US FDA Preparing For Less-Than-Ideal COVID-19 Vaccine Studies
Executive Summary
The best vaccine development program would include robust clinical trials, CBER Director Marks says in an interview, but that depends on what’s happening with viral transmission on the ground.
Sponsors of COVID-19 vaccines in development are encouraged to meet with the US Food & Drug Administration “as early as they would like” to start designing Phase II/III trials, Center for Biologics Evaluation & Research Director Peter Marks said in an 21 April podcast interview with Prevision Policy. (See link at the end of the story for the full audio.)
At last count, there are approximately 70 vaccines in development against the SARS-CoV-2 virus. Three are in Phase I – from Moderna Inc., Inovio Pharmaceuticals Inc., and CanSino Biologics. The design of Phase II/III trials will largely depend on the safety and efficacy profile in animal models, as well as whether or not the novel coronavirus is circulating on the ground.
The best-case scenario would be a rigorous development program with good data from randomized clinical trials. But, Marks cautioned, all that depends on whether the virus is still circulating when Phase II/III trials are ready to begin. “We are going to have to see what we have on the ground at the time and what circumstances bring us.”
In the absence of circulating virus, FDA could look at whether antibody protection is a predictable biomarker. But, he acknowledged, that could potentially require a conventional, large clinical trial to demonstrate efficacy. If the virus is circulating, a Phase II/III trial could be set up using real-world evidence to compare different waves of vaccinated patients.
“It’s not perfect. I will acknowledge right away there are certain people at the NIH who I’m sure would like to tell me that that’s a horrible design,” Marks during a webinar hosted by the Commonwealth Fund and the Alliance for Health Policy on 17 April.
“The real issue here is in trying to get things move fast,” he said, and acknowledging that long-term data may not be possible before widespread vaccination.
In the meantime, CBER is open to all ideas. “We’d like to entertain and discuss in an open fashion all of the possible designs. In this particular situation, we can’t dismiss out of hand any potentially useful design – be it real-world evidence based, traditional or otherwise.”
CBER has established a triage system to handle any incoming inquiries or submissions. (Also see "Gene Therapy May Pack US FDA’s Calendar This Fall; CBER Staffs Up" - Pink Sheet, 23 Apr, 2020.)
‘Meticulously Rapid Development’
However sponsors proceed, CBER will be implementing what Marks referred to as “meticulously rapid development.” He used the analogy of an airline pilot in trouble to illustrate his point: “If you had to take off in a plane quickly, the pilot doesn’t just throw the checklist out the window. The pilot still goes through the checklist, they just do it quickly; and they make sure that everything they do, they do with a purpose.”
CBER Director Peter Marks
“We are going to have to be exactly the same way. We are going to have the clear focus that we have to have a safe and effective vaccine,” Marks said. “We have to check all the boxes that that vaccine meets the standards that we come to expect from vaccines. But while we’re doing that, we shouldn’t be having periods where we’re not doing incredible due diligence pursuing this rapidly. It is a very careful balancing act.”
“We are going to do whatever we can to move things forward,” Marks said during the webinar. CBER is “working with the various sponsors of the vaccines to most effectively look at their pre-clinical data, understand as much as we can about the characteristics of these vaccines, help people develop development plans that are most efficient at understanding whether their candidate will get to levels of protection that we really want, and taking them forward.”
CBER will be closely monitoring for any changes to the COVID-19 virus that could affect development projects. “Right now, there have not been mutations that would fundamentally alter vaccine development programs in terms of targets that they are going after. But we will have to be very vigilant for any changes, and in which case the hope would be that if that did occur, it would be much like an influenza stain change-type supplement.”
The “ideal vaccine,” Marks said, “is one that when we get to a certain number of people vaccinated, with a certain efficacy with the vaccine, we get herd immunity and we wipe things out. That’s what happened with smallpox, and what’s happening with measles and polio. And so, you’d like to have very high efficacy. If you don’t get there, we would probably take the next best thing, because having some people protected is better than having no people protected.”
“But if you have a vaccine that does have relatively less efficacy, you end up with a situation like we have with seasonal influenza, where you have only a portion of the population protected,” he said.
“We can’t have perfection be the enemy of the good. On the other hand, that’s the reason for trying our hardest right now ... and using a smart development approach right up front so that you try to make the best choices right now.”
Considering An EUA
The situation on the ground in terms of viral circulation and spread – and the strength of the evidence – will also dictate whether FDA would consider issuing an Emergency Use Authorization for a vaccine candidate. (Also see "COVID-19 Vaccines: Ex-FDA Leaders Urge High Bar For Emergency Use Authorization" - Pink Sheet, 5 Apr, 2020.)
NIH National Institute of Allergy and Infectious Diseases Director Tony Fauci has suggested an Emergency Use Authorization as a possibility for a COVID-19 vaccine. Marks explained what he believes the profile would need to be for a vaccine to qualify for EUA consideration.
“If there was widespread circulation and we have very good safety data and very promising efficacy data from a Phase II study, and a combination of study from Phase I-II and very good data from animal models that we trust – could you imagine getting to an EUA in that setting? Possibly. On the other hand, if you didn’t have circulating virus, but you wanted to just get people vaccinated, I don’t think you would see that.”