Was the drug detected in blood at toxic levels?
+1
0
0
8) Was the reaction more severe when the dose was
increased, or less severe when the dose was
decreased?
+1
0
0
9) Did the patient have a similar reaction to the same
or similar drug in any previous exposure?
+1
0
0
10) Was
the ADR confirmed by any objective
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evidence?
+1
0
0
• What causality
assessment can do
• What causality assessment
cannot do
•
•
•
•
•
Decrease disagreement
between assessors
Classify relationship likelihood
(semi-quantitative)
Mark individual case reports
Education / improvement of
scientific assessment
•
•
•
•
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Give accurate quantitative
measurement of relationship likelihood
Distinguish valid from invalid cases
Prove the connection between drug
and event
Quantify the contribution of a drug to
the development of an adverse event
Change uncertainty into certainty
Questions?