Coronavirus artist impression

COVID-19: The European medicines regulatory network’s response to the pandemic

The COVID-19 pandemic continued to be the number one priority for EMA and the European medicines regulatory network in 2021. EMA recommended four more vaccines for approval in 2021 that formed the basis of the largest mass vaccination campaign ever seen in the EU. EMA also recommended five new COVID-19 treatments that brought much needed therapy options for people who had contracted the virus.

This also required intensive safety monitoring to enable quick action where needed.

The network's operation under these circumstances relied on the existing health threats preparedness plan, the mobilisation of experts from the COVID-19 EMA pandemic Task Force (COVID-ETF), and the close collaboration with international regulators and ECDC. The rapid scientific advice on the development of COVID-19 medicines and the accelerated agreement of paediatric development plans, both activated in 2020, continued to be deployed successfully throughout 2021.

Support to developers of COVID-19 vaccines and treatments

Scientific advice is one of EMA’s key tools to support the sound development of medicines. During the pandemic, developers could send a request at any time to the Agency to receive expedited advice within a maximum of 20 days. Developers received guidance and direction from EMA on the best methods and study designs to generate robust information for their future medicine or vaccine.

EMA provided a fast-track procedure for paediatric investigation plans (PIPs). A PIP describes how a COVID-19 vaccine or treatment will be studied in children and must be agreed with EMA ahead of any marketing authorisation application. This fast-track procedure enabled reduction of the timeline for PIP review from the usual 120 days down to 20 days, as needed.

COVID-19 procedures in 2021

Preparing for variants - guidance for vaccine developers

As the pandemic unfolded, SARS-CoV-2 evolved and several new variant strains were identified worldwide in 2021. Data indicated that variants could impact the level of protection against infection and disease provided by COVID-19 vaccines.

While the authorised vaccines remained effective in preventing severe disease and hospitalisation, it became an urgent public health priority to define an expedited regulatory process for adaptation of the vaccines to protect against variants, if needed. Based also on discussions at international level on how to approach variants and vaccines in a coordinated way, EMA issued guidance outlining the requirements for manufacturers' planning to modify their COVID-19 vaccines to address coronavirus variants.

Rapid evaluation and approval processes

The use of rolling reviews continued to enable the rapid assessment of COVID-19 vaccines and treatments. Rolling review allows EU experts to scrutinise the evidence from studies on a medicine or a vaccine as soon as it becomes available, and before a formal marketing authorisation application is submitted. Once EMA decides that sufficient data are available, the company is invited to submit a formal application, which is then processed under a shortened timetable.

Four vaccines and five treatments were granted a marketing authorisation in 2021

Extending vaccine manufacturing capacity

One of the major challenges for the EU was to ensure an adequate supply of vaccines to support the large-scale roll-out in national vaccination campaigns. Throughout 2021, EMA was able to quickly approve new manufacturing sites and lines, additional suppliers of raw materials and other manufacturing changes to enable a rapid scale-up of the production of Comirnaty, Spikevax, Vaxzevria and COVID-19 Vaccine Janssen. This was done through proactive planning, communication and by following accelerated assessment timetables. The number of approved manufacturing sites rose from 19 to 52 during the year, leading to a huge increase in vaccine supply in the EU and in third countries through the COVID-19 Vaccines Global Access (COVAX) initiative.

Vaccination in children

All COVID-19 vaccines were initially approved in adults only. The approvals of two of the vaccines, Comirnaty and Spikevax, were extended to younger age groups during the course of 2021 as additional data became available. While these age groups are generally at low risk of severe infection, SARS-CoV-2 can also cause severe disease in younger people.

2021 milestones in children and adolescents

Booster doses

Available data showed that immunity against COVID-19 from initial vaccination waned gradually over time and that protection from infection and symptomatic disease also declined. Therefore, in 2021, boosters were authorised to restore the protection offered from primary vaccination. EMA provided timely recommendations on booster schedules for three of the authorised vaccines: Comirnaty, Spikevax and COVID-19 Vaccine Janssen.

Heterologous vaccination

Safety monitoring of COVID-19 vaccines and treatments

The EU has a comprehensive safety monitoring and risk management system, which ensures that measures are in place for detecting any potential new risks, conducting rigorous scientific assessments of all safety data and introducing any necessary mitigating actions early on.

Throughout 2021, EMA issued monthly safety updates for every authorised COVID-19 vaccine. Safety updates reflect data collected and assessed since the vaccine’s authorisation, including data from EudraVigilance (the EU’s centralised database of suspected side effects), data from the companies’ monthly safety reports required for COVID-19 vaccines, as well as from independent studies coordinated by European authorities. This allows regulators to swiftly assess data emerging from a range of different sources and take appropriate regulatory action to protect public health, if needed.

EMA’s main recommendations on safety issues following monitoring of COVID-19 vaccines and treatments:

April: EMA concluded that thrombosis with thrombocytopenia syndrome (TTS) (blood clots with low blood platelets) should be listed as a very rare side effect of Vaxzevria, formerly COVID-19 Vaccine AstraZeneca, and that TTS should be added as a new very rare side effect for COVID-19 Vaccine Janssen.

June: EMA recommended that people with a medical history of capillary leak syndrome (CLS) must not be vaccinated with Vaxzevria, and that CLS should be included as a very rare side effect in the product information.

July: EMA recommended listing Guillain-Barré syndrome as a very rare side effect of COVID-19 Vaccine Janssen and listing myocarditis and pericarditis as new side effects in the product information of Comirnaty and Spikevax. EMA also recommended that people with a medical history of CLS must not be vaccinated with COVID-19 Vaccine Janssen, and that CLS should be included as a very rare side effect in the product information.

August: EMA recommended including immune thrombocytopenia as an adverse reaction for COVID-19 Vaccine Janssen.

September: EMA recommended listing Guillain-Barré syndrome as a very rare side effect of Vaxzevria.

October: EMA recommended listing venous thromboembolism (VTE) as a very rare side effect of COVID-19 Vaccine Janssen in the product information, to raise awareness especially in people with an increased risk of VTE. In addition, transverse myelitis was also listed as a side effect. EMA also recommended listing immune thrombocytopenia as a side effect in the product information of Vaxzevria.

December: EMA assessed data on the known risk of myocarditis and pericarditis following vaccination with Comirnaty and Spikevax, including evidence from two large European epidemiological studies, and concluded that the risk for both of these conditions is overall very rare.

EMA also took steps to use real-world data from clinical practice to monitor the safety and effectiveness of COVID-19 treatments and vaccines. EMA has contracted institutions specialised in observational research to conduct several research projects, which were still ongoing at the end of the year:

  • safety monitoring of COVID-19 vaccines in the EU;
  • natural history of coagulopathy and use of antithrombotic agents in COVID-19 patients;
  • early safety monitoring of COVID-19 vaccines;
  • impact of COVID-19 infection and medicines in pregnancy;
  • multicentre cohort studies on the use of medicines in COVID-19 patients;
  • infrastructure for the monitoring of the coverage, safety and effectiveness of COVID-19 vaccines.

 

covid-19-vaccines-safety-updates

Mobilising expertise from across the network

The unprecedented mobilisation of experts through the European medicines regulatory network continued throughout 2021 and proved to be one of the key success factors supporting fast-track development and marketing authorisations of safe, effective and high-quality medicines and vaccines for COVID-19.

EMA and its scientific committees were supported by COVID-ETF, a group bringing together experts from across the EU network to facilitate rapid and coordinated regulatory action on medicines and vaccines for COVID-19.

In 2021, the activities of the Task Force included:

  • reviewing available scientific data on potential COVID-19 medicines and identifying promising candidates;
  • requesting data from developers and engaging with them in preliminary discussions;
  • offering scientific support to facilitate clinical trials conducted in the EU for the most promising medicines for COVID-19;
  • providing feedback on development plans of COVID-19 vaccines and treatments when formal rapid scientific advice was not feasible;
  • advising the Scientific Advice Working Party (SAWP) or the Committee for Medical Products for Human Use (CHMP) on formal scientific advice and assessments of COVID-19 medicinal products;
  • contributing to the activities of the Pharmacovigilance Risk Assessment Committee (PRAC) on emerging safety issues related to COVID-19 vaccines and treatments;
  • ensuring close cooperation with stakeholders and relevant European and international organisations.

Transparency

In 2021, EMA continued to implement exceptional measures to maximise the transparency of its regulatory activities regarding vaccines and treatments for COVID-19 during evaluation and after approval.

EMA published the European public assessment reports for COVID-19 vaccines and treatments swiftly, only one or two days after authorisations were granted.

In addition, EMA and Health Canada worked collaboratively to publish the full clinical data reviewed as part of the regulatory approval process for COVID-19 vaccines and therapeutics. EMA and Health Canada are the only two regulators worldwide publishing such comprehensive information.

This international partnership showed the shared commitment of both authorities to ensuring that the public has as much information as possible to make decisions regarding vaccination and treatment. 

 EMA and Health Canada’s joint commitment to openness and transparency support global research, allow for public scrutiny and reinforce society’s trust in COVID-19 vaccines as mass vaccination campaigns continue to be rolled out across the EU, Canada and the rest of the world.

Emer Cooke, EMA’s Executive Director

 

 During the COVID-19 pandemic, EMA is implementing exceptional measures to try and maximise the transparency of its regulatory activities on treatments and vaccines for COVID-19 that are approved or are under evaluation. EMA is doing this by shortening its standard publishing timeframes and publishing information it does not normally publish for other medicines.

European Ombudsman iThis statement was provided by the European Ombudsman in her decision that refusal of public access to documents relating to the manufacturing of mRNA vaccines against COVID-19 did not constitute maladministration.

Crisis communication, tackling disinformation, stakeholder engagement

Social media has amplified an 'infodemic’ where massive amounts of information are shared and disinformation and misinformation can easily spread. Mis- and disinformation around COVID-19 vaccines and treatments had a massive public health impact in 2021 as it undermined trust in authorised medicines, scientists, regulators and other public health authorities and limited the uptake of life-saving vaccines. In 2021, EMA intensified its media monitoring and social listening activities, carefully scrutinised public queries and closely collaborated with other EU entities and international public health bodies to identify harmful health advice and address concerns in a timely manner.

Providing the general public with factual, complete and up-to-date information about its activities to fight the pandemic remained a major goal for EMA in 2021. This was ensured through frequent updates on EMA’s website for the general public, regular press briefings and media interviews with EMA key experts, as well as frequent social media posts that increased visitors’ engagement.

 

Key figures on EMA’s COVID-19 communication

  • 18 press briefings were organised throughout 2021 to meet the huge media interest in EMA’s COVID-19-related activities. 
  • Around 200 news announcements were published and 56 media interviews took place to inform the public about key milestones in medicine assessment or new initiatives related to the pandemic response.
  • Approximately 1,000 updates were shared on EMA’s official Twitter and LinkedIn accounts. The updates have been shown on users’ news feeds almost 80 million times.
  • More than 6,500 direct interactions between EMA and patients and healthcare professionals were registered.
  • The COVID-19 related content on EMA's website attracted more than 10 million visits last year.

More than ever, EMA reached out to the public to respond to their questions and concerns. It engaged with patient and healthcare professional organisations and the general public through information sessions, public meetings and consultations to increase the effectiveness of its public health communications.

In 2021, EMA held three public meetings on COVID-19 to explain how the Agency assesses and monitors COVID-19 vaccines and heard directly from European citizens about their needs and concerns. The meetings were held virtually and broadcast live. They were attended by thousands of people, who had the opportunity to ask questions to EMA experts live.

 

Disinformation leading to judicial challenges

Despite EMA’s unprecedented transparency efforts on COVID-19 vaccines, six legal challenges were initiated against the conditional marketing authorisations and/or an extension of indication for COVID-19 vaccines authorised in 2020 and 2021.

In all cases the European General Court sided with EMA and the European Commission, dismissing all actions for annulment as inadmissible.

Coordinating the network’s response to shortages

A global health emergency, such as the COVID-19 pandemic, can drive a sudden surge in demand for certain medicines necessary for specific treatments, which could lead to shortages. 

In 2021, the EU network continuously monitored the supply of human and veterinary medicines in the EU and the impact of the increased production of COVID-19 medicines during the pandemic on the availability of other (non-COVID-19) medicines. In addition, the Agency has continuously monitored ongoing or anticipated shortages of medicines used to treat COVID-19 patients in intensive care units (ICUs) through the industry single points of contact known as 'i-SPOCs'. Information received from the i-SPOCs has been shared with the steering group for decision-making, when needed.

In June 2021, the EU Executive Steering Group on Shortages of Medicines Caused by Major Events adopted a reflection paper with recommendations to support forecasting of demand for human medicines across the EU in exceptional situations like the COVID-19 pandemic. The reflection paper is publicly available.

The document built on the experience gained by EU authorities in 2020, during the first wave of the pandemic, and presented a common methodology to predict the demand for medicines for use in intensive care units. 

The EU network also launched a pilot phase to forecast demand data for a small number of medicines (five medicines used in ICU setting), based on the principles and methodology described in the reflection paper. The pilot phase proved to be successful in demonstrating the practical implementation of the approach for forecasting demand data. In addition, the aggregated results from the pilot were robust and representative of the actual demand in the EU or the European Economic Area (EEA).

International collaboration

As Chair of the International Coalition of Medicines Regulatory Authorities (ICMRA), EMA led the global efforts to streamline and align regulatory requirements for medicine development and approval. Throughout 2021, EMA chaired or co-chaired a series of workshops and strategic meetings to exchange information, develop joint approaches and provide recommendations on key aspects of medicine development and benefit-risk evaluation during the pandemic.

 

Key ICMRA actions and recommendations in 2021
 

In December 2020, EMA started to pilot the ‘OPEN’ initiative to increase international collaboration on the EU rolling review and evaluation of COVID-19 vaccines and therapeutics. Regulators from Australia, Canada, Japan, Switzerland and the World Health Organization (WHO) participated in the pilot under the terms of existing confidentiality arrangements.

In 2021, all the vaccines and therapeutics against COVID-19 approved in the EU were assessed under OPEN, and more are currently under review.

The discussions under OPEN aimed to actively engage international partners, allowing regulators to accelerate and align on decisions. Through its partnership with WHO, EMA also contributed to global health by breaking down regulatory barriers and facilitating access and equity for COVID-19 vaccines and therapeutics.

Joint activities with ECDC

In 2021, EMA and the European Centre for Disease Prevention and Control (ECDC) kicked off a new initiative aimed at strengthening post-marketing monitoring of the safety, effectiveness and impact of COVID-19 vaccines in the EU and the EEA.

As part of this initiative, EMA and ECDC jointly coordinated and oversaw a number of observational studies funded from the EU budget and conducted in several European countries. In line with their respective mandates and in collaboration with EU/EEA countries, EMA led research on safety monitoring, and ECDC took the lead regarding studies on the effectiveness of the vaccines. Throughout the year, this work was supported by a Joint Advisory Board (JAB), composed of representatives of the European Commission, the EU/EEA National Immunisation Technical Advisory Groups (NITAGsiNITAGs have the role of making evidence-based recommendations to Member States to support national decisions around vaccines and their use.) collaboration organised by ECDC, members of the COVID-ETF, the CHMP and the PRAC. The JAB was established as a consultative body to advise on the prioritisation, design, conduct and interpretation of the independent post-authorisation observational studies. It provides guidance on operational aspects related to the implementation of these studies, as needed.

 

 EMA and ECDC were ideally placed to coordinate such studies. In 2021, we worked very closely together to set up, execute and assess the data and we will continue to do so, alongside the European Commission and the Member States.

Emer Cooke, EMA’s Executive Director

 

As part of this collaboration, EMA and ECDC communicated regularly on the COVID-19 situation in the EU and made recommendations, among others, on the use of COVID-19 vaccine additional and booster doses. The expert recommendations published by the two EU Agencies were intended to help decision makers for national vaccination campaigns ensure that the maximum number of EU citizens were protected as quickly as possible against the virus.

As an example, EMA and ECDC reviewed available evidence and provided technical recommendations and advice on heterologous vaccination against COVID-19, either in the primary course or as a booster, to provide scientific grounds and flexibility to vaccination schemes.

Lessons learned from the COVID-19 response

EMA and the European medicines regulatory network introduced a variety of measures and regulatory flexibilities as part of their response to the COVID-19 crisis. A lessons-learned exercise was initiated in 2021, and although this is still ongoing, several learnings have already emerged as important elements, some of which will be implemented as part of EMA’s extended mandate:

  • Provide rapid and coordinated feedback to medicine developers during a crisis.
  • Establish a mechanism and resources to ensure sustainability of the COVID-ETF for future crisis preparedness.
  • Establish a mechanism to enable rapid advice and approval of large, well-designed trials, to avoid fragmentation in clinical research.
  • Establish pan-European research investigator networks with effective infrastructural support, to enable large trials by public research bodies or industry.
  • Improve collection, coordination and analysis of health data across the EU.
  • Enhance data analytics to support public confidence in the regulatory supervision of vaccines and therapeutics.
  • Invest in real-world evidence to complement evidence from clinical trials.
  • Reflect on the need to establish a framework on the use of labelling and serialisation flexibilities in public health emergencies.
  • Support research to define optimal tools for risk communication and data visualisation.
  • Strengthen collaboration and communication with ECDC, national public authorities and the NITAGs, who are national experts advising on vaccination programmes coordinated by ECDC.
  • Strengthen international collaboration and explore ways to increase harmonisation and speed of data sharing.
  • Coordinate and support Members States’ activities in preventing and mitigating supply disruptions of critical medicines during crises.
  • Support EU-level coordination and scientific, technical and clinical evaluation of certain medical devices and in-vitro diagnostics during emerging health threats.
Response to the pandemic and early learnings that will help reshape medicines in the post COVID-19 era

Read more about EMA’s response to the COVID-19 pandemic in these papers: