EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection

EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health... Drug Saf (2018) 41:665–675 https://doi.org/10.1007/s40264-018-0647-1 SPECIAL ARTICLE EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection 1 1 1 2 • • • • Rodrigo Postigo Sabine Brosch Jim Slattery Anja van Haren 3 1 1 1 • • • • Jean-Michel Dogne ´ Xavier Kurz Gianmario Candore Francois Domergue Peter Arlett Published online: 9 March 2018 The Author(s) 2018. This article is an open access publication Abstract The analysis of safety data from spontaneous European Union regulatory network. Driven by the full reporting systems has a proven value for the detection and implementation of the 2010 pharmacovigilance legislation, analysis of the risks of medicines following their placement EudraVigilance has undergone further enhancements on the market and use in medical practice. EudraVigilance together with a major revision of its access policy, taking is the pharmacovigilance database to manage the collection into account the use of the new individual case safety and analysis of suspected adverse reactions to medicines report standard developed by the International Council for authorised in the European Economic Area. EudraVigi- Harmonization of Technical Requirements for Pharma- lance first operated in December 2001, with access to the ceuticals for Human Use and the International Organiza- database being governed by the EudraVigilance access tion for Standardization. The aim of the broadened access policy. We performed a literature search including data up is to facilitate more effective safety monitoring of autho- to December 2016 to demonstrate how the data from rised medicines, to make more data available for research EudraVigilance has been used in scientific publications. and to provide better access to information on suspected We describe the results, including by type of publication, adverse reactions for healthcare professionals and patients. research topics and drugs involved. In 50% of the publi- In November 2017, the new full functionalities of cations, the data are used to describe safety issues, in 44% EudraVigilance were launched, including the extensive to analyse methodologies used in pharmacovigilance web access to data on suspected adverse drug reactions and activities and in 6% to support clinical perspectives. We the possibilities for academic research institutions to also outline a description of the use of the database by the request a more extensive dataset for the purposes of health research. The main objective of this article is to describe the new access to the database together with the opportu- nities that this new access can bring for research. It is intended to promote an appropriate use of the data to support the safe and effective use of medicines. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40264-018-0647-1) contains supple- mentary material, which is available to authorized users. & Rodrigo Postigo rodrigo.postigo@ema.europa.eu European Medicines Agency, 30 Churchill Place, Canary Wharf, London E14 5EU, UK Medicines Evaluation Board, Utrecht, The Netherlands ´ ´ ´ ´ Agence Federale des Medicaments et des Produits de Sante (Member of the Pharmacovigilance Risk Assessment Committee), Brussels, Belgium 666 R. Postigo et al. information supplementing and updating initial reports). In total, 402,690 cases were submitted from interventional Key Points clinical trials and 7,546,183 from the post-authorisation setting of the medicinal products. Of the cases submitted New EudraVigilance functionalities and the from post-authorisation, 64% (4,838,460) were submitted increased level of access facilitate more effective from outside the EEA and 36% (2,707,723) from EEA monitoring of the safety of medicines. Six different countries. During the course of 2017 alone, 1,076,811 stakeholder groups with different levels of access individual cases were transmitted from post-authorisation, have been defined 418,383 from EEA countries. Of those, 84,372 were Since November 2017, academic research directly submitted by European patients and consumers institutions have the possibility to request extended through national competent authorities (NCAs) in the access to EudraVigilance data, opening more Member States and marketing authorisation holders possibilities for scientific and medical research (MAHs). The EEA country distribution of patients’ reports analysed by Banovac et al. in 2017 [7] showed that the Scientific publications using EudraVigilance data highest number of reports originated from the Netherlands, have increased since 2010 and analyse a wide range followed by the UK, Germany, France and Italy. The same of safety issues, medicinal products, therapeutics five countries contributed 77% of all healthcare profes- areas, and pharmacovigilance topics and methods sional reports to EV. In May 2017, following a period of technical develop- ment, guideline updates, engagement with the stakeholders and an independent system audit, the EMA Management Board announced that the EV database has achieved full 1 Introduction functionality [8]. This triggered the application of both the simplified reporting rules for NCAs and MAHs and the EudraVigilance (EV) is the system for collecting, manag- extended access to the database with the goal to further ing and analysing suspected adverse drug reactions (ADRs) support the safety surveillance of medicinal products in the to medicines authorised in the European Economic Area EU, increase transparency and enable greater use of the (EEA). The European Medicines Agency (EMA) operates data by stakeholders, including researchers. the system, which became operational in December 2001, on behalf of the European Union (EU) medicines regula- tory network [1]. 2 Use of EudraVigilance Data On 4 February, 2016, 15 years after the pharmacovigi- lance database was launched, submissions to EV reached In this section, we review the use of EV data up to 10 million individual case safety reports (ICSRs), making it December 2016, including published reviews, with the aim one of the biggest spontaneous reporting systems in the to provide an overview of their use for health research. The world. This milestone coincided in time with significant launch of the enhanced system functionalities and the new technical enhancements and with a major revision of the access to data provide the research and medicine safety EV access policy aimed at increasing the utility and communities with the opportunity to make a much greater accessibility of the ICSR data in line with the pharma- use of this data source, and this review therefore serves covigilance legislative requirements [2–4], and thereby at both as an inspiration and a challenge. further contributing to public health protection. Use of EV data by the EU regulatory network includes a Since November 2005, the electronic reporting of sus- summary of areas such as signal detection and evaluation, pected ADRs is mandatory in the EEA [2, 3]. The sub- PSUR assessments [9] and referrals. During 2017, the mission of ADRs from both marketed use and from trials is number of signals prioritised and analysed by the Phar- based on the standards agreed at the level of the Interna- macovigilance Risk Assessment Committee was 82 and tional Council for Harmonization of Technical Require- overall, the source of 63% included data from EV. ments for Pharmaceuticals for Human Use [5] and the In addition to the use of EV by the EU regulatory net- International Organization for Standardization [6], which work, other groups such as healthcare professionals and allow for a structured and standardised way safety infor- patients can obtain information on ADR data submitted to mation is to be collected and exchanged. EV via the ‘European Database of Suspected Adverse Drug By the end of 2017, EV held a total of 12,451,826 Reactions Reports’ [10] (hereinafter referred to as the ICSRs, referring to 7,948,873 individual cases (one case ‘ADR website’). This information is available from the can relate to more than one ICSR owing to follow-up EMA website with guidance on the interpretation of the EudraVigilance Medicines Safety Database: Publicly Accessible Data 667 Fig. 1 Publications using EudraVigilance data up to 31 December, 2016, classified per country of author and type of publication (as per the classification stated in EMBASE). Absolute numbers. EMA European Medicines Agency data. In 2017, the ADR website registered an average of methodologies (e.g. signal detections methodologies, 17,068 visits per month. pharmacovigilance in paediatric population) or ADR To have an overview about how EV data has been used reporting patterns (e.g. consumer reports, medication in research and scientific publications, a search in errors); and (3) ‘clinical perspectives’ when the EV data EMBASE [11], PubMed and PubMed Central [12] was were used to support clinical practice and treatment guid- conducted using specific keywords [see the Electronic ance discussions. Supplementary Material (ESM)]. This provides an illus- Figure 2 shows the citations distributed by year of tration of the use of the data with the aim of informing publication (a) and the main classification of the publica- researchers about how EV can be used. The search inclu- tions (b). Within the time distribution, there is a marked ded publications up to 31 December, 2016 and retrieved increase after 2012–2013 probably driven by the imple- 105 citations referring to publications that contain data mentation of the 2010 pharmacovigilance legislation and from EV. the increased accessibility of the data, including through Ninety percent of the publications derived from coun- the release of the public ADR website [10]. tries within the EEA and 10% from the rest of the world. Together with the EV data, the publications are sup- Figure 1 shows a distribution of the publications per ported by other sources of information. These include country of the main author (a) and type of publication (b). spontaneous reporting systems such as the World Health Sixty-one percent of the citations from the UK were pub- Organization (WHO) global database of individual case lished by EMA personnel. safety reports (VigiBase) [13], the US Vaccine Adverse The publications were classified in: (1) ‘safety issues’ Event Reporting System [14], the US FDA Adverse Event when they describe a safety signal, characterisation of a Reporting System [15], NCAs databases and safety data- risk or characterisation of the general safety profile of the bases from MAHs. Furthermore, data is provided from drug; (2) ‘pharmacovigilance topics’ when the data were electronic health records databases, health insurance com- used to analyse a pharmacovigilance activity, research panies, legal datasets and patient registries. In 63% of the 668 R. Postigo et al. Fig. 2 Publications per year and the main classification of the publications using EudraVigilance data up to 31 December, 2016. Absolute numbers Fig. 3 Anatomical Therapeutic Chemical (ATC) code classification of the drugs analysed in the publications using EudraVigilance data to describe safety issues up to 31 December, 2016. Absolute numbers. excl excluding EudraVigilance Medicines Safety Database: Publicly Accessible Data 669 publications retrieved, EV is the sole spontaneous reporting category related to signal detection methods includes system used for the research. publications under the scope of the IMI PROTECT project The specific drug-related safety issues are summarised for which public funding was allocated [17–19]. in the ESM for this article including the drugs involved and Figure 5 provides the classification of the pharma- the databases used for the analysis. The classification of covigilance topics yielded by the literature search. drugs for which data are analysed in the 53 (50%) publi- One of the first publications on signal detection methods cations related to safety issues shows interests in a wide in EV refers to the validation study performed by the EMA range of therapeutic areas, from medications administered to quantify the benefit that can be obtained by adding signal presumably to relatively healthy populations, such as detection using the proportional reporting ratio to estab- vaccines, to antineoplastic agents used in patients affected lished pharmacovigilance methods. The study determined by a significant disease burden. Figure 3 provides the that statistical analysis has the potential to provide signif- classification of the drugs analysed in these publications icant early warning on adverse reactions to medicines [20]. classified by Anatomical Therapeutic Chemical code [16] Since then, 22 other publications have used EV data to with the exception of the last three sets of drugs (‘drugs investigate signal detection methods. Choosing the prescribed in geriatric setting’, ‘antibiotics’ and ‘all prod- thresholds, comparison of disproportionality measures, ucts in the database’) that cannot be allocated to a specific development of a score for the prioritisation of torsado- Anatomical Therapeutic Chemical code. genic signals and analysis of variables that could influence Figure 4 provides the MedDRA System Organ Classes signal detection in well-established products are among the of the 53 publications describing safety issues with the topics covered. Based largely on the research conducted exception of the 11 publications aimed at characterising the under the auspices of IMI PROTECT Work package 3 entire safety profile of the drugs. Two publications are (signal detection) [19][21], the EMA announced in 2015 allocated to two different System Organ Classes. the revision of the guidance of screening for adverse The 46 (44%) publications describing general pharma- reactions in EV [17]. The final guideline was published in covigilance topics contain research to analyse methodolo- December 2016 [22]. This represents an important example gies, especially on statistical signal detection, together with of research-based improvement in regulatory practice. descriptions of specific situations that should to be taken The six publications related to clinical perspectives refer into consideration when analysing safety data (e.g. paedi- to the use of novel oral anticoagulants, in light of the atric population or ADR reports from consumers). The experience with dabigatran [23–26], information systems Fig. 4 MedDRA System Organ Class distribution for the specific safety issues described in the publications using EudraVigilance data up to 31 December, 2016. Absolute numbers. incl including 670 R. Postigo et al. Fig. 5 Classification of the pharmacovigilance topics analysed using EudraVigilance data up to 31 December, 2016. Absolute numbers. ADRs adverse drug reactions for translational pharmacogenomics [27] and the use of The collaboration with the WHO is also being sodium-glucose co-transporter 2 inhibitors with insulin for strengthened by making available all suspected ADRs the treatment of type 2 diabetes [28]. reported in the EEA to the Uppsala Monitoring Centre and EV has undertaken the pertinent technical and process modifications to achieve this. With the aim of increasing transparency and to facilitate the conduct of safety moni- 3 Changes in Adverse Drug Reaction Reports Management and Access to EudraVigilance toring and research, the level of access to EV has also been Data enhanced. In addition to the full data access provided to the EU regulatory network, MAHs are to have access to the The EU pharmacovigilance legislation adopted in 2010 extent necessary to comply with their pharmacovigilance introduced significant changes in the management of obligations and an appropriate level of access is provided reports of suspected ADRs and placed EV as the single to healthcare professionals and the public while guaran- European hub for ICSR exchange and access. These teeing personal data protection. changes include the submission of patient’s reports, non- The EMA Management Board endorsed a revision of the serious ADRs that occurred in the EU, and ADRs arising EudraVigilance access policy in December 2015 that from all uses of the medicinal products and not only those determines the level of access by stakeholder groups con- restricted to authorised use. sidering the need to protect personal data. This version of In the area of signal detection, EV plays a key role in the access policy takes into account the International determining new risks, new aspects of known risks and Council for Harmonization of Technical Requirements for changes in the benefit-risk balance of medicinal products Pharmaceuticals for Human Use E2B(R3) [30] standard to [2]. This comes with an explicit mandate for the EU reg- determine the level of access for all ICSR data elements. ulatory network and the MAHs to monitor the data in EV. The revision of the access policy categorises stake- During the decision-making process, the Pharmacovigi- holders into six groups incorporating as new stakeholders lance Risk Assessment Committee has a central role in the WHO–Uppsala Monitoring Centre and medicines reg- scientific assessment in relation to signal management, ulatory authorities in third countries (outside the EEA). covering all aspects of risk management. An analysis Nevertheless, the most significant update of the access published to describe signals during the first 18 months of policy is in the level of access, the number of data fields the Pharmacovigilance Risk Assessment Committee con- available, and the availability of new tools to access and firmed the importance of spontaneous reporting in signal analyse the data. Table 1 outlines the access provided and detection [29]. the tools for the different stakeholder groups. EudraVigilance Medicines Safety Database: Publicly Accessible Data 671 Table 1 Level of EudraVigilance access provided by stakeholder group Group Stakeholder Type of cases Access given (summary) Access method I Medicines regulatory authorities in All cases Complete access (Level EVWEB and EEA Member States, the European 3—272 data fields) EVDAS Commission and the EMA II Healthcare professionals and the Spontaneous Aggregated data ADR website public Line listing of individual cases and ICSR form (Level 1—53 data fields) III Marketing authorisation holders EVPM cases Aggregated data with EVDAS statistical output (eRMR) Line listing of individual cases (Level 1—53 data fields) EVPM cases containing suspect/interacting XML file and ICSR form EVWEB substances related to their products (Level 2A—228 data fields) XML file (Level 2B—230 data fields, including the narratives) EVPM cases previously submitted by the Complete access (Level EVWEB specific marketing authorisation holders and 3—272 data fields) medical literature monitoring cases IV Research organisations EVPM cases Level 2A—228 data fields Research request submission to Data format will depend the EMA on the nature of the request V WHO-UMC EVPM cases XML file (level 2C—134 Data transfer data fields) between EMA and WHO- UMC VI Medicines regulatory agencies in EVPM cases Level 2C—134 data fields. Request third countries submission to Data format will depend the EMA on the nature of the request ADR adverse drug reaction, EEA European Economic Area, EDBMS EudraVigilance database management system, EMA European Medicines Agency, eRMR electronic reaction monitoring report, EVDAS EudraVigilance data analysis system, EVPM EudraVigilance post-authorisation module, EVWEB EudraVigilance web application, ICSR individual case safety report, WHO-UMC World Health Organization-Uppsala Mon- itoring Centre The EVWEB is the interface to the EDBMS and allows registered users to create, send and view ICSRs The EVDAS supports European Union pharmacovigilance safety monitoring activities with the main focus on signal detection and evaluation of ICSRs A spontaneous report is an unsolicited communication by a healthcare professional, or consumer to a competent authority, marketing autho- risation holder or other organisation (e.g. regional pharmacovigilance centre, poison control centre) that describes one or more suspected adverse reactions in a patient who was given one or more medicinal products. It does not derive from a study or any organised data collection system [31]. Spontaneous reports are identified in the database by the mandatory field ‘type of report’ provided by the senders at the time of the ICSR submission The EVPM includes cases with type of report ‘spontaneous’, ‘other’ and ‘not available to sender (unknown)’ plus reports from studies (including ‘individual patient use’ and ‘other study’) 4 Research Organisations European interest organisations whose principal objective is to promote scientific and technological cooperation in In the context of EV access, academic research organisa- Europe [32]. Until November 2017, the level of access to EV data provided to academia and research organisations tions should be understood as public or private higher education establishments awarding academic degrees, was limited to the same set of data elements publicly available in the ADR website. This is reflected in some of public or private non-profit research organisations whose the publications that analysed EV data for safety primary mission is to pursue research, and international 672 R. Postigo et al. Aggregated data Research Direct access ADR reports website Data analysis instuon www.adrreports.eu Level 1 (53 data fields) Line lisngs Individual cases data ICSR forms Fig. 6 Access to Level 1 EudraVigilance data by research organisations. ADR adverse drug reaction, ICSR individual case safety report Fig. 7 Access to Level 2A EudraVigilance data by research organisations. EMA European Medicines Agency assessments. The revision of the access policy extends the amongst others, body weight and height, medical and access to data for research to provide the possibility for a family history, past drug history, death details and infor- more thorough analysis of the data, hence contributing to mation concerning the parent for the parent–child reports. the promotion and protection of public health and fostering The reaction section contains ten extra data elements innovation of scientific and medical research. Research including the start and end dates of the reaction and the institutions can directly access level 1 data via the ADR identification of the country where the reaction occurred. website and can also request the EMA level 2A data sets. The drug section includes 49 extra data elements including Figures 6 and 7 provide an overview of how research the product name for non-centrally authorised medicinal institutions can access EV data. products, strength, dates for the first and last drug admin- The data provided in the ADR website include aggregated istration, cumulative dose to first reaction, gestation period information based on numbers of spontaneous cases stratified at the time of exposure and batch/lot numbers. Further- by different parameters (e.g. number of cases by age group, more, the data set contains 13 additional data elements for sex, geographic origin, reactions groups, time distribution). the results of tests and procedures relevant to the investi- From November 2017, the ADR website provides the possi- gation of the patient. To comply with data protection bility to retrieve data for the individual cases based on some requirements, the case narratives, containing free text, are core data elements (level 1) within the ‘patient characteris- not provided to research organisations. tics’, ‘reactions/events’ and ‘drugs information’ sections. To obtain level 2A access, the interested institutions However, the data provided to research institutions upon should submit a request via the EMA website [33](http:// request contain a significant increase in the potential www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/ number of data elements (level 2A) provided and the landing/ask_ema_landing_page.jsp&mid=) with details on access is extended to all cases submitted to the the research methodology, potential impact on public EudraVigilance post-authorisation module, therefore not health, a signed copy of the confidentiality undertaking restricted to spontaneous cases, and includes reports from [32] and a copy of the approval of the research protocol by non-interventional post-authorisation studies. Within the an ethics committee/review body. Following the analysis of patient characteristics section and compared with level 1, the data, researchers should make all possible efforts to level 2A provides 83 extra data elements including, publish the outcomes of the research and for information purposes only, should provide a copy of the articles to the EMA ahead of publication. Non-interventional studies are considered studies where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not 5 Data Protection decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. Non-interventional post- The need to maintain the confidentiality of the identity of authorisation studies are identified in the database by the mandatory individuals in compliance with EU personal data protection fields ‘type of report’ and ‘study type where the reactions events legislation [34, 35] is one of the key drivers of the EV occurred’. EudraVigilance Medicines Safety Database: Publicly Accessible Data 673 access policy and the levels of access have been developed activities during assessments and can provide significant considering data protection in conjunction with the public information when determining causal associations. health needs and pharmacovigilance obligations for the At the same time as the new access is in place, the different stakeholders. Users of EV should comply with the International Council for Harmonization of Technical data protection requirements and should have appropriate Requirements for Pharmaceuticals for Human Use measures in place to protect the information [32]. E2B(R3) standard is implemented in EV with the subse- In this context, it is especially important to avoid the quent advantages derived from the new data structure and identification of individual patients from the data available data elements. These will bring advantages for data anal- in the ADR website published by the EMA. Level 1 access ysis (e.g. in the old format, seriousness criteria are reported is based on this principle while providing meaningful at the level of the case whereas these are reported at the information on suspected ADR reports. Table 2 outlines level of the individual reactions in the new format). Safety additional measures taken in the ADR website to avoid the assessors should be well aware of the differences between identification of individual patients. the old and the new format when analysing the data. The enhanced access to the data is also expected to trigger more engagement with academia. Up to November 6 Discussion 2017, the information from EV publicly available could have been considered acceptable for patient use but not Particularly since 2011, there has been a constant increase optimally for research purposes [36]. The extended access in the number of research publications that considered data provides research institutions with a rich data source and from EV and this likely reflects the growing recognition of there is therefore a unique opportunity to conduct research how the database can contribute to drug safety. The sus- for public health. pected ADR data in EV have provided a foundation to identify safety signals and characterise risks. Furthermore, the data have allowed the investigation of new method- 7 Conclusion ologies for signal detection as well as specific situations such as paediatrics, vaccines, pandemics, consumer reports Pharmacovigilance is an essential discipline for the pro- and traceability of biological products. motion and protection of patient and public health. In the In 2016, Fouretier et al. [36] performed an analysis of 11 EEA, the EU regulatory network formed by the European pharmacovigilance databases with open access to charac- Commission, the NCAs and the EMA has a key role terise the accessibility of the relevant data in those systems. together with the MAHs on the safety surveillance on In their study, the EV access was considered to be ‘med- medicinal products. ium’, mainly based on the fact that EV did not provide The EU legislation places the EV database in a core role public access at the level of the individual cases in the in the management of reports of suspected adverse reac- ADR website. This assessment and the perception of EV tions and in determining changes in the safety profile of the will change drastically with the recent implementation of medicinal products once they are used in everyday medical the new access specified in the revised access policy. practice. For over 16 years, EV has demonstrated its value The main implication for MAHs following the release of especially in the area of signal detection, providing a tool the new EV system and extended access is the obligation to to analyse the safety data submitted. monitor the data for their substances and products. The Although EV has been fully accessible to the EMA and extended access provided at the level of the substance the NCAs in the countries that belong to the EEA, the brings the opportunity for MAHs to fully assess the data access provided in the past to other stakeholders has been and provides greater transparency during assessment and more limited. The new extended EV access provides a decision making. The applied statistical analysis follows an unique platform for all stakeholders to use the data evidence-based methodology [22] and this provides a according to their needs, interest and pharmacovigilance common understanding about how statistical signal detec- obligations. This enhanced access brings opportunities for tion has been implemented in EV. a broader involvement in safety monitoring, for increased Apart from the power demonstrated by statistical transparency, for collective collaborations, for methods methods within large spontaneous reporting systems [37], improvement and for innovation in safety research. statistical signal detection should be complemented by We call on patients, healthcare professionals, MAHs, scientific assessment and medical judgement, taking into research institutions, the WHO, non-EEA regulatory consideration what is known about the product. The authorities, NCAs in the EEA Members States and the detailed analysis of individual cases remains one of the key EMA to embrace the opportunities provided by the new EudraVigilance system to be better informed, to better 674 R. Postigo et al. Table 2 Adverse drug reaction website: additional measures for data protection Measures The information provided in the 53 data elements (level 1 access) individually or in combination would not lead to the identification of individual patients, for instance, date of birth, or free text fields are not provided Within the details of the individual cases, the country where the reaction occurred is not provided. The ‘country’ data field is displayed as EEA or non-EEA. This is to prevent the identification of patients where there are a small number of cases per country The product name for non-centrally authorised medicinal products is replaced by the substance name. Product names can potentially lead to the identification of the country where the reaction occurred The Worldwide Case Identification Number is replaced by the EV local report number as the country code is normally included in the Worldwide Case Identification Number The sender organisation is displayed as ‘EEA regulator’ for cases submitted by regulatory authorities from the EEA to avoid the identification of the country A threshold is applied if the number of individual cases available for a specific country is less or equal to 3. In this instance, the total number of cases for the specific country is not provided to reduce the risk of patient or reporter identification EEA European Economic Area, EV EudraVigilance 2. European Commission. Directive 2001/83/EC of the European manage product risks, to better understand the science of Parliament and of the Council of 6 November 2001 on the pharmacovigilance and, ultimately, to better promote Community code relating to medicinal products for human use. public health. https://ec.europa.eu/health/documents/eudralex/vol-1_en. Acces- sed 31 Jan 2018. Acknowledgements The authors gratefully acknowledge the contri- 3. European Commission. Regulation (EC) No. 726/2004 of the bution made by Luis Pinheiro. European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervi- Compliance with Ethical Standards sion of medicinal products for human and veterinary use and establishing a European Medicines Agency. https://ec.europa.eu/ Funding No sources of funding were received for the preparation of health/documents/eudralex/vol-1_en. Accessed 31 Jan 2018. this review. 4. European Commission. Commission Implementing Regulation (EU) No. 520/2012 of 19 June 2012 on the performance of Conflict of interest Rodrigo Postigo, Sabine Brosch, Jim Slattery, pharmacovigilance activities provided for in Regulation (EC) No. Xavier Kurz, Gianmario Candore, Francois Domergue and Peter 726/2004 of the European Parliament and of the Council and Arlett are employees of the European Medicines Agency. Jean- Directive 2001/83/EC of the European Parliament and of the Michel Dogne´ is a member of the Pharmacovigilance Risk Assess- Council. https://ec.europa.eu/health/documents/eudralex/vol-1_ ment Committee, as well as an employee of the Federal Agency for en. Accessed 31 Jan 2018. Medicines and Health Products of Belgium. Anja van Haren is an 5. The International Council for Harmonisation of Technical employee of the Medicines Evaluation Board of the Netherlands and Requirements for Pharmaceuticals for Human Use (ICH). http:// she acts as a co-chair of the EudraVigilance Expert Working Group. www.ich.org/home.html. Accessed 31 Jan 2018. 6. International Organization for Standardization. https://www.iso. Disclaimer The views expressed in this article are the personal views org/home.html. Accessed 31 Jan 2018. of the authors and may not be understood or quoted as being made on 7. Banovac M, Candore G, Slattery J, Houy¨ez F, Haerry D, Genov behalf of or reflecting the position of the agencies or organisations G, et al. Patient reporting in the EU: analysis of EudraVigilance with which the authors are affiliated. data. Drug Saf. 2017;40(7):629–45. https://doi.org/10.1007/ s40264-017-0534-1. Open Access This article is distributed under the terms of the 8. European Medicines Agency. 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EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection

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Medicine & Public Health; Drug Safety and Pharmacovigilance; Pharmacology/Toxicology
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Abstract

Drug Saf (2018) 41:665–675 https://doi.org/10.1007/s40264-018-0647-1 SPECIAL ARTICLE EudraVigilance Medicines Safety Database: Publicly Accessible Data for Research and Public Health Protection 1 1 1 2 • • • • Rodrigo Postigo Sabine Brosch Jim Slattery Anja van Haren 3 1 1 1 • • • • Jean-Michel Dogne ´ Xavier Kurz Gianmario Candore Francois Domergue Peter Arlett Published online: 9 March 2018 The Author(s) 2018. This article is an open access publication Abstract The analysis of safety data from spontaneous European Union regulatory network. Driven by the full reporting systems has a proven value for the detection and implementation of the 2010 pharmacovigilance legislation, analysis of the risks of medicines following their placement EudraVigilance has undergone further enhancements on the market and use in medical practice. EudraVigilance together with a major revision of its access policy, taking is the pharmacovigilance database to manage the collection into account the use of the new individual case safety and analysis of suspected adverse reactions to medicines report standard developed by the International Council for authorised in the European Economic Area. EudraVigi- Harmonization of Technical Requirements for Pharma- lance first operated in December 2001, with access to the ceuticals for Human Use and the International Organiza- database being governed by the EudraVigilance access tion for Standardization. The aim of the broadened access policy. We performed a literature search including data up is to facilitate more effective safety monitoring of autho- to December 2016 to demonstrate how the data from rised medicines, to make more data available for research EudraVigilance has been used in scientific publications. and to provide better access to information on suspected We describe the results, including by type of publication, adverse reactions for healthcare professionals and patients. research topics and drugs involved. In 50% of the publi- In November 2017, the new full functionalities of cations, the data are used to describe safety issues, in 44% EudraVigilance were launched, including the extensive to analyse methodologies used in pharmacovigilance web access to data on suspected adverse drug reactions and activities and in 6% to support clinical perspectives. We the possibilities for academic research institutions to also outline a description of the use of the database by the request a more extensive dataset for the purposes of health research. The main objective of this article is to describe the new access to the database together with the opportu- nities that this new access can bring for research. It is intended to promote an appropriate use of the data to support the safe and effective use of medicines. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40264-018-0647-1) contains supple- mentary material, which is available to authorized users. & Rodrigo Postigo rodrigo.postigo@ema.europa.eu European Medicines Agency, 30 Churchill Place, Canary Wharf, London E14 5EU, UK Medicines Evaluation Board, Utrecht, The Netherlands ´ ´ ´ ´ Agence Federale des Medicaments et des Produits de Sante (Member of the Pharmacovigilance Risk Assessment Committee), Brussels, Belgium 666 R. Postigo et al. information supplementing and updating initial reports). In total, 402,690 cases were submitted from interventional Key Points clinical trials and 7,546,183 from the post-authorisation setting of the medicinal products. Of the cases submitted New EudraVigilance functionalities and the from post-authorisation, 64% (4,838,460) were submitted increased level of access facilitate more effective from outside the EEA and 36% (2,707,723) from EEA monitoring of the safety of medicines. Six different countries. During the course of 2017 alone, 1,076,811 stakeholder groups with different levels of access individual cases were transmitted from post-authorisation, have been defined 418,383 from EEA countries. Of those, 84,372 were Since November 2017, academic research directly submitted by European patients and consumers institutions have the possibility to request extended through national competent authorities (NCAs) in the access to EudraVigilance data, opening more Member States and marketing authorisation holders possibilities for scientific and medical research (MAHs). The EEA country distribution of patients’ reports analysed by Banovac et al. in 2017 [7] showed that the Scientific publications using EudraVigilance data highest number of reports originated from the Netherlands, have increased since 2010 and analyse a wide range followed by the UK, Germany, France and Italy. The same of safety issues, medicinal products, therapeutics five countries contributed 77% of all healthcare profes- areas, and pharmacovigilance topics and methods sional reports to EV. In May 2017, following a period of technical develop- ment, guideline updates, engagement with the stakeholders and an independent system audit, the EMA Management Board announced that the EV database has achieved full 1 Introduction functionality [8]. This triggered the application of both the simplified reporting rules for NCAs and MAHs and the EudraVigilance (EV) is the system for collecting, manag- extended access to the database with the goal to further ing and analysing suspected adverse drug reactions (ADRs) support the safety surveillance of medicinal products in the to medicines authorised in the European Economic Area EU, increase transparency and enable greater use of the (EEA). The European Medicines Agency (EMA) operates data by stakeholders, including researchers. the system, which became operational in December 2001, on behalf of the European Union (EU) medicines regula- tory network [1]. 2 Use of EudraVigilance Data On 4 February, 2016, 15 years after the pharmacovigi- lance database was launched, submissions to EV reached In this section, we review the use of EV data up to 10 million individual case safety reports (ICSRs), making it December 2016, including published reviews, with the aim one of the biggest spontaneous reporting systems in the to provide an overview of their use for health research. The world. This milestone coincided in time with significant launch of the enhanced system functionalities and the new technical enhancements and with a major revision of the access to data provide the research and medicine safety EV access policy aimed at increasing the utility and communities with the opportunity to make a much greater accessibility of the ICSR data in line with the pharma- use of this data source, and this review therefore serves covigilance legislative requirements [2–4], and thereby at both as an inspiration and a challenge. further contributing to public health protection. Use of EV data by the EU regulatory network includes a Since November 2005, the electronic reporting of sus- summary of areas such as signal detection and evaluation, pected ADRs is mandatory in the EEA [2, 3]. The sub- PSUR assessments [9] and referrals. During 2017, the mission of ADRs from both marketed use and from trials is number of signals prioritised and analysed by the Phar- based on the standards agreed at the level of the Interna- macovigilance Risk Assessment Committee was 82 and tional Council for Harmonization of Technical Require- overall, the source of 63% included data from EV. ments for Pharmaceuticals for Human Use [5] and the In addition to the use of EV by the EU regulatory net- International Organization for Standardization [6], which work, other groups such as healthcare professionals and allow for a structured and standardised way safety infor- patients can obtain information on ADR data submitted to mation is to be collected and exchanged. EV via the ‘European Database of Suspected Adverse Drug By the end of 2017, EV held a total of 12,451,826 Reactions Reports’ [10] (hereinafter referred to as the ICSRs, referring to 7,948,873 individual cases (one case ‘ADR website’). This information is available from the can relate to more than one ICSR owing to follow-up EMA website with guidance on the interpretation of the EudraVigilance Medicines Safety Database: Publicly Accessible Data 667 Fig. 1 Publications using EudraVigilance data up to 31 December, 2016, classified per country of author and type of publication (as per the classification stated in EMBASE). Absolute numbers. EMA European Medicines Agency data. In 2017, the ADR website registered an average of methodologies (e.g. signal detections methodologies, 17,068 visits per month. pharmacovigilance in paediatric population) or ADR To have an overview about how EV data has been used reporting patterns (e.g. consumer reports, medication in research and scientific publications, a search in errors); and (3) ‘clinical perspectives’ when the EV data EMBASE [11], PubMed and PubMed Central [12] was were used to support clinical practice and treatment guid- conducted using specific keywords [see the Electronic ance discussions. Supplementary Material (ESM)]. This provides an illus- Figure 2 shows the citations distributed by year of tration of the use of the data with the aim of informing publication (a) and the main classification of the publica- researchers about how EV can be used. The search inclu- tions (b). Within the time distribution, there is a marked ded publications up to 31 December, 2016 and retrieved increase after 2012–2013 probably driven by the imple- 105 citations referring to publications that contain data mentation of the 2010 pharmacovigilance legislation and from EV. the increased accessibility of the data, including through Ninety percent of the publications derived from coun- the release of the public ADR website [10]. tries within the EEA and 10% from the rest of the world. Together with the EV data, the publications are sup- Figure 1 shows a distribution of the publications per ported by other sources of information. These include country of the main author (a) and type of publication (b). spontaneous reporting systems such as the World Health Sixty-one percent of the citations from the UK were pub- Organization (WHO) global database of individual case lished by EMA personnel. safety reports (VigiBase) [13], the US Vaccine Adverse The publications were classified in: (1) ‘safety issues’ Event Reporting System [14], the US FDA Adverse Event when they describe a safety signal, characterisation of a Reporting System [15], NCAs databases and safety data- risk or characterisation of the general safety profile of the bases from MAHs. Furthermore, data is provided from drug; (2) ‘pharmacovigilance topics’ when the data were electronic health records databases, health insurance com- used to analyse a pharmacovigilance activity, research panies, legal datasets and patient registries. In 63% of the 668 R. Postigo et al. Fig. 2 Publications per year and the main classification of the publications using EudraVigilance data up to 31 December, 2016. Absolute numbers Fig. 3 Anatomical Therapeutic Chemical (ATC) code classification of the drugs analysed in the publications using EudraVigilance data to describe safety issues up to 31 December, 2016. Absolute numbers. excl excluding EudraVigilance Medicines Safety Database: Publicly Accessible Data 669 publications retrieved, EV is the sole spontaneous reporting category related to signal detection methods includes system used for the research. publications under the scope of the IMI PROTECT project The specific drug-related safety issues are summarised for which public funding was allocated [17–19]. in the ESM for this article including the drugs involved and Figure 5 provides the classification of the pharma- the databases used for the analysis. The classification of covigilance topics yielded by the literature search. drugs for which data are analysed in the 53 (50%) publi- One of the first publications on signal detection methods cations related to safety issues shows interests in a wide in EV refers to the validation study performed by the EMA range of therapeutic areas, from medications administered to quantify the benefit that can be obtained by adding signal presumably to relatively healthy populations, such as detection using the proportional reporting ratio to estab- vaccines, to antineoplastic agents used in patients affected lished pharmacovigilance methods. The study determined by a significant disease burden. Figure 3 provides the that statistical analysis has the potential to provide signif- classification of the drugs analysed in these publications icant early warning on adverse reactions to medicines [20]. classified by Anatomical Therapeutic Chemical code [16] Since then, 22 other publications have used EV data to with the exception of the last three sets of drugs (‘drugs investigate signal detection methods. Choosing the prescribed in geriatric setting’, ‘antibiotics’ and ‘all prod- thresholds, comparison of disproportionality measures, ucts in the database’) that cannot be allocated to a specific development of a score for the prioritisation of torsado- Anatomical Therapeutic Chemical code. genic signals and analysis of variables that could influence Figure 4 provides the MedDRA System Organ Classes signal detection in well-established products are among the of the 53 publications describing safety issues with the topics covered. Based largely on the research conducted exception of the 11 publications aimed at characterising the under the auspices of IMI PROTECT Work package 3 entire safety profile of the drugs. Two publications are (signal detection) [19][21], the EMA announced in 2015 allocated to two different System Organ Classes. the revision of the guidance of screening for adverse The 46 (44%) publications describing general pharma- reactions in EV [17]. The final guideline was published in covigilance topics contain research to analyse methodolo- December 2016 [22]. This represents an important example gies, especially on statistical signal detection, together with of research-based improvement in regulatory practice. descriptions of specific situations that should to be taken The six publications related to clinical perspectives refer into consideration when analysing safety data (e.g. paedi- to the use of novel oral anticoagulants, in light of the atric population or ADR reports from consumers). The experience with dabigatran [23–26], information systems Fig. 4 MedDRA System Organ Class distribution for the specific safety issues described in the publications using EudraVigilance data up to 31 December, 2016. Absolute numbers. incl including 670 R. Postigo et al. Fig. 5 Classification of the pharmacovigilance topics analysed using EudraVigilance data up to 31 December, 2016. Absolute numbers. ADRs adverse drug reactions for translational pharmacogenomics [27] and the use of The collaboration with the WHO is also being sodium-glucose co-transporter 2 inhibitors with insulin for strengthened by making available all suspected ADRs the treatment of type 2 diabetes [28]. reported in the EEA to the Uppsala Monitoring Centre and EV has undertaken the pertinent technical and process modifications to achieve this. With the aim of increasing transparency and to facilitate the conduct of safety moni- 3 Changes in Adverse Drug Reaction Reports Management and Access to EudraVigilance toring and research, the level of access to EV has also been Data enhanced. In addition to the full data access provided to the EU regulatory network, MAHs are to have access to the The EU pharmacovigilance legislation adopted in 2010 extent necessary to comply with their pharmacovigilance introduced significant changes in the management of obligations and an appropriate level of access is provided reports of suspected ADRs and placed EV as the single to healthcare professionals and the public while guaran- European hub for ICSR exchange and access. These teeing personal data protection. changes include the submission of patient’s reports, non- The EMA Management Board endorsed a revision of the serious ADRs that occurred in the EU, and ADRs arising EudraVigilance access policy in December 2015 that from all uses of the medicinal products and not only those determines the level of access by stakeholder groups con- restricted to authorised use. sidering the need to protect personal data. This version of In the area of signal detection, EV plays a key role in the access policy takes into account the International determining new risks, new aspects of known risks and Council for Harmonization of Technical Requirements for changes in the benefit-risk balance of medicinal products Pharmaceuticals for Human Use E2B(R3) [30] standard to [2]. This comes with an explicit mandate for the EU reg- determine the level of access for all ICSR data elements. ulatory network and the MAHs to monitor the data in EV. The revision of the access policy categorises stake- During the decision-making process, the Pharmacovigi- holders into six groups incorporating as new stakeholders lance Risk Assessment Committee has a central role in the WHO–Uppsala Monitoring Centre and medicines reg- scientific assessment in relation to signal management, ulatory authorities in third countries (outside the EEA). covering all aspects of risk management. An analysis Nevertheless, the most significant update of the access published to describe signals during the first 18 months of policy is in the level of access, the number of data fields the Pharmacovigilance Risk Assessment Committee con- available, and the availability of new tools to access and firmed the importance of spontaneous reporting in signal analyse the data. Table 1 outlines the access provided and detection [29]. the tools for the different stakeholder groups. EudraVigilance Medicines Safety Database: Publicly Accessible Data 671 Table 1 Level of EudraVigilance access provided by stakeholder group Group Stakeholder Type of cases Access given (summary) Access method I Medicines regulatory authorities in All cases Complete access (Level EVWEB and EEA Member States, the European 3—272 data fields) EVDAS Commission and the EMA II Healthcare professionals and the Spontaneous Aggregated data ADR website public Line listing of individual cases and ICSR form (Level 1—53 data fields) III Marketing authorisation holders EVPM cases Aggregated data with EVDAS statistical output (eRMR) Line listing of individual cases (Level 1—53 data fields) EVPM cases containing suspect/interacting XML file and ICSR form EVWEB substances related to their products (Level 2A—228 data fields) XML file (Level 2B—230 data fields, including the narratives) EVPM cases previously submitted by the Complete access (Level EVWEB specific marketing authorisation holders and 3—272 data fields) medical literature monitoring cases IV Research organisations EVPM cases Level 2A—228 data fields Research request submission to Data format will depend the EMA on the nature of the request V WHO-UMC EVPM cases XML file (level 2C—134 Data transfer data fields) between EMA and WHO- UMC VI Medicines regulatory agencies in EVPM cases Level 2C—134 data fields. Request third countries submission to Data format will depend the EMA on the nature of the request ADR adverse drug reaction, EEA European Economic Area, EDBMS EudraVigilance database management system, EMA European Medicines Agency, eRMR electronic reaction monitoring report, EVDAS EudraVigilance data analysis system, EVPM EudraVigilance post-authorisation module, EVWEB EudraVigilance web application, ICSR individual case safety report, WHO-UMC World Health Organization-Uppsala Mon- itoring Centre The EVWEB is the interface to the EDBMS and allows registered users to create, send and view ICSRs The EVDAS supports European Union pharmacovigilance safety monitoring activities with the main focus on signal detection and evaluation of ICSRs A spontaneous report is an unsolicited communication by a healthcare professional, or consumer to a competent authority, marketing autho- risation holder or other organisation (e.g. regional pharmacovigilance centre, poison control centre) that describes one or more suspected adverse reactions in a patient who was given one or more medicinal products. It does not derive from a study or any organised data collection system [31]. Spontaneous reports are identified in the database by the mandatory field ‘type of report’ provided by the senders at the time of the ICSR submission The EVPM includes cases with type of report ‘spontaneous’, ‘other’ and ‘not available to sender (unknown)’ plus reports from studies (including ‘individual patient use’ and ‘other study’) 4 Research Organisations European interest organisations whose principal objective is to promote scientific and technological cooperation in In the context of EV access, academic research organisa- Europe [32]. Until November 2017, the level of access to EV data provided to academia and research organisations tions should be understood as public or private higher education establishments awarding academic degrees, was limited to the same set of data elements publicly available in the ADR website. This is reflected in some of public or private non-profit research organisations whose the publications that analysed EV data for safety primary mission is to pursue research, and international 672 R. Postigo et al. Aggregated data Research Direct access ADR reports website Data analysis instuon www.adrreports.eu Level 1 (53 data fields) Line lisngs Individual cases data ICSR forms Fig. 6 Access to Level 1 EudraVigilance data by research organisations. ADR adverse drug reaction, ICSR individual case safety report Fig. 7 Access to Level 2A EudraVigilance data by research organisations. EMA European Medicines Agency assessments. The revision of the access policy extends the amongst others, body weight and height, medical and access to data for research to provide the possibility for a family history, past drug history, death details and infor- more thorough analysis of the data, hence contributing to mation concerning the parent for the parent–child reports. the promotion and protection of public health and fostering The reaction section contains ten extra data elements innovation of scientific and medical research. Research including the start and end dates of the reaction and the institutions can directly access level 1 data via the ADR identification of the country where the reaction occurred. website and can also request the EMA level 2A data sets. The drug section includes 49 extra data elements including Figures 6 and 7 provide an overview of how research the product name for non-centrally authorised medicinal institutions can access EV data. products, strength, dates for the first and last drug admin- The data provided in the ADR website include aggregated istration, cumulative dose to first reaction, gestation period information based on numbers of spontaneous cases stratified at the time of exposure and batch/lot numbers. Further- by different parameters (e.g. number of cases by age group, more, the data set contains 13 additional data elements for sex, geographic origin, reactions groups, time distribution). the results of tests and procedures relevant to the investi- From November 2017, the ADR website provides the possi- gation of the patient. To comply with data protection bility to retrieve data for the individual cases based on some requirements, the case narratives, containing free text, are core data elements (level 1) within the ‘patient characteris- not provided to research organisations. tics’, ‘reactions/events’ and ‘drugs information’ sections. To obtain level 2A access, the interested institutions However, the data provided to research institutions upon should submit a request via the EMA website [33](http:// request contain a significant increase in the potential www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/ number of data elements (level 2A) provided and the landing/ask_ema_landing_page.jsp&mid=) with details on access is extended to all cases submitted to the the research methodology, potential impact on public EudraVigilance post-authorisation module, therefore not health, a signed copy of the confidentiality undertaking restricted to spontaneous cases, and includes reports from [32] and a copy of the approval of the research protocol by non-interventional post-authorisation studies. Within the an ethics committee/review body. Following the analysis of patient characteristics section and compared with level 1, the data, researchers should make all possible efforts to level 2A provides 83 extra data elements including, publish the outcomes of the research and for information purposes only, should provide a copy of the articles to the EMA ahead of publication. Non-interventional studies are considered studies where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not 5 Data Protection decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. Non-interventional post- The need to maintain the confidentiality of the identity of authorisation studies are identified in the database by the mandatory individuals in compliance with EU personal data protection fields ‘type of report’ and ‘study type where the reactions events legislation [34, 35] is one of the key drivers of the EV occurred’. EudraVigilance Medicines Safety Database: Publicly Accessible Data 673 access policy and the levels of access have been developed activities during assessments and can provide significant considering data protection in conjunction with the public information when determining causal associations. health needs and pharmacovigilance obligations for the At the same time as the new access is in place, the different stakeholders. Users of EV should comply with the International Council for Harmonization of Technical data protection requirements and should have appropriate Requirements for Pharmaceuticals for Human Use measures in place to protect the information [32]. E2B(R3) standard is implemented in EV with the subse- In this context, it is especially important to avoid the quent advantages derived from the new data structure and identification of individual patients from the data available data elements. These will bring advantages for data anal- in the ADR website published by the EMA. Level 1 access ysis (e.g. in the old format, seriousness criteria are reported is based on this principle while providing meaningful at the level of the case whereas these are reported at the information on suspected ADR reports. Table 2 outlines level of the individual reactions in the new format). Safety additional measures taken in the ADR website to avoid the assessors should be well aware of the differences between identification of individual patients. the old and the new format when analysing the data. The enhanced access to the data is also expected to trigger more engagement with academia. Up to November 6 Discussion 2017, the information from EV publicly available could have been considered acceptable for patient use but not Particularly since 2011, there has been a constant increase optimally for research purposes [36]. The extended access in the number of research publications that considered data provides research institutions with a rich data source and from EV and this likely reflects the growing recognition of there is therefore a unique opportunity to conduct research how the database can contribute to drug safety. The sus- for public health. pected ADR data in EV have provided a foundation to identify safety signals and characterise risks. Furthermore, the data have allowed the investigation of new method- 7 Conclusion ologies for signal detection as well as specific situations such as paediatrics, vaccines, pandemics, consumer reports Pharmacovigilance is an essential discipline for the pro- and traceability of biological products. motion and protection of patient and public health. In the In 2016, Fouretier et al. [36] performed an analysis of 11 EEA, the EU regulatory network formed by the European pharmacovigilance databases with open access to charac- Commission, the NCAs and the EMA has a key role terise the accessibility of the relevant data in those systems. together with the MAHs on the safety surveillance on In their study, the EV access was considered to be ‘med- medicinal products. ium’, mainly based on the fact that EV did not provide The EU legislation places the EV database in a core role public access at the level of the individual cases in the in the management of reports of suspected adverse reac- ADR website. This assessment and the perception of EV tions and in determining changes in the safety profile of the will change drastically with the recent implementation of medicinal products once they are used in everyday medical the new access specified in the revised access policy. practice. For over 16 years, EV has demonstrated its value The main implication for MAHs following the release of especially in the area of signal detection, providing a tool the new EV system and extended access is the obligation to to analyse the safety data submitted. monitor the data for their substances and products. The Although EV has been fully accessible to the EMA and extended access provided at the level of the substance the NCAs in the countries that belong to the EEA, the brings the opportunity for MAHs to fully assess the data access provided in the past to other stakeholders has been and provides greater transparency during assessment and more limited. The new extended EV access provides a decision making. The applied statistical analysis follows an unique platform for all stakeholders to use the data evidence-based methodology [22] and this provides a according to their needs, interest and pharmacovigilance common understanding about how statistical signal detec- obligations. This enhanced access brings opportunities for tion has been implemented in EV. a broader involvement in safety monitoring, for increased Apart from the power demonstrated by statistical transparency, for collective collaborations, for methods methods within large spontaneous reporting systems [37], improvement and for innovation in safety research. statistical signal detection should be complemented by We call on patients, healthcare professionals, MAHs, scientific assessment and medical judgement, taking into research institutions, the WHO, non-EEA regulatory consideration what is known about the product. The authorities, NCAs in the EEA Members States and the detailed analysis of individual cases remains one of the key EMA to embrace the opportunities provided by the new EudraVigilance system to be better informed, to better 674 R. Postigo et al. Table 2 Adverse drug reaction website: additional measures for data protection Measures The information provided in the 53 data elements (level 1 access) individually or in combination would not lead to the identification of individual patients, for instance, date of birth, or free text fields are not provided Within the details of the individual cases, the country where the reaction occurred is not provided. The ‘country’ data field is displayed as EEA or non-EEA. This is to prevent the identification of patients where there are a small number of cases per country The product name for non-centrally authorised medicinal products is replaced by the substance name. Product names can potentially lead to the identification of the country where the reaction occurred The Worldwide Case Identification Number is replaced by the EV local report number as the country code is normally included in the Worldwide Case Identification Number The sender organisation is displayed as ‘EEA regulator’ for cases submitted by regulatory authorities from the EEA to avoid the identification of the country A threshold is applied if the number of individual cases available for a specific country is less or equal to 3. In this instance, the total number of cases for the specific country is not provided to reduce the risk of patient or reporter identification EEA European Economic Area, EV EudraVigilance 2. European Commission. Directive 2001/83/EC of the European manage product risks, to better understand the science of Parliament and of the Council of 6 November 2001 on the pharmacovigilance and, ultimately, to better promote Community code relating to medicinal products for human use. public health. https://ec.europa.eu/health/documents/eudralex/vol-1_en. Acces- sed 31 Jan 2018. Acknowledgements The authors gratefully acknowledge the contri- 3. European Commission. Regulation (EC) No. 726/2004 of the bution made by Luis Pinheiro. European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervi- Compliance with Ethical Standards sion of medicinal products for human and veterinary use and establishing a European Medicines Agency. https://ec.europa.eu/ Funding No sources of funding were received for the preparation of health/documents/eudralex/vol-1_en. Accessed 31 Jan 2018. this review. 4. European Commission. 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Drug SafetySpringer Journals

Published: Mar 9, 2018

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