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August 12, 2020 Pharmacovigilance

EMA Vaccine Applications for COVID-19 Explained

Hanneke Dominicus Consultant

Preventive vaccines are a special kind of medicinal product, as they are administered before a disease instead of during. You are probably familiar with preventive vaccines from your own or your children’s childhood vaccination programs. This blog is on preventive vaccines only.

First of all, vaccines in the regulatory field should be treated just as any other medicinal product: a vaccine should be safe and effective, tested in a sufficient number of humans, and have a favorable risk-benefit balance. It should have the ‘normal’ product information, risk management plan, and the same regulatory obligations for application as (non)clinical overview.

These basics touch on the important difference as well: we accept a lot of risks for seriously ill patients, but we don’t accept a lot of risks for (still) healthy people. Population-based, we accept more risks when the disease is almost always fatal and more lives can be saved by vaccination. Individual-based, we accept less risks if the disease is almost not fatal nor with serious consequences (or if we think it is).

What makes vaccines different?

When you inject ‘healthy’ people with something to protect them from harm, risks weigh more because of the possible negative effects. For example, remember the commotion on autism as an adverse effect of the mumps/measles/rubella vaccine (it isn’t), or narcolepsy as an adverse event of the pandemic H1N1 2009 Flu vaccine (it seems to be). Though vaccination protects us from diseases, which most of the time outweighs the vaccination risks, there seem to be ongoing discussions of vaccinations, for example from the antivac-movement or some religious groups.

A concrete difference is that vaccines have some class effects in common (e.g. sore arm or low-grade fever) that apply to all vaccines in general. With other medications, each group of antibiotics has its own class effects and class effects mostly do not overlap. In fact, all vaccines could be regarded as one class and have class effects unrelated to the antigen or the disease. Also, the circumstances for administering vaccines are different from other medications, e.g. often delivered in groups at work or school, and not strictly directly prescribed by physicians.

In pandemic times, there is more attention for vaccines than ever before. Neither the pandemic Influenza vaccines or the Ebola vaccines received as much attention on a global scale as possible COVID-19 vaccines. On July 27th of this year, EMA had finalized 17 scientific advice procedures for potential medicines to treat COVID-19, with a further 15 ongoing. EMA had also been in contact with the developers of 154 potential COVID-19 treatments and 38 potential COVID-19 vaccines.

Why does the path to availability take so long?

Let’s get to the business of a vaccine application procedure. Originally, there used to be a time from cradle to registration of about 10 years. But now, as the coronavirus is threatening people around the world, e.g. the EMA states that: “Vaccine development timelines are difficult to predict. Based on past experience, EMA estimates that it might take at least until the beginning of 2021 before a vaccine against COVID-19 is ready for approval and available in sufficient quantities to enable widespread use.” The Director-General of the WHO, issued a warning last week that it could take longer. But even in the case of a shortened procedure, safety regulations must always be met.

First, you need to have the appropriate antigen (whole inactivated virus, part of the virus). Then it should become a vaccine (injectable, soluble, safe storage). From there it should be tested, first non-human, then in humans. You should be able to produce it in high quantities and store and transport it safely. And finally, it should show a positive effect with a favorable risk profile. When combined as a whole, you can see why vaccine development is a lengthy process.

The first in-human testing of COVID-19 vaccines have started. What do such vaccine studies look like?

Vaccine studies are different from medicine studies, not only because far more subjects need to be included (thousands, instead of hundreds or less) but the adjuvant needs special attention. The risk management plan plays an important role here.

As vaccines are biologicals, biological guidelines apply:

These guideline details and other useful information are available at: https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/biologicals/biologicals-active-substance#vaccines-section.

EMA provides guidelines on what needs to be included in studies for vaccines specifically. The current guidance on clinical evaluation of vaccines is relatively ‘old’ and in 2018, EMA issued a new version of which the consultation has now ended. However, the current guideline is still under revision, and the new version is not effective yet. The new version, (EMEA/CHMP/VWP/164653/05 Rev. 1, April 2018), addresses, as opposed to normal medicine studies, the need to include children, the elderly, and pregnant women in the clinical studies for vaccines. There is a tendency to actively request more information than before about these groups and especially about vaccination in pregnant women. Remember the Flu pandemic 2009, where in fact so many women were exposed to the vaccine without it having been tested in more than an incidental case. That is an experiment in the general population, and it would have been better to have more data before. The elderly may have lower or higher responses to vaccines. Therefore, it is important that adequate dose-finding studies are conducted for vaccines proposed for elderly use, and that all age subgroups are investigated (e.g.  65-74 years, 75-84 years and 85 years or more) to determine whether different doses and/or regimens are needed as age increases. The advice is to read the new guideline as well when developing a vaccine.

How does EMA help?

During the current pandemic, EMA is trying to achieve fast registrations for COVID-19 vaccines. That is e.g. reflected in more flexibility, shortened timelines, and rapid agreement on pediatrics. The rolling review and the accelerated assessment have been instituted, and announcements/EPARS/PIs are published much sooner. EMA is also publishing information it does not normally publish for other medicines, to keep developers updated.

So, requirements are the same, but are happening on an accelerated timeline! In the list below some of these EMA measures are included.

Rapid scientific advice
  • Free of charge (in accordance with the decision of EMA’s Executive Director )
  • No pre-specified submission deadlines
  • Review is reduced to a maximum of 20 days (from 40-70 days)
  • Flexibility on type and extent of briefing dossier, agreed on a case-by-case basis
Rapid agreement of pediatric investigation plans (PIPs) and rapid compliance check
  • No pre-specified submission deadlines
  • Review of a PIP is reduced to a minimum of 20 days (from 120 days). Exact timeline depends on complexity of PIP and the preparedness by the sponsor to respond to questions
  • EMA decision following a review is reduced to 2 days (from 10 days)
  • Possibility for developer to provide a focused scientific documentation, agreed on a case-by-case basis
  • Compliance check can be reduced to 4 days if necessary
Rolling review
  • EMA’s Committee for Medicinal Products for Human Use (CHMP) reviews data as they become available on a rolling basis, while development is still ongoing
  • Several rolling review cycles can be carried out during the evaluation of one product as data continue to emerge, with each cycle lasting around two weeks depending on the amount of data to be assessed
  • Each submission occurs in eCTD format with an application form, a Module 2 overview and responses to a cumulative listing of all outstanding questions from previous review cycles
  • Once the data package is complete, the developer submits a formal marketing authorization application which is then processed under a shortened timetable
Accelerated assessment
  • Can be considered for medicines and vaccines not undergoing a rolling review
  • Review is reduced to 150 days (from 210 days) or less after validation of a complete application

What about postmarketing?

After expedited approvals, when the vaccine is available to the general population, post-authorization monitoring is of the utmost importance. The use of real-world data (RWD) has become more and more important in the last years but will be even more significant when these huge operations take place. For European territory, the Utrecht University is preparing infrastructure for gathering all data. Utrecht scientists will lead a European project that is funded by the European Medicines Agency (EMA) with the aim to create European preparedness to monitor the benefits and safety of the new coronavirus vaccines, when they come to the market.

Curious what is happening in the Corona vaccine field?

It is easy to find all ongoing observational and clinical trials:



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