COVID-19: European medicines regulatory network’s response to the pandemic
The COVID-19 pandemic has caused pain and hardship for hundreds of millions of people in the world. It has cost the lives of millions and has affected the health of many more.
As the SARS-CoV-2 virus ripped through societies in the EU and fundamentally reshaped how we live, work and interact with people, the scientific community rose to the challenge. Unparalleled mobilisation and sharing of information between scientists, industry, regulators, healthcare professionals, patient representatives and public health bodies around the globe resulted in the approval in the EU of a first vaccine against this new disease and another two undergoing rolling review in less than a year. Development of new treatments and vaccines is going on at an unprecedented rate, giving us confidence that pharmaceutical interventions can play an important role in getting the pandemic under control.
EMA together with its partners within the European medicines regulatory network (EMRN) played a key role in the EU’s response to the pandemic from the outset. Within days of the World Health Organization declaring the novel coronavirus outbreak a public health emergency of international concern (PHEIC), WHO's highest level of alarm, EMA initiated its public health threats plan on 4 February 2020 to be ready to support the development of new treatments and vaccines.
Lockdown measures, including factory closures, quarantine requirements and travel restrictions had a profound impact on all areas of healthcare. There were concerns that the resulting impact on global supply chains could lead to shortages, both for medicines that were critically important for use in intensive care units looking after COVID-19 victims, but also for medicines that patients across the EU were reliant upon to treat their conditions.
Limitations in hospital access for patients not suffering from COVID-19 meant that treatment protocols for certain diseases had to be changed, requiring regulatory approval. Developers of medicines required urgent guidance on how to conduct clinical trials in a situation where participants had to shield at home and could no longer attend hospital appointments.
EMA and the network of national competent authorities (NCAs) had to adapt activities and processes to ensure a rapid response to the pandemic whilst maintaining core regulatory activities to protect public and animal health. A business continuity plan set out the principles for operating core activities; existing resources were reallocated and priorities shifted to meet these objectives.
Staff at EMA and across EMRN have demonstrated their strong commitment to the protection of the health of European citizens. Their contributions spanned from early scientific advice during the development, the rapid evaluation and approval of treatments and vaccines to the robust safety monitoring in the post-authorisation setting. The Agency also led efforts to align regulatory requirements with international regulators, thereby further facilitating medicine development and approval. EMA and the EU network were committed from the start to maximising the transparency of their activities to build EU citizens’ trust in the new medicines and vaccines and the understanding of the scientific data underpinning their recommendations.
From guided development to accelerated approval procedures
From early on in the pandemic, EMA took action promptly and adapted its procedures to achieve the authorisation of safe and effective treatments and vaccines within the shortest possible time frame.
Rapid and agile development support
EMA activated its plan for managing emerging health threats on 4 February 2020 and, as part of this plan, encouraged developers of potential vaccines or treatments for COVID-19 to get in touch through a dedicated mailbox to discuss their strategy for evidence generation. Through these early interactions, EMA provided preliminary informal feedback on development plans and identified products that were mature enough to benefit from rapid scientific advice.
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 for expedited advice in no more than 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.
Another fast-track procedure was provided for paediatric investigation plans (PIPs). The timeline for an EMA review was reduced from 120 to 20 days. PIPs describe how a medicine will be studied in children and must be agreed with EMA ahead of any marketing authorisation application.
To further advise medicine developers, EMA also published guidance outlining the clinical evidence required for the approval of vaccines. While the exceptional context of the pandemic requires special regulatory considerations for approval, the guidance highlights that the benefits and risks of COVID-19 vaccines need to be properly assessed based on detailed information on manufacturing, non-clinical data and results of well-designed clinical trials.
Rolling review and fast-track approval
Once the development of a promising medicine or vaccine is nearing completion, EMA’s key tool to speed up its assessment during a public health emergency is the rolling review. This tool is foreseen in EMA’s public health threats plan. It was used throughout the year and allowed EU experts to scrutinise the evidence on a medicine or a vaccine as soon as it became available from ongoing studies, and before a formal marketing authorisation application was submitted. Once EMA decides that sufficient data are available, the company should then submit a formal application, which is then processed under a shortened timetable.
During the COVID-19 pandemic, EMA's conditional marketing authorisation (CMA) has been used to expedite the approval of treatments and vaccines. This is in line with EU legislation which foresees the use of this type of authorisation to fast-track the approval process during public health emergencies to save lives. It allows a marketing authorisation to be granted as soon as enough data become available to demonstrate that a medicine's benefits outweigh its risks, with robust safeguards and controls in place post-authorisation.
While a CMA is a tool to speed up the approval process, it also guarantees that the medicine assessed complies with the EU standards of safety and efficacy. It gives the EU authorities the control and safeguards needed to recommend a medicine or vaccines roll-out across the EU.
At the end of 2020, two medicines for COVID-19 were granted a CMA after having been assessed through a rolling review:
the therapeutic Veklury
the vaccine Comirnaty
The authorisation of the first COVID-19 vaccine, less than a year after the pandemic was declared, was the result of unparalleled mobilisation of scientists, industry, regulators, healthcare professionals, patient representatives and public health bodies around the globe. EMA's robust, science-based consensus opinion on the safety, efficacy and quality of the vaccine provided the EU Member States with a firm scientific foundation for the roll-out of their vaccination programmes and a continuing framework for control and supervision of the vaccine.
Once medicines for COVID-19 are authorised, EMA and the NCAs in the EU continue collecting and assessing data to ensure that they are used in the safest way, based on the most up-to-date evidence.
The safety of COVID-19 medicines is monitored according to guidance set out by EMA and NCAs in the good pharmacovigilance practices (GVP), which applies to all medicines and vaccines.
The EU has a comprehensive safety monitoring and risk management (pharmacovigilance) system, which ensures 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.
For vaccines, the pharmacovigilance plan for COVID-19 vaccines outlines how relevant new information emerging after the authorisation and uptake of COVID-19 vaccines during the pandemic will be collected and promptly reviewed. The plan comprises new obligations for companies that will have to submit monthly safety reports in addition to the regular updates foreseen by the legislation. This is particularly important for vaccines due to the exceptionally large European vaccination campaigns that involve healthy individuals.
Furthermore, EMA published guidance to support pharmaceutical companies’ preparation of risk management plans (RMPs) for COVID-19 vaccines. It addresses specific aspects such as information on vaccine safety in special populations, including pregnant women, the elderly or patients with co-morbidities.
EMA also took steps to use real-world data from clinical practice to monitor the safety and effectiveness of COVID-19 treatments and vaccines and other medicines used for COVID-19. EMA contracted different consortia specialising in observational research to conduct several research projects, including on:
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;
natural history of coagulopathy and use of antithrombotic agents in COVID-19 patients.
Real-world monitoring complements EMA's regular safety monitoring activities. These data will provide insights into very important aspects, such as the impact of the infection and medicines in pregnancy, and will allow us to understand better the disease and adjust our recommendations as needed.
All these measures were put in place to allow regulators to collect emerging data from a wide range of sources and to take swift regulatory action to protect public health whenever needed.
The authorisation of new medicines for COVID-19, and in particular new vaccines, will only make a difference in the fight against COVID-19 if there is a high uptake. For this reason, EMA implemented exceptional measures to maximise the transparency of its regulatory activities on medicines for COVID-19 during evaluation and after approval. This will allow healthcare professionals and citizens to take well-informed decisions about treatments and vaccines based on facts. The publication of more extensive information also allows further independent scrutiny within the scientific community.
Notably, EMA resumed its landmark policy on the publication of clinical data supporting marketing authorisations for COVID-19 medicines. This programme was suspended at the end of 2018 as a result of the Agency’s move from London to Amsterdam. While it remained suspended due to business continuity linked to the COVID-19 pandemic and human resource constraints, EMA decided to exceptionally publish clinical data for COVID-19 medicines, given the unprecedented public interest in this information. By the end of 2020, EMA had published the clinical data supporting the authorisation of Veklury.
Crisis communication and stakeholder engagement
One of EMA’s top priorities throughout the pandemic has been to provide the general public with factual, complete and up-to-date information about its activities to fight the pandemic in a timely manner.
EMA’s approach has been to communicate proactively on complicated issues, even when uncertainties and unknowns remained. Being clear and transparent and communicating quickly and honestly to protect public health has been EMA’s guiding principle.
The Agency has strengthened its engagement with the media, which serve as an important emergency information system during a crisis, through the organisation of interviews with experts and press briefings to explain complex concepts and via the dissemination of factual information on social media.
These activities have increased the Agency’s visibility and public awareness of its role in fighting the pandemic, the resulting broad coverage helping to convey reliable information to the public.
More than ever, EMA has reached out to the public to respond to their questions and concerns. It has engaged with patient and healthcare professional organisations and the general public at large through information sessions, public meetings as well as consultations to increase the effectiveness of public health communications.
Key figures on EMA communication tools:
A special COVID-19 landing page was designed to make information related to the pandemic response more visible and easily accessible.
15 webpages were created reflecting the various aspects of EMA’s work, from collaboration with international regulators to guidance for developers and companies. Extensive information in lay language on how vaccines for COVID-19 are developed, authorised and monitored and about data requirements for approval was also made available on the EMA website.
93 news announcements were published to inform the public about key milestones in medicine assessment or new initiatives about the pandemic.
63 media interviews and close to 1,000 direct interactions with the media and the general public.
Two press briefings, attended by over 180 reporters, were organised in May and December 2020 to meet the huge media interest in EMA’s COVID-19-related activities; 326 unique articles were published in the first 24 hours after the May press briefing.
On 11 December 2020, EMA held its first public meeting on COVID-19 to explain how the Agency assesses and monitors COVID-19 vaccines and hear directly from European citizens about their needs and concerns. The meeting was held virtually and broadcast live. It was attended by more than 3,500 people, who had the opportunity to ask questions to EMA experts live.
Mobilising expertise from across the European network
The unprecedented mobilisation of experts through the European network 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.
In April 2020, as part of its health threats plan to fight COVID-19, EMA established the COVID-19 EMA pandemic Task Force (COVID-ETF). The group brought together the best expertise from the European medicines regulatory network and ensured a fast and coordinated response to the pandemic.
It was instrumental in:
conducting exploratory reviews of investigational products;
identifying the most appropriate regulatory pathway for ensuring that potential treatments and vaccines are approved and available as swiftly as possible;
providing rapid scientific advice on questions from medicine developers on their development plans, endorsed by EMA’s Committee for Medicinal Products for Human Use (CHMP);
interacting with academia or sponsors/investigators of clinical trials not funded by industry;
advising on start of rolling reviews and timing of CMA applications.
Thanks to its agile structure and strong human commitment, COVID-ETF has been instrumental in bringing together all the best expertise from across the European medicines regulatory network and facilitating fast decision-making by EMA scientific committees.
Coordinating the network’s response to shortages
Ensuring the continued availability of medicines for European patients during the COVID-19 pandemic has been high on the agenda of EMA and the European medicines regulatory network.
The EU network is continuously monitoring the supply chains of human and veterinary medicines in the EU and the impact of the increased use of these medicines during the pandemic.
Although most medicine shortages are normally dealt with at national level, during the COVID-19 pandemic, EMA acted as a central coordinator, supporting Member States' activities in preventing and mitigating supply disruptions.
In March 2020, the EU Executive Steering Group on Shortages of Medicines Caused by Major Events was established to provide strategic leadership for urgent and coordinated action.
In April, it launched an enhanced fast-track monitoring system with an initial focus on medicines used in COVID-19 patients in intensive care units (ICUs) that were in high demand early in the pandemic, such as anaesthetics, antibiotics, resuscitation medicines and muscle relaxants.
The monitoring system allows regulators to:
detect and monitor common issues across Member States;
spot patterns in medicines supply;
anticipate future supply disruptions early;
identify EU/EEA-wide measures to address disruption issues.
Each pharmaceutical company had to appoint an industry single point of contact (i-SPOC) responsible for reporting on ongoing or anticipated shortages of medicines used to treat COVID-19 patients. EMA compiles the information it receives from the i-SPOCs and shares it with the steering group for decision-making.
Although the supply situation of some medicines improved in the course of 2020, global supply challenges remain.
The European medicines regulatory network established key pillars in 2020 to help prevent and mitigate medicine shortages. Moving forward, this system will be further developed and contribute to strengthening the network’s overall response to supply issues, in particular during public health emergencies.
As Chair of the International Coalition of Medicines Regulatory Authorities (ICMRA), EMA led the global efforts to streamline and align regulatory requirements to facilitate medicine development and approval. Throughout 2020, EMA chaired or co-chaired a series of workshops and strategic meetings to exchange information and provide joint directions and recommendations on key aspects of medicine development and benefit-risk evaluation during the pandemic.
One of the key recommendations of the coalition was to stress the need for large, well-designed, controlled clinical trials to generate sound evidence on the effects of therapeutics or vaccines against COVID-19. This type of conclusive evidence is necessary to enable rapid development and approval of treatments and vaccines against COVID-19.
The group also outlined principles for trial design, specified concrete actions that COVID-19 clinical trial investigators should take when collecting, analysing and reporting data, and issued a pledge towards medicine developers to continue running clinical trials for as long as feasible, as this will allow the collection of critical data in support of further regulatory actions and vaccine deployment.
EMA shared the study protocols and code books with other regulators in ICMRA to facilitate joint utilisation and safety evaluation, as well as building more sustainable infrastructure for benefit-risk evaluation in pregnancy after the pandemic.
Early lessons from the COVID-19 response
Building on the experience from the 2009 H1N1 pandemic, EMA expanded the rolling review as a systematic tool to fast-track the assessment of data and prepare for speedier approvals. By allowing EU experts to scrutinise emerging evidence and question applicants early on, it proved to be a key enabler of fast-track assessment. Combined with the CMA, this approach allowed experts to reach a robust, science-based consensus opinion within the shortest time frame while ensuring that the medicine or vaccine meets the rigorous EU standards for safety, efficacy and quality and that comprehensive data will still be generated post-approval.
Early dialogue with medicine developers and academia helped EMA and experts of the EU network to keep abreast of emerging new technologies and prepare for them. The COVID-ETF supported this scientific work throughout the process, from the provision of advice to developers early in the development to steering scientific discussions at key milestones. The group played a major role in bringing together the best and most relevant expertise from across the EU network in an agile and proactive manner, and allowed quick and coordinated regulatory actions, based on sound scientific assessment. The critical role of the COVID-ETF in supporting the EU Member States and the European Commission with the rapid authorisation of medicines and vaccines was fully acknowledged. As a result, the European Commission announced in October 2020 that EMA will be tasked with formally establishing such a task force to lead the scientific response to any future public health emergency as part of the Agency’s extended mandate.
International cooperation that took place under the umbrella of ICMRA allowed steering research efforts and emphasised the need for the sound development and generation of robust data. Reaching agreements amongst regulators from all corners of the world on key aspects of medicine development and vaccine safety monitoring was a significant achievement and paved the way for even further cooperation and regulatory alignment.
Also, the public meeting organised by the Agency to explain how EMA assesses and monitors COVID-19 vaccines was acknowledged as an important tool for explaining complex concepts to the public, addressing some misunderstandings and responding to the public’s questions and concerns. Following the positive feedback received after the meeting, it was agreed that similar meetings would be held throughout the pandemic.