FDA Shares Phase 3 Moderna COVID-19 Vaccine Data, Advisory Committee Agenda

On Thursday, the US Food and Drug Administration (FDA) Vaccines and Related Biologic Products Advisory Committee (VRBPAC) will gather to discuss whether or not they will grant an Emergency Use Authorization (EUA) application to Moderna’s mRNA-1273.

The messenger RNA (mRNA) vaccine was created in collaboration between Moderna and investigators from the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID). The phase 3 trial data will be evaluated in a full-day meeting by a panel of experts, along with input from the public. A vote will then be taken on the therapy’s benefit-risk ratio for its prospective use as a preventive vaccine for confirmed COVID-19.

The meeting comes a week after Pfizer and BioNTech were granted an EUA by the FDA for their BNT162b2 vaccine, which was the first vaccine approved for the coronavirus disease 2019 (COVID-19) in the United States. All signs point to a similar outcome for Moderna.

The phase 3 data submitted to the FDA as part of the EUA application can be found here.

Phase 3 Trial Makeup

The ongoing randomized, stratified, observer-blind, placebo- controlled study has included 30,351 participants who were randomized 1:1 to receive intramuscular injections of either 100 μg of mRNA-1273 or a placebo. The vaccine was administered in 2 doses given 28 days apart in adults who were 18 years of age or older.

The participants were stratified by age and health risk into 3 groups:

• 18 to <65 years of age and not at risk for progression to severe COVID-19
• 18 to <65 years of age and at risk for progression to severe COVID-19
• ≥65 years of age

The latter 2 groups constituted 41.4% of the study population. The risk for progression to severe was based on underlying comorbidities, including diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease, or infection with HIV.

Included in the study were 24,907 (82.1%) participants who were considered to be at occupational risk for acquiring the SARS-CoV-2 infection, of whom 7613 (25.1%) were healthcare workers.

Trial Goals

Investigators sought a primary endpoint of vaccine efficacy for mRNA-1273 against COVID-19 occurring at least 14 days after the second dose in participants negative for SARS-CoV-2 at baseline.

The second primary efficacy endpoint included preventing severe COVID-19 and death due to the disease. Also included was disease occurring at least 14 days after the first or second dose of the vaccine, regardless of a prior SARS-CoV-2 infection.

Efficacy Findings

At the interim analysis, the mRNA-1273 vaccine was found to have an efficacy of 94.5% (95% CI 86.5-97.8% against confirmed COVID-19 14 days after the second dose in participants without evidence of a prior SARS-CoV-2 infection. In total, 11 cases of severe COVID-19 were observed, but all of them occurred in the placebo group.

Efficacy after just 1 dose of the vaccine was found to be 80.2% (95% CI, 55.2-92.5) in a median follow up time of 28 days. This cannot support a conclusion on single dose efficacy though, due to the fact that the numbers of participants and time of observation are limited.

Data was submitted as an amendment after the initial EUA request from a final efficacy analysis. However, the FDA has not yet independently verified the data from this dataset. The final scheduled efficacy analysis on the primary endpoint, demonstrated an efficacy of 94.1% (95% CI, 89.3-96.8). A lower efficacy was observed in participants ≥65 years of age compared to that in younger adults 18 to <65 years of age.

Safety Outcomes

The primary safety goal in the trial was to describe how safe the vaccine was after both 1 and 2 doses. Participants reported local reactions, systemic events, and antipyretic/pain medication usage from day 1 through day 7 after each dose. Participants who received the vaccine had a higher proportion of adverse events in comparison to the placebo group in the 7 days following its receival. The overall rate of adverse events were lower in the participants who had a positive SARS-CoV-2 baseline.

The rate of solicited local and systemic adverse reactions within 7 days of each dose were assessed through all groups. Across both of the age cohorts, the most frequently recorded local adverse reaction was pain, reported by 83.7% of vaccine recipients after the first dose (2.8%) and 88.4% after the second dose (4.1%). The median durations of pain were reported to be 2 days after dose 1 and 3 days after dose 2.

Participants in the age cohort of 18 to <64 years reported the highest rates of pain after the second dose, with 90.1% reporting any pain and 4.6% reporting Grade 3 pain. In the subgroup analyses of adults ≥65 years of age, the rates of solicited reactions were comparable to those observed in all of the participants.

Regarding unsolicited adverse events, a higher frequency was reported in the vaccine group (21.9%) compared to the placebo group (19.4%) within 28 days. These were primarily attributed to local and systemic reactogenicity. Participants who reported severe unsolicited events after any vaccine dose was 1.4%. These included headache, myalgia, arthralgia, injection site erythema, and injection site pain. 13 total deaths were reported in the trial, with 2 in the age cohort of >75 years who both had pre-existing cardiac disease.

The VRBPAC meeting

The meeting takes place Thursday morning through the early evening, with a panel of FDA experts hosting an open session to discuss whether the evidence available shows that the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older.

The planned sessions, as per the FDA’s shared agenda, include:

• Presentation on Emergency Use Authorization
• Considerations for placebo-controlled trial design if an unlicensed vaccine becomes available
• Sponsor Presentation
• Q&A for Sponsor Presenters
• FDA Presentation

The FDA’s advisory committee’s votes have historically aligned with eventual marketing decisions. Considering the current rise of the COVID-19 pandemic and fears of a continuing second wave, coupled with the approval of Pfizer’s vaccine last week, an EUA approval is anticipated for mRNA-1273 by the VRBPAC.