Comparison of agreement and rational uses of the WHO and Naranjo adverse event causality assessment tools

Causality assessment of adverse events (AEs) is the standardized and detailed assessment of individual case safety reports for the likelihood of involvement of the suspected drug/s in causing the particular AE. The basic knowledge of causality assessment is indispensable for healthcare professionals as uncertainty of the potential causal relationship between drug and AE remains one of the major reasons of under-reporting in pharmacovigilance. Methods for causality assessment of AEs can be broadly categorized as expert judgment/global introspection (GI), Bayesian methods and algorithms. Despite the availability of a number of methods, no true gold standard exists. The World Health Organization (WHO) GI method and the Naranjo adverse drug reaction (ADR) Probability Scale, although the two most widely used and accepted causality assessment methods in both clinical and experimental settings, have not been validated so far. Hence, it becomes very important to explore the extent to which various methods agree with each other. The comparison of agreement between various methods of causality assessment has been reported by few researchers from the west. In a previous study, the agreement between various algorithms and the WHO GI method was reported as 21–56%. However, due to the fact that extent of agreement between two methods may vary in different settings owing to the understanding, judgment and interpretation by experts and personnel assessing the causality, the present study aimed to compare the agreement between the WHO and Naranjo methods in an Indian setting, with a focus to identify the reasons for their mutual disagreement and address peculiar issues related to their practical applicability. To the best of our knowledge, no such comparison has been performed previously in India. The study was conducted at the Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences (PGIMS), Rohtak, Haryana, India, which is a regional pharmacovigilance center under the Pharmacovigilance Programme of India (PvPI). We randomly selected 200 forms from all the ADR proformas collected within the period June 2012–June 2013. Causality assessment was performed by two well-trained independent clinical pharmacologists by applying the two methods – WHO and Naranjo – on each ADR proforma, after which they discussed the causality with each other and discrepancies, if any, were solved. Agreement between the two algorithms was compared using the Cohen’s weighted kappa statistic. For the present study, 200 ADR forms were included. The cases represented a wide spectrum of manifestations, the most common being cutaneous (28%) and gastrointestinal (22%) [Figure 1]. The mean age of the studied population was 35 ± 16 years, with more than 65% males (male/female: 133/67). The number of different branded/generic drugs suspected for causing ADRs was 173. A total of 34 (17%) ADRs were labeled as serious according to the WHO criteria. The use of concomitant medications was present in 108 (61%) cases. All the 200 AEs were probably or possibly caused by the suspected drugs. Causality was probable in 134 cases and possible in 42 cases with both methods. On the other hand, 24 cases were labeled as possible according to the WHO and probable according to the Naranjo algorithm. None of the cases was labeled as certainly/definitely or unlikely to be caused by the suspected drug/s. Full agreement between the two methods was seen in 88% (134 probable + 42 possible) cases while 12% (24) cases had partial agreement [Table 1]. Kappa analysis demonstrated a moderate to good agreement between the two scales (value of kappa coefficient = 0.701).