Causality Assessment in Pharmacovigilance

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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ObjectivesIntroduction
Methods
Journey of
Presentation
Purpose
FactorsConclusion

3. Introduction
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CausalityAssessmentinPharmacovigilance:
Pharmacovigilanceisthescienceandactivityrelatedtothedetection,evaluation,understandingand
preventionofsideeffectsandotherdrug-relatedproblems.Animportantaspectofpharmacovigilanceisthe
assessmentofcausality.Itassessesthelikelihoodofsuspectedadversedrugreactions(ADRs)causedbya
particulardrug.
Causalityassessmenthelpsidentifyandquantifyrisksassociatedwithdruguse.Thismayinfluenceregulatory
decisions,prescribingpractices,andpatienteducation.Itisalsoacomplexandchallengingprocessthat
requirescarefulconsiderationofmultiplefactorsandathoroughunderstandingofthepharmacologyand
pathophysiologyofsuspectedADRs.

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)
ØMany 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’sFrench
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 care met.
Possible: When only criteria a is met.
Unlikely: When criteria aand bdo 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: Finallywhen 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 Eventorlaboratorytestabnormality,withplausibletimerelationshiptodrugintake
Cannotbeexplainedbydiseaseorotherdrugs
Responsetowithdrawalplausible(pharmacologically,pathologically)
Eventdefinitivepharmacologicallyorphenomenologically(i.e..anobjectiveandspecificmedicaldisorder
orarecognizedpharmacologicphenomenon)
Rechallengesatisfactoryifnecessary
Probable/likely Eventorlaboratorytestabnormality,withreasonabletimerelationshiptodrugintake
Unlikelytobeattributedtodiseaseorotherdrugs
Responsetowithdrawalclinicallyreasonable
Rechallengenotrequired
Possible Eventorlaboratorytestabnormality,withreasonabletimerelationshiptodrugintake
Couldalsobeexplainedbydiseaseorotherdrugs
Informationondrugwithdrawalmaybelackingorunclear
Unlikely Eventorlaboratorytestabnormality,withatimetodrugintakethat(butnotimpossible)
Diseaseorotherdrugsprovideplausibleexplanation
Conditional/unclassifiedEventorlaboratorytestabnormality
Moredataforproperassessmentneeded,or
Additionaldataunderexamination
Unassessable/unclassified Reportsuggestinganadversereaction
Cannotbejudgedbecauseinformationisinsufficientorcontradictory
Datacannotbesupplementedorverified.

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:
ØDangaumou'sfrenchmethod
ØKramer et al. method
ØNaranjo et al. method (Naranjo scale)
ØBalanced assessment method (Lager et al.)
ØSummary time plot (Castle et al.)
ØCiba geigymethod (Venuletet al.)
ØRoussel Uclafcausality assessment method (RUCAM)
ØMaria and Victorino(M and V) scale
ØDrug 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 drugrather 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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TheNaranjoadversedrugreactionprobabilityscale;Toassesstheadversedrugreaction,
pleaseanswerthefollowingquestionnaireandgivethepertinentscore
YesNoDon’t
Know
1.Aretherepreviousconclusivereportsonthisreaction?
2.Didtheadverseeventoccurafterthesuspecteddrugwasadministered?
3.Didtheadversereactionimprovewhenthedrugwasdiscontinuedoraspecificantagonistwas
administered?
4.Didtheadversereactionreappearwhenthedrugwasreadministered?
5.Aretherealternativecauses(otherthanthedrug)thatcouldhaveontheirowncausedthe
reaction?
6.Didthereactionreappearwhenaplacebowasgiven?
7.Wastheblooddetectedintheblood(orotherfluids)inconcentrationsknowntobetoxic?
8.Wasthereactionmoreseverewhenthedosewasincreasedorlessseverewhenthedosewas
decreased?
9.Didthepatienthaveasimilarreactiontothesameorsimilardrugsinanypreviousexposure?
10.Wastheadverseeventconfirmedbyanyobjectiveevidence?
+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:
Thismethodonlyexplainsthecausalityofoneindividual
druganditdoesnotexplainsthecausalityoccurreddueto
druginteractions.

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
•NaranjoCA,BustoU,SellersEM,SandorP,RuizI,RobertsEA,JanecekE,etal.Amethodforestimating
theprobabilityofadversedrugreactions.ClinPharacolTher.1981;30:239–45.
•SegerD,BarkerK,McNaughtonC.MisuseoftheNaranjoAdverseDrugReactionProbabilityScalein
toxicology.ClinToxicol(Phila).2013Jul;51(6):461-6.doi:10.3109/15563650.2013.811588.Epub2013Jun
18.PMID:23777343;PMCID:PMC3887443.
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15. Thank You!
www.clinosol.com
(India | Canada)
9121151622/623/624
[email protected]
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