EMA/FDA update on the safety of Comirnaty® and the
analysis of adverse events for Covid-19 vaccines
Authors: Raphaelle Beau-Lejdstrom, PhD Pharmaco-epidemiology
Irene Rina-Fermont, MD MSc., Immuno-hematology,
Published date: 09 March 2021
A- Updates on Safety from the 1rst EMA Safety Report
The EMA recently issued its first update on Comirnaty® on January 28th, 2021. The investigation of reports of anaphylactic reactions and the risk of death following the vaccination in frail elderly individuals by professionals did not suggest a safety concern.
The reports note that a recent analysis in the United States estimated the frequency of anaphylaxis as approximately 11 cases per million doses of Comirnaty administered
The review of anaphylaxis cases led very early to recommendations such as the need to stay in the premises of the vaccination centers for at least 15 minutes, to have all treatment of anaphylaxis at hand, and to check the patient history of allergy.
“Given concerns which arose from Norway about deaths reported in frail elderly individuals after vaccination with Comirnaty, the Pharmacovigilance and Risk Assessment Committee (PRAC) reviewed the current reports of suspected side effects with fatal outcome in individuals of any age. This review did not suggest a safety concern. In many cases concerning individuals above 65 years of age, the progression of (multiple) pre-existing diseases seemed to be a plausible explanation for death. In some individuals, palliative care had already been initiated before vaccination.”
The EMA report concludes that “The benefits of Comirnaty in preventing COVID-19 continue to outweigh any risks, and there are nor recommended changes regarding the use of the vaccine.” neither a change in the list of adverse reactions [ 2] )
The MHRA (UK Medicine Agency) publishes weekly reports of adverse reactions. The report on 25 February notes about the Bell’s Palsy. (“a temporary weakness or paralysis (lack of movement) of the muscles in one side of the face. It is the most common cause of facial paralysis. For most people, facial paralysis is temporary. Viral infections such as those with herpes viruses have been linked to Bell’s palsy.”.)
The number of reports of facial paralysis received so far is similar to the expected natural rate ( the number expected to occur by chance in the absence of vaccination) and does not currently suggest an increased risk following the vaccines.
In all aspects, the MHRA reaches the same conclusion as the EMA.
Most countries (e.g USA and the whole EU) have systems in place of spontaneous reporting. This means that when a potential adverse effect occurs, health professionals and patients can and are strongly encouraged to submit these reports to the health authority or the pharmaceutical industry that will send them to the competent health authorities. Anyone can report a side effect.
EMA (European Medicine Agency) committed to full transparency and to keep patients and healthcare professionals fully informed to make their choice on COVID19 vaccination.
All adverse events reports related to COVID19 vaccines are available on EudraVigilance (www.adrreports.eu) and are updated weekly. Similarly, in the USA, adverse effects reported in relation to the COVID19 vaccine are available online for download from their website (FDA VAERS database).
The EMA definition of an adverse event is “An untoward medical occurrence after exposure to a medicine, which is not necessarily caused by that medicine.” This definition includes as well vaccines These are events that have occurred concurrently with vaccination and require further inquiries. They are not systematically causal.
For instance, if someone reports a “sore throat” concomitant to vaccination, this is not yet sufficient to automatically conclude that this event is related to the vaccination. The same applies to serious events or deaths as a number of these are expected to occur frequently in the general population.
These databases are open to the public for transparency. However, for the reasons stated above, the review of these reports by the general public may be uninformative.
FDA and EMA have systems in place for the analysis of these events in real-time designed to detect potential safety signals. The potential of these databases to generate safety signals has been validated in many scientific studies. To generate a signal, we use the frequency of reports for each of these events of interest but we also measure what is called “disproportionality measures”. With this type of measure, we want to know if one event is reported for this vaccine disproportionately compared to all other reports from other vaccinations in the database.
Once a signal has been detected, we use known pre-approval clinical trials data and big anonymized databases of medical records such as the one held by the Health Ministry in Israel on all Israeli citizens, in which we search for the occurrence of the same events, then to perform a full pharmaco-epidemiological analysis to know if we can classify this signal as a potential risk. These analyses can sometimes take some weeks/months to be completed and to reach a conclusion on a potential /confirmed causality or to invalidate the causality link.
The French medicine agency (ANSM) issued an update report on the safety of Comirnaty on February 18th, 2021. A signal related to hypertension and cardiac arrhythmias has been confirmed although most of these cases were transitory and quickly reversible and do not change the benefit/risk balance of Comirnaty. No other signals emerged during this update.
B- Planned and ongoing studies
1- Pediatric Investigation Plan
“A pediatric investigation plan” (PIP) for Comirnaty is in place. This describes how the company will collect data on the vaccine’s efficacy and safety for its potential use in children”. To be completed step by step before 2023. 
Study 1 (C4591001) Double-blind dose-finding study of safety, tolerability, and immunogenicity of 2 different SARS-CoV-2 vaccine candidates (adults only) (part 1) and placebo-controlled efficacy, safety and immunogenicity study of (BNT162b2) in adolescents from 12 years to less than 18 years of age (and adults) (part 2) for prevention of COVID-19
Study 2 (C4591007) Double-blind, controlled, dose-finding safety and immunogenicity study of BNT162b2 in children and adolescents from 5 years to less than 18 years of age for prevention of COVID-19
Study 3 Double-blind, controlled, dose-finding, safety, and immunogenicity study of BNT162b2 in children from birth to less than 5 years of age for prevention of COVID-19
Study 4 Open-label, uncontrolled, safety and immunogenicity study of BNT162b2 in immunocompromised children from birth to less than 18 years of age for prevention of COVID-19
2- Other studies
In addition to the spontaneous pharmacovigilance activities, observational studies are led by the EU Member States. 
Early safety monitoring of COVID-19 vaccines in the EU Member States will analyze Real World Data, or how the vaccine behaves in real life.
Led by EU PE&PV Research Network, coordinated by Utrecht University: Pharmacoepidemiology and Clinical Pharmacology - Universiteit Utrecht (uu.nl) Started on 1 February, results December 2021.
Many other studies are required from Pfizer BioNTech as described in the Risk Management Plan of Cominarty, for instance for use in pregnancy and breast feeding.
Centres for Disease Control and Prevention (CDC) COVID-19 Response Team, Food and Drug Administration: Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of PfizerBioNTech COVID-19 Vaccine: United States, December 14–23, 2020. MMWR. 2021; 70 (2): 46-52 (epub 6 Jan 2021).