It’s now 100 days since the first COVID shot was given in the largest mass vaccination campaign in U.S. history. With more than 2 million shots administered daily, more vaccines are going in arms each day in America than in all of the clinical trials combined.
Each vaccine’s clinical trial had 30,000-40,000 participants and was required to produce data for at “least two months after completion of the full vaccination regimen to help provide adequate information to assess a vaccine’s benefit-risk profile.” Today, that means we are getting more and more real-world data from a larger and more diverse group than any clinical trial could ever hope to produce.
And as vaccine makers continue to seek FDA authorization, the real-world data also require intense scrutiny. According to the CDC, the current vaccine safety monitoring program is one of the most intense ever. But how does it work — and is it intense enough?
Aaron Kesselheim, MD, JD, MPH, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital in Boston, joins us on this week’s episode to answer that question and explain the possible shortfalls, as well as what you should know if you need to report something.
The following is a transcript of his interview with “Track the Vax” host Serena Marshall:
Marshall: I wanted to start out for those who may be not familiar with how the U.S. does post-marketing surveillance of vaccines — what happens after the FDA gives approval for a vaccine?
Kesselheim: Well after the FDA gives approval for a vaccine, the vaccine can be made more widely available and oversight of the vaccine actively shifts to what’s often called post-market surveillance.
There are a number of different overlapping systems that the U.S. has in place related to monitoring vaccines on the market to ensure that they are still showing the same activity that we expected them to have in their preapproval trials.
And that there aren’t any emerging side effects that we might not have seen in the preapproval studies. Because there might be rare side effects that, you know, even in a study of 20 or 30 thousand people may not have happened. Or may have happened a very small number of times. But then when you start giving the vaccine to tens of millions or hundreds of millions of people, those kinds of side effects can emerge.
Marshall: And we sort of saw that play out, right, with the anaphylactic shock and reactions that occurred once the mRNAs started to roll out?
Kesselheim: Yes. Once the first vaccines rolled out through the Emergency Use Authorizations, there were a couple of reports in the newspaper about people having, as you said, anaphylaxis or some reactions to them that we didn’t necessarily observe in the preapproval studies. That led physicians and other providers to change the way that they administer the vaccines, to ensure that people were being monitored more closely for a certain period of time after the vaccine.
Marshall: And you mentioned a multi-layered system that’s in place. How many reporting systems are there? If it really comes down to it, it’s not just one that’s looking at what could go wrong with the vaccines after it’s been approved?
Kesselheim: Right. Well, there are three different major systems of post-market surveillance. There’s what’s called VAERS or the Vaccine Adverse Event Reporting System. This is more of a passive, spontaneous reporting system in which clinicians and manufacturers, and even the public can voluntarily report adverse events to the government to have to learn about them. That’s one major way of identifying safety issues.
Another way of identifying safety issues is through post-market studies that the manufacturer agrees to do upon approving the product. And so there might be additional prospective trials potentially in kids or pregnant women or other smaller populations; but still, obviously, a very important population of patients to understand how the vaccine works. And so sometimes the manufacturers agree to do those kinds of studies upon drug approvals.
And then the third major way is through observational data or registries, in which people who get the vaccine through normal routine care have that experience and any kind of follow-up symptoms reported. Either through formal reporting of that to a registry that collects a certain number of people and then evaluates the data, or through much larger insurance claims that could also be used to study side effects through observational studies of these larger real-world experiences. Those are kind of the three major pillars of oversight.
Marshall: Now when it comes to the COVID vaccines, we’re seeing all three of those pillars being employed, correct?
Kesselheim: Well, so far with the COVID vaccine, you know —
Marshall: You hesitated there. So I’m assuming that’s probably a no?
Kesselheim: Well, I mean, I think that there are a lot of ways that the post-market surveillance of the COVID vaccine could be going better. I think that we are seeing a lot of spontaneous reporting. And we are seeing a lot of local institutions keeping track of people who receive vaccines and sort of mini registries in a sense. So far in the U.S. we’ve only had vaccines available through Emergency Use Authorizations.
We haven’t yet had those kinds of formal post-approval studies that have been developed and designed for these trials. So we haven’t really seen that yet.
And the other major issue is, right now a lot of vaccines are being given outside of healthcare systems, through public, state government supported vaccine delivery websites and the goal here being to get as many vaccines as quickly as possible into people as quickly as possible.
And that’s absolutely the right thing to do. But as a result of that, we’re not getting as much sort of rigorously collected observational data as we might plan to get in the weeks and months that follow when the vaccines become formally approved by the FDA and are more likely to be administered through healthcare settings where the experiences are more likely to be registered in these large databases. I think there are ways that the post-market vigilance related to them could be optimized.
Marshall: Now that’s an interesting point, Dr. Kesselheim, because I think a lot of folks are really worried and concerned about that long-term data and that that data is still out. And what it sounds like you’re saying is that the post-marketing surveillance really isn’t up to par with these EUA approved vaccines compared to full approval. So is that something people should be concerned about, that it’s not really at the same standard right now?
Kesselheim: Well, I mean, I think it’s certainly something that policymakers, the people in the Biden response team and people who help sort of organize and run our healthcare systems, people in the CDC, hopefully, it’s those people, I think, are the people who should be concerned about this kind of thing.
Hopefully, they are taking steps to move us in the direction of where we have a more comprehensive, rigorous collection of vaccine experience data going forward. I don’t necessarily think that individual people should be as concerned about this yet. I mean, I think I would just want to make clear that everything we know about these vaccines thus far suggests that they’re extremely effective and are extremely safe.
And so there’s nothing that should make people concerned about taking the vaccines at this point, if it’s their turn to get it. But I do think that it is something that policymakers and, you know, people organizing the vaccine response should be taking into account going forward. So that we can get this standard safety information in a reasonable timeframe and in a rigorous way so that we can evaluate it. And that’s how we learn more about every new drug and vaccine that reaches the market.
Marshall: What a lot of people want to know though, especially with the mRNA vaccines, is what does the long-term data show? Because it hasn’t been approved by the FDA previously, even in an emergency use, until COVID. So when you’re looking at this post-marketing surveillance and getting the information, how do we instill confidence in those individuals who say, well, you’re now not maintaining a database that’s not to the proper standard. And we don’t have the long-term data on it?
Kesselheim: Right. And I think that this is an important conversation to be having. It is important to recognize that this is a novel vaccine technology. Fortunately it turns out it’s extremely effective in this case. And I think that it’s also important to recognize that even if these systems were in place, the whole process of developing a vaccine and testing it in response to that has kind of taken place over the last nine to 12 months.
Long-term data, it’s going to take a long time for that data to kind of accumulate and for us to be able to analyze it. Even if under the best of circumstances this whole ongoing learning about mRNA vaccines and about the COVID vaccines are going to continue over the next months and years.
What I’m just saying is we should be taking steps now to ensure that process is as efficient as possible. But I don’t think there’s necessarily anything anybody can do to try to make these things happen quicker than they are going to happen anyway, because these things, you know, it takes time to gather this information and analyze it appropriately.
And see what happens to people months and years out of a vaccine. So we’re going to be continuing to learn about these vaccines for the next months or years, anyway.
Marshall: Yeah, we can’t jump forward in time, unfortunately, to see in a year or two, how they work. But to that point, is there a timeline for how long you have to report an adverse event?
Kesselheim: There is not a timeline. I think that, and again, this is also something that listeners should realize, is that the public can report adverse events. There are mechanisms for — you don’t have to necessarily go through your doctor. Or go through the pharmaceutical company.
You can try to report them yourself. And right, you felt something that you want to report, and that happened 30 minutes after the vaccine, or it happened a week after the vaccine. That’s still within your right and ability to report.
And then the scientists at the CDC and FDA, and other experts can use that information in the context of all the other reports to try to understand if there is a signal or if the experience that you had was unrelated to the vaccine.
Marshall: So because the COVID vaccines were developed under a public health emergency, vaccine developers aren’t liable for those serious problems that may emerge. Is that similar to liability with other vaccines and other manufacturers?
Kesselheim: That is true. And because of the context and the sort of Emergency Use Authorization that the vaccines are currently being made available, that limits the liability of the manufacturers.
And yes, we also have a system in place for childhood vaccines. So for manufacturers of childhood vaccines, there is a no-fault administrative remedy system for the very, very, very small number of children who are injured by childhood vaccines. And so there’s kind of a formal administrative process for them to go through and to get compensation for whatever injuries. And the reason we have that is because these, the childhood vaccines that we have for measles and mumps and other conditions like that, are so very important to have. And so very important for everybody to, you know, to take. That for the extremely small number of people who are injured by them, we need to also have available a system to compensate people for their injuries under those conditions.
And so what we have is, what the law has set up in place, a kind of an administrative, no-fault system, sort of like worker’s compensation. Where you report the injury and if it looks like it’s one of the injuries that’s known to be connected to a vaccine, then you get compensation. You don’t have to go through litigation and, you know, sort of a long process of the court system to go through.
Marshall: And that’s the same for COVID?
Kesselheim: It is similar. There is, at least for right now, while these COVID vaccines are under EUAs. There is a kind of a comparable system for compensating people who have serious injuries.
Marshall: Now with childhood vaccines, they’ve been studied for decades. I mean, I believe I saw a statistic that’s one of the most studied medical advancements in history. But with these EUA vaccines, COVID vaccines, should we expect to see more adverse events reported, especially given the short time turnaround? And it’s a pandemic vaccine, than those childhood vaccines, because we are administering to an effectively wider group of people, everyone, the entire American population?
Kesselheim: I think you’re absolutely right that we’re going to see more adverse events reported. But I think the reason that we’re gonna see them is because COVID-19 and the COVID vaccines are top of everybody’s mind and everybody’s lives are being affected by it in various ways. And everybody’s talking about them.
There’s actually data showing that, that there’s this effect that you can have, that when you bring public attention to a particular drug or a particular vaccine, then that can lead more people to think about whether or not symptoms that they might’ve had, might’ve been connected to it, then lead them to report adverse events.
And so this effect is, you know, observed when a new drug hits the market. And similarly with these new vaccines and everybody’s talking about them, it’s likely that we’re going to get a lot of adverse events reported. And I think that that’s to be expected and that’s also something that we can plan for; something that the people at the CDC and FDA can adjust for when they’re doing their calculations.
You know, when you bring your kid into the pediatrician for a vaccine, for so many people, that’s just such a routine thing that if the kid two days later has a coughing fit, you might think that that’s just a normal virus…
Marshall: Normal cough.
Kesselheim: And not think about the vaccine you had a couple of days ago. Because everybody’s talking about COVID-19 and the COVID vaccine. So constantly. I think more people are going to be attuned to the fact that like: “Oh, I had a coughing fit. Two days ago, I had the vaccine, maybe they are related… maybe I should report that.”
Marshall: Yeah. So that’s an interesting point because what it sounds like you just described is related events, but not necessarily causation events and that doesn’t have to be met to report to VAERS?
Kesselheim: No, you can report anything you want. Part of the complexity of evaluating VAERS data is trying to understand what might be a signal of causation and what might not be and to try to separate the wheat from the chaff in that way. Trying to figure out what might be a causative event and what is sort of true and unrelated.
Marshall: Yeah, I was just looking at the various data and I saw a lot of people reporting things like flushing or arm pain, but there were also some reports of things such as foaming at the mouth. Seven people had reported that. So we don’t necessarily know if that report was a cause — that foaming of the mouth was caused by the vaccine, just simply that somebody had that happened to them and they themselves attributed it to the vaccine?
Kesselheim: Exactly, maybe that person had just very vigorously brushed their teeth or something like that. And so they’re not, we’re not really sure what to attribute that forming at the mouth to.
Marshall: When that data gets crunched should we expect to see differences in adverse events between the one-dose and two-dose shots?
Kesselheim: I think that it’s certainly possible that you’ll see differences in adverse events. So the one-dose shot is not an mRNA vaccine, it’s an adenovirus vector, right, so given the fact that it’s a different vector, you might expect to see different side effects or, you know, different kinds of things reporting.
And so, yes, so, that those are things that you’ll have to try to take into account. It’s actually, you know, all of this that we’re talking about, this is what makes the VAERS data so complicated and so challenging as a way of trying to draw any firm conclusions about the safety issues related to the vaccine. And it’s kind of why you need those two other pillars. The follow-up studies and the observational studies as well. To all supplement each other, to try to triangulate around a particular conclusion.
Marshall: So when you get the shot, how do you know the difference, that your immune system is simply working and you’re having a lingering side effect of a robust immune response and that something is actually wrong that you should report to the VAERS system? How does an individual differentiate?
Kesselheim: That’s, I think, impossible because every person is experiencing what they experience. This is why we don’t make scientific decisions based on anecdote. This is why we do controlled studies, controlled prospective studies to try to make decisions about a drug’s effect or a vaccine’s effectiveness and its safety, as well.
So what I would suggest for each individual person is that they should keep in mind what the kinds of side effects they’re expected to receive based on their conversations with their provider. And if they feel like their side effects are different than that, or there is a particularly concerning feeling that they’re experiencing, then they should just report that. Everyone reporting their data together.
Again, then it’s up to the scientists and the experts at the CDC and the FDA to evaluate that information and try to bring together all of those individual experiences to try to draw some conclusions from them. So I think from an individual point of view, it’s impossible to tell that and people should just use their best judgment about what they do or don’t want to report.
Marshall: But it’s not always up to the scientists at the FDA, right? I mean, even the perception of a serious problem can lead to a market withdrawal. We saw that with Lyme disease vaccines. The manufacturer withdrew the vaccine from the market, even though it seemed to work. So in some ways, those anecdotes do have lasting and serious impact. And that’s something we could see with these mRNA ones and now the adenovirus vectors if the public doesn’t gain confidence.
Kesselheim: Absolutely. And this is why I think public trust in the FDA and the CDC; and public trust in the process for getting these products on the market, and open, clear communication about these products with the public is so important. Because we need the public to feel like and believe that our public health experts are managing what they need to manage and doing it and doing it correctly.
And I think that unfortunately what we saw throughout much of 2020 was a substantial lack of trust in part due to, you know, decisions and statements made by people in the government about the vaccines in particular. But also about other products that made people wonder whether or not the communications that were happening about the vaccines were being driven by political reasons rather than being driven by what is in the public’s best interest.
Because I think that if the public trusts the FDA and the public trusts the CDC and the public believes that they’re being spoken to in a clear and truthful way, then the public will be more likely to listen to the messaging that they get from those sources. And they will be likely to trust in the safety of the vaccines.
If that doesn’t happen, then I think that unfortunately, a lot of people will then turn to the internet or to their crazy uncles and be more likely to listen to them. And those kinds of things can lead people to have vaccine hesitancy and other things like that, that aren’t science driven.
Marshall: Yeah, those anecdotes though, that you hear from your, you know, quote unquote crazy uncle, as you put it, do stick with you. And they do stick with people who are concerned that the safety data for these vaccines isn’t there, especially long-term.
So when you, as an expert, are looking at VAERS and these safety monitoring systems, what can you tell our listeners that will instill confidence in them that this long-term data monitoring is being done to the standard necessary?
Kesselheim: First of all, I think that it’s very important to recognize that everything we know about the vaccines indicates that these vaccines are extremely effective and extremely safe. And there are these various systems that the FDA and the CDC has in place to continue to monitor the safety of vaccines.
And I think that we need to make sure that those systems are up and running and running to their maximum capacity as quickly as possible, and as effectively as possible. And that they have adequate resources behind them. I think that the public can also feel confident that in this new presidential administration, that the scientists are gonna feel not inhibited to talk about what’s actually going on. And that people will learn about emerging issues, if there are any, as soon as possible and in as clear a way as possible.
And so I think that given all of that, the sort of vast weight of the data is in favor of taking the vaccines, given what a severe disease this is and what the impacts it’s had on society. And so I think people should feel confident that the systems are in place, that there are extremely well-trained scientists running it. And that there will be systems going forward to inform people about emerging issues and make adjustments to vaccine doses or recommendations for boosters or whatever, that will be science-based in the future. And I think that that’s why it’s so important that we have people that we put in charge of the FDA and the CDC and places like that, that can instill that kind of confidence.
Marshall: And transparency. It sounds like the foundation of science. Right. All right. Well, thank you so much for joining us.
Kesselheim: Thanks for having me.