Peter W. Marks, MD, PhD, and Stephen M. Hahn, MD, return to JAMA's Q&A series to discuss the Pfizer/BioNTech and Moderna vaccines: the data, the weekend's EUA designation (Pfizer/BioNTech), and the process for future full licensure and postmarketing safety surveillance.
Dr Marks directs the US FDA's Center for Biologics Evaluation and Research (CBER).
Dr Hahn is commissioner of the US Food and Drug Administration.
Recorded December 14, 2020.
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>> Howard Bauchner: Hello and welcome to Conversations with Dr. Bauchner. Once again, it is Howard Bauchner, Editor in Chief of "JAMA." And I'm thrilled. I'm here with Steve Hahn, who's the Commissioner of the Food and Drug Administration. And Peter Marks. Peter's the Director of the Center For Biologic Evaluation and Research, CBER, who's been much in the news because his center's responsible for ensuring the safety and effectiveness of biological products, including vaccines. Steve, what's the last two weeks been like for you?
>> Stephen Hahn: So it's been actually a very positive time. We made a promise, Howard. You know, I spoke to you about this several months ago. We made a promise to the American people, to American doctor that's we would follow a process led by the science and the data. That we would do a thorough review. And we would uphold the gold standard that FDA is with respect to safety and effectiveness of vaccines and medical products. Including transparency, which I think everyone saw last week with the vaccine-related biologic advisory committee. So to me we kept that promise to the American people. Dr. Mark's team did an amazing job, heroic job reviewing a complex set of data. And really getting it out there and having a very robust discussion. And then moving quickly to issue the emergency use authorization. So there's been pressure, no question about it. Pressure of the moment. The fact we have 3,000 plus people dying every day. It's a tragedy. But our teams responded. Peter responded. And we stood by the American people. And we followed the data and the science. And I'm incredibly proud of the agency for that.
>> Howard Bauchner: Steve, I want to personally congratulate you. I know you made that pledge on this conversation almost two months ago, and you honored it. And I'm sure it was not easy. And I just want to thank you, personally I want to thank you. And on behalf of the scientific community, I want to thank you. So, Peter, how big was the application? And how many people worked on looking at the data?
>> Peter Marks: Yeah. So, you know, I'm going to say because these are electronic applications, the technical information that came in was several hundred pages of written text. And then I can't tell you how many reams of paper the tables, figures and listings would actually have been on. So there was a lot of, there was a lot that was looked over here. And we had about a total of 150 people working on various pieces of the application. Some of them almost really nonstop worked through the holiday period of Thanksgiving to make sure that we could get this done as quickly as possible.
>> Howard Bauchner: Steve, when the UK announced that they had approved the Pfizer vaccine so quickly, did you feel like you were going to have to call up the FDA advisory board and say, we're going to move up the meeting from that, I think it was last Thursday to Monday because we have to approve it right away? Did you feel like you wanted to change the process when the UK announced approval?
>> Stephen Hahn: Howard, absolutely not. I can unequivocally tell you that was not something we were going to do. Dr. Marks and I have been working since the summer, early summer on the timeline associated with it. And Dr. Marks, who knows this in great detail, really outlined what that would be. And what our scientists would need to do to actually make a decision. And so any movement of that would have meant we would be compromising our scientific review. And we both have been out there telling everyone that we weren't going to do that. So it wasn't an issue of being obstinate. It was an issue of sticking to the fact that we needed the time to do a thorough scientific review. And as we said, we go line by line in the data. We just don't look at a scientific publication. We certainly just don't look at a scientific press release from a company. Our scientists look at the data and do this sort of analyses that you saw at last week's meeting. So we needed that time to get this thorough review done, and that's exactly what we did. So under no circumstances would it have been considered to change that date because we needed the time to get the information done and do it right.
>> Howard Bauchner: Yeah, I was pleased to see that some leaders in the scientific community, particularly Tony, Dr. Fauci said, let the FDA do their thing. This is who they are. This is what they should do. I'm hoping that that was perceived as support.
>> Stephen Hahn: We're very grateful for the support of the scientific and academic community here. And I think went a long way toward continuing to support the process that we put in place.
>> Howard Bauchner: Peter, right before we came on, you mentioned that actually there's differences for EUAs for a drug versus an EUA for vaccine. And you're going to face many more of these. I know there's a hearing this Thursday for the Moderna vaccine. I think there's other phase three trials that are being completed and will submit EUAs. Could you explain the difference between an EUA for a vaccine versus a drug? And what will happen next around further approval?
>> Peter Marks: Right. So, first of all, I should say there's no difference in statute. So this is not like a legal distinction. This is something that we've imposed on ourselves at FDA through our guidance, the EUA guidance for COVID-19 vaccines. And that's because our usual standard for medical products for approval of a drug or biologic is the substantial evidence of effectiveness standard. Evidence from adequate and well-controlled trials that something has substantial evidence of effectiveness. That's kind of our gold standard. For the emergency use authorization, which was power that was given to us after the terrorist attacks of 9/11 when there was declared public health emergency. Where maybe, you know, you might have medical products that hadn't been all the way through development that could have helped people with a disease that was chemical, biological or radionuclear caused. The bar was set at the product may be effective, and its known potential benefits had to outweigh its known potential risks. Now, for a preventative vaccine, it just, that is probably a little bit lower than we would like to see. Because we want to have people have confidence that, when they get vaccinated, they are going to know that vaccine has a good chance of protecting them against the disease they're getting vaccinated against. And that it's a very safe product. And for that reason in our guidance we set forth notice that what we're doing here is making sure that the standard is that there has to be clear and compelling evidence that the vaccine is effective from well-designed, phase three clinical trials. And so, although not quite the same BLA standard, the evidence we're going to have for effectiveness is very much like that we would have for a biologics license application. But the one place that it's a little shorter for us or a little less close is to the duration of safety follow-up that we'd have. Which would normally be six months or a year. But we're making up for with a pharmacovigilance plan that's very robust.
>> Howard Bauchner: Yeah, we'll return to the post-licensure safety issues that have come up with a number of drugs over the last couple years. And to ensure that there's follow-up from the companies. Steve, so you produce this document. You widely distribute it. I got it. I've read through it a few times. What surprised you about the data? Were there any surprises when you looked through the final report, Steve? I was just curious.
>> Stephen Hahn: No. I, there weren't a lot of surprises. Peter and I have been talking about this for some time. Peter's team has been reviewing this on a rolling basis. Not surprised, but so impressed by the detail and the thoroughness that Peter's team put into this. And it's not just me blowing smoke, Howard. Just when you read it, when you understand, when you saw the presentations last week, it really gave clarity to what our career scientists do. And what's goes into our incredibly thorough review. I was particularly interested in some of the analyses that were done to look almost, if you will, a fishing expedition for side effects. And how thorough that was. And how that gave me great confidence in the decision-making that had taken place. So I don't think there, for me personally, that there were any big surprises.
>> Howard Bauchner: Now, Peter, you have like 100 people talking to you all day long either by e-mail or by phone or you're doing conferences. Did anyone say, hey, did you look at page 492 and see this line? Wow, that's a surprise. Were there surprises for you and the group of reviewers, Peter?
>> Peter Marks: You know, people actually, we looked at various pieces. And people did actually call out specific pieces of the file to have a look at. I think, actually, let me just back up to, you know, if there was anything that I could consider one of the most pleasant surprises I have had in a long time. 2020 is a year that I think, if I could get out a big eraser and erase a lot of stuff with, I would do. But a moment of true joy was when we saw the data on the 95 percent effectiveness of the first vaccine out of the gate. I mean, that was just, because, first of all, we were worried that, would you be able to, I mean, if you listen to Tony Fauci several months ago.
>> Howard Bauchner: Right.
>> Peter Marks: We were worried that we'd even be able to get a vaccine.
>> Peter Marks: This year. Or even into next spring for, against this vaccine. We weren't sure we could make a good vaccine. And then to have a vaccine that had 95 percent effectiveness, what looked like across all different kind of populations, both young and old. Granted with greater certainty in some populations than others. That was just really exciting.
>> Howard Bauchner: Yeah, no, I do think it's worth congratulating the scientists at Pfizer and hopefully Moderna. They, it's been a difficult year. You know, there's often a lot of chatter about pharmaceutical houses or other start-ups. But in this case, the scientists at Pfizer and hopefully at Moderna have, and other companies, have really distinguished themselves this year. There's been many, many challenges. But the science that brought us vaccines is extraordinary. And it really is a compliment to all of the investigators that have gone before and the current group of investigators at those two companies. What's the plan? So meeting and follow-up, I think is two months, if I read it correctly. I think both of you are well aware that the greatest concern of people who have been vaccine hesitant has been safety. I think the data about efficacy is extraordinary. We'll get a chance to see it from the Moderna group formally this week. Both mRNA vaccines. And when I spoke to John Ioannidis, he said, I prefer two small trials than just one large trial. Now, this be two large trials. Same biological approach. So if the numbers are the same, that will actually be very encouraging. Particularly in the high risk groups, older than 65, where the confidence interval is very wide. And we'll be able to compare. But without doubt, for the public, the biggest concern has been safety. Steve, what's the plan for post-licensure surveillance?
>> Stephen Hahn: So post-authorization, and I'll ask Peter to give a little bit more detail about this. But we recognized exactly what you just said, Howard. And that is that, although this situation is urgent and we needed to expedite both the development process or help expedite as well as the review process. We recognized that sort of, we had to get at least that two months meeting follow-up of data. Because Peter's team had done a review of our previous vaccine approvals and also what was in the literature and really estimated that the majority of serious events should be picked up during that time period. So we had confidence about that. But recognizing that it isn't the full length of follow-up. We need to have in place a very robust mechanism for collecting data, particularly around safety. But I'll also mention efficacy, duration of protection, et cetera. And in Peter's guidance, and what we made clear, that it is for a minimum of two years. And so we'll be using a variety of means, including partnering with the Centers For Disease Control. Also claims data, which will be, should be a rich source. And also mining electronic health records, of course, recognizing the protection of patient privacy. So all hands on deck for that one. And a very robust pharmacovigilance approach to monitor for safety events. And the partnership with CDC will be really important here. And I don't know if, Peter, you want to add to that?
>> Howard Bauchner: Yeah, Peter, are there questions, just if you could elaborate, on safety? Because it is, I think we can't spend enough time on it because it's so critical to the public. And then there are, there remain questions about, and when I spoke to Tony, I knew the questions already. We know it protects against disease. But there are other questions, not just about length of protecting against disease, but protecting against infection. So if you could comment on both those issues, Peter.
>> Peter Marks: Yeah, let me start by taking the, my three questions that I'd love the genie to answer now, if I could. But, unfortunately, we're going to do the scientific work to get them answered. And then I'll talk about safety. So the first question is duration of protection. How long will people be protected with this vaccine? Is it going to be months and months? Or is it going to go years? The second is, will this vaccine prevent asymptomatic transmission? In other words, with asymptomatic carriers of the, will people just be protected against disease with the virus, from the virus? Or will this abrogate transmission of this? And the other piece of this, which we haven't been thinking about as much, but I have to think of as a public health professional is, if this virus subtly drifts.
>> Peter Marks: Kind of like flu can drift.
>> Peter Marks: Is this vaccine going to have a robust enough, evoke a robust enough immune response that it will protect against these drifted strains of the S-protein? Because it's really only, these are S-protein vaccines, these mRNA vaccines. Will that protect? Now, the good news is, as mRNA, they can be shifted pretty quickly. But it would be nice to know. So those are three things. But now getting to safety. We very much are committed to understanding as much as we can about the safety of these vaccines. We know that, as these are deployed in millions of individuals, we'll get a better sense of what's going on. We're absolutely committed to making sure the public is aware of any safety findings that we see once we've really dogged them down and made sure that we understand them. We have to be careful here because, as we deploy these vaccines, you know, safety signals come. We have to make sure we understand that they're real and that they're meaningful. And once we understand that, we're not going to hesitate to make sure the providers and patients or individuals getting vaccinated are aware of this. So that will happen because we have these ongoing safety surveillance systems in conjunction with Centers For Disease Control and Prevention. And that's actually also an important point to bring out here, that FDA, cross-government collaborations can be very powerful. The combination of CDC's safety surveillance and our safety surveillance, we're going to apply that full portfolio of safety surveillance systems to make sure that we do our best to understand what's going on here.
>> Howard Bauchner: Peter, I just want to emphasize for people who are listening. And I know Steve's an oncologists. So I don't think there's any reason to think that any vaccine induces cancer. So people, 500,000 people are diagnosed with cancer each year. I don't think people are concerned that you get a vaccine and then you develop cancer. But people have heart attacks every day. And they have strokes every day. And so now we know that the number of 20,000, hopefully will go to a few million over the next couple weeks. So people are going to have heart attacks and strokes proximal to the time of getting the vaccine. That does not mean that the vaccine caused that event. And I don't think we as professionals can emphasize that enough to the public. Steve, can you comment on that issue? And then you, Peter?
>> Stephen Hahn: Yeah, Peter and I talk about this a lot. It's one of the reasons that we need to collect as much evidence and data as possible. Because we need to understand what the background is of these very common events. And then reassure the public and be transparent about it, for example, if we aren't seeing anything, that it's at the background base level. And, Howard, you're right. I mean, Peter and I, you, we've all taken care of patients. People will get this if we explain it to them and we're transparent about it. And so I think having this conversation about those background events, I mean, vaccines are going to be given to people who are in long-term care facilities. And we know things happen, medical events happen to those individuals as well. So having some tracking of those data and being able to communicate about this is just so important.
>> Howard Bauchner: Peter.
>> Peter Marks: Yeah, two points I'd like to make is that this is, what Commissioner Hahn just said was, is really important. And what you just said is really important. Because we have such a microscope focused on collecting these adverse events. We don't want to get into a panic like, those may remember a few months ago, Korea, South Korea had a panic around influenza vaccine. That influenza vaccine was leading to excess deaths in the elderly populations, 70 and 80 year olds. Well, it just so happened that they were doing such good safety surveillance that they were picking up the natural death rate in that population. And when they went back and looked, it was just, they had a very good influenza campaign. And it was just the natural rate that they would expect. So we have to be careful. Now, that doesn't mean, and that, I want to make sure that people understand. That doesn't mean we're going to pass by, it's our duty to look very closely at this. And we take that very seriously. So that should really be known. Another thing that vaccination, though, it's important to understand here in terms of the totality of benefit here. Vaccines in this case will not only have the benefit of preventing COVID-19 disease. If they can get us back to a normal environment sooner, they're going to help prevent a lot of other diseases. Because if you look at the recent publications of the excess mortality rates.
>> Howard Bauchner: Yeah, right.
>> Peter Marks: From people not getting routine care, you know, that's not a good thing either. So the vaccines here, probably a good graduate student project for someone to figure out totally how each vaccine really benefits here more than just by preventing the disease, COVID-19 disease itself.
>> Howard Bauchner: Right. "New York Times" had a nice lead article yesterday about this excess mortality. And they referred to three publications "JAMA's" had by Steve Woolf. Because Steve's really tried to be careful about saying, we count deaths very well. So we know how many deaths usually occur every month, and then you know how many have occurred this year. And there's that excess number. A couple questions have come in, and I'd like to just ask the two of you about them. Can the guests address patients with allergy? Now, this has emerged because of some of the early reports from the UK that has made, I think, will make people in the U.S. anxious. Less so for the first group that will get it because they'll get it within hospitals. But comments about people with a history of allergy and whether they should get the vaccine when it ultimately becomes available?
>> Stephen Hahn: Yeah, Peter, why don't you take that. You wrote the.
>> Peter Marks: Very happy to take that one. I think we have looked at this very closely. And what we would say is that, unless you've had an allergy that was severe, a severe allergic reaction to a vaccine or a known vaccine component. Probably the most common things that are components of this vaccine that someone might have had an allergic reaction to might be polysorbate or polyethylene glycol. But unless you've had an allergic reaction to a vaccine, we're not concerned with people going to get vaccinated. As a precaution, for the time being, whether they're hospitals or whether they're going to be other facilities, we're saying that there should be the ability to treat an anaphylactic reaction. But, you know, we say that with other vaccines as well. That's not just special for, that's just something for newly deployed vaccines that we would say. And we're comfortable with that. We've looked at the database in the, that was put together. And that's why it's helpful to have a database of 22,000 people. And there were not an excess of allergic reactions that was significant. So we're pretty comfortable with this. Obviously, we're going to monitor this very closely. And we'll give physicians additional advice, providers additional advice if we see anything new turn up.
>> Howard Bauchner: Bell's palsy, four cases. Not uncommon post-immunization. It always becomes a struggle to know if it's just background noise or if it's related to the vaccine. But it comes up with almost every vaccine. I'm a pediatrician so those data I'm familiar with. Comment about Bell's palsy.
>> Peter Marks: So I'll take that one because we've added that to the list. So we have this list of 20 things that we're going to query the large databases for. That's an easy one to use claims base databases and the electronic health record. We'll get data on that pretty quickly and see if it is indeed. Our hypothesis, our working hypothesis is this just was an imbalance in background rates like we've seen in other trials. But we'll make sure that we're going to actually query for that just to bring that question to close.
>> Howard Bauchner: Steve, this week a few million doses are going to be shipped. It's complicated. I'm actually confident that we can manage a few million. Now, when we get to tens of millions, I am more anxious about the infrastructure. What role does the FDA play now in the manufacturing and shipping? Do you monitor up to the time that it's in the box and getting ready to be shipped? I don't know what the FDA role becomes after approval.
>> Stephen Hahn: Well, Peter is, commonly says, and it's true, our work is not done after issuing an EUA. First of all, I think having conversations like this, being clear about the issues around allergies. Bell's palsy. Our follow-up system for surveillance. Those are really critical issues. Peter and I had a call with groups from the OB-GYN community, talking about the risk associated with pregnancy.
>> Howard Bauchner: Yeah.
>> Stephen Hahn: Risk-benefit ratio. All of these things are part of our job. Now, also we, Peter's group has done a terrific job of helping to provide support to all developers of vaccines around raw materials and the supply chain associated with vaccines. So that's another one of our core responsibilities. As well as ensuring, number one, that the manufacturing of vaccine, every vaccine that comes off the line meets our high standards and that GMP is being used to manufacture. But, number two, that the storage conditions are appropriate for the vaccines. And so we do actually get involved in ensuring that we're comfortable that those conditions are being followed. And our teams are working on that. As you can imagine with the first two vaccines, that's part of the issues [inaudible].
[ Multiple Speakers ]
>> Howard Bauchner: Peter, you said, if you were a genie, you'd like three more questions to be answered. You know, protecting against infection. How long it would last. And I think there was a third. Could you be that genie for a few minutes? What are your instincts tell you about length of protection? And protecting against asymptomatic disease or spreading of infection? What does the Genie in your bottle say?
>> Peter Marks: Yeah, so the genie in my bottle says that we can extrapolate a little from those who were immunized earliest on the current trials. Because we at least know that there's probably a duration of protection of several months. It's probably not just two months, okay. It's probably at least, probably on the order of four to six months. The question is, will it reach out to a year? Hopefully yes. But I think we'll have those data in the not to distant future. And we'll have real data because of the people who are being followed on the trial. Asymptomatic transmission will be harder to know for sure. I'm going to tell you my hope is that, since in animal studies it does look like these vaccines led to cessation of asymptomatic shedding, that will hopefully be the case. But we don't know for sure. I believe that NIH is contemplating a study in this regard. Because at this point in time where we have so much COVID-19 around, it's not that hard to do a study in which do you nasal swabs routinely on a relatively healthy population, college-age population perhaps, to see how many, the vaccine might prevent shedding in, versus a placebo group. So this could be something that would get to that. And I know that that's being discussed right now. So that will hopefully, again, get data here. Otherwise, we're just going to have to use observational data. Which one can do, but it's not going to be quite as clean. And then, obviously, for strain drift, that we will, we have lots of different public health agencies across the globe collecting the different strains that are there. And we'll be keeping a close monitor on that to make sure that we don't see changes in the S-protein that would make us worry that our current vaccine might lose its effectiveness.
>> Howard Bauchner: Steve, I feel like I have to ask you one final question. And I do want to read something from, what came in over the e-mail. You know, there had been reports that Friday difficult day for you. And I want you to be able to comment publicly just in a conversation. What was Friday like for you?
>> Stephen Hahn: Friday was a really great day for the American people. And it was a really good day for FDA. But, most importantly, the American people. And as we begin to have some hope and light about turning this pandemic around and maybe seeing the end of it, I certainly, you know, there has been pressure to move as quickly as possible because of the urgency of this pandemic. And there's been a lot of externalities, noise, if you will, that certainly a lot of people have heard. But, Howard, I can tell you, Peter, I, our teams have been steadfast that we'll use science and data to guide this. We're not going to let politics enter into this. And this isn't about me. This isn't about any one individual. This is about the American people and following the science and data. So when I reflect back on Friday, my one thought is very happy and very hopeful because our scientists have determined that a vaccine was safe and effective. And that means a lot to our country.
>> Howard Bauchner: Well, congratulations to the two of you. Peter to your entire team, I wish I could give them all masks or kisses or hugs. It's been a long year. And for us to recover economically, for us to recover socially and mentally, we really do need these vaccines to be effective. To be distributed. And used wisely. I want to read one last comment. I thank the FDA for their diligence and commitment to the health of our country. Many more good wishes. I wish the two of you a Happy New Year. Stay healthy. And thanks so much for joining me today.
>> Peter Marks: Thank you so much.
>> Stephen Hahn: Thank you, Howard.
>> Howard Bauchner: See you, Steve. Bye, Peter.
>> Peter Marks: Bye-bye. Take care.
>> Stephen Hahn: Bye-bye.
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