December 10, 2020 -- A COVID-19 vaccine candidate from Pfizer-BioNTech, BNT162b2, passed a major milestone today when a U.S. Food and Drug Administration (FDA) advisory committee determined that the benefits of the candidate in preventing COVID-19 outweigh its risks. The advice of the committee will likely lead to the issuance of an emergency use authorization (EUA) for the vaccine by the FDA within days.
The EUA for the Pfizer-BioNTech COVID-19 vaccine candidate was the main topic of discussion at the December 10 meeting of the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC), which advises the Center for Biologics Evaluation and Research (CBER). The committee voted 17-4 with one abstention to recommend the vaccine be approved.
The meeting kicked off with FDA deputy director Dr. Doran Fink, PhD, presenting information about emergency use authorizations. Fink discussed the agency's legal authority to issue EUAs and the criteria for determining whether the agency will issue an EUA for a COVID-19 vaccine.
Regarding today's committee meeting, Fink explained that the agency must "decide whether to make the vaccine available to millions of Americans."
Specifically, the committee members were asked to vote on the following question:
"Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech COVID-19 vaccine outweigh its risk for use in individuals 16 years of age and older?"
When VRBPAC met on October 22, the group set expectations for the issuance of COVID-19 vaccine emergency authorizations. The agency expects quality and consistent manufacturing data, compelling safety and efficacy data supporting a favorable benefit-risk scenerio, and plans for further evaluation. In the meeting materials and submissions to the FDA, the sponsors presented a variety of data including safety and efficacy data from an average of two months' worth of follow-up data from trial participants.
In questions from the committee after his presentation, Fink explained that the FDA would like any vaccine that is issued an EUA to undergo continued evaluation and eventually move toward licensure, for instance with a biologics licensure application (BLA). Typically, the FDA would require at least six months' worth of follow-up safety data to support licensure. Since the data submitted by Pfizer-BioNTech averages two months of follow-up data, the agency would expect the company to continue evaluation of the vaccine until satisfaction of the requirements for full licensure are met. To this end, Pfizer announced that it plans to submit a BLA by April 2021.
Fink's presentation was followed by three speakers from the U.S. Centers for Disease Control and Prevention (CDC) who discussed various aspects of public health including epidemiology tracking of COVID-19 (COVIDnet to track hospitalizations and patient characteristics), joint efforts by the U.S. government to track vaccine safety and effectiveness in targeted populations (including V-safe and Genesis HealthCare efforts), and vaccine distribution plans with special considerations for the candidate.
Based on COVIDNet data, older adults in long-term care facilities and healthcare personnel are recommended to be priority groups for vaccine administration. Many early CDC efforts to track vaccine effectiveness will focus on these groups. The CDC will be committed to evaluating the real-world performance of vaccines, especially in light of distribution challenges associated with the Pfizer-BioNTech vaccine -- namely, the timing of the two-dose regimen and varying cold chain conditions.
About Pfizer-BioNTech's COVID-19 vaccine
Pfizer-BioNTech submitted an EUA request to the FDA on November 20 for their vaccine candidate, BNT162b2. The vaccine is administered intramuscularly as a series of two 30-µg doses of diluted vaccine solution 21 days apart. BNT162b2 encodes the full-length spike protein with two-point mutations to proline within the central helix domain to lock the spike protein in an antigenically preferred prefusion conformation. The mutant RNA is formulated in lipid nanoparticles, which enables transfection of the RNA into host cells after injection. In the cytosol of the cell, the RNA is translated to the viral protein. The spike antigen incorporates into cellular membranes and induces an adaptive immune response.
Pfizer provided supporting evidence regarding the safety and efficacy of the vaccine prior to the meeting and the results were presented for the committee during the afternoon session of the meeting.
A phase I/II dose level-finding study was conducted in Germany, followed by an ongoing randomized, placebo-controlled phase I/II/III registration study. The latter began as a phase I/II study in the U.S. and was expanded to a global phase III study enrolling approximately 44,000 participants. Safety data from 38,000 participants with an average of two-month follow-up after the second dose of the vaccine (30 µg of BNT162b2) demonstrated that the vaccine was safe and well-tolerated. The incidence of serious adverse events and deaths were low. There was mild or moderate local pain at the injection site after the first and second doses but it resolved fairly quickly.
The candidate elicited robust SARS-CoV-2 neutralization titers and subunit 1-binding immunoglobulin G (IgG) levels in young and older adults. It also elicited strong Th1-biased CD4+ responses and strong CD8+ T-cell responses. The vaccine efficacy was determined to be 95% for the primary end point of preventing COVID-19 at least seven days after the second dose of the vaccine was given. Pfizer's analysis indicates that there is a high probability that the true vaccine efficacy is at least 90%. There were a total of eight cases of COVID-19 in the vaccine group compared to 162 cases in the placebo group.
The FDA's review and committee discussion
There were 94 cases in interim analysis on November 4 and 170 cases included in final analysis on November 14. The FDA's review of the data also indicated a vaccine efficacy rate of 95% for the first primary end point of preventing COVID-19. Other data from the FDA's review were similar to data presented by Pfizer. Notably, post hoc efficacy data revealed that previously exposed individuals do have the potential for reinfection. Also, there were a small number of adverse events that might indicate an allergic reaction in the vaccine group.
Significant time was dedicated to discussing if placebo patients within clinical trials should have access to the vaccine if it is given EUA. Pfizer plans to offer eligible participants in the placebo group with the option to receive the vaccine. These participants will have the option to remain blinded through the end of the study, which would maintain the integrity of the clinical trial. As the study needs to collect data for 24 months post vaccination, any placebo individuals who drop out of the study could affect the quality of the study.
Another topic of concern among committee members and the public was the length of follow-up data presented by Pfizer. With BLA safety standards for other vaccines, specified by the agency, there are concerns that the two months of data is not sufficient to draw sound conclusions about the safety of the product.
Along this same line, several committee members offered that they would like to see more data from diverse participant populations. This data would allow the companies and regulators to more precisely estimate vaccine effectiveness in specific populations. However, the companies remain committed to collecting data for a period of two years for all clinical trial participants.
After deliberation, the committee voted on the potential benefits of BNT162b2 in preventing COVID-19 in individuals older than the age of 16. In a 17 for, 4 against, and 1 abstain vote, the committee gave a positive answer to the FDA and the agency is expected to make a determination on the EUA request within days, if not hours.