VRBPAC to hear of high – and early – efficacy for Pfizer’s COVID vaccine

Regulatory NewsRegulatory News
| 08 December 2020 | By Kari Oakes 

In briefing documents that came online the morning of 8 December, the US Food and Drug Administration (FDA) presented its analysis of the efficacy and safety data for the first vaccine against COVID-19 to be considered for administration in the US. The agency’s assessment largely squares with the high efficacy and favorable safety profile reported by the vaccine’s co-sponsors, Pfizer and BioNTech.
The briefing documents were provided by Pfizer/BioNTech and FDA in advance of the 10 December Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting to consider the investigational messenger RNA (mRNA) vaccine BNT162b2 for emergency use authorization (EUA).
Pfizer/BioNTech and FDA agreed about the overall 95% efficacy of the two-dose vaccine regimen. FDA’s subgroup analysis of the available Phase 3 clinical trial data was also in agreement with the sponsor’s, finding high efficacy across all subgroups, including older participants and those with obesity -- a prevalent risk factor for serious complications of COVID-19. Both Pfizer and FDA also highlighted analysis showing a sharp drop in COVID-19 cases after just one dose of the vaccine.
The sponsor’s application is supported by interim analyses of safety and efficacy data from the 44,000-participant Phase 3 randomized, double-blinded placebo-controlled trial of a 2-dose vaccine regimen. (RELATED: Pfizer files EUA for COVID vaccine; FDA sets adcomm for 10 December, Regulatory Focus 20 November 2020)
By mid-November 2020, efficacy data were available for 36,621 participants randomized 1:1 to receive placebo or vaccine. In participants who did not have evidence of SARS-CoV-2 infection at any point before 7 days after receiving the second dose, vaccine efficacy (VE) in preventing confirmed COVID-19 cases from that point in time forward was 95%. Eight cases of COVID-19 occurred in the vaccine group, compared with 162 COVID-19 cases among those who received placebo.

“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,” wrote FDA in its briefing document. The agency also noted that analysis of data supporting secondary efficacy endpoints “suggested benefit” for the vaccine in preventing severe cases of COVID-19 and in preventing disease in people who previously had SARS-CoV-2 infection.
The vaccine appeared to slow the rate of COVID-19 infections after just one dose: “Based on the cumulative incidence curve for the all-available efficacy population after Dose 1, … COVID-19 disease onset appears to occur similarly for both BNT162b2 and placebo groups until approximately 14 days after Dose 1, at which time point, the curves diverge, with more cases accumulating in the placebo group than in the BNT162b2 group,” wrote FDA in referring to a figure depicting the cumulative incidence curves for the control and vaccine arms of the study.
Since all participants included in the per-protocol efficacy analysis did receive two doses of vaccine, only limited conclusions can be drawn from the observed reduction in cases after the first dose, noted FDA: “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.”
However, Pfizer’s analysis of VE after the first dose and before the second dose of vaccine was 52.4%, with a 95% confidence interval of 29.5-68.4%. Though these post hoc results carry the limitations noted by FDA, they are nearly identical with the cutoff points set by the agency in its guidance for sponsors seeking EUAs for COVID-19 vaccines. In the EUA guidance, FDA said it was looking for point-estimate efficacy of “at least 50%” from a placebo-controlled trial, with the lower bound of the confidence interval set at greater than 30%. (RELATED: FDA issues COVID-19 vaccine EUA guidance after clash with White House, Regulatory Focus 06 October 2020)
In terms of safety, both FDA and Pfizer found that serious adverse events (AEs) occurred no more frequently in the vaccine arm than in the group receiving placebo. Investigators found a numeric imbalance in cases of Bell’s palsy, with four cases in the vaccine arm and zero cases in the placebo arm. “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,” noted FDA. However, the agency is recommending surveillance for Bell’s palsy cases as the vaccine is deployed at scale.
Constitutional symptoms such as fatigue, low-grade fever, headache, muscle and joint aches and chills were all more common among vaccine recipients. Symptoms were more pronounced among younger vaccine recipients than in those aged over 55 years. Also, as expected, reactogenicity-related AEs were more common after the second vaccine dose. Injection site pain and local redness and swelling were also common and seen more frequently in those receiving the vaccine. After the second dose of the study medication, almost half of vaccine recipients (45%) reported taking medicine for fever or pain, compared with 12.6% of placebo recipients.
In its briefing documents, FDA expressed satisfaction with the chemistry, manufacturing and controls (CMC) data the sponsor provided: “FDA has reviewed the CMC data submitted to date for this vaccine and has determined that the CMC information is consistent with the recommendations set forth in FDA’s Guidance on Emergency Use Authorization for Vaccines to Prevent COVID-19,” wrote the agency.  “As such, FDA has determined that the Sponsor has provided adequate information to ensure the vaccine’s quality and consistency for authorization of the product under an EUA.”
FDA VRBPAC materials


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