How to Determine the Drug-Reaction Relationship in Adverse Drug Reaction?

1. CAUSALITY
ASSESSMENT OF ADRs
Nazmi Liana Azmi

2. 2
The trickiest
part when
filling up the
ADR form?
Which one to
choose?

3. INTRODUCTION

4. 4

5. “A young woman sustained a fractured
pelvis in an automobile accident and was
essentially confined to bed for the next
month. She continued to take her
prescribed oral contraceptive pills; one
month after accident she was hospitalized
for an acute pulmonary embolus. There was
no evidence of thrombophlebitis.”
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AN EXAMPLE..

6. 6
So is the pulmonary
embolus is due to the
PELVIC FRACTURE or
MEDICATION or
BOTH or NOT
RELATED at all?

7. “Pelvic fractures and the use of oral
contraceptive pills have each been
associated with pulmonary embolus, but
ascribing the embolus specifically to either
the fracture or the medication is clearly
impossible in this example.”
7

8. METHODS OF
CAUSALITY
ASSESSMENT

9. ✘ Karch & Lasagna’s scale
✘ Kramer & Hutchinson’s scale
✘ Najaranjo’s scale
✘ WHO assessment scale
✘ French imputation system
✘ Australian system
✘ European ABO system
✘ Bayesian neural network
✘ Yale algorithm 9
METHODS

10. 1. The association in time (& place) between drug
& event
2. Pharmacology (+ previous knowledge of ADRs)
3. Medical plausibility (characteristic signs &
symptoms, laboratory tests & pathology)
4. Likelihood / exclusion of other causes
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ASSESSMENT CRITERIA

11.  Application site reactions
 Immediate reactions
 Pharmacological effects (Type A)
 Immunological reactions (Type B)
 Congenital malformations
 Cancer
11
IMPORTANCE OF CRITERIA MAY
DIFFER FOR DIFFERENT TYPES OF
REACTIONS

12.  Type A effects: phamacokinetic
 Type B effects: immunological
 Other effects: variable time relationship (time
to onset, course, outcome, dechallenge,
rechallenge)
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TIME RELATIONSHIP

13. 1ST approach:
Previous knowledge of the drug being associated
with the adverse event is asked for:
 Karch & Lasagna
 Kramer & Hutchinson
 Naranjo
 Several national centres
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APPROACHES IN CURRENT SYSTEM

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NARANJO’S SCALE

15. 2nd approach:
Previous knowledge of the drug being associated
with the adverse event is NOT asked for:
✘ WHO assessment scale
✘ French imputation system
✘ Australian system
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APPROACHES IN CURRENT SYSTEM

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When the question about
previous knowledge is NOT
asked, the past experience is
usually taken into any later
review of a series of reports
(follow-ups)
Thus, the causality assessment
is a part of a 1ST STEP

17. To standardized ADR
reporting in Malaysia, use
WHO ASSESSMENT SCALE
to determine its causality
17

18. ✘ NOT a common causality grading
✘ Event / laboratory test abnormality with PLAUSIBLE TIME
RELATIONSHIP to drug intake
✘ Event CANNOT BE EXPLAINED BY CONCURRENT DISEASE
/ OTHER DRUGS / CHEMICALS / NO CONCOMITANT DRUG
✘ PLAUSIBLE RESPONSE TO WITHDRAWAL – usually
recover without any treatment
✘ Confirmed with POSITIVE RECHALLENGE / SPECIFIC
LABORATORY TEST (patch test)
✘ Event DEFINITIVE - no other possible explanation
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CERTAIN

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Only that particular drug
No concomitant drug
Or specific laboratory test
Plausible time relationship
CERTAIN
Recover without treatment

20. ✘ COMMON causality grading
✘ Event / laboratory test abnormality with REASONABLE
TIME RELATIONSHIP to drug intake
✘ Event UNLIKELY TO BE ATTRIBUTED TO CONCURRENT
DISEASE / OTHER DRUGS / CHEMICALS
✘ REASONABLE RESPONSE TO WITHDRAWAL – usually
recover without any treatment
✘ RECHALLENGE NOT NECESSARY
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PROBABLE

21. ✘ COMMON causality grading
✘ Event / laboratory test abnormality with REASONABLE
TIME RELATIONSHIP to drug intake
✘ Event COULD BE EXPLAINED BY CONCURRENT DISEASE /
OTHER DRUGS / CHEMICALS
✘ LACK OF INFORMATION ON WITHDRAWAL
✘ NO RECHALLENGE
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POSSIBLE

22. ✘ Event / laboratory test abnormality with IMPROBABLE
(BUT NOT IMPOSSIBLE) TIME RELATIONSHIP to drug
intake
✘ Event MORE LIKELY CAN BE EXPLAINED BY
CONCURRENT DISEASE / OTHER DRUGS / CHEMICALS
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UNLIKELY

23. ✘ INSUFFICIENT / CONTRADICTORY INFORMATION
✘ Cannot be supplemented / verified
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UNCLASSIFIABLE

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IN A NUTSHELL, USE THIS RULE OF THUMB

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THANK YOU FOR YOUR
ATTENTION!
Any questions?
Contact me at:
nazmiliana@moh.gov.my
0179224977