First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports

Background: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting. Methods: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated. Results: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were reanalysed using three categories. This demonstrated a better validity. Conclusion: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance

A tailor-made approach for causality assessment for ADR reports on drugs and vaccines

PURPOSE: To estimate causation of adverse drug reaction (ADR) reports, causality methods were developed from a theoretical perspective. In daily practice, not all information is relevant or available, decreasing the applicability. We developed a new causality documentation tool (CausDoc) where an algorithm is combined with expert judgement. The aim of this study is to test the validity and reliability of CausDoc for ADR reports on drugs and vaccines. METHODS: CausDoc provides 9 structured relevant questions. If information is available, an answer will be chosen. If not, the question is excluded. Causality outcome is based on the sum score of all answers divided by the included questions: ≤30%: unlikely, 31% to 70%: possible, 71% to 90%: probable, and >90%: certain. Other relevant information is taken into account by expert judgement in the final step by adjusting the outcome to a limited extent. After testing face validity on 12 ADR reports, sensitivity and specificity were tested on 40 ADR reports, compared with the Naranjo algorithm and WHO AEFI criteria, using the expert panel's judgements as a standard. Inter-rater reliability was tested using weighted Cohen kappa coefficient. RESULTS: Average sensitivity and specificity with CausDoc were 47% and 83% for drugs (29% and 78% with Naranjo) and 72% and 89% for vaccines (65% and 87% with WHO AEFI criteria). Reliability between the 2 couples of assessors: κ 0.48 and 0.75. CONCLUSIONS: CausDoc shows a better performance and allows for a better documentation of ADRs in clinical practice. This approach is useful in assessing the causality of adverse drug reactions

Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions

Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6–110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6–72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor