Causality assessment

Using causality models

Prof E. P. van Puijenbroek, MD, PhD

October 2018
Learning Objectives

• Know the difference between extrinsic and intrinsic causality

• Be able to apply two different causality models
•WHO model
•Naranjo algorithm
Outline

• Extrinsic and intrinsic

factors
• Causality models
• Practical examples
Question 1

It is important to annotate the strength of the causal

relationship between drug and adverse drug reaction

1. Agree
2. Do not agree
Question 2

Do you think it is possible to determine the strength of the

causal relationship between drug and adverse drug reaction?

1. Agree
2. Do not agree
 Extrinsic factors
“How well known is this ADR?”

• Literature and product information

- MEB / EMA
- Medline

• Background Incidence
- Literature

• Prescription data
- GIPdatabank.nl

• Databse
- Lareb (NL)
- Eudravigilance (EMA), Vigibase (WHO)
 Intrinsic factors
“What patient- or drug related factors play a role?”

• Pharmacological plausibility
- kinetic, dynamic, chemical structure
- latency, dechallenge
- co-medication

• Patient-related
- indication, comorbidity, renal function
- Drug metabolism
Outline

• Extrinsic and intrinsic

factors
• Causality models
• Practical examples
 When to use causality assessment?

• Regulatory requirements: e.g. causality assessment for

each report mandatory when submitting reports to
EMA
• Publications of case reports
• Individual patient care
Agbabiaka TB1,Savovic J,Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31(1):21-37.
Agbabiaka TB1,Savovic J,Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31(1):21-37.
Types of causality models

• Expert judgement/global introspection: individual

assessments based on previous knowledge and
experience.
• Algorithms: set of specific questions to estimate
te strength of the causal relationship.
• Probabilistic methods (Bayesian approaches):
Transform the prior estimate of probability into a
posterior estimate of probability of drug
causation.
 WHO causality definitions
• CERTAIN
a clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which
cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge)
should be clinically plausible. The event must be definitive pharmacologically, using a satisfactory rechallenge procedure if
necessary.

• PROBABLE/LIKELY
A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to
be attributed to concurrent disease or other drug or chemicals, and which follows a clinically reasonable response on withdrawal
(dechallenge). Rechallenge information is not required to fulfil this defenition.

• POSSIBLE
A clinical event, including laboratory test abnormality, with a reasonable timne sequence to administration of the drug, but which
could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or
unclear.

• UNLIKELY
A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal
relationship improbable, and in which other drug, chemicals or underlying disease provide plausible explanations.
WHO classification
 Naranjo algorithm

• Systematic causality assessment

- 10 questions
- Sum score
- 63 cases from the literature
- only 3 assessors

Naranjo et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;239-245
Naranjo algorithm - elements
Naranjo algorithm – sum score

≥9 certain
5-8 probable
1-4 possible
≤0 unlikely
Outline

• Extrinsic and intrinsic

factors
• Causality models
• Practical examples
 Case 1

• Reporter: pharmacist
• Female, 60 years
• Complaints: flu-like symptoms
• Suspect drug:
risedronate (Actonel®) 1x / week 35 mg for osteoporosis
• Concomitant-medication:
omeprazole and lormetazepam
 Description symtoms

• Severe symptoms: muscle pain neck and shoulders,

headaches, fever and general malaise, about half a day after
ingestion

• Complaints take approximately 5 days

• After next intake same complaints increased

How do you rate the Text
causality?

1. Unlikely
2. Possible
3. Probable
4. Certain

Why?
 Course of reaction

• Switch to risedronate 5 mg once daily

no effect on any of the symptoms

• Medication changed into

alendronate (Fosamax®) 1x / week, 70 mg
no complaints anymore
 Background information

• Summary of Product Characteristics

• Literature
• Reported ADRs (WHO)
 Background information

• Flu syndrome
Flu syndrome was reported in 9,8% of patients enrolled in phase 3
Paget’s disease clinical trials with risedronate (Prod Info Actonel®, 2002).
• Flu-like symptoms
Flu-like symptoms (muscle pain, bone pain, hot flushes, increased
sweating) have been reported with the use of ibandronate (Anon, 1996).
• Flu-like symptoms
nonspecific flu-like symptoms including fever, chills, bone pain,
arthralgia, and myalgia have been described in some patients treated
with zoledronic acid…
 Background information

• WHO:
- > 150 reports of flu-like symptoms and bisphosphonates
Reporting Odds Ratio:
● Alendronate 0,92 (0,69-1,24)
● Pamidronate 10,7 (8,29-13,85)
● Risedronate 3,51 (2,20-5,59)
● Zoledronate 11,0 (7,98-15,17)

- Association flu-like symptoms + alendronate n.s.

- Association other bisphosphonates and this ADR statistical signal
Naranjo score

≥9 certain
5-8 probable
1-4 possible
≤0 unlikely
 Summary

• Causation may be difficult to assess in practice

• There are various models of causality in use

• Validation leaves much to be desired, situations in

which they are applied are often too specific
Learning Objectives
• To be able to use two different causality model for the
assessment of adverse drug reactions
- Causality scheme of Naranjo
- Knowing the difference between extrinsic and intrinsic
causality

• Evaluation of a case report, using elements that play a role

in the assessment of ADRs
 Exam question –example 1
• Causality assessment van be divided into intrinsic and extrinsic factors. Classify
the factors in the base below:
• A female patient, aged 60 years, suffered from dizziness due to orthostatic
hypotension, a few hours after every administration of metoprolol for
tachycardia. The dizziness resolved after 6 hours. Dizziness is described in the
Summary of Product Characteristics (SmPC) of metoprolol as a frequently
occuring adverse drug reaction (ADR). The patient’s medical history indicates
that she also had sleep disorders and uses temazepam (a benzodiazepine).
Which if the following classifications is TRUE?

A. Description of the ADR in the SmPC and the frequency of the ADR are both
intrinic factors

B. Orthostatic hypotension can pharmacologically be explained, which is an

extrinsic factor

C. A positive dechallenge and a positive rechallenge are both intrinsic factors.

D. Concomitant drug tamezepam can cause dizziness, which is an extrinsic factor.

 Exam question – example 2
The Naranjo algorithm is a tool that can be used in the causality assessment of
possible adverse drug reactions. In this algorithm, the following aspects play a role:

1) Severity
2) Dechallenge
3) Rechallenge
4) Alternative causes

Which of the following statements is correct? 

a)1 and 2 are true, 3 and 4 are false

b)2,3 and 4 are true, 1 is false
c)All statements are true
d)All statements are false
 Literature causality assessment

Taofikat B. Agbabiaka, Jelena Savovi, Edzard Ernst. Methods for Causality Assessment of Adverse Drug
Reactions A Systematic Review. Drug Safety 2008; 31 (1): 21-37
Anonymous. The use of the WHO-UMC system for standardised case causality assessment. Website Uppsala
Monitoring Centre. http://www.who.int/medicines/areas/quality_safety/safety_efficacy/
WHOcausality_assessment.pdf
Naranjo et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther
1981;239-245
Thank you for
your attention