Causality assessment is the process of determining whether a particular drug or medical intervention is the cause of an adverse event or reaction that has occurred in a patient. The following are some key principles and factors that are considered in causality assessment: Temporal relationship: The timing of the adverse event in relation to the drug or intervention is a key factor in causality assessment. If the adverse event occurs shortly after the drug is administered or the intervention is performed, this may suggest a causal relationship. Biological plausibility: The biological mechanisms by which the drug or intervention could cause the adverse event should be considered. If there is a plausible biological mechanism for the adverse event, this may support a causal relationship. Alternative explanations: Other factors that could have caused the adverse event, such as pre-existing medical conditions, should be considered and ruled out before attributing the event to the drug or intervention. Dose-response relationship: If there is a clear dose-response relationship between the drug or intervention and the adverse event, this may suggest a causal relationship. Rechallenge: If the adverse event reoccurs when the drug or intervention is readministered, this may provide further evidence for a causal relationship. There are several methods for conducting causality assessment, including the Naranjo algorithm, the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system, and the Liverpool Causality Assessment Tool (LCAT). These methods use different criteria and scoring systems to evaluate the likelihood of a causal relationship between the drug or intervention and the adverse event.

1. Welcome
CAUSALITY ASSESSMENT
SYEDA SANIYA IFTEQAR
PHARM. D
035/022023
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Objectives
Introduction
Methods
Journey of
Presentation
Purpose
Factors
Conclusion

3. Introduction
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Causality Assessment in Pharmacovigilance:
Pharmacovigilance is the science and activity related to the detection, evaluation, understanding and
prevention of side effects and other drug-related problems. An important aspect of pharmacovigilance is the
assessment of causality. It assesses the likelihood of suspected adverse drug reactions (ADRs) caused by a
particular drug.
Causality assessment helps identify and quantify risks associated with drug use. This may influence regulatory
decisions, prescribing practices, and patient education. It is also a complex and challenging process that
requires careful consideration of multiple factors and a thorough understanding of the pharmacology and
pathophysiology of suspected ADRs.

4. Objectives
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§ Establish a relationship between drugs and events.
§ Signal detection (“a possible causal relationship between an adverse event and a drug where the relationship
was previously unknown or incompletely documented”).
§ Provides a better assessment of the benefit and harm profile of medicines.
Plays an important role in evaluating ADR reports for early warning systems and regulatory purposes.

5. Methods
How is causality assessed?
(Evaluation method for causal relationship)
Ø Many researchers have developed different methods of assessing causality using different criteria, such as:
• Chronological relationship between drug administration and occurrence of ADR,
• Screening for drug and non-drug related causes,
• confirmation of response by in vivo or in vitro testing
• Past similar event information, etc.
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6. Methods classified under three broad categories
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Expert Judgement /
Global Introspection
Algorithms Probabilistic Methods
• Swedish method by
Wilhelm et al
• World Health
Organization (WHO)
• Uppsala Monitoring
Centre (UMC)
• Causality Assessment
criteria
• Dangaumou’s French
Method
• Kramer et al method
• Naranjo Scale
• Balanced assessment
method
• Drug Interaction
Probability
• Scale (DIPS)
• Australian Method
• Bayesian Adverse
Reactions Diagnostic
Instrument (BARDI)
• MacBARDI
Spreadsheet

7. Causality Association
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Certain: When all the four criteria(a, b, c, d) are met.
Probable: When criteria a, b and c are met.
Possible: When only criteria a is met.
Unlikely: When criteria a and b do not meet.
ØBeside these four categories, ADR can also be categorized into:-
Unclassified/Conditional: Applied when more data is needed and such data is being
sought or is already under examination.
Unassessable/ Unclassifiable: Finally when the information in a report is incomplete or
contradictory and cannot be verified, then it is Unclassifiable.

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Causality term Assessment criteria (all points should be reasonably complied)
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 (i.e.. an objective and specific medical disorder
or a recognized pharmacologic phenomenon)
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 lacking or unclear
Unlikely Event or laboratory test abnormality, with a time to drug intake that (but not impossible)
Disease or other drugs provide plausible explanation
Conditional/unclassified Event or laboratory test abnormality
More data for proper assessment needed, or
Additional data under examination
Unassessable/unclassified Report suggesting an adverse reaction
Cannot be judged because information is insufficient or contradictory
Data cannot be supplemented or verified.

9. Types Of Algorithms Method
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There are many algorithmic methods of causality assessment but no single algorithm is accepted as the “gold
standard”, because of many shortcomings.
Important Algorithmic Methods:
Ø Dangaumou's french method
Ø Kramer et al. method
Ø Naranjo et al. method (Naranjo scale)
Ø Balanced assessment method (Lager et al.)
Ø Summary time plot (Castle et al.)
Ø Ciba geigy method (Venulet et al.)
Ø Roussel Uclaf causality assessment method (RUCAM)
Ø Maria and Victorino (M and V) scale
Ø Drug Interaction Probability Scale (DIPS)

10. Naranjo et al. method (Naranjo scale)
• Naranjo et al. method is a widely accepted method.
• This method is used to determine the likelihood of whether an ADR (adverse drug reaction) is actually due to
the drug rather than the result of other factors.
• It consists of ten questions that are answered as "yes”, "no”, "unknown" (don't know)
• These answers are assigned via a score termed Definite, Probable, Possible Or Doubtful.
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Definite:
When a total score
of ≥ 9
Probable:
When a total score
of 5 - 8
Possible:
When a total score
of 1 - 4
Doubtful:
When a total score
of < 0

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The Naranjo adverse drug reaction probability scale; To assess the adverse drug reaction,
please answer the following questionnaire and give the pertinent score
Yes No Don’t
Know
1. Are there previous conclusive reports on this reaction?
2. Did the adverse event occur after the suspected drug was administered?
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was
administered?
4. Did the adverse reaction reappear when the drug was readministered?
5. Are there alternative causes (other than the drug) that could have on their own caused the
reaction?
6. Did the reaction reappear when a placebo was given?
7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic?
8. Was the reaction more severe when the dose was increased or less severe when the dose was
decreased?
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
10. Was the adverse event confirmed by any objective evidence?
+1
+2
+1
-1
-1
+1
+1
+1
+1
0
-1
0
-1
+2
0
0
0
0
0
0
0
0
0
0
0
0
0
Limitation:
This method only explains the causality of one individual
drug and it does not explains the causality occurred due to
drug interactions.

12. Purpose
Causality assessment in pharmacovigilance serves several important purposes:
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Pharmacological
Research
Signal Detection
Risk
Management
Identification of
potential safety
concerns

13. Factors
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Temporal Relationship
Dose-Response Relationship
Rechallenge
Pharmacological Plausibility

14. Reference
• Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, et al. A method for estimating
the probability of adverse drug reactions. Clin Pharacol Ther. 1981;30:239–45.
• Seger D, Barker K, McNaughton C. Misuse of the Naranjo Adverse Drug Reaction Probability Scale in
toxicology. Clin Toxicol (Phila). 2013 Jul;51(6):461-6. doi: 10.3109/15563650.2013.811588. Epub 2013 Jun
18. PMID: 23777343; PMCID: PMC3887443.
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15. Thank You!
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