Risks for Fast-tracked COVID-19 Vaccines

Paul Anderson: Welcome to Smart Health Care Safety from ECRI, the most trusted voice in healthcare, committed to advancing effective evidence- based care. I'm your host, Paul Anderson, and over the past 12 years, I've overseen our patient safety, risk, and quality membership programs here at ECRI. Tens of thousands of healthcare leaders rely on us as an independent, trusted authority to improve the safety, quality, and cost- effectiveness of care across all healthcare settings worldwide. You can learn more about our unique capabilities to improve outcomes at www. ecri. org. We're recording this podcast from our respective home offices as we practice, and encourage all of you to practice, good social distancing, to help limit the spread of COVID. Today's episode is part of ECRI's ongoing response to the COVID- 19 pandemic. We'll discuss ECRI's recent position paper on the fast track development of COVID- 19 vaccines, in which we warn that rushing to deploy vaccines before all the data has been collected and evaluated could lead to increased risk for patients, not to mention harm to public trust in vaccines in general. To get us started, I'll ask our guest to introduce himself.

Dr. Marcus Schabacker: Hi Paul. I am Dr. Marcus Schabacker. I'm an anesthesiologist and intensivist. I'm an affiliated associated professor at the Stritch Medical School of Chicago, and I'm the CEO and president of ECRI.

Paul Anderson: So I thought we could start by describing the current situation as we understand it today with regard to COVID- 19 vaccine development. And I'll say, you know, we're recording this here in the sort of early fall of 2020. Can you give us some sort of quick overview of where we are in terms of the development process and what that process has been like to date?

Dr. Marcus Schabacker: Yeah, it's been like no other, to be honest with you. We are in the final stages of the clinical development. So we typically, in pharmaceutical development and vaccine development, differentiate between the early in lab development, and then we'll go to the clinical development, which is typically phase one, phase two, phase three, four before it gets to approval. And typically for vaccines, that takes anywhere between two to three years. We are barely 10 months into this process, and one company actually has already concluded their patient recruitment. Or I should say vaccine subject recruitment, because obviously, they're not patients, and is in the follow- up phase. So that has never been done before. It's a tremendous effort on side of the pharmaceutical companies, on side of the regulators to make that possible. And quite frankly, taxpayers because they are funded it. You know, most companies who are in this Operation Warp Speed program have received billions of dollars in taxpayers' money.

Paul Anderson: And my understanding of that is that part of the reasoning, the rationale, is by removing some of the financial risk for these developers by having sort of the taxpayer backing, right? We may be able to, incentivize might not be the right word, but by removing some of the financial risks, we can help them accelerate that development. Is that sort of a fair characterization?

Dr. Marcus Schabacker: It's incentivizing deliberately, yes. The US government and other governments around the world have given guarantees to, you know, to buy certain amounts of, millions of dosages of the new vaccines. And that has taken the financial risk out of the equation for those companies. And they have, you know, dramatically accelerated and streamlined their operations. And, you know, the interesting piece is that we also using very new technology as vaccine platforms. The two leading candidates who were the first along, which is Pfizer and Moderna, both using the MRNA technology, where messenger RNA is inserted into the human cell to then create the antibodies. That has not been used in vaccines before. So that's an additional factor here which, when we talking about safety and effectiveness of the vaccines, we need to keep into consideration.

Paul Anderson: So if the sort of end result of this Operation Warp Speed, or maybe through the intermediate result I guess, would be finding vaccines that we think are safe and effective and authorizing them through this emergency use authorization process, or EUA. And that differs from the more traditional process that you laid out that can take Two to three years, which we refer to as the BLA process. Other than sort of the compressed timeframe, can you lay out some of the differences between those two processes?

Dr. Marcus Schabacker: Yeah. What the BLA process usually looks like is of course, the safety and effectiveness of the vaccine, but it also looks at what's called the CMC, chemistry, manufacturing, and controls. And to the agency's credit, they didn't make any major compromises in this part. So that is looking really at the good manufacturing practice, right? How is the vaccine developed? How's it tested in the lab? And then how is it manufactured and what controls, quality controls, do the companies have in place to provide a consistent and safe and sterile vaccine? So the agency, based on what we heard in the public hearing last week, hasn't made too many compromises in allowing companies to take short cuts, which is good, which makes us very comfortable. I think the major difference is that typically, you would see a more extended timeline for those clinical trials. We took a look at the clinical trials, clinical trial design. They're pretty robust. So their statistical methods, the way they have subgroupped the study population, all that is pretty solid. I think the largest objection we have was with the emergency use authorization is that it only requires in its current form. And I read recently that, given the hearing, FDA might reconsider their position. It would only require about two months of data to follow up. And the rationale for that was, and is, that typically, if you see severe adverse events from typical vaccines, then you see that within four to five, six weeks. So the Guillian- Barre Syndrome, which is often thrown out there as a major neurological complication, typically manifests itself four to six weeks after vaccination. Our argument is a little different. Our argument is, we're of course concerned about the safety, but more or equally concerned about effectiveness. So that's where we think that the two months is just not sufficient.

Paul Anderson: And, you know, I mean, I think I understand why there's a lot of public interest in getting a vaccine out as quickly as possible, right? I mean, that's natural, right? But what are some of the risks if it's rolled out before we have, and I think you sort of flagged like, six months as a, you know, as a baseline? What are some of the risks if we roll this out before all of that necessary data is collected and understood?

Dr. Marcus Schabacker: Well, we see two key risks. One is an actually effectiveness risk, right? So if we think, based on the early studies or early analysis, the vaccine is more effective than it is actually is, it can actually worsen the pandemic. Because if you then vaccinated and you go and stop your safe behavior, like wearing a mask, social distancing, hand- washing because you think you're vaccinated and you're safe, that might be true. So for example, we always kind of talk about this in a way as, let's assume the vaccine is effective to prevent severe cases, but it's not effective in preventing mild cases. So you are mildly symptomatic, or maybe not symptomatic at all, but you carry the disease. So you become a super spreader. All those vaccinated people, if they stop behaving safely, become super spreaders and might even worsen the pandemic because we have this false sense of security or safety and effectiveness. That's one, and the second one is really around, you know, how clinical trials are typically conducted is that you, and this is no different than this trial, that you set a target on what study population you want to get. And in this trial is differentiated by age, for example, but the FDA has also made very clear, to be comfortable we need people of color. We need certain age groups. We need socioeconomic diverse statuses because we've learned that, you know, COVID is disproportionately hitting people of color, people in socioeconomic difficult situations, people with comorbidities, preexisting diseases and so on. What happens in a typical clinical trial is that, when you're trying to get to all those different populations, you start your recruiting process. Initially, you get people who are highly motivated to participate in those trials. That is typically not the ones I just described. People of color are reluctant to participate. People with comorbidities are reluctant to participate. People in socioeconomic difficult situations are reluctant to participate. So you get to them, but typically it's later in your study. Now we have concluded the study, we are in the follow up time, we're saying we're looking at two months, those are the ones which are latest in the study. So we might not even get to them if we restrict our look on the two months. So we don't even know if, either is a safety issue for people with comorbidities and other things, and/or is effective for those people who are most susceptible to severe disease. So that's why we're saying we really need to have the entire cohort for six months, because only then we can judge its effectiveness and safety. And then the third component is the duration of the effectiveness. If we only look at two months, it might be fine. It might be work for two months, but then have a steep fall off because the antibodies get, you know, dissolved in the body and not protect beyond that. A, again, it could worse than the pandemic, but B, it could be really a false sense of security for people, and we would approve a vaccine which eventually shows or proves not to be effective. And then we would have lost the trust of the public in our ability to develop a safe and effective vaccine. And that's, to me, actually, the biggest concern. There's already high amount of suspicion out there in regards to this vaccine, because it has been so politicized and there has been undue political pressure on the FDA and the pharma companies to rush this through. If we now bring something out which doesn't work well, has any of the things I mentioned before, it's going to take us years before we recover from those and can convince the public that the vaccine is actually working.

Paul Anderson: And I think, especially when you consider that in combination with all the other vaccine skepticism that pre- existed the pandemic, all the sort of anti- vaccination-

Dr. Marcus Schabacker: Anti- vaxxers, yes.

Paul Anderson: ...Conspiracy theories and so on. Layering those things on top of each other is just going to compound them.

Dr. Marcus Schabacker: Absolutely. And that's where... You know, I coined this, not my phrase, but I'm using it and saying, go slow to go fast. So if we just take four more months, it's going to be so much more robust. We're going to have so much more data. We have so much more knowledge that it then allows us to really, assuming we have an effective and safe vaccine at that time, we can then dramatically increase the acceptance of this and drive it forward into the population, get everybody vaccinated. But if we don't do this right, a lot of people are very hesitant to either take it or give it to their loved ones. By the way, except for one clinical trial, which is not finalized yet and is not one of the first two, none of the clinical trials include pediatric patients.

Paul Anderson: Interesting.

Dr. Marcus Schabacker: So if you think want the vaccine out fast so you can vaccinate your children, that ain't going to happen anytime soon anyway.

Paul Anderson: Right. And let me tell you, I desperately want my children back in school.

Dr. Marcus Schabacker: I'm all for that. But as I said, let's go a little slow to go fast.

Paul Anderson: Do it safe. A hundred... Yes. I thought about asking you to take out a crystal ball, right? And predict what the next six months or a year are going to look like for vaccine development and distribution. But I think maybe that's not fair. So instead, let me ask it this way. Can you sort of describe, and I think you've hinted at this or talked about aspects of this throughout our conversation, what is the best case, ideal scenario that you could see playing out, again from sort of the last quarter of 2020 through the beginning part of 2021? What's the best case scenario that sets us up for sort of long- term public health?

Dr. Marcus Schabacker: So the realistic best case scenario is, let's take six months from now where these studies wrap up, which gets us into the first quarter of, end of first quarter of 2021. We then can conclude we have a safe and effective vaccine. By the way, one thing, if I may, just in parenthesis, one thing which came out of the hearings as well, which again, is an argument for doing six months, is if you take a look at two months into this clinical trials and think you have an effective vaccine, it becomes ethically very difficult to continue your blinded trial and give only, you know, give placebo to a subset of patients. From medical ethical perspective, that becomes very difficult, and quite a few experts raised concern about that. Because now you stopping essentially your clinical trial, which was designed to include more patients, which are, you know, getting placebo so you truly have a controlled study. And the only way you could do this then later would be to have two vaccines comparing to each other to see if one is more effective than the other, but that's taking even longer. Right? So there's another argument for you, why you really want to get the six months data. So the ideal scenario coming back to that is really, wait the six months. At the end of March, conclude that you have a safe and effective vaccine, and by then have developed a really solid, thought through distribution plan, because that's another big problem we're going to have. There's easy ones, right? There's easy ones. Say frontline healthcare workers. Easy. The paramedics who go into homes of people. Easy. After that, it becomes really difficult. So when we did H1N1, we distributed the vaccine based on population amount in each state. So each state got it, and then the state government decided on [ inaudible 00:18:08]. That ain't a smart way to do this because we know that we have inaudible taken to extremes, right? So Florida has a significant higher number of plus 65 people, which we know have a higher risk versus, you know, somewhere in the Midwest. And so we really have to think through, and we have to get similar to what the FDA did in getting an expert panel together. We have to get another expert panel together and think about a federally controlled distribution of the vaccines and a plan on how you're going to vaccinate people. And one thing which was discussed there as well is, very likely that we're going to need two shots. Two shots of those vaccines. So how do you organize that the person who has the first shot get the second shot of the same vaccine? Because if they got the shot from another vaccine, which by that time might be approved. So we'll really have to think through the distribution and the logistics of this. And, you know, the White House is saying, well, we got it under control. We got the Army lined up. That ain't going to cut it. So we really have to have a federally driven, federally controlled, and thought out plan through experts, not through the people in the White House who, you know, have not a lot of experience in vaccination. No disrespect to anybody. But you really need to rely crosstalk on the experts there in figuring out the distribution based on risk. And as I said, the first group is pretty clear, but after that, it becomes quite difficult to determine who that is. And how do you organize those logistics? Yeah, I would suggest at this time, if we had an vaccine today and would start vaccinating, it would not be a pretty sight.

Paul Anderson: So ECRI's role going forward, I mean, I'm going to sort of assume that we're obviously keeping an eye on these clinical trials, right?

Dr. Marcus Schabacker: Oh, absolutely.

Paul Anderson: We all have professional and personal interest in them, you know. And we'll be making... You know, as these clinical trials work through their processes, you know, sort of fair to say that we'll continue to be as appropriate issuing position papers and other statements to say...

Dr. Marcus Schabacker: Sorry, Paul. Yes, that's exactly what we're doing. So we'll keep a close eye on this. We're going to continue to work with all involved. We're going to continue to scrutinize the public information and we're going to make our voice heard. We have done it in the past and we will continue to do so. As you know, we speak in truth to power, no matter who the power is in. And we have no constituency other than the patient out there, or in this case, the population at large. We have no allegiance to anybody else as a non- for- profit organization. Our mission is to advance evidence based and effective healthcare. And that's what's very much at stake here.

Paul Anderson: Great. Dr. Schabacker, Thank you so much.

Dr. Marcus Schabacker: Thank you, Paul.

Paul Anderson: You can find ECRI's position paper, Fast Tracking COVID- 19 Vaccine Approval. Rushing to the Finish Line May Result In Tripping and Falling, on our website at www. ecri. org. You'll find it as part of our COVID- 19 resource center, which includes free and shareable resources for the healthcare community, including information on our review of imported N95 style masks, which found that some KN95 masks could be putting healthcare workers at risk. Be sure to subscribe to smart healthcare safety on Spotify, iTunes, Google Play, or wherever you get your podcasts to get our latest episodes. We welcome your feedback. Visit us at ecri. org/ podcasts or email us at ecri- podcasts @ ecri. org.