12-08-2020, 11:52 AM
Here's the report:
https://www.fda.gov/media/144245/download
Here's the efficacy analysis:
More in Table 6 (overall) and Table 8 (important subgroups). One really cool thing is figure 2 (page 30). The curves between the placebo and vaccinated group start diverging 14 days after the first dose. This suggests that although two doses may be needed to generate lasting immunity, one dose is adequate to start giving people enough immunity to prevent infection. This is great news! It means that the vaccines will start having an effect earlier (and that probably if the booster dose is delayed that will be ok). As the review notes, "Based on the number of cases accumulated after Dose 1 and before Dose 2, there does seem to be some protection against COVID-19 disease following one dose; however, these data do not provide information about longer term protection beyond 21 days after a single dose." They also note that "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." So you would never approve the vaccine for one dose, but it means that if someone doesn't get their second dose (or it is delayed), they will probably still have some (maybe substantial) immunity.
The data on severe cases is on page 31; it suggests about 90% efficacy, but we are dealing with small numbers.
Here's the safety analysis:
Looking at the data, about 1/3 of volunteers developed moderate or severe fatigue after the second dose and a quarter had moderate or severe headache. A substantial number of placebo recipients also had these symptoms, which goes to show how strong the placebo effect is.
Six volunteers in the study died, but four of them were in the placebo group, which goes to show the role of chance distribution in safety events. They note that more patients in the vaccine group had appendicitis than placebo (8 to 4). These are things to keep track of when the vaccine is given to millions of people, but likely represent a chance imbalance. From the report: "The cases were considered unrelated to vaccination by the study investigators and occurred no more frequently than expected in the given age groups. FDA agrees that there is no clear basis upon which to suspect that this imbalance represents a vaccine-related risk."
Section 8, starting on page 46 has a nice breakdown of the benefits, risks, and unknowns, and is worth reading if you want a deep dive into the vaccine. That will be the basis for the EUA. I expect it will be granted as I didn't see anything in the report that would be a red flag (or even a yellow flag) for this. The benefits are pretty clear and would be considered a home run, though I'll be interested in seeing things like long-term protection. The potential benefit seven days after the first dose is an unexpected bonus (caveats I mentioned aside). The risks are basically a decent chance (1/4 to 1/3) that you will feel like crap for a day, which seems similar to the shingles vaccine. Compared to the risk of developing COVID-19, even if "mild", I'll take the vaccine any day and twice on Sunday.
BC
https://www.fda.gov/media/144245/download
Here's the efficacy analysis:
Quote:In a mid-Novemberanalysis of 36,621 participants randomized 1:1 to vaccine or placebo who were included in the per-protocol efficacy analysis population of participants without evidence of SARS-CoV-2 infection prior to 7 days after completion of the vaccination regimen, efficacy in preventing confirmed COVID-19 occurring at least 7 days after the second dose of vaccine was 95.0%, with 8 COVID-19 cases in the vaccine group and 162 COVID-19 cases in the placebo group. Subgroup analyses of the primary efficacy endpoint showed similar efficacy point estimates across age groups, genders, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19. Secondary efficacy analyses suggested benefit of the vaccine in preventing severe COVID-19, in preventing COVID-19 following the first dose, and in preventing COVID-19 in individuals with prior SARS-CoV-2 infection, although available data for these outcomes did not allow for firm conclusions.
More in Table 6 (overall) and Table 8 (important subgroups). One really cool thing is figure 2 (page 30). The curves between the placebo and vaccinated group start diverging 14 days after the first dose. This suggests that although two doses may be needed to generate lasting immunity, one dose is adequate to start giving people enough immunity to prevent infection. This is great news! It means that the vaccines will start having an effect earlier (and that probably if the booster dose is delayed that will be ok). As the review notes, "Based on the number of cases accumulated after Dose 1 and before Dose 2, there does seem to be some protection against COVID-19 disease following one dose; however, these data do not provide information about longer term protection beyond 21 days after a single dose." They also note that "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." So you would never approve the vaccine for one dose, but it means that if someone doesn't get their second dose (or it is delayed), they will probably still have some (maybe substantial) immunity.
The data on severe cases is on page 31; it suggests about 90% efficacy, but we are dealing with small numbers.
Here's the safety analysis:
Quote:Safety data from approximately 38,000 participants≥16 years of agerandomized 1:1 to vaccine or placebo with a median of 2 months of follow up after the second dose suggest a favorable safety profile, with no specific safety concerns identified that would preclude issuance of an EUA. Available safety data from all participants enrolled through the November 14, 2020 data cut-off ( N=43,252, which includes late enrollment of additional adolescent and adultparticipants), was consistent with the safety profile for the approximately 38,000 participantswith median follow-up of 2 months and also did not raise specific safety concerns. 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 afterDose 2 than after Dose 1, and were generally less frequent in participants≥55 years of age (≤2.8%) as compared to younger participants (≤4.6%). The frequency of serious adverse events was low (<0.5%), without meaningful imbalances between study arms. Among non-serious unsolicited adverse events, there was a numerical imbalance of four cases of Bell’s palsy in the vaccine group compared with no cases in the placebo group, though the four cases in the vaccine group do not represent a frequency above that expected in the general population. Otherwise, there were no 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. With the exception of more frequent, generally mild to moderate reactogenicity in participants <55 years of age, the safety profile of BNT162b2 was generally similar across age groups, genders, ethnic and racial groups, participants with or without medical comorbidities, and participants with or without evidence of prior SARS-CoV-2 infection at enrollment.
Looking at the data, about 1/3 of volunteers developed moderate or severe fatigue after the second dose and a quarter had moderate or severe headache. A substantial number of placebo recipients also had these symptoms, which goes to show how strong the placebo effect is.
Six volunteers in the study died, but four of them were in the placebo group, which goes to show the role of chance distribution in safety events. They note that more patients in the vaccine group had appendicitis than placebo (8 to 4). These are things to keep track of when the vaccine is given to millions of people, but likely represent a chance imbalance. From the report: "The cases were considered unrelated to vaccination by the study investigators and occurred no more frequently than expected in the given age groups. FDA agrees that there is no clear basis upon which to suspect that this imbalance represents a vaccine-related risk."
Section 8, starting on page 46 has a nice breakdown of the benefits, risks, and unknowns, and is worth reading if you want a deep dive into the vaccine. That will be the basis for the EUA. I expect it will be granted as I didn't see anything in the report that would be a red flag (or even a yellow flag) for this. The benefits are pretty clear and would be considered a home run, though I'll be interested in seeing things like long-term protection. The potential benefit seven days after the first dose is an unexpected bonus (caveats I mentioned aside). The risks are basically a decent chance (1/4 to 1/3) that you will feel like crap for a day, which seems similar to the shingles vaccine. Compared to the risk of developing COVID-19, even if "mild", I'll take the vaccine any day and twice on Sunday.
BC
![[Image: nejmoa2034577_f3.jpeg]](https://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/0/nejm.ahead-of-print/nejmoa2034577/20201210-01/images/img_xlarge/nejmoa2034577_f3.jpeg)
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