Upload
augustine-sutton
View
215
Download
1
Tags:
Embed Size (px)
Citation preview
Clinical causality assessment
I. Ralph EdwardsR.H.B Meyboom
Causality assessment Perspectives
• patient• treating doctor• drug manufacturer• drug control authority
Causality assessmentThree 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, patho-logical 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
– traditional remedies
• Effects of underlying disease or conditions• Main factors to consider
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
• Signal detection• Drug regulation• Scientific publications• Data exchange
What causality assessment can do
• Decrease disagreement between assessors
• Classify relationship likelihood (semi-quantitative)
• 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?