We analyze the evidence so far on ivermectin for COVID-19 and Aduhelm (aducanumab) for Alzheimer’s Disease.

Dr. Vinay Prasad is a UCSF heme/onc doc who specializes in clinical trials and medical decision-making. He is a regular on the show, check out all our episodes here.
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– [Zubin] Vinay Prasad, Dr. Vinay Prasad back, drinking his coffee. We’re gonna talk about ivermectin, censorship, adoliminimimab?!? Well, how do you pronounce it?

– [Vinay] Aducanumab I think.

– [Vinay] Oh, heck yeah. The Alzheimer’s drug, let’s get into it, man.

– [Vinay] If you forget how to pronounce it, you gotta take it.

– [Zubin] Uh yeah, hey, if it works.

– [Vinay] Yeah, if it works.

– [Zubin] If it doesn’t bankrupt Medicare in the United States, we’ll get into that. So look, man, last time we met, we kind of casually discussed this ivermectin.

– [Vinay] Just off the cuff. It wasn’t part of our scripted remarks.

– [Zubin] And it turns out almost everything that we said, we stand by, having then dug deeper. Let’s dig into this because it’s become a big deal. Pierre Kory, Bret Weinstein, they’ve gone on like Rogan’s show saying, this is an emergency, ivermectin could save the world, it’s a miracle drug, speaking in a lot of hyperbole. You’ve looked now at the data and so have I in more depth, what’s your take on this, man?

– [Vinay] I’ve read it, I’ve read it in depth in detail.

– Oh dear.

– And so now I’m ready to explain.

– Yes.

– [Vinay] Let me start by giving people some background, I think. I think one of the reasons why this captivates people so much is that throughout this whole pandemic, we’ve always been looking for sort of a solution. We’ve looked for therapies that will lower the risk of dying for somebody who has the disease, prevent you from getting the disease, and we’ve had one therapy that’s really, you know, hits the ball out of the park. And that’s the vaccines,. With a 95% relative risk reduction for symptomatic disease.

– [Zubin] In gold standard trials of randomized controlled trials, well designed.

– [Vinay] Multiple randomized controlled trials, well-designed, and not only do you improve the endpoint of any symptomatic COVID, but you also reduced severe COVID, hospitalizations, and death, all in randomization. So, everything falls in line, can’t do better than that. That’s really the home run.

– Right.

– [Vinay] But there’s also always an interest in drugs and pills and therapies. And we’ve seen this with hydroxychloroquine, Tocilizumab, dexamethasone, and now ivermectin, I think has fallen to favor. And I went back and I looked through all the meta analytic evidence, the paper by Pierre Kory, papers by other people, and got a sense of what the literature shows. And before I tell you that, let me give you one more piece of background, which is sort of what explains my offhanded attitude towards this, which is when you start talking about a pill for any condition, particularly an infectious disease, I don’t think like people who are watching this, who are not in medicine or not in drug development, really understand pre-test probability. So, what do I mean by that? Every year tens of thousands, or hundreds of thousands of candidate compounds for diseases gets explored by drug companies. We’re talking about tens of thousands of cancer drug compounds, hundreds of drug compounds for Alzheimer’s, or pre-Alzheimer states, many compounds for cardiovascular disease and diabetes. These get explored by drug companies. For every single one of these compounds that meets a certain threshold of exploring, there is some preclinical data that suggests it might help, you have some cell culture study, some mouse study that says this cancer drug might fight pancreas cancer or colon cancer. So, I think those of us who follow drug development closely, we know that all the time you’re hearing about quote unquote promising things. And I did a paper a couple of years ago with Ryan Waters where we looked at academic papers that labeled something a highly promising strategy and we followed them out 25 years into the future. And we found that 5% of those things had actually translated into clinical practice, or some low percentage.

– Really small.

– [Vinay] So my point, yes. And then that’s the first point, which is that even when people do robust, basic science, have good mechanistic science, the odds are against you that you found something that actually helps people.

– [Zubin] And that’s what you mean by pre-test probability. So, the likelihood going into this thing that any therapeutic is going to work is very low.

– [Vinay] And I think that’s something that people don’t appreciate and you have to know about drug development before you even think about any drugs and it doesn’t have to do with ivermectin. Doesn’t have to do the hydroxychloroquine. It just has to do with everything. It’s that things often sound plausible. They often have a good mechanism of action. They often have some molecular story you can tell yourself, this is especially true for repurposed products, which are products that are approved for one purpose and then applied to something else. There’s no shortage of stories in cancer medicine about how Metformin or statins or aspirin, or this, that, or the other will improve cancer outcomes. So that’s one piece of data. The next thing, observational data, a big class of the data that they were offering in support of the claim is countries that did ivermectin versus countries that didn’t do ivermectin, hospitals that did ivermectin versus places that didn’t, patients who got ivermectin versus those who didn’t. These are classical observational studies. In other words, we let doctors do whatever they wanna do. Patients get whatever they want. And then later we go back and see what happened to people who got certain things. This type of study design for drug efficacy is very problematic. There are lots of differences between places that do something and places that don’t do something. And there a lot of differences between people you do it in and people you don’t do it in and you can’t always adjust for those things after the fact or post-hoc. So, I think that’s one of the challenges with that whole observational data set. And in fact, many of the people who are staunch proponents of ivermectin, the same study, if it was brought to show them that masks “work,” or masks don’t work, they would rightly be dismissive of those studies as confounded by other variables.

– [Zubin] Yeah, yeah. There’s almost an emotional attachment to this thing working. I don’t think it’s almost, I think it’s an actual emotional attachment.

– [Vinay] It has become quite passionate.

– [Zubin] It’s become that way. And it’s compounded by the fact, which we’ll talk about that YouTube and these, the big tech oligopolies have taken it on themselves to censor this content which now really, really, really further tribalizes and emotionalizes something that should have just been a scientific discussion. So, we’ve talked about pre-test probability of therapeutics being low. We’ve talked about observational studies being not great. And again, really looking at confounders. Like, I mean, there’s so many differences in populations that have decided to use ivermectin and haven’t, and other things like that, that it’s impossible to make a real cogent statement.

– [Vinay] And there’s also another type of fallacy called ecological fallacy , where you look at a group of people and there could actually be an inverse relationship, but it get masked by the group you look at, there are lots of complicated reasons why observational studies are unreliable, but to prove that they’re unreliable, let’s just say that that’s just not the standard of drug development. If I was making a new compound XYZ456 and I was offering it as a cure for COVID-19, no one would allow me to deploy it in a hospital and then do an observational study. You’d make me do a randomized or a controlled clinical trial.

– [Zubin] Right, right, and the argument that this is a really safe drug, which by the way, there’s no therapeutic that we have, including vaccines, that don’t have potential downside, right?

– [Vinay] Yeah, I mean, I guess that’s something people said, which is we can talk about which is like while you’re uncertain, isn’t it better to give it a shot? I think that’s something worth talking about. It’s broader than ivermectin. This is something that has existed throughout the literature, but hydroxychloroquine very recently was a drug that people felt like, well, we know what the safety margins are. We’ve been giving it to people with rheumatoid arthritis for a long time. We understand it. We know it’s relatively safe and it is relatively safe. But the question is always, does it have a net benefit or a net decrement? And now in pooled meta analysis by Catherine Axfours, who’s a postdoc at Stanford, there appears to be a pooled decrement for hydroxychloroquine. In other words, people died. They estimate something like possibly up to 100,000 people globally because of administration of hydroxychloroquine. So, my point is just even a drug with a really wonderful safety profile or window, you need to do the controlled studies because you really don’t know if it has a net benefit or a net decrement, and you need to exclude those facts. So, it’s not a reasonable strategy just to quote, give something a try if it’s promising. If you did that, 95 out of 100 times, or even more, you will fail and some of those times you’ll actually hurt people. And maybe the net effect will be decremental.

– [Zubin] Which, by the way, I think this conversation will come back when we talk about children and mRNA vaccines, myocarditis, et cetera. Talk about the same thing.

– And aducanumab.

– [Zubin] Yes, which we will talk about at the end of this segment. So, all right, so now we have observational studies. We have the pre-test probability, but I’ll throw in one other piece of this, which is biological plausibility. So, initially they said, you know, in test tubes and in vitro, this thing inhibits viral replication or whatever. At doses, which are hyper, hyper, hyper, what’s given to be safe in humans, right? So, in the actual doses that are given in humans, that virological effect is not even really seen in vitro. So, now they’re positing, well, maybe there’s an anti-inflammatory effect. Maybe there’s an immune modulating effect. So, there are a lot of drugs we give that we have no idea how they work, but the original biological plausibility is now not even really there, the thing that even prompted them to go down this rabbit hole.

– Fascinating. And biological plausibility is cheap. And it’s cheap for a few reasons. One, you’re making the point that it may even be incorrect here. They don’t even have it, but it’s also cheap in the sense that you can generate it for anything in any circumstance, I would contend. For instance, let’s say you had some cancer, you wanted a drug and you just took that cancer and he grew it in a thousand Petri dishes. You can squirt this compound on it and you can do intracellular assays and you will find something that sounds a little bit promising. And if you are allowed after the fact to kind of pick and choose which experiment you put forward, which scientists are, they can craft stories. And in fact, the simplest proof that this is cheap is that the pharmaceutical industry, their goal for better or worse, they want to get a drug that works to make money. I mean, that is their goal. And they have not really been able to leverage the fact that like which preclinical test tube studies guarantee that things work. If they were good at it, they’d be succeeding even more than they are.

– [Zubin] Right, right, exactly right. And it’s funny because you’re using the big pharma argument here on a case that’s been argued that, oh, it’s big pharma controlling the dialogue.

– We talk about that.

– We’ll talk about that, for sure, yeah.

– So I mean, I think, the big tech and the big pharma controlling the dialogue, I think are points that need to be dismissed quickly. I mean, the one thing I’d say about the big pharma thing is people say like, “Oh, look, we can’t do these studies for ivermectin because it’s a cheap generic drug and no one will make a lot of money from it working.”

– Correct.

– Well, that’s what dexamethasone was.

– That’s what I said, yeah. Dexamethasone, explain that. And they haven’t, they can, they’re like, well, but that jubba jub, you know. It’s really not an argument that holds weight. It’s also the other thing is that all these big tech oligopolies and other things are able to pressure journals and stuff into not publishing this data, or not allowing funding for randomized control trials, or not peer reviewing, or whatever, that implies a conspiracy that implies a high level of competence in these organizations to do this.

– [Vinay] Which they don’t have.

– [Zubin] Both of you and I know they don’t have that competence.

– [Vinay] Well, I will say one thing, the big tech fucked up by censoring their videos and I think that’s a huge mistake and I’m gonna point out some ironies in a second when we talk about this Alzheimer’s drug, but they shouldn’t have censored their video because you know what? People have the right to go and make videos and say what they believe to be true. And this is a game where the goal is to actually like change people’s minds by using good arguments. So, I think big tech was wrong and big tech is also hypocritical, which I’ll tell you in a minute, but let’s talk about the best data that they have. And that is a couple of meta-analytic studies of randomized controlled trials that have been done. Randomized control trials are great. They help solve three problems in figuring out if something causes something. So, one is the confounding problem, which is that if you don’t randomly assign people the therapy, there might be differences in those who got it versus those who don’t. Randomization minimizes I think differences due to confounding and equilibrates outcomes distributions in the absence of an effective therapy. So, that’s one of the virtues of randomization. They sort of balance or minimize. They don’t perfectly balance. They just reduce differences in measured and unmeasured things. The next thing they do is it marks a time zero. This is also a tricky thing, but it marks in stone, when something starts is the moment of randomization, we mark it down, that’s the moment. And the reason that matters is that one of the challenges in observational studies is if you go backwards and look at somebody who got some therapy, one of the things about people who got a therapy in the past, versus those who didn’t get, was people who got a therapy, they lived long enough to get it. What do I mean by that? Imagine some drug that they only give on the fifth day you’re in the hospital. A lot of doctors after five days in the hospital, they try some new drug, right? In order to get that drug, you have to live for five days. So, the people in the group that quote didn’t get the drug, some of those people include people who died in two hours or five hours. They could never get the drug. And so, this is something called, immortal time or guarantee time. It’s just a classic problem. Randomization puts that down. And the third thing randomization does is it limits multiple hypothesis testing. It limits multiplicity. The number of times you can explore a phenomenon and retrospective observational studies. There’s no limit. It’s just as much as people can churn out data.

– [Zubin] So, you define your end points upfront, you randomize, and that reduces the confounders, and the timing bias, and the multiplicity bias.

– [Vinay] Yes and the multiplicity bias is a big bias because if you do 100 randomized control trials and you accept a nominally significant P value of 0.05, on average five of those trials will be positive by the pre-defined conditions.

– Exactly.

– [Vinay] You specified that. So I think, okay, so this is why randomization is good. So, they have a bunch of randomized trials. Good for them. The challenges with the randomized trials they do have are they’re not always preregistered. They’re not always published in places that are peer reviewed. They have very low sample size. There are some questions about their protocol and things like that. And they met all the things that I speculated they would have done when we first talked about this, that they were generally poor quality, not the kind of randomized control trials you can hang your hat on.

– [Zubin] And actually included in the meta analysis where these were the big weighted trials that provide a lot of the oomph in these meta analyses and they were assigned according to one analysis, these levels of confidence like how high quality is the data? Now that’s a little subjective.

– [Vinay] Correct.

– [Zubin] And so, a few of them were assigned very high quality levels of data when in fact, you look, there’s bias. The lack of pre-registering is interesting. Why is that important? What does that mean?

– [Vinay] Oh, well, I mean, I guess I would say it’s a huge challenge in the space of randomized controlled trials, which is that you want a registry of all, I mean, what’s the goal of like, what do we want? We want to know of all the studies that were ever conducted, what were the things you measured? And let’s look at all of that data. And the fact is that historically, they’ve been people who run clinical studies and they don’t register those studies. In other words, they don’t log that they’re doing them. And then if they don’t go the way they want,

– They just disappear.

– they disappear. I mean, they don’t intentionally disappear them. They just don’t have an incentive to push them forward and publish them. If they go a way you want, they appear. The problem with that is then what appears is a distortion of what actually occurred?

– [Zubin] Yes, it’s a publication bias, which has been, that’s the accusation leveled by the Infectious Disease Society of America against the ivermectin guys, is that there appears to be publication bias. These trials haven’t been pre-registered, every single one is possible.

– Not all of them.

– [Zubin] Not all of them.

– [Vinay] But some good ones are coming. And I think that’s a valuable point is that, I mean, if you were to look at the totality of the currently done randomized control trials, and let’s just not say it’s ivermectin, let’s just say it’s some new cancer drug. I would put two thumbs down and so would the FDA because it’s not the caliber of evidence that can move you from that pre-test probability of very low odds in your favor to something that’s actually plausible that it works, just because they’re small, they’re fragmented. There’s some issues around the primary end point. The primary end point has to be the thing you most care about and not something else. Otherwise you run the same problem of selectively reporting, subsequent end points or secondary end points if they happen to fit your narrative, but not reporting them if they don’t.

– [Zubin] Moving the goalposts more or less. Yeah, after the fact, right. And you know, what’s interesting about this. So, the meta analyses that were done, they have been held up as, oh well, meta analysis is even better than randomized control trial because it’s a collection of different randomized controlled trials and you look at it. But the thing is, if the stuff that makes up that data, if it’s garbage, then you get garbage out.

– [Vinay] GIGO and I say it’s like a juicer. It only tastes as good as what you put in. And right now we’re putting some rotten fruit in that juicer. It’s just a shitty juice.

– [Zubin] It’s a shitty juice. And and of the interesting things that came out of our first discussion on this, where we just kind of casually talked ’cause I brought it up because I had just watched-

– [Vinay] Got us in trouble.

– [Zubin] Kory on Weinstein’s show and Weinstein’s show and I was so, I was very put off by the way that they framed everything. It was all framed in appeals to emotion and these kinds of things and that was upsetting enough to me that I was like, hey, let’s just quickly talk about this. Now having had some time to really go through, I’m still quite upset. In fact, possibly more so in that this really, you know, even the way that we’re doing this is indicative of kind of how we’ve set up society now. We fragmented into these different tribes that no longer can agree even on a single source of truth. So, you can look at the same meta analysis and say, “Well, but you know,” and move the goalposts or say, “Oh, well, see this shows the mainstream narrative is correct” and so on. But ultimately, if you look at a bunch of doctors that look, we’ve, who have experience, you go, we’ve been burned by so many things that we’ve been told, oh, this is a great drug. And this is-

– Highly promising.

– [Zubin] Highly promising,

– Highly promising.

– Highly promising.

– Vinay] small, randomized study suggests benefit. We’ve been burned by that. That’s the other thing that I don’t think people really appreciate. We’ve been burned by that so many times.

– So many times.

– [Vinay] In fact, somebody might’ve written a book on that called “Ending Medical Reversal.” That was literally the theme of the book. Yeah, it was literally at the end of the book. But Weinstein, to his credit, I mean, he was right about one thing, which is that we ought not have censored a dialogue about lab leak.

– Agree, agree.

– [Vinay] And he’s right about this in a sense, we ought not sensor dialogue around ivermectin. I agree with him wholeheartedly. I’m just saying my pre-test probability was low and it’s still low, but they’re five studies ongoing that’s gonna change, that’s gonna give us an answer, one way or the other. And they might be right. I mean, that’s not the problem here. The problem is, do you act on the existing evidence? And I think that’s probably no.

– [Zubin] Yeah, I actually want them to be right.

– [Vinay] Of course, we want successful drugs.

– [Zubin] I wanna be able to come here and go hey, I stand by everything I said being skeptical. They’re right, now I’m gonna promote this thing full of force. I’ll get Kory on here and be like, you were a visionary, but I stand by the fact that you were behaving like, you know, oh, by the way. So after we did that show, he went on Twitter and referred to us as celebrity fuckwit doctors.

– [Vinay] I wish I was a celebrity.

– [Zubin] I know, me too. I was like, thank you for the upgrade. It’s funny ’cause I think Gorski was in the thread and he was like, “Oh, they’re talking about me.” And I’m like, no.

– [Vinay] Fuckwit doctors, wow. Okay, well, you know, what do I know?

– [Zubin] So again, it gets to the whole idea of the appeal to emotion, ad hominems. I’m guilty of it from time to time ’cause I get very emotional when I see shit that I’ve been through before. And I’m like, I’ve seen this play.

– [Vinay] One more point on this. Okay, so the ivermectin. The other thing we need to separate is that what when people say ivermectin works or doesn’t work, I mean, I think there’s at least five different places we could be talking about so, are we even talk about the same thing? So one, you could take a drug. If you come into contact with someone with SARS‑CoV‑2 to prevent you from acquiring SARS‑CoV‑2, that’s a sort of a chemoprophylaxis sort of agent. You could, if you come down with mild symptoms or test positive, you could take a drug to avert bad symptoms or hospitalization. If you are hospitalized, you can take a drug that prevents you from dying or from requiring mechanical ventilation. If you require oxygen or mechanically ventilated, you could take a drug to prevent you from dying. And if you are mechanically ventilated you could prevent, in other words, based on the severity of what’s happened to you. And the next thing is what’s the dose of ivermectin? In these randomized phase two small studies, the dose ranges like so widely that they need to sort that out. Like a medicine is not just, it works or doesn’t. Medicines work under certain conditions called an indication, which is what is the indication to take the medicine, which is the dose of the medicine, the strength of the medicine, the purpose you’re taking it for, and what it might do for you under those purposes? And they’re just lumping together all these studies with different doses that vary widely over a log, you know, over a factor of 10 from all different purposes. And that’s also doesn’t make a lot of sense as a doctor. It’s like a drug that treats advanced cancer and early cancer all in one, you know?

– [Zubin] Yeah, yeah, yeah, exactly. There’s so much heterogeneity in the approaches that were used, and again, now to the Kory gang’s defense, they’ll say, “Well, this is just the data that we were able to get because no one’s funding a big randomized control trial.”

– [Vinay] But they are, there’s five ongoing.

– [Zubin] And now they are. And the same thing happened with vitamin C sepsis.

– [Vinay] With Marik.

– [Zubin] Marik protocol. Marik was on my show, really good guy, very smart guy, but never really quite, the original observational before-after trial, and he was using terms like miracle cocktail and so on, it was very similar. Now he’s, of course, involved in ivermectin.

– [Vinay] Again, he’s a coauthor with Kory on this paper and he’s at the Eastern Virginia?

– [Zubin] Eastern Virginia, yeah.

– [Vinay] And by all accounts he’s a good critical care doctor.

– [Zubin] Yeah. Great, great.

– [Vinay] I think that condition had a similar problem, sepsis, a condition that is very common and also with lottery like odds that what you have is actually transformative and Marik believed that he had several drugs that were commonly used that would cure, have 100% cure rate in sepsis and he had some small, uncontrolled case series that suggested that it looked pretty promising, quote, highly promising. And now we’ve run randomized control trials that show, you know, doesn’t work, doesn’t work better than what we’re otherwise doing.

– [Zubin] And what’s interesting about that as you know, he then was quite upset with the results of those and said, “They did the trials wrong. They dosed it too late. They didn’t give enough.” Whatever the arguments are. And the question is, where do you stop? Like what, you know, how much money did we spend on those randomized trials?

– [Vinay] How much zinc do they give, ZDogg?

– [Zubin] Exactly. Was it given with hydroxychloroquine or not? I mean, but this is, you know?

– [Vinay] But, you know, we joke a little bit, but this is also, this is a tale as old as time. I mean, there was a study in 1993 of different types of lymphoma drugs, that were being given at the time, “New England Journal” paper and it showed that, you know what the older drugs we were giving CHOP, it’s better than all these new fangled things. Okay, the letter to the editor of that article says, well, the reason it didn’t work was X, Y, or Z, they didn’t give the right dose and they didn’t do this, they didn’t do that. Every time there is a major negative study that contradicts what some doctors believed worked, they will always manufacturer a reason why it doesn’t meet their threshold. But the challenge in biomedicine is not to show that a study didn’t work under all circumstances, it’s to prove under what circumstances something actually helps. That’s the challenge of biology. And looked at another way, ivermectin, whatever drug, you have a human organism that for better or worse has evolved over millennia, millions of years, to be tuned to handling foreign exogenous stresses, from viruses to you name it. And what you’re saying is that I have some little chemical substance that if I add it to this human body, I can improve the outcome over the body’s natural compensatory mechanisms. That’s a tall order. I mean, that’s challenging. Medicine is not an easy business. Throughout the history of medicine, probably most medicine people have given, actually hurt people or didn’t work. Only in the last, maybe 100, 150 years, we actually better than not working.

– In some cases.

– In some cases. We’re just gettin’ there. And so, you know, people have to have some humility that I think we have a distortion, the mRNA vaccine story was so successful. A little bit of chance, a lot of bit of good science, but a little bit of chance. I think people in the public, they believe that like when doctors are clever and think of something that works, those generally work, the answer is it generally don’t work, even though they’re clever and think of it.

– [Zubin] And I think you kind of put your finger on it, which is the body’s natural ability to do stuff is the key. So therapeutics often, if they do work, they’re probably leveraging something in the body that naturally works. Vaccines are a great example. That’s why I consider vaccines a kind of almost a different class of therapeutic, because they’re just saying, oh hey, immune system, we’re gonna get you to work a little better.

– [Vinay] Yeah, they train you to recognize part of the damaging thing without the damaging part.

– [Zubin] Without the damaging part. And there’s clever hacks to do that, mRNA is one of them. _ they’re very clever.

– [Zubin] That you hope has less side effects than the actual thing itself. And that’s the idea. With therapeutics it’s very different.

– [Vinay] Yes, but therapeutics is very different. I think that’s an important point to make, yeah.

– [Zubin] It’s very different. And not only that, but humans are so complex, I think it’s interesting to see that the tribalization, so the same group of ivermectin people that are really like, “You’re stifling this truth. You’re in big pharma’s pocket.” Some of them are people that would, you know, you smoke weed all day to deal with anxiety, inhaling all those toxins. Or they would say, well, natural stuff is the only thing that matters so I’m gonna take a de-worming antiparasitic agent to prevent this infection. And it’s like, well, I actually think your immune system is more natural than that.

– [Vinay] I mean, yeah. I think that, well, you know, COVID would have 100% fatality rate if the body’s immune system did nothing. So, we’re debating the IFR 0.5, 0.7, 0.2, you know, that’s what we’re debating, but no one is saying it’s 100% lethal and it’s not. And what you’re saying is with your ivermectin, you’re gonna improve that a few percentage points. I don’t know what they claim it’ll improve it, but they believe they’ll improve it some. Actually I do know what they claim. The other thing about this phase, the meta analysis, is that the point estimate of benefit is a whopper.

– Yeah.

– [Vinay] It’s a huge benefit, I think.

– [Zubin] 56% mortality benefit?

– [Vinay] Yeah, it was about like it has a ratio of like 0.5, so it’s like half of the risk of death is averted.

– [Zubin] It’s stunning.

– [Vinay] And I think the editorial was entitled, “Too Good to Pass Up” or “Too Good to Be True” or something like that.

– That’s right, that’s right.

– [Vinay] And why do we say that? So, that’s the other bit of background you need to know. Is that again, first there’s the lottery like odd something works, but then of the things that do work, most of what we do in biomedicine is modest to marginal effect sizes. We have very few effect sizes that large. In fact, I’ve done some papers where we look across all biomedicine devices, drugs, surgery, almost nothing is that good? And that’s because the human body is marvelously well attuned in both sickness and health, and it’s really hard to improve upon it in that large degree. So, that’s another reason to be actually skeptical, I think, of ivermectin is that it is a whopper of a relative risk reduction suggesting that there are potentially some unreported studies or some bias in the fragmented small studies that are available.

– [Zubin] Yes, and I think that that publication bias is a real phenomenon. Kory on Weinstein’s podcast basically denied that that was it. He’s like one of the reason that it’s so positive is that it’s a perfect drug, basically. It’s actually that good, which I can’t think of a drug. I cannot think of a single drug that’s like that. Can you?

– [Vinay] I mean, probably imatinib, Gleevec, is probably one of our strongest drugs.

– [Zubin] Gleevec against that particular form of?

– [Vinay] Leukemia.

– [Zubin] Leukemia, yeah.

– [Vinay] I mean we probably have a few. You can look up this paper we did on parachutes where we looked at very large treatment effects and he who shall not be named, John Ioannidis, has a nice paper, very large treatment effects in “JAMA,” I think 2012 with Tiago Pereira. The other thing about Kory, the other thing I wanna say is there are lots of Korys. What do I mean? For every one of these putative drugs that might be beneficial for SARS -CoV-2, there is a Kory. The Kory of hydroxychloroquine was Didier Raoult, isn’t he that Frenchman? The Kory for convalescent plasma are maybe the folks from Johns Hopkins, you know. And maybe convalescent plasma worked based on the titer, that’s the other thing. And maybe it doesn’t work in low titer, but it works in high titer. And based on the body’s production of antibodies., Now the recovery study has some nice complex analysis. There’s a Kory for every one of these therapies. And so if retrospect, somebody says, “Well, this Kory was right.” It could have been this Didier Raoult was right. Or it could have been this other person was right. And my point is that there’s a multiplicity here as well. You’ll tell a story of how people suppressed you based on who happened to be the winner, but not based on all the people who offered a strong opinion and throughout SARS-CoV-2, and throughout, you know, this is a phenomenon that’s true in all things, from predicting presidential elections to whatever. If somebody comes out early and they make a very strong prediction and they are vindicated, people believe everything they say there on.

– [Zubin] Everything afterwards.

– [Vinay] Even if it was just chance that they got lucky the first time.

– [Zubin] And I think this actually applies very directly to Kory, for example, who was saying early on, we should give lots of steroids in these escalating doses. Which by the way, no one actually looked at the exact protocol he was using, but is it as effective as whatever they ended up with dexamethasone? But so, he wasn’t entirely wrong.

– [Vinay] I see, yes.

– [Zubin] So then, then, you know, and he takes care of these patients, right? So it’s kind of like, all right, and the same, Weinstein was correct about hypothesizing about lab leak.

– [Vinay] Or correct that we shouldn’t censor it.

– [Zubin] We shouldn’t censor it.

– [Vinay] Who knows if he’s right or wrong about the actual answer.

– [Zubin] Nobody knows the answer to that, yeah. And nobody I may ever know, but we should explore it. We shouldn’t censor it. And okay, so now that gets to the Alzheimer’s.

– [Vinay] Yeah, let’s connect this. So this Alzheimer’s drug, this is a drug that’s also, you know, it’s ivermectin of Alzheimer’s. I mean, what do I mean by that? I mean, Alzheimer’s is similar. Low pre-test probability anything actually helps in Alzheimer’s after many years of exploring, we have very few drugs that do anything. Alzheimer’s is a devastating condition, affects 6 million Americans. It robs us of who we are. I mean, it’s one of the worst things, I think, that afflicts people, it hurts the person afflicted and hurts all the loved ones and its economic toll is catastrophic because often it not only does the afflicted person unable to participate, but all their loved ones participate in caregiving for this person. Sometimes they have to quit their job and things like that. It has a devastating toll. So, we would do anything for a drug that actually reverses or prevents Alzheimer’s. It’s the holy grail of drug development. They’ve tried for years. You know, there have been many, many compounds that came through, targeting amyloid or amyloid pathways, and mostly they have failed, i.e. they failed to actually slow the trajectory of deterioration or improve symptoms for people with Alzheimer’s. Finally comes aducanumab, this Biogen drug, and this was a drug that had a very small, uncontrolled phase one, two study. They saw reductions in amyloid protein and they launched two paired, randomized control trials. The nice thing about two large randomized trials is that if they’re both positive, you really know that what you’ve found is efficacious. It has a much greater post-test probability, post-study probability that this actually works if they’re both positive. What they found was that actually both were halted for futility. One was rip-roaringly futile and the other had a change in dose mid-protocol, but the overall trial looked pretty negative. Later, a year later, Biogen looked back at that data and then they sliced and diced it a little bit and they said, maybe at this high dose, maybe there’s some signal. And that’s what led to the more recent FDA review.

– [Zubin] Wow, so actually the original RCTs. were stopped for futility, meaning it just wasn’t working.

– [Vinay] Yeah.

– [Zubin] By the company. And then they went back and did exactly what you said you shouldn’t do.

– Slice and dice.

– [Zubin] Which is slice and dice, change the end points, change the analysis.

– [Vinay] Yeah, and they put a lot of weight on the amyloid plaque reduction because in fact, it does look like on brain scans it reduces amyloid plaque. But the question is-

– What’s the outcome?

– [Vinay] Yeah, do people actually like, remember who they are and start doing better in their lives? And they also had some changes in dose midstream and they argued that at this higher dose, it actually worked, but at the lower dose, it didn’t, and the overall trial was muddied by the lower dose. So we like, again, we always tell some biological story of like, why it woulda worked if only. This is the, oh, vitamin C sepsis woulda worked if you crank up the zinc, or I don’t know.

– Whatever it is.

– Squirt a little orange juice on the top, I don’t know. That’s what people tell themselves. People love to find. So, it went to the FDA drug advisory committee, the Peripheral And Central Nervous System Committee, of which there are really good thoughtful policy experts. I know they’re good ’cause a few of them have resigned.

– [Zubin] In protest, yeah.

– [Vinay] In protest and they voted ten-zero-one, one abstention, not to approve this drug. This did not have, the pretest probability is low, the … is inconclusive. We don’t know. And if it is approved, it’s gonna be approved for an Alzheimer’s population that’s millions of people at which may potentially have huge expenses, but actually they didn’t even look at the price, just strictly on the merits they said, no go. Then at the 11th hour, the FDA granted approval, but it gave an accelerated approval. This means that the FDA has said, you haven’t proven to us that people with Alzheimer’s actually have reduced symptoms, or feel better, or live longer, or anything like that. You’ve proven to us that the amyloid protein in the brain is lower and we believe that reduction is quote, “reasonably likely to predict” clinical benefit down the road. And so, we’re giving you a provisional or an accelerated approval for this. The problem with this is in 2018, the same FDA had issued guidance saying that amyloid reduction is not suitable for accelerated approval because we don’t know amyloid reduction is quote, reasonably likely to predict. So, they have literally reversed their prior guidance. This is what led to three members of the panel resigning. And this is what led to a lot of consternation. This and one other fact. This drug, the label is, anyone with Alzheimer’s. 6 million Americans. If one in three of these people actually take the drug at Biogen’s price at 56k per year, you’re talking about $112 billion outlay by Medicare for this drug. That is a sum that will dwarf the other drugs. It’s a sum that will slowly bankrupt our society. And so, that’s the state of aducanumab. I guess, to be honest, in some ways it’s even worse than ivermectin ’cause it costs a fortune and may bankrupt society.

– [Zubin] It’s an order of magnitude worse because it’s institutionalized mainstream nonsense instead of fringy social media nonsense. Like I’m gonna rant for a second because $116 billion we’re happy to spend for an Alzheimer’s drug that doesn’t work, potentially, by any standards of evidence that we currently hold dear. Clearly there are influences on FDA from not just pharma, but from the Alzheimer’s Association of America.

– [Vinay] Which takes money from this pharma company.

– [Zubin] Which takes money from pharma, purportedly to help people with this disease that is devastating, not just to them, but to their family members. $116 billion, you could cure food deserts. You could build communities that create connection, exercise, purpose, that would prevent more Alzheimer’s disease probably than we’re, have any chance of treating with a therapeutic.

– [Vinay] For 56k you can give every Alzheimer’s patient their own caregiver to come to their house and take care of them, which is something that will work way better than this drug.

– [Zubin] Oh my God. So, this is why stuff like this is why things like the ivermectin things emerge because nobody can trust a system that reifies this as something that’s doable.

– [Vinay] You know, when Trump ran for office, he said, “The system is rigged.” Aducanumab is the rigging of the system. And here’s why I think it’s really deeply rigged. What are they doing? They’re selling you a drug and they say, “This is the drug for your health. This is the drug for Alzheimer’s. You don’t like Alzheimer’s, this is the drug for that.” Do they have any credible data that you’re better off if you have Alzheimer’s and take this drug? They have no credible data at all. What does the drug actually do? It’s a liquid that comes in a bag that they make. And they give you this drug and it cost them a tiny fraction to make it so most of the money you’re paying is their profit. And then what you’re getting in your arm may not be helping your Alzheimer’s at all. I think what they’ve created is a financial product. It’s not a medical product. It’s a product that takes the wealth of society off the backs of middle-class Americans and even poor Americans who are paying taxes. It takes all that money and pours it into Medicare and Medicare gives it to the shareholders of Biogen pharmaceuticals and they give in exchange something that they’re saying is for your health, but it might just be saltwater in your veins for all of the good it does for your Alzheimer’s. So, it is a financial product that is, I think, a regressive tax. It taxes average people and consolidates hands in wealthy shareholders. It is a sort of a feudal system and it’s all done in the name of health which makes it more sinister and perverse.

– [Zubin] It’s modern feudalism. It further exacerbates a wealth inequality that’s been exacerbated from the beginning and the pandemic made an order of magnitude worse. I had a doc on here, Angela Bymaster, runs a free clinic in San Jose that’s subsidized by concierge. So, she takes rich people.

– Interesting.

– [Zubin] Gives them concierge care so that she can then subsidize TWO patients who are poor and give them concierge care. And she did this poem in front of the Santa Clara Board of Supervisors that basically said, oh, we’re all in this together in the beginning of the lockdowns, except for our poor people. It’s like boats on the Titanic. The rich guys get the lifeboats, everybody else can drown. And all the pandemic has done is made this worse now, but this is institutionalized feudalism. Exactly as you said, and where’s the outrage? Like it’s minimal.

– Yeah.

– Right?

– [Vinay] In fact it should be, I mean, as much as I’m critical of the ivermectin people, and I do not believe you should use ivermectin now, pending those results.

– Pending the results, yeah. And we wanna be proven wrong.

– [Vinay] And if any of those five or, not if any, but if any of the five convincingly show me that it works, I’ll switch my practice. I’m irritated about those people, but I’m much more irritated about these people these aducanumab. These are the people who are bankrupting our society. And these are the people, so now let’s talk about the social media. I just find it ironic. YouTube going through their little platform and they’re censoring all the videos of ivermectin that don’t fit their narrative.

– Misinformation.

– And soon they’re gonna be running ads for this shitty drug, aducanumab

– [Zubin] Totally.

– [Vinay] So, the same company is very happy to extol the benefits of unproven therapies if the pharmaceutical sponsor wants to pay for an ad, but they’re very quick to censor people extolling the benefits of other unproven therapies that are cheaper. And so to some degree, I am sympathetic to these people who feel like that there is some unfairness in the system. There is, I think, because if ivermectin was some multi-billion dollar drug or something, and they could get some bullshit accelerated approval, but from the point of view of a patient, they’re both quite similar, which is patients and doctors want to give things that we know actually work. And none of this evidence is credible. They’re all offering low credibility evidence and we need to generate good evidence. So, I think that it’s a very interesting paradox that these Facebook and Twitter, half their ads are for drugs that are low quality evidence. And then they simultaneously sensor people talking about low-quality evidence. What’s the difference?

– [Zubin] Yeah, or a brand name, new drug that does the same thing, a generic old drug does with like an incremental, cherry picked subgroup analysis benefit for one particular race or something. It’s like, come on guys, really? But then again, I think we’re at a point now where we’ve, first of all, we’ve tribalized truths. You can’t find truth, whether ivermectin or whatever it is, then what we’ve done is the financial incentives and institutional capture of things like FDA and all that, generate legitimate conspiracy thinking. People are like, well, but this is it. That’s not, that’s just the system. There’s no conspiracy there. That’s just how it’s been built. So, how do you change all this? And that’s a subject of a different show, but I think there are ways that we can actually leverage the same tools that we are already developing that are causing us so much consternation to actually turn it around and have actually something better than democracy where people actually can weigh in on issues that matter in a way that’s where you leverage AI to actually create what a Daniel Schmachtenberger calls a semantic mean. So, people can actually express their desires in a way that the people are actually heard, as opposed to the people are manipulated by large, special interest into voting for crap that they never even thought of. So, either we go to destruction as a people, or we go to this next stage of evolution.

– [Vinay] You’re optimistic, but I worry about us for a few reasons.

– You should.

– [Vinay] Because as you point out, the pandemic, and you’ve been one of the few, you know, had good people on who really pointed this out, it has exacerbated these things. And so I think the average, middle class, lower class people in this society, working class people, the system is choking them. I mean, it’s strangling them, it’s strangling their wages. And when you do that to a body politic and deprive them of education, upward mobility, you make them pay for aducanumabs in their taxes that just consolidate wealth. There’s only so much they can take and politicians will come by and they will seize upon the desperation and the apathy and the hopelessness. And they will say what they think the culprit is. And the population will have no ability to differentiate that it is really esoteric, structural changes in government and regulation that need to be done to fix this problem. Instead, it’s so easy to demonize the other or foreigners or immigrants or whatever, you know, boogeyman we wanna empower. And so, I worry that our political system is extremely volatile. In the next 15 years, we could see anything from a total right wing, fascist, to some-

– [Zubin] Communist state.

– [Vinay] To somebody in the name of progressivism, but actually offers a incredibly illiberal agenda.

– [Zubin] Yeah, exactly. Exactly., as has been offered, exactly. On Independence Day, I did a rant in my backyard where I said, you know, this is an interesting thing about the U.S.. We’re forced by our body politic to think in short terms, in terms of what’s the next election, two years of any election cycle is spent trying to get reelected. It’s all about the special interest and moneyed interests, pushing for their own agendas and that includes the big tech oligopolies, which we’ve ceded to them, basically the social media landscape that hyper stimulates us and hacks our evolutionary drive to hate each other. And we’ve let them do that for profit without any bigger agenda for social good, which we all might agree on. Like, oh, there’s some good things we could do. Well, then maybe we should do that. So, but what are the other systems of government in the world that are currently active? You have the autocrats in China. And you have the Putins. Do you think they don’t have incentives to think long-term? They do. They have no disincentive to think long-term. And they have control of their population. They have control of the companies they can do whatever they want. So, do we want them to then control narratives because they’re more in a position to do that. They’re more in a position to manipulate us through our own systems that were designed with good intent. So, who are we as a people? Is it time we woke up to government 3.0? So anyway, but that’s a whole ‘nother subject. So, I think we did a thing here. We’re gonna do more things today, but this one is important. And one thing I wanna say. So this is the thing, the ivermectin crowd online, they are characters. So, in the comments is gonna be tons of hate. Just expect it. I’m gonna see it below. You’re gonna see it below. And I think it’s, again, an indicative thing of like, what we’re actually saying is we don’t think the data yet is compelling enough to say give it and we’ve given all the reasons why. We’re trying to act in good faith. When those randomized control trials come out and they show a benefit.

– If they do.

– If they work, then we will come right back here and be like, guess what? Here’s why you should use ivermectin. We stand by what we said before because we were skeptical appropriately and now we’re not because we have the data that we’re comfortable.

– Yeah, I guess, I mean, the whole purpose I think is like, not that anyone is good or bad here, or not that we know the answer, but that the reason why one generally has skepticism to claims of any drug for any disease, are the principles we outlined, low pre-test probability, these types of science is not historically reliable. There are many examples. And the data presented to date don’t really change that pretest probability all that much because it’s small, fragmented, possibly subject to many biases. And then the right studies are really just around the corner. It’s not that far away. So, it doesn’t hurt to wait. And, I guess the last thing I’d just say is that people say, well, somebody said the precautionary principle, like, oh, when you don’t know, just try things,. I guess in medicine, if we really did that, I mean, I think to some degree we did. So, I wanna just point out that we did a lot of quick-

– [Zubin] Masks.

– [Vinay] I think that, yeah. And we’ll talk about that in the next segment about at least, particularly for children and social, and closing down the economy and all these things.

– Schools.

– [Vinay] All these things. Okay, but when it comes to like just pills we give in the body early on in the pandemic, people were throwing all sorts of things into patients, TPA, all sorts of crazy things that may have contributed to an elevated CFR, Case Fatality Rate, early in the pandemic that came down just from the lack of iatrogenic injury. So, I think it is very dangerous to just throw drugs into people. And if you have that philosophy, the precautionary principle, you are supporting the aducanumabs of the world, ’cause these companies will prey upon your precaution. They’ll give you every drug for every disease based on some bullshit end point, some uncontrolled study, they’ll bankrupt society because they’re saying that, oh, you know, just on the safe side, we could try it, can’t make it worse, right? Although it has side effects, it has brain edema and other terrible side effects for this aducanumab. So, I just wanna say, be careful that whether it’s a fringe, social media theory or a pharmaceutical drug product, the rules of evidence are the same. And I will administer them with the same vigor.

– [Zubin] Two celebrity fuckwit doctors, keeping it moderately to severely real. All right, guys, share the video. Look, I gotta do the usual pitch to subscribe to the show, click the notification bell if you’re on YouTube. If you’re on Facebook, just follow the show, share the show, leave a comment, like it, because that juices these algorithms which are manipulating us. So, if we wanna get actual information out that we think is helpful, we have to play these stupid games that the oligopolies have designed until we don’t. And one day we won’t. One way not to play the game is sign up for Locals, zdoggmd.locals.com. It’s off the social media grid. It’s funded by subscribers. You can also sign up for free. We have real community there and they can’t censor us. They can’t shut us down. All right, guys, I love you. Thanks Vinay. Until next time, we out, peace.