This document discusses causality assessment of adverse drug reactions (ADRs). It introduces ADRs as a leading cause of morbidity and mortality. Causality assessment estimates the strength of relationship between drug exposure and adverse reactions through various methods, including expert opinion, algorithms like the WHO causality assessment scale and Naranjo scale, and probabilistic approaches. No method is accepted as the gold standard due to reliance on expert knowledge and experience.

1. Welcome
Causality Assessment of Adverse Drug Reactions
Isha Kakodker
MSc Medical Biotechnology
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2. Index
• Introduction
• What is causality assessment?
• How does the Assessment of ADR start?
• Methods of causality assessment of ADR
• Opinion of experts, clinical judgement or global introspection methods
• WHO Causality Assessment Scale
• Algorithms
• Naranjo causality assessment scale
• Probabilistic or Bayesian Approaches
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3. Introduction
• Adverse drug reactions (ADRs) are considered as one among the leading causes of morbidity and
mortality.
• In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the
therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product
related to any dose should be considered adverse drug reactions.
• The phrase responses to a medicinal product means that a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled
out.
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4. Introduction
• Any untoward medical occurrence in a patient or clinical investigation subject administered a
pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
• An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with the use of a medicinal
(investigational) product, whether or not related to the medicinal (investigational) product.
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5. What is Causality
assessment?
• Causality assessment of ADRs is a method used for estimating the strength of relationship
between drug(s) exposure and occurrence of adverse reaction(s).
• Assessment of causality relationship is highly subjective based on an individual assessment.
• Temporal or possible association is sufficient for an ADR Report.
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6. If an ADR is suspected, Assessment starts
with collection of data pertaining to
• Patient Demographics
• Medications including OTC drugs
• Comprehensive ADR Details:
Ø Description of the reaction
Ø Time of onset
Ø Duration of the reaction
Ø Complication of sequel
Ø Treatment of the reaction
Ø Outcome of the treatment
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7. Methods of causality assessment of
ADR
1) Opinion of experts, clinical judgment or global introspection methods
2) Algorithms (with or without scoring) or standardized assessment methods
3) Probabilistic or Bayesian approaches
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8. Opinion of experts, clinical judgement or
global introspection methods
• Causation is established based on clinical judgment.
• Expert or panel of experts
• Based on the knowledge and experience of experts
• Examples are
Ø WHO and Uppsala Monitoring Centre
Ø Visual Analogue Scale Method
Ø Swedish Regulatory Agency method
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9. WHO Causality Assessment
Scale
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Certain
Probable
Possible
Unassessable/Unclassifiable
Unlikely
Conditional/Unclassified
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10. WHO Causality Assessment
Scale
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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
Event definitive pharmacologically or phenomenological
Re challenge (if necessary)
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11. WHO Causality Assessment
Scale
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PROBABLE
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
Re challenge not necessary
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12. WHO Causality Assessment
Scale
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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 lacking or unclear
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13. WHO Causality Assessment
Scale
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UNASSESSABLE
A report suggesting an adverse reaction
Cannot be judged because of insufficient or contradictory
information.
Report cannot be supplemented or verified
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14. WHO Causality Assessment
Scale
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UNLIKELY
Event or laboratory test abnormality with a time to drug
value that makes a relationship improbable
Diseases or other drugs provide plausible explanations
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15. WHO Causality Assessment
Scale
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CONDITONAL
Event or laboratory test abnormality
More data for proper assessment needed
Additional data under examination
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16. WHO Causality Assessment
Scale
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PROBABLE
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
Re challenge not necessary
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17. Algorithms
• Usually in the form of questionnaire
• Not accepted any method as “Gold Standard” Why?
• Based on the knowledge and experience of experts
• Examples are
Ø Naranjo’s causality assessment scale
Ø Karch and Lasagna’s scale
Ø Kramer’s scale
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18. NARANJO CAUSALITY ASSESSMENT
SCALE
How do you interprete Naranjo
Scale?
• > 9 Definite
• 5-8 Probable
• 1-4 Possible
• < 0 Unlikely
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19. Probabilistic or Bayesian Approaches
• Involve the transformation of prior probability into posterior probability of drug causation.
• Examples are
Ø BARDI (Bayesian Adverse Reactions Diagnostic Instrument)
Ø MacBARDI
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20. Thank You!
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