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Drug Saf
Drug Saf
Drug Safety
0114-5916
1179-1942
Springer International Publishing Cham

38987419
1451
10.1007/s40264-024-01451-3
Review Article
The STAR Compass to Guide Future Pharmacovigilance Based on a 10-Year Review of the Strengthened EU System
http://orcid.org/0000-0002-7798-6117
Bahri Priya priya.bahri@ema.europa.eu

1
Genov Georgy 1
Arlett Peter 1
Šarinić Viola Macolić 1
Korakianiti Evdokia 1
Nolte Alexis 1
Huber Martin 23
Straus Sabine M. J. M. 34
1 https://ror.org/01z0wsw92 grid.452397.e European Medicines Agency (EMA), Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
2 https://ror.org/05ex5vz81 grid.414802.b 0000 0000 9599 0422 Federal Institute for Drugs and Medical Devices, Bonn, Germany
3 grid.452397.e EMA Pharmacovigilance and Risk Assessment Committee, Amsterdam, The Netherlands
4 https://ror.org/05mv4rb84 grid.491235.8 0000 0004 0465 5952 Medicines Evaluation Board, Utrecht, The Netherlands
10 7 2024
10 7 2024
2024
47 10 941956
29 5 2024
© The Author(s) 2024
2024
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This article reflects on the 2010 pharmacovigilance legislation of the European Union (EU). Its legislative aim of better patient and public health protection through new responsibilities for pharmaceutical companies and regulatory bodies is considered to have been achieved and is well supported by the good pharmacovigilance practices ‘EU-GVP’. For future progress, we set out a vision for high-quality pharmacovigilance in a world of ongoing medical, technological and social changes. To deliver this vision, four principles are proposed to guide actions for further progressing the EU pharmacovigilance system: synergistic interactions with healthcare systems; trustworthy evidence for regulatory decisions; adaptive process efficiency; and readiness for emergency situations (the ‘STAR principles’). Like a compass, these principles should guide actions for building capacity, technology and methods; improving regulatory processes; and expanding policies, frameworks and research agendas. Fit for the future, the EU system should achieve further improved outputs in terms of safe, effective and trusted use of medicines and positive health outcomes within patient-centred healthcare.

issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcKey Points

Four principles are suggested to further progress pharmacovigilance in the European Union (EU) and achieve better outputs in terms of safe, effective and trusted use of medicines and positive health outcomes within patient-centred healthcare	
These principles should guide actions for system improvements through addressing challenges and using opportunities that arise from the ongoing medical, technological and social changes our world is facing	
The suggestions are a result of an in-depth review of data and of insights into the regulatory pharmacovigilance system of the EU, 10 years after its current legal basis became applicable in 2012	

Introduction and Objective

The year 2022 marked the 10th anniversary of the coming into application of legislation that profoundly changed and strengthened pharmacovigilance in the European Union (EU) [1, 2]. Since then, we have observed multiple drivers for change of a global and interdependent nature, which have been accelerated during the SARS-CoV-2 coronavirus disease (COVID-19) pandemic and now require adapted medicines regulatory strategies. In particular, these drivers concern the following.Health and healthcare, including:

changing patterns in burden of disease and health challenges, new diagnostic methods, innovative platforms for medicines, personalised medicines, increasing patient-centred, home-based and virtual delivery of healthcare.

Data and media technology, including:

ongoing digitalisation of daily life and healthcare with real-world data collection, new methods for data analytics and evidence generation, artificial intelligence, changes in news and social media platforms, information-seeking and interactive behaviours, misinformation and disinformation threats.

Societal developments, including:

increasing self-organisation of people in virtual networks, varying levels of trust in governments and science, increasing expectations and demands of people for participation in health policy and decision making and evidence generation with patient-reported outcome and patient experience data.

Economic and environmental issues, including:

existing global economic and social inequalities, geopolitical challenges, climate change, growing interdependence across areas and regions, which also impact on supply of medicines and access to healthcare and medicines.

Public health emergencies, including:

emergencies arising from the above changes or from humanitarian or political crises, specific issues such as antimicrobial resistance, infectious diseases and substance use disorders [3–13].

The 10-year anniversary of the operation of the 2010 legislation stimulated us to review and reflect on its implementation and impact, with the objective to provide, from an EU regulators’ viewpoint, a vision and principles to guide actions for further progressing high-quality pharmacovigilance in our changing world.

We want to share the reflections and guiding principles with all stakeholders of EU pharmacovigilance and consider that these may also be of global interest, given that the EU system has become a model for many jurisdictions around the world.

The 2010 European Union (EU) Pharmacovigilance Legislation

The 2010 legislation changed pharmacovigilance in the EU profoundly. Motivated by estimates at the time that about 5% of all hospital admissions and almost 200,000 deaths yearly in the EU were due to an adverse reaction to a medicine, the European Commission set as its legislative aim to strengthen and rationalise EU pharmacovigilance at regulatory and industry level [14]. As medicines use constitutes a high proportion of therapeutic interventions, pharmacovigilance and its risk management are essential for the protection of patient and public health. Pharmacovigilance spans from the pre- to post-authorisation phase of medicines and hence overcomes the limitations of the safety database established from pre-authorisation clinical trials by collecting and assessing data from diverse patient populations in everyday healthcare.

The EU medicines regulatory networks comprises the competent authorities (regulatory bodies) of the EU Member States, the European Medicines Agency (EMA) and the European Commission. Member States have been operating national pharmacovigilance systems since the 1960s, with the first EU Pharmaceutical Directive of 1965 as a common framework with requirements for quality, safety and efficacy for granting and maintaining marketing authorisations [15, 16]. In 1995, the EU regulatory pharmacovigilance system was established under the coordination of the then new EMA [17, 18]. Over the following years, adjustments to the legislation included a risk management approach to more proactively identify and minimise risks with medicines [19–22].

In 2004, the European Commission initiated a study into the EU pharmacovigilance system [23], conducted public consultations and an impact assessment, and considered recommendations from the ‘EU Risk Management Strategy’ (ERMS; a leadership group of the EU regulatory pharmacovigilance system) [24] and from patient representatives at EMA [25]. At the time, a particular need was to create a system that would also function robustly and efficiently after the EU enlargements in 2004, 2007 and 2013, which almost doubled the number of Member States (now 27). Prepared with this comprehensive multistakeholder input, the 2010 legislation was adopted. In 2012, an Implementing Regulation was added for technical and operational details [26]. The specific objectives of the 2010 legislation can be summarised as:strengthen regulation of medicines in the post-authorisation phase;

strengthen the evidence-base for safety-related regulatory action;

strengthen quality and efficiency of pharmacovigilance;

strengthen transparency, communication, stakeholder engagement and international collaboration for pharmacovigilance purposes [14, 27].

An overview of how the EU regulatory pharmacovigilance system works under the 2010 legislation was published [28], as well as a review of the first 18 months of operation. This review demonstrated more systematic and proportionate risk management planning, greater coordination of real-time safety signal management, and faster risk assessment, decision making and updates to product information. It also looked forward to implementing all new legal provisions for efficiency gains and resource reallocation to increase the delivery of the legislative objectives [29]. From 2013 to 2016, the Member States’ regulatory bodies came together under their project ‘Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action’ to obtain an overview of how the national pharmacovigilance systems met their new requirements and to develop training, best practice tools and collaborative working practices for increasing capacity [30]. The EU regulatory network has closely monitored the implementation, impact and utility of the new legislation through 3-yearly assessments of the evolving system, with the latest assessment published in 2023 [31–33].

Reflections on the 2010 EU Pharmacovigilance Legal Provisions

Our reflections relate to the contributions of key legal provisions in fulfilling the specific legislative objectives. They are based on our observations and insights as some of the EU regulators closest to the design, implementation and monitoring of the legislation, based on data from the regular EU system assessments and the SCOPE Joint Action, as well as results from studies conducted by EMA and others over the first 10 years of operation. They also take into account the experiences with the safety surveillance for vaccines and therapeutics against COVID-19 (see Table 1 for this analysis).Table 1 Reflections on key provisions of the 2010 EU legislation on pharmacovigilance

Objective: Strengthen regulation of medicines in the post-authorisation phase	
Central role of PRAC in medicines safety

Legal provisions: The 2010 legislation established the PRAC as a new scientific committee at EMA, replacing the previous PhVWP, which had no explicit legal basis and no power to issue legally binding recommendations. PRAC has a central role in EU pharmacovigilance, regulating medicines safety with the mandate for issuing recommendations to the CHMP at EMA and the competent authorities in Member States for legally binding safety action on medicines across the EU [55]

Reflections: A review of the first 18 months of PRAC operations demonstrated positive results in terms of more systematic and proportionate risk management planning, greater coordination of real-time signal management, and faster risk assessment, decision making and updates to product information [29]. This trend of success has continued, and PRAC now addresses around 2000 agenda items per year. From 2012 to 2022, PRAC assessed 5954 RMPs for new and existing medicines, 7479 PSURs, 751 signals of potential new risks or new aspects to known risks, 69 safety concerns subject to referral procedures, 1841 protocols and 829 reports of PASS, and safety data for a total of 1377 renewal or conditional renewal applications or annual reassessments (calculated by summing up annual figures)

	
Legally binding nature of PRAC recommendations across the EU

Legal provision: A crucial novelty from the 2010 legislation has been the legally binding nature of PRAC recommendations for NAPs, resulting from procedures such as referrals, signals and PSUSAs

Reflections: This has ensured that updates to the terms of marketing authorisation and product information and other regulatory actions for NAPs are implemented rapidly and consistently across all Member States. Since 1995, EMA has had a key role for medicines authorised centrally by the European Commission for the entire EU (CAPs), while EMA’s role for NAPs authorised by Member States has grown slowly over time. In November 2009, just as the 2010 legislation was under final drafting, the prominent withdrawal of benfluorex (Mediator) in France [56] triggered an analysis by EMA as to whether the new legislation would prevent delayed regulatory action for NAPs. This analysis concluded that by means of the various new legal provisions (regarding signals with legally binding PRAC recommendations; triggers for referral procedures; and PASS that could be imposed by PRAC on marketing authorisation holders also for NAPs) safety concerns for NAPs would be dealt with in a quicker and more stringent manner by PRAC and benefit from the new strength of the system at EU level. Nevertheless, the EC adopted additional legislation in 2012 to clarify and strengthen provisions, in particular for referral procedures [57]. Despite successful and timely conduct of the procedures for NAPs by PRAC, we consider that the regulatory implementation of PRAC recommendations from PSUR assessments could be further streamlined at national level for fast updates to the terms of marketing authorisation consistently in all Member States

	
Proactive risk management

Legal provision: The 2010 legislation demands that all applications for new marketing authorisations include an RMP that proposes safety data collection and risk minimisation in the post-authorisation phase

Reflections: From 2012 to 2022, PRAC assessed 5954 RMPs. However, it was an immediate outcome of the 2010 legislation that a high number of RMPs, around 98,000, were submitted to the competent authorities in Member States for NAPs, including generic medicines. This legal provision aimed to strengthen the proactivity of pharmacovigilance in terms of evidence generation and advice on safe use. While this is important for new innovative medicines, the need for RMPs for new generic medicines where the innovator product does not carry a safety concern in its RMP has been debated within the EU regulatory network as creating administrative burden with minimal improvement in pharmacovigilance

	
Objective: Strengthen the evidence-base for safety-related regulatory action	
Collecting reports of suspected adverse reactions from any use of medicines

Legal provision: Definitions in the 2010 legislation were changed to include in the concept of adverse reaction those adverse events that may be due to overdose. Furthermore, those that may be due to medication errors, off-label use, misuse, abuse, or occupational exposure to medicines were included, following the new legal text that adverse reactions may arise from use of the medicinal product within or outside the terms of the marketing authorisation or from occupational exposure

Reflections: These changes were in line with international agreements to which the EU had contributed [58]. By this broadening of the adverse reaction concept, the scope of pharmacovigilance activities was broadened too, thereby ensuring that onward reporting by marketing authorisation holders and actions to protect patient and public health cover the full range of situations with medicines use. PRAC issued a specific guide on the recording, coding, reporting and assessment of medication errors in 2015 [59]

	
Collecting reports of suspected serious and non-serious adverse reactions

Legal provision: All suspected adverse reactions reported from the EU, including non-serious reactions as a specific new requirement under the 2010 legislation, and all serious suspected adverse reactions reported from outside the EU must be submitted by marketing authorisation holders and competent authorities in Member States, within strict legally binding time frames, to EudraVigilance, the EU database and analytics system for ICSRs

Reflections: As a result of these requirements, the broadened adverse reaction concept and direct patient reporting, as well as due to newly authorised medicines, the number of ICSRs in EudraVigilance has been increasing steadily, e.g. by 19% in 2017 from around 1.2 to nearly 1.5 million ICSRs, and by a further 37% in 2018 to over 2 million ICSRs, about half of which came from the EEA (EU + Norway, Iceland and Liechtenstein). Looking at serious reactions alone, these ICSRs also increased from around 1.1 million in 2015 (290,000 from the EEA) to about 1.4 million in 2018 (425,000 from the EEA), and the upward trend continued, with a peak in 2021 due to ICSRs for COVID-19 vaccines [32–34]. Areas for improvement identified from the safety surveillance of COVID-19 vaccines include the need for better and consistent data collection across Member States (e.g. on stratified exposure) to support signal assessment in all population groups, risk contextualisation as well as safety communication [60]

	
Collecting reports of suspected adverse reactions directly from patients

Legal provision The 2010 legislation ensured that patients in all Member States can report suspected adverse reactions to the national spontaneous reporting system directly, i.e. without the need to ask their healthcare professional to report

Reflections This has empowered patients to engage in safety surveillance, and a remarkable increase of ICSRs directly from EU patients was observed in EudraVigilance shortly after the EU-wide implementation of the provisions, with 39,247 ICSRs in 2014 and a steady increase to 244,162 in 2018, 223,253 in 2019 and 200,733 in 2020 [32–34]. For COVID-19 vaccines, more than half of ICSRs came directly from patients, and the roll-out of these vaccines led direct EU patient reporting to a total of 850,923 in 2021 and 702,643 in 2022 [34]. Direct patient reporting has made spontaneous reporting more comprehensive, e.g. in relation to the impact of adverse reactions on patients and the potential for medication errors, and detected some signals more quickly. The growing number of ICSRs directly from patients suggests that the 2010 legislation impacted positively on patient involvement and empowerment [61–63]. The SCOPE Joint Action has offered a mutual learning opportunity for Member States and developed tools and strategies to improve their national spontaneous reporting systems and increase the quantity and quality of reports, including by means of web-based reporting forms and an EU-wide awareness campaign via social media in 2016 [30]

	
Additional monitoring status for increasing spontaneous reporting

Legal provision: To increase spontaneous reporting of suspected adverse reactions by both patients and healthcare professionals, the 2010 legislation introduced, mainly for recently authorised medicines, a black triangle symbol in the product information with text explaining that this product is under additional monitoring and all suspected adverse reactions should be reported

Reflections: Reviews have not demonstrated an added value in terms of increasing spontaneous reporting [64–68]

	
Revised benefit-risk scope of PSURs

Legal provision: The 2010 legislation enlarged the scope of PSURs for a more purposeful analysis of the overall benefit-risk balance, based on all data on safety, efficacy and effectiveness

Reflections: PSURs have traditionally had a strong role in safety surveillance, both for new medicinal products for which PSURs are submitted 6- and 12-monthly and for older products for which PSURs cover longer time periods in a risk-proportionate manner. Enlargement of the PSUR scope by means of the 2010 legislation has shown utility for CAPs and, during the efficient active substance-based PSUSA procedures, for NAPs. From 2012 to 2014, only CAP PSURs and CAP+NAP PSURs in PSUSA procedures were assessed by PRAC (876 PSURs/PSUSAs in total), while NAP PSURs continued to be assessed at a national level and through the previous Member States’ PSUR work sharing framework. In 2015, PRAC also took over NAP PSUSAs (2015–2022, 6540 CAP/CAP+NAP/NAP PSURs/PSUSAs in total, of which about one-third have been NAP PSUSAs). This was underpinned by best practice guidance and training modules developed by the SCOPE Joint Action, to support competent authorities in Member States in strengthening continued benefit-risk assessment of medicines through systematic approaches and methods applications [30]. However, the quality of PSURs submitted by marketing authorisation holders has not always been optimal; in particular, data on benefits and risks have not always been integrated in the PSURs appropriately. In addition, exposure data for the whole EU or Member States were included in <50% of PSURs, and 13% did not contain any EU or global exposure data at all, although including a type of exposure data is legally required in PSURs [69]. For the safety surveillance of COVID-19 vaccines, PSURs have been complemented in a flexible manner by monthly summary safety reports during the first months of marketing, to support timely and continuous benefit-risk evaluations for these new vaccines used widely during the pandemic

	
Data collection through post-authorisation studies, including on RMM

Legal provision: A further key addition of the 2010 legislation was the EU-harmonised regulatory supervision of non-interventional PASS together with the new legal power to impose PASS, as well as PAES, on marketing authorisation holders

Reflections: The EU regulatory network has not yet used to full extent its powers to impose evidence generation through PASS, and instead tended to include many PASS in the RMP at a reduced level of regulatory oversight and enforceability. Furthermore, feasibility assessments should improve study designs and conclusiveness of results. PASS include studies evaluating RMM, and in this respect, PRAC is particularly concerned over limited robustness of evidence. More than half of the PASS for RMM evaluation submitted by marketing authorisation holders to PRAC between 2016 and 2019 had methodological issues and were therefore inconclusive [70]. Furthermore, major shortcomings in the marketing authorisation holders’ PASS reports have been identified with regard to describing the theoretical and practical bases of the RMM design in terms of target populations, their information needs and the steps taken to support the implementation of RMM in healthcare [71]. PAES have only been imposed in specific cases, e.g. for marketing authorisations under exceptional circumstances. However, requesting PAES more frequently to understand which patients may benefit most from a medicine, including special populations and patients using the medicine long-term, would improve the evaluation of the benefit-risk balance in the post-authorisation phase. In addition to studies conducted by marketing authorisation holders, we consider that targeted regulator-initiated RWE studies should complement the evidence available on benefits, risks and use of medicines, as well as RMM

	
Objective: Strengthen the quality and efficiency of pharmacovigilance processes	
Quality management of pharmacovigilance systems

Legal provision: The 2010 legislation underpinned quality management of pharmacovigilance systems of marketing authorisation holders, competent authorities in Member States, and EMA specifically for resource management in relation to capacity and sufficiency, compliance management with process requirements, record management, and system audits

Reflections: EU-GVP elaborates these requirements by applying the 9001-2008 ISO Standards [72] and defines seven quality principles adapted from this standard for marketing authorisation holders and regulatory bodies: (1) meeting needs of patients, healthcare professionals and the public; (2) providing managerial leadership for quality; (3) involvement of all persons within an organisation with assigned responsibilities; (4) following a quality cycle for improvements; (5) organising structures and processes for proactive, risk proportionate, continuous and integrated conduct of pharmacovigilance; (6) considering all available evidence on the benefit-risk balance for decision making on a medicine; and (7) fostering good cooperation between all parties [38]. EU-GVP has fostered a systems approach to pharmacovigilance that is considered of fundamental importance for high-quality and efficient performance. EMA developed its pharmacovigilance quality management system accordingly. To support quality management at competent authorities in Member States, the SCOPE Joint Action developed a toolkit and training modules [30]

	
Pharmacovigilance inspections

Legal provision: The 2010 legislation formalised the conduct of pharmacovigilance inspections which determine and facilitate the marketing authorisation holders’ compliance with their obligations

Reflections: The inspections are conducted by competent authorities in Member States in cooperation with EMA according to a risk-based programme. The quality management toolkit developed by the SCOPE Joint Action includes specific guidance for inspectors, especially on their information exchange with assessors [30]. Most inspections of marketing authorisation holders are announced, but it may be appropriate to conduct unannounced inspections or to announce an inspection at short notice. On average, around 500 inspections per year have been conducted under the national pharmacovigilance inspection programmes and around 10 inspections per year have been requested by PRAC/CHMP. During the lockdowns and travel restrictions due to the COVID-19 pandemic in 2020 and 2021, inspections continued, mostly conducted virtually

	
Work sharing of the EU pharmacovigilance regulatory system

Legal provision: For efficiency, mechanisms for work sharing between Member States and a framework for shared use of resources with central coordination by EMA (including maintenance of central databases) and a prominent role of PRAC have been formalised or newly installed through the 2010 legislation

Reflections: These work sharing mechanisms include the PSUSA procedure for the EU single assessment of PSURs for medicinal products containing the same active substance and authorised in more than one Member State. This has been facilitated by a common EU PSUR repository established by EMA. Furthermore, data and signal management benefit from work sharing schemes. In addition, harmonisation of safety concerns listings in RMPs for NAPs for which data exclusivity has expired has been initiated by CMDh [73]

	
Data management

Legal provision: Since November 2017, in accordance with the 2010 legislation, EudraVigilance is the single point in the EU for collecting reports of suspected adverse reactions, which centralised and hence simplified previous ICSR submissions to each Member State. New responsibilities for EMA under the 2010 legislation include central monitoring of selected scientific literature sources and entering of suspected adverse reactions reported in the literature into EudraVigilance, as well as central provision of EU ICSR information to the VigiBase database of the pharmacovigilance programme of WHO, replacing previous national processes. Furthermore, EMA now has legal responsibilities to set up and maintain a PSUR repository, a register for post-authorisation studies and a database of medicinal products authorised in the EU centrally or nationally

Reflections: EMA established the EudraVigilance database and data analytics system for ICSRs in 2001 and now maintains a range of further databases: PSURs are now centrally submitted and stored in the EU PSUR repository; information on all EU medicinal products is submitted and stored in the public Article 57 database; and PASS/PAES records are available in a public online register. These databases and the simplifications resulting from the central literature monitoring for suspected adverse reactions and the central information provision for EU ICSRs to WHO have brought major efficiency gains for the EU pharmacovigilance system regarding data management. However, while the central literature monitoring has been a successful service from EMA, it necessitated change and resources from marketing authorisation holders, particularly at the time of implementation, which in the short term, likely increased administrative burden before delivering the longer-term benefit for signal detection and evaluation from reduced duplicate reports in EudraVigilance. It is foreseen that increasingly artificial intelligence tools can support pharmacovigilance data activities, such as managing PASS, PAES, ICSRs and signal detection [74, 75]

	
Signal management

Legal provision: Based on the 2010 legislation, signal management has been organised with a new process involving PRAC, coordinated across the EU and supported with analytics functions at EMA for PRAC signal assessments

Reflections: For CAPs, EMA monitors ICSRs in EudraVigilance and data from the scientific literature. For NAPs, 1873 active substances or fixed combinations thereof are currently monitored under the work sharing scheme between competent authorities in Member States. A study on EMA’s experience with the new signal process during the first 6 years (2012–2018) concluded positively on the process delivery, with the review of 26,000 potential signals resulting in 453 signals assessed by PRAC, of which about half warranted product information updates (including 17 via a referral procedure) [50]. Between 2012 and 2021, PRAC conducted more than 700 signal procedures, of which more than half led to changes in the product information or other regulatory action. PRAC issued such legally binding recommendations promptly for both CAPs and NAPs, to be published by EMA and translated by the competent authorities in Member States for fast and harmonised implementation. The signal procedure is a more agile approach in comparison with a referral procedure and has allowed for faster updating of product information, whenever a referral procedure for a broader benefit-risk assessment and greater stakeholder involvement was not warranted. Where this, as well as requests for further data analyses and RMM proposals from marketing authorisation holder(s), was judged to be warranted, signal assessments have led to the initiation of a referral. Methodological improvements, such as statistical algorithms for timeliness of signal detection, have evolved over time, supported by an expert and stakeholder group [76] and the PRAC SMART Working Group [50]. The SMART Working Group also acknowledges the importance of the work of the SCOPE Joint Action. The SCOPE Joint Action had identified challenges, such as the terminology used in the national signal management processes and leading to complexities in the interpretation and implementation of the existing legislation, as well as the need for data sources, resources and training [30]. In 2016, the SCOPE Joint Action developed a best practice guide and training modules to address these challenges. This guide also identified benefits of heterogenicity in signal management processes between Member States, allowing for processes that are efficient for the given national database and for complimentary signal detection across the EU [77]. The EU regulatory signal management system underwent a major stress test with the application of an enhanced toolkit for the safety surveillance of COVID-19 vaccines [60], given rapid vaccine deployment in large populations resulting in almost 1 million EU cases of suspected adverse reactions submitted to EudraVigilance for more than 700 million vaccine doses administered in 2021 (for all medicinal products, EudraVigilance contained almost 13 million ICSRs). This stress test clearly demonstrated the efficiency of the EU signal management process. This was recognised worldwide [78] when a signal for a very rare condition, later termed TTS, was detected for the COVID-19 vaccine Vaxzevria, and the risk was identified quickly with the help of further academic research and an observed-versus-expected events analysis of EudraVigilance data performed jointly by EMA and PRAC. With this, regulatory action, following early communication, could be taken within less than 1 month for Vaxzevria and, prior to deployment, for Jcovden, a similar COVID-19 vaccine. The update of the product information included advice for early detection and management of TTS [79, 80]. Spontaneous reporting of suspected adverse reactions remains the most common source for signals, and their detection and assessment belongs to the essential processes of pharmacovigilance. Hence, the introduction of a signal management process for evidence-based and efficient regulatory decision making at EU level is a key success of the 2010 legislation. Regarding the utility of mandating ICSR submission for non-serious reactions, a study at EMA demonstrated a small increase in the sensitivity of routine statistical signal detection without affecting its efficiency, as well as a small impact with some new signals of disproportionate reporting detected and some disappearing when including reports of non-serious reactions in the calculations. These discordant signals of disproportionate reporting had specific characteristics with respect to the type of medicinal products and adverse event profiles, which will require a future study on utility and impact with longer-term data [81]

	
Evaluation of the effectiveness of RMM

Legal provision: The 2010 legislation introduced responsibilities for both marketing authorisation holders and the EU regulatory network to monitor outcomes of RMM

Reflections: In 2017, PRAC established their Strategy on Measuring the Impact of Pharmacovigilance Activities (‘PRAC Impact Strategy’) for systematically evaluating outcomes of major regulatory interventions, including intended and unintended effects of RMM [34]. As a positive consequence, PASS evaluating RMM have been requested from marketing authorisation holders (79 PASS 2016–2020), and since 2017, EMA has commissioned studies to investigate wider issues with RMM using RWE (13 studies finalised by the end of 2022) [82]. However, PRAC remains concerned over limitations of RMM effectiveness. Most prominently, RMM imposed for valproate in 2014 did not reach patients and led to a second referral procedure in 2017/2018 resulting in a new RMM programme. A systematic literature review at EMA in 2018 found 229 studies evaluating regulatory safety action taken inside or outside the EU and concluded that effects of regulatory safety actions remain largely unquantified, that unintended consequences were rarely evaluated and that there was a lack of robustly applied methods [83]. The 2010 legal provisions for evaluating RMM continue to be highly important for improving RMM and closing the pharmacovigilance quality cycle. Challenges for the effectiveness of RMM are seen specifically in the implementation of RMM in the various healthcare systems of Member States. The PRAC recommendations therefore allow competent authorities in Member States to facilitate implementation with adaptations of RMM in line with the local requirements and opportunities. The evaluation of RMM effectiveness needs to take this into account for appropriate outcome measurements in the applicable healthcare settings and populations

	
Objective: Strengthen transparency, communication, stakeholder engagement and international collaboration for pharmacovigilance purposes	
Patient and healthcare professional members of PRAC

Legal provision: Following successful pilot observership of patient representatives at the previous PhVWP, the 2010 legislation established PRAC with a member and an alternate each from the patient and healthcare professional communities

Reflections: This has been a major opportunity for PRAC to consider practices, experiences and perspectives from everyday life and healthcare. However, the volunteering patient and healthcare representatives have voiced challenges with contributing to all topics discussed at PRAC within the short procedural timeframes. To foster further trustful engagement between PRAC and patient and healthcare professional communities, key discussions at PRAC and their outcomes are regularly presented to the EMA Patients’ and Consumers’ as well as the Healthcare Professionals’ Working Party

	
Public hearings and other engagement events

Legal provision: The 2010 legislation has provided PRAC with the option to call a public hearing

Reflections: Thus far, there have been two hearings, one in 2017 on valproate and congenital and developmental disorders after in utero exposure, and one in 2018 on quinolone and fluoroquinolone antibiotics and persistent adverse reactions. Both hearings informed PRAC discussions and outcomes. The hearing on valproate was specifically instrumental for deciding on a pregnancy prevention programme for risk minimisation that includes regular counselling of women on the risks and family planning for their informed choices [84, 85]. The success of this small number of public hearings warrants systematic consideration of using hearings for safety issues. Therefore, EMA now supports PRAC for each referral procedure with an analysis of the nature and impact of the potential risk and regulatory actions and of stakeholder interests with a view to the utility of a possible public hearing. PRAC also has other options for stakeholder engagement, such as written consultations, scientific advisory groups and dedicated meetings with clinical experts and targeted stakeholders. Between 2015 and 2019, PRAC initiated 130 engagement events for 71 medicinal products. The majority of these events were written consultations, mostly for the review of draft safety communication documents, while 22 events involved deeper forms of engagement with in-person interactions. These included invitations to patient and healthcare professional representatives to expert meetings on safety concerns. EMA analysed past key engagement events with applying a risk governance framework, to establish a systematic approach to organising public hearings and other forms of engagement as most appropriate for different risk scenarios. Public hearings are particularly warranted in scenarios where risks and RMM are subject to different or even opposed perspectives across different patient and healthcare professional groups [86]

	
Engagement for risk minimisation

Legal provision: The 2010 legislation introduced responsibilities for both marketing authorisation holders and the EU regulatory network to consider options for risk minimisation and prevention and take appropriate RMM as necessary

Reflections: Besides research results and concerns about limitations in RMM effectiveness, target populations might even not be aware of additional RMM materials; e.g. the SCOPE Joint Action found an awareness among general practitioners of below 64% [30]. Therefore, one of the PRAC Impact Strategy’s deliverable is a process for stronger involvement of patients and healthcare professionals with regard to RMM, with the goal to consider RMM options prior to decision making with stakeholder input and increase RMM effectiveness. For this purpose, conceptual work resulting in defining engagement for pharmacovigilance purposes and delineating its dimensions of breadth, width and texture was undertaken [87], as well as reviews into the modalities and utility of public hearings and other stakeholder engagement options applying implementation and risk governance theories. From this, pilotable recommendations have been derived to guide PRAC in their commitment towards more systematic, deepened and tailored engagement practices and a dialogue with stakeholders that focuses on enabling factors of RMM implementation in healthcare, to inform decisions on RMM and the monitoring of RMM implementation and effects [85, 86]. An approach for participatory and multidisciplinary research into risk communication across the various interlinked patient, healthcare and public settings for formative and evaluative purposes has been proposed, also with a view to improving RMM [88]

	
Transparency

Legal provision: The 2010 legislation demanded that PRAC membership, agendas, recommendations and minutes are published, and introduced significant changes in the way reports of suspected adverse reactions collected in EudraVigilance are provided to the public on a dedicated EMA website [89]

Reflections: As a consequence of this, transparency operations were moved to higher levels, with EMA dedicating major resources. The public Article 57 database on medicinal products authorised in the EU and the public online register for PASS/PAES records (which marketing authorisation holders are required to use for making information on their studies and the results available to the public) add further to transparency. This high level of transparency is now recognised in global comparisons [90]

	
Communication

Legal provision: The 2010 legislation mandated from EMA, in collaboration with Member States and the European Comission and in consultation with stakeholders, to set up and maintain a webportal for disseminating information on medicinal products authorised in the EU, including specific pharmacovigilance information. It also mandated that each Member State sets up and maintains a national medicines webportal that shall be linked to EMA’s webportal

Reflections: To fulfil this mandate, EMA enhanced its website. Communication to increase public understanding of risks with medicines, trust in the regulatory system and safe medicines use by patients and healthcare professionals has been a major commitment by EMA. In addition, the legally demanded transparency had to be supported by effective communication, as per experts’ advice [91], because technical documents, e.g. PRAC minutes, are not designed for communication with the public. EMA’s communication teams therefore provide a range of document types tailored for patients, healthcare professionals and journalists, e.g. medicines overviews in all EU languages with generally understandable terms and the PRAC Highlights reporting from each PRAC meeting. EMA also collaborates with Member States for coordinating consistent information to the public from the EU regulatory network at national and EU level, which recognises the crucial role competent authorities in Member States have in interacting with patients and healthcare professionals. A media content analysis performed by EMA during an assessment in 2015 for human papilloma-virus vaccines identified the need to inform the public about safety surveillance methods and risk governance policies, in addition to safety concerns and assessment outcomes [92]. Best practice guidance on risk communication for competent authorities in Member States was developed by the SCOPE Joint Action, building on its multidisciplinary collaboration and findings that these national competent authorities, together with professional bodies, are the senders most trusted by the public [30]. During the COVID-19 pandemic, EMA increased their communication activities with, for example, regular written safety updates on the COVID-19 vaccines and oral media briefings involving the PRAC Chair and EMA’s heads of pharmacovigilance and of data analytics and methods. Specifically for Vaxzevria and its TTS risk, EMA worked with external risk communication experts to, for the first time, visualise a benefit-risk balance [93]. This obtained positive feedback from stakeholders. Given ongoing changes in media technology and societal expectations linked to various trust levels regarding science and governance, the EU regulatory network needs to maintain their focus on communication regarding safety of medicines

	
International collaboration

Legal provision: The 2010 legislation demanded central provision of information on EU ICSRs from EudraVigilance to the VigiBase database of WHO’s pharmacovigilance programme

Reflections: Since EMA’s establishment, there has been a legal requirement to collaborate with WHO on pharmacovigilance matters of international relevance, and the 2010 legislation reinforced this collaboration. Overall, EMA has always been highly engaged in international collaboration through multiple channels, including WHO, ICH [39], CIOMS [94] and bilateral agreements with regulatory bodies outside the EU. Building on regular teleconferencing with the US FDA since 1999, EMA established an international cluster for sharing information between EMA and the US FDA on safety issues, pharmacovigilance policies and anticipated regulatory action and communication prior to decision making and publication [95], now also involving the Japanese Pharmaceuticals and Medical Devices Agency and Health Canada. The Australian Therapeutic Good Administration has also been a long-standing collaborative partner in the area of pharmacovigilance. The safety surveillance of the COVID-19 vaccines has massively increased the existing collaboration with WHO and regulatory bodies outside the EU, also using the framework of the ICMRA. Pharmacovigilance had already been a key topic of ICMRA [96]. Furthermore, EMA has regularly been providing support to regulatory capacity building for pharmacovigilance in Africa and Asia, and currently shares its experience to support the establishment of the African Medicines Agency [97]

	
CAP centrally authorised product, CHMP Committee for Medicinal Products for Human Use, CIOMS Council for International Organizations of Medical Sciences, CMDh Coordination Group for Mutual Recognition and Decentralised Procedures – Human, COVID-19 SARS-CoV-2 coronavirus disease, EEA European Economic Area, EMA European Medicines Agency, EU European Union, GVP Good Pharmacovigilance Practices, ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICMRA International Coalition of Medicines Regulatory Authorities, ICSR individual case safety report, ISO International Organization for Standardization, NAP nationally authorised product, PAES post-authorisation efficacy study(ies), PASS post-authorisation safety study(ies), PhVWP Pharmacovigilance Working Party, PRAC Pharmacovigilance Risk Assessment Committee, PSUR periodic safety update report, PSUSA PSUR single assessment, RMM risk minimisation measure(s), RMP risk management plan, RWE real-world evidence, SMART Signal Management Review Technical Working Group of PRAC, SCOPE Joint Action Strengthening Collaboration for Operating Pharmacovigilance in Europe Joint Action, TTS thrombosis with thrombocytopenia syndrome, US FDA United States Food and Drug Administration, WHO World Health Organization

Overall, we consider that the 2010 legislation achieved to strengthen and rationalise pharmacovigilance for better patient and public health protection through establishing new legal responsibilities for marketing authorisation holders (pharmaceutical companies), the regulatory bodies in Member States and EMA, notably:Scientific committee: The Pharmacovigilance Risk Assessment Committee (PRAC) was established as a new scientific committee at EMA, with a central role for regulating safety in the pre- and post-authorisation phases and taking regulatory actions that are legally binding across the EU for medicines authorised either by the European Commission centrally or by Member States nationally.

Regulatory tools: New or strengthened regulatory tools (including risk management plans, post-authorisation studies, direct patient reporting of suspected adverse reactions, signal management, single EU assessments of periodic safety update reports, and reviews of medicines through referral procedures) have facilitated an increasingly proactive and consistent approach to medicines safety, complemented by improvements in efficiency of database infrastructures, evidence generation, regulatory processes and actions, and communication.

Transparency: Transparency was increased with public PRAC membership lists, agendas, recommendations and minutes, and public access to reports of suspected adverse reactions collected in EudraVigilance.

Stakeholder engagement: Engagement of key stakeholders, such as patients, healthcare professionals and academic researchers, has been broadened and deepened through tools to facilitate reporting of suspected adverse reactions, stakeholder reviews of draft communication documents, and invitations to patient and healthcare professional representatives to expert meetings, public hearings resulting in instrumental input to regulatory decision making, and research projects.

Evaluation of regulatory actions: The PRAC Strategy on Measuring the Impact of Pharmacovigilance Activities [34] systematically evaluates patient health-relevant outcomes of major regulatory actions.

During the last 3 years, the COVID-19 pandemic was a major, prolonged stress test for the system, which continued to be fully operational and delivered high-quality and efficient safety surveillance and communication for COVID-19 vaccines and new or repurposed therapeutics, while pharmacovigilance activities for all other medicines continued without compromise of standards [35].

Recently, the European Commission published their legislative proposals for the revision of the entire EU pharmaceutical legislation [36]. These proposals maintain the pharmacovigilance system provisions of the 2010 legislation with only very minor changes. This is a strong indicator of success of the 2010 provisions, as the European Commission’s proposals are based on a profound review and extensive stakeholder feedback.

A key enabler of the successful implementation and maintenance of pharmacovigilance systems of regulatory bodies and pharmaceutical companies in accordance with the 2010 legislation has been the ‘Good Pharmacovigilance Practices’ (EU-GVP) [37] (see Fig. 1), issued in 2012 to replace previous EU guidance. Fundamentally, EU-GVP introduced a systems approach to safety governance and pharmacovigilance conduct, with quality management as an integral part. This means applying good practice principles to all its tasks for achieving defined quality objectives and continuously monitoring systems to complete an iterative learning and improvement cycle [38] (see Fig. 2). Given a new modular guidance structure, each pharmacovigilance process has its own EU-GVP module (12 in total) with two main sections—one detailing the regulatory scientific process and applicable international standards, and one further describing the roles and responsibilities of pharmaceutical companies and regulatory bodies in the EU. The international standards are mainly those established through the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) [39, 40]. Each module also contains process-specific quality management and transparency requirements, and outlines applicable options for stakeholder engagement. With supplementary guidance chapters for special product types (at present, biologics and vaccines) and patient populations (at present, pregnant or breastfeeding women and children), as well as a definitions annex, EU-GVP provides comprehensive guidance. The crucial role of public communication for pharmacovigilance is reflected in a dedicated process module and additionally in sections of the product type- or population-specific chapters to advise on tailoring of communication. Subject to wide stakeholder consultations before finalisation and updating, EU-GVP is a participatory policy that responds to emerging needs and supports progress in conducting pharmacovigilance activities. EU-GVP has also been recognised as a resource for jurisdictions outside the EU (e.g. [41–47]).Fig. 1 Overview of the guidelines on ‘Good Pharmacovigilance Practices’ issued by the European Medicines Agency and the Heads of Medicines Agencies in the European Union (EU-GVP) [37]

Fig. 2 Cycle of the pharmacovigilance quality management system defined in ‘Good Pharmacovigilance Practices’ issued by the European Medicines Agency and the Heads of Medicines Agencies in the European Union (EU-GVP) [26, 38]

While considering the achievements of the 2010 legislation, we have also identified areas for further development of the EU regulatory pharmacovigilance system (see Fig. 3). How to address these areas by optimising the use of existing legal provisions is part of our vision described in the following section.Fig. 3 Achievements and areas of further development through implementation of the 2010 EU pharmacovigilance legislation. EU European Union, PRAC Pharmacovigilance Risk Assessment Committee, PASS post-authorisation safety studies, PSURs periodic safety update reports, PAES post-authorisation efficacy studies

Envisioning the Future and Guiding Principles for Pharmacovigilance in a Changing World

Ongoing Initiatives

In 2019, EMA published its predictions for the ongoing decade: smarter collection and management of individual case safety reports with digital technology and international standards; increased use of real-world data for monitoring the performance of medicines in healthcare in terms of both safety and effectiveness; and improved engagement of patients and healthcare professionals that translates into positive patient health outcomes [48]. Furthermore, in 2020, the EMA’s regulatory science strategy highlighted real-world evidence (RWE) and stakeholder engagement as strategic priorities for pharmacovigilance [49]. Since then, major initiatives have been supporting the realisation of these predictions, in particular:The PRAC Signal Management Review Technical (SMART) Working Group fosters innovative methods for more sensitive and precise signal detection and management, including for special populations and risks with medicines’ abuse, misuse, overdose, medication errors and occupational exposure [50].

The Data Analysis and Real World Interrogation Network (DARWIN EU) promotes timely and reliable RWE from healthcare databases across Europe and establishes an infrastructure for post-authorisation studies investigating the use, safety or effectiveness of medicines, background incidences of medical events, data on diseases for contextualising benefit-risk considerations, effectiveness of risk minimisation measures (RMM), impact of regulatory actions or patient preferences in European populations [51–53]. For generating EU RWE through independent post-authorisation studies specifically for vaccines, EMA and the European Centre for Disease Prevention and Control (ECDC) have initiated the Vaccine Monitoring Platform (VMP) [54].

The PRAC Risk Minimisation Alliance (PRISMA) pilots enhanced stakeholder engagement by PRAC to obtain more and earlier input from patient and healthcare professional networks on the feasibility of implementation of RMM options, questions to be discussed in wider stakeholder events, and outreach strategies for the implementation of RMM in healthcare by collaborating with key stakeholders.

Vision for the Future EU Regulatory Pharmacovigilance System

Building on these initiatives, we envision to address the areas for further development (see Fig. 3) and progress pharmacovigilance that is fit for the future in a world of medical, technological and social changes (see Sect. 1) with the following 10 elements:In the interest of all patient population groups and health equity, the EU regulatory pharmacovigilance system should streamline timely implementation of consistent safety-related actions for all medicines across Member States, independently from their route of marketing authorisation, and with implementation adapted to national healthcare systems.

The contextual understanding of diseases, exposure to medicines, healthcare systems and the performance of medicines in terms of safety, risk minimisation as well as effectiveness in everyday healthcare in the EU should be deepened for more comprehensive benefit-risk assessments and important updates to the product information.

Multiple data sources and multidisciplinary methods should be used and improved for real-time monitoring and assessment of risks, RMM (including their enablers and barriers to achieve intended outcomes) and effectiveness of medicines in consistent formats, based on study feasibility assessments, and in a complementary manner with cross-validation of findings.

Targeted real-world data studies commissioned or conducted by regulators should supplement the important evidence base legally required from pharmaceutical companies, which should likewise be extended and improved.

Advances in technology, including artificial intelligence, should be leveraged to deal with large volumes of data and enable efficient assessment.

Proactive input from and research with patient and healthcare professional communities to support decisions and design of RMM should be sought within frameworks for their impartial contributions, and focus on risk minimisation behaviours and how these can be effectively integrated in local healthcare processes.

Communication on risks and RMM should be contextualised in ways that support patients and healthcare professionals in making individual therapeutic choices and using medicines appropriately.

Regulators should outreach to patient and healthcare professional communities and public health bodies to foster the appropriate use of medicines and build societal trust in medicines regulation and safety surveillance.

All pharmacovigilance activities, such as spontaneous reporting of suspected adverse reactions, post-authorisation safety studies, and RMM development and implementation, should be integrated in patient-centred healthcare, and hence require strong healthcare system engagement.

The EU regulatory pharmacovigilance system should be prepared to respond efficiently to different emergency situations.

The STAR Compass to Guide Actions to Further Progress Pharmacovigilance

To realise this vision, actions for progressing the EU regulatory pharmacovigilance system within the quality cycle may:build further capacity, technology and methods;

drive improvements of existing regulatory processes; and

expand policies, frameworks and research agendas

and should be guided by the following four principles:Synergistic interactions with healthcare systems;

Trustworthy evidence for regulatory decisions;

Adaptive process efficiency;

Readiness for emergency situations.

By their first letters, these guiding principles can be remembered by the acronym ‘STAR’. Like a compass, they are meant to orient improvement actions towards increasing the output of pharmacovigilance activities in terms of safe, effective and trusted use of medicines and positive health outcomes within patient-centred healthcare (see Fig. 4).Fig. 4 Compass of STAR guiding principles for progressing high-quality pharmacovigilance in a changing world

Actions for progress in accordance with these principles should not only address the ongoing changes but make use of the opportunities arising from the changing world. The STAR principles therefore top up the established pharmacovigilance quality principles [38] and add the following foci:Synergistic interactions with healthcare systems: While medicines regulatory bodies regulate medicinal products but not healthcare delivery, regulatory engagement with stakeholders has evolved over the last decades, with a focus now not only on interacting but on benefiting from the opportunities of increasingly networked societies and digitally linked systems, and on creating synergies between activities led by different stakeholders. We consider that synergistic interactions, which respect the responsibilities of each stakeholder party, may support stakeholders in converging on pharmacovigilance objectives and engage healthcare leaders more in the safe use of medicines within patient-centred care.

Trustworthy evidence for regulatory decisions: Medicines regulatory bodies have long been legally required to assess all available evidence and therefore established standards and guidance for the robustness of data and increasingly multidisciplinary analytical methods. However, the additional focus now is that stakeholders and the public overall trust the evidence as robust and unbiased and can appreciate the appropriateness of regulatory decisions even when there are limitations in the available evidence. The contextual understanding of diseases, healthcare systems and medicine use and its outcomes is meant to increase the evidence base for regulatory decisions and to provide common ground for stakeholder engagement, where regulators adopt increased knowledge of the clinical situations patients and healthcare professionals are dealing with.

Adaptive process efficiency: Strengthening efficiency has been achieved with the 2010 legislation; however, the focus now is to foster the capacity of pharmacovigilance systems to adapt efficiency swiftly and smoothly to the challenges and opportunities of the medical, technological and social changes in the world.

Readiness for emergency situations: While pandemic preparedness as well as business continuity planning have been established at EMA for decades, the focus now is on being ready both through proactivity as well as responsiveness to imminent or developing, foreseen or unforeseen emergencies of a wider range, arising from the ongoing changes or crises.

Conclusions

We consider that the 2010 legislation achieved its aim to strengthen and rationalise pharmacovigilance in the EU for better patient and public health protection. A key enabler of its successful implementation has been the guidance for pharmaceutical companies and regulatory bodies in EU-GVP, introducing a systems approach to safety governance and pharmacovigilance conduct with quality management. The EU regulatory system demonstrated strength, efficiency and resilience during the COVID-19 pandemic, and delivered high-quality safety surveillance for COVID-19 vaccines and therapeutics, as well as all other medicines.

We have also identified areas for further system development by optimising the use of existing legal provisions. To address these areas and progress high-quality pharmacovigilance in a world of medical, technological and social changes, we set out a vision and propose four principles, the STAR compass. These principles should guide actions to further develop the EU regulatory pharmacovigilance system by orienting it towards our vision of safe, effective and trusted use of medicines and positive health outcomes within patient-centred care.

This should lead to pharmacovigilance further evolving from its originally mainly reactive approach with reviewing spontaneously reported suspected adverse reactions (which remain a vital data source), through the increasingly proactive approach with conducting epidemiological studies (now based on digitalised ‘big data’), towards an interactive approach with stakeholder engagement and participatory tools and events.

The success of the 2010 legislation would not have been possible without the resource investment and commitment of all stakeholders, i.e. regulators, pharmaceutical industry, researchers, healthcare professionals and patients, in their respective area of responsibilities, and we are grateful for this. Further progress will require continued collaboration at EU and international level. Through sharing our reflections, vision and proposed guiding principles, we underline our continued commitment to serve patient and public health.

Acknowledgements

This article is dedicated to the memory of Noël Wathion (11 September 1956–12 August 2023), former EMA Deputy Director, in acknowledgement of his leadership in establishing and strengthening the EU pharmacovigilance system. Noël’s vision, dedication and humanity guided all of us in our public health mission. The views expressed in this article are the authors’ personal views and may not be understood or quoted as being made on behalf of or reflect the position of their employers, or of the EMA or one of EMA’s committees or working parties

Declarations

Funding

No specific funding was received for the conduct of this study.

Conflict of interest

Priya Bahri, Georgy Genov, Peter Arlett, Viola Macolić Šarinić, Evdokia Korakianiti, Alexis Nolte, Martin Huber, and Sabine M.J.M. Straus have no conflicts of interests to declare.

Ethics approval

This article did not require ethics approval as no research in humans or animals was conducted for the purpose of this article.

Consent to participate

This article did not require consent to participate as no research in humans was conducted for the purpose of this article.

Consent for publication

This article did not require consent to publication as no research in humans was conducted for the purpose of this article.

Availability of data and material (data transparency)

Data sharing is not applicable to this article, as no datasets were generated or analysed for the purpose of this article.

Code availability (software application or custom code)

Not applicable to this article.

Author contributions

This article was developed in three steps. The first step was an in-depth discussion between PB, GG, PA, EK and SS on their observations and insights. Based on this discussion, a discussion with AN, and data from the regular EU system assessments, the SCOPE Joint Action, and studies, PB prepared the analysis in Table 1, developed the guiding principles and provided a first draft of the manuscript for comments by GG, PA, EK, AN and SS. As a second step, the revised draft was critically reviewed and expanded by VMS and MH. As a third step, all authors independently provided their views on the priority elements for consolidating the vision of future pharmacovigilance. All authors reviewed the mature draft, which was finalised by PB, GG and PA for journal submission. The revised manuscript addressing the journal’s reviewers’ comments was reviewed by all authors. All authors read and approved the final version of this manuscript.
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