CAUSALITY ASSESSMENT OF SUSPECTED AEs

Dr. Retesh Kumar

Head, Global PhV Department04/21/23

What is causality ssessment?

• 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

Why causality assessment?How we do Causality Assessment?

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Major uses of causality assessment

• Risk benefit assessment

• Signal detection

• Evaluation of ADR reports

• Regulatory purposes

An essential component of Pharmacovigilance contributing to better:

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Causality assessmentThree 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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• Temporal sequence• Previous experience/Drug info• Drug Level• Alternative aetiological candidates• Dechallenge/Rechallenge• Plausibility• Concomitant drugs• Objective evidence• Background epidemiological data

Assigning Causality: Relevant criteria

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Decision based on the information

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Quantitative EstimateConfirmation: 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 Algorithm or standardized assessment

method Probabilistic or Bayesian approaches

• Expert expresses judgment: Considering all available data relevant to suspect ADR- Most widely used

• Advantages: • Similar to clinical diagnosis • Straight forward• Easy to use

• Disadvantages:• Poor reproducibility• Inter & Intra rater disagreements• No standardized evaluation

• Problem specific flowchart / decision table approach- Structured and standardized approach

• Advantages: • Quick and simple to use• Higher Inter & Intra rater reliability• High degree of consistency and reproducibility

• Disadvantages:• Lacks flexibility• Inconsistent use of terminology

• Specific findings in a case to transform a prior into a posterior probability –Most logical method/ Gold standard

• Advantages: • Open ended• Highest reproducibility

• Disadvantages:• Complex and extensive calculations• 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

• Event or laboratory test abnormality • More data for proper assessment needed• Additional data under examination

Unassessable /

Unclassifiable

•Report suggesting an adverse reaction •Cannot be judged because information is insufficient or contradictory •Data cannot be supplemented or verified04/21/23

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 evidence?

+1 0 0 04/21/23

• What causality

assessment can do• Decrease disagreement

between assessors

• Classify relationship likelihood (semi-quantitative)

• Mark individual case reports

• Education / improvement of scientific assessment

• What causality assessment cannot do

• 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

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Questions?