CBER Raising Bar on Future Covid Vaccines
Memos posted on FDA’s Web site from CBER director Vinay Prasad suggest the agency is raising the bar on future Covid-19 vaccination approvals. For example, as part of the agency’s approval last week of the upcoming Covid-19 seasonal vaccines, Prasad wrote in one memo that CBER is now demanding post-marketing commitment studies “roughly 5 to 10 times larger than historically accepted.”
He noted that a required safety and immunogenicity study in the indicated population may help “unlock a key scientific question in vaccine regulation: at what threshold of antibody production, if any, are Covid-19 vaccines protective against Covid-19 caused by SARS-CoV-2. CBER OCD can use this information to improve vaccine regulation. Is it possible that current Covid-19 vaccines actually fail those who need them the most — the immune compromised — because they generate insufficient antibodies in the groups who would most benefit? Or instead, is current Covid-19 vaccine policy doing justice for these Americans?”
Prasad said his decision to require safety and immunogenicity studies from Covid-vaccine makers was based on several considerations: “First, the prior standard in CBER was acceptance of small immunogenicity studies using human sera, largely aimed at demonstrating numerical improvements in antibody formation against prevailing strains. These studies lacked formal statistical prespecification and power to test a clear scientific hypothesis.” He said that the previous studies were largely conducted to provide “nominal justification for a strain change, even while there has been substantial uncertainty in whether such changes were necessary and/or beneficial.”
Additionally, CBER is setting a higher bar for claims recommending the administration of multiple vaccines together. In a separate Prasad memo, he said vaccine makers will need to conduct large, randomized controlled trials before they can claim that Covid-19 shots can be safely and effectively given at the same time as other vaccines, such as influenza or RSV. Earlier approvals for concurrent vaccination were based on small studies measuring antibody levels, he wrote, adding that they were too limited to prove that combining vaccines actually protects against illness or to detect potential safety concerns.
“Such small trials are inherently incapable of adequately documenting safety signals,” the memo stated, noting that post-marketing studies also have limits because people who choose to receive multiple vaccines together often differ from those who space them out. Prasad acknowledged that giving multiple vaccines in a single visit could improve compliance with annual immunizations. But he cautioned that simultaneous administration may also interfere with the effectiveness of one or more shots or raise the risk of side effects.
Going forward, the agency will require larger studies powered to detect clinical outcomes such as symptomatic Covid-19, influenza, or RSV, as well as severe disease and adverse events. The trials would begin by testing whether co-administration is no worse than giving vaccines separately and could go on to test whether it is superior by improving adherence. Without such evidence, Prasad said the study cannot confirm that concurrent vaccination “is both safe and effective.”