Convergence: Marks admits 'knucklehead' messaging missteps with bivalent boosters, touts RWE for vaccines

Regulatory NewsRegulatory News | 13 September 2022 |  By 

Clockwise from top left: Phyllis Arthur, Amy Scott-Billman, Peter Marks, Marco Cavaleri

PHOENIX, AZ – The US Food and Drug Administration’s (FDA) top vaccines regulator, Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), said that the agency could have better communicated the strength of the evidence it had in support of the bivalent mRNA COVID-19 vaccine boosters it authorized last month.
Since authorizing the updated vaccines, the agency has faced criticism for authorizing the vaccines without requiring new clinical trials. Instead, the agency looked at nonclinical data for the bivalent vaccines containing the original SARS-CoV-2 strain and the Omicron BA.4/5 subvariants, in addition to the “totality of available evidence,” including data on the vaccines’ monovalent predecessors and clinical data for a bivalent vaccine containing the BA.1 lineage.
Speaking at RAPS Convergence 2022, Marks said, “I’ll take the knucklehead award on this one” for not emphasizing the “highest level” of evidence that the agency had to support its decision.
“Unfortunately, when you lead with ‘there were mouse studies that showed immunogenicity,’ the press picked that up,” Marks lamented. “Let me turn this around for you. You’re dealing with two vaccines, which combined have been given to more than half a billion people, over a billion doses administered … We understand the safety profile of these vaccines remarkably well. Two separate manufacturers, on three separate occasions, with the Beta, Delta, and the [Omicron] BA.1 variant, made novel vaccines compositions … to address those variants and they studied them in humans, and each time they found vaccines that were safe, obviously in a modest number of individuals, but also highly immunogenic.”
Marks added that the BA.4/5 subvariant is not that far off from BA.1. “It’s somewhere between 10 and 20 amino acids off, which is not that far off … from some of the influenza strain changes that may occur, which by the way, is something that we routinely do without any clinical data from year to year.”
“I think if we would have communicated it more like that, we would have probably had less of the issues than we did. I’m the first to admit it, because I probably was the knucklehead who did it,” Marks said, noting that he would be “shocked” if the bivalent vaccines did not prove to be immunogenic.
Marks also stressed that time was of the essence in authorizing the updated boosters. “In the setting of these variants, trying to get ahead was really important because what we saw – what happened in the previous attempts – we just fell behind so far that deploying the vaccines didn’t make as much sense,” he said.
Phyllis Arthur, vice president, infectious diseases and diagnostics policy at the Biotechnology Innovation Organization, agreed with Marks, noting that past attempts at variant-adapted boosters were “always behind the peak” and need to be deployed while the variant they target is still relevant.
But she stressed that public health officials need to find better ways to communicate with the lay public about the science backing vaccines that don’t come off as condescending.
“All of us who are close to vaccine R&D and research understand immunobridging and how you do it, and this is the future,” she said. “This sounds really, really like a shortcut to your basic person. I am struggling with the communications on this because I do think the mountain of evidence around these vaccines and their use worldwide – hundreds of millions of people have had a very strong immune response to these products, and the real-world evidence of their impact on hospitalization and death and sickness is quite clear.”
“How do we explain to people who say, ‘My kid is not a mouse’?” Arthur asked. “We’re going to have to teach people how to think of this as an extension of the data because right now we’re trying to treat it as new, when in actuality it’s not new.”
Arthur also said that committing to clinical trial diversity can help build trust in the process.
“Particularly since vaccines are generally population health … I think everybody has to renew their commitment to keeping that part going in the future,” she said. “People need to see that people who look like them – whatever that means – are part of the evaluation process, part of the science discussion, part of the clinical trial participation. That is going to be pivotal going forward on the clinical trial side, that we’re all committed to that work that’s required to have broad clinical trial participation so that people see themselves in the data … that’s a huge part of equity.”
Real-world evidence
The panelists also discussed how real-world evidence (RWE) and real-world data (RWD) can and is being used in the vaccine space.
“We do know that real-world data, real-world evidence is being used, but how can we ensure that we can use it even more broadly, properly, to create that totality of information and data for decision-making, and I do think it has a role in vaccines and other modalities, including monoclonal antibodies and things for prophylaxis and treatment in the future,” said Amy Scott-Billman, VP and global head of regulatory affairs for vaccines and immune therapies at AstraZeneca.
She noted FDA’s guidance on RWD/RWE issued under the 21st Century Cures Act and said that further guidance on the topic expected under the Prescription Drug User Fee Act (PDUFA VII) agreement will “further illuminate the expectations around conduct of studies, quality of data, presentation of data and information.”
Compared to other areas such as oncology, where there is more comfort around speeding treatments to market and getting confirmatory evidence later, Arthur said there “is a lot less comfort doing that in the vaccine space, partly because of the way the products are used.”
“The recommending bodies are sort of looking for a little more of the classic data, and we in industry, along with regulators, are moving toward … ‘this is enough data to get you an authorization or approval, and then we’ll get the rest of the data when you’re on the market, and there’s some discomfort there in this space.” Arthur said.
Marks stressed that heavier reliance on real-world evidence will become a reality in vaccine development.
“Real-world evidence in the vaccine space is a reality of where we’ll be headed because it’s actually an area where, at least when things are working in the United States, we know we can do it. We’ve seen what can be done in the influenza space, and in fact, we’ve seen that for influenza, you can actually get better data using real-world evidence than you can almost with randomized trials,” Marks said, citing the ability to decipher information that payers really care about, like how many people are hospitalized with influenza.
“Our problem is that we have a very chopped-up system of electronic records and some of these are related to our individual state laws, etc., and we’ll have to work to overcome some of these things in the future,” Marks said.
“I am a very big supporter of where real-world evidence can bring us here, and in fact we’ve used it now in a variety of settings to help us get certain aspects of vaccine approvals across the finish line,” Marks said.
Marco Cavaleri, head of biological threats and vaccine strategy at the European Medicines Agency (EMA) said that RWE can be used earlier with vaccines than it can for other medicines.
“We do real-world evidence in the vaccine space much earlier than in other areas like pharmaceuticals because the estimate of vaccine effectiveness tends to be less biased and it’s easier to trust this data, which otherwise cannot be generated,” Cavaleri said.
“Overall, I think in the pandemic it was really clear. There were a lot of randomized clinical trials conducted in support of the initial approval but in these studies the number of cases of severe COVID-19 was extremely limited. We were talking about maximum 10-11 cases, even after a study of 40,000, so clearly these studies don’t have the power to really look into this endpoint. They don’t have the capacity to look into all the possible populations,” he added.
Despite efforts to be more inclusive and enroll participants from different subpopulations or with different co-morbidities, Cavaleri said, “You could not cover everyone. After the approval [of the COVID-19 vaccines] I went straight into a large meeting with nephrologists from Europe and they asked me a question I could not answer because in the trials … people with kidney disease, they were not included, and it was very difficult to say much.”
Vaccine platforms
While vaccine platforms, such as the mRNA platforms used by Pfizer-BioNTech and Moderna to develop their COVID-19 vaccines could generate candidate vaccines in record time during the pandemic, numerous technologies exist and could be useful in this or future public health crises.
“Although the mRNA platforms, for instance, are wonderful in many regards, they are not a cure-all for all infectious diseases. I think we can already show examples where we know that for certain infectious diseases the mRNA platforms will not provide the kind of immunity that we need,” Marks said. “It’s another tool in our armamentarium that we will have.”
Instead of putting too many eggs in one basket, Marks said he thinks it would be beneficial to map various infectious diseases to platforms that might have the best chance of success.
“If we do our work properly, we will have a variety of platforms and then map infectious diseases or classes of infectious diseases to platforms and that mapping may well help us when we move forward again,” Marks said. For example, he said that mRNA vaccines may turn out to be more useful when you need a good antibody response.
Cavaleri noted that the mRNA platforms were especially useful due to their speed. “It’s true that there are certain platform technologies that seem to be better placed for coming up rapidly with vaccines that can be approved,” he said.
Scott-Billman said that one of the advantages of platforms is that once you have gained experience with them, “You can really rely on a lot of the information and data that are generated with the first couple of iterations of the usage and the application of platforms and be able to rely on that so as not to necessarily have to repeat a lot of that information but focus on the new information for the new target that you need to inform decision-marking.”
“There is a lot to be said for the future in the need for additional convergence, additional reliance mechanisms and harmonization across the globe, including with various authorities and with industry to make sure we can get on the same page as much as we can,” she added.
Marks said that one of the exercises that should be undertaken as the pandemic recedes is to “look at the platforms that did not perform the way we had hoped they would and think about why they didn’t and what we could do to improve them.”
Without “trying to diss them,” Marks said that protein-based vaccines were “a disappointment in our ability to move them forward rapidly during this pandemic, despite the fact that we have recombinant technologies, and this has been pointed to repeatedly as kind of the savoir of us in influenza.”
“Especially thinking about that for influenza pandemics of the future where we have licensed vaccines in this area, I think we do want to think about what do we need to do to be able to scale up that manufacturing. What is it, is it a cell line issue? Is it bioreactor issues? I think it’s probably a combination of a variety of things, but I think we want to look back there and say, ‘What happened with protein-based vaccines?’ Because some would have predicted that they shouldn’t have lagged as much as they did in this process,” Marks said.
Marks also commented on the recent news that CBER has hired David Kaslow, chief scientific officer at the public health nonprofit PATH, to head up its Office of Vaccines Research and Review.
“Dr. Kaslow is going to be a fantastic addition for us … he is very committed to trying to make sure that we are able to address the public health demands that we have continued to have year after year with emerging infectious diseases and to help us build essentially the bench strength that we’re going to need at the agency to be able to rapidly address the various issues that come up,” Marks said.


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