FDA Vaccine Advisory Committee Ex Summary
FDA Vaccine Advisory Committee Ex Summary It is long, but just over a page from a 54 page document. Those who want it all can get it at the link posted above.
Moderna COVID-19 Vaccine
VRBPAC Briefing Document
1. Executive Summary
On November 30, 2020, ModernaTX (the Sponsor) submitted an Emergency Use Authorization (EUA) request to FDA for an investigational COVID-19 vaccine (mRNA-1273) intended to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine is based on the SARS-CoV-2 spike glycoprotein (S) antigen encoded by RNA and formulated in lipid nanoparticles (LNPs). The proposed use under an EUA is for active immunization for the prevention of COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. The proposed dosing regimen is 2 doses, 100 μg each, administered 1 month apart.
The EUA request includes safety and efficacy data from an ongoing Phase 3 randomized, double-blinded and placebo-controlled trial of mRNA-1273 in approximately 30,400 participants. The primary efficacy endpoint is the reduction of incidence of COVID-19 among participants without evidence of SARS-CoV-2 infection before the first dose of vaccine in the period after 14 days post-dose 2. In an interim analysis conducted using a data cutoff of November 7, 2020, a total of 27,817 participants randomized 1:1 to vaccine or placebo with a median 7 weeks of follow-up post-dose 2 were included in the per-protocol efficacy analysis population of participants without evidence of SARS-CoV-2 infection prior to vaccination.
Efficacy in preventing confirmed COVID-19 occurring at least 14 days after the second dose of vaccine was 94.5.0% (95% CI 86.5%, 97.8%) with 5 COVID-19 cases in the vaccine group and 90 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 (11 protocol-defined severe COVID-19 cases in the placebo group vs. 0 cases in the vaccine group), 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 some of these outcomes did not allow for firm conclusions. Efficacy data from the final scheduled analysis of the primary efficacy endpoint (data cutoff of November 21, 2020, with a median follow-up of >2 months post-dose 2) demonstrated a VE of 94.1% (95% CI 89.3%, 96.8%), with 11 COVID-19 cases in the vaccine group and 185 COVID-19 cases in the placebo group and was consistent with results obtained from the interim analysis. The VE in this analysis when stratified by age group was 95.6% (95% CI: 90.6%, 97.9%) for participants 18 to <65 years of age and 86.4% (95% CI: 61.4%, 95.5%) for participants ≥65 years of age. A final secondary efficacy analysis also supported efficacy against protocol-defined severe COVID-19, with 30 cases in the placebo group vs. 0 cases in the vaccine group.
Safety data from a November 11, 2020 interim analysis of approximately 30,350 participants ≥18 years of age randomized 1:1 to vaccine or placebo with a median of 7 weeks of follow-up after the second dose supported a favorable safety profile, with no specific safety concerns identified that would preclude issuance of an EUA. These safety data are the primary basis of FDA’s safety review. On December 7, 2020, the Sponsor submitted additional follow-up data from these participants with a cutoff of November 25, 2020, which represents a median of 9 weeks (>2 months) of follow-up post-dose 2. Key safety data from this later submission, including death, other serious adverse events, and unsolicited adverse events of interest were independently verified and confirmed not to change the safety conclusions from the interim safety analysis.
The most common solicited adverse reactions associated with mRNA-1273 were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%); severe adverse reactions occurred in 0.2% to 9.7% of participants, were more frequent after dose 2 than after dose 1, and were generally less frequent in participants ≥65 years of age as compared to younger participants. Among unsolicited adverse events of clinical interest, which could be possibly related to vaccine, using the November 25, 2020 data cutoff, lymphadenopathy was reported as an unsolicited event in 173 participants (1.1%) in the vaccine group and 95 participants (0.63%) in the placebo group. Lymphadenopathy (axillary swelling and tenderness of the vaccination arm) was a solicited adverse reaction observed after any dose in 21.4% of vaccine recipients <65 years of age and in 12.4% of vaccine recipients ≥65 years of age, as compared with 7.5% and 5.8% of placebo recipients in those age groups, respectively. There was a numerical imbalance in hypersensitivity adverse events across study groups, with 1.5% of vaccine recipients and 1.1% of placebo recipients reporting such events in the safety population. There were no anaphylactic or severe hypersensitivity reactions with close temporal relation to the vaccine. Throughout the safety follow-up period to date, there were three reports of facial paralysis (Bell’s palsy) in the vaccine group and one in the placebo group. Currently available information is insufficient to determine a causal relationship with the vaccine. There were no other notable patterns or numerical imbalances between treatment groups for specific categories of adverse events (including other neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to mRNA-1273.
The frequency of serious adverse events was low (1.0% in the mRNA-1273 arm and 1.0% in the placebo arm), without meaningful imbalances between study arms. The most common SAEs in the vaccine group which were numerically higher than the placebo group were myocardial infarction (0.03%), cholecystitis (0.02%), and nephrolithiasis (0.02%), although the small numbers of cases of these events do not suggest a causal relationship. The most common SAEs in the placebo arm which were numerically higher than the vaccine arm, aside from COVID-19 (0.1%), were pneumonia (0.05%) and pulmonary embolism (0.03%).
With the exception of more frequent, generally mild to moderate reactogenicity in participants <65 years of age, the safety profile of mRNA-1273 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.
This meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) is being convened to discuss and provide recommendations on whether, based on the totality of scientific evidence available, the benefits of the mRNA-1273 COVID-19 Vaccine outweigh its risks for use in individuals 18 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.