EMA COVID-19 vaccines against SARS-CoV-2(2019nCoV) studies for approval guidance

· 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?
· 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?
· 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 will only approve a vaccine for COVID-19 after a thorough evalutation demonstrating the same high standards of quality, safety and efficacy required for any other vaccine approved in the EU.

What types of studies are needed to approve a COVID-19 vaccine?

A company developing a COVID-19 vaccine must submit an application to EMA containing data from various studies:

Pharmaceutical quality studies
Non-clinical studies
Clinical studies

Pharmaceutical quality studies

Pharmaceutical quality studies provide information about the vaccine’s quality. This includes:

· the vaccine’s active components, purity and other ingredients (e.g. stabilisers);
· the way the vaccine is manufactured and controlled;
· the vaccine's stability and shelf life;
· how best to store the vaccine.

A company developing a COVID-19 vaccine also needs to provide detailed information to justify the use of each ingredient in the vaccine, as well as the manufacturing technology it is using.

It can only produce the vaccine in approved, certified facilities. It needs to show that the vaccine's manufacture will be consistent in those facilities.

It must also maintain agreed high standards for each batch of the vaccine that is released after it has been authorised.

Companies must show that commercial batches of vaccines are of the required quality, because sometimes they produce them at a much larger scale than batches used in clinical studies.

Non-clinical studies

Like all medicines, vaccines undergo non-clinical or laboratory studies before they are tested in humans.

These studies are carried out in the laboratory. They show whether the vaccine might cause safety problems, which could include effects on reproduction or development in extreme cases.

In addition, companies often carry out these types of non-clinical studies:

· Immunogenicity studies: these look at the types of immune responses a vaccine brings about. For example, they can look at the formation of antibodies or at long-term immune responses by 'memory cells' in the immune system;
· Animal-challenge studies: these look at whether animals given a COVID-19 vaccine are protected from disease when exposed to SARS-CoV-2, the virus that causes COVID-19 disease;
· Biodistribution studies: some types of vaccine require these to show how the vaccine reaches the tissues and organs in the body.

Clinical studies

Clinical studies are studies in humans that show how safe and efficacious a vaccine is.

For COVID-19 vaccines, these studies need to look at immune responses, efficacy and safety.

National authorities and ethics committees in each country authorise and regulate clinical studies for COVID-19 vaccines. This safeguards the safety and rights of the volunteers taking part in the studies. It also ensures that the data generated by the studies are robust.

Clinical studies with authorised or investigational medicines in the EU have to comply with good clinical practice (GCP). This covers international ethical and scientific quality standards for designing, recording and reporting studies in humans.

Compliance with these standards provides assurance that the rights, safety and wellbeing of study participants are protected, and that clinical-study data are credible.

If there are concerns over the conduct of a clinical study or the integrity of the clinical study data during the scientific evaluation of a vaccine, the CHMP will consider;inspecting the study site and will request an inspection if necessary.

EMA works in close collaboration with international partners, sharing information on inspections and facilitating inspections when they are needed.

For more information, see Clinical trials in human medicines

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For more information, see:

What are efficacy studies?

Efficacy studies are large studies that evaluate the benefit of a medicine. For vaccines, these studies usually involve thousands of volunteers. The main efficacy studies for COVID-19 vaccines involve tens of thousands of participants.

Developers first test first the vaccine's efficacy in people who have not previously come into contact with the virus that causes COVID-19 disease. These people are more difficult to protect than people who have already come into contact with the virus. They represent the majority of the general population.

The feasibility of determining whether a vaccine can protect people against disease depends on whether the virus is circulating and on whether there are any cases of disease that can be prevented.

How is the efficacy of COVID-19 vaccines studied?

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 the company carrying out the study do not know who has received the vaccine and who has received the control. This is important to avoid errors 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.

For more information, see the statement published by members of the International Coalition of Medicines Regulatory Authorities (ICMRA) in July 2020: ICMRA statement on clinical trials

Did you know..?

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 number of people infected;
the number of severe cases of a disease;
the severity of the disease.

The reduction in 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.

How many participants take part in efficacy studies and for how long?

Regulators need at least one main efficacy study in many thousands of participants (over 30,000) to rapidly detect a sufficient number of cases of disease that allows concluding on how much protection 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.

Did you know..?

The efficacy studies may continue for two years or more, 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.

For more information, see:

- COVID-19 vaccines: development, evaluation, approval and monitoring: Monitoring vaccine safety and use in real life

What is the level of efficacy that can be accepted for approval?

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.

As an example, 'vaccine A' could have a lower efficacy than 'vaccine B'. However, vaccine A could have other advantages, such as:

· fewer side effects;
· easy storage and delivery;
· better results in a specific age group or type of population.

In spite of this, medicine developers should design studies to demonstrate a rate of efficacy of at least 50%.

What do the different efficacy levels mean?

In a study measuring how well a vaccine prevented people from becoming ill from COVID-19:

Efficacy	What it means
50%	that there were 50% fewer cases among people who received the vaccine compared with those who did not (i.e. the vaccine prevented 50% of cases)
90%	there were 90% fewer cases among people who received the vaccine compared with those who did not (i.e. the vaccine prevented 9 out of 10 cases)
100%	nobody who received the vaccine got the disease

Which benefits might not be known when a COVID-19 vaccine is initially approved?

When EMA first approves a vaccine, some benefits may still be uncertain. The benefits will only become clearer after the vaccine is in use.

Over time, regulators may get more information about:

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.

How is safety studied before approval?

Clinical trials will 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 will have received the vaccine at the time of evaluation. This will allow regulators to assess side effects that affect at least 1 in 1,000 vaccinated people.

Did you know..?

As most side effects occur within four to six weeks after receiving a vaccine, 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

What data have to be provided for special populations and age groups?

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 disease. 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 disease.

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 planned for once there is sufficient information from studies in adults and adolescents.

For more information, see

What studies are needed after approval?

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.

For more information, see:

How are clinical studies carried out in other parts of the world?

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:

EMA COVID-19 vaccines against SARS-CoV-2(2019nCoV) studies for approval guidance

Table of contents

What types of studies are needed to approve a COVID-19 vaccine?

Pharmaceutical quality studies

Non-clinical studies

Clinical studies

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 do the different efficacy levels mean?

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?

How are clinical studies carried out in other parts of the world?

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