A Q&A with the FDA’s top vaccine regulator amid a fresh wave of disinformation

Vaccination policy in the United States could be in line for some fundamental changes, if Donald Trump is reelected and delivers on promises that long-time vaccine skeptic Robert Kennedy Jr. said the former president has made — including giving Kennedy authority over the country’s health agencies in a second Trump administration.

Even if none of that comes to pass, vaccine fatigue and disinformation abound in the wake of the Covid-19 pandemic. Public health authorities promoting vaccine use do so in an ever more challenging climate.

At a public forum last week, Peter Marks, the top vaccine regulator for the Food and Drug Administration, said the way to counter the movement is by being transparent. 

“We have to be steadfast in this. Answer questions, be honest, that will ultimately take the day over the misinformation and disinformation, which is being done for non-health purposes,” he said during a panel discussion on fall vaccinations organized by the group Champions for Vaccine Education, Equity and Progress.

STAT reached out to Marks, the director of the FDA’s Center for Biologics Evaluation and Research, to talk about how vaccines are regulated in this country. He agreed, though the FDA stated in advance that he would not comment on individuals involved in the current political debate or anything they have said.

The following transcript of the conversation has been lightly edited for length and clarity.

Broadly speaking, we’re seeing a lot of vaccine skepticism lately. It’s in the news often. There’s a lot of misinformation out there. I don’t know, though, that we actually are seeing a huge drop in vaccination rates. I know there’s been some decline. Certainly for some vaccines, like the Covid vaccines, there’s been a drop-off. Is there more noise than actual reality around this topic?

I think we don’t know the full extent of the adverse effect on vaccination. We won’t know that until we see pockets of kids who haven’t gotten certain vaccines coming down with infectious diseases. 

The problem is that it doesn’t take vaccination rates to drop off that much to start getting into problems here, where you lose herd immunity. So, I don’t disagree with you in the statement that it’s not like the sky is falling, but there are clearly pockets of people who have started to perhaps not take all of the appropriate vaccines. And there’s this kind of concept of ‘I’ll take the vaccines that I feel are important rather than the ones that are recommended.’ So I do think there’s some concern there that this could get worse. And we just don’t know the extent of the damage that’s been done to date.

Some of the skepticism appears to be rooted in claims that manufacturers don’t have to generate safety data before bringing a vaccine to market. Can you address that?

Vaccines are among the most well-monitored products. By definition, we cannot approve a vaccine unless the benefits greatly outweigh any risk. 

The average vaccine, before it gets an approval in the United States, has been studied in something like 22,000 people treated with the vaccine. That’s the average. Some trials are smaller, some are more than that. The Covid vaccines had about 40,000 to 50,000 when they were ultimately approved, about 20,000 to 25,000 treated with a vaccine when they were [issued an emergency use authorization]. 

The bottom line is that there is a lot of safety data that we obtain before they go to market. And that’s in the clinical trial setting where there’s mandatory reporting of all adverse events, period. Not just serious adverse events but adverse events and serious adverse events. And then after licensure of these vaccines, there is reporting through the multiple overlapping safety systems.

We have the Vaccine Adverse Event Reporting System [VAERS], which seems to be very hard for people to understand. It’s basically a way for anyone [to report] any kind of adverse event, whether or not they know it to be related, after having a vaccine. So patients can report. Doctors can report. Other health care providers. Even companies. 

And then we sort that out on the back end by getting additional data to figure out whether things truly are related or not. Now, part of the problem that we get into is that because that involves getting protected health information, the public doesn’t see what we see at the end of the day in terms of any potential relationship. 

So, for instance, if somebody had a heart attack within a week of having a vaccination, VAERS will not show if that person has had a long history of cardiovascular problems?

That’s precisely correct. VAERS would not show the fact that they got the flu shot perhaps while they were hospitalized for unstable angina. And they had a heart attack while they were in the hospital. We sort it out on the back end.

The other safety systems are also very powerful, such as Sentinel Best, an active safety surveillance system. We have [data from] tens of millions of lives captured, either in health care-claims databases and/or electronic health records. We get data that’s obviously been de-identified. The confidentiality is maintained. But what we’re able to do is look at a population of individuals who have been vaccinated and a population who has not been vaccinated and see if certain adverse events — could be heart attacks, could be neurologic events such as Guillain-Barré syndrome [GBS], which we regularly look [for] with influenza vaccine, which we’ve looked for with respiratory syncytial virus vaccines. We constantly monitor that. And we actually make the data public. When we find things, we publish them or we post them on our websites. 

Those who deny that the system is working just need to look at recent events. For instance, with the Janssen Covid vaccine, where we relatively rapidly within a few months of its deployment realized that it had a very serious adverse event — this thrombotic thrombocytopenia syndrome. It was identified. We warned providers. We relabeled the vaccine. And ultimately that vaccine, it’s not available anymore because Janssen decided that after all of the warnings on it, they would not proceed with a biologics license application and they withdrew the emergency use authorization. 

So we do find things. Just like we often report a slight increase in risk of Guillain-Barré syndrome with the influenza vaccine. By the way, these are tough studies because there’s a background incidence of Guillain-Barré syndrome with flu infection too. 

In fact, the rate of GBS is higher after flu infection than it is after flu vaccination, isn’t it?

Right!

I want to talk to you more about the post-licensure efforts, but first I want to ask you a little more about the pre-licensure activity. One of the things some critics of vaccines say is that they’re not tested in placebo-controlled double-blinded trials. If it’s a brand new vaccine for a new indication — like the new RSV vaccines — they were tested in double-blinded placebo-controlled trials. 

The initial Covid vaccines were [tested in] double-blinded placebo-controlled trials. 

The problem is that you get into these crazy criticisms where it’s almost like you can’t win for losing. 

And in terms of a second-in-class vaccine — a new flu vaccine, for instance — or a next-generation vaccine improving on existing products, why is it that you can’t test them against placebo? 

It’s very simple. When something becomes the standard of care, to deprive somebody of that standard of care is problematic. Instead you might test one vaccine against another, to see if [the new vaccine is] superior. That’s how the high-dose influenza vaccines were ultimately approved. It wasn’t against placebo, it was high-dose influenza vaccine against standard-dose influenza vaccine. 

That reveals how you establish the efficacy of new vaccines for diseases where vaccines already exist on the market. What about safety? You don’t give those second-generation or competitor vaccines a pass on safety, do you? If you’re bringing a new flu shot to market, it also has to do all the safety testing, doesn’t it? 

That’s exactly right. We basically have a requirement for a certain number of individuals to receive a vaccine and have safety data on it before we’ll approve that vaccine. The safety data set still has to be robust before we’ll give it an approval. 

There is no skimping on safety in the vaccine world. We have very little risk tolerance when we give medicines or vaccines to healthy people. By definition, where we set the bar for vaccines is different from where we set them for other medical products because most people don’t want something bad to happen with them after they go get the flu vaccine. So we have to set the bar very high.

I think it’s also true that the bar is set higher still for vaccines for children. Covid vaccines weren’t approved for use in kids for about a year after they were for adults; you folks were criticized for this. There are people who would like the FDA to require manufacturers to test in pregnant people and in children at the same time as in adults. But there is this practice of effectively making sure something is safe in adults before going to kids. Is that correct? 

That is generally the case.  There are situations where we might have gone more rapidly into children. But with Covid-19, the magnitude of the problem in kids was not apparent until the Omicron wave. So the urgency was not there early in the pandemic. Had it been there, we might have moved a little faster, because the prospect of direct clinical benefit to children would have been clearer. 

Remember, in early 2020 Covid-19 was viewed as a disease mainly of older people and adults. And the number of kids affected originally was pretty small. It wasn’t until Omicron that this became a real issue. 

You were talking before about the follow-up work done after vaccines come to market and I think that what’s been happening with the RSV vaccines is a good example. There appeared to be a potential signal of GBS with a couple of the vaccines. And this is being followed closely. And in fact, the Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on how vaccines should be used, has been quite conservative in its recommendations for those vaccines. It wants answers about the risk of GBS before it recommends them more broadly. 

That’s another example of the fact that people are watching very closely. And the focus on vaccine safety, I think it’s mirrored by the fact that you have not just one but two vaccine advisory committees. You have FDA’s advisory committee [the Vaccines and Related Biological Products Advisory Committee] that meets and discusses the risk-benefit profile of vaccines. And then you have the ACIP that looks at an even broader swath of data because they can look at real-world evidence and data that FDA doesn’t look at. And they once again are looking at safety data to see if they feel that, even for an FDA-approved vaccine, whether it should be deployed across the population that it might have been approved for. 

You mentioned earlier that you almost can’t win for losing with some of these arguments. One of the things that I find interesting is that the agencies share information. So there’s been discussion publicly about the GBS risk with the RSV vaccines. On the one hand that might actually feed the anti-vaccine concerns, but if you didn’t, wouldn’t you be just roasted forever? 

Being transparent about these issues is the right thing to do. And probably the most important thing to do is to try to continue to educate people that there are small risks with vaccines but those small risks are greatly outweighed by their potential benefits. 

We have to make sure that people understand that with our vaccines, we don’t approve them unless we think that the number of deaths or the number of serious illnesses prevented [by them] greatly, greatly outweigh any adverse effects from the vaccines. 

That’s a bit challenging, though, isn’t it? Because you’re talking about benefits across the population versus risk to the individual? 

But the chance that an individual, for instance with a Covid-19 vaccine, [will experience] a serious adverse event is remarkably small. And the chance of benefit to the individual is not insignificant. And obviously the older you are, the greater the potential benefit with that particular infectious disease. 

When you think about something like measles, measles is an infectious disease that kills children. You don’t need to be a rocket scientist for that one because outside of the United States, in Asia and Africa, there are still 90,000-plus kids that will die of measles encephalitis or pneumonitis in the next year because they just don’t have access to a measles vaccine. And before the advent of the measles vaccine, it was something like 2.5 or three kids per million in the United States died per year of measles. Now we have an effective vaccine. 

Yes, there’s a rare — it’s like a one in 50,000, I think — risk of febrile seizures after measles vaccination. [The FDA later clarified that an estimated 3 in 10,000 children experience febrile seizures after measles vaccination, but there are no lasting effects.] And there’s an even smaller risk of blood clotting disorders. But at the end of the day, what you’re doing is preventing an infectious disease, which if it were to become widespread in the United States again, would likely cost one in 1,000 children their lives. 

So that’s the kind of calculus you’re taking. An occasional adverse event, an occasional potentially serious [adverse event] at the rate of one in tens of thousands in order to save one in 1,000. 

I think one thing we have learned about vaccination: If we’re honest about this, if we’re transparent, hopefully people will understand the benefits-risk [calculations] here and feel confident in their use, knowing that the risks are very small, the benefits are very much present.