The document provides an overview of causality assessment in pharmacovigilance, which is essential for understanding the relationship between drug treatments and adverse effects. It outlines methods for conducting causality assessments, including expert judgement and various algorithms, along with established criteria for categorizing adverse drug reactions (ADRs). Additionally, it emphasizes the significance of accurately assessing causality to minimize patient suffering and optimize drug safety monitoring.

1. CAUSALITY
ASSESSMENT
Gaurav Chhabra
M-Pharm II Sem.
(Pharmacology)
UIPS, Panjab University,
Chandigarh

2. INTRODUCTION
PHARMACOVIGILANCE
Pharmaco + Vigilance
(Medicines) (To Watch)
According to WHO-:
 Science and activities relating to the detection, assessment,
understanding and prevention of adverse effects and any other drug
related problems.
 This applies throughout the life cycle of a medicine equally to the
pre-approval stage as to the post approval.

3. Adverse reaction: “A response to a medicine which is
noxious and unintended, and which occurs at doses
normally used in man”
Adverse event: Any new clinical experience that occurs
after starting a medicine, not necessarily a response to a
medicine, and is recorded without judgement on its
causality.

4.  These adverse drug reactions (ADRs) not only add to the suffering
of patients but also increase morbidity and mortality along with a
financial burden on society.
 The overall incidence of ADRs in hospitalized patients is estimated
to be 6.7 %( range 1.2–24.1%) and that of fatal ADRs 0.32% (0.1–
0.85%)
 Data indicates that in patients who experience ADRs death rates are
19.18% higher and the length of hospital stay is 8.25% higher.
 Total medical costs for patients with ADRs are increased by an
average of 19.86%
 So to minimize the suffering of the patient from ADRs, there is an
establishment of causal relationship is done between drug and their
adverse events, called as Causality Assessment.

5. CAUSALITY ASSESSMENT
Definition:-
 Causality assessment is the assessment of relationship between a
drug treatment and the occurrence of an adverse event.
 It is also used to evaluate and to check that the particular treatment
is the cause of an observed adverse event or not.
 It is an essential part of ADR report and important task, conducted
by National Pharmacovigilance Programme in each country.

6. 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.

7. How The Causality Assessment is Performed ?
(Methods Of Causality Assessment)
 Many researchers developed various methods of causality assessment by using different
criteria like-
Chronological relationship between the administration of
the drug and the occurrence of the ADR,
Screening for drug and non drug related causes,
Confirmation of the reaction by in vivo or in vitro test,
Previous information on similar events etc.
 But there is No universally accepted method for assessing causality of ADRs.

8. METHODS
Classified under three broad categories
Expert Judgement/ Algorithms Probabilistic Methods
Global Introspection Dangaumou’s french method Australian method
 Swedish method by Kramer et al. method Bayesian Adverse Reactions
Wilholm et al Naranjo scale Diagnostic Instrument (BARDI)
 World Health Organization Balanced assessment method MacBARDI spreadsheet
(WHO) - Uppsala Monitoring Drug Interaction Probability
Centre (UMC) causality Scale(DIPS) etc.
assessment criteria
Causality Assessment Of Vaccine Related
Adverse Events

9. (A) EXPERT JUDGEMENT/GLOBAL INTROSPECTION
 It is a process in which an expert expresses judgement about possible drug causation by
considering al available data relevant to a suspected ADR.
 Assessment of ADR is either done by single expert evaluator or by a group of expert
evaluators.
 As evaluation and assessment of ADR by these experts is purely based on their respective
knowledge and experience about the subject of interest.
 Two methods based on expert opinion or global introspection.
(1) Swedish method by Wilholm et al.
(2) World Health Organization (WHO) - Uppsala Monitoring Centre (UMC) causality
assessment criteria.

10. (A)(2) World Health Organization (WHO) - Uppsala
Monitoring Centre (UMC) causality assessment
criteria
 Widely and globally accepted method.
 WHO-UMC system provides practical tool for assessment of case reports for International drug monitoring
 System is used to detect unknown and unexpected adverse drug reaction.
Assessment is based on 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 (de-challenge).
d) Response to drug re-administration (re-challenge).
 the level of causal association is grouped into four categories which are based on a number of the above criteria
being met.
CONTI……….

11. Causality association
 Certain
 Probable
 Possible
 Unlikely
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 are not met.
 Beside 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.

12. 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 (ie. 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 makes a relationship improbable
(but not impossible)
 Disease or other drugs provide plausible explanation
Conditional/unclassifie
d
 Event or laboratory test abnormality
 More data for proper assessment needed, or
 Additional data under examination
Unassessable/unclassif
iable
 Report suggesting an adverse reaction
 Cannot be judged because information is insufficient or contradictory
 Data cannot be supplemented or verified.

13. IN SIMPLE WAY
 Certain – Good timing, no other cause, withdrawal response
plausible, rechallenge “definitive”
 Probable – Good timing, other cause unlikely, withdrawal
 Possible – Good timing, other causes possible
 Unlikely – Poor timing, other causes more likely
 Unassessable – Insufficient or contradictory information

14. 14
Categories of Causality using WHO Causality
Assessment Criteria
Very likely
Probable
Possible
Vaccine reaction
Injection Reaction
Programmatic error
Coincidental events
Unclassifiable
Insufficient evidence
to classify
Unlikely
Unrelated

15. EXAMPLE: CERTAIN
 Dizziness ¾ hour after ingestion of an oral antihypertensive drug with
no concomitant drugs – AE stops on stopping drug (positive
dechallenge) & restarts when taken again (positive rechallenge).
 Injection site reaction 30 seconds after a subcutaneous injection.
 A large tablet gets stuck in the pharynx (obstruction) while swallowing
it & it has to be removed in the ER.

16. EXAMPLE: PROBABLY
 Thrombocytopenia after taking an oncology drug.
 Diarrhea after ampicillin.
 Vaginal candidiasis after an antibiotic for bronchitis.
EXAMPLE: POSSIBLY
 Abnormal liver function tests after taking an antihistamine.
 Headache.
 Dyspepsia after a tablet or capsule.

17. Examples: 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?

18. CASE REPORT-1
 Female-76 years
 Rx
Pamidronic acid I.V. - 23/08/06
 Other medications- Letrozole, simvastatin
 Adr.- Synovitis, influenza like symptoms, skeletal pain. : 23/08/06
 Dechallenge- Reaction abated
 Letrozole, Simvastatin
 Que. - Assessment related to the drug?
Probable

19. CASE REPORT-2
 Female-68 years
 Rx
Pamidronate- 30mg. - 15/01/97
 Adr.-Arthrosis, Arthritis aggravated. 18/01/97
 Outcome- Not recovered
 Dechallenge- Negative
 Que. - Assessment related to the drug?
Possible

20. Case Report-3
 2 month old child was given 2nd dose of OPV, Hib, hepatitis B vaccine & measles (first dose). Child had
blocked nostrils but otherwise in good health. Baby had protruding umbilical hernia. Mother was asked
about any illness and stated he had a blocked nose. Nurse prescribed paracetamol syrup x 3 days and gave
stat dose of nasal decongestant for blocked nose. Nose was blocked at first immunization as well. Mother
lives on farm – too far from hospital. Baby breast fed later and last feeding was 02:00 that night. Mother
became worried when child was breathing very rapidly. Mother-in-law was called and told mother that child
probably had cold symptoms and told mother not to worry. Mother went back to sleep and awoke at 5am.
Child was found dead beside her.
 is this a
a) vaccine reaction?
i) expected?
ii) unexpected?
b) programmatic
c) coincidental
d) unknown
e) injection reaction
 What is your level of certainty?
 likely, probably, possible, unlikely or unclassifiable
 What factors were considered when deciding on causality?
Mother reported that she gave the child
paracetamol syrup that afternoon as she
thought the injection site was painful. Post
mortem done and found that cause of death
was food aspiration.

21. Case Report-4
 7 month of child with history of neonatal asphyxia
 No prior history of seizures
 Developed repeated generalised clonic and occasional myoclonic seizures after
DTP3 (29/7).
 Onset – 24 hours – high fever and seizures
 Seizures continued even after fever.
 Increasing frequency of seizures not responsive to carbamazepine
 Some improvement with benzodiazepine
 Delayed milestones
 CT scan – mild cortical atrophy
Assessment: possible precipitation
of
underlying neurological problems
with febrile episode post-injection

22. (2) ALGORITHMS
 It consists of a problem-specific flow chart with step-by-step instruction on
how to arrive at an answer.
 Actually, its form contain some questionnaire, whose answers provide the
causality of particular ADR.
 It give structured and standardized methods of assessment in a systematic
approach.
 Assessment of ADRs based on parameters such as
Time to onset of the ADR or temporal sequence,
Previous drug/adverse reaction history,
Dechallenge and Rechallenge

23. Types Of Algorithms Method
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 are-
 Dangaumou’s french method
 Kramer et al. method
 Naranjo et al. method (Naranjo scale)
 Balanced assessment method (Lagier et al.)
 Summary time plot (Castle et al.)
 Ciba geigy method (Venulet et al.)
 Roussel Uclaf causality assessment method (RUCAM)
 Maria and Victorino (M and V) scale
 Drug Interaction Probability Scale (DIPS)

24. (B)Naranjo et al. method (Naranjo scale)
 Widely accepted method
 Method used 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.
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.

25. Table:- 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 Do not
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
+2
-1
-1
+1
+1
+1
+1
0
-1
0
-1
+2
+1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Total score
0– Doubtful
1–4 Possible
5–8 Probable
≥9 Definite
Limitation-:
Method only
explains the
causality of one
individual drug
Not explains the
causality occur due
to drug interactions

26. (3)-PROBABILISTIC OR BAYESIAN
APPROACHES
 Causality assessment based on study of prior probability and posterior probability.
 The prior probability is calculated from epidemiological information.
 The posterior probability combines this epidiological background information with the
evidence in the individual case.
 This method allows the simultaneous assessment of multiple causes.

27. (3)(1)Bayesian Adverse Reactions
Diagnostic Instrument (BARDI)
 BARDI is used to calculate the odds in favour of a particular drug causing an adverse
event compared with an alternative cause(posterior odds)
 The posterior odds factor is calculated by considering six assessment subsets: one deals
with background epidemiologic or clinical trials information (the prior odds) and the other
five deal with case specific information (the likelihood ratios).
PsO = PrO × LR(Hi) × LR(Ti) × LR(Ch) × LR(De) × LR(Re)
• Pro(the prior odds)- epidemiologic or clinical trials information
• The five likelihood ratios (LRs) deal with any information of differential diagnostic value
under
• patient history (Hi)
• timing of the adverse event with respect to drug administration (Ti)
• characteristics of the adverse event (Ch)
• drug dechallenge (De)
• drug rechallenge (Re)

28. (4) CAUSALITY ASSESSMENT OF VACCINE
RELATED ADVERSE EVENTS
 Vaccines are administered on large scale to healthy individuals, children, infants and neonates.
 So vaccines must meet with high degree of safety.
 Method developed by the Advisory Committee on Causality Assessment (ACCA) in Canada.
 ACCA is composed of specialist in pediatrics, epidemiology, infectious diseases, immunology,
neurology, pathology, adverse event surveillance, and microbiology
 They review individual cases in a systematic stepwise manner to categorize them on a specially
designed causality assessment form.
 This causality assessment form consists of seven sections.
Section one Section two Section three
Section four Section five Section six
Section seven

29.  Section one-: Section one relates to the reason for reporting and whether the committee agreed with
both the diagnosis that was made and the statement of severity.
 Section two-: Section two takes the evaluators through several important factors like frequency of
occurrence of adverse events, similar events known to occur with other diseases, vaccine-event
interval compatible with event, similar symptoms in past, concomitant drugs or other conditions;
for assessment of causality.
 Section three-: Section three relates to causality assessment by using WHO-UMC criteria.

30.  Section four-: Section four permits brief summary of case with important elements and
discussion which contributed to the final assessment of causality.
 Section five-: Section five permits recommendations for improving immunization or case reporting
procedures to be written.
 Section six-: Section six considers whether the case could be useful for Educational purpose.
 Section seven-: Section seven considers whether the case could be useful for publication.

32. iamgauravchhabra@gmail.com