1) The document discusses various methods for assessing causality of adverse drug reactions (ADRs), including the WHO causality assessment categories and Naranjo probability scale. 2) The WHO categories include certain, probable, possible, unlikely, conditional/unclassified, and unassessible/unclassifiable based on factors like temporal relationship, dechallenge/rechallenge responses, and alternative explanations. 3) The Naranjo scale uses a scoring system to evaluate ADR reports and determine if the reaction is definite, probable, possible, or doubtful. It considers similar factors as the WHO categories.

1. 1
Causality Assessment

2. Adverse Event:
Any untoward medical occurrence that may present during
treatment with a pharmaceutical product but which does not
necessarily have a causal relationship with the treatment.
ADR:
A response to a drug which is noxious and unintended, and which
occurs at doses normally used in man for the prophylaxis,
diagnosis, or therapy of disease, or for the modification of
physiological function
AE vs. ADR
2

3. The Universe of Adverse Events
3

4. AE ----ADR
 How do we go about attributing a reaction to a
drug ?
4
Causality
assessment

5.  Spontaneous reports of known drugs
 Reports from ongoing clinical studies
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Casuality Assessment......

6. The different methods share common factors:
a. The temporal relationship (time to onset)
b. Existing information about the ADR
c. Pharmacological plausibility
d. Exclusion of other causes
e. Dechallenge or dose reduction
f. Rechallenge or dose increase
g. Drug interactions
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Evaluation of a suspected ADR

7. Methods of causality assessment
 WHO assessment scale
 Naranjo's scale
 European ABO system
 Karch and Lasagna's scale
 Kramer scale
 Yale logarithm
 Spanish imputation system
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8. WHO Causality Categories
 Certain
 Probable/Likely
 Possible
 Unlikely
 Conditional/Unclassified
 Unassessible/Unclassifiable
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9. WHO Causality Categories
Certain
 Event or laboratory test abnormality, with plausible temporal
relationship to the drug.
 Cannot be explained disease or other drugs.
 Response to withdrawal plausible
 Event definitive pharmacologically or immunologically
 Rechallenge (positive, if performed)
 Key feature: Positive rechallenge
12
Eg.
Dizziness 1/2 hour after ingestion of an oral antihypertensive drug with no
concomitant drugs -- AE stops on stopping drug (positive dechallenge) & restarts
when taken again (positive re-challenge)

10. Probable
 Event, lab test abnormality with reasonable time
relationship to drug intake
 Unlikely to be attributed to disease or other drugs
 Clinically reasonable response to withdrawal
 Rechallenge not required
 Key feature: Positive dechallenge
WHO Causality Categories
13
Egs.
o Diarrhea after ampicillin which recovers after stopping Ampicillin

11. Possible
 Event or laboratory test abnormality, with reasonable time
relationship to drug intake.
 Could also be explained by concurrent disease or other
drugs.
 Information on drug withdrawal lacking or unclear
 Key feature: other explanations for the event
are possible
WHO Causality Categories
14
Egs –
o Abnormal liver function tests after taking AKT in patient with HIV

12. Unlikely
 Event or laboratory test abnormality with a time to drug intake that
makes a relationship improbable (but not impossible).
 Diseases or other drugs provide plausible explanations.
 Key feature: several factors indicate strongly that the event
is not a reaction
Egs –
o Cancer of the colon diagnosed after 3 doses of an antibiotic
WHO Causality Categories
15

13. Conditional/Unclassified
 Event or laboratory test abnormality.
 More data for proper assessment needed.
 Or additional data under examination.
 Key feature: Can’t assess with the information available
Unassessable/unclassifiable
 Cannot be judged because of insufficient or contradictory
information.
 Report cannot be supplemented or verified
 Key feature: Data elements concerning the event are
inadequate and will not be available
WHO Causality Categories
16

14. WHO Causality Categories – In summary
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Categories Time
sequence
Other drugs/
disease ruled
out
Dechallenge Rechallenge
Certain Yes Yes Yes Yes
Probable Yes Yes Yes No
Possible Yes No No No
Unlikely No No No No
European Journal of Internal Medicine, 2009; 20: 3-8.

15. 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 Or a specific
antagonist given?
+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
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The Naranjo Probability Scale

16. Definite ≥ 9
Probable - 5-8
Possible - 1-4
Doubtful ≤ 0
Advantages:
• Simple and brief, most extensively used.
• Reduction in inter-rater disagreement and uncertainty
Limitation:
 Intended to assess the likelihood of an ADR with only one drug,
not from interactions between drugs.
 Reliability established in adults but not in children
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The Naranjo Probability Scale

17. Case Studies
Causality Assessment
for Spontaneous ADRs
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18. Case Study 1
 Mr ABC, a 54 years old male, was prescribed
 Tab Ofloxacin 200 mg 12 hrly for uncomplicated cystitis. After 1
day of therapy he started getting nightmares and hallucinations.
 The physican asked him to stop Ofloxacin. He did not have
nightmares after that. 3 years later, he was admitted for a
surgical procedure and was given Ofloxacin parenterally.
 That night he again had nightmares and hallucinations.
Hospitalization stay was increased for further management.
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19. Adverse Event – Nightmares, hallucinations
Suspected Drug – Ofloxacin
Serious - Yes
22
Case Study 1

20. Evaluation of a suspected ADR
23
 The temporal relationship (time to onset) -Yes
 Existing information about the ADR – exists
 Pharmacological plausibility – CNS effects of
fluoroquinolones
 Exclusion of other causes – no other drugs or cause
responsible
 Dechallenge or dose reduction - improvement
 Rechallenge or dose increase – reaction recurred

21. Certain
24
 Plausible time relationship to drug intake
 Cannot be explained by other drug or disease
 Dechallenge- improvement
 Re-challenge positive

22. 35 years old male, Mr. ABC, received the following medications
for sinusitis
Tab. Levofloxacin 500 mg p.o. 24 hourly
Tab. Paracetamol 500 mg p.o. 8 hourly
Tab. Bromhexine 8 mg p.o. 8 hourly
Case Study 2
25

23. The next day, patient developed maculopapular rash with
itching on the upper limb and abdomen.
Subsequently, Tab. Levofloxacin was withdrawn and
replaced with another antimicrobial.
The rash subsided over 2 days.
The other medications were continued.
Case Study 2
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24. Adverse Event- Maculopapular rash
Serious - No
Suspected Drug- Levofloxacin
Concomittant medication- Bromhexine, Paracetamol
The reaction subsided on drug withdrawal- Dechallenge positive
27
Case Study 2

25. Evaluation of a suspected ADR
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 The temporal relationship (time to onset) –Yes
 Existing information about the ADR – Yes
 Pharmacological plausibility – Yes
 Exclusion of other causes – other drugs were cont.
 Dechallenge or dose reduction - improvement
 Rechallenge or dose increase – not given

26.  Event or laboratory test abnormality, with reasonable
time relationship to drug intake.
 Unlikely to be attributed to disease or other drugs.
 Dechallenge- improvement.
 Re-challenge not required / not done
Probable
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27. Case Study 2a
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 In the same case, if all 3 drugs were stopped?
 All 3 drugs will be included in the suspected drug list.
 Causality will be Possible as either of the 3 drugs could be
responsible

28. 42 years male patient came to skin OPD with chief complaints of,
 Itching (generalized)
 Swelling around eyes since 2 days
 Swelling of lips
4 days back he consulted a private dental practitioner for toothache
who prescribed following medications
 Tab Diclofenac 50 mg – stopped after 2 days of administration
 Tab Azithromycin 500mg – continued
31
Case Study 3

29.  In skin OPD, Diclofenac was stopped and patient was admitted in
wards & managed by antihistaminics, steroids
 Reaction is Serious : Required hospitalization
 OUTCOME : Patient was improving symptomatically.
 According to WHO scale of Causality assessment :- Probable.
a) Unlikely caused by other drugs/disease
b) Reasonable drug-event temporal relation
c) Dechallenge response positive.
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Causality assessment of AE

30. Causality assessment by Naranjo 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 reappear 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
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31. Total Score - 6
As per Naranjo Scale
Definite ≥ 9
Probable - 5-8
Possible - 1-4
Doubtful ≤ 0
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The Naranjo Probability Scale

32. Dr XY reported a case of a 22 years old female Mrs. DKNY, of
immune-compromised status who was given anti-retroviral therapy:
Tab. Stavudine 30 mg 12 hrly
Tab. Lamivudine 150 mg 12 hrly
Tab. Nevirapine 200 mg 12 hrly
Few months later, patient developed tingling, numbness followed
by weakness of both the upper & lower limbs and difficulty in
walking.
Case Study 4
35

33. Adverse Event- Peripheral Neuropathy
Serious – Yes -results in persistent or significant
disability/incapacity
36
Case Study 4

34. Evaluation of a suspected ADR
37
 The temporal relationship (time to onset) – Yes
 Existing information about the ADR - Dose–dependent
peripheral neuropathy is the major adverse effect of
Stavudine.
 Pharmacological plausibility - Yes
 Exclusion of other causes – Up to 35% of HIV infected
individuals will develop a peripheral neuropathy due to HIV
itself, a similar presentation may occur secondary to drugs such
as zalcitabine, didanosine, and stavudine.
 Dechallenge or dose reduction- No information
 Rechallenge or dose increase- No information

35. o Reasonable time relationship to drug intake.
o Suspected Drug- Stavudine
o Concomittant medication - Lamivudine, Nevirapine
o Could also be explained by disease - The reaction
Neuropathy may be caused by the disease (HIV) in this
case
o Information on drug withdrawal may be lacking
Possible
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36. 39
Examples 1
A 65 year old male, obese, smoker, hypertensive, type 2
diabetic (poorly controlled) with hypercholesterolemia starts a
new drug and has an inferior wall myocardial infarction 8 days
after starting.
 Related to the drug?
Some More Examples

37. 40
 But…
 His BOTH parents were smokers & have elevated cholesterol
and are 98 years old alive & fairly well.
 He only took one dose and stopped because it gave him
headaches. The terminal half life is 20 minutes.
 His 20 year old dog died the day before and this was very
stressful.
 He worked in his garden for 5 hours the day of the attack.

38. 41
 A pregnant woman takes a drug early in her pregnancy
to prevent a miscarriage (spontaneous abortion).
 Fourteen years later her daughter develops cancer of
the vagina.
 Related to the drug?
Example 2

39. 42
DES
 Diethylstilbestrol (DES) is an estrogen that prescribed DES to
pregnant women to prevent miscarriages.
 An estimated 5-10 million pregnant women and the children born of
these pregnancies were exposed to DES in the US.
 In 1971 a study identified DES as a cause of a rare vaginal cancer
in girls and young women who had been exposed to DES before
birth (in utero).
http://www.cdc.gov/des/consumers/about/history.html
Example 2

40. Case Studies
Causality Assessment
for ADRs in Clinical Studies
43

41. 44
 Patient with history of IHD with DM was on Insulin analog (IP)
since one year
 Patient was brought to the site with history of drowsiness, poor
verbal output, decreased movements of upper limb and lower
limb, decreased oral intake since few days.
 AE Term/Diagnosis: Stroke
 Drug was continued
Case study 1

42. 45
Drug history
Name of the
concomittent Drug
Dose Frequency Stop Date
Aspirin 150 OD Ongoing
Atorva 10 OD Ongoing
Metoprolol 25 OD Ongoing
Voglibose 0.2 OD Ongoing
Metformin 500 TDS Ongoing

43. 46
Evaluation of causality assessment
 Event and drug intake had temporal association
 The event could also be explained by disease / other drugs
 Relationship of drug withdrawal and event could not be assessed as
drugs are continuing and also the progression or resolution of event
(stroke) cannot be assessed.
 Literature search of IP and other ongoing drugs indicated
increased risk of stroke in “these” patients on treatment.
 CAUSALITY as per the WHO assessment scale - “POSSIBLE”

44. How does this reporting help?
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45. Major uses of causality Assessment
 Signal detection
 Drug regulation
 Scientific publications
 Regulatory (compensation)
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46. 53
IPC – NCC - PvPI Directives
for
Causality Assessment

47. 54
54

48. Comparison of method used for ADR
assessment
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Saudi Pharmaceutical Journal (2016) 24, 485–493

49. FDA site -----
“For any individual case report, it is rarely possible to know with a
high level of certainty whether the event was caused by the
product.
Rigorous pharmacoepidemiologic studies, such as case-control
studies and cohort studies with appropriate follow-up, are usually
employed to further examine the potential association between a
product and an adverse event.”
56
https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf
Causality Assessment – disagreement
of scales

50. 58
 Causality Assessment is a very important process which needs a lot of skill ,
literature search and commitment.
 Numerous published methods are available for causality assessment and
these have their advantages and disadvantages.
 There is an inherent subjectivity of judgements in performing causality
assessment which may vary from assesor to assesor.
 As important is Causality Assessment it is also a very
tricky Job
Conclusion

51. Thank you
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