Causality Assessment Of Adverse Drug Reactions Research Articles

638 5-Aminosalicylate (5-ASA) Induced Nephrotoxicity in Inflammatory Bowel Disease

Introduction Nephrotoxicity is a rare idiosyncratic reaction to 5-ASA therapy. The precise pathogenic mechanisms are unknown. This study aims to a) describe the clinical features of this rare complication b) explore underlying mechanisms and c) identify clinically useful predictive genetic markers so these drugs can be avoided, or monitoring intensified, in high-risk patients. Here we report the clinical features. Methods Patients were identified and recruited from 185 sites (130 UK). Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine after starting 5-ASA and medical opinion implicating 5-ASA justified drug withdrawal. An adjudication panel assessed causality from case report forms using the validated Liverpool Adverse Drug Reaction Causality Assessment Tool. Results 154 patients were recruited. 19 patients were excluded following adjudication. The cohort included patients with Crohn’s disease, ulcerative colitis and indeterminate colitis (42%, 55%, 4% respectively). 74% of cases were male. Nephrotoxicity was seen with all aminosalicylates including 1 patient treated with topical therapy only. Nephrotoxicity occurred at a median age of 36.5 yrs (range 15.4–88.4 yrs). Two patients had a confirmed family history of 5-ASA-induced nephrotoxicity. 78% were detected by routine blood monitoring. Only 45% of cases recovered completely after drug withdrawal, with 18 requiring renal replacement therapy (14 transplantation). The median time for peak creatinine after commencing 5-ASA was 3.5 yrs (range 0.16–43.4 yrs). There was no evidence that time on 5-ASA treatment was associated with a higher peak creatinine or the likelihood of full recovery (p = 0.87). Women were more likely to reach full recovery than men (p = 0.00148; OR 8.26; CI 2.46–34.94). There was no evidence that early withdrawal of 5-ASA led to a higher likelihood of complete recovery. There was no difference in recovery between the three disease groups on logistic regression analysis. Conclusion This is the largest and most detailed study of 5-ASA induced nephrotoxicity to date. Whilst the incidence is low, the morbidity is high with 13% of patients requiring renal replacement therapy and 55% of patients failing to return to a normal creatinine after 5-ASA withdrawal. The next step is to carry forward these patients to a genome-wide association analysis, to be performed in February 2013. Disclosure of Interest None Declared

Comparative evaluation of adverse drug reaction reporting forms for introduction of a spontaneous generic ADR form

Despite comprehensive and stringent phases of clinical trials and surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after the drug is marketed. ADR reporting is an important aspect of an efficient and effective pharmacovigilance program. Although Medwatch, Yellow Card, CDSCO form, etc. are the protocol forms of ADR collection and reports, a number of countries design and use their respective ADR forms. This review compares similarities and dissimilarities of 13 ADR forms of countries representing their geographical location. This study extracted 73 data elements mentioned in 13 different ADR forms. Only 13 elements were common. An ADR form of Malaysia and Canada covers the highest number of data 43, while Brazil falls to the opposite end with a number of 17 data elements in lieu with the Generic ADR Form. The result of this review highlights 58 data elements of the proposed generic ADR form which ensures that requisite reporting information essential for correct causality assessment of ADRs are included. The proposed “Generic ADR form” could be adopted worldwide mandatorily for reporting any/all ADRs associated with marketed drugs.

Adverse drug reaction reporting by nurses: analysis of Italian pharmacovigilance database

The aim of this study was to describe the pattern of adverse drug reaction (ADR) reports sent by Italian nurses after the enactment of the law involving them in the pharmacovigilance system. We also compared the quantity and quality of reports by nurses with those of reports by hospital physicians sent in the same period. We analysed the reports sent to the Italian pharmacovigilance database by nurses from January 2004 to December 2010. Only reports with ADRs causality assessment defined as definite, probable or possible were included in the analysis. The nurses' reports were compared with those sent by hospital physicians in the same period. We excluded from this analysis reports associated with vaccines. A total number of 1403 reports by nurses have been evaluated. The percentage of nurses' reports of ADRs, which were serious, were 22.9% lower than the 44.9% of reports by physicians, whereas the proportion of probable ADR reports were higher among nurses than hospital physicians (76% vs 67%). Nurses put more emphasis than physicians on application site disorders (log OR = 0.91, 95%CI = 0.55-1.27), skin reactions (log OR = 0.81, 95%CI = 0.70-0.92) and nervous system reactions (log OR = 0.28, 95%CI = 0.11-0.44), whereas physicians more frequently report blood, platelet and liver disorders. Six drugs are present in both the top 10 drugs reported by nurses and hospital doctors. This study gives evidence for the potential capacity of nurses to improve the detection of ADRs.

Development and Inter-Rater Reliability of the Liverpool Adverse Drug Reaction Causality Assessment Tool

AimTo develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT).MethodsA comparison between seven assessors of a new CAT, formulated by an expert focus group, compared with the Naranjo CAT in 80 cases from a prospective observational study and 37 published ADR case reports (819 causality assessments in total).Main Outcome Measures Utilisation of causality categories, measure of disagreements, inter-rater reliability (IRR).ResultsThe Liverpool ADR CAT, using 40 cases from an observational study, showed causality categories of 1 unlikely, 62 possible, 92 probable and 125 definite (1, 62, 92, 125) and ‘moderate’ IRR (kappa 0.48), compared to Naranjo (0, 100, 172, 8) with ‘moderate’ IRR (kappa 0.45). In a further 40 cases, the Liverpool tool (0, 66, 81, 133) showed ‘good’ IRR (kappa 0.6) while Naranjo (1, 90, 185, 4) remained ‘moderate’.ConclusionThe Liverpool tool assigns the full range of causality categories and shows good IRR. Further assessment by different investigators in different settings is needed to fully assess the utility of this tool.

Methods for Causality Assessment of Adverse Drug Reactions

Numerous methods for causality assessment of adverse drug reactions (ADRs) have been published. The aim of this review is to provide an overview of these methods and discuss their strengths and weaknesses. We conducted electronic searches in MEDLINE (via PubMed), EMBASE and the Cochrane databases to find all assessment methods. Thirty-four different methods were found, falling into three broad categories: expert judgement/global introspection, algorithms and probabilistic methods (Bayesian approaches). Expert judgements are individual assessments based on previous knowledge and experience in the field using no standardized tool to arrive at conclusions regarding causality. Algorithms are sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship. Bayesian approaches use specific findings in a case to transform the prior estimate of probability into a posterior estimate of probability of drug causation. The prior probability is calculated from epidemiological information and the posterior probability combines this background information with the evidence in the individual case to come up with an estimate of causation. As a result of problems of reproducibility and validity, no single method is universally accepted. Different causality categories are adopted in each method, and the categories are assessed using different criteria. Because assessment methods are also not entirely devoid of individual judgements, inter-rater reliability can be low. In conclusion, there is still no method universally accepted for causality assessment of ADRs.

Child Overdose: The Value of the French Pharmacovigilance Causality Assessment Method

BackgroundIn France, the regional pharmacovigilance centres manage drug overdose as adverse drug reactions (ADRs) using the French ADR causality assessment method, and some poison control centres (e.g. in Paris) do likewise for the most serious cases. AimThe aim of the study was to analyse and compare the chronological and semiological scores calculated with this method, in cases of drug overdose and ADRs in children recorded in the French pharmacovigilance ADR database. ResultsIn total, 7963 cases were analysed. The distribution of semiological criteria in drug overdose and ADR cases differed significantly (G-test), with a similar result for chronological criteria (but to a lesser degree). ConclusionThe distinction of two types of criteria in the French ADR causality assessment method appears useful for analysing cases of drug overdose in children. This finding triggers a renewed interest in the use of this method of causality assessment of drug overdose in children, and possibly in adults.

Causality assessment of adverse drug reactions using decision support and informatics tools

AbstractInformatics information organizing techniques have been applied to the causality assessment of adverse drug reactions since the 1970s. There has not appeared an easily applied and accurate method. The problem has to do with low quality and poorly organized input information or the attempted application of methods that are too rigid for some problems and inapplicable for others. Potentially the best current method, based on Bayesian probability, is difficult to use because of low quality or quantity of information. This handicap requires extrapolations which tend to result in a form of numerical global introspection. We suggest that the problem might be approached by using a generalized decision support algorithm which can be used with many different decision methods and proper informatics support for the immediate environment of the assessor in drug safety. The decision support algorithm we apply is based on an analytical hierarchical process algorithm implemented in the software CRITERIUM©. We give as an example the application of the algorithm to a suspected adverse drug reaction, cholestatic jaundice, as a result of treatment by chloropromazine. However, to support any decision‐making method, the information and informatics environment around the decision‐maker must be planned and developed. A set of requirements that best reflect adverse drug reaction causality assessment needs is discussed.