FormalPara Key Points

The paper provides insights into the key role of the European Union medicines regulatory network (European Medicines Agency (EMA), National Competent Authorities in Member States and the European Commission) in the safety monitoring of COVID-19 vaccines.

Discussed aspects include the assessment of safety topics in relation to COVID-19 vaccines in the context of a mass vaccination campaign, with more than 2 million spontaneous reports of suspected adverse reactions in association with COVID-19 vaccines received by EMA by the end of 2022.

As per its mandate of assessing the safety of human medicinal products, the EMA Pharmacovigilance Risk Assessment Committee recommended the update of the product information of COVID-19 vaccines with adverse reactions for which the accumulated evidence at the time of the assessment was sufficient to suggest that causal association is at least a reasonable possibility (e.g., myocarditis, thrombosis with thrombocytopenia syndrome and heavy menstrual bleeding).

1 Introduction

The COVID-19 pandemic required a global effort to make effective vaccines available to the public in a timely and efficient manner to prevent people from developing severe disease, thus reducing hospitalisations. Following the distribution and administration of the vaccines, a large volume of safety information had to be managed in a short time. In the European Union (EU), the medicines regulatory network, comprised of the National Competent Authorities (NCAs) in EU Member States (MSs), the European Medicines Agency (EMA) and the European Commission (EC), played a key role in the response to the pandemic.

The World Health Organisation (WHO) declared a Public Health Emergency of International Concern (PHEIC) on 30 January 2020, further characterised the outbreak as a pandemic on 11 March 2020, and concluded that the PHEIC could be considered over on 5 May 2023 [1]. EMA initiated its Public Health Threats Plan on 4 February 2020, to support the development of new vaccines and treatments [2], and established the Emergency Task Force (ETF) to provide scientific support on medicinal products targeting the emergency [3].

Shortly before the authorisation of the first COVID-19 vaccines, EMA published the Pharmacovigilance Plan of the EU regulatory network for COVID-19 vaccines [4], building on the experience gained during the 2009 (H1N1) influenza pandemic. This plan proved essential for the timely and efficient organisation of activities, resources and priorities, thus enabling a rapid crisis response.

As for all the medicinal products authorised in the EU/EEA, suspected adverse reactions following administration of COVID-19 vaccines have been continuously reported to the European database, EudraVigilance (EV), operated by the EMA on behalf of the network. The first ever spontaneous case report in association with a COVID-19 vaccine was submitted to EV on 30 December 2020, after which their number increased rapidly (over 2.2 million such reports received by the end of 2022), in line with the expansion of the vaccination campaigns in MSs. The handling of this extraordinary influx of data represents a significant achievement, made possible through the network’s efforts and continuous commitment to public health, rapid scientific assessments, flexible regulatory tools and sharing of worldwide expertise.

We describe the role of the EU regulatory network in the safety monitoring of COVID-19 vaccines, providing an insight into challenges, particularities and outcomes of the scientific assessment and regulatory decisions, in the complex environment of the pandemic. The period covered is from the beginning of 2021 (start of vaccination campaign) until the end of 2022. We aim to describe (a) how the safety of COVID-19 vaccines is reviewed in the EU, (b) examples of the evidentiary documentation for labelling an adverse reaction, (c) challenges of performing a rapid and solid scientific assessment, (d) the flexible regulatory tools used, (e) measures for proactively addressing public concerns, and (f) the global effort and collaboration.

We refer to the four COVID-19 vaccines, namely the mRNA platform vaccines: Comirnaty (authorised on 21/12/2020) and Spikevax—previously COVID-19 Vaccine Moderna (authorised on 06/01/2021), and the adenoviral platform vaccines: Vaxzevria—previously COVID-19 Vaccine AstraZeneca (authorised on 29/01/2021) and Jcovden—previously COVID-19 Vaccine Janssen (authorised on 11/03/2021), as these were used predominantly in the EU/EEA to impede the spread of the virus during these years. By mid-June 2023 [5], the EU/EEA exposure to the original versions of these vaccines exceeded 534 million doses for Comirnaty, 128 million doses of Spikevax, followed by 56 million doses of Vaxzevria and 16 million doses of Jcovden, respectively.

2 The Continuous Safety Review of COVID-19 Vaccines in the European Union (EU)

2.1 The Role of the Pharmacovigilance Risk Assessment Committee (PRAC)

The PRAC is EMA’s committee responsible for assessing the safety of human medicinal products. It convenes once per month and includes members from all EU/EEA countries, healthcare professional/patients’ and EC representatives. The Committee is responsible for providing recommendations to the Committee for Medicinal Products for Human Use (CHMP) on all aspects relating to pharmacovigilance and risk management systems, including on the detection, assessment, risk minimisation and communication relating to adverse drug reactions [6]. While PRAC covers all matters related to pharmacovigilance, the CHMP is responsible for issuing opinions with regards to marketing authorisation status, after assessing the entirety of the evidence. When the assessed evidence shows convincingly that the benefits of the vaccine are greater than any potential risks, the CHMP issues a positive opinion. During the pandemic, international regulatory authorities were invited to participate to the PRAC and CHMP plenaries, according to their topic of interest.

As with all centrally authorised medicinal products, each COVID-19 vaccine has a Rapporteur, selected among the PRAC members nominated by an EU/EEA MS, whose role is to lead on assessments (supported by their national team).

PRAC leads the assessment of all pharmacovigilance procedures such as Periodic Safety Update Reports (PSURs), Post-authorisation Safety Studies (PASSs), and safety signals. In the context of mass vaccination, to promptly identify any new safety concerns, the PRAC assessed additionally expedited Summary Safety Reports (SSRs), initially monthly, then every 2 months. In total, 56 SSRs were assessed until December 2022 [7], when in view of the expanding availability of real-world evidence, the PRAC switched to routine 6-monthly PSUR submissions. PSURs allow for a cumulative assessment of safety in the context of a medicinal product’s benefits and risks [8]. PASSs aim to complement data collected in clinical trials, to characterise important identified and potential risks and missing information [9].

2.2 COVID-19 Signals Discussed at PRAC

We refer to safety signals as defined in the Guideline on Good Pharmacovigilance Practices, Module IX—Signal management (Rev 1) [10], as information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association (e.g., changes in frequency, severity) between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action. In the context of safety monitoring, only signals related to adverse reactions are considered.

In procedural terms, after a signal is detected, it needs to be confirmed by the Rapporteur before being further analysed and prioritised by the PRAC. Subsequently, different stakeholders (e.g., Marketing Authorisation Holders (MAHs), authors of independent studies) collaborate with the PRAC to submit requested data or comment on study findings. Unlike in a non-pandemic setting, where most signal procedures are adopted in writing (i.e., without discussion) at the initial stage, all COVID-19 vaccines’ signals were brought to PRAC plenary, thus allowing members to discuss and refine the recommendations, including any late-breaking information.

As an outcome of continuous safety monitoring of COVID-19 vaccines, including review of spontaneous reports in EV and in the scientific literature, 18 safety signals were prioritised and discussed by the PRAC (Table 1). A safety signal can refer to more than one vaccine. For eight of them, the accumulated evidence at the time of assessment was sufficient to establish a causal association, thus allowing for an update of the product information. The EU product information, which is continuously updated in line with the developing scientific knowledge, is publicly available, and serves, alongside other materials (e.g., country-specific), as a resource for vaccine safety data, supporting stakeholders such as NCAs, healthcare professionals, and the public in their decisions related to vaccines. The section below provides some insights into this assessment.

Table 2 Overview of COVID-19 vaccines signals assessed by the PRAC (with initial discussion in 2021–2022)
Full size table

For the remaining signals, no update of the product information was recommended, these being further subject to ‘routine pharmacovigilance/monitoring in the PSURs’. These pharmacovigilance activities may include safety monitoring and signal detection based on various sources (e.g., EV, literature), from which any significant findings are brought to the attention of the regulatory authorities, as per routine practice. Safety topics assessed for mRNA and adenoviral vector vaccines may provide a background for assessment of similar platform vaccines in the future. Notwithstanding signal procedures, specific adverse reactions were added to the labelling following PRAC assessments of SSRs or PSURs (Table 2).

Table 3 Overview of adverse reactions in relation to the COVID-19 vaccines labelled following SSRs/PSURs throughout 2021–2022
Full size table

3 Insights into the Assessment of Several Safety Signals

3.1 High-Profile Signals

Shortly after authorisation of the vaccines, the PRAC established that a causal association between the adenoviral platform vaccines and the thrombosis with thrombocytopenia syndrome (TTS), as well as between the mRNA vaccines and myocarditis/pericarditis was likely. The particularities of the evaluation of these signals have been previously described [11]—in both, EV data as well as observed-to-expected (O/E) analyses, played a crucial role.

For myocarditis/pericarditis evaluation, two observational studies [12, 13] provided the attributable risk of vaccination. Estimates of the number of excess cases of myocarditis were reflected in the product information as follows: 0.26 (French data) and 0.57 (Nordic data) per 10,000 vaccinated for Comirnaty, 1.3 and 1.9 per 10,000 vaccinated, respectively, for Spikevax. This risk evaluation considered the second dose of mRNA vaccine in young male vaccinees compared to unexposed.

In the case of TTS, the EU network received initial notifications of suspected adverse reactions from independent teams, including from Austria and Norway [14]. In the absence of a case definition and a Medical Dictionary for Regulatory Activities (MedDRA) term, the signal was initially investigated based on case reports in which embolic and thrombotic events (Standardised MedDRA Query, SMQ) were co-reported with manually adjudicated MedDRA terms suggestive of thrombocytopenia.

On 7 April 2021, following an Ad Hoc Expert Group organised by EMA, PRAC recommended an update of the Vaxzevria product information with TTS. While the product information does not include an attributable risk of vaccination, it informs that severe and very rare cases of TTS have been reported post-marketing, that the reporting rates after the second dose are lower compared to after the first dose and that most of the cases of TTS occurred within the first three weeks following vaccination. The risk was further contextualized in a referral (Art. 5.3 of Reg 726/2004) [15, 16].

For myocarditis/pericarditis, the existence of MedDRA terms made the reactions easier to describe. The measure of disproportionate reporting (Reporting Odds Ratio, ROR) in EV increased significantly around the time of EU labelling in July 2021 (Fig. 1), after findings from large population studies in Israel and the USA were published [17, 18]. The need to better characterise the adverse reactions’ frequency, severity or gender distribution resulted in the conduct of two studies, one in the Nordic countries and one in France. Both study consortia made their preliminary findings available for PRAC assessment (e.g., in the case of the Nordic consortium, these findings were assessed even before their publication on 20 April 2022) [12]. The recommendation for labelling was issued on 2 December 2021, confirming that the risk was more significant after the second vaccine dose in younger men.

3.2 Ad hoc Safety Studies by the European Medicines Agency (EMA)

To support the assessment of the signals of vulval ulceration with Comirnaty [19] and pemphigus and pemphigoid with the mRNA vaccines and Vaxzevria [20], EMA conducted two studies (using data sources to which the Agency has direct access). Both signals were initiated by the network following case series of vulval ulceration in adolescent girls [21] or bullous conditions [22, 23] involving several COVID-19 vaccines.

The EU network capability to (a) describe the use of Comirnaty in the general population and (b) estimate incidence rates of vulval ulceration in the general and exposed female population was paramount. A self-controlled case series (SCCS) study was conducted to further investigate a causal association. No differences were found in post-vaccination incidence rates of vulval ulceration compared to incidence rates from time not-at-risk, nor in the 30 or 90 days after receiving the respective vaccines (Comirnaty, Spikevax or Vaxzevria).

In the case of pemphigus and pemphigoid signal, EMA calculated the incidence rates using a cohort design in the UK general population and patients visiting general practices in Spain. A SCCS was also performed as a sensitivity analysis. No consistent associations were seen based on these studies. The studies are publicly available in the EU PAS Register [19, 20].

3.3 New Aspects of Known Adverse Reactions

While hypersensitivity reactions were added to the product information of COVID-19 vaccines [24, 25] based on pre-authorisation studies, new aspects of hypersensitivity were labelled following authorisation, based only on the review of clusters of spontaneous post-marketing case reports. These new aspects include anaphylactic reactions (Vaxzevria), erythema multiforme (EM) (mRNA COVID-19 vaccines), and localised swelling in persons with a history of dermal filler injections (Comirnaty). Published, medically verified reports of EM [26, 27] including skin biopsies and topical corticosteroid treatments contributed to the understanding of these reactions. Based on cumulative data assessed in SSRs, the product information of Spikevax was updated to include the median number of days to onset of injection site reactions, as well as urticaria with either acute onset (within a few days) or delayed onset (up to approximately 2 weeks), respectively [28].

3.4 Challenges of Drawing Conclusions from Consumer Data

Changes to menstruation are not routinely collected in clinical trials. Following vaccines' authorisation, cases of heavy menstrual bleeding (HMB) have been flagged as disproportionate in EV [29] since mid-2021, mainly based on consumer reports. These cases, while often lacking case definition details, and often containing solely the event in relation to time after the vaccination played an important role in the detection of this signal. The scale of reporting to national spontaneous databases [30, 31] was crucial to draw the attention of the EU network and direct resources to process the EV data to further investigate menstruation irregularities (i.e., heavy bleeding and lack of menstruation). About a tenth of the cases were reported by healthcare professionals.

In January 2022, the Norwegian Public Institute [32] issued a survey of the occurrence of menstrual disturbances in 18- to 30-year-old women after COVID-19 vaccination, which was the basis for the PRAC to initiate the signal procedure of HMB. As in the case of the myocarditis/pericarditis signal, the PRAC benefited from collaboration with authors of independent studies who made preliminary data available for assessment (the relevant article was published in January 2023 [33]).

Ultimately, HMB was added to the EU labelling on 27 October 2022, with unknown frequency. Several independent observational studies on the association were published at the time of the PRAC recommendation and later on [34,35,36]. Both the spontaneous reports and the observational research pointed to a transient and non-serious nature of changes to the flow of menstruation.

3.5 Labelling in Specific Patient Groups

In specific patient groups, namely with relapse of capillary leak syndrome (CLS) or experiencing corneal graft rejection (CGR) following COVID-19 vaccination, the signal assessment relied solely on data from EV case reports or published in scientific journals. Subsequently, PRAC recommended restriction of the use of adenoviral vector vaccines in patients with a history of CLS [37], as at that time, review of available data showed that severe cases of CLS following vaccination occurred, including with fatal outcome. No restriction of use was recommended for mRNA platform vaccines, as in their case, the PRAC considered newly available data, including unique experiences from vaccination in specific patient registries. The EurêClark Study Group showed that in patients with CLS/Clarkson disease, the burden of COVID-19 infection leads to severe disease flares, with a high fatality rate. The researchers concluded that the benefit/risk ratio favours COVID-19 vaccination in these patients, under pre-medication with intravenous immunoglobulins [38].

No product information update was recommended for the CGR signals, as the assessed evidence did not suggest that a causal association was at least a reasonable possibility. While the cases were reported in close temporal association with vaccination, with several providing good documentation (i.e., literature cases), there was no clear mechanism of action, no signal of disproportionality observed in EV, no imbalance in the O/E analysis, as well as no increased rates of CGR observed during the pandemic [39]. The challenges with the assessment of this signal have been described elsewhere [40].

4 Challenges of the Safety Assessment During the COVID-19 Pandemic

All medicinal products, including vaccines, have benefits and risks, which are continuously assessed throughout their life cycle. During the COVID-19 pandemic, the scientific assessment was hampered by the COVID-19 disease burden itself, i.e., difficulties in disentangling risks caused by the infection versus the vaccines. Adverse events observed in the population during mass vaccination that had incidence rates exceeding the expected ranges were considered a priori more likely causally associated with the vaccines.

4.1 Aetiologies Overlapping with SARS-CoV-2 Infection

Several well-designed natural history disease or observational studies suggested multi-organ complications in individuals suffering from COVID-19. A large SCCS from England found that the risk of myocarditis is greater after SARS-CoV-2 infection and that the risk after COVID-19 vaccination, albeit present, remains modest [41, 42]. The signal of myocarditis/pericarditis emerged at the time when these conditions were increasingly observed following COVID-19 infection. Review of the effects of COVID-19 on the heart showed that over two-thirds of those infected (including young and asymptomatic individuals) have some degree of inflammation/myocarditis, thus predisposing to cardiovascular events [43]. The signals of histiocytic necrotising lymphadenitis (Kikuchi-Fujimoto disease) or multisystem inflammatory syndrome (MIS) were investigated while their aetiologies were not fully elucidated, and both were increasingly observed after COVID-19 disease itself [44, 45].

4.2 Broad Case Definitions and Medical Dictionary for Regulatory Activities (MedDRA) Terms

The myocarditis/pericarditis signal was assessed based on the 30 May 2021 Brighton Collaboration interim case definition, which was then updated several times to reflect the necessary level of detail [46]. The lack of MedDRA terms created an additional layer of complexity. In the case of TTS, no MedDRA matching term existed at the time of signal identification in March 2021 (Table 1). The initial PRAC discussion used broad case definitions within embolic and thrombotic events (SMQ), co-reported with a list of terms describing thrombocytopenia, with manual adjudication of cases to describe the new clinical entity. ‘Thrombosis with thrombocytopenia syndrome’ was added as a preferred term (PT) and low-level term (LLT) in MedDRA version 24.1, in September 2021 [47].

The signal of MIS in children (initial PRAC discussion September 2021) was assessed simultaneously with the addition of the term ‘Multisystem inflammatory syndrome in children’ and ‘Multisystem inflammatory syndrome in adults’ as MedDRA PTs (version 24.1.) [47], while previously no specific term existed for the condition in children.

4.3 Availability of Vaccine Exposure Data in the European Economic Area (EEA)

Since O/E analyses [48] were used by PRAC to identify adverse events with incidence rates exceeding the expected unvaccinated population ranges, both vaccine coverage data and background incidence rates of events were required. While data on vaccine exposure in the EU/European Economic Area (EEA) has been widely accessible, as published by the European Centre for Disease Prevention and Control (ECDC) since the early days of the pandemic, vaccine coverage data by gender was not readily available. This was a limitation when assessing risks differently distributed across sexes, for example, myocarditis observed mainly in males and after the second dose. Observed cases were collected from EV for all O/E analyses, with inherent limitations of spontaneous reporting systems, including lack of information on the total population exposed to the medicinal product (denominator), some cases not meeting the case definition criteria, and under-reporting—although the latter was less likely for serious events such as myocarditis. To address these limitations, sensitivity analyses adjusting for under-reporting were performed. The O/E analyses were useful for signal strengthening (i.e., validation).

4.4 Generation of Observational Studies to Further Characterise Adverse Reactions

To support PRAC’s safety assessments and characterise new safety issues, EMA contracted 11 studies to consortia specialising in observational research, such as pharmacoepidemiological studies using large EU electronic healthcare databases, vaccine effectiveness studies and studies on patient-reported information. Six of these studies were completed and five were ongoing as of December 2022.

The studies utilised population-based healthcare databases across Europe, thus providing generalisable data, for example, ARS Toscana Database, PEDIANET (Italy); FISABIO, BIFAP and SIDIAP (Spain); PHARMO (Netherlands); CPRD (UK); GePaRD (Germany); SNDS (France); Norwegian Health Registers; and Danish Registries.

Early generation of background incidence rates was facilitated by the EMA-funded ACCESS [49, 50] (vACCine covid-19 monitoring readinESS) project as of mid-December 2020, but some challenges remained for safety issues not prespecified or not previously described in the scientific literature (TTS), or for background incidence rates of relatively common symptoms (HMB) [51].

Studies were also commissioned to characterise adverse reactions that emerged with COVID-19 vaccines (e.g., characterisation and quantification of risk of TTS and COVID-19 vaccines [52], characterisation of the occurrence of cases of myocarditis and pericarditis after vaccination with mRNA vaccines [53]).

5 Flexible Regulatory Procedures for COVID-19 Signals

A signal procedure [54] routinely follows a 60-day timetable (i.e., 60 days for the MAH to provide data, and 60 days for the Rapporteur’s assessment, including MSs and MAHs comments), or a 30-day timetable, if deemed urgent.

Timetables shorter than 30 days were applied in nine procedures, for example, at the first and subsequent discussions of myocarditis/pericarditis signal. Similarly, all procedures for the TTS signal with Vaxzevria and Jcovden were expedited. The shortest time between two consecutive PRAC recommendations was approximately 2 weeks (this occurred four times). To enable rapid decision-making, seven extraordinary PRAC meetings were convened during 2021 [55], in addition to the routine monthly plenaries. Safety topics for vaccines sharing the same technology (Comirnaty with Spikevax or Vaxzevria with Jcovden) were often investigated as a class effect, as per previous practice with other vaccines (e.g., Cervarix, Gardasil/Silgard and Gardasil-9 [56]). In addition, according to the data available, simultaneous assessment of signals for multiple vaccines was also carried out (e.g., signal of MIS or CGR). This ensured that PRAC recommendations were issued on the same day for the respective vaccines, providing the advantage of comprehensive communication with stakeholders.

To allow for a thorough review when several topics awaited regulatory scrutiny, the signal of HMB was assessed through work-sharing between Rapporteurs, which demonstrated the flexibility and prioritisation of PRAC, in the interest of public health.

Another example of expedited decision-making was the implementation of changes to the product information. A variation is a change to the terms of a Marketing Authorisation [57], which can be requested by PRAC following regulatory procedures (e.g., signal procedures, PSURs). The usual timeline for amending the product information is 2 months from the publication of the PRAC signal recommendation (routinely published monthly, post-PRAC plenary), alongside translations in the 24 EU/EEA languages.

Fifteen signal procedures resulted in an update of the product information. The time span for submission of the respective variations ranged from 4 working days after publication (e.g., signals of EM, HMB, CLS with Spikevax) to 2 weeks (anaphylactic reaction with Vaxzevria, localised swelling in persons with history of dermal filler injections with Comirnaty) (Table 3).

Table 3 Examples of expedited updates of the product information following publication of the PRAC recommendation
Full size table

In eight signal procedures, the variations were submitted ahead of the publication of the PRAC recommendation (Table 4). Translations were prioritised for the Vaxzevria—CLS and immune thrombocytopenia signals, followed by expedited product information updates. The time span from the day of the PRAC recommendation ranged from only two consecutive days (for the two variations submitted for each of the signal procedures of TTS with Vaxzevria and Jcovden) to four consecutive days (for the myocarditis/pericarditis initial signal procedure and myocarditis/pericarditis—Nordic study signal with mRNA platform vaccines).

Table 4 Examples of expedited update of the product information ahead of publication of the PRAC recommendation
Full size table

6 Transparency Measures and Proactive Communication of Safety Issues Discussed in PRAC

Transparency [58] on the safety of COVID-19 vaccines played an important role in maintaining public trust and understanding the regulatory process and actions taken.

Since 2012, snapshots of EV data are made publicly available and updated weekly at https://www.adrreports.eu/. In anticipation of public interest, this tool was enhanced with tailored access to all COVID-19 vaccines [59]. Nevertheless, EMA noted misrepresentation of this data circulating in articles and on social media, mostly due to its misunderstanding. Several online visuals have used EMA’s and EV’s graphics/logo without the Agency’s consent, thus allowing for the spread of false information and risking further vaccine hesitancy. Dedicated webinars for fact checkers were organised on how to correctly use and interpret www.adrreports.eu, and on the monitoring of the safety of COVID-19 vaccines.

EMA published the assessment reports of the TTS [60], myocarditis/pericarditis [61, 62] and HMB [63, 64] signals. In addition, EMA published Comirnaty PSURs and PRAC PSUR assessment reports, thus providing insight on how the vast amount of safety data was processed by the EU regulators [65].

To tackle misinformation, EMA continued to provide science-based data through all its communication channels, engaged in social media, responded to queries from journalists, and organised press briefings and public stakeholder meetings [66]. Following authorisation of the COVID-19 vaccines, a dedicated EMA webpage provided the latest information, including on changes to the product information, relevant studies, as well as monthly safety updates.

6.1 Media Attention

Public concerns regarding menstrual disorders in COVID-19 vaccinees were covered by the media, thus signals of HMB or amenorrhea were of high interest. EMA investigated the impact of media attention on menstrual bleeding and COVID-19 vaccines in the EU/EEA and the reporting trends of HMB to EV. The analysis found some media stimulation on EV case reports. In this context, EMA provided regular information on the progress of the review and reassured regarding no evidence to suggest that the menstrual disorders have any impact on reproduction and fertility. A review by the EU network indicated that mRNA COVID-19 vaccines do not cause pregnancy complications and are as effective at reducing the risk of hospitalisation and deaths in pregnant as in non-pregnant women [67].

High media interest was also observed for the signals of TTS and myo- and pericarditis. For the latter, since the MedDRA term existed prior to the emergence of the signal, higher reporting was observed after EMA communications on the topic, which peaked following the PRAC label update at the beginning of July 2021 (Fig. 1).

Fig. 1
figure 1

Dynamic reporting odds ratio (ROR) for worldwide cases for COVID-19 vaccines and myocarditis/pericarditis. Spikevax Original (INN elasomeran) and Comirnaty Original (INN tozinameran) were used for a pooled ROR calculation. The suspected adverse reaction was defined using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms ‘myocarditis’ and ‘pericarditis’. The dashed line represents the lower bound of the 95% confidence interval (LCI) threshold, with a signal of disproportionate reporting considered in the presence of at least three cases and the LCI of the ROR ≥ 1. MedDRA Medical Dictionary for Regulatory Activities; PT  Preferred term; ROR Reporting Odds Ratio

Full size image

6.2 Understanding of Cases of Suspected Side Effects with Reported Fatal Outcome

The EV database analyses information by grouping cases by type of suspected ADR. As more than one suspected ADR may have been included in a single case report, the total number of ADRs will never match the number of individual cases. This also applies to the total number of cases of suspected ADRs for which a fatal outcome has been reported. Therefore, an overestimation of the actual total number of cases for a vaccine may occur when one sums up the case figures published by EMA by suspected ADR type.

Cases of suspected ADRs with reported fatal outcome shortly after use of any medicine or vaccine may create concern. This becomes apparent during mass vaccination campaigns. A given medical event (whether fatal or not) may not have been caused by the vaccine, or it may have been caused by the vaccine but was not the cause of death. Fatal events can happen in the context of a complexity of causal factors. In extremely rare instances, adverse reactions can have a fatal outcome, as in the case of TTS. Following investigation of causality, specificities and frequency of occurrence, EMA issued dedicated communication (e.g., DHPCs, press briefings) when a new safety issue represented a truly serious adverse reaction [68].

7 International Collaboration

As part of the EU Health Union [69], EMA collaborated with its partners in the EU regulatory network, the EC (Directorate-general For Health And Food Safety and Health Emergency Preparedness And Response Authority) and the ECDC.

In May 2022, EMA and ECDC established a Vaccine Monitoring Platform (VMP) in accordance with the regulation on EMA's reinforced role and ECDC’s extended mandate. The VMP’s roles include maintenance of a system for prioritisation, initiation, registration and supervision of vaccine studies at EU level, as well as facilitation and coordination of the conduct of post-authorisation safety and effectiveness studies to monitor vaccine performance and impact over time.

The pandemic has been a powerful booster for collaboration between EMA and regulatory bodies and public health agencies such as the Centres for Disease Control and Prevention, US Food and Drug Administration, Health Canada, UK Medicines and Healthcare Products Regulatory Agency, WHO, Therapeutic Goods Administration, Japanese Pharmaceuticals and Medical Devices Agency, Ministry of Health of Israel, National Immunization Technical Advisory Groups. A broad network of independent researchers and experts was deployed for the review of COVID-19 vaccines. EMA has been chairing the International Coalition of Medicines Regulatory Authorities, thus supporting the exchange of information, the strategic directions, the work-sharing efforts among regulators and researchers, and the approaches to address common challenges [70]. These exchanges were based on already-existing agreements [71], but also ad hoc, time-limited, COVID-19-specific agreements. Harmonisation of actions was achieved through provision of advance notice of anticipated regulatory actions and their scientific rationale.

8 Conclusion

Throughout the COVID-19 pandemic, the EU Regulatory Network played a crucial role in the early identification and evaluation of safety issues, rapid communication to the public, and inclusion in the product information when warranted. The lessons learned from the pandemic are applied for improving future pharmacovigilance activities, enabling the EU Regulatory Network to be better prepared for potential future public health emergencies, including in safety monitoring of future pandemic vaccines. Lessons learned applicable to pharmacovigilance relate to the importance of crisis preparedness, agile structures for real-world safety monitoring, network collaboration and resources, flexible regulatory procedures, international collaboration, transparency, stakeholder engagement and communication [72].

In the EU, preparedness proved essential for timely and efficient organisation of activities, resources and priorities, enabling a rapid crisis response. Spontaneous data played a crucial role for the early detection of emerging safety issues. Enhanced collaboration allowed addressing challenges and leveraging experience. The safety monitoring of COVID-19 vaccines required tailored tools, combination of scientific methods and contextualisation of risks, complemented by real-world monitoring through EMA-funded pharmacoepidemiological studies. Accelerated assessments were possible due to flexible regulatory tools and EU network experts’ commitment. The enhanced measures for publication of COVID-19 vaccines data, communication and public engagement played an important role in maintaining public confidence.

The EU regulatory network will continue to closely monitor the safety of the COVID-19 vaccines, evaluate emerging data, and make information on vaccines and regulatory decisions easily accessible for the public.