The FDA’s Related Biologic Products Advisory Committee meeting on Thursday will be the US’ first public forum on phase 3 data for a COVID-19 vaccine, a possible prelude to approval.
On Thursday, the US Food and Drug Administration (FDA) Vaccines and Related Biologic Products Advisory Committee (VRBPAC) will consider the merit for the first Emergency Use Authorization (EUA) application for a coronavirus 2019 (COVID-19) vaccine candidate.
BNT162b2, the two-dose messenger RNA (mRNA) vaccine from Pfizer and BioNTech, will undergo a full-day meeting in which its associated phase 3 data from an ongoing, multi-national assessment will be scrutinized and weighed by a panel of experts, with public input, before being voted on as either indicative of a positive or negative benefit-risk ratio for its prospective use as a preventive vaccine for confirmed COVID-19.
In short, the committee meeting on Thursday will be the US’ first public forum on phase 3 data for a COVID-19 vaccine, and will most likely preclude the first emergency authorization and immediate distribution of a vaccine for the population.
Here is the phase 3 data Pfizer submitted to the FDA, as part of BNT162b2’s EUA application.
Phase 3 Trial Makeup
In the phase 2/3 evaluable efficacy data submitted to the FDA, the Pfizer trials’ population includes 37,796 patients, of whom 37,088 (98.1%) completed the two-dose regimen of either BNT162b2 or placebo (split 1:1). At the time of EUA submission, just 13 patients had withdrawn from assessment due to an adverse event.
The evaluable population observed for vaccine efficacy included 49.4% females, 81.9% white participants, 9.8% African American participants, 4.4% Asian participants, and <3% from other racial groups. Another 26.2% of participants were of Hispanic/Latino descent, and 21.4% were ≥65 years old.
Median participant age was 51 years, and frequently reported comorbidities included obesity (35.1%), diabetes (8.4%), and pulmonary diseases (7.8%). More than three-fourths (76.7%) of participants were from the US.
Overall, comorbidities were reported in 46.2% of all observed patients. Just 545 patients administered BNT162b2 had baseline evidence of previous SARS-CoV-2 infection.
Investigators sought a primary endpoint of vaccine efficacy for BNT162b2 against confirmed COVID-19 in participants without evidence of prior SARS-CoV-2 infection prior to 7 days after their second dose.
The second primary efficacy endpoint included vaccine efficacy of the candidate against confirmed COVID-19 in participants with and without such prior infection evidence. Investigators counted cases from 7 days after dose 2 for both endpoints, as that is the suggested time to developed immunity.
Among participants without previous SARS-CoV-2 infection prior to 7 days after their second dose of BNT162b2, vaccine efficacy against confirmed COVID-19 at least 7 days following their second dose was 95% overall (95% CI, 90.3 – 97.6). Investigators observed just 8 COVID-19 cases in the treatment group, versus 162 cases in the placebo group.
Vaccine efficacy in this participant population was slightly greater for those aged 16-55 years old (95.6%; 95% CI, 89.4-98.6) than those >55 years old, who are deemed at greater risk of COVID-19 severity (93.7%; 95% CI, 80.6-98.8).
In the second primary endpoint including participants with and without prior SARS-CoV-2 infection before and during vaccination regimen, vaccine efficacy at least 7 days after dose 2 was 94.6% (95% CI, 89.9-97.3). Again, the rate of COVID-19 cases among vaccinated patients (n = 9) versus placebo (n = 169) was substantial.
Investigators again observed a slightly improved vaccine efficacy rate among patients 16-55 years old versus >55 years old in this population.
In subgroup analyses—in which “at risk” is defined as having at least 1 of the Cahrlson comorbidity index items or a body mass index (BMI) of ≥30, indicating obesity—the vaccine was associated with a 95.4% efficacy among individuals at risk of COVID-19 severity (95% CI, 87.8-98.8). Though the population was too small to perceive absolute interpretability, at-risk participants aged ≥65 years were associated with a 91.7% vaccine efficacy (95% CI, 44.2-99.8).
The key secondary endpoint of severe COVID-19 cases was observed in just 4 participants following ≥7 days after the second dose. Among them, just 1 had received BNT162b2. That said, the FDA noted the participant was not hospitalized, did not seek further medical care, and did not have risk factors for severe disease; the participant’s severe diagnosis was based on oxygen saturation levels of 93% at clinical visit.
In the phase 2/3 safety population, investigators indeed observed a greater proportion of vaccine recipients reporting adverse events versus placebo recipients, largely driven by solicited adverse events in the 7 days following vaccination, as well as unsolicited adverse events corresponding to reactogenicity symptoms among participants not in the trial’s reactogenicity subset.
That said, investigators observed a balance of rates of serious adverse events, deaths, and trial withdrawals among the treatment groups.
Regarding solicited local reactions among participants aged 18 years and older, injection site pain was the most frequently reported event; it was more frequently reported among younger patients after the second dose of BNT162b2, and was generally characterized as moderate. Injection site swelling and redness were reported far less frequently among participants, and similarly across age groups.
Regarding solicited systemic events including fever, fatigue, headache, chills, vomiting, diarrhea, and new or worsened muscle/joint pain, frequency was greater again among younger patients. Participants overall experienced more frequent and more severe systemic adverse events after dose 2.
Among all age groups, the most common events were fatigue, headache, and new or worsened muscle pain.
Regarding unsolicited non-serious adverse events, investigators observed an imbalance of lymphadenopathy (n = 64) cases in vaccinated patients versus placebo (n = 6), as well as 4 vaccinated cases of Bell’s palsy.
“The observed frequency of reported Bell’s palsy in the vaccine group is consistent with the expected background rate in the general population, and there is no clear basis upon which to conclude a causal relationship at this time, but FDA will recommend surveillance for cases of Bell’s palsy with deployment of the vaccine into larger populations,” they wrote.
Investigators also reported 3 serious adverse events in the BNT162b2 group related to the vaccine itself: shoulder injury, ventricular arrhythmia, and lymphadenopathy. Six total trial participants died during the trial; 2 being from the vaccine group. One patient experienced cardiac arrest 62 days following their second dose and died 3 days later; the other died from arteriosclerosis 3 days after the first dose.
“All deaths represent events that occur in the general population of the age groups where they occurred, at a similar rate,” the FDA wrote.
Lastly, investigators reported no specific safety concerns by participant age, race, ethnicity, medical comorbidities, or prior SARS-CoV-2 infection. Pregnancy outcomes only included 23 female participants through the trial cut-off date of November 14, and are otherwise unknown beyond a couple of unsolicited adverse events to occur in the placebo group.
From Thursday morning through the early evening, an advisory panel consisting of FDA experts will host an open session to discuss Pfizer’s EUA for BNT162b2, for the prevention of COVID-19 in-persons aged 16 years and older.
Their multi-item agenda features opportunities for open public hearings, Q&A sessions at the conclusion of set presentations, and finally, a committee discussion and voting period on the merit of the EUA.
In the history of the FDA, advisory committee votes have very frequently aligned with eventual marketing decisions. There is anticipation—given the nature of the COVID-19 pandemic and collaboration between federal agencies, vaccine developers, and manufacturers to mitigate risks—that EUA approval and BNT162b2 distribution could shortly follow the VRBPAC decision.
Last week, the UK Medicines & Healthcare Products Regulatory Agency (MHRA) granted emergency use authorization for BNT162b2. Prioritized patients in the UK have begun receiving their first dose of the vaccine this week.
This story originally appeared in Contagion®.