Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions

What is already known about this subject In pharmacovigilance, many methods have been proposed for causality assessment of adverse drug reactions. Expert judgement is commonly used to evaluate the causal relationship between a drug treatment and the occurrence of an adverse event. This form of judgement relies either explicitly or implicitly on causality criteria. What this study adds Our study compares the judgements of five senior experts using global introspection about drug causation and seven causality criteria on a random set of putative adverse drug reactions. Even if previous publications have shown poor agreement between experts using global introspection, few have compared judgements of well trained pharmacologists, familiar with using a standardized causality assessment method. To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0-0.05), unlikely (0.06-0.25), doubtful (0.26-0.45), indeterminate (0.46-0.55), plausible (0.56-0.75), likely (0.76-0.95), and certain (0.96-1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only 'doubtful' showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item 'risk(s) factor(s)' (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion 'reaction at site of application or toxic plasma concentration of the drug or validated test'. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38. This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced.