A controversial memo calling for a major overhaul of vaccine clinical trials is generating strong pushback from public health experts and former FDA commissioners.
While the stated aim of the proposed revamp outlined by CBER Director Dr. Vinay Prasad is to improve vaccine safety, critics argue it’s not supported by evidence and may put patients at risk. Either way, sponsors and teams must be prepared for what could be a major pivot from past practices, said Gary Zammit, founder of Clinilabs, a central nervous system-focused clinical research organization.
In the memo, released in an internal FDA email a few weeks ago, Prasad outlined major changes to long-standing FDA practice that would require more vaccine trials to show real-world proof that vaccines prevent illness, rather than relying on the FDA’s long-accepted surrogate endpoint — the patient’s immune response to the shot, or immunobridging. This requirement for clinical endpoints would apply to “most” new vaccine approvals, including those targeting pregnant women, or label expansions for a new group, such as children. Prasad also said the regulator also plans to make sweeping changes to the “evidence-based catastrophe” of annual flu vaccine approvals.
If turned into policy, the changes would raise the bar for vaccine trials to be “more consistent with what they already require in other areas of medicine,” Zammit said.
But a group of former FDA commissioners, including Dr. Robert Califf and Dr. Scott Gottleib, wrote in a New England Journal of Medicine Perspective that vaccine trials are already rigorous, and that the potential changes could substantially slow the rollout of critical vaccines, potentially putting millions of Americans at risk.
“The new framework rejects the agency’s long-standing reliance on ‘immunobridging’ studies for well-understood vaccines with extensive safety data,” they wrote. “Because these viruses change frequently, repeating large-scale efficacy trials for every new seasonal strain is not feasible within the time needed to update the vaccines.”
They were also critical of the decision to announce sweeping changes in a staff memo instead of using the formal FDA process designed for highly consequential policy revisions.
“Under the Administrative Procedure Act and the FDA’s Good Guidance Practices, changes of this magnitude should be developed by guidance or regulation, with broad consultation within the agency, meaningful opportunity for public comment, and often public advisory-committee input,” the former FDA commissioners wrote.
Prasad’s view
The basis for the proposed change is another flashpoint.
Prasad said a review of the Vaccine Adverse Event Reporting System linked at least 10 child deaths to COVID-19 vaccines, which raised potential safety issues with the current approvals process.
VAERS is a passive, self-reporting system with data that isn’t independently verified. But Prasad said the agency arrived at the estimate of childhood deaths related to the vaccines after 96 VEARS reports were analyzed by FDA officials, adding that “the real number is much higher.”
Still, the evidence Prasad presented drew criticism from both former FDA commissioners and current FDA staff. Also not mentioned were the more than 2,000 American children who died from COVID-19 or studies that have shown vaccination can improve outcomes.
“Reasonable scientists should engage in open debate about how best to shape recommendations for children at lower risk for Covid-19, but substantial evidence shows that vaccination can reduce the risk of severe disease and hospitalization in many children and adolescents,” the former FDA commissioners wrote.
Prasad argued that comparing children who died from vaccination with those who died from the infection would be a false approach because it’s unclear how many fewer kids would have died if they were given the shot, especially considering most vaccinated people have also had the virus.
Preparing for change
For companies running vaccine trials, several challenges may lie ahead.
“I don't think that the requirements themselves represent the challenge, because this is the type of work that we do in clinical development all the time,” Zammit said.
But if sponsors are not used to conducting these longer, randomized controlled trials it might take longer to comply.
“They may not have the teams and the processes in place to now pivot instantly,” he said.
For most teams, the difficulty will lie in integrating new processes, Zammit said.
“The team has to absorb those new regulatory requirements into their processes and into their systems to make sure they're delivering what's going to be needed to produce a successful drug application,” he said, adding that teams that don’t communicate well can run into trouble.
“There could be contentious disagreements about what the objectives should be. And then internally, if a team is not functioning efficiently, it can mean poor protocol designs and poor study designs that don't meet the regulatory expectations fully,” Zammit said.
As of now, it’s not clear when or if changes to vaccine trials policy will be made official. According to the memo, the Office of Vaccine Research and Review and the Office of Biostatistics and Pharmacovigilance will now write guidelines to reflect the changes. While Prasad said he’s “open to vigorous discussions and debate on these topics,” he also invited staffers who don’t agree with these “core principles and operating principles” to resign.
