COVID-19 vaccines: development, evaluation, approval and monitoring
The European Medicines Agency (EMA) plays an important role in enabling the development, scientific evaluation, approval and monitoring of COVID-19 vaccines in the European Union (EU).
Vaccines for COVID-19 are developed, evaluated and approved according to current scientific knowledge and applicable regulatory guidelines and legal requirements.
Figure 1: Overview of vaccine development and approval stages
Like all medicines, COVID-19 vaccines are first tested in the laboratory (e.g. studies on their pharmaceutical quality and studies to check first the effects in laboratory tests and animals).
Vaccines are then tested in human volunteers in studies called clinical trials. These tests help confirm how the vaccines work and, importantly, to evaluate their safety and protective efficacy.
Standard vaccine development
Standard vaccine development is a long process and studies are done in sequential steps.
Companies first make small batches and do small scale studies to characterise and optimise the production process. They perform studies to determinate a suitable formulation that can keep vaccine components stable to the end of its shelf life.
Then the company decides whether to continue development and scale up production. To assure that the vaccine meets its intended quality profile and complies with regulatory standards, the company develops a suitable and effective quality control strategy.
Studies on pharmaceutical quality look at the individual vaccine components, the final formulation to be used and at the whole manufacturing process in detail.
The vaccine developer conducts more studies in laboratory models, using in vitro studies (e.g. cells in culture) or animal models (in vivo studies), to show how the vaccine triggers an immune response and works to prevent infection.
Finally, the vaccine developer studies the vaccine in three phases of clinical trials, with larger numbers of volunteers in each phase.
For approval, companies must also show that large scale commercial manufacturing consistently produces vaccines of the required quality.
Scaling up production and adaptations to commercial manufacturing can continue in the post-authorisation phase.
Did you know..?
Clinical trials in human medicines, including those for COVID-19 vaccines, are authorised and managed at national level in the EU. National competent authorities and ethics committees ensure that studies are scientifically sound and conducted in an ethical manner.
Human pharmacology studies (phase I trials) generally involve between 20 and 100 healthy volunteers to confirm if the medicine behaves as expected based on laboratory tests. This can establish:
Therapeutic exploratory studies (phase II trials) involve several hundred volunteers. The purpose of this phase is to study the best doses to use, the most common side effects and how many doses are needed.
These studies also check that the vaccine triggers a good immune response in a broader population. In certain cases, it could also provide some preliminary indications of how well the vaccine will work (efficacy).
Clinical efficacy and safety studies (phase III trials) include thousands of volunteers. This phase shows how efficacious the vaccine is at protecting against the infection compared with placebo (dummy) or alternative treatment and what are the less common side effects in those receiving the investigational vaccine.
The reduction in number of people with symptoms, severe disease or diagnosed with the infection can help to measure the efficacy of the vaccine.
For information on ongoing COVID-19 clinical trials in the European Economic Area (EEA), see COVID-19 vaccines: research and development.
For more information, see:
- Approval of vaccines in the European Union: European Vaccination Information Portal
- Authorisation of medicines
- Clinical trials in human medicines
Fast-track vaccine development in a public health emergency
Vaccine development for COVID-19 vaccines continues to be fast-tracked globally. Development is compressed in time, applying the extensive knowledge on vaccine production gained with existing vaccines.
Early scientific advice from regulators helps speed up development. EMA additionally offers informal consultation with its COVID-19 Task Force (ETF) and rapid scientific advice. COVID-19 vaccine developers can receive prompt guidance and direction on the best methods and study designs to generate robust data. For more information, see:
Advising companies on regulatory requirements helps ensure that standards of quality, safety and efficacy are embedded early in the process and are taken into consideration when planning fast track development. Channeling resources and efforts at various levels ensures that high standards are maintained in the development and in the assessment of the dossiers.
Figure 2: Indicative timelines for COVID-19 vaccines compared with standard vaccines
Use the buttons below to compare:
Vaccine manufacturers and academics use established production systems already used for safe and effective vaccines. In addition, they continuously research novel approaches to producing and developing vaccines, and some of the advances made to date are also applied to developing vaccines for COVID-19.
Some vaccines for COVID-19 are developed using novel methods intended to increase the volume and speed of production compared to other types of vaccines, enhance product stability and bring about strong immune responses.
Other vaccines are developed using existing methods used for vaccines for other diseases, making it easier to use existing production facilities to produce COVID-19 vaccines at a large scale.
Companies may use various approaches to reduce development timelines while ensuring high standards and adherence to legal requirements, such as:
- mobilising more human resources simultaneously to analyse results from earlier studies more quickly and map out next steps in terms of resources, funding and regulatory strategy;
- combining clinical trial phases or conducting some studies in parallel where safe to do so.
Companies have also expanded manufacturing capacity and large-scale production to facilitate vaccine deployment without delay once approved. In the EU, the European Commission has provided support to facilitate vaccine development and deployment as quickly as possible.
Some vaccine developers started manufacturing their COVID-19 vaccine before obtaining an EU marketing authorisation. This allowed them to be ready to distribute doses rapidly enough to meet demand once they were authorised.
Developers must still uphold the same good manufacturing practice (GMP) standards that apply in the EU to all vaccines.
All pharmaceutical manufacturers need a manufacturing licence from the national competent authority where they operate. National competent authorities carry out GMP inspections to check that manufacturers comply with EU standards, the conditions of their licence and the marketing authorisation if obtained.
The European medicines regulatory network has sped up the approval of new manufacturing lines and manufacturing sites for COVID-19 vaccines. The EU's labelling and packaging requirements are also more flexible for COVID-19 vaccines to enable rapid roll-out.
For more information, see:
Figure 3: Key components of vaccine development - standard vaccines compared with COVID-19 vaccines
COVID-19 vaccines must be approved according to the same standards that apply to all medicines in the EU
COVID-19 vaccine development is compressed in time, applying the extensive current knowledge on vaccine development.
COVID-19 vaccine development mobilises more resources simultaneously.
COVID-19 vaccine development is supported by early, continuous dialogue between developers and a dedicated group of regulatory experts.
Companies are expanding manufacturing and production capacity to ensure efficient vaccine deployment.
Did you know..?
EMA is not involved in providing incentives to developers of COVID-19 vaccines, other than enabling access to regulatory procedures, such as providing free scientific advice for vaccine development. EMA also has no role in negotiating potential vaccine availability, funding or deployment at EU or national level.
For more information on these topics, see:
COVID-19 vaccines can only be approved and used if they comply with all the requirements of quality, safety and efficacy set out in the EU pharmaceutical legislation. For more information, see Authorisation of medicines.
In view of the pandemic, EMA and regulatory agencies in Europe are diverting resources to speed up processes and reduce timelines for the evaluation and authorisation of COVID-19 vaccines.
Robust regulatory framework and scientific expertise in the EU
The EU’s pharmaceutical legislation ensures that vaccines are only approved after scientific evaluation has demonstrated that their overall benefits outweigh their risks.
A vaccine's benefits in protecting people against COVID-19 must be far greater than any side effect or potential risks.
EMA ensures that scientific experts evaluating medicines do not have any financial or other interests that could affect their impartiality. For more information see Handling competing interests.
A high level of transparency, which opens EMA’s scientific evaluation work to public scrutiny, safeguards the independence of EMA's scientific evaluations. For more information, see Transparency: exceptional measures for COVID-19 medicines.
Scientific evaluation and approval processes
To gain approval for a vaccine in the EU, the vaccine developer submits the results of all testing / investigations to the medicines regulatory authorities in Europe. This is part of a marketing authorisation application.
Figure 4: Evaluation and approval steps for COVID-19 vaccines
Most COVID-19 vaccines in the EU will be evaluated by EMA via the centralised procedure (which is mandatory for any vaccine using biotechnology).
EMA's expert scientific committees on human medicines (CHMP and PRAC) carry out EMA's evaluations. EMA has set up the multidisciplinary COVID-19 EMA pandemic Task Force (COVID-ETF) bringing together key experts from across the European medicines regulatory network to ensure a fast and coordinated response to the pandemic.
EMA also collaborates with international experts during the review of COVID-19 vaccines through the OPEN initiative, launched in December 2020. OPEN allows non-EU regulators from Australia, Canada, Japan, Switzerland, as well as WHO, to take part as observers in the scientific evaluation of EMA’s ETF and CHMP, while maintaining their scientific and regulatory independence.
For more information see:
- The evaluation of medicines, step-by-step
- Authorisation of medicines
- From laboratory to patient: the journey of a centrally authorised medicine
- Committees, working parties and other groups
- EMA COVID-19 assessments ‘OPEN’ to non-EU regulators (04/02/2021)
- World Health Organization (WHO)
Did you know..?
A vaccine is introduced into national healthcare systems only after regulatory approval and thorough quality control. The details differ for each EU Member State but each batch released onto the EU market is always tested prior to release.
Stringent testing is done by the company holding the marketing authorisation and batches must meet the specifications approved by authorities.
For vaccines used in public health immunisation programmes, an official medicines control laboratory performs an additional independent control for each batch of vaccine. This independent control is referred to as Official Control Authority Batch Release (OCABR) and includes testing of agreed quality parameters and compliance check of the manufacturer’s own test results.
For more information, see:
According to the EU pharmaceutical legislation, the standard timeline for the evaluation of a medicine is a maximum of 210 active days.
However, EMA treats marketing authorisation applications for COVID-19 products in an expedited manner. This allows the timeline for evaluation to be reduced to less than 150 working days.
For this scope, EMA can use its rolling review procedure for promising medicines for COVID-19. This allows EMA to begin assessing data as they become available during the development process, to expedite the subsequent formal marketing authorisation application assessment even further.
Figure 5: Standard evaluation process compared with rolling review of COVID-19 vaccines
When an evaluation is complete, EMA has the option of recommending a conditional marketing authorisation, a type of approval for medicines addressing unmet medical needs, and in particular those to be used in emergency situations in response to public health threats recognised by the WHO or the EU.
For more information, see Accelerated procedures for COVID-19 treatments and vaccines.
Did you know..?
A conditional marketing authorisation guarantees that the approved vaccine:
Conditional marketing authorisation is a tool that allows regulators to approve a medicine quickly and in a pragmatic manner when there is an urgent need.
A conditional marketing authorisation is different from an emergency use authorisation, which some countries use to permit the temporary use of an unauthorised medicine in an emergency situation. An emergency use authorisation is not a marketing authorisation.
EU legislation foresees that conditional marketing authorisation is used as the fast-track authorisation procedure during public health emergencies to speed up approval and save lives.
It is the most appropriate tool to grant access to a vaccine to all EU citizens at the same time and to underpin mass vaccination campaigns.
The scientific evaluation needs to show that a vaccine’s benefits in protecting people against a specific disease, like COVID-19, are far greater than any potential risk.
Like any medicine, vaccines have benefits and risks. Even highly effective vaccines are not one hundred per cent effective in preventing disease or one hundred per cent safe in all vaccinated people.
At the time of approval, the main body of evidence for vaccine safety and efficacy comes from large, controlled, randomised clinical trials. As part of such trials, selected volunteers are randomly given either the vaccine being tested or a placebo injection. They are then monitored under controlled conditions, in line with strict protocols.
After approval, many people will be vaccinated. Certain rare or very rare side effects may only emerge when millions of people are vaccinated. EU law requires that the safety of vaccines is monitored while they are in use in routine clinical practice.
Safety information on COVID-19 vaccines is available:
The EU has a comprehensive safety monitoring and risk management (pharmacovigilance) system, which ensures measures are in place for:
- providing advice to minimise risk;
- reporting suspected side effects;
- conducting studies after authorisation;
- detecting any potential side effects;
- conducting rigorous scientific assessments of all safety data;
- introducing any necessary mitigating actions early on.
Competent authorities may carry out safety and efficacy studies after authorisation and can also require a marketing authorisation holder to carry out such studies as an obligation of the authorisation. Public health authorities responsible for vaccination programmes will also conduct other studies.
Studies collecting effectiveness data give additional information, for example, on long-term protection, on the need for and timing of booster doses, or on the effectiveness of a vaccine against new variants, to complement the ‘efficacy’ data obtained in clinical trials before the vaccine was authorised.
For more information, see:
- Pharmacovigilance: Overview.
- Monitoring vaccine safety and reporting side effects: European Vaccination Information Portal
Figure 6: Pharmacovigilance cycle
Large scale monitoring activities in the pandemic context
Regulators and vaccine developers are also mobilising extra resources to monitor safety and manage risk during the pandemic. This is important because exceptionally large numbers of people receive COVID-19 vaccines once they are authorised; many more than the large numbers who have been receiving the vaccines in clinical trials. In addition, people vaccinated as part of mass vaccination campaigns are more diverse than those selected to take part in trials.
Figure 7: How vaccine safety is studied
This plan also ensures that regulators can take any appropriate regulatory actions and communicate these to the public as quickly as possible.
The monitoring activities in the plan apply to all vaccines, but they take place on a larger scale during this pandemic:
- Collecting exposure data to COVID-19 vaccines
- Adopting specific safety signal detection and management measures
- Setting up a European infrastructure for monitoring COVID-19 treatments and vaccines
- Using real-world data from clinical practice
- Applying exceptional transparency measures
EMA's guidance on preparing risk management plans for COVID-19 vaccines helps marketing authorisation applicants develop risk management plans for COVID-19 vaccines:
These risk management plans set out how the company will monitor and report on safety and how it will characterise and manage risks following authorisation of a COVID-19 vaccine.
For a period of at least six months after authorisation, companies responsible for COVID-19 vaccines need to submit monthly safety summaries for COVID-19 vaccines, in addition to periodic safety update reports. They also need to put processes in place to manage a high volume of safety reports. They need to carry out further studies on COVID-19 vaccines that receive a conditional marketing authorisation.
Additional considerations in this guidance address traceability tools that can help record who has received which vaccine and from which batch.
EMA publishes the full body of the risk management plans for all authorised COVID-19 vaccines, in line with its exceptional transparency measures for COVID-19 medicines.