Agnès Lillo-Le Louët

Appraisal of the MedDRA conceptual structure for describing and grouping adverse drug reactions.

Computerised queries in spontaneous reporting systems for pharmacovigilance require reliable and reproducible coding of adverse drug reactions (ADRs). The aim of the Medical Dictionary for Regulatory Activities (MedDRA) terminology is to provide an internationally approved classification for efficient communication of ADR data between countries. Several studies have evaluated the domain completeness of MedDRA and whether encoded terms are coherent with physicians’ original verbatim descriptions of the ADR.MedDRA terms are organised into five levels: system organ class (SOC), high level group terms (HLGTs), high level terms (HLTs), preferred terms (PTs) and low level terms (LLTs). Although terms may belong to different SOCs, no PT is related to more than one HLT within the same SOC. This hierarchical property ensures that terms cannot be counted twice in statistical studies, though it does not allow appropriate semantic grouping of PTs. For this purpose, special search categories (SSCs) [collections of PTs assembled from various SOCs] have been introduced in MedDRA to group terms with similar meanings. However, only a small number of categories are currently available and the criteria used to construct these categories have not been clarified.The objective of this work is to determine whether MedDRA contains the structural and terminological properties to group semantically linked adverse events in order to improve the performance of spontaneous reporting systems.Rossi Mori classifies terminological systems in three categories: first-generation systems, which represent terms as strings; second-generation systems, which dissect terminological phrases into a set of simpler terms; and third-generation systems, which provide advanced features to automatically retrieve the position of new terms in the classification and group sets of meaning-related terms.We applied Cimino’s desiderata to show that MedDRA is not compatible with the properties of third-generation systems. Consequently, no tool can help for the automated positioning of new terms inside the hierarchy and SSCs have to be entered manually rather than automatically using the MedDRA files. One solution could be to link MedDRA to a third-generation system. This would allow the current MedDRA structure to be kept to ensure that end users have a common view on the same data and the addition of new computational properties to MedDRA.

Implementation of automated signal generation in pharmacovigilance using a knowledge-based approach

Automated signal generation is a growing field in pharmacovigilance that relies on data mining of huge spontaneous reporting systems for detecting unknown adverse drug reactions (ADR). Previous implementations of quantitative techniques did not take into account issues related to the medical dictionary for regulatory activities (MedDRA) terminology used for coding ADRs. MedDRA is a first generation terminology lacking formal definitions; grouping of similar medical conditions is not accurate due to taxonomic limitations. Our objective was to build a data-mining tool that improves signal detection algorithms by performing terminological reasoning on MedDRA codes described with the DAML+OIL description logic. We propose the PharmaMiner tool that implements quantitative techniques based on underlying statistical and bayesian models. It is a JAVA application displaying results in tabular format and performing terminological reasoning with the Racer inference engine. The mean frequency of drug-adverse effect associations in the French database was 2.66. Subsumption reasoning based on MedDRA taxonomical hierarchy produced a mean number of occurrence of 2.92 versus 3.63 (p < 0.001) obtained with a combined technique using subsumption and approximate matching reasoning based on the ontological structure. Semantic integration of terminological systems with data mining methods is a promising technique for improving machine learning in medical databases.

Exploiting heterogeneous publicly available data sources for drug safety surveillance: computational framework and case studies.

ABSTRACT Objective: Driven by the need of pharmacovigilance centres and companies to routinely collect and review all available data about adverse drug reactions (ADRs) and adverse events of interest, we introduce and validate a computational framework exploiting dominant as well as emerging publicly available data sources for drug safety surveillance. Methods: Our approach relies on appropriate query formulation for data acquisition and subsequent filtering, transformation and joint visualization of the obtained data. We acquired data from the FDA Adverse Event Reporting System (FAERS), PubMed and Twitter. In order to assess the validity and the robustness of the approach, we elaborated on two important case studies, namely, clozapine-induced cardiomyopathy/myocarditis versus haloperidol-induced cardiomyopathy/myocarditis, and apixaban-induced cerebral hemorrhage. Results: The analysis of the obtained data provided interesting insights (identification of potential patient and health-care professional experiences regarding ADRs in Twitter, information/arguments against an ADR existence across all sources), while illustrating the benefits (complementing data from multiple sources to strengthen/confirm evidence) and the underlying challenges (selecting search terms, data presentation) of exploiting heterogeneous information sources, thereby advocating the need for the proposed framework. Conclusions: This work contributes in establishing a continuous learning system for drug safety surveillance by exploiting heterogeneous publicly available data sources via appropriate support tools.

Descriptions of Adverse Drug Reactions Are Less Informative in Forums Than in the French Pharmacovigilance Database but Provide More Unexpected Reactions

Background: Social media have drawn attention for their potential use in Pharmacovigilance. Recent work showed that it is possible to extract information concerning adverse drug reactions (ADRs) from posts in social media. The main objective of the Vigi4MED project was to evaluate the relevance and quality of the information shared by patients on web forums about drug safety and its potential utility for pharmacovigilance. Methods: After selecting websites of interest, we manually evaluated the relevance of the content of posts for pharmacovigilance related to six drugs (agomelatine, baclofen, duloxetine, exenatide, strontium ranelate, and tetrazepam). We compared forums to the French Pharmacovigilance Database (FPVD) to (1) evaluate whether they contained relevant information to characterize a pharmacovigilance case report (patient’s age and sex; treatment indication, dose and duration; time-to-onset (TTO) and outcome of the ADR, and drug dechallenge and rechallenge) and (2) perform impact analysis (nature, seriousness, unexpectedness, and outcome of the ADR). Results: The cases in the FPVD were significantly more informative than posts in forums for patient description (age, sex), treatment description (dose, duration, TTO), and outcome of the ADR, but the indication for the treatment was more often found in forums. Cases were more often serious in the FPVD than in forums (46% vs. 4%), but forums more often contained an unexpected ADR than the FPVD (24% vs. 17%). Moreover, 197 unexpected ADRs identified in forums were absent from the FPVD and the distribution of the MedDRA System Organ Classes (SOCs) was different between the two data sources. Discussion: This study is the first to evaluate if patients’ posts may qualify as potential and informative case reports that should be stored in a pharmacovigilance database in the same way as case reports submitted by health professionals. The posts were less informative (except for the indication) and focused on less serious ADRs than the FPVD cases, but more unexpected ADRs were presented in forums than in the FPVD and their SOCs were different. Thus, web forums should be considered as a secondary, but complementary source for pharmacovigilance.

Comment on the editorial by M. Wybier entitled: “Transforaminal epidural corticosteroid injections and spinal cord infarction”

We read with great interest the editorial of Marc Wybier [1] entitled ‘‘Transforaminal epidural corticosteroid injections and spinal cord infarction’’. Indeed, our regional pharmacovigilance centre is in charge of the evaluation of all serious neurological complications (i.e. paraplegia, quadriplegia and brain infarction) reported in France after transforaminal and epidural steroid injections. This editorial is useful to inform clinicians about this risk and the importance of reporting to the pharmacovigilance network any cases they could be aware. Effectively, better knowledge of all cases that occurred in France and a good documentation of them should be very useful to guide our conclusion. However, the so-called ‘‘domestic’’ and unpublished data exposed by Dr Wybier should be interpreted with caution. Effectively, the French data presented in the editorial are still fragmented and result from the preliminary review of spontaneous reports registered in the national pharmacovigilance database, performed in May 2008. According to the good pharmacovigilance practices, these cases reported to the French pharmacovigilance network must be confronted to the spontaneous cases recorded by the marketing authorisation holders (MAH) of all injectable steroids available in France. Potential cases from the MAH will be available in the middle of October 2008. It is therefore too early to draw conclusions about a safer route of injection or a safer product, as Dr Wybier recommended. Since the end of our first review, a new case of paraplegia after interapophyseal injection at the lumbar level was reported. Concerning the suspected products, the cases published worldwide involved most of the injectable steroids available: prednisolone, betamethasone, methylprednisolone and triamcinolone. The MAH data are needed to ensure that no case has been reported with cortivazol and to know if cortivazol is frequently used in this indication, before its use can be recommended. While awaiting the complete results of the national inquiry, the French Health Products Safety Agency (Afssaps) has

CorrespondenceComment on the editorial by M. Wybier entitled: “Transforaminal epidural corticosteroid injections and spinal cord infarction”

We read with great interest the editorial of Marc Wybier [1] entitled ‘‘Transforaminal epidural corticosteroid injections and spinal cord infarction’’. Indeed, our regional pharmacovigilance centre is in charge of the evaluation of all serious neurological complications (i.e. paraplegia, quadriplegia and brain infarction) reported in France after transforaminal and epidural steroid injections. This editorial is useful to inform clinicians about this risk and the importance of reporting to the pharmacovigilance network any cases they could be aware. Effectively, better knowledge of all cases that occurred in France and a good documentation of them should be very useful to guide our conclusion. However, the so-called ‘‘domestic’’ and unpublished data exposed by Dr Wybier should be interpreted with caution. Effectively, the French data presented in the editorial are still fragmented and result from the preliminary review of spontaneous reports registered in the national pharmacovigilance database, performed in May 2008. According to the good pharmacovigilance practices, these cases reported to the French pharmacovigilance network must be confronted to the spontaneous cases recorded by the marketing authorisation holders (MAH) of all injectable steroids available in France. Potential cases from the MAH will be available in the middle of October 2008. It is therefore too early to draw conclusions about a safer route of injection or a safer product, as Dr Wybier recommended. Since the end of our first review, a new case of paraplegia after interapophyseal injection at the lumbar level was reported. Concerning the suspected products, the cases published worldwide involved most of the injectable steroids available: prednisolone, betamethasone, methylprednisolone and triamcinolone. The MAH data are needed to ensure that no case has been reported with cortivazol and to know if cortivazol is frequently used in this indication, before its use can be recommended. While awaiting the complete results of the national inquiry, the French Health Products Safety Agency (Afssaps) has