Marks on COVID-19 vaccine efficacy, EUAs and challenge trials

Regulatory NewsRegulatory News | 09 July 2020 |  By 

A week after the US Food and Drug Administration (FDA) issued guidance on vaccines to prevent coronavirus disease (COVID-19), Peter Marks, director of the Center for Biologics Evaluation and Research, shed light on the reasoning behind the agency’s 50% efficacy threshold and where the agency stands on challenge trials and emergency use authorizations (EUAs).
Efficacy and approval
In its guidance, FDA said it expected sponsors to demonstrate a vaccine is at least 50% effective in a placebo-controlled trial, with an adjusted lower bound of >30%. (RELATED: FDA issues COVID-19 vaccine guidance, setting 50% effectiveness threshold, Regulatory Focus 30 June 2020).
During a teleconference with the Alliance for a Stronger FDA on Wednesday, Marks explained that the 50% figure is based on what the agency could tolerate for efficacy. “Can we show you some calculation of how we got there? No,” he said, noting that the agency does not typically set specific efficacy targets in its vaccine guidance.
“If you go much lower than 50% then the lower bounds of things start to get to a place where vaccines may have very little efficacy,” Marks added. “On the other hand, if we held that number at 70% to 80% … we may not have a vaccine until there’s herd immunity that’s occurred naturally.”
However, Marks said that eradicating the virus will likely require a more effective vaccine. “We’re going to need a vaccine that’s probably in the order of 70% effective and 70%, at least, of the population is going to need to take it,” he said.
Based on those parameters, Marks said that pivotal trials for COVID-19 vaccines will need to be large. “Large means tens of thousands of people, probably … somewhere between ten to fifteen thousand individuals in each arm of a randomized trial to get to the kind of power that you need here.”
Marks could not comment on how quickly vaccine could be available but said, “We’re not going to have one in early fall, it’s going to take months.”
As stated in the agency’s guidance, Marks stressed that accelerated approval is not appropriate until there are compelling surrogate endpoints.
“Given the current lack of data that we have informing immune correlates of protection, we’re telling people that the clinical development program should pursue traditional approval, based on direct evidence of vaccine efficacy,” Marks said. “After a few vaccines come through the pipeline, we may understand what a good immune correlate of protection is, but we don’t yet know that antibodies are the be-all-end-all of protecting against COVID-19.”
Marks also expanded on whether the agency would consider issuing an emergency use authorization for a COVID-19 vaccine.
“We really believe that the most likely situation in which an emergency use authorization would be issued would be after some interim analysis that shows vaccine efficacy and safety, before a formal submission is made to the FDA of a licensure application and FDA has had a chance to do its normal review,” he said.
Challenge Trials
One of the more eyebrow-raising aspects of FDA’s guidance was a section discussing the potential for challenge trials, or controlled human infection models, wherein volunteers are intentionally exposed to a pathogen. In its guidance, FDA suggests that such trials could be entertained, “If it is no longer possible to demonstrate vaccine effectiveness by way of conducting clinical disease endpoint efficacy studies.”
“Why can’t we do that for COVID-19?” Marks asked, “Well, there are probably a couple reasons. One of which is that you don’t have something that cures COVID-19 100% of the time or near 100% of the time.” Marks said there are other issues that would need to be worked out before such trials would be feasible, including improving our understanding of the disease and determining which strain of the virus to use.
“This could be a way towards really facilitating getting an answer, if we had a rescue treatment and if we knew more about the relationship between carriage and infection, but right now it gives people some ethical heartburn and scientifically it’s complicated,” Marks said.
That said, Marks said FDA would consider proposals for challenge trials based on what was in the protocol and the circumstances at the time. “It’s not a ‘no’, it’s a ‘we’ll see,’” he said.
Marks added that it might be more feasible to conduct challenge trials when there are more effective therapeutics available to treat the disease. “If we have monoclonal antibodies that are really good at shutting down the disease, that could be a game changer.”
Safety and quality
Marks said that one of the things that “scares me more than anything else is that a third or half of Americans are hesitant about taking a vaccine [for COVID-19].” Marks stressed that part of FDA’s job is to assure that an eventual vaccine is safe and high quality.
“For any of these vaccines targeting SARS-CoV-2, important things for us from the standpoint of our guidance… will be things like consistency of manufacturing, and the need for manufacturing processes and controls that have appropriate steps in them, the need to have facilities inspected to produce vaccines under good manufacturing practices, that’s important because we really do need to make sure that these are going to be high quality products that when we say they’re safe, they really are,” Marks said.


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