CAUSALITY

ASSESSMENT OF
SUSPECTED ADVERSE
DRUG REACTION

INTRODUCTION
Spontaneous reporting system data
acquisition, assessment, presentation and
interpretation.
Causality assessment part of the 1st step
in case assessment and is based on a
general system that is intended for all
reactions and all drug.

 Standardized case causality assessment

has become a routine at
pharmacovigilance centre around the
world.
Decrease the ambiguity of the data and
prevention of erroneous conclusion
It neither eliminates nor quantifies
uncertainty but, at best, categorizes it in a
semi quantitative way

Causality

It does not matter if there if uncertainty about whether

the reaction is associated with the drug being taken;if
there is a suspicion that this is the case, then it should be
reported.

Factors to consider in assessing causality:

1.

Nature of the reaction

There are some adverse reactions which are commonly

caused by medicines; for instance acute dystonias,blood
dyscrasias and skin reactions ( Stevens Johnson
syndrome,toxic epidermal necrolysis).
When such conditions seen you should consider the
possibility that they have been caused by a medicinal
product.

2.Timing
The time from when the drug was started until the
reaction develops may be a characteristic of the reaction.
For example ,anaphylaxis usually develops with in a few
minutes of parenteral drug admini.
Alternatively some reactions develop months or years
later and may be related to a cumulative effect of the
traditional drug.In very rare cases the effect may be
observed in the next generation for example
diethylstilbestrol and vaginal cancer.

3. Relationship to dose
Adverse reactions are often dose related and may be
minimized by reducing the dose of the drug being taken.
If the symptoms resolve when the medicine stopped, this
suggests that the symptoms were associated with the
medicine although it could be coincidental. The process
of recovery after stopping a suspected medicinal product
is classified as positive dechallenge.
In contrast ,if a medicine is reintroduced and the
symtoms recur,this strongly suggests that the medicine is
responsible. This process is classified as positive
rechallenge.However
following
serious
ADR,
rechallenge is seldom justifiable.

4. Other possible causes

You may need to consider other possible causes
for the symptoms being experienced.For instance
could the symptoms be manifestations fo the
patients underlying illness or another disease.
The patient may be taking other
medicines( including prescriptions and self
medications) which could be responsible, also
possibility of an interaction between two
medicines .

A careful analysis of spontaneous reports can

only alert signal and cofirm an
association. In certain circumstances one
high quality and carefully documented
report with a succesfull dechallenge and a
positive rechallenge may have sufficient
internal validity to decide a causal
association. Othe than this scenario
spontanious
case
reports
cannot
demonstrate a definite causal relationship

Uses of Causality Assessment

What it can do?
Decrease disagreement between
accessor.
- Classify uncertainty
- Mark individual case reports
- Improve the scientific basis of
assessment
-

Methods of Causality Assessment

There were several method that can be use to make a
causality assessment of ADRs reports.
The literature (9 points of consideration Morges,
Switzerland , 1981)
Probability calculation (Bayes Theorem)
Aetiological Diagnostic Systems (Bnchious group
method)
French imputation systems
The European ABO Systems
The US Reasonable Possibility Systems
The Naranjo ADR Probability Scale

WHO Causality Categories

The literature (9 points of consideration

Morges, Switzerland , 1981)
1.
2.
3.
4.
5.
6.
7.
8.
9.

Drug given prior to event?

Reaction at site of application?
Drug/ADR interval compatible with the event?
ADR immediately follows drug administration and is
of acute onset?
Rechallenge positive?
Dechallenge positive?
Were concomitant drugs stopped at the same time?
Same adverse reaction to this drug before?
Adverse reaction known with the suspected drug?

Probability calculation
(Bayes Theorem)
The Formula
Pr(DCE I AC) = Pr (AC I DCE) x Pr (DCE)
Pr(OCE I AC)

Pr (AC I OCE) Pr (OCE)

Pr Probability
AC Additional character
DCE Drug Cause Event
OCE Other Cause Event

Aetiological Diagnostic Systems

(Bnchious group method)

a)
b)
c)
d)

Using a diagnosis scheme:

Diseases definition
Clinical appearance and pathology
Signs of severity
Aetiology (various possible causes) and
diagnosis
e) Evidence implicating a drug
f) Chronological criteria
g) Management

French imputation systems

Intrinsic Factor

French imputation systems

Extrinsic Factor

The European ABO Systems

Using 3 basic causality categories
A Reports including good reasons and
sufficient documentation to assume causal
relationship
B Reports containing sufficient information to
accept the possibility of causal relationship .
O Reports where causality is, for one or another
reason not assessable.

The US Reasonable Possibility Systems

Using a criteria
- Temporal relationship
- Similar problem with the same drug
- Similar problem with a related drug
- Confounding by drug
- Confounding by disease
- Clinical plausibility
- Dechallenge/rechallenge
- Quality of reports need follow up
- Discuss with clinical experts

The Naranjo ADR Probability Scale

Questions

Yes

No

Dont
Know

1) Are there previous conclusive reports on this

reaction?

+1

2) Did the ADR appear after the suspected drug was

administered?

+2

-1

3) Did the ADR improve when the drug was

discontinued?

+1

4) Did the ADR appear with re-challenge?

+2

-1

5) Are there alternative causes for the ADR?

-1

+2

6) Did the reaction appear when placebo was given?

-1

+1

7) Was the drug detected in blood at toxic levels?

+1

8) Was the reaction more severe when the dose was

increased, or less severe when the dose was decreased?

+1

9) Did the patient have a similar reaction to the same

or similar drug in any previous exposure?

+1

10) Was the ADR confirmed by any objective evidence?

+1

The Naranjo Probability Scale

The score :> 8 = Highly probable
5-8 = probable
1-4 = possible
0 = doubtful

WHO Causality Categories

C1 Certain
C2 Probable
C3 Possible
C4 Unlikely
C5 Unclassifiable

WHO Causality Categories

C1: Plausible time, not related to
underlying condition, concurrent
disease, other drugs or chemicals,
related pharmacologically, +ve
dechallenge, +ve rechallenge
C2: Reasonable time, unlikely to be
related to concurrent disease, other
drugs,+ve dechallenge, no rechallenge

CAUSALITY ASSESSMENT
C3: Reasonable time, may be due to
concurrent disease, other drugs, no
information on dechallenge
C4: Improbable temporal relationship, other
confounding factors such as drugs, chemicals,
underlying disease
C5: Insufficient information to analyse the
report

Case causality
assessment
How close is the relationship
between drug and event?
Did the drug cause the event?

How to assess causality?

 Assessing the strength of the relationship

between the drug and the event.
Can seldom say without any doubt that a
specific drug caused a specific reaction
Use the accumulation of case reports at
national level is immensely valuable
providing the means for determining real
cause and effect.
Use epidemiological studies to confirm
causality

Definitions
Dechallenge withdrawing the drug(s) and
recording the outcome improved or not
improved
Rechallenge giving one drug again under
the same conditions as before and
recording the outcome recurrence or no
recurrence.

Literature Sources for ADR

Information
WHO Publication
- Pharmacovigilance A to Z
- Dictionary of Pharmacovigilance
- Stephens Detection of New Adverse
Drug Reactions
- To Heal and Harm
- WHO Pharmaceutical Newsletter
- Signal Analyses of ADR in WHO
Database

Electronic Reference Searches

E-mail Alerts USFDA Medwatch
Electronic Table of Content (E-ToC)
- Lancet (http://thelancet.com)
- BMJ (http://www.bmj.com)
- NEJM (http://content.nejm.org)
SCIRUS for scientific information only
(http://www.scirus.com/srsapp)
Free medical journal
(http://www.freemedicaljournals.com)
PLoS Medicine
(http://medicine.plosjournals.org)

 Medscape
(http://www.medscape.com)
Medical News Today
(http://www.medicalnewstoday.com)
Medsafe, New Zealand
(http://www.medsafe.govt.nz)
Lareb - Netherland Pharmacovigilance
(www.lareb.com)
WHO Vigisearch, Vigibase, Vigimed
(Sorry!!! This is for members only)