How vaccines are tested, licensed and monitored

The standard for testing and monitoring of vaccines is higher than it is for most other medicines because they are one of the few medical treatments given to healthy people - mainly healthy children.

This means that the level of acceptable risk is much lower than it might be in some treatments e.g cancer.

It can take many years for a vaccine to pass through all the stages described below. In the case of the MenB vaccine, for example, it took 15 years from the first publication of the genome (the complete set of genetic information in an organism) to the vaccine being licensed for use.

There are various stages that a vaccine must go through before use. These include;

Research and development:

This stage begins with reviewing the work that other scientists have done before.

Once this has been fully explored, the development of a new idea can begin.  Scientists will either come up with a new idea completely or will make changes to an existing idea.

Then the laboratory work can begin. Initially, the vaccine is tested on cells - this is called ‘in vitro’ testing.  Then, vaccines are tested on animals, often mice. This is called ‘in vivo’ testing.

The vaccine must pass these rigorous safety tests in this stage and demonstrate that the vaccine can cause an immune response in animals before moving on to the next stage.

Phase 1:

This is the initial stage of testing a vaccine in humans and involves a small group of adult participants, usually up to 100 people.

This is carried out to make sure that the vaccine does not have major safety concerns in humans and to work out the most effective dose.

Phase 2:

The next stage involves a larger group of participants, usually several hundred people, and may be from the target population. This stage checks that the vaccine works consistently, and scientists look at the immune response created by the vaccine. Doctors also start looking for potential side effects of the vaccine.

Phase 3:

The final stage of testing is in a much larger group of people, usually several thousand.

Phase 3 trials gather information on how well the vaccine has worked in humans (sometimes called the vaccine's efficacy), and the vaccine's safety. In Europe, more than 3000 participants are usually needed for the safety assessment before it can be licensed.

This means looking at whether the vaccine generates a level of protection that would prevent disease and provides evidence that the vaccine can either reduce the number of cases of that disease or reduce the harm caused by the disease to the individual.

It also gives a better chance of identifying rarer side effects not seen in the phase II study.

Human challenge model:

Sometimes, a ‘controlled human infection model’ (CHIM) is used to speed up the development of a vaccine. This type of carefully controlled study is where a healthy, fully consenting volunteer is deliberately infected with a disease, usually to test how well the vaccine works.  The volunteer is then monitored very closely, and if they become symptomatic, they are offered an effective treatment.

This is usually carried out during phase 2 or phase 3 of a clinical trial and can speed up the lengthy process of developing a vaccine.

Expert scientists and clinicians review data from the laboratory pre-clinical studies, clinical trials, manufacturing, and quality controls, and consider the conditions for its safe supply and distribution before licensing.

In the UK, the Medicines and Healthcare products Regulatory Agency  (MHRA) is responsible for regulating all medicines and medical devices by ensuring they work well and are acceptably safe. They also make sure that, for most people, the product’s advantages far outweigh the disadvantages.

The National Institute for Biological Standards and Control (NIBSC) is part of the MRHA that conducts independent laboratory testing so that each batch of vaccine meets the expected standards of safety and quality.

Even after licensing, vaccines continue to be monitored. The manufacturer of the vaccine may continue to test for safety, effectiveness, and other potential uses of the vaccine. This is sometimes called a phase 4 study, or post-license monitoring.

Although vaccines undergo rigorous testing before they are licensed for use, it is important that the safety of vaccines is monitored on an ongoing basis, as with all licensed drugs. In the UK this is undertaken by the MHRA through the Yellow Card Scheme. Reports of suspected side effects are sent to the MHRA by the manufacturers, (who are obliged to pass on any reports of suspected side effects that are defined as serious), health professionals, and, since 2005, patients themselves.

The data are evaluated each week and the reported side effects are compared against the expected side effects as detailed in the information sheet for the vaccine. If a previously unidentified reaction emerges, or the frequency of reactions is not in line with what is expected, then the MHRA will investigate.

Potentially, new side effects will be added to the product information leaflet, or for more serious side effects, warnings may be issued for specific groups of people who should not receive the vaccine.

In rare circumstances, the vaccine may be withdrawn from use.

You can find detailed information on the scheme here, and data on Yellow Card reports for individual products here.

The vaccine and the trials used to test it must meet the regulations laid down by the following authorities:

• ICH-GCP (International Conference on Harmonisation of Good Clinical Practice) - international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects
• Declaration of Helsinki (1964; 2008) - Ethical principles for medical research involving human subjects
• EU Clinical Trials Directive - enshrined in UK law by the Medicines for Human Use (Clinical Trials) Regulations (2004)
• RCPCH Guidelines for the ethical conduct of medical research involving children (2000)
• The Commission on Human Medicines (CHM) provides advice on the safety, efficacy and quality of vaccines. CHM is the government’s independent expert scientific advisory body established in October 2005.

In addition, for trials in the UK, the vaccine and the trial must receive individual approval from the Medicines and Healthcare products Regulatory Agency (MHRA), while the trial itself must be approved by the following authorities:

• An NHS Research Ethics Committee (see more information on the NHS Health Research Authority website )
• The local NHS Research and Development office, support and advises researchers in meeting the requirements of the UK regulatory framework (see more information on the framework )
• The Health and Safety Executive (HSE) for certain types of trials

In the European Union, the European Medicines Agency (EMA) supervises the regulation of vaccines, along with other drugs. See European Medicines Agency - EMA.

At an international level, the World Health Organization (WHO) makes recommendations via a committee for biological products (see WHO Expert committee on Biological Standardization). Many countries adopt such standards set out by the WHO.