Setting

EudraVigilance (EV) is the central database of reports of suspected spontaneous ADR reports and ADRs reported in clinical trials for all medicinal products authorized in the European Economic Area (EEA) [15]. In compliance with the EU pharmacovigilance legislation, ADRs are reported to EV by regulatory agencies in member states where the ADR occurred. EV was set up in December 2001 to facilitate the electronic reporting of ADRs in the EEA. Data should be transmitted in accordance with the ICH E2B (R2) standard [15]. The minimum information required for an ADR report to enter the EV database is the following parameters: type of reporter, patient, at least one suspected active substance/medicinal product, and at least one suspected ADR (Volume 9A) [15]. The EV database is not publically accessible, and authorisation for data access was given by the European Medicines Agency. By 2012, consumer reporting was officially accepted in 5 European countries: Denmark, the Netherlands, Norway, Sweden and the United Kingdom [1]. Before July 2012, countries were only requested to forward serious consumer ADR reports to the EV database [16].

Study design

The study comprised all ADR reports occurring from 2007 to 2011, located in the EV database and reported by consumers for nervous system medications (ATC group N). The content of the reports was analysed with respect to seriousness, categories of ADRs classified by system organ class (SOC) and medications. The unit of analysis was one ADR. Patients’ age was dichotomized into two groups: children (0-17-year-olds) and adults (18 +).

Classification of ADRs by type

The different types of reported ADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) [18]. Serious ADRs were defined as: fatal, life-threatening, requiring hospitalisation or prolongation of existing hospitalisation, resulting in persistent or significant disability/incapacity in the reporter’s assessment, in a congenital anomaly/birth defect and other medically important conditions. All other ADRs are classified as non-serious [18].

Classification of medications by anatomical therapeutic chemical (ATC) group

The ATC system is a system for classifying medicinal products according to their primary constituent, the organ or system on which they act and their chemical, pharmacological and therapeutic properties [19]. Medicinal products are classified at five different levels. The medicines are divided into 14 main groups (first level), with one pharmacological/therapeutic subgroup (second level), and the fifth level is the chemical substance [18]. As the ADR data provided by EMA did not contain any information about ATC codes, these were added manually to the data file. The medicinal products reported are referenced based on their active substance and in this article we present ADR data at ATC level 1 and 5 [19].

ADRs by type and seriousness

ADRs by therapeutic groups

ADRs by type and seriousness

The most frequently reported ADRs for nervous system medications were of the type nervous and psychiatric disorders and this finding was expected due to the mechanism of action of the reported nervous system medications. Additionally, a large number of ADRs of the type general disorders and administration site conditions and gastrointestinal disorders were reported, and this finding was also in line with results in previous consumer studies [5–13]. More than one half of reported ADRs were serious, however this reporting pattern was not surprising, since countries were not requested to report non-serious ADRs to the EV database during the study period [16].

ADRs by therapeutic groups

The largest number of ADRs was reported for antiepileptics and antidepressants, which can be explained by the frequent use of these medications in adults [20]. A high number of ADRs were reported for varenicline but only few were serious. In 2007, based on consumer reports in the USA, there was a high media attention on the increased risk of serious ADRs such as suicidal ideation and occasional suicidal behaviour, erratic behaviour and drowsiness reported for varenicline leading to black box warnings in the USA (July 2009) [21]. The ADR signal was later confirmed in a meta-analysis [22]. The high number of ADRs reported for varenicline by European consumers could have been stimulated by this media attention; however, the majority of reported ADRs were non-serious. For pregabalin a large number of the ADRs “drug ineffective/drug effect decreased” were reported, probably because this side effect can easily be assessed, and is very obvious compared to many other types of ADRs. To evaluate whether ADRs reported for pregabalin and varenicline can act as early warning for new ADR signals more in-depth analysis of the ADR reports should be conducted.

Strengths and limitations of this study

The strength of this study is that data comprised all ADRs reported by consumers in Europe, which were forwarded to the EV database during a five-year period and present in the database by March 2012. A major limitation to this study is that we do not know to which extent the causality of these ADRs can be confirmed, and this has implications for the interpretation of the findings [2]. The value of consumer reports in detection of new ADR signals remains unclarified due to the lack of information about causality. In this study, we did not evaluate the validity of the consumer reports since we only had access to the data entered into the EV database and not the original reports. Spontaneous reporting systems suffer from various barriers, such as incomplete recognition of ADRs, administrative barriers to reporting and low data quality, all of which may result in under-reporting of important serious and rare events [2]. ADRs that are non-serious or already known may be over-reported; however, this study provides information on reported ADRs, and this information contributes to broadening the knowledge on medicine safety. Before July 2012 countries were only obliged to report serious consumer reports to EV, which may explain the large number of serious ADRs found, and the low number of non-serious consumer reports. Therefore there may be additional non-serious consumer ADR reports present in the regulatory agencies. With the new pharmacovigilance regulation that came into force in July 2012 the share of serious consumer reports in EV will probably decline although the total number of consumer reports is expected to increase.

Hence, it is not possible to generalize from data reported to the EV database to the other EU member states. Spontaneous reports are an important source of information about new and previously unrecognized ADRs, and the value of spontaneous reporting schemes lies in their ability to act as hypothesis-generating procedures [2]. Therefore, EMA should continue to systematically survey and analyse ADRs reported by consumers in order to signal previously unknown ADRs. Another important issue to be investigated in future studies is to which extent individuals suffering from ADRs later recover from the reported reactions.