First, the pathogen is analysed and tested to determine which components of the virus the human immune system reacts to and can build up protection against (via antibodies and the cellular immune response).
This step is followed by the design of the vaccine: Which vaccine platform is suitable and which additives should be used?
As part of the pharmacological/toxicological studies, the vaccine’s immunogenicity, i.e. its ability to produce a specific immune response against the target pathogen, is tested on animals. In addition, potential toxicological properties are investigated, including by the repeated administration of a higher vaccine dose (repeat-dose toxicity). These studies also examine the distribution of vaccine components in the organism, local reactions, potentially harmful effects on fertility and embryonic development, inflammatory parameters after vaccination, vaccination protection levels, and any indications of an intensification of infection.
Once it has been proven that the vaccine can be reliably and consistently manufactured at a level of quality suitable for human use, it is tested in phase 1 to phase 3 clinical trials on volunteers who have received comprehensive information. The tolerability, safety and efficacy of the vaccine candidate are tested clinically. If there is sufficient data from the quality-assured, consistent manufacture of a high-quality vaccine product, as well as satisfactory results from the preclinical and clinical trials, an application can be submitted for marketing authorisation.
For the countries of the European Economic Area (EEA), the assessment procedure for COVID-19 vaccines is coordinated by the European Medicines Agency (EMA). The EMA’s vaccine assessment is carried out by experts from the national medicines authorities of the EU member states and the EEA countries in the Committee for Medicinal Products for Human Use (CHMP), in cooperation with the CHMP’s Biologics Working Party (BWP) and the Pharmacovigilance Risk Assessment Committee (PRAC). If the vaccine meets all the legal conditions relating to medicinal products and the risk-benefit ratio is favourable, the CHMP issues a positive opinion with a recommendation for authorisation, on the basis of which the European Commission can issue the marketing authorisation. The authorised vaccine product can then be marketed and used on humans after batch testing is carried out by the Paul-Ehrlich-Institut in Germany.
In Germany, the recommendation as to which groups of people should be vaccinated against an infectious disease and at which times is issued by the Standing Committee on Vaccination (Ständige Impfkommission, STIKO) at the Robert Koch-Institut, in which the Paul-Ehrlich-Institut is represented as a guest.
Updated: 25.07.2024
In Germany, the Paul-Ehrlich-Institut is responsible for the authorisation of vaccines, i.e. the evaluation of quality, safety and efficacy as well as pharmacovigilance (drug safety) after authorisation.
The Standing Commission on Vaccination (Ständige Impfkommission, STIKO), located at the Robert Koch Institute (RKI), prepares vaccination recommendations based on data on the efficacy and safety of the respective approved vaccines so that vaccines can be used optimally. For this purpose, the STIKO incorporates the assessments of the Paul-Ehrlich-Institut on the safety of vaccines.
After a vaccine has been authorised, all reports of suspected adverse reactions or vaccine complications are continuously recorded and evaluated. The monitoring of side effects by the Paul-Ehrlich-Institut on the basis of suspected case reports of side effects and vaccine complications assists in the rapid detection of new risk signals for the use of vaccines and other biomedicines. The Paul-Ehrlich-Institut uses pharmacovigilance measures to not only quickly detect new risk signals, but also to take or initiate measures to reduce risks when needed. This is done both nationally and at European level.
The Paul-Ehrlich-Institut publishes on a regular basis safety reports on reported suspected cases in Germany following vaccination against COVID-19.
Updated: 28.03.2024
During the pivotal clinical trial testing the safety and efficacy of a vaccine candidate, normally phase 3 or 2/3, the study participants are assigned randomly to one of two groups. One group is vaccinated with the vaccine candidate (the “verum group”), while the control group is given a placebo or another vaccine. Care is taken to ensure that both groups have a similar composition (e.g., in terms of age, gender, etc.) and that there is a comparable risk of infection. A laboratory-confirmed symptomatic infection or illness that occurs at a specific point in time after vaccination is then recorded in both groups and the frequency is compared. A calculated efficacy of 90% means that the number of infections or illnesses that occurred in the vaccinated group within a certain time was reduced by 90% compared to a non-vaccinated control group (e.g. n = 10 vs. 100 cases with groups of the same size).
Updated: 12.08.2024
The centralised procedure, which is coordinated by the European Medicines Agency (EMA), is the standard procedure for the marketing authorisation of a medicinal product in Europe.
In the centralised procedure, the evaluation of a marketing authorisation application for a new medicinal product takes up to 210 working days. During this time, the medicines experts representing the national medicines authorities of the EU Member States at the EMA assess the documents submitted by the applicant on the quality, safety, efficacy and benefit-risk ratio of the vaccine candidate.
The evaluation period is interrupted by one or two "clock-stops". During a clock-stop, the applicant prepares answers to questions asked by the Committee for Medicinal Products for Human Use (CHMP). The maximum duration of a clock-stop depends on how much time the applicant believes they will need to answer the questions. The CHMP must approve the clock-stop duration. In general, the first clock-stop lasts three to six months, while the second lasts one to three months.
In total, the assessment of a new medicinal product normally takes around one year.
Updated: 25.07.2024
In the EU, there are three standardised procedures, each of which permits early marketing authorisation under certain conditions:
In addition to these procedures, medicine developers can participate in a voluntary programme for accelerating the marketing authorisation process, the PRIME scheme of the European Medicines Agency (EMA).
In order to accelerate the authorisation of COVID-19 vaccines as much as possible in the early stages of the pandemic, the rolling review procedure was used. This procedure was intended for precisely this type of pandemic health situation.
Updated: 19.04.2024
In the accelerated assessment procedure, the timeframe for regulatory assessment is reduced from 210 days to 150 days. The prerequisite is that the European Medicines Agency (EMA) must approve the medicine developer’s request for an accelerated assessment.
This procedure is possible for medicinal products that are of major interest for public health, e.g. because they target a disease for which there is currently no treatment option or address an unmet medical need.
Updated: 28.03.2024
A conditional marketing authorisation is a marketing authorisation that is linked to certain conditions. It can be granted for a medicine in the interest of public health,
if the CHMP finds that all the following requirements are met:
Conditional marketing authorisations are valid for one year and can be renewed annually. They can be converted into a full marketing authorisation.
The marketing authorisation holder is required to fulfil specific obligations (ongoing or new studies, and in some cases additional activities) in the specified timeframe with a view to providing comprehensive data that confirms that the benefit-risk balance continues to be positive.
Once all obligations have been conclusively fulfilled and, as a result, more comprehensive data on the medicinal product has been obtained, the marketing authorisation is converted into a normal authorisation with unlimited validity that is not subject to any specific obligations. Initially, this will be valid for five years, but can be extended for an unlimited validity.
Updated: 28.03.2024
In very rare cases, a marketing authorisation under exceptional circumstances can be granted. In such cases, the European Medicines Agency (EMA) and the European Commission, as the authorising body, understand that the comprehensive clinical data that is usually required cannot be provided, but that there is a reasonable assumption that a medicinal product can help patients in the event of a high medical need.
If the usually required clinical data cannot be produced for a particular treatment option or a particular medicinal product, it would not be in the interests of the patients concerned to formally insist on compliance with this requirement. This may be the case if a disease is very rare (orphan disease) or if there are ethical concerns about specific studies in the therapeutic situation.
This form of marketing authorisation is linked to particularly strict conditions: the authorisation is reviewed annually and is generally not converted into a standard marketing authorisation. Almost all the medicinal products concerned are for rare diseases (orphan drugs).
Updated: 16.04.2024
A conditional marketing authorisation is granted with the requirement that the applicant will provide the required comprehensive data within an agreed timeframe.
A marketing authorisation in exceptional circumstances is granted if it is unlikely that the normally required comprehensive data can be collected. This applies, for example, to very rare disorders (orphan diseases). This approval route does not generally lead to a standard marketing authorisation.
Updated: 28.03.2024
Regulation (EC) No 1234/2008 of the European Commission ("amending Regulation") defines a type-II variation as a major variation to a marketing authorisation, i.e. a variation that may have a significant impact on the quality, safety or efficacy of a medicinal product.
The Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) is responsible for assessing most of the variations considered type-II variations and recommends or opposes the approval of the variation.
Studies on quality, safety, or efficacy are required for the application review procedure, depending on the nature of the medicinal product variation.
The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) is also involved in the procedure for type-II variations affecting clinical safety.
For the first type-II variations for the Comirnaty and Spikevax vaccines, studies on quality and non-clinical studies on tolerability and immunogenicity were carried out using a suitable animal model as well as clinical trials with volunteer trial participants.
Immunogenicity describes the ability of a vaccine to elicit a targeted immune response. The vaccines' immunogenicity was tested by determining the blood levels (titre) of neutralising antibodies against the SARS-CoV-2 virus variant Wuhan and the Omicron BA.1 subvariant. Neutralising antibodies can prevent or reduce the viral infection of cells. This process required a superiority of the adapted vaccines over the Omicron BA.1 subvariant in comparison to the previous vaccines. Superiority was to be indicated by the detection of a statistically significant increase in titres of neutralising antibodies against the subvariant BA.1.
The superiority was demonstrated in clinical trials.
In the subsequent type-II variations of the mRNA vaccines Comirnaty and Spikevax, which contain both the mRNA of the original coronavirus (Wuhan) and the mRNA of the Omicron variants BA.4-5 (identical spike protein), the clinical data available for the previous type II variations were also taken into account for the evaluation. Data on quality and the manufacturing process was also evaluated.
Updated: 25.07.2024
The development of vaccines for new pathogens is a complex and laborious process that usually takes several years.
Before being authorised, a vaccine candidate must successfully complete all the phases of medicinal product development. This begins with the isolation and characterisation of the pathogen and the identification of suitable antigens. Antigens are the components of the pathogen that are intended to bring about the immune protection. This step is followed by the development of the vaccine candidate, the preclinical investigations and the clinical trials in phase 1 (immunogenicity), phase 2 (tolerability, dosage) and phase 3 (statistically significant data on safety and efficacy). In order for a vaccine to be authorised, its quality, safety and efficacy must be proven. In addition, its benefits must clearly outweigh the risks. COVID-19 vaccines are also developed and authorised in accordance with this principle.
During the pandemic, the COVID-19 vaccines were assessed in Europe via the centralised marketing authorisation procedure, which is coordinated by the European Medicines Agency (EMA). In the event of a positive assessment, the Committee for Medicinal Products for Human Use (CHMP) at the EMA issues an opinion to the European Commission with a recommendation for authorisation. The European Commission decides on the marketing authorisation of a vaccine product in Europe and thus also in Germany. After being authorised, the vaccine can be marketed in the EU Member States, including the EEA states, and can be made available to all members of the public.
The coronavirus pandemic presented the modern world with unprecedented economic, social, and health-related challenges. Vaccines were the most effective way to contain the pandemic and to protect ourselves from COVID-19. This understanding motivated all the experts involved in vaccine development to work together more closely and to make processes more efficient, without compromising on due care and diligence. This also led to significant optimisation of the process flows and time saved in development.
Vaccine developers benefit from early and ongoing scientific and regulatory advice from medicines agencies. This scientific advice is initially provided on a national level, and then in the case of advanced development on a European level. It prepares the pharmaceutical company for the regulatory requirements that will need to be observed during development, for the requirements in terms of the content of applications for the approval of clinical trials, for marketing authorisation and for batch release. It makes a smooth submission process possible without undue delays.
A rolling review procedure for marketing authorisation allows the vaccine manufacturer at an early stage – even while the clinical phase 3 trial is still ongoing – to submit individual data packages for a preliminary assessment for marketing authorisation and to answer any questions that arise during the regulatory evaluation of the application. In this way, parts of the application dossier can be checked, improved and assessed before the actual application is submitted. Once all the necessary documents for marketing authorisation have been submitted and the marketing authorisation application has been made, processing will take significantly less time. The assessment process therefore starts much earlier. The rolling review procedure precedes the marketing authorisation application with the submission of the complete data packages.
The Paul-Ehrlich-Institut has also used the rolling review procedure for the approval of clinical trials.
Clinical trials, which generally take place one after the other, are combined, e.g. phase 1 with phase 2 or phase 2 with phase 3. Organisational processes, for example the recruitment of test subjects for two phases of the clinical trial, can be bundled into one process. In addition, the necessary investigations can be combined.
In the development of a COVID-19 vaccine, scientists were able to build on preparatory research work that had already taken place into other coronaviruses and corresponding vaccine developments, e.g. the SARS coronavirus in 2003 and the MERS coronaviruses. These coronaviruses, which are similar to SARS-CoV-2, triggered the SARS epidemic in 2002/2003 and the MERS (Middle East Respiratory Syndrome) epidemic in 2012.
Updated: 19.04.2024
