Published on Feb 18, 2021

Video Transcript

[MUSIC PLAYING] JOHN WHYTE: Welcome, everyone. You're watching "Coronavirus in Context." I'm Dr. John Whyte, chief medical officer at WebMD. We're spending a lot of time talking about vaccines. But we can't forget about the role of therapeutics for those persons who have caught COVID and are having a serious case. And there's been some recent changes in when and how we should use convalescent plasma.

So to help explain these changes, I've asked Dr. Peter Marks. He's the director for the Center for Biologics Evaluation and Research at the US Food and Drug Administration. Welcome back, Dr. Marks.

PETER MARKS: Thanks very much for having me.

JOHN WHYTE: Let's just take a minute and remind our audience-- we have a lot of folks from Medscape, but also consumers-- what is convalescent plasma?

PETER MARKS: So convalescent plasma is the blood plasma that's taken from an individual who has been infected with COVID-19 and who's recovered from the infection. In some cases, they might not even have known they had the infection, but they obviously did. And they might have antibodies that have been detected and told they had COVID-19, or they might have had a PCR test when they were sick with COVID, were told they had COVID-19, and afterwards, after they recover and they're fully recovered, they're eligible to potentially donate convalescent plasma, which is usually taken by plasmapheresis. People are put on a machine for about an hour, and the blood products taken out. And the blood cells are given back to the person. The plasma is taken off.

JOHN WHYTE: Now, the FDA authorized the use, under an emergency use authorization, of convalescent plasma in August of last year. And recently, you revised that authorization-- actually, in many ways made it more restrictive. Let's go over what the change in the EUA is.

PETER MARKS: Right. So the emergency use authorization that was issued in August was a very broad emergency use authorization, because at that time we were relying on the evidence at the time which said that it appeared that convalescent plasma could potentially benefit a broad swath of people. And we weren't really sure who it might benefit the absolute most. We knew it was best when given in high titer, and we knew that it seemed to be best in people who were treated earlier. But we couldn't rule out that it was having some benefit to people later on in the course of disease.

JOHN WHYTE: And at that time, they didn't have to be hospitalized.

PETER MARKS: We always required that the patients be hospitalized. It was always hospitalized patients. And what happened, then, is over the course of the past few months-- we follow the literature very closely-- there have been studies that have come out of various places. Some have been negative for convalescent plasma-- they said that it's not had a beneficial effect. Others have been quite positive.

And over the course of time, we've looked closely at them, and we sorted them out. And it became pretty clear that when people were treated early on with high-titer convalescent plasma, they seemed to be showing some benefit. And when you treat late, you just don't see that benefit. Particularly when you treat people who have been on a ventilator, it just-- with the rare exception of people who have defects in immunity, people who have diseases like hematologic malignancies like chronic lymphocytic leukemia-- those people, they may benefit late on, because they don't make antibodies.

But for the large majority of people who have normal immune systems, if you treat late, convalescent plasma is not seeming to benefit, whereas if you treat early, within the first few days after diagnosis, the data are increasingly supporting that there is some benefit there. It's not a massive benefit. It's a modest benefit.

JOHN WHYTE: How would you articulate that benefit?

PETER MARKS: I can cite the data that we have from roughly 20,000 individuals who received 1 unit of convalescent plasma. Roughly half of those people got high titer and half of them got low titer of various levels. And the people who got the higher-titer plasma had about a 2-percent absolute reduction in mortality at seven days, which translates into about a 15-percent relative reduction if they were not intubated.

If they were intubated, they were on a ventilator, then there really wasn't any benefit. So those data really helped push us along towards saying it was time to kind of narrow down the emergency use authorization to say, look, don't use this late in people who are intubated-- that is, on a ventilator. Use it early on or earlier on in the course of disease.

Now, your next question might be, why not just use it as an outpatient? Hum. And the answer is--

JOHN WHYTE: Now you're interviewing yourself.

PETER MARKS: Nah. I might as well do that. I've done this enough. But the reason why we're not there yet is because we're waiting for some very well-designed studies that are being conducted, one by the National Heart, Lung, and Blood Institute, which will give us a good answer about the potential benefit in that setting.

JOHN WHYTE: Well, that's why I was asking you about hospitalized patients. Because if we talk about-- you mentioned it has to be used early on in the disease-- but what about severity of disease? Because many patients that aren't coming to the hospital until they're much further along-- so how do you do it, in the sense you want to do it early on, within those first couple of days, but sometimes we're telling patients not to come to the hospital or to the ER. So how do we balance that? So what's the severity of disease?

PETER MARKS: I think right now the way we balance it is we say that if you're somebody who's got early disease and you're interested, get onto the and find one of the sites around you that might be doing outpatient clinical trials with convalescent plasma. There are a number of sites doing that.

But I think, otherwise, when people are admitted to the hospital, it's probably a good thing for physicians to think right away, is this somebody for whom convalescent plasma may make sense? Again, if someone's intubated in that first couple days, maybe not. On the other hand, if someone needs supplemental oxygen, those patients did seem to benefit.

JOHN WHYTE: Now, let's talk about the person's underlying immune response, their humoral immunity. So who are those patients? Many patients are often asking about, what if they're immunocompromised? What do they qualify for? Talk to our listeners about what's that patient population-- because that's a component, their underlying immunity function.

PETER MARKS: So it's a great question. And we've actually kept up with the case reports that have been coming out. They're not trials, but they're a case series that have come out from around the globe, and it's very convergent. If you treat people who don't make a sufficient amount of antibody, either because they have a primary immunodeficiency syndrome or because they have [INAUDIBLE] cancer, and they can't make them, if you treat them, even if you seem to treat those people late, they seem to have benefit.

And there are some amazing case reports-- obviously, it's always N-of-1-- case reports, you always have to take with a grain of salt-- but where people even very late on have had very good responses clearing viremia. So that kind of makes sense, right? Because if you're not able-- what we think, at least, that the antibodies are doing here-- the antibodies in convalescent plasma are acting like an antiviral, right? And if you give it early, they're acting like an antiviral would early on in getting things under control. Later on in the course of disease, where there are other organ damage effects, that's not the best time for an antiviral. And for those who are immunocompromised, it may be that they just have ongoing viremia, and you need to clear it. And giving them convalescent plasma helps take care of that.

JOHN WHYTE: One question we have gotten asked, Dr. Marks, is for those patients who have been fully immunized, are they able to donate plasma?

PETER MARKS: So it's a great question. And it's one we're still debating. Right now, if people have not had COVID-19 and get immunized-- so they're people who are COVID-19-negative to start, then get immunized-- we're not considering them as convalescent plasma donors, because they're making antibodies against just the S protein that are in the current generation of mRNA vaccines that are authorized.

We don't know, in terms of the convalescent plasma response that we're seeing, how much of the benefit is from the S-protein antibodies versus N-protein antibodies or other antibodies that are there. And until we have a little better idea on that, we're a little hesitant to swing over to have vaccinated individuals donate.

But this is an absolutely great question, because we're very much looking into this now. It would be nice to understand, because soon we're going to have a large population of people who will be fully vaccinated, probably with high titers of S antibodies, and it would be nice to know this. So stay tuned. We do that for other infectious diseases, and maybe we'll see it coming for COVID-19 soon enough.

JOHN WHYTE: Tell us how staff are doing. You had your general work that you had to do, in terms of vaccines, other biologics. Now you have the whole issue of COVID. How is everyone managing it?

PETER MARKS: Well, I have to say, we are incredibly lucky at FDA. We have a staff that has risen to the occasion in an amazing way. They're keeping the normal freight moving. And while they're keeping the normal freight moving, they are taking care of the avalanche of COVID-19-related applications.

Now, in some areas, there are a little lower number of applications than in others. But if you look, for instance, in the vaccine area, there is an avalanche there. And they're doing an incredible job keeping up. Same thing with, actually, some of the cellular therapies that have come in, and even the antibody therapies, et cetera. There are lots of them, right?

Our folks have done just an incredible job pitching in. People who have a little less work pitch in to those who are almost getting underwater in work. So it's been really wonderful. It has taken its toll. People are getting a little tired. And we're trying to make sure that we take care of people. But we're very lucky that people have really had such commitment to public health.

JOHN WHYTE: Absolutely. And then finally, all these emergency use authorizations that are happening across the agency-- do you expect sponsors to apply for full licensure in a few months?

PETER MARKS: Yeah. So I-- for the vaccine sponsors in particular, we've told them that if they want to come in for an EUA, they should expect-- it's actually in our guidance-- they should expect that they're going to come in for a biologics license application. And so that's why the work isn't going to end soon, because as we're now dealing with some of the emergency use authorizations where the vaccines are becoming more mature, they've been in use for a little bit, I would suspect in the not-too-distant future we may see their biologics license applications. And so there will be kind of a cohort that will come along of license applications in the coming months.

JOHN WHYTE: Well, Dr. Marks, I want to thank you for taking the time, the work that you and all the staff at the Center for Biologics Evaluation and Research and all of FDA are doing to keep us all safe.

PETER MARKS: Thanks so much for having me today.

JOHN WHYTE: And if you have any questions about COVID, drop me a line. You can email us at [email protected] as well as post it on Facebook, Twitter, and Instagram. Thanks for watching.