FDA REVIEW OF THE PFIZER-BIONTECH COVID-19 VACCINE

The following is an extract from the briefing document released by the US Federal Drug Administration (FDA) ahead of the December 10, 2020 meeting of the Vaccine and Related Products Advisory Committee (VRBPAC) to review the Pfizer-BioNTech COVID-19 Vaccine.

This meeting of the VRBPAC is being convened to discuss and provide recommendations on whether:

1. based on the totality of scientific evidence available, it is reasonable to believe that the Pfizer-BioNTech COVID-19 Vaccine may be effective in preventing COVID-19 in individuals 16 years of age and older, and
2. the known and potential benefits of the Pfizer-BioNTech COVID-19 Vaccine outweigh its known and potential risks for use in individuals 16 years of age and older.

The committee will also discuss what additional studies should be conducted by the vaccine manufacturer following issuance of the EUA to gather further data on the safety and effectiveness of this vaccine.

SUMMARY OF THE EFFICACY 
The data submitted in this EUA request were consistent with the recommendations set forth in the FDA Guidance on Emergency Use Authorization for Vaccines to Prevent COVID-19 and met the prespecified success criteria established in the protocol.

In the planned interim and final analyses, vaccine efficacy after 7 days post Dose 2 was 95%, (95% CI 90.3; 97.6) in participants without prior evidence of SARS-CoV-2 infection and >94% in the group of participants with or without prior infection. Efficacy outcomes were consistently robust (≥93%) across demographic subgroups.

Efficacy against severe COVID-19 occurring after the first dose was 88.9% (95% CI 20.1, 99.7), with an estimated vaccine efficacy (VE) of 75.0% (95% CI -152.6, 99.5) (1 case in BNT162b2 group and 4 cases in placebo group) against severe COVID-19 occurring at least 7 days after Dose 2.

Among all participants (regardless of evidence of infection before or during the vaccination regimen), 50 cases of COVID-19 occurred after Dose 1 in the BNT162b2 group compared with 275 cases in the placebo group, indicating an estimated VE of 82% (95% CI: 75.6%, 86.9%) against confirmed COVID-19 occurring after Dose 1, with VE of 52.4% (95% CI: 29.5%, 68.4%) between Dose 1 and Dose 2.

 
The efficacy observed after Dose 1 and before Dose 2, from a post-hoc analysis, cannot support a conclusion on the efficacy of a single dose of the vaccine, because the time of observation is limited by the fact that most of the participants received a second dose after three weeks. The trial did not have a single-dose arm to make an adequate comparison.

TAKE HOME MESSAGE: 

1. The vaccine is highly effective in preventing and treating COVID-19 disease
2. This high efficacy is observed starting right after the first dose is administered
3. The duration of efficacy after the first dose cannot be ascertained
4. Therefore, a second dose maybe needed to sustain efficacy

SUMMARY OF THE SAFETY 
The information provided by the Sponsor was adequate for review and to make conclusions about the safety of BNT162b2 in the context of the proposed indication and population for intended use under EUA.

The number of participants in the phase 2/3 safety population (N=37586; 18801 vaccine,18785 placebo) meets the expectations in FDA’s Guidance on Development and Licensure of Vaccines to Prevent COVID-19 for efficacy, and the median duration of at least 2 months follow-up after completion of the 2-dose primary vaccination series meets the agency’s expectations in FDA’s Guidance on its Emergency Use Authorization for Vaccines to Prevent COVID-19.

The all-enrolled population contained more participants >16 years of age, regardless of duration of follow-up (43448; 21720 vaccine, 21728 placebo). The demographic and baseline characteristics of the all-enrolled population and the safety population were similar.

Although the overall median duration of follow-up in the all-enrolled population was less than 2 months, because the protocol was amended to include subpopulations such as individuals with HIV and adolescents, the data from both populations altogether provide a comprehensive summary of safety.

Local site reactions and systemic solicited events after vaccination were frequent and mostly mild to moderate. The most common solicited adverse reactions were injection site reactions (84.1%), fatigue (62.9%), headache (55.1%), muscle pain (38.3%), chills (31.9%), joint pain (23.6%), fever (14.2%); severe adverse reactions occurred in 0.0% to 4.6% of participants, were more frequent after Dose 2 than after Dose 1, and were generally less frequent in adults >/=55 years of age (</=2.8%) as compared to younger participants (</= 4.6%).

Among adverse events of special interest, which could be possibly related to vaccine, lymphadenopathy was reported in 64 participants (0.3%): 54 (0.5%) in the younger (16 to 55 years) age group; 10 (0.1%) in the older (>55 years) age group; and 6 in the placebo group. The average duration of these events was approximately 10 days, with 11 events ongoing at the time of the data cutoff. Bell’s palsy was reported by four vaccine participants. From Dose 1 through 1 month after Dose 2, there were three reports of Bell’s palsy in the vaccine group and none in the placebo group. This observed frequency of reported Bell’s palsy is consistent with the expected background rate in the general population.

There were no other notable patterns or numerical imbalances between treatment groups for specific categories of non-serious adverse events (including other neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2 vaccine.

A total of six (2 vaccine, 4 placebo) of 43,448 enrolled participants (0.01%) died during the reporting period from April 29, 2020 (first participant, first visit) to November 14, 2020 (cutoff date). Both vaccine recipients were >55 years of age; one experienced a cardiac arrest 62 days after vaccination #2 and died 3 days later, and the other died from arteriosclerosis 3 days after vaccination #1. The placebo recipients died from myocardial infarction (n=1), hemorrhagic stroke (n=1) or unknown causes (n=2); three of the four deaths occurred in the older group (>55 years of age). All deaths represent events that occur in the general population of the age groups where they occurred, at a similar rate.

The frequency of non-fatal serious adverse events was low (<0.5%), without meaningful imbalances between study arms. The most common SAEs in the vaccine arm which were numerically higher than in the placebo arm were appendicitis (0.04%), acute myocardial infarction (0.02%), and cerebrovascular accident (0.02%), and in the placebo arm numerically higher than in the vaccine arm were pneumonia (0.03%), atrial fibrillation (0.02%), atrial fibrillation (0.02%) and syncope (0.02%). Appendicitis was the most common SAE in the vaccine arm. There were 12 participants with SAEs of appendicitis; 8 in the BNT162b2 group. Of the 8 total appendicitis cases in the BNT162b2 group, 6 occurred in the younger (16 to 55 years) age group and 2 occurred in the older (>55 years) age group (one of the cases in the older age group was perforated). One of the 6 participants with appendicitis in the younger age group also had a peritoneal abscess. Cases of appendicitis in the vaccine group were not more frequent than expected in the general population.

TAKE HOME MESSAGE

1. The vaccine is generally safe with only minor adverse events observed in most people who take the vaccine
2. Adverse reactions are mostly non-life threatening and may include pain and rashes at the injection site, fever, chills, headache, etc.
3. However, in certain individuals with pre-existing conditions and older age groups, deaths were reported after the first and the second dose. It is not clear whether the deaths were related to the vaccine.

CONCLUSION
The Pfizer mRNA vaccine will save your life. When it comes to your turn to take the vaccine, all you ought to do is stick out both arms and ask them, “Which one do you want to stick the needle?”