Coronavirus in Context: The Importance of Rigorous Data Analysis When Discussing COVID Studies

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You're watching "Coronavirus in Context." I'm Dr. John Whyte, Chief Medical Officer at WebMD. Today I'm joined by my friend and colleague Dr. Eric Topol, the founder and director of the Scripps Research Translational Institute and an avid tweeter. Eric, thanks for joining me.

Oh, it's always good to be with you, John. Thanks.

I call you an avid tweeter because your Twitter feed is terrific. You succinctly give us the latest data, the latest evidence about where we are with COVID. But you know, we were talking right before we started about how often, sadly, there is a lot of negative responses to what-- Oh.

--you're presenting as facts and data.

All right. Thanks, John. I've been on Twitter for over a decade. So I've actually had a chance-- almost 11 years now-- to kind of see the trends, at least, you know, from my perspective. And, uh, until the pandemic there was a little bit of anti-science that I would see in response to posts.

But what happened during these months in 2020 has been nothing short of, um, outrageous, uh, horrific. Basically every day, you know, I get attacked for facts, truth, evidence. You know, many days I've thought, John, I, I just better stop. But you know, I use Twitter as a way to archive what I read.

Mhm.

So, uh, you know, years ago it became my main archival means of, of tracking, you know, the, the things that I want to look back at. [LAUGHS] So I might just go back and do that without Twit-- I don't know.

Yeah. And you--

But it's been, it's been been challenging.

I wanted to get your thoughts just because you're, you're deep in the data on all of this, on, on where your best guess is on treatment. And you know, even on your criticisms on convalescent plasma, we've seen the same issues in terms of Remdisivir and others. We chan-- when-- since when do we change outcomes, Eric, [LAUGHS] you know, at the end--

Yeah, yeah.

--of a study design? That we're saying we're looking at death, and no, no, we're not looking at death anymore. Now we're looking at time to leave the hospital. How is that good science?

I-- it's not good science. Um, when, when we make antibodies from COVID-19, we make lots of antibodies, and not just IgM but of course IgG. And it turns out that when you look in-depth at these antibodies, mo-- any clones any of us would make--

Mhm.

--most of them have no neutralizing capacity.

Right.

So it's only a, a tiny fraction in most people that do the job, that take down the virus. So the problem is you give this convalescent plasma to a person to-- who's sick, and most of the antibodies they're going to get are not going to do anything.

Now, unfortunately it's such a great altruistic thing. I've been sick. I've had an infection. I want to help other people. And it's been, of course, nurtured. And that part's really good. The problem is there's this illusion that the plasma infusion is going to have all this potent, neutralizing antibody. That's not the case.

That's why we have programs of neutralizing antibodies that are very potent, that are proven, pure, you know, basically, uh, ideal. This is a very suboptimal--

Well, ideal, but also, say, you know, if we're injecting monoclonal antibodies, they also can have untoward effects as well. And, you know--

Sure.

--also impacting--

So, so can plasma. You know, some of the problems that we can't screen out that could be virus pathogens, for example, we may not know that for years, just like what happened with hep C. And who knows? So the point is is that it's not safe.

Monoclonal antibodies uh, uh, engineered, that are potent, they may not be. But at least it's pure. That is, it's pure IgG neutralizing antibodies, not diluted with a very small fraction. So biologically this doesn't have legs that it's going to be saving life in a pro-- in a big proportion. Maybe it'll have a small modest effect. But, you know, that's about as good as we can ask for.

Now-- and it's, it's actually a big deal to get this, you know, convalescent plasma fractionated to, to patients. It's not like it's a little-- it's an expensive and arduous task.

Mhm.

Other programs-- like you saw what hydroxychloroquine did. That was another FDA emergency approval that had to be revoked because of lack of safety and lack of efficacy, you know, months later, pressured by the president with out-- outrageous aggressive promotion of hydroxychloroquine--

But, but to be fair, but to be fair, even in good times, you know, Dr. Hamburg would-- as-- who you know very well, would say at FDA you're criticized either way. You either approve a drug too fast or you approve a drug too slow, right?

Yeah.

People could say, it's an emergency, right? We're in a pandemic that occurs once a century, Eric. We have to try things.

Right. No, I-- I'm with you, John. And I, I don't want to hold back anything. I'm--

No! I'm glad you're-- I don't think you are are holding back. You shouldn't.

Yeah. I just want to make sure that we have a signal because--

Right.

--hydroxychloroquine we knew could have some cardiac arrhythmia side effects. We knew there were, you know, more cardiac arrests in certain studies, like a doubling. And, you know, it wasn't like a, a, uh, slam dunk there.

What, what regulatory flexibility should they have used? And we should want to use regulatory flexibility during these times. So what was the right mechanism?

The right mechanism would be-- you know, in each of these cases, we have insufficient data, uh, from randomized trials. There certainly weren't any randomized trials of hydroxychloroquine at the time. Now, the Remdisivir was a different story because as you pointed out, John, aptly, they changed the goalposts from survival in a relatively small trial of 1,000 patients, uh, uh, approximately, to recovery time.

And that was significant. And the p value for survival was 0.06. So there was this trend. But unfortunately it was not a large enough trial to determine survival. And what was happening-- after the convalescent plasma, to add insult to injury, here again the commissioner of FDA issues we're broadening the indications for Remdisivir under emergency approval based on no prospective, meaningful, randomized data. Very small study. There were--

I didn't think you would be a supporter of data that's trending because you have to have [LAUGHS] your data points, right? If we always said if something's 0.06, to point-- that, that might not even get published.

Well, I, I don't think there's any magical p-- p-value.

No.

0.05. The fact that the mortality was reduced to that extent, that, that-- and the fact that it helped recover, you could say, OK, well, Remdisivir helps in severe COVID-19. OK. And you want more replication. Fine.

That, I can see. But the point about then giving it a broadened indication, essentially, by the EUA, to say anyone who goes in the hospital should get Remdisivir. Uh, well, this is expensive. It's in short supply. The data are weak, flimsy.

I mean, this is just one more thing in this I don't have the evidence. I don't have the data. But we're going to give approvals for things.

Now, your point I can't emphasize enough, which is in a pandemic you don't want to withhold anything that could help people.

Mhm.

But at the same time you don't want to promote things that lack evidence. So there is a fine, delicate balance. And, uh, you know, dexamethasone, for example, went through the right trial. Over 6,000 people, improved surviv-- survival substantially. That's the kind of data we should have--

--patient population, right, an-- and--

Yeah. That's--

Right.

That's the data we need to be--

Right.

--certain, to be confident of anything.

Well, let-- let's give some confidence [LAUGHS] to people now that we've criticized all potential options, Eric. Uh, where do you see therapeutics going? On your radar screen what do you think has the, the best chance in terms of--

Well, I mean, I do think, um, there are some good things on the horizon. The first that we touched on were the neutralizing antibodies because they are so potent. And they are good because as soon as you have the diagnosis you can basically squash the infection. Um, so you wouldn't progress, and they should be helpful even in someone who's in the early phases. Not severe.

They won't develop immunity, though, correct?

No. But they should be good for at least a couple few months, which is important--

OK.

--in a person who otherwise could be very high risk for, for, uh, uh, you know, morbidity and mortality. So--

OK.

--I think there. But the problem with those is they're relatively expensive. They're not so easy to make at scale. You know, the, the, the dream that I talked about with Tony Fauci-- I know you did talk with him as well-- but that you could actually give it sub-q, you know, yourself. That we would have it available to all high risk people if need be, that kind of thing.

We're not going to have that. But that would be, you know, the fantasy--

Yeah.

--of a very effective treatment.

Now, the other one which is preventive. And that's what I emphasize here is the treatments we have so far-- dexamethasone, and, you know, more modest effective Remdisivir, are late benefits when someone's really sick. We want treatments that prevent this-- you know, the toll of the, the disease of COVID-19.

So the one that has the best data right now is, is interferon. To give people interferon, which as you know is the natural, innate immunity. It's the first line of defense. It consists-- it-- of cytokines and Interferon.

Now, it turns out that this virus, this nasty virus, is very good at deactivating your interferon response. And some people don't have a very good interferon response at all, uh, and particularly with age and male sex and all sorts of ri-- risk factors. And some even genetically. Even, you know, young and healthy, don't have the ideal interferon response.

So the idea here is give people an inhaled interferon early.

Yep.

And there are many studies now, both, uh, observational and small randomized studies, that support that. So I think that will emerge-- I hope, I hope-- as useful.

Um, there are many other repurposed drugs out there. But those two, you know, monoclonal antibodies and interferon, uh, basically supplement, if you will. Those look the most promising right now. Uh, I wish they were going to be defi-- definitive evidence, like, yesterday. But we're still a little bit aways from that.

Well, let's talk about the vaccine and where you think we are. I want to first address, you know, the elephant in the room of, you know, a clinical hold on AstraZeneca's vaccine development program. That's a good thing, though, Eric, isn't it? Isn't that showing the system is working?

Yeah.

This is serious adverse event. Transverse myelitis. Not completely uncommon in a vaccine trial. Note it. Trial put on hold. Success, in a way, that the process is working?

Well, we don't know, John, too many details. Uh, we know that, uh, in July, there was a temporary hold on the trial. Someone had-- a, a participant had multiple sclerosis. We don't know too much about that. But they-- and it was deemed not to be related to vaccine.

And now we have basically a cousin of MS with this transverse myelitis, uh, which could be from a virus. It could be from an immune disorder.

Mhm.

You know, we don't know. And we don't know the-- it-- it's a woman who's apparently getting much better. But we don't know exactly what--

That's right.

--uh, what was going on in terms of temporal sequence. So fuzzy. Uh, but you def-- until you know you definitely want to put the trial on hold. And you-- you're right. This is the way it's supposed to work. It does work. I mean, trials all the time have temporary holds, large trials.

Mhm.

And uh, you, you basically wait. You don't enroll anyone else until you, you know, really study what happened because you don't want to have something like that happen again.

So yes, it's-- we, we don't know enough right now. But, um, I do think that there are a lot of things about the vaccine trials that it's critical we do know. We don't have the data analysis plans from these companies.

Right.

And these trial lists, that these are done by academics. But they are working with companies. We don't have their stopping rules that we-- are known as part of that data analysis plan. It's not been transparent except for what's--

I was going to say--

--put on clinicaltrials.gov.

--we need more transparency.

Yeah.

I mean, it's, it's-- as you know, it's common that there's not transparency in development programs. But given a pandemic, we can't be having information parsed out by press releases and abstracts. Everyone has to--

That's right.

--know, know the data, both good and bad. As, as you know, when things aren't approved, typically we don't get the information. But in this situation, wouldn't you agree we have to really argue for complete transparency?

Right. This is a very delicate matter in many dimensions. For one, we-- as we discussed, we have this FDA Foundation Trust issue.

Mhm.

We have a president who is using this vaccine as a way to promote his election, uh, campaign. So we have that in the background.

Then we also have the issue of call-- making the call prematurely on a trial whereby if it's based on a limited number of infections, these are moderate or severe infections, you're extrapolating that to tens of millions of healthy people--

Yeah.

--that you're going to give a vaccine to. And once you basically-- you stop the trial-- I mean, it's like you can't go back. And then, you know, people say, well, that's it. And then you find out potentially bad things later, and then you lose the, the trust of the entire public, which is already compromised and fragile.

So everything's on the line. All the high quality, high velocity science that got us to this, uh, you know, very--

Which we should celebrate, right? Look at the innovation--

Yeah.

--that we've had to get to this point of Phase III. Wha-- what's your prediction though, Eric? When do you think, based on, you know, your knowledge of the process, as well as what's going on, that we would have a drug for-- and I'm going to, you know, parse words for the audience-- true approval, not an emergency use authorization?

So full approval based on Phase III, probably with a Phase IV, [INAUDIBLE] postmarket surveillance. When's that time frame?

I, I think we'll see it if we let things do naturally, um, in the first part of the new year. You know, any time in that first quarter, perhaps. Uh, ideally, with enough confidence that the efficacy is solid and that we haven't run into, you know, any significant, adverse, serious, proportionate, uh, adverse reaction. We're-- it's, it's impossible to have, uh, zero adverse events.

Yeah.

The hope is that it's exceptionally low.

No serious adverse events.

Yeah. I mean, I think once you treat 100 million people around the world, or billions of people, you're going to see antibody enhanced, uh, immune, uh, uh, re-- reactions, or immunopathologic reactions. I mean, we're going to likely see that. But hopefully it's at, you know, 0.000 whatever percent incidence.

I want to see, you know, this thing where you don't interrupt a natural experiment that you design because if you stop early the chances that you have stopped it at a point of exaggerated benefit, right.

What are you optimistic about?

I'm actually optimistic about everything. [LAUGHS] You wouldn't know it.

Doesn't sound like it.

No, I-- I'm optimistic--

I'm teasing you.

--we'll, we'll have a vaccine. It'll be safe, with those caveats I mentioned, and effective if we are patient. I'm optimistic we will have, you know, other repurposed drugs like I-- or new monoclonal antibodies.

I'm optimistic that, uh, with the right leadership we'll-- we will model and get more people in the country to use the things that we-- that-- the measures that we need to do like wearing masks and, uh, trying to keep distance, and avoiding crowds, and, you know, all that sort of stuff. So if we get things on track we can prevail over this. I'm confident of that.

But we've been very impatient, very divided, uh, you know, in terms of this-- to start-- as you started it, the, the, uh, the animus and anti-science. We have got to get much better education--

Sure.

--and buy-in of the public that, you know, things like masks and vaccines are, are good. Right now we have people who are not, uh, believing that.

Well, we don't want to be anti-science. That's what we started with. But we also don't want to be sloppy science too, as we've talked about in terms of data analysis.

Dr. Topol, I want to thank you for sharing your insights. I want to thank you for helping educate us here today, as well as every day that you do on Twitter. And we're going to check in with you, if we can, i-- in a couple months to, to see where we are in the latest data around vaccines.

Thank you, John. I'm always happy to talk to you, and I look forward to more interactions.

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