Novavax redesigns U.K. trial to align with global COVID-19 vaccine trials
Company expects to start U.S. pivotal trial at end of November
Novavax has modified the U.K. Phase III trial of its COVID-19 vaccine candidate to ensure that it could support EMA approval and, the company believes, potentially support authorization or approval in the U.S.
EMA recommended changes to the design of the U.K. Phase III trial of NVX-CoV2373 to align with trials that are being conducted by other manufacturers around the world, Gregory Glenn, president for R&D at Novavax Inc. (NASDAQ:NVAX), told BioCentury.
The company has two other shots on goal for demonstrating safety and efficacy of its adjuvanted protein vaccine through an ongoing Phase II trial in South Africa and a Phase III trial that it plans to start in the U.S. and Mexico in November with support from Operation Warp Speed. Novavax is starting its U.S. Phase III trial a month later than planned because of delays in scaling up manufacturing; it now expects to start the pivotal trial at the end of November.
While the U.S. trial will be designed to support FDA authorization, Glenn acknowledged that the fast-moving situation, including the possibility that competing vaccines could gain authorization this year, could make it difficult to complete the trial. If that happens, he believes the U.K. trial could support U.S. authorization.
EMA has told Novavax that the South Africa trial, which includes an arm with HIV positive participants, could potentially support European approval, he added.
All of the trials will administer two doses of NVX-CoV2373, each containing 5 µg of protein antigen with 50 µg of Novavax’s Matrix‑M adjuvant, 21 days apart.
Glenn told BioCentury in September that the U.K. trial was originally designed to have two primary endpoints: prevention of symptomatic COVID-19 and prevention of moderate or severe COVID-19. He also reported that the company planned to take advantage of MHRA’s tolerance for a lower bound of the 90% confidence interval of 20%, which would allow it to reach statistical significance with a smaller trial than would be required to reach the 30% lower bound required by FDA.
In an interview on Oct. 27, Glenn said EMA had asked Novavax to align its U.K. Phase III trial with global COVID-19 trials by selecting a single primary endpoint and by increasing the lower bound of the confidence interval to 30%.
To meet the tighter confidence interval, Novavax increased the trial size by 5,000 participants to 15,000.
The trial is being conducted in partnership with the U.K. government’s Vaccines Taskforce.
More than 5,500 individuals have enrolled in the trial to date, said Glenn, who added that Novavax is “giving a lot of attention to including minorities and high-risk groups” that are especially important to FDA and other global regulators.
The protocol calls for unblinding the trial when 152 participants have been diagnosed with symptomatic COVID-19, an increase from the 116 events required in the previous protocol. Interim analyses are planned at 66 and 110 events.
There is controversy about the merits of approving or authorizing COVID-19 vaccines based on interim analyses, but Glenn contends that in the face of a deadly pandemic, such a decision would be justified. “The interim analysis has very stringent success criteria; you still have to meet the lower bound of 30%.”
While Novavax’s preference was to include prevention of moderate or severe disease as a co-primary endpoint, EMA insisted on a single primary endpoint, and uncertainty about the time it would take to accrue a sufficient number of severe or moderate cases led the company to select symptomatic COVID-19 in serologically negative individuals as the primary endpoint, Glenn told BioCentury.
The key secondary endpoint according to the study protocol is symptomatic moderate or severe COVID-19 in participants who were serologically negative for SARS-CoV-2 at baseline.
“If we get a win on the primary endpoint, we will be able to evaluate prevention of moderate or severe disease,” and if successful on the latter endpoint, the company expects to be permitted to include that data on the label, Glenn said.
At the Oct. 22 meeting of FDA’s Vaccines and Related Biologics Product Advisory Committee, some panel members called for revising trial endpoints to focus on serious disease.
However, Doran Fink, deputy director of FDA’s Division of Vaccines and Related Products Applications, argued that the symptomatic disease endpoint is sensitive. “There are multiple examples of vaccines where the data do appear to show they are most effective against more severe disease, less so against less severe disease, and even less against asymptomatic infection.”