Causality Assessment of Adverse Drug Reactions

1. Causality Assessment:
Rationale and Need
Dr Sahil Kumar
Department of Pharmacology
Maulana Azad Medical College

2. OUTLINE
Definition of ADR
ADR reporting goals
Pharmacovigilance Programme of India
Causality Assessment
Drugs withdrawn due to ADRs
Causality Assessment Scales
•WHO-UMC Scale
•Naranjo Scale
Exercises

3. What constitutes an Adverse Drug Reaction (ADR)?
"A response to a drug which is noxious and
unintended, and which occurs at doses
normally used for the prophylaxis,
diagnosis or therapy of disease, or for the
modification of physiological function.”
(WHO Technical Report Series, 498, 1972)

4. An ADR can be:
 Unfavorable and unintended sign
 Symptom
 Disease
 Abnormal laboratory finding

5. Examples of unwanted effects:
 Symptoms - Headache, Nausea
 Physical findings- ↑ BP, Lump, Pallor, Edema
 Abnormal lab values- Deranged Liver Function
tests, Decreased hemoglobin)
Overdoses

6. ADR Reporting : Goals
•Increase awareness about medicines/medicine
product induced morbidity.
•Foster a culture of ADR reporting in professionals.
•What to report and what not to report ?
•Causality not prerequisite.
•Set up a mechanism for reporting.
•Provide feedback to health professionals about safety
issues.

7. ADR Reporting : Misconceptions
•All serious ADRs are known before drug is marketed
•Causality assessment difficult
•Reporting only when absolutely certain
•A stray report is of no particular significance

8. What is a signal?
•“An alert from any available data source that a
drug may be associated with a previously
unrecognised hazard is quantitatively or
qualitatively different from existing
expectations”
(Davies’s Textbook of ADRs)

9. What is spontaneous ADR reporting?
•Methodology for monitoring safety of
marketed medicines
•System of collation and analysis of reports of
suspected ADRs [by Health Professionals]

10. Goal
To ensure that the benefits of use of
medicine outweighs the risks and thus
safeguard the health of the Indian
population.
Pharmacovigilance Programme of India

11. • The Central Drugs Standard Control Organization
(CDSCO), Directorate General of Health Services under
the aegis of Ministry of Health & Family Welfare,
Government of India in collaboration with Indian
Pharmacopoeia commission, Ghaziabad initiated a
nation-wide Pharmacovigilance programme for
protecting the health of the patients by assuring drug
safety.
• Indian Pharmacopoeia commission, Ghaziabad is a
National Coordinating Centre (NCC).
Pharmacovigilance Programme of India (PvPI)

12. CDSCO Zonal and subzonal centers
• North – Ghaziabad and Chandigarh
• South – Chennai, Hyderabad , Bengaluru
• East – Kolkata
• West – Mumbai, Ahmedabad

14. CAUSALITY ASSESSMENT

15. Consider the following two situations:

16. ◦ Rakhi, a 56 year old female complained of
burning sensation while urinating and fever
with chills for past 3 days.
◦ She was prescribed Tablet Norfloxacin 400 mg
twice daily for three days.
◦ 10 days later she had an episode of abdominal
pain. After investigations, she was found to
have right sided colorectal carcinoma.

17. Ravi Kumar, a 50 yr old male and known case of
Type 2 Diabetes Mellitus having a Fasting Blood
Glucose-110mg/dl, HbA1c 7.5% was maintained
on Tab Glibenclamide 5mg twice daily for the
last 6 months.
2 days ago he had a binge of alcohol at a party.
An hour later he was brought to emergency with
throbbing headache, palpitations, sweating,
vomiting & mental confusion.
On examination he showed disorientation,
flushing, Pulse rate- 104 per min, BP- 120/80
mmHg, RR- 22 per min, Blood sugar- 112 mg/dl

18. Which of these events is likely to be associated
with the drug given?
What could be the factors which can establish
a drug to be the causative agent of an event?

19. Some incidents from the past…

20. Phocomelia – Thalidomide
Disaster

21. •Thalidomide first marketed (1957) in West
Germany.
•To alleviate morning sickness in pregnant
women.
•Throughout the world ~10,000 cases; only 50%
survived.
•Australian obstetrician William McBride &
German pediatrician Widukind Lenz suspected
a link b/w birth defects and the drug in 1961.
•In the US, pharmacologist Frances Kelsey
withstood pressure and refused FDA approval to
market thalidomide, saying further studies were
needed.

23. The Nimesulide Controversy:
The importance of correct
Causality Assessment

28. Pioglitazone &
Bladder Carcinoma

29.  Pioglitazone approved in 1999 as an adjunct to
exercise and diet to improve glycemic control in
adults with type 2 diabetes mellitus.
 On June 9, 2011 the French Agency for the
Safety of Health Products decided to withdraw
pioglitazone due to high risk of bladder cancer.
 Germany's Federal Institute for Drugs and
Medical Devices also advised doctors not to
prescribe it until further investigation of cancer
risk had been conducted.

31. •Reports about an increased risk of bladder
cancer in patients exposed to pioglitazone led
to its withdrawal from the French market.
•US-FDA did not suspend the market
authorization but added a black box warning
for bladder cancer risk.
•Indian drug regulatory authorities
withdrew pioglitazone in June 2013 but
then revoked the ban due to lack of sufficient
evidence and recommendation by the Drug
Technical Advisory Board (DTAB).

32. Some other examples…
Name Drug Class Marketing
year
Observation Withdrawal
Troglitazone Anti-
diabetic
1997 Hepatotoxicity 1997
Cisapride Prokinetic 1993 QT prolongation 2000
Rofecoxib
(Vioxx)
NSAID 1999 Cardiovascular
events
2004
Gatifloxacin Quinolones 1999 Dysglycemia 2005
Sibutramine Anti-
Obesity
1995 Cardiovascular
events
2010

33. Causality assessment
Causality assessment of ADRs is a
method used for estimating the strength of
relationship between drug(s) exposure and
occurrence of adverse reaction(s).
42

34. Causality assessment
Two approaches
•Individual case safety reports (ICSRs)
•Single reports of suspected reactions
•(spontaneous reporting)
•Epidemiological
•Large numbers of reports of events
43

35. If an event has occurred, it could be due
to the suspected drug or due to….

36. Four Basic Criteria:

37. Ideal System?

38. What data are needed?
•All medicines near the time of the event
•dates
•doses
•indications
•The event description
•date of onset
•duration to onset
•event dictionary term
47

39. What data are needed?
•Results of dechallenge & rechallenge
•Outcome of the event
•Patient medical history
•past diseases of importance eg hepatitis
•Other current diseases (co-morbidities) eg
•tuberculosis
•diabetes
48

40. Two definitions
Dechallenge: the outcome of the event after
withdrawal of the medicine
resolved, resolving, resolved with sequelae, not
resolved, worse, death, unknown
Rechallenge: following dechallenge and
recovery from the event, the medicines are tried
again, one at a time, under the same conditions
as before and the outcome is recorded
recurrence , no recurrence, unknown, (no rechallenge)
49

41. The data elements and more
•We use all the information available on the
report, and
•Our pharmacological knowledge, and
•Our knowledge of previous reports received,
and
•Our search of the WHO database (VigiSearch)
50

44. 1. CERTAIN
•Event with plausible time relationship
•No other explanation -disease or drugs
•Event definitive -specific problem
•Positive dechallenge
•Response to withdrawal plausible
•Key feature: Positive rechallenge
53
WHO causality assessment scale

46. 2. PROBABLE
•Event with plausible time relationship to drug
intake
•No other explanation
•Response to withdrawal (dechallenge) clinically
reasonable
•No rechallenge, or result unknown
•Key feature: Positive dechallenge
55

48. 3. POSSIBLE
•Event with plausible time relationship to drug
intake
•Could also be explained by disease or other
medicines
•Information on drug withdrawal lacking or
unclear
•Key feature: other explanations for the event
are possible
57

50. 4. UNLIKELY
•Event with a duration to onset that makes
a relationship improbable
•Diseases or other drugs provide plausible
explanations
•Event does not improve after dechallenge
•Key feature: several factors indicate
strongly that the event is not a reaction
59

51. 5. UNCLASSIFIED (conditional)
•An adverse event has occurred, but there
is insufficient data for adequate
assessment and
•Additional data is awaited or under
examination
•Nature of event makes it impossible to
attribute causality (needs epidemiological studies)
•Key feature: Can’t assess with the
information available
60

52. 6. UNASSESSABLE (unclassifiable)
•A report with an event
•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
61

55. NARANJO PROBABILITY SCALE

58. EXERCISES

59. Case I
•Lakshman Singh, a 45 yr old man (Wt- 60kg) and
known case of Pulmonary Tuberculosis was stabilized
on intensive regimen of DOTS-ATT (Isoniazid-
10mg/kg/day, Rifampicin-10mg/kg/day, Pyrazinamide-
25mg/kg/day and Ethambutol-20mg/kg/day) since last
one month. Since last 2 weeks he developed persistent
vomiting, loss of appetite and yellow discoloration of
urine.
On examination, he showed signs of jaundice like
yellowish discoloration of skin and sclera.
Investigations revealed Total Serum Bilirubin- 10mg/dl,
AST-500U/ml, ALT- 550U/ml.

60. Case II
Vibha, a 22 year old woman (Wt-52kg) and known case
of paranoid schizophrenia was stabilized on Tab
Haloperidol 20 mg once daily for last 2 months. About 2
weeks ago, she presented in neurology OPD with
complaints of tremors, rigidity and akinesia.

61. Case III
•Adarsh, 19 year old male, presented in emergency with
breathlessness and wheezing.
• He had a throbbing headache while he was writing exam
in his college. The invigilator gave him 2 dispersible
tablets of Disprin (Aspirin-350 mg each) to get quick
relief.
•Past History - In the past he had been allergic to dust
and smoke but he never took any treatment. He always
experienced throbbing headache when his exams were
near, for which he used to take a tablet of Crocin
(Paracetamol-500mg) and got relieved.
-On examination his BP 120/80mmHg and Pulse was
74/min.

63. THANK YOU