Causality assessment of adverse drug reaction

1. Causality Assessment Scale
Presenter:-
Dr Arun Singh
Second Year Resident Doctor
Department of Pharmacology
SMS Medical College,Jaipur

2. Learning
Objectives
Introduction
Classification of ADR
Definition of Causality Assessment
Objectives of Causality Assessment
Methods
Categories of Causality Assessment
World Health Organization (WHO)–
Uppsala Monitoring Centre (UMC)
Some Case Examples
Naranjo Scale

3. Introduction
• The ethymological roots for the word “pharmacovigilance” are :
pharmakon (Greek for drug) and vigilare (Latin for a keep watch).
• World Health Organization (WHO) defined the ADR as “response
to a drug, which is noxious and unintended, and which occurs at
doses normally used in man for prophylaxis, diagnosis or therapy of
disease, or for the modification of physiological function.

4. • The main goal of pharmacovigilance
is thus to promote the safe and
effective use of health products, in
particular by providing timely
information about the safety of health
products to patients, health care
professionals, and the public.
• The ultimate goal of
pharmacovigilance is to accurately
characterize and optimize the
befits/risk ration of a health product
throughout its life cycle.

5. Terminology
• Adverse drug reaction(ADR): It is a non intended reaction to the
drug where a positive (direct) causal relationship between the
event and the drug is thought, or has been proven, to exist.
• Adverse event (AE): Any new clinical experience that occurs
after commencing a medicine. By definition, the causal
relationship between the AE and the drug is unknown.
• Causal relationship: It is said to exist when a drug is thought to
have caused or contributed to the occurrence of an adverse drug
reaction.

6. Classification of Adverse drug reactions
 Adverse drug reactions are classified into six types (with
mnemonics):
(A)Dose-related (Augmented)
(B)Non-dose-related (Bizarre)
(C)Dose-related and time-
related (Chronic)
(D)Time-related (Delayed)
(E)Withdrawal (End of use)
(F)Failure of therapy
(Failure).

7. Definition
• Causality assessment is the assessment of relationship between a
drug treatment and the occurrence of an adverse event.
• It is basically used for estimate and to investigate that the
particular treatment is the cause of an observed and adverse event
or not.
• It is an essential part of ADR report and important task, conducted
by National Pharmacovigilance Programme in each country.

8. Objectives of Causality Assessment
• Provide relationship between the drug and events.
• Signal detection (“a possible causal relationship between an
adverse event and a drug, the relationship being unknown or
incompletely documented previously.”)
• Provide better evaluation of the benefit/harm profiles of drugs.
• Plays as an essential part of evaluating ADR reports in early
warning systems and for regulatory purposes.

9. Methods of Causal Assessment
• Many researchers developed various methods of causality
assessment of ADRs by using different criteria like chronological
relationship between the administration of the drug and the
occurrence of the ADR, screening for non-drug related causes,
confirmation of the reaction by in vivo or in vitro tests, and
previous information on similar events attributed to the suspect
drug or to its therapeutic class, etc.

10. Three broad categories of various methods of causality
assessment:
1.Expert judgment/global introspection
2.Algorithms
3.Probabilistic methods (Bayesian approaches)

11. Expert judgment/global introspection
• Expert judgments are individual assessments based on previous
knowledge and experience in the field using no standardized tool to
arrive at conclusions regarding causality.

12. Swedish method
by Wilholm et al.
198
World Health
Organization
(WHO)–Uppsala
Monitoring Centre
(UMC) causality
assessment criteria

13. Algorithms
Algorithms are sets of specific questions with associated scores for
calculating the likelihood of a cause-effect relationship.
It is a clinical instrument in the form of a questionnaire that gives
detailed operational criteria for ranking the probability of causation
when an ADR is suspected.

14. Dangaumou’s
french method
Kramer et al. 1974
method
Balanced
assessment
method (Lagier et
al. 1983)
Summary time plot
(Castle et al. 1984)
Cibageigy method
(Venulet et
al.1980)
Loupi et al. 1986
method
Maria and victorino
(M and V) scale
Naranjo scale
Roussel Uclaf
causality
assessment
method (RUCAM)

15. Probabilistic methods
(Bayesian approaches)
Bayesian approaches use specific findings in a
case to transform the prior estimate of
probability into a posterior estimate of
probability of drug causation.
The prior probability is calculated from
epidemiological information and the posterior
probability combines this background
information with the evidence in the individual
case to come up with an estimate of causation.

16. Australian method
Bayesian Adverse Reactions Diagnostic Instrument (BARDI)
MacBARDI spreadsheet

17. • WHO causality assessment scale and Naranjo probability scale are the
widely used and commonly preferred in most of the practices.

18. World Health Organization (WHO)–Uppsala Monitoring
Centre (UMC) causality assessment criteria
WHO causality assessment scale is majorly used scale for the
assessment of the causal relationship of case reports and has been
developed during the International Drug Monitoring Programme in
discussion with national centers.
It is basically a combined assessment taking into account the
clinical-pharmacological aspects of the case history and the quality
of the documentation of the observation.

19. • The WHO–UMC causality assessment method includes the following
four criteria :
a) Time relationships between the drug use and the adverse event.
b) Absence of other competing causes (medications, disease process
itself).
c) Response to drug withdrawal or dose reduction (dechallenge).
d) Response to drug readministration (rechallenge).

20. Causality association
1.Certain
2.Probable
3.Possible
4.Unlikely
Certain:-When all 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 are not met.

21. • Besides these four categories, ADR can also be categorized into:-
Unclassified/Conditional
Unassessable/Unclassifiable
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.

22. Basic terminologies in WHO-UMC Causality Assessment scale
• Challenge: Giving of the drug to the patient during the AE or
treatment.
• Dechallenge: Stopping of the drug, usually after an adverse event (AE)
or at the end of a planned treatment.
Dechallenges may be complete or partial, i.e., the drug is fully stopped
or decreased in dose and the AE may fully disappear or only partially
decrease.
• Positive dechallenge: AE disappears after the stopping of the drug.
• Negative dechallenge: This refers to the AE doesn't disappear after the
stopping of the drug.

23. • Rechallenge: Restarting of the same drug after having stopped it,
usually for an AE.
Rechallenges may also be complete or partial.
• Negative rechallenge: This is the case where the AE does not recur
after the drug is restarted.
• Positive rechallenge AE recurs after restarting the drug.
• Prechallenge: This is a new term that refers to the use of the same drug
at some point in the past.

25. Examples : Certain
Dizziness starts 45 minutes later administration of the
antihypertensive drug with no concomitant drugs-AE stops on
stopping drug (positive dechallenge) & restart when taken again
(positive rechallenge).
Injection site reaction 30 seconds after a subcutaneous injection.
A large tablet gets suck in the pharynx (obstruction) while swallowing
it & it has to be removed in the ER.

26. Example: Probably
Thrombocytopenia after taking an
anticancer drug.
Diarrhoea after taking ampicillin.
Vaginal candidiasis after an
antibiotic for bronchitis.

27. Example: Possibly
ABNORMAL
LIVER
FUNCTION
TESTS AFTER
TAKING AN
ANTIHISTAMI
NE.
HEADACHE DYSPEPSIA
AFTER A
TABLET OR
CAPSULE.

28. Example: Unlikely
Cancer of the colon diagnosed after 3 doses
of an antibiotic.
Myocardial infarction 3 weeks after taking
a drug that has a terminal half life of 10
minutes.
Auto accident but…..-Did the drug cause
dizziness which caused the accident?

29. Case Example-1.
• A female disease, 55 years old with osteoporosis disease.
• Prescriber give Pamidronate 30 mg on 05/03/2021
• Patient report adverse drug reaction like arthrosis, arthritis aggravated
on 07/03/2021.
• Outcome-Not recovered
• Dechallenge-Negative
Q. Assessment related to the drug? Possible

30. Case Example-2.
• A female disease, 63years old with Paget’s disease(hypercalcemia of
malignancy).
• Prescriber give Pamidronate acid I.V. on 12/03/2021
• Other medications-Letrozole, Simvastatin.
• Patient report adverse drug reaction like synovitis, influenza like
symptoms, skeletal pain on 12/03/2021.
• Dechallenge-Reaction abated
• Letrozole, Simvastatin
Q. Assessment related to the drug?
Probable

31. Case Example-3.
• A male 28 years old health worker, during covid-19 pandemic disease
want to done covishield vaccination
• He goes to vaccination centre to take covishield vaccine at morning on
15/03/2021.
• After vaccination, he report adverse drug reaction like injection site
pain, myalgia and mild fever at night on 15/03/2021.
• Outcome-recovered(rechallenge)
Q. Assessment related to the drug?
Certain

32. Naranjo scale
• Naranjo scale assesses the causality using the traditional categories of
definite, probable, possible and doubtful.
• A ten-elemental questionnaire with yes, no and unknown replies are
developed.
• Based on the replies, the score has been determined into categories.
• Limitation: The Naranjo Scale does not address the points needed in
the assessment of the causality of possible drug interactions.