Updates from Prof. Arturo Casadevall

MNT: The FDA granted EUA for plasma therapy on August 23, but this decision sparked some controversy. What is your take on the matter?

Prof. Casadevall: The first thing I would say is that all the issues of controversy have been [based on] newspaper reports. The truth is that I don’t even know if there is any real controversy. I think that it’s been reported to be a controversy. But let’s just assume that what they reported is correct.

I [and Prof. Nigel Paneth] wrote an op-ed in The Wall Street Journal a couple of weeks ago, arguing that the issue seems to be [based on] differences on the degree of certainty. That is, the FDA made this decision based on its regulatory power for the laws of the land that say that once […] the information is there that [a treatment] may be effective and that it is reasonably safe, that they can issue an EUA. That’s what it says.

Everyone, including myself, feels that just because an EUA has been issued doesn’t necessarily mean that one has proven beyond reasonable doubt the efficacy of plasma.

[Given] the regulatory landscape [of] the FDA, this was, in our mind, the correct decision. It is also the correct decision to continue to do randomized clinical trials. So these two are not in conflict with one another.

Because in many places, there is no randomized clinical trial. So if you get sick in a place and you go to a hospital where there is no randomized clinical trial, you can’t even join to be able to be randomized to the plasma group.

So, what this decision says is [that] the available data suggest[s] that this [therapy] may be effective if given early with a sufficient amount of antibodies.

That’s the decision. In the meantime, it is very important to continue to do all we can to establish efficacy.

MNT: Some have expressed a worry that, like vaccines, plasma therapy may be pushed out too soon.

Prof. Casadevall: You know, I’m not worried about that. I will tell you that I worked with the government scientists, the FDA, [and] the people who made this decision for months before it was [taken], and I can assure you — and I can assure [your readers] — that these government scientists are very devoted and dedicated people, and I’m not worried about that myself, based on what I know.

I think that when the regulatory agencies give the go-ahead, it will be based on science. And I would say to you, look at hydroxychloroquine: Based on the initial results, [the FDA] issued an EUA, [but] when the data was not there [to support the initial findings], they pulled it.

And that’s very important to keep in mind — that these agencies are responding to the available knowledge. And we’re in the middle of a pandemic, and we’ve got to try to make the best decisions with the available information.

MNT: The last time we spoke, in May, there was less research and less evidence around the safety and efficacy of plasma therapy for COVID-19. How has the research around plasma therapy developed since?

Prof. Casadevall: There has been a lot of new evidence. The evidence comes in four categories. The first one is — we now have reports [from] five randomized control trials.

Three had to be stopped prematurely because they ran out of [participants]. That’s in China, in Spain, and in the Netherlands.

And then there are two [more]. One was completed in India, and it did not show an effect [on] mortality, but there were problems in the study because over a third of the units did not have antibodies.

So that is a problem in the study itself. And then there is another small study from Iraq, [a] randomized control trial, showing that [plasma therapy] reduced mortality.

So the data that you have out there in the randomized control trials is suggestive that this is doing some benefit, but it’s not conclusive for a variety of issues, ranging from the changing epidemic to the problems with trials.

Then, you have the observational studies, and those are suggesting that, if given early, [convalescent plasma] is associated with a great reduction in mortality. [By] great, I mean about half.

And the two studies that I would point people to look at [are] the Houston Methodist [Hospital] study, published in the American Journal of Pathology, and then there’s one from [Mount] Sinai [Icahn School of Medicine], published in Nature Medicine.

The third piece of data — it comes from the FDA themselves, where they looked at a large number of people in a cohort that didn’t have a control [group].

But it didn’t matter, [because] when you looked at it, you saw that if you gave [convalescent plasma] early and if you gave a significant amount, there was less mortality than if you gave it late or if you gave less.

In that study, there is a really important piece of data. There is a dose response. And whenever [we] see a dose response in science, we tend to consider that [to be] very important because it’s part of what we use for assigning causality — that is, causality that [the] antibody is the active agent.

And then the fourth piece of data is coming from experiments of nature. These are people who don’t have antibodies because of congenital disease. When they get COVID-19, it becomes intractable.

And then [for] the administration of plasma — even though these are case reports, they are powerful evidence that when you give the plasma, you shut down viral replication and you clear it.

So what I would say to you is, do we have the definitive data today? No, definitive data is coming. Numerous randomized control trials have been done in the United States, in England, and [in] other parts of the world, and we will know more in the next few months, but it’s October 9 [at the date of this interview]. As you look at the data that we have today, it is suggesting that the early administration of plasma with sufficient titer is beneficial.

MNT: Based on the information that has emerged from the studies conducted since May and until now, have your views about plasma therapy changed in any way?

Prof. Casadevall: Certainly there is a massive amount of data available in October that was not available in May, and most of it is positive.

So [some important things that] we learned is that this is a therapy that is going to take a while to figure out how to make work well, that this is not a simple therapy, that you need to have a set amount of antibodies in the plasma, that you need to give it early, [and] that it works best in non-intubated patients.

We did not know any of this in May. In fact, I would argue that if we had designed a randomized control trial then, it would have become obsolete by now, because the information used to design the trial would have been superseded by what we have learned since then.

So I think that we have learned a lot since then.

MNT: With the research that you were involved in, what were the main challenges, and how do you think you might overcome them in future trials?

Prof. Casadevall: So [one of the trials] I’ve been involved with [is] the Mayo study, [where] Michael Joyner was the [principal investigator]. So the challenge there is to try to understand efficacy in a situation where you don’t have a control group. And that is a big challenge. It hasn’t been done before, and yet, I think that we learned a lot from that.

At Hopkins, we have two randomized control trials. They’re headed by David Sullivan and Shmuel Shoham, and these are in the outpatient space. And when we talked in May, they were theoretical.

Since then, they have been put in place, and they are rapidly accruing [participants]. The most important thing that we learned is how hard it is to set up randomized control trials in the middle of a pandemic and to keep them going when the [number of] cases switch from one part to another.

For example, one of the things that have become very apparent is that these trials are very difficult to do in any one location.

So the trials now in the U.S. [take place] in many states because the epidemic changes, you know. You had [a high number of cases in] New York City in March and April, and then you had [the same in] Arizona in the summer, and now it is moving to the Midwest.

So that is the big lesson, but the good thing is that they’re in place, they’re recruiting, [and] they’re very clean studies, because they’re happening in the outpatient space.

These [participants] are not [taking] corticosteroids. They’re not on remdesivir. They are at home, and if they’re sick, you give them a unit of plasma and you ask the question: “Do [they] progress?”

Or, the other trial looks at prophylaxis. [The participants] are at home. They’re exposed [to SARS-CoV-2] because a family member may have [COVID-19]. If you give them human plasma, do you prevent disease?

So these [studies] are happening, and I guess what you asked me [was], if we had to do everything over again, what have we learned? I think the most important thing to have learned is that […] we need to think about flexible trial design, because even if you had been able to get all the resources and get going in March and April, the information that we have learned on a weekly basis often makes the assumption that you start with obsolete.

And one of the great challenges in getting really good information in the middle of a pandemic, where science is generating information by the week, is the ability to do flexible clinical trial design that would allow some of these things to happen. And this falls into the science of clinical trials, and I think “trial” is an issue on how to go forward.

MNT: Earlier, you also mentioned a lack of resources. What resources did you feel you were missing?

Prof. Casadevall: Early on, there were very [few] resources. The only resources that we had was … the Bloomberg Philanthropies gave us some money, and the state gave us some money. We used that money to set up the clinical trials, which, months later, the government funded very well. We are funded now by the Department of Defense.

So I think the early lesson is that [receiving] money upfront can make a big difference. Because the early days are critical. The other thing that we have learned is … think about it, if you were designing a clinical trial in March or April, you didn’t have the assays.

They had not been validated. How would you have decided what plasma to use when the antibody assays and the neutralization assays and all that [were] being validated very rapidly? It’s another example of the need for flexibility, and we need to think [about] how to do this thing and how to do it better, because humanity is going to be confronting other pandemics.

And the question is, you know, how are we going to do it when bird flu comes, or when another pox virus or something [comes], or coronavirus number seven?

Out of this experience, one of the things that I hope people focus on is that the line of defense — humanity’s line of defense — is science.

You know, the military budget doesn’t help you against coronavirus.

And […] the line of defense, science‚ was actually pretty stressed before this began, you know, with funding cuts in most places, problems […] with employment and all that. Yet it is amazing when you think over 100 vaccines are in development.

We can always do things better, but we also have to celebrate the tremendous amount of work that has gone on and the options that are available in October as a result of having a vibrant worldwide scientific enterprise.

MNT: It is sometimes easier to judge than it is to celebrate, especially when the world is in this atmosphere of anxiety, where people do not always understand what is going on, and they may start to lose trust in science. So, on a related note, what will it take to conclusively prove or disprove the efficacy of plasma therapy for COVID-19?

Prof. Casadevall: I think that certainly having a large, well-designed randomized control trial, where the plasma is given early, in high amounts … if you got [confirmation of] efficacy [in such a trial], then it would be very convincing.

If you do not get efficacy, then I am the first person to say to you: “We read all the trials, bias has crept in.”

Because we need to retain equipoise — as a scientist, one always has to basically say what will convince you that it didn’t work. And to me, it would have to be a confirmation from those [new] trials.

Trials in which this is done in patients who are intubated, or [where] there are problems with the plasma, are inconclusive. One of the most frustrating things is that a lot of the information that is coming out is simply inconclusive.

[This is] not because people aren’t working really hard to [find conclusive evidence], but because the trials [were] often designed without all the information that was needed.

The best example of that appears to be the Indian trial — a massive amount of effort … [I have] great admiration for my Indian colleagues, but when this decision was made to seek plasma, a lot of their donors had mild disease. Mild disease does not result in high antibody titers. They didn’t know that when [the trial] was set up.

But I will tell you, plasma has already given humanity a tremendous piece of information. It is safe. It cleared the way for monoclonals. It cleared the way for a lot of things.

Back in May, when we were talking, there was still a lot of discussion of an antibody-dependent enhancement. Are you going to give anti-antibodies to a patient? Are you going to trigger a cytokine storm [by doing that]?

None of that happened. So the great use of plasma […] [in] over 100,000 patients established the safety of giving antibodies to somebody who’s sick.

That is a huge contribution, because we heard, for example, that monoclonal antibodies … they are now trying to push them forward with a fraction of the experience, but that experience is resting on the plasma experience.

That is a big, big, big contribution.

And the other thing is that we — certainly [if we are based] in well-resourced areas — we have a tremendous responsibility to figure out what’s going on with plasma, because in regions that don’t have a lot of resources, this is going to have to be the therapy for the next few months, even years, because monoclonal antibodies are going to be unaffordable. We don’t have, in the immediate future, any new antiviral[s].

So plasma may be — in the U.S., in well-resourced areas — plasma may be a stopgap between a time in which you have nothing to a time when you have monoclonals and you have other reagents. [M]uch of the world may still need plasma, and we need to figure out when and how and if to use it, because that information can be life saving in those circumstances.

MNT: One last question: How long until we know when, how, and if to use plasma therapy for COVID-19?

Prof. Casadevall: Since we talked in May, we have learned that [plasma therapy] is safe, we have learned that [it has to have] high titer, and we have learned that you have to use it before people get ventilated.

So I think that there is a very high probability that, in the next 2 months, some of these trials will provide additional information. My hope is that they are conclusive.

However, if you publish a trial with 1,000 people where the average day when the plasma was given was day 8, day 10, that’s not conclusive. But I would say that if you go to PubMed and if you go to the archives and if you look [for] “convalescent plasma,” you would see an enormous amount of information that has been generated since May.

And the information is already telling you that [it] is [safe], and if you’re going to use it, use it early and make sure that the plasma has sufficient antibody content.

So I think that those are tremendous advances in relatively few months, when you consider what the situation is.

MNT: Thank you so much for your time and for all of the updates. Do you have any final remarks for our readers?

Prof. Casadevall: I would say that papers are coming out by the week, and […] I urge the [readers] and I urge anyone who’s interested to approach the data carefully […] [and] ask the question: Did they give [convalescent plasma] early, did they give enough, and what were the conditions of the [trial]?

And you can often find that information [in the studies]. And certainly, even when [convalescent plasma] is given late, we’re not getting [conclusive] results or side effects. But [in terms of establishing] the efficacy — it’s early [days].

And for those of you who are planning clinical trials, please incorporate this information into [the study papers], because it’s very important to have conclusions.