CAUSALITY ASESSMENT
by -Romeo F. Quijano, M.D. 12/08/22
– Determination of whether there is a reasonable possibility that the product is causally related to the
adverse event. Causality assessment includes, for example, evaluation of temporal relationships,
dechallenge/rechallenge information, association with (or lack of association with) underlying disease,
presence (or absence) of a more likely cause, and biologic plausibility.
Causality assessment is not required for spontaneous (unsolicited) reports that are serious and
unexpected.
WHY?
• Because they are presumed to be possibly related. It should be emphasized that manufacturers should
not separate out those spontaneous reports they receive into those that seem to themselves to be
causally related to drug exposure and those they consider not causally related. A physician in making a
spontaneous report to a manufacturer is indicating that the observed event may be due to the drug, i.e.
the physician suspects that the event is a reaction.” (CIOMS I)
“For spontaneous reports, the applicant should assume that an adverse
experience or fatal outcome was suspected to be due to the suspect drug or
biological product (implied causality).” (FDAGuidance, 2001)
“For rare events, the expected rate in a clinical trial database would be zero. Thus,
if even a few cases (sometimes even a single case) of a rare life- threatening
event occurred when none was expected, that would represent a serious safety
problem for a drug product.”
“Causality judgments are much more difficult for uncommon (ex. Less than 1 in
1000 serious adverse events) where there are no useful comparisons to control
groups. The reviewer therefore must form a judgment as to the plausibility of
drug-relatedness for the individual cases based on certain criteria such as:
– Was the patient in fact exposed to drug and did the AE occur after drug
exposure?
– Did the patient have a clinical experience that meets the criteria for the adverse
event of interest?
– Is there a reasonably compelling alternative explanation for the event?
– Is the AE of a type known to be associated with drug exposure?
(Ref:Ref: Causality assessment of ADRs-Colbert
https://www.health.gov.il/UnitsOffice/HD/MTI/Drugs/risk/Conferences/Documents/
First-Causality-Israel-2013.pdf
Additionally,
-- Is the AE observed to have occured in different places under similar exposures
(ex. Exposure to a similar drug or vaccine, similar circumstances, etc).
- Is the observed event consistent with a pathogenic event or mechanism
demonstrated in credible scientific studies (e.g. animal, in-vitro laboratory
studies)?
In causality assessment, any judgement must be guided primarily by patient’s
rights and well being and must therefore be exercised under the guidance of the
precautionary principle (Ref. Precaution, Environmental Science, and Preventive Public Policy,
Joel Tickner (ed.), Island Press, Washington DC, December, 2003.)
In accordance with the ICH-E2A guideline, the definition of an adverse reaction
implies at least a reasonable possibility of a causal relationship between a
suspected medicinal product and an adverse event. An adverse reaction, in
contrast to an adverse event, is characterised by the fact that a causal
relationship between a medicinal product and an occurrence is suspected. For
regulatory reporting purposes, as detailed in the ICH-E2D guideline, if an event is
spontaneously reported, even if the relationship is unknown or unstated, it meets
the definition of an adverse reaction. Therefore all spontaneous reports notified by
healthcare professionals, patients or consumers are considered suspected
adverse reactions, since they convey the suspicions of the primary sources,
unless the reporters specifically state that they believe the events to be unrelated
or that a causal relationship can be excluded. (Ref: VI.A.2.1.1. Causality,
EMA/542040/2014, superseded version, Page 5/90)
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-
pharmacovigilance-practices-module-vi-management-reporting-adverse-
reactions_en-1.pdf
