In general, before a vaccine can be authorised (approved), a company must carry out a lengthy process to test the vaccine and evaluate:
- Efficacy: that the vaccine protects against disease
- Safety: any side effects associated with vaccination
- Quality: that the vaccine is manufactured in accordance with the applicable standards
Due to the covid-19 pandemic, fast track procedures were introduced for the approval of covid-19 vaccines. For more information see section "Fast track procedures".
How vaccines are tested in clinical studies
1. Preclinical:
Before a vaccine can be tested on humans, research scientists must conduct a series of preclinical studies. These include both in vitro (laboratory analyses) and in vivo studies (animal studies). These studies determine any potential side effects (adverse reactions) and the ability of the vaccine to induce immune responses.
2. The three phases of clinical development:
Phase 1 – An initial dose is given to a small group of volunteers. The safety of the vaccine is evaluated at this stage. Different doses of the vaccine are tested in order to select the most appropriate dose.
Phase 2 – During this phase, the safety and ability of the vaccine to induce an immune response (immunogenicity) is evaluated amongst hundreds of volunteers that can include subgroups of participants according to age and health status.
Phase 3 – These are large controlled clinical studies that include thousands of volunteers. This phase evaluates whether the vaccine protects against disease and collects data on side effects. Many of the coronavirus vaccines are being tested on anything from 3,000 to 60,000 people.
Each clinical phase may have several studies in order to obtain answers to different questions. Some manufacturers conduct clinical studies in several phases in parallel. In some cases, several clinical phases may also be incorporated within one clinical study.
Quality requirements for the vaccine
From development to and large-scale manufacture of a vaccine, many standards must be followed in order to document the pharmaceutical quality of the vaccine (consistency of manufacture). This includes data on purity, ingredients and stability (shelf life) of the vaccine, as well as the conditions for its manufacture.
Fast track procedures
Covid-19 is a global crisis. During a pandemic, it is vital that a vaccine is made available as soon as possible. The benefits and risks associated with vaccines are always evaluated against the risk of serious illness and death.
The European Medicines Agency (EMA) is shortening a number of procedures in order to facilitate rapid development and authorisation. Although the EMA is facilitating faster procedures, it is essential for approval that sufficient evidence of efficacy, safety and quality are available.
- Rolling review: The EMA normally requires that all data are available before a company applies for a marketing authorisation (approval). However, a rolling review procedure has been introduced, where the data are evaluteted in several stages (rolls). Once sufficient data are available, the company can apply for a marketing authorisation. This procedure is used in circumstances when there is a serious threat to public health, such as a pandemic.
- Accelerated procedure: The processes for evaluating an application for marketing authorisation is shorter than normal. The standard procedure takes 210 days, but for anaccelerated procedure, it takes just 150 days.
Authorisation of covid-19 vaccines
The European Medicines Agency authorises covid-19 vaccines once the benefits and risks based on data from the clinical trials have been evaluated. Vaccines are only authorised if the benefits outweigh the risks.
Conditional approval
In urgent cases where there is an unmet medical need, the authorities can authorise a vaccine before they have received all the documentation that is normally required. This is known as a 'conditional approval' and provides an opportunity to secure fast access to a vaccine during a pandemic.
A conditional approval is granted based on fulfilling all of the following criteria:
- the benefit-risk balance of the medicine is positive
- it is likely that the applicant will be able to provide comprehensive data post-authorisation
- the medicine fulfils an unmet medical need
- the benefit of the medicine's immediate availability to patients is greater than the risk inherent in the fact that additional data are still required
In order to be granted conditional approval, legal requirements must be met where the vaccine manufacturer is to provide EMA with additional data on a continuous basis following the conditional authorisation. Conditional authorisations are granted for a period of one year and can be extended annually. Once the authorities have received all the agreed documentation, a conditional authorisation can be amended to a full authorisation (marketing authorisation).
What we know at the time of authorisation
- Each vaccine has an acceptable effect, but we do not know how long the effect will last.
- Common and less common side effects, but probably less about side effects in children, the elderly and pregnant women. Many of the larger clinical studies have not set an upper age limit for participation. Most companies aim to include individuals in risk groups, such as the elderly, in order to obtain the broadest possible evidence of efficacy and side effects.
- We know about side effects which develop during the days and weeks after administration of the vaccine, but we cannot rule out rare side effects or the possibility of side effects which appear long after vaccination.
The European Medicines Agency (EMA)
Both full marketing authorisations and conditional marketing authorisations are based on recommendations from EMA, which are adopted by the European Commission. Such authorisations will also apply in Norway.
The role of the Norwegian Medicines Agency
The Norwegian Medicines Agency plays an active role in the European medicines collaboration assessing the efficacy and safety of vaccines, and that the vaccines are manufactured in accordance with applicable quality requirements. We monitor vaccines closely once they have been rolled out in order to detect any new, unexpected and serious side effects. We do this together with all other countries where the vaccine has been rolled out.
Vaccines are monitored particularly closely by the medicinal authorities. In addition to the pharmaceutical quality tests that are conducted by the vaccine manufacturer, each vaccine batch is tested by an independent regulatory laboratory before it is released onto the market. The Norwegian Medicines Agency has one of these laboratories in the European collaboration of official medicines control laboratories (OMCL).
It is the Norwegian Institute of Public Health that recommends which authorised vaccines should be introduced and who should be vaccinated and how the vaccines will be used.
Surveillance and following-up of side effects
Clinical studies involve a relatively small group of participants over a limited period of time and under controlled conditions. Once a vaccine is rolled out, it is used by a much larger and more diverse group of people. They may have other illnesses and may be taking other medicines at the same time, which can influence the side effects that can arise. Although serious side effects to vaccines are rare, some can only be detected once a vaccine has been rolled out and given to many more people and more diverse groups than in the clinical studies. It is therefore important that vaccines are monitored for as long as they remain on the market.
The use of pandemic vaccines are closely monitored in order to rapidly detect any side effects. Reporting by both healthcare professionals and patients is key to detecting new, unexpected and serious side effects.
For more information see reported suspected adverse reactions of covid-19 vaccines.
Melde.no
Healthcare professionals can report suspected side effects following vaccination using an electronic form via melde.no.
Private individuals can report side effects using an electronic form via helsenorge.no.
Reports on side effects can be linked to data from other national health registries and compared with international health registries. This provides us with a better basis for assessing causation, which in turn will lead to better patient safety.
