Transcript Clinical causality assessment

Clinical causality assessment
I. Ralph Edwards
R.H.B Meyboom
Causality assessment
Perspectives
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patient
treating doctor
drug manufacturer
drug control authority
Causality assessment
Three Key Questions
• Can the drug cause the adverse
reaction?
• Has the drug caused the adverse
reaction?
• Will the drug cause the adverse
reaction?
Causality assessment
• how likely is it that this medication is
the cause of this problem in this
particular patient?
• making a differential diagnosis
Categories of disease
aetiology
• Sufficient causes.
On exposure to a
sufficient cause, the disease will inevitably follow.
(Type A effects.)
• Necessary causes.
Although exclusion of a
necessary cause inevitably prevents the disease,
exposure is not invariably followed by development
of the disease. (Type B effects.)
• Contributory causes.
Increase the risk of
a given disease. Exclusion leads to reduction in
frequency but not eradication of the disease.
(Type C effects.)
Approaches to causality
assessment
• individual expert
• panel of experts
• formal algorithm
– decrease inter-individual differences
– improve validity?
– time consuming
Causality assessment
First step
• Make sure you have access to all
available details
Data elements relevant to
causality assessment
• Age, sex and medical history
• Identified suspected and other drugs,
doses, routes, start stop dates and
indications for use
• Description of adverse event, including
clinical data, laboratory results and date
of onset (or interval)
• Treatment, course and outcome
Four assessment criteria
• The association in time (place) between
drug administration and event
• Pharmacology (features, previous
knowledge of side effects)
• Medical plausibility (characteristic signs
and symptoms, laboratory tests, pathological findings)
• Likelihood or exclusion of other causes
Causality assessment
• Reasonable time relationship
– pharmacokinetics
– type of reaction
• Site of reaction
• Dose-response
– effect of dose reduction
– effect of re-exposure
• Known actions of the drug
• Other drugs taken
Causality assessment
• Are there previous conclusive reports on this
reaction?
• Did the ADR appear after the suspected drug was
administered?
• Did the ADR improve when the drug was
discontinued or a specific antagonist was
administered?
• Did the ADR reappear when the drug was
readministered?
• Was the ADR confirmed by objective evidence
Causality assessment
• Are there alternative causes that could on their own
have caused the reaction?
• Did the ADR reappear when a placebo was given?
• Was the drug detected in the blood (or other fluids)
in concentrations known to be toxic?
• Was the ADR more severe when the dose was
increased or less severe when the dose was
decreased?
• Did the patient have a similar ADR to the same or
similar drugs in any previous exposure?
WHO Causality Categories
Certain
• Event or laboratory test abnormality, with plausible
time relationship to drug intake, cannot be explained
by disease or other drugs
• Response to withdrawal plausible (pharmaco-logically,
pathologically)
• Event definitive pharmacologically or
phenomenologically (An objective and specific medical
disorder or a recognised pharmacological
phenomenon)
• Rechallenge (if necessary)
WHO Causality Categories
Probable
• Event or laboratory test abnormality,
with reasonable time relationship to
drug intake, unlikely to be attributed to
disease or other drugs
• Response to withdrawal clinically
reasonable
• Rechallenge not necessary
WHO Causality Categories
Possible
• Event or laboratory test abnormality,
with reasonable time relationship to
drug intake, could also be explained by
disease or other drugs
• Information on drug withdrawal lacking
or unclear
WHO Causality Categories
Unlikely
• Event or laboratory test abnormality,
with a time to drug that makes a
relationship improbable (but not
impossible)
• Diseases or other drugs provide
plausible explanations
WHO Causality Categories
Conditional/Unclassified
• Event or laboratory test abnormality
• More data for proper assessment
needed or additional data under
examination
WHO Causality Categories
Unassessable/Unclassifiable
• A report suggesting an adverse reaction
• Cannot be judged because of
insufficient or contradictory
information
• Report cannot be supplemented or
verified
Major uses of causality
assessment
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Signal detection
Drug regulation
Scientific publications
Data exchange
What causality assessment
can do
• Decrease disagreement between
assessors
• Classify relationship likelihood (semiquantitative)
• Mark individual case reports
• Education / improvement of scientific
assessment
What causality assessment
cannot do
• 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 adverse event
• Change uncertainty into certainty
Questions for the future
• Causality assessment as a routine of all
reports, or only in selected cases?
• One general system, or special systems
adapted to specific adverse reactions?