COVID-19 vaccines: studies for approval
Table of contents
- What types of studies are needed to approve a COVID-19 vaccine?
- What are efficacy studies?
- How is the efficacy of COVID-19 vaccines studied?
- How many participants take part in efficacy studies and for how long?
- What is the level of efficacy that can be accepted for approval?
- What clinical data is needed to approve a variant-specific vaccine?
- Which benefits might not be known when a COVID-19 vaccine is initially approved?
- How is safety studied before approval?
- What data have to be provided for special populations and age groups?
- What studies are needed after approval?
- Monitoring COVID-19 vaccines in the real world
- How are clinical studies carried out in other parts of the world?
The European Medicines Agency (EMA) needs many detailed studies to confirm that a vaccine is safe, provides adequate protection and is of suitable quality. As a public-health body safeguarding medicines in the European Union (EU), EMA only recommends approval of a vaccine for COVID-19 after a thorough evaluation demonstrating the same high standards of quality, safety and efficacy required for any other vaccine approved in the EU.
Efficacy studies are large studies that evaluate the benefit of a medicine. For vaccines, these studies usually involve thousands of volunteers.
Developers first test the vaccine's efficacy in people who have not previously come into contact with the virus that causes COVID-19 - the so-called ‘naive populations’. People who have either come into contact with the virus or have been vaccinated present a certain level of immunity. This might need to be considered in the results if such individuals are included in efficacy studies.
The feasibility of determining whether a vaccine can protect people against COVID-19 depends on whether the virus is circulating and on whether there are any cases of disease that can be prevented.
In efficacy studies, volunteers randomly receive either the vaccine or an alternative. This alternative could be a vaccine that does not protect against COVID-19 or a placebo (a dummy treatment).
Normally, the doctors, clinical study participants and clinical trial personnel carrying out the study do not know who has received the vaccine and who has received the control. This is important to avoid biases when interpreting study results.
The studies measure efficacy ‘endpoints’ to see how well the vaccine works in the study and the level of protection it offers to participants.
Regulatory agencies recommend that the main endpoint (primary endpoint) should be how well a vaccine prevents laboratory-confirmed COVID-19 disease of any severity. This means how well the vaccine prevents symptomatic disease in people infected with SARS-CoV-2 as confirmed by a laboratory test.
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Efficacy studies also look at other relevant 'secondary endpoints', which give an idea of the other benefits of the vaccine. For example, a vaccine may reduce:
The reduction in the number of people needing hospitalisation or mechanical ventilation or the reduction in the number of deaths can help measure the efficacy of the vaccine in reducing disease severity.
As it becomes less feasible to conduct an efficacy study, for example because more and more people have already been exposed to COVID-19 or have been vaccinated against the virus, the immunogenicity of the vaccine (e.g. levels of antibodies or other types of immune responses induced by the vaccine) can be used instead as a surrogate for efficacy. This is also based on the knowledge accumulated on COVID-19 since 2020.
EMA advises companies to discuss their development plans with the Agency in order to identify the most appropriate studies to support approval.
For the approval of variant-specific vaccines, companies need to demonstrate that they have better immune response against the variant than existing vaccines.
For the initial approval of COVID-19 vaccines intended for a primary vaccination course, regulators usually require at least one main efficacy study in many thousands of participants. This enables regulators to reliably detect a sufficient number of cases of disease, which helps determine the level of protection that a vaccine can provide.
Initially, companies analyse the main study results after a few months of follow-up and submit the results to regulators, including EMA. This allows regulators to approve vaccines as soon as possible after the results confirm that the vaccine’s benefits exceed any potential risk. Study participants continue to be followed for at least two years.
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The continuation of efficacy studies is meant to allow the company to collect information on long-term protection and safety. This means that the company will collect some of the follow-up data after approval, when the vaccine is being used widely. This is acceptable, because regulators will have concluded that the data initially assessed are sufficient to show the vaccine’s efficacy and safety.
Observational studies will also collect data on the effectiveness of the vaccine in real life, allowing for the monitoring of its performance in a timely manner. This allows medicine developers and regulators to take actions if necessary.
EMA has not set a minimum level of efficacy for approval. This is because it looks at the overall balance of safety and efficacy for each vaccine individually before concluding on whether or not it will approve the vaccine.
For example, a vaccine could have other advantages, such as:
- very few side effects;
- easy storage and delivery;
- good results in a specific age group or type of population that may respond less well to other types of vaccines.
Nevertheless, medicine developers have been asked to design studies to demonstrate a rate of efficacy of at least 50%.
For the approval of variant-specific vaccines, companies need to demonstrate that these adapted vaccines have better immune response against the variant than originally authorised vaccines.
The Agency’s recommendations on the possible authorisation of adapted vaccines are taken based on all the evidence submitted.
To tackle rapidly emerging variants, EMA has approved adapted booster vaccines based on all available evidence. This includes quality as well as non-clinical and clinical data from previous evaluations of comparable subvariants and / or other variants of concern. This has enabled EMA to extrapolate the impact of changes in vaccine composition on the immune response.
Approving variant-specific vaccines should be coordinated globally, considering all emerging data. This should include data on the impact of a particular virus variant on the effectiveness of the approved vaccines. It should also include information on the variant’s transmissibility and on the severity of disease it causes.
EMA is working with developers to define suitable development programmes for variant vaccines, including the type of clinical trials they can carry out to provide adequate evidence to support the approval of the adapted vaccines in the EU.
The Agency had previously issued guidance outlining the requirements for manufacturers planning to modify their COVID-19 vaccines, including the data that they needed to provide.
However, as the situation with the Omicron subvariants is rapidly evolving, some aspects of this guidance may no longer apply. EMA advises developers to discuss their specific product development plans with the Agency.
For more information, see:
- Adapted vaccine targeting BA.4 and BA.5 Omicron variants and original SARS-CoV-2 recommended for approval (12/09/2022)
- First adapted COVID-19 booster vaccines recommended for approval in the EU (01/09/2022)
- Global regulators discuss path towards regulatory alignment on response to Omicron variant (13/01/2022)
- Reflection paper on the regulatory requirements for vaccines intended to provide protection against variant strain(s) of SARS-CoV-2
When EMA first approves a vaccine, some benefits may still be uncertain. The benefits only become clearer after the vaccine is in use.
Over time, regulators get more information about:
- protection against severe disease and death;
- asymptomatic cases after vaccination, i.e the number of people who get infected with the virus but do not develop symptoms. This is important because these people can still spread the virus to others;
- whether the vaccine can reduce the spread of the virus in the community. Reducing transmission will depend on many factors, including how many people get vaccinated;
- the vaccine’s effectiveness in the real world, i.e. outside the controlled setting of clinical studies.
Clinical trials have to show that the benefits in protecting people against COVID-19 are far greater than the risks and the potential risk of side effects.
Several thousand individuals receive the vaccine at the time of evaluation. This allows regulators to assess side effects that affect at least 1 in 1,000 vaccinated people.
Adapted vaccines are expected to be as safe as the originally authorised COVID-19 vaccines. This is because the modifications in the composition of adapted vaccines are minor and EMA has extensive safety data on the originally authorised vaccines.
Also, the safety profile of adapted vaccines, measured as local and systemic side effects, was not significantly changed compared to the originally authorised vaccines.
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As most side effects occur within four to six weeks after receiving a vaccine, for the originally authorised vaccines safety data have to cover at least six weeks after completion of vaccination, for approval purposes. However, the studies will follow volunteers up for at least a year to see if there are any longer-term side effects.
Side effects of a new vaccine that are so rare that affect less than 1 in 10,000 people can only be detected after collection of very large data sets. This is likely to be feasible only once large numbers of people have received the vaccine.
A robust safety monitoring plan is in place in the EU to gather and evaluate any side effects that may arise during vaccination campaigns promptly.
For more information, see
Initially, vaccine studies focus on adults, including older adults, as well as people with underlying diseases that put them at particular risk of severe COVID-19. Some studies may also include adolescents from 16 years of age.
People above 65 years of age should represent at least a quarter of the total number of participants in studies. This group is at greatest risk of severe COVID-19.
Results from earlier safety and immunogenicity testing determine whether these people should be included in large clinical studies.
Studies should also include people from ethnic minorities.
Investigations into the use of COVID-19 vaccines in children are carried out once there is sufficient information from studies in adults and adolescents.
For more information, see
Data from long-term clinical studies on safety and efficacy are important for a number of reasons. These data allow the assessment of how protection against COVID-19 evolves over time, such as if the level of antibodies in the blood might go down after some time.
Long-term data are also important to assess whether there is any risk of vaccine-associated enhanced disease (VAED). VAED is a condition that would occur when a vaccinated person subsequently infected with a virus develops a more severe disease than they would have had if they were not vaccinated.
This has been seen in animal models given vaccines against SARS or MERS (different types of coronaviruses causing severe disease) and never with humans given such SARS or MERS vaccines. VAED has not been seen with COVID-19 vaccines in any studies done so far.
Long-term clinical studies help monitor how effective vaccines are and how long they protect people against COVID-19. This can help determine whether booster doses are needed.
Protection against COVID-19 has been shown to decrease as a result of the spread of new variants that can better evade the immune protection.
Adapted vaccines against variants of concern of SARS-CoV-2 have started to be approved in the EU. Long-term safety studies are also being carried out.
For more information, see:
Since the COVID-19 pandemic affects people worldwide, it is important for companies developing COVID-19 vaccines to generate robust evidence that meets the needs of regulators around the globe. This is why EMA and other medicines’ regulators have agreed key principles on how to carry out clinical trials for COVID-19 vaccines.
Companies applying for approval of a vaccine in the EU must ensure that clinical studies meet stringent EU requirements no matter where in the world they took place.
For more information, see: