Convalescent Plasma & The Failures of COVID Research (w/Dr. Marty Makary)

[Zubin] Hey everyone, Dr. Z. Welcome to The ZDoggMD Show. Marty Makary, Dr. Marty Makary, is a Professor of Surgery at the Johns Hopkins. We’re gonna call it, what up, Marty, the Johns Hopkins, and author of “Unaccountable” and “The Price We Pay”. You’re all over the news. You’re like the talking head for the COVID, that I actually trust. And we’re just gonna talk about stuff and things. What are we talkin’ about, Marty? Welcome to the show. Welcome back to the show.

[Marty] Good to see a Z, I missed ya. And we have not been reunited in person during COVID-19. It’s, I’ve thought about breaking protocol, just to come out there and see ya.

[Zubin] You know what? I wear a mask made of lace. It’s a placebo mask and I’m, I’m part of a trial where, we think I’m wearing a mask, but it’s really placebo, and then someone else is wearing an N95. So if you wanna be part of that study, that N-of-2, please come on down and see me in the Bay area. There’s not much COVID up here.

[Marty] Well, I wear a mask, and a gaitor, and an N95, and a face shield, and an orthopedic space suit.

[Zubin] Well, if you believe, if you believe the press misrepresentation of the gaitor data, gaitor-date, the gaitor actually negates all the effects of the other masks, and actually makes everything worse. So by just, by putting that one layer of gaitor fabric, you’re pretty much killing grandma. So I just wanted you to know that.

[Marty] I, it’s funny, I’ve been wearing a mask most of my adult life, and then for some reason, all of a sudden, right now, I don’t enjoy wearing a mask in public. It does not make sense.

[Zubin] What? Okay, tell me if this is crazy. I felt the weirdest I’ve ever felt first putting a mask on those months ago, when people were talking about masking up, and I go into Safeway, our local grocery store, whatever, with the mask on, I feel like everyone’s looking at me. I have this deep sense of shame. And I almost feel like it’s worse because we’re doctors. We’re not, we, we would never, it’s like the kind of like, dude that goes and wears his scrubs out in public. Like, yeah, these are OR scrubs, and you know, you’re like, “Oh, are they?” Right, I mean, like from the movie, “Rushmore”, it’s just, it’s, it’s obnoxious. And so I always had this weird sense of shame masking. And now it’s like, culturally, especially in the Bay area, if you don’t wear a mask, you feel like you’re naked. Like, like someone’s gonna call the cops. Do you have that in D.C.?

[Marty] I’ve heard, I’ve heard people can be, accost others who are not wearing a mask on the street, but I think most people are, are reasonable about it now, and most people are wearing masks. And it took a long time for everybody to get religion. I think it took everybody knowing somebody who got really sick or, you know, a loved one or something. Did you see Chris Chen got COVID-19 and he survived, but I think he was in like, in the ICU, and he was sick and had trouble breathing. He wrote about it in “STAT” news.

[Zubin] Chris Chen of “Chen Med”?

[Marty] Yeah, Chris Chen of “Chen Med”, the CEO of “Chen Med”.

[Zubin] I didn’t hear that. Is he, is he older? Like older than 60?

[Marty]44.

[Zubin] What? He was in the, in the, in the hospital?

[Marty]Yeah, this is like really starting to hit home for you and me, right? I mean, 44, total picture of health. I mean the guy, I think he played college football. He’s in great shape, right? The absolute, last person you’d ever think has metabolic syndrome. I don’t think, I mean, he basically said he’s healthy in the article, and a really good article in “STAT” by Chris Chen. I mean talk about, you know, hitting home. I mean, here was a guy who basically said, “I know every beep in the ICU, you know, I’ve worked in the ICU for many years, and all of a sudden, those beeps were for me.” And a really good article, really incredible humility, humility, not just with him, but that entire organization.

[Zubin] I will have to check it out, and you know, “Chen Med” is one of those orgs that’s like, “Iora” like “Turntable”, like, you know, this kind of direct primary care model. And so it kinda hits home, but you’re right, it’s like, you have to know somebody, right? If you’re like, in a town where there’s not a lot of cases, it’s natural human impulse to say, “Well, I’m not, I don’t wanna put a mask on. Why would I do that? That’s crazy talk.” And it takes time for this thing to surge through different communities. You know, what’s going on? Have you been to New York recently or no?

[Marty] Yeah, I went to New York once. It was about 30% of the normal foot traffic, and maybe 20% of the normal street traffic. So it was very strange. Maybe a quarter of the businesses are shuttered up, either went out of business, or just closed for the time being. Restaurants were only seating people outdoors, when I was there, you know, it’s a little sad. I mean, how many people do you know who have basically said, “I’ve moved out of New York, and I’m really never planning to move back.”

[Zubin] Yeah. Yeah, and it happened in San Francisco, too. They’re all moving out to the suburbs, and driving up my real estate costs, which is good, ’cause now’s the time to sell, Marty.

[Marty] Well, the real estate agents say that having a Zoom room is now part of the conversation.

[Zubin] Oh my gosh, oh my gosh. You know, it’s kinda funny. That’s what I have here. This is my Zoom room. It’s like a safe room. Like, you know, there’s a code to get in. You know, it’s separate from the family. It’s a huge asset now, actually. Maybe we should design like, a plug and play Zoom room for doctors to have tele-health visits with their patients, that doesn’t involve like, a cat or a baby showing up and smearing feces.

[Marty] This is my Zoom room, my office, my call room, and my minor procedure room.

[Zubin] Oh man, so how are, as a surgeon, you specialize in pancreas, right? Like how, how are you, do you do a lot of tele-health? I imagine just for followups, or how’s that working for you?

[Marty] Our hospital is doing some tele-health. I think, you know, with, in my particular area of surgical oncology, and what I’m doing now, which is kind of focusing on the pancreas islet transplant, auto transplant procedure, we were kind of, I guess, shut down for a little bit for COVID, and recently sort of started back up. So things are good. You know, the hospital’s quiet, it’s strange. I kinda miss the community, to be honest with you. Like, even the support staff that are working from home. I’m ready for this thing to be over.

[Zubin] Yeah, I think all of us are. You know, I, I did a rant that I haven’t released, basically saying, “I’m really tired of this. I think that there’s a lot of catastrophizing that happens where people think it’s never gonna be over, where they’re extrapolating the current situation to the rest of their lives and they’re losing hope.” And I think that’s simply not true. If you look at past pandemics, you know, you get through it, you get over it. And I actually think that we will attain a vaccine, plus or minus some community immunity, plus or minus there’s innate immunity, plus or minus improvements in treatments, but we have to science the crap out of it, and get through it, and stop, you know, this doom and gloom, like we’re, we’re over it. And I think, you know, we need to open up and do, do it wisely. Use the things we’ve learned. You know, I think these blunt instruments of lockdowns now, so late in the game, don’t don’t make sense, but what do you think?

[Marty] I mean, they closed beaches, I think in, are beaches still closed in California? I mean, you talk about the safest place in the world. It’s gotta be a beach, right? I mean, you know, ventilation, like, you know, you could never design, right? A nice sea breeze. You’ve got an open area. You’re outdoors, UV light pounding on people. I mean, closing beaches made, never made any sense to me. I mean, I guess if people are all, you know, group hugging at a beach. You can’t have too many people close to each other, but I don’t get the closing beaches part.

[Zubin] I don’t get closing beaches. I don’t get compelling people to wear masks on outdoor trail systems, because that’s what they make us do. I’m like, “Really?” Oh, well you might pass close to an old person. We’ll watch what happens. People turn away. They cover their mouth when they’re passing other people. This is like, you know, nanny state gone insane at some point, right? You just go, “Why, why where’s the data for this?”

[Marty] Well, that is, you know, that is not the primary vehicle of spread. Our battle is not giving the, spreading the infection on hiking trails, right? That is, is gotta be, you know, one, one millionth of the number of cases. Actually, they did a study in, in Asia that looked at super spreading events, and out of all super spreading events, I think out of 31, two were outdoors. And so the reality is that this is primarily now, something where the science has caught up, and we have to evolve our strategy to recognize that it’s poor ventilation, primarily driven indoors, in people that are exhaling for some prolonged period of time, and it’s proportional to the amount that you exhale. If you’re singing, you know, karaoke bars in Japan were associated with a very high rate of super spreading, right? It’s a lot of loud, micro-droplet, over a prolonged period of time indoors. So I think we’re learning. The question is, can our, our healthcare system learn as fast as we’re learning from observations?

[Zubin] And that’s the question, right, because we are, again, our knowledge base is expanding. We’re like, okay, this whole idea of stay inside is crazy. Get out, stop discouraging people from going outside by forcing them to wear a mask when they walk on a trail, or not go to a beach. And it’s, and again, this is nobody’s fault, because they just didn’t know, but now we know, so now it is their fault, if they’re still doing this, but getting back to the healthcare system, and this is kinda your specialty. What’s going on? We were totally unprepared for this disaster. I mean, what happened here?

[Marty] Well, I think our healthcare system was not set up for emergencies, and never was set up for a health crisis. And I’m not just talking a virus health crisis. You could argue the same for an earthquake, a mass shooting, fires, any health emergency, okay, and now we’re seeing it with this massive strain from a viral pandemic. Our healthcare system is set up for peace time protocols. All the processes are set up for peace time. The IRB meets once a quarter, or once a month. Why, because in peace time, they’re evaluating studies, you know, at that pace. And then all of a sudden you wanna do a study on COVID and guess what? You can’t do it because you don’t have the IRB waiver, not approval, because it has de-identified information from the data, you don’t have the waiver, and the IRB meets once a month, so you’ve got a wait, okay. Mayo Clinic does a study on convalescent plasma. Okay, it was posted on MEDRX on August 12th, okay. 35,000 patients-

[Zubin] The pre-print server, yeah.

[Marty] Yeah, 35,000-

[Zubin] Yeah, and just for, sorry, just for people who don’t know, just the people who aren’t in medicine, IRB is Institutional Review Board. It’s the committee that kind of determines the ethics, and so on of your, of your study.

[Marty] Yeah, and the IRB really sort of served an important role after the Tuskegee experiment where, horrible things were done to minority communities to, you know, with really no supervision. I mean, terrible experiments that should have never been conducted, and it was a really, it was a horrible thing. So IRB has basically said, “We’re going to protect research from harming people without any, you know, for, for no good reason.” Well, they have massively overstepped that role of protecting, you know, patients and vulnerable populations, to now saying, “Oh, you know, this study doesn’t seem like it would be valuable enough of a contribution to research, or we’d like it, but you’d have to add this part, or you have to include this.” It’s like, “Wait a minute, that’s the role of the journal.”

[Zubin] Right, right, and then, now you were talking about the 35,000 patient, convalescent plasma study.

[Marty] And by the way, I think the IRB today, hinders a lot of great research. I believe that. Now they also serve a protective function, and you do see that, right, but they, they can be a bureaucratic hurdle. Why don’t we have more clinical trials? I was just talking about this with Vinay Prasad. We chatted for “MedPage Today”.

[Zubin] Yeah, and you’re the editor-in-chief, yeah.

[Marty] Yeah, so I did it in my role there. So we, we basically talked about why are not more people in clinical trials, right? In our own field of oncology, why doesn’t everybody with cancer go on some trial, or at least get offered participation in a trial, so we can learn? And the reality is that these trials are clunky, and they’re bureaucratic and they’re hard to set up, and they’re expensive. Why? In part, because of things like, the IRB process. Now that process needs to be there. We need some external review of, of research, but it doesn’t have to be as clunky. I don’t have to fill out a 62 page form to do de-identified data research that has nothing to do with drug safety. And so these are the, these are the problems in healthcare that get magnified, when all of a sudden, we have a health crisis. For example, Mayo Clinic did a giant study on convalescent plasma. You’ve heard about, you know, this big buzz about convalescent plasma lately. 35,000 people, okay, during a health crisis, when, for at least for the first two weeks of that article submission, it was submitted on August 12, 1000 Americans or more were dying a day. The journals, okay, take it with their own rules, and we can only review it in sequence. Only one journal at a time. You can’t submit to two journals. It’s their own rules. It’s their games, right? It’s not with the patient in mind. Okay, then they send it to somebody. Voluntarily, some doctor without pay, will review it on their own time, then send it back, and then some editor will make a decision, okay? Can that be expedited? Can we get input during a health crisis faster than a month? What, what are they doing? When they get this article, showing that convalescent plasma has a real world, clear cut survival benefit, and that benefit is dose dependent. The more antibodies in the convalescent plasma, the Mayo Clinic researchers found, the greater their survival benefit. Okay, clearly convalescent plasma works. When Chris Chen got sick, guess what they gave him? Convalescent plasma. If you or I are in the ICU with COVID, guess what we’re gonna ask for? Convalescent plasma among other things, okay. What the hell are the journals doing, sitting on this manuscript for four weeks? It’s 10 pages. You’re not, you don’t, you’re not going to the hospital to review, interview the subjects. I mean, the journal just reads the 10 page output, okay. Now we’re in a health crisis right now. Review this thing in 24 hours, and turn it around.

[Zubin] Now, was it, is the paper you’re talking about, is that a randomized trial, or is that the retrospective trial looking at dosing of plasma without a placebo group?

[Marty] It was the retrospective review. So it was their experience with 35,000. In total, 70,000 Americans have gotten convalescent plasma, with no statistical significant untoward events, and a clear survival benefit in a lot of these large series. Okay, we use convalescent plasma at Johns Hopkins. We have from early on, and that’s, the reason it works is, it has antibodies in it, right? The same thing vaccines are designed to produce. What are we doing? First of all, what are we doing giving this to 70,000 people without any randomization? Second of all, now that we have 70,000 data points, what are we doing arguing with the FDA, when they give an emergency use authorization, right? You had people flipping out, all right. You had people flipping out, including a piece I saw in “Medscape”, flipping out that, you know, Dr. Hahn approved convalescent plasma for an emergency use authorization. That’s not even an approval. That just means that some, you know, doctors can freely use their discretion to give convalescent plasma to patients sick with COVID-19, without having to be formally enrolled in an IRB trial. Okay, how bad has it gotten, that we cannot use convalescent plasma, because somebody is saying, “You don’t have a placebo trial”, when you have all of this data, okay. There’s no placebo controlled study to prove that parachutes work and there shouldn’t be. Zubin, it would be unethical to give somebody placebo, and deny them convalescent plasma today in the United States. And if we’re so stuck on these rigid protocols, during a health emergency, if we can’t combine a promising and safe small molecule to do a phase one and phase two combined trial, I mean, what are we doing? Just letting people die? And I’m not saying this is what we do in peacetime, but when you have a quarter, and we’re gonna lose a quarter million Americans at this pace, right? When you have this many people who have lost their lives, I mean, I think today it said about 190,000, it’s time to redesign our systems, redesign our study design, redesign our approvals, meet more regularly as an IRB, provide expedited review. The, the FDA will now get back to you in seven days, if you submit a drug, if it’s for COVID, okay. What would the world look like if they did that routinely, right? If they did that for cancer drugs? So there’s a lot of lessons here, but one of them is we’ve gotta move faster. The dexamethasone study, okay, from the UK, that trial showed about a 33% reduction in mortality. I mean, you talk about maybe the largest reduction in mortality that we’ve seen has probably come from steroids. Why are we learning about that in June, okay? The pandemic hit us in March. Why does it take us all of this time, and the clunky processes and the reviews? Meanwhile, in the UK, they looked at dexamethasone in a randomized controlled trial, that they designed early and we got, and they got the results, and the world benefited from it. We were invited, the United States was invited to participate in that recovery trial, and the U.S. declined. Why? Because we didn’t think the study design was as elaborate as was necessary. You can pick apart any study, okay, and we did this. I remember Harvard School of Public Health, in our Epi class. They gave you seven articles. Everyone got seven different articles, and you had to rip those articles apart, and they were in all the top journals. And you know what? You can do it. You can rip any article apart. The question is, is there beyond a reasonable judgment of some degree of rationality, is, does there appear to be greater benefits than there are risks? And that is the real question that we need to be asking in a health crisis, in an emergency. This is an emergency.

[Zubin] And I think, you know, and, this idea of distinguishing between emergency times and peace times is very important. Now, so playing devil’s advocate, because I agree with you on a lot of this, it’s like, our science is slow at the best of times. In war time, it ought to be really fast, and you should be able to enroll patients. So IRB ought to be modulated. Peer review ought to be modulated, but what probably shouldn’t be modulated is what you said, people then looking at the data and going, “Okay, is there a reasonable doubt that this thing makes sense? Is there harm that can potentially happen?” With convalescent plasma, there wasn’t seen a lot in this data set of, you know, 35,000 plus, odd 70,000 patients, but, and then the question of randomized controlled trials taking away bias is important. And you brought up one thing which was, and there’s a couple of things I want to follow up on. One thing is, why wasn’t that just done as a randomized trial in the beginning? Like why, there’s probably a higher bar to it, or just answer that for me? Like, why, why didn’t they just randomize that in the beginning? Is it just because they didn’t think of it until after we started giving convalescent plasma, or what was going on, do you think, knowing that you’re not involved?

[Marty] Well, I’ll, I’ll tell you what Vinay Prasad and I concluded in our conversation is that, there’s a, there are a tremendous amount of barriers in the way of doctors studying things in a way that they want to study them. There are a huge number of bureaucratic steps. There’s expense with limited funding, right? We have historically been funding drugs that give marginal benefits for things like, cancer survival, and lifestyle drugs. Our system is basically set up for that. Is it set up to study anticoagulation in the ICU during COVID-19? No, no, what drug company is gonna sponsor if anticoagulation in an ICU is going, where’s that money gonna come from? The NIH division of anticoagulation? No. Where’s the funding for food, right, for understanding foods that are, you know, food that is pro-inflammatory and anti-inflammatory? Where’s the funding for studying environmental exposures that cause cancer? Zero, right, except the one giant study that came out of the movie, “Dark Waters”, which showed that yes, in the one of the 100 plus forever molecules, inert synthetic molecules live in the human body of every American, this one molecule studied, causes cancer, all sorts of different types of cancers, and neurological problems. That was one study of one of the 100 plus inert molecules from environmental exposures. Why did we study that one? Because there was a giant lawsuit, all explained in the movie, “The Devil We Know”, in the Hollywood version with Mark Ruffalo, “Dark Waters”. The largest public health study ever done was conducted as a result of a lawsuit with DuPont. They studied one of these forever molecules, and found a strong association with many different kinds of cancers, I’m sure, including the cancer I operate on, and neurological problems and all other things. So we wonder, “Oh, why is there more autism? Why is there more, you know, Alzheimer’s?” Could it possibly be that there are all sorts of environmental exposures that no one has ever studied, because we don’t fund those studies? We fund a reactionary approach. We fund drugs that we can throw at people, not what causes some of these underlying problems.

[Zubin] That’s a fundamental to how we treat disease, too. We don’t prevent it. We don’t focus on those things. We focus on the Band-Aids after the fact. One interesting thing, though, that I’ve realized the more older I get with studies is, you can have associations and correlations, but then when you really try to unwind them with a, you know, a randomized trial, you find that no, they were actually correlates, not causation. So maybe you’re seeing this stuff in the blood, but these, the people who would have that in the blood, live next to a radiation source, or a chemical factory or something, or there’s other things. How do you think about that? How do you tease that out?

[Marty] That’s why I think the, the result that an association is dose dependent says a lot, okay. And granted, we can never prove with 100% certainty that anything is true in science, okay, but you have a lot of data points, and you start putting them together, and it is enough to inform our decisions. About 60% of all decisions we make in medicine are purely discretionary, with no science or evidence to support doing one thing or the other. That is in the words of the editor-in-chief, of JAMA, Howard Bauchner, okay.

[Zubin] Yeah, I believe that.

[Marty] The reality is, if we, if we are making a lot of discretionary decisions, can we learn from things besides randomized trials? I’m not saying we don’t do the randomized trials. Actually, I’m saying we should do, and do more of them, but can we learn from other things? Can we learn from that one patient, who has an incurable cancer, and is still alive at 20 years? Okay, can we learn from the patient who has, I heard recently of a case on Peter Attia’s podcast, of a woman who has MS, okay. She believes that she has been able, and she’s a physician, she has been able to manage it much better than other people with MS, by changing the food that she eats, and she has a whole logic and rationale to it. I don’t know if she has, you know, beat MS or is doing much better with MS, but I do believe we can learn from her, okay. And we can learn from individuals as much as we can learn from groups sometimes. You know, there’s a case at Johns Hopkins of a guy with a glioblastoma multiforme. Years ago, I mean, this is, this has been presented over and over again, at local and national conferences, but the patient’s a longterm survival of this really incurable cancer type. What happened? Well, decades ago, it turns, turns out if you go back and look at what happened, there was an infection of the surgical resection bed, okay. Something happened there. I don’t know if it triggered an immune response. I don’t know if the infection chewed away at the tentacles of the cancer in the surgical resection bed. I don’t know, but we can learn from that case, and we don’t only learn from randomized controlled trials. We can learn from direct observations, from case series, from the wisdom of practicing doctors in the front lines of medicine, from before and after study designs, from controlled historical controls, from improvements over time, from dose dependent relationships in the absence of placebo. So we can learn from these other types of study designs. And by the way, people who think randomized controlled trials are the only gold standard, if I hear that one more time, I’m gonna vomit. Vinay Prasad has published that like, roughly half of those randomized controlled trials published in these journals get overturned when they get repeated, or subsequent research comes out.

[Zubin] So there’s bias in the design of the trial?

[Marty] These are what are called medical reversal, right?

[Zubin] Right. Medical reversal. Vinay has been on my show and he’s coming back on this week actually, because he’s local here, and I really like what he says. You know, one interesting thing, because we started this thing, we ought to have more therapeutics, and so on that have been studied. His whole thing is the bar for, say, cancer therapeutics ought to be even higher than it is because we have, we let so much garbage through and it actually causes harm. And what are your thoughts on that in terms of this research milieu?

[Marty] Why are we funding tiny, incremental improvements in science? Why aren’t we funding the big ideas? Why aren’t we funding novel things, right? I mean, you talk to, you talk to researchers in the field of say, Alzheimer’s, they’re gonna give you massive alternative hypothesis of what’s happening with Alzheimer’s. Now are those getting the NIH grants? No. We find incremental benefits, so we can get our little abstracts presented at our meeting, and stand by the poster, and explain to the four people that walk by, that this is what we think is happening, and then you add it to your resume. And then when you go to get a job, or a residency, or promotion, they say, “Oh, it looks like you presented four times at a national”, what kind of game is this, right? If we actually funded things that matter to patients, we would fund the things that they actually are interested in. Like, when I tell somebody, “It looks like you have a pancreatic cancer.” Do you know what one of the most common questions I get is, right off the bat?

[Zubin] “Is it something I ate? Is it something I drank? Is it something I did?”

[Marty] Yeah, what, “Is it something I, what caused it?” I mean, that’s, what’s on their mind, right? And am I gonna go into the fact that, you know, my dad practiced in the coal mine region of Northeastern central Pennsylvania, and as a hematologist, he saw this incredible breadth of leukemia and lymphoma, that he was certain was associated with the coal mine region, but he could never get funding to, you know, I mean, he, he could, I mean, I’m not saying it’s impossible, he certainly could, but it’s, it’s uphill. If he tries to get funding because there’s a clinical trial of a new chemotherapy and is, you know, for a cancer, that’s a million times easier to get, than studying some of these underlying drivers of human illness.

[Zubin] Mm-mm it’s tough, dude. And you know, it’s, it’s weird. Rarely in an interview, do I just sit back and listen. You’re passionate about this. You’ve been doing research all your life. You know what’s wrong, what works, what doesn’t work, and during this time, when it’s so urgent, I have a question which is, and then again, just back to the, my question is how do we fix this? Right, but, but before I forget, one of the criticisms that Stephen Hahn got was that he’s just misrepresenting the magnitude of that data. So looking at the retrospective data, saying, it’s a 35% improvement on the, so what was your take on all that, ’cause-

[Marty] Yeah, I mean, he was excited. He was excited, you know, and there might’ve been other, you know, reasons to be excited. Like, you know, it would look good to have some good news. I don’t know, but there was a survival benefit in that study, which, you know, I think one of the few people that actually read it, because it was a pre-publication release. The survive, the mortality went from about 11% to 8%. Now, if you were to ask me, “What was the finding?” I wouldn’t describe that to you as a 35% reduction in mortality, right. When a patient comes and talks to me and says, “You know, what, if I have it done laparoscopically?” I don’t say “There’s an 87% reduction in surgical site infections.” I don’t say that. I say, “You know, if you have it done open, the surgical site infection rate is about 10%. If we do it laparoscopically, it’s about 1%.” Right, so-

[Zubin] Absolute difference, yeah.

[Marty] And let’s be honest, we’re in an election season. He works for President Trump. There’s a lot of haters out there, but to anyone who thinks we should not have, the FDA should not have given an emergency use authorization to the community doctor in rural Georgia, who wants to give convalescent plasma to his patient, but can’t, because it does not have an FDA EUA, then, you know, to, to them, I would say, “That authorization should have come a long time ago, probably should have come after we had 10,000 patients who took convalescent plasma, and the safety had been established.” We have a century of experience with convalescent plasma. The mechanism works. It’s plausible. It’s scientifically sound. It worked for Ebola. It appears to have early, you know, survival benefit in that early population that got convalescent plasma. Now fast forward, and we’ve got 70,000 people, and a Mayo Clinic report with a clear cut survival benefit. And somebody’s gonna say, “No, we can’t let doctors use this because there’s no placebo.” I mean, it would be unethical to give somebody placebo today, now, with all of that data.

[Zubin] Let me ask a question. Well, so, and then that’s one of the, that’s one of the criticisms of EUAs is well, okay, and once you give an emergency use authorization, then it becomes unethical to give a placebo, and now you can’t do the randomized controlled trial.

[Marty] Good.

[Zubin] What do you say about that?

[Marty] Yeah, good. I mean no one should be getting placebo. I mean, you’re gonna tell somebody, “Oh yeah, we’re concerned about you not surviving from this COVID-19, you know, ARDS.” We’re gonna enroll you in a study where you may not get convalescent plasma, and then you’ll be on it. Maybe you’re honest enough to tell them, “If you don’t enroll in this study, we can just give it to you.”

[Zubin] Just give it to you, yeah. So what’s gonna happen, yeah.

[Marty] Yeah, so, I mean, yeah, if you can look at 70,000 patients and this dose dependent survival benefit, and tell me that, that’s not convincing enough to give it, even though it’s safe, it’s a safe drug, and we have to subject people to a placebo? Then I would say, “They’re walking a fine line with the, with, you know, with playing with the ethics of trials, because I do not believe there is the equipoise to justify administrating placebos, that is, for this drug at this time.”

[Zubin] So, so let’s back into something that’s been politically charged around that, that also has this kind of valence to it, hydroxychloroquine. What are your thoughts around that, and how that’s been managed?

[Marty] I was, you know, I was hoping, as I think a lot of doctors were, that there would be a survival benefit, but the studies have shown that there really is not a survival benefit. There have been a number of studies done, and one or two have suggested or shown a survival benefit, but they had worse study design than the ones that showed no benefit. And so we gotta be scientific, right? We’ve gotta let the data speak for itself, and let the better studies interpret the poorer studies.

[Zubin] Let, let me, so that’s why I asked that question, because what you just did, was you showed that you’re a scientist, and not a politically charged activist. And the reason I say that is, the way you were passionate about blood, convalescent plasma, what you’ll see in the comments, and because we’re in a crazy election season, what you’ll see is people saying, “Well, you know, yeah, well, he goes on the news and he, you know, you know, maybe he’s a conservative, and this and this and that. And of course, he’s gonna want blood plasma, because it’s going to get Trump reelected, right?” So then you ask, “Well, so what about hydrochloric, hydroxychloroquine?” And you say, “Well, I looked at that data. I wanted it to work. It doesn’t, so far as we can tell, the study design was poor in the things that showed.” And that’s my interpretation of it as well. I have not looked at the primary blood convalescent plasma data, so the fact that two, two science minded people agree, means that you can take the political valence, and shove it up your butt, because it’s not, it’s not gonna color our ultimate decision. That’s very powerful, especially for an audience that doesn’t know what to believe anymore. They don’t know who’s telling them truth, who’s politically motivated. I mean, what are your thoughts around this?

[Marty] Well, first of all, I don’t know why everybody feels like they have to pick a side on everything.

[Zubin] It’s a tribal badge, yeah. It’s like a tribal badge.

[Marty] It is, and, and honestly, you know, there are legitimate things to criticize the President for, but if he says something that is correct, or that you believe in, you don’t have to criticize it, just because it’s coming from him. And I believe that with everybody, right? When somebody on rounds, who says dumb things a lot, says something that actually should be considered with a patient, if you’ve got the open mind to consider things, right, and that’s what we try to create with the surgical checklist, is a culture where people feel comfortable speaking up. And everybody in leadership, as the captain of the ship, we, as physicians, have an open mind to take those considerations in the best interest of the patient. Not, “Oh, this is a person I’ve gotta retaliate against, because they said something that was not useful last time.” How does anyone read the Mayo Clinic study on 35,000 patients, and in their heart, tell a patient that I’m not gonna give you convalescent plasma, and instead, puts you on a study where you could get placebo. Yes, we have this allegiance where we worship some higher, you know, scientific advancement concept. And I believe in science, but do they really, if that was their own mother or father, are they gonna put them on placebo? I mean, yes, early on, yes. The first 100 patients who got convalescent plasma, 1000 patients, 10,000 should have been randomized, until that trial closed. We didn’t get that, okay? For whatever reason, maybe their IRB met once every five years and they didn’t get approval. Maybe there was no funding. I don’t know, okay. Maybe there weren’t, who knows, but now that we have the data, have an open mind, look at it, and interpret that data, and make a reasonable decision. And I think that’s what distinguishes a scientist from a hack, which is what you see on this thing all the time, right?

[Zubin] Yeah.

[Marty] The echo chambers of, of social media.

[Zubin] I have nothing to add to that. That is absolutely the conversation we need to be having. We need to revolutionize how we do the science. We need to streamline it during wartime and peacetime. We need to focus on the high, high value outcomes, which means not this marginal, oh, we, you know what, the number needed to treat, to see a benefit with my new statin is 3,046, and you’ll save one nonfatal heart attack, so that’ll get us approved by FDA. This is insane, and yet, that’s how we’re monetized. That’s how we do it, and like you said, that’s how I get the thing on my resume. I can then go present this thing, and it’s safe, instead of asking the real big, hard question, which every researcher in their heart has those questions, they just know they’ll never get funded in a way, that’s streamlined in a way to actually test this. And the, and the risks of actually having that concept fail and show nothing are so high. And the negative study bias, meaning the, those don’t get published as much as positive outcomes, or positive studies. It becomes a science crisis. Combine that with reproducibility problems, like you said, with even randomized controlled trials, and you have the urgent need to transform our scientific endeavor. Not throw it under the bus, not become anti-scientific, not go to crystals and witchcraft and woo, but just fix what we know can work. I mean, right? That’s what it feels like.

[Marty] And it’s, you know, it’s not just in research, by the way. How about hospitals having capacity resilience, right? Where’s that expandability? Where’s that adaptation to be able to, to respond to a health crisis, right. When there’s a hurricane blowing through Houston, right. Do they have enough vent? Do they have extra ventilator capacity or are they running things so tight that you just cannot possibly do, anything will throw off the system, right?

[Zubin] We saw it in Katrina, you know, we see it in the pandemic. They are running so close to, because that’s how you make money. How can you, you know, you’re gonna hire all these staff and keep them on standby? How are they gonna pay for that? So how, what, what are, what’s our, I mean, when medicine is a business like that, then it has to be run like that. And then something happens and you’re like, “Well, there’s gonna be a delay of five months before we can spin up enough PPE and enough staff to manage it.”

[Marty] It reminds me of the TSA, when I go through the airport. You know, it’s like you, somebody in front of me forgets to take their belt off and they walk through the thing, and they scold that individual. Then they come back into the line angry, and scold every person in line, telling them, “You have to take your belts off, right, and take your laptop off”, ’cause somebody just forgot to take their laptop out. And it’s like, what is this reactionary approach? This is illogical, it’s non-scientific, and that’s exactly what we do in healthcare, right? We scramble, we don’t have adaptive systems set up early. And then when things happen and they go bad, we think, “Oh, this shouldn’t have happened.” Why are we shopping for drugs and PPE in China? Like, can we fix that, or is that something that’s just gonna keep going, right? There’s a lot of these issues. And I think the new term now that we’re hearing a lot, is resilience, healthcare resilience, hospital resilience. And hopefully there’s some important lessons here that we’re gonna learn and act on.

[Zubin] I think you nailed it, and as I run out a disk card space, ’cause I’ve got two shows and forgot to delete one of them, we’ll have to wrap it up, but one, I wanna, this has been fun, dude, and like, we had no, we had no agenda going into this, it was, let’s just talk about what we wanna talk about, and I thought you brought up things that people need to hear, man. And, and here’s the thing, I think the term is, it’s Nassim Taleb’s term, which is anti-fragility, anti-fragile. So you used the word, resilience. Resilience means, a system resists change. So in other words, you come punching at it with a problem and it’s like, “No problem. I’m resilient”, right, but anti-fragility, as opposed to fragile, where you come at it and it crumbles, which is what our system actually did, in the face of the pandemic. Anti-fragility is where a system is designed in a way that when a challenge comes, it actually adapts quickly like an organism, evolves, and gets stronger than it ever was, in a way that it can adapt to challenges in an exponentially better way. And that’s what little kids do when they are, when they have certain levels of stress, certain challenge, which we’ve now been protecting them from, by helicoptering them around, and they get stronger, and more adaptable, more able to conflict resolve. That’s what kids do. That’s what organisms do. Why can’t our healthcare system and our institutions do that? Be more anti-fragile. Our financial system was fragile. It fell apart in 2009. You need an anti-fragile system. That’s where Taleb got his thing from. So that’s what we’re hoping for, and at least these conversations may at least set us the problem, so that we can start working on solving it, yeah?

[Marty] I love it.

[Zubin] Dude, Marty Makary, man, that was fun. When are you gonna interview me for “MedPage”? I want some serious street cred, dude.

[Marty] You will be the next guest on “MedPage”. You let me know when and we’ll do a nice interview.

[Zubin] I love it. I’ll throw most of the nudity and all of the cursing in it, ’cause I know that’s your audience there.

[Marty] If you could do 20% less cursing, I think it’ll meet the bar.

[Zubin] That’s, you know what? That’s a statistically significantly less amount of cursing-

[Marty] Actually, you’ve had to do, what am I saying? There’s been zero, you’ve done zero, not . And I’ve heard that you stopped cursing in the last 50 or so episodes. I haven’t watched them. I’m not caught up yet, but that’s what I heard.

[Zubin] I’ve made it, I’ve made cursing a special thing I do only for my subscribing supporters who pay 4.99 a month to see me talk every night. And for those guys, it’s like F this, F that, S this S that. I had this effin’ conversation with effin’ Marty Makary, and we effin’ did this, and they’re paying for that HBO level of quality, but the rest of the world, I just want them to share it with their mom. And so, even though, you know their mom curses like a sailor at home, they don’t know that, so they won’t share unless I stop cursing. So I keep it clean for the masses.

[Marty] Well, I know we’ve got some moms that read “MedPage”, so I’ll find out what our policy is.

[Zubin] Well, speaking of moms, my Mom sees you on the news all the time and told me, I think I might’ve mentioned this to you before. “Oh, Dr. Makary, he’s been on your show a couple of times. He seems like he knows what he’s talking about.” And I’m like, “Looks can be deceiving, Mom. Let’s have him on my show.” All right, Marty Makary, thanks for being back on the show. Z[Marty]Pac, share this thing. This is an important discussion. Leave a comment. Are you a researcher? Do you work on an, are you on an institutional review board? Do you have, do you have strong feelings about, you know, the data on convalescent plasma? If you’ve read it, if you’ve read the piece, let us know what you think. Share the video, become a supporter, if you love democracy. I just have to say that Marty, because you know, it just feels right, and we out. Peace.