Published on Dec 28, 2020

Video Transcript

[MUSIC PLAYING] DR. JOHN WHYTE: Welcome, everyone. I'm Dr. John Whyte, Chief Medical Officer at WebMD, and welcome to Coronavirus in Context. We're going to do the show a little differently today. I'm delighted to be joined by a co-host, someone many of you know, Dr. Eric Topol, who is the Editor-in-Chief of Medscape. And our guests today are Dr. Stephen Hahn, the Director of the Food and Drug Administration, and Dr. Peter Marks, the Director for the Center for Biologics Evaluation and Research at the FDA. Gentlemen, thanks for joining me.


DR. STEPHEN HAHN: Thank you, John.

DR. PETER MARKS: Thank you.

DR. JOHN WHYTE: Well, Eric and I had a coin toss and I won, so I get to ask the first question. And I'm going to give it to Dr. Hahn. And I want to ask you what has been on many people's minds. A lot of folks have been talking about how the data is so compelling, in terms of safety and efficacy. So then the question becomes, if that's the case, why an emergency use authorization and not a full approval?

DR. STPEHEN HAHN: Well, John, it gets to the heart of the issue of what an EUA emergency use authorization is, and that's a special authority given to us by Congress after 9/11 and the attacks to expedite medical products. And really, just very simply, the major difference between an EUA for a vaccine and a biological license application is the amount and the complexity in the manufacturing data that we would need to seeing a biological license application, as well as the duration of follow up for safety.

But I want to make one thing clear, as Dr. Marks and his team were very clear in the guidance that we issued, both in June and in October, that we needed to see very compelling evidence. And the actual term we used was "clear and compelling evidence" of safety and efficacy from at least one randomized clinical trial for a vaccine. So those criteria are very similar to what we would use for a biological license application.

So in terms of at least the initial assessment of efficacy and safety, very robust data we received, very similar to what we would sort of expect from a biological license application. And what we'll do moving forward is work with the companies for that full application, get additional manufacturing data, but also get additional safety and follow up data. And Dr. Marks and the CDC have put in a terrific post-marketing pharmacovigilance surveillance system to pick up any additional safety issues that might arise.

DR. ERIC TOPOL: Well, you know, the EUA and the two vaccines now out there in the US is really extraordinary. So I want to start off just by congratulating you, Steve and Peter, and what you've done over the last couple of months is just extraordinary. I mean, considering all that you're up against-- that is, we had nothing, and then you also had all sorts of external, unnecessary pressures. And you were basically in a fishbowl to try to get this thing through.

So I think it's extraordinary, and I know how hard you all have been working to get where we are, which is just momentous. So it doesn't go without appreciation. And I want to just say, on behalf of all the medical community, and I'm sure the public, to see the FDA-- this is their crowning achievement-- transparent, everything vetted with the external experts, internal at the FDA. I mean, it's just remarkable.

Now, the EUA was tightened along the way, I think back in October. And then maybe, I don't know, Peter or Steve, you could just give us some insights because that was an important step that you all took to make sure that you got where we actually wound up, which is two complete trials which demonstrated replication of such extraordinary efficacy.

DR. PETER MARKS: I think the issue here is that we tried to be very clear about what we needed to see. And it's something that we've been thinking all along, but we thought it would be very important to make clear that if we were going to have data on these vaccines that made people feel comfortable using them, they needed to have the kind of safety data that allowed us to have confidence that the great majority of adverse events would have been seen.

And we know that it takes-- from studies that have been done before, it takes in general about 42 days when most of the adverse events occur. And if you look at various studies that have been done, two months median follow up allows you to get the large majority of adverse events associated with vaccine administration. It's true that there can be some later events that come along, but the great majority occur within that period.

So by putting that condition there, it allowed us to give people confidence about the adverse events that we might see. But it also allowed us to know that these vaccines didn't just cause some transient immune response, that at least there was a median duration of immune response of two months or longer. And that was another piece of this. Because you could imagine, especially when using new classes of vaccines that you could see some unexpected things. So I think that combination of safety and efficacy, a median two months follow up for the population was something that allowed us then to have a confidence in what the output here was.

DR. ERIC TOPOL: Yeah, well, you got the full efficacy endpoints for both the Pfizer, BioNTech, and the Moderna trial. So that was just-- everything was just remarkable there. And another point that is, I think that a lot of people don't understand the medical community is a contribution that you made with respect to this concept of Operation Warp Speed.

My understanding, Peter, is this was your brainchild, and you're a Star Trekkie.


And that you had this kind of incredible--

DR. JOHN WHYTE: I don't know he's going to take credit for the name.


Well let's hear that. Yeah.

DR. ERIC TOPOL: --crazy idea that we could all do this pretty quickly. Can you tell us about this eureka moment about what turned out to be Operation Warp Speed?

DR. PETER MARKS: Yeah, Operation Warp Speed started from something that we started internally at FDA, which was Project Warp Speed, which was, how could we internally speed up the regulatory advice that we would give to product developers.

And then it gradually morphed into something more when it became apparent that a number of the manufacturers, the vaccine manufacturers were talking about timelines that were a little bit less aggressive than we were comfortable with, in terms of when they thought they would have a vaccine. I mean, there was timelines being talked about of not having a vaccine until summer of 2021. And when looking at modeling exercises, we were able to see that that was not really going to be a great thing, because we knew, we could already predict that we were going to have issues this fall and winter.

So that led us to kind of feel the need to escalate this and have conversations with the companies and ultimately snowballed into Operation Warp Speed. And thanks a lot to Commissioner Hahn for supporting moving ahead with this and advancing this up through the secretary. So I'm very grateful to Commissioner Hahn for his leadership in supporting this. I think it helped wake us all up as a community that we have to do something, and I'm glad that it took off.

DR. JOHN WHYTE: I do want to ask you, Dr. Marks, a little more about the safety data and efficacy data. Because even when we talk about Operation Warp Speed, in some ways we should be celebrating innovation. But people are concerned, because they're not hearing enough about how we didn't cut corners, how we were able to innovate and no steps were cut in terms of safety and efficacy.

But you addressed the issues of safety, that it's consistent with other studies, that most adverse events or serious adverse events we're going to see in 60 days and we're continuing to evaluate that. But on the efficacy side, I wanted to ask you, because there's been an argument by some that it wasn't the best measurements. We're looking at symptomatic infection at a certain number of days, post-vaccine. You know, should we be looking at different types of antibody? Should we be looking at and other outcome measures? And I recognize the studies are ongoing. But can you explain to our listeners about the efficacy data and how those endpoints were chosen and were the correct endpoints in your decision-making?

DR. PETER MARKS: I think the idea here of using a clinical endpoint of disease prevention that you could come to reasonably, in a reasonable amount of time, I think it was a very-- these were event-based trials based on that, and I think it worked out actually quite well.

In general, what we've seen with vaccines is if you can prevent mild to moderate disease, you generally have a beneficial effect on severe disease. I mean, think about it with influenza vaccine. That's how it works there too. Even if you're not completely protected against flu by flu vaccine, you generally can show an effect of actually lessening severe disease. The same thing for any number of other diseases.

So although some would say, well, we should have had a more severe disease endpoint, some would have said, oh, well, you haven't done an asymptomatic carrier study, the problem was to try to actually swab people's noses daily for 30,000 people, that was going to be a real challenge. So I think what this was, was a balance of a somewhat pragmatic approach with what I think is a very valid endpoint, a disease endpoint, which I think we'll follow up.

Now the most important place to build next is, can we see that their immune correlates of protection from the blood samples that have been obtained that help us understand for our next trials moving forward, do we have an immune correlative protection so we don't have to use clinical endpoints?

DR. JOHN WHYTE: And what is that immune correlate that you're looking at?

DR. PETER MARKS: So I think the immune correlates that we'll look at were obviously the antibody levels and in some cases will be the T-cell, the immune responses that we're seeing, whether it be a T-cell response or a humoral immune response will be hopefully things that will correlate with protection here.

DR. ERIC TOPOL: I wonder, Steve, I can go back on the timing issue, because one of the things that I think a lot of people don't realize is this hyper accelerated schedule from a sequence of the virus January 10th to the beginning of phase I, II trials of Moderna in March, and then the seamless-- you know, you don't stop after phase I and II, you go to phase III. Everything is moving.

And then, on the other hand, critique that, oh, well, how come the UK got to get their approval, whatever, a week or 10 days earlier? Can you speak to-- you pulled out all the stops to move this so fast. And then you get from the flak about the UK getting a review earlier. Can you kind of balance this out for us?

DR. STEPHEN HAHN: You be. Really, really terrific question. So you really nailed it, Eric, that Peter and his team, what they did-- worked very early on with the developers of vaccines to reduce the time in between the different phases, if you will, of development, to compress that time schedule, not to cut corners in the development, but to go seamlessly from animal studies into phase I and then phase I to phase II and then phase II, and then of course had to wait for the events for phase III. And on the side of the regulatory assessment, working on a rolling basis with the companies, having frequent communications also significantly helped reduce the time that we would need with respect to review of this.

So I'm going to sneak this up front. We at FDA did not see this as a competition among regulatory agencies around the world. And I can't speak to what any other regulatory agency looked at. What I can tell you is that Dr. Marks' team, in the past, for an application of this size, let's talk about Pfizer, it would normally take three or four months to fully review that and vet all the data.

Remember, FDA, unlike any other regulatory agency goes line by line in the data. We do our own number crunching. We do our own statistical analysis. Eric, you know how this is, and John, in medicine, if you don't verify and actually do your own analysis, you're relying upon other people's assumptions and the way they look at the data. We have to get this right for the American people. So we did that.

And so when people ask questions about pregnant women, people who had renal failure and other issues, we were able to look at the data and come back with answers or not, and say, look, there's not enough data there. If you look at the issue around allergies, that was something that we looked into in the data and we could provide great confidence about what the data from the clinical trials showed.

So this is what distinguishes FDA. And I am incredibly proud of the heroic efforts that the people at CBER did. The reviewers and Peter-- I mean, three weeks, basically, for the Pfizer BioNTech vaccine application, and 2 and 1/2 weeks for the Moderna application, really record time, but at the same time, did their incredibly thorough review. They are truly heroes.

DR. ERIC TOPOL: Well, you know, I have to say, I've been doing clinical trials since the 1980s, making me very old, but, you know, I've never seen anything. These are the two largest-- a couple of the largest trials in medical research history, and 74,000 people. It's really quite extraordinary how you got all this done so fast. Now you set a new standard which will not be easy to replicate.

DR. STEPHEN HAHN: No, that's true Eric. And, you know, I think the other part of this-- the other thing that should instill confidence is that two trials, 30,000, 44,000, when you look at the average trial for a vaccine that Dr. Marks and his team has reviewed in the last couple of years, it's in the low 20s. I think it's 21,125 is the average. So really a lot of data.


DR. JOHN WHYTE: Let's talk about children. I asked Dr. Fauci about that yesterday. And as you know, Dr. Hahn and Dr. Marks, even in my time at FDA, we would say, children are not mini-adults. So we don't necessarily extrapolate findings in adults in children less than 12, recognizing that there are changes based on age.

So as we talk about the reopening of schools, as we talk about the symptomatic and asymptomatic journey of the disease in children, tell us your thinking, in terms of what needs to be done in terms of studies in children, whether that needs to be a priority, or we have enough information and we should focus resources on the adult population.

DR. PETER MARKS: Really this is a great question. And we have to study children, because the only way we're going to stop the COVID cycle is to immunize enough of the population that we don't have individuals that are mainly asymptomatic-- although children do get COVID-19 symptomatically-- but we're going to need to stop the spread. So we're going to need data in children, and we're going to need data that we can trust.

And that means we're going to have to do clinical trials in the manner in which we've done them for other vaccines, which means we'll do age de-escalation. So in the very near future we'll probably see trials starting where you'll see 12 to 15-year-olds enrolled in the first cohort, followed by 7 to 12-year-olds, followed by younger children.

And those will be critical to have those studies, especially because it's not totally clear that these vaccines will be absolutely safe from extrapolation in those younger populations, because we do see this inflammatory syndrome, and we want to make sure that we're not going to see something there that is unexpected. So we do have to study them. We can't treat them as mini-adults. And those studies will get started.

Now the hope too is that we'll be able to use some of what we've gained, in terms of immune cohorts of protection to accelerate that study. But we need the safety data in those populations for sure.

DR. ERIC TOPOL: One of the things that's come up now in the post-EUA is the single dose story. And so, as you both know very well there was a sign of efficacy that was somewhat anticipated starting about 10 days after the first dose in both the trials, Pfizer and Moderna. And there are some people advocating studying that, and more worrisome are people advocating that you should just take the one dose because then you won't have to deal with side effects or logistics or whatever.

Can you speak to this? Because I think there are some real concerns about potential drop off of efficacy. And it's the only thing that was tested was two doses.

DR. PETER MARKS: You know, this one, I just-- this is something that-- I understand the temptation here. But we spent all this time and effort doing really good science, right. We actually tried to do the science right, and then, oh, we're just going to-- we'll just throw it all out and just--

DR. JOHN WHYTE: One's better than none, isn't it, Peter? One's better than none.

DR. PETER MARKS: Yeah. Well, one's better. But actually there are social scientists that will tell you that one could be worse than none if what one does is makes you throw out all of the protection you're taking and rely on something that might not be true.

So let me just tell you why you need the science. We know that there's a trend towards-- it looked like, right, that there was about 50% efficacy between dose one and dose two with the Pfizer vaccine, for example. And the problem is that nearly everyone got both doses of the vaccine. So we don't know if after one dose you could have 50% protection but maybe it only lasts for two months.

DR. ERIC TOPOL: Or less, yeah.

DR. PETER MARKS: And so we just don't know what that answer is. So I think, as Dr. Topol noted, it's not crazy to actually study this. It's a reasonable question for study. But to just go off and do this, I think it's-- I don't want to say something too critical, but I think it's not exactly responsible. Because people need to know-- the reason why I see health care providers sending me pictures where they're smiling, despite the fact that you can see it hurt that the vaccine went in or they felt kind of crummy the next day, is because they know that they're doing so with the risk of that discomfort, balanced by a benefit of a vaccine that they know to be 95% effective.


DR. PETER MARKS: And that kind of calculus gives people confidence. If you have something that, well, maybe it's 50% but we really don't know how long it lasts, I think that's not a good risk benefit calculus to give people, and I think that undermines vaccine confidence.

DR. JOHN WHYTE: But I think the problem too is people are misinterpreting the data.


DR. JOHN WHYTE: Some people are saying it's 90% effective after does one. They're not taking those points that you're considering. I know Dr. Topol got the vaccine. I'm getting the vaccine next week. May I ask you gentlemen, are you scheduled to get the vaccine? Have you gotten it already?

DR. STEPHEN HAHN: John, I have not gotten it, and I'm waiting for my provider to tell me when it's appropriate for me to get in line and get it. But I can tell you, there's no hesitation on my part. When it's my turn, I'm going to take the vaccine. I do have an adult child who's gotten it, because he's a health care worker, and tolerated it very well.

DR. PETER MARKS: And I'm in the exact same position. I'm lined up-- as soon as it comes my turn, I'm there. So it's just a matter of us getting to-- those of us who are essentially office workers, we're a little lower on the list here.

DR. JOHN WHYTE: I want to ask all of you, and including Dr. Topol, because Dr. Topol, you've been such a great communicator on your Twitter page. So many of us let's turn there, including during the advisory panels to see, what is Dr. Topol talking about? And I don't know how you always have these great images and charts and graphs. I mean, I can't pull it together.

So having said that, how do we interpret-- and let's be honest, it's on everyone's mind-- these mutations in the strain?

DR. ERIC TOPOL: I'm really glad you brought that up, John, because I did want to ask Steve and Peter about this. Because we have this so-called B117 variant in the UK and other countries, but predominantly seen in the UK. It has 23 mutations. There's a couple in the spike protein which are particularly incriminating. And it's also one of those mutations is shared by a South African variant, this so-called N501Y.

And what's interesting-- and I just posted a really deep discussion about this with one of our guru structural biologist. He talked about the molecular high-five, the two tyrosines and how this could really make this virus entry into the cell facilitated, which is more transmission.

But what I wanted to ask Steve and Peter was, OK, we're going to probably see further drift and evolution of this virus. We're already starting to see it beyond the pandemic dominant 614, the D614G. So there's going to be a need for booster shots at some point, whether it's at one year or whenever. Do we have to go through trials at that point? What's going to be your stance regarding these adjustments or tweaks on the vaccine to take into account the drift of the virus? Because this virus unfortunately is not going away.

DR. STEPHEN HAHN: No. Eric, I'm going to let Peter answer that last question from a regulatory point of view. But just the other thing that this is important for is the diagnostic tests.


DR. STEPHEN HAHN: Do the variants-- are the test going to have the same level of sensitivity specificity predictive value that they do now? And it's something that our teams at CDRH are all over and are actually looking at right now. So, Peter, with respect to vaccines.

DR. PETER MARKS: Yeah, no. So great question on vaccines, because I think we are, unfortunately-- this virus is starting to look like it wants to become like Flu Two, Son of Flu, or Father of Flu, with this kind of strain drift.

The nice thing about the flu though, is it's set up for us a very nice paradigm for strain change supplements. And so we will not need-- I think especially with the mRNA-based vaccines, I think we know how they work, right. We will probably just have to set up, essentially what will be strain changes.

It might be the first time we do it, we'll check an immunogenicity study. But it's not going to have to be another 30,000 patient clinical trial. Those immunogenicity studies are usually 400 patients, just to make sure that we have the right check of what's coming out. And even that may not be necessary after we check at the first one or two times. So I think we'll have a way of evolving here with these.

And that brings to mind that the three things that we really need to know right now that I'd love to know is, do these vaccines stop asymptomatic transmission, how long will they give us protection, and what will be their spectrum, in terms of dealing with these various mutants that seem to be coming up? Which, uh. You just--


DR. PETER MARKS: You just wonder where it's going to go now. It keeps me up at night.

DR. JOHN WHYTE: I got to ask the first question. I want to give Dr. Topol the option to ask the last question.

DR. ERIC TOPOL: I had two quick questions for you before wrapping up if I could. One is, to just give us a word about your view on these rare, severe allergic reactions. The word out there is it could be the polyethylene glycol or it could be the lipid nanoparticles. That's one question.

And the other one, if you could just speak to-- this is that superhuman vaccine immunity that is better than the typical person, that the concept that you had 3% of people in the Pfizer trial, 2.2% in Moderna that turned out that they were previously infected with COVID. And so the fact that you had a readout now of people who had a prior infection, who got placebo or got vaccine, what does that tell us about the vaccine-induced immunity versus the native intrinsic infection response?

So if you could just give us a little response on the allergy and this concept of vaccine versus natural infection immunity.

DR. PETER MARKS: This concept of natural versus vaccine-induced immunity-- I think the most important piece for me that I'd draw from that is that we're not seeing this antibody dependent enhancement. If you got vaccinated and it already had the virus, we're not seeing an adverse effect there. And that's consistent between both of the vaccine trials, which is reassuring to us.


DR. PETER MARKS: Because we can't-- it would be very cumbersome to screen people for infection before vaccinating them. I think the CDC has recommended 90 days, if you've actually had COVID-19 before you go get vaccinated. But--

DR. JOHN WHYTE: Or received monoclonal antibodies.

DR. PETER MARKS: Right. Right. Exactly. Exactly. So I think that that makes sense. And so that's where I'll leave it with that one because of the time.

The allergic reactions-- something we are working very closely with the Centers for Disease Control and Prevention and with the companies to make sure we keep very good track of. I know every day I get an update. This good news is, as we're seeing them settle out, I think it's not like the number of them are increasing wildly. I think we're going to see these as events that are going to be in the range, hazard a guess of in the range of one in 50,000 something, one in 100,000.

But thankfully they have been generally controllable with typical measures such as epinephrine and-or hydrocortisone. We're going to have to keep looking at them, and we're going to try to delve into what is causing them. We will be looking into seeing whether these could be- could these these IgE antibodies to polyethylene glycol? We will look into that and try to determine what we can to try to help make these vaccines as safe as possible to use.

DR. ERIC TOPOL: Great. Thank you.

DR. JOHN WHYTE: Dr. Hahn, I want to give you the final word.

DR. STEPHEN HAHN: Just really appreciate being able to do this. We're very concerned and continue to work on the issue of hesitancy and confidence. I'm incredibly proud of CBER in the work that they did and the transparency associated with it, and the 17,000 employees at FDA who have just, again, been heroic throughout the pandemic. So thanks for the opportunity for us to join you today.

DR. ERIC TOPOL: Well, you've really taken the FDA in this time-- you've got to be so proud of what you're able to accomplish getting these two over the goal line so fast and changing the whole way that we get out of this mess, which is a real mess. So we're so grateful to you and all the people you work with to make this thing happen, and in such an extraordinary way and speed that we'll go back to Peter's Project Warp Speed. But it really paid off. So we thank you both and everyone.

DR. JOHN WHYTE: Let me echo that on behalf of WebMD and Medscape. You really have provided us now the opportunity to crush the pandemic, and vaccination is that pathway to return to normalcy. So thank you both.

DR. PETER MARKS: Thank you so much.

DR. STEPHEN HAHN: Take care. Thanks, John.