Causality Assessment

© 2015 Cognizant
 About the Author

Created By: Isha Shukla

Credential Registered Pharmacist

Information: 3.5 years experience in PV, 2 years experience in Training
Version and 2.1.0, 12-Mar-2015
Date:

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 Icons Used

Hands on
Questions Tools Exercise

Coding Test Your Reference

Standards Understanding

A Welcome
Demonstration Break Contacts

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 Do You Know

• It is desirable that Adverse Drug Reactions (ADRs) should be objectively

assessed and presented based on an acceptable ‘Probability Scale’

• The causality assessment systems are proposed by :

– World Health Organization Collaborating Centre for International Drug

Monitoring
– Uppsala Monitoring Centre (WHO–UMC), and
– Naranjo Probability Scale

• These are generally accepted and most widely used methods for causality
assessment in clinical practice as they offer a simple methodology

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 Causality Assessment
Overview
• Causality assessment is an important part of case assessment

• It is based on a general system that is intended for all reactions & all drugs

• Standardized case causality assessment has become a routine at

pharmacovigilance centre around the world

• It aims in decreasing the ambiguity of data and preventing erroneous

conclusions

• It neither eliminates nor quantifies uncertainty but, at best, categorizes it in a

semi-quantitative way

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 Causality Assessment :
Definition

• Causality assessment is the method by which the extent of

relationship between a drug and a suspected reaction is
established For the purposes of IND
(Investigational New
Drug) safety reporting,
‘reasonable possibility’
means there is evidence
to suggest a causal
relationship between
the drug and the
adverse event

- 21 CFR part 312

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 Causality and Case Processing

• Unsolicited Reports
– Reporter’s assessment of causality is often not explicit
– Standard Adverse Event (AE) form:
• Reporter selects `related’, `not related’ `unknown’ or `not provided’ for
each drug-event pair
• Unsolicited reported events are considered related, for the purpose of
case processing and regulatory reporting, unless reporter says `not
related’
• Solicited Reports
– Investigator codes events as related or not related to the study drug
– Some instruction for the investigator are provided in the study protocol
– Suspected Unexpected Serious Adverse Reaction (SUSAR): `Reaction’
implies `related’
– In case of disagreement-consider related because in study , both
investigator and sponsor independently assess causality
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 Causality Assessment :
Objectives
• To classify AEs
• To decide the nature of further enquiries
• To satisfy regulatory requirements
• To aid in signal detection
• To aid in writing Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk
Evaluation Reports (PBRER)

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 Why Causality Assessment?

• An inherent problem in pharmacovigilance is that most case reports concern

suspected Adverse Drug Reactions (ADRs)
• ADRs are rarely specific for the drug, diagnostic tests are usually absent and a
rechallenge is rarely ethically justified
– In practice few ADRs are ‘certain’ or ‘unlikely’; most are somewhere
in
between these extremes, i.e. ‘possible’ or ‘probable’
• Most outcomes have multiple interacting causes
• In an attempt to solve this problem many systems have been developed for a
structured and harmonised assessment of causality
• None of these systems, however, have been shown to produce a precise and
reliable quantitative estimation of relationship likelihood
• Nevertheless, causality assessment has become a common routine procedure
in pharmacovigilance
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 Causality Assessment : Benefits

• Decrease disagreements between assessors

• Classify relationship likelihood (semi-quantitative)

• Mark individual case reports

• Education / improvement of scientific assessment

• Signal detection

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 Causality Assessment :
Limitations
• Give accurate quantitative measurement of relationship likelihood

• Distinguish valid from invalid cases

• Prove the connection between drug and event

• Quantify the contribution of a drug to the development of an AE

• Change uncertainty into certainty

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 Causality Assessment : Other
Important Definitions
Dechallenge -:
• Process of withdrawing the drug(s) and recording the outcome – improved or
not improved
• If the event improves after discontinuing suspect drug, dechallenge is
positive

Rechallenge -:
• Process of giving drug again under the same conditions as before and
recording the outcome – recurrence or no recurrence
– If the event recurs after restarting suspect drug, rechallenge is
positive
– A rechallenge may be intentional when a prescriber decides that
the
benefit of rechallenge will outweigh its risk
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 Dechallenge and Rechallenge

• Positive Dechallenge = AE disappears

• Positive Rechallenge = AE reoccurs

• Negative Dechallenge = AE does not disappears

• Negative Rechallenge = AE does not reoccur

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 AE Assessment: Process Flow

The causality assessment for all ADRs is made by the Medical Reviewer or designee

Medical Reviewer

Data Entry and Peer Medical Reviewer enters data in Validation of AE

review Adverse Event Reporting System Report

Options Available for Drug Relationship Assessment

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 Causality Assessment : 3 Key
Questions

• Can the drug cause the ADR?

• Has the drug caused the ADR?
• Will the drug cause the ADR?

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 Bradford Hill’s Criteria

• Strength of evidence : Signal strength is estimated by data mining approaches

(based on relative risk or odds ratio data)
• Consistency : A trend is observed across studies
• Specificity : The presence of identifiable factors that lead to the AE
• Plausibility : A biological mechanism that is known to cause the AE
• Temporality : Relationship between time of drug administration and
subsequent development the AE
• Biological Gradient : Exposure (dose)–response relationship
• Coherence : Similar signal strength with reports for related events
• Experimental Evidence : Clinical trials, challenge, rechallenge
• Analogy : Analogous examples with chemically similar drugs, not necessarily of
the same class

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 Causality Assessment : Key
Elements
• Reasonable time relationship
– Pharmacokinetics
– Type of reaction
• Site of reaction
• Dose-response
– Effect of dose reduction
– Effect of re-exposure/re-challenge
• Known actions of the drug
• Other drugs taken
– Traditional remedies
• Effects of underlying disease or conditions
• Main factors to consider

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 How To Assess Causality?

• Global Introspection : Causality inference obtained via clinical judgment, such

as with an expert panel

• Algorithms : Sets of specific questions with associated scores for calculating

the likelihood of a cause-effect relationship

• Bayesian Approaches :
– need a probability for causality calculated from available knowledge (prior
estimate)
– need the specific findings in a case, which combined with the background
information, determines the probability of drug causation for the case
(posterior estimate)

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 Points to consider for
evaluation of an ADR
• The temporal relationship (time to onset)
– There should be a plausible temporal relationship between exposure and
the onset of the suspected ADR, taking into consideration the
pharmacological characteristics of the suspected drug
– For short-term reactions, e.g. flushing with nifedipine, the relevant time to
onset is the time between the last dose and the onset of the reaction. For
long-term reactions, e.g. hepatitis with methotrexate, the relevant period
is the time from the beginning of the therapy and ADR onset

• Existing information about the ADR

– The event described had been previously reported as an ADR in clinical
trials, post-marketing studies, case reports
– If the event is not documented anywhere else, it does not necessarily
mean that it cannot occur with the suspected drug
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 Points to Consider for
evaluation of an ADR (Contd..)
• Pharmacological plausibility
– Most type A reactions are pharmacodynamic and pharmacokinetic
plausible, though easy to diagnose
– However, the recognition of type B reaction might be difficult if previous
reports on that particular ADR are not available
• Exclusion of other causes
– Alternative causes (other than the suspected drug) such as patient’s
underlying disease or other drugs cannot explain the reaction
• De-challenge or dose reduction
– Recovery or condition improvement after stopping the drug or after the
dose reduction is supportive for a causal relationship, particularly when
the timing of the recovery/condition improvement is consistent with the
pharmacological characteristics of the drug; some ADRs might be
irreversible
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 Points to Consider for
evaluation of an ADR (Contd..)
• Rechallenge or dose increase
– The recurrence of the ADR after dose increase or rechallenge is a strong
indicator of causality
– Rechallenge is justifiable only if the benefit to the patient outweighs the
risks of the reaction’s recurrence, as in some cases the reaction
(especially
type B reactions) may be more severe or even fatal on repeated
exposure

• Drug interactions
– If a drug interaction is suspected in causing the ADR, plausible temporal
relationship with the introduction or withdrawal of the interacting drug is
an important consideration in causality assessment

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 Test Your Understanding

• Process of giving drug again under the same conditions as before and
recording the outcome :
– Challenge
– Dechallenge
– Rechallenge
– None of the above

• Objective of performing causality assessment is to includes :

– To classify AEs
– To satisfy regulatory requirements
– To aid in signal detection
– All of the above

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 Test Your Understanding

• Causality assessment involves assessing the relationship between the event

and drug

– True
– False

• Causality assessment can be done to distinguish valid & invalid cases & to
prove the connection between drug and event

– True
– False

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 Causality Assessment –
Algorithms & Scales
• Several methods are used for causality assessment of ADRs reports:

• The literature (9 points of consideration – Morges, Switzerland , 1981)

• Probability calculation (Bayes’ Theorem)
• Aetiological – Diagnostic Systems (Bénchiou’s group method)
• French imputation systems
• The European ABO Systems
• The Naranjo ADR Probability Scale
• WHO Causality Categories

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 The Literature

• (9 Points Of Consideration – Morges, Switzerland , 1981)

1. Drug given prior to event?

2. Reaction at site of application?
3. Drug/ADR interval compatible with the event?
4. ADR immediately follows drug administration and is of acute onset?
5. Positive rechallenge?
6. Positive dechallenge?
7. Were concomitant drugs stopped at the same time?
8. Same ADR to this drug before?
9. ADR known with the suspected drug?

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 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

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 Aetiological – Diagnostic Systems
(Bénchiou’s Group Method)

• Using a diagnosis scheme:

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

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 French Imputation Systems –
Intrinsic factor
• Published in 1978 by J. Dangoumou, J.C. Evreux et
J.Jouglard
• Updated in1985 by B. Bégaud, J.C. Evreux;J. Jouglard et
Lagier

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 French Imputation Systems
Contd..

• Extrinsic Factor

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 French Imputation Systems
Contd..

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 The European ABO Systems

• Using 3 basic causality categories

Sr. No. Category Reports

Reports including good reasons and sufficient

1 A documentation to assume causal relationship

Reports containing sufficient information to accept the

2 B possibility of causal relationship

Reports where causality is, for one or another reason not

3 O assessable

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 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
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 Welcome Break

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 The Naranjo ADR Probability
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 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

• The score are as follows:

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

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 WHO Causality Categories

Sr. No. Category # Category Name Comment

Plausible time, not related to underlying condition, concurrent
1 C1 CERTAIN disease, other drugs or chemicals, related pharmacologically,
+ve dechallenge, +ve rechallenge

PROBABLE / Reasonable time, unlikely to be related to concurrent disease,

2 C2 LIKELY other drugs, +ve dechallenge, no rechallenge
Reasonable time, may be due to concurrent disease, other
3 C3 POSSIBLE drugs, no information on dechallenge
UNLIKELY Improbable temporal relationship, other confounding factors
4 C4 such as drugs, chemicals, underlying disease
CONDITIONAL/
5 C5 UNCLASSIFIABLE Insufficient information to analyze the report

UNASSESSIBLE/ Report suggesting an ADR which cannot be judged because

6 C6 UNCLASSIFIABLE information is insufficient or contradictory, and which cannot
be supplemented or verified

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 Example 1

• A consumer reported that she experienced itchy red rashes on 26-Aug-20XX

while on therapy with warfarin for thromboembolism prophylaxis since 24-
Aug-20XX
• The patient did not have any history significant for allergy. Concomitant
medication included per oral ranitidine 150 mg twice daily since 1996 for GERD
(gastro esophageal reflux disease)

• On 26-Aug-20XX morning, the patient woke up feeling itchy all over, and
discovered that her forearm was covered with red, raised skin patches
– A dermatologist was consulted who suggested discontinuing warfarin and
treatment with topical lotion. Two days later on 28-Aug-20XX, the rash had
resolved
• According to the dermatologist, rechallenge will be done after one week. No
further information is available at the time of the report

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 Example 2

• Initial report received on 12-Dec-20XX from a physician

• A 37-year-old male patient experienced left knee joint swelling eleven days
after therapy with Aspirin was discontinued. The exact dates or dosages were
not mentioned
• Medical history included osteoarthritis. Concomitant medication included
Indomethacin for joint pain (when necessary) for the past 12 years
• The patient had been receiving Aspirin for cardiac prophylaxis for the past two
years and was having abdominal distress of late
– A diagnosis of gastritis was made and aspirin was discontinued
– Eleven days later, after returning home from strenuous work out in the
gym, the patient noticed the swelling in his left knee
• The patient is being evaluated and no further information was available at the
time of the report38

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 Example 3

• Initial report received from French Health Authority on 30-Jan-20XX. A 52 year

old female was diagnosed with squamous cell carcinoma on 12-Jan-20XX
while on therapy with Lisinopril for heart failure

• No concomitant medications were reported

• Medical history included a blue nevus on left lateral aspect of neck and
status post appendectomy (1996)
• The patient had been receiving Lisinopril for the past seven months (since Jul-
200X) and was hospitalized on 10-Jan-20XX for neck skin biopsy

• The results were positive for squamous cell carcinoma

– Lisinopril is being continued

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 Expressing Causality –
Some Examples
• A causal association cannot be ruled-out
– A causal association can never be ruled-out by an individual case

• It is possible that the event was caused by Drug X …

– Possible has many shades of meaning

• Insufficient information for an adequate assessment

– Often true, but for certain drug-event pairs, no additional information will
help assess causality.
– ICSR is not necessarily helpful for all drug-event pairs

• The case was confounded by…

– Risk factors/alternative explanations are not necessarily confounders

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 Lend A Hand

• Should causality assessment be a routine activity of all reports, or only in

selected cases?

• One general system, or special systems adapted to specific ADRs?

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 Questions

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 Test Your Understanding

• Evaluation of a ADR can be done based on the following parameter :

– Temporal relationship
– Pharmacological plausibility
– Dechallenge/Rechallenge
– All of the above

• Which of the following is not included in the categories of disease etiology

– Sufficient causes
– Necessary causes
– Contributory causes
– Alternative causes

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 Test Your Understanding

• Which of the following is not one of the method used for causality assessment
of ADRs reports:
– French imputation systems
– Signal detection system
– Naranjo ADR Probability Scale
– WHO Causality Categories

• Which of the following does not fit in Naranjo causality scores :

– Highly probable
– Probable
– Possible
– Unclassifiable

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 Summary

• Causality considerations are important in benefit–risk

assessment
• It is important that all sponsors present the causality
assessment for the ADRs associated with their company
drug

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 Source

• http://who-umc.org
• http://www.who.int/medicines/areas/quality_safety/safety_
efficacy/S.AfricaDraftGuidelines.pdf
• Edwards IR, Biriell C. Harmonisation in Pharmacovigilance.
Drug Safety 10(2): 93-102, 1994

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Causality assessment

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