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On June 7th, 2021 FDA approved the amyloid beta-directed antibody aducanumab (Aduhelm) for the Treatment of Alzheimers. This approval of aducanumab was not without controversy. Actually, let me restate that. The approval of aducanumab was a hot mess, inside a dumpster fire, inside a train wreck.

After the approval, three members of the FDA advisory panel, which unanimously was not in favor of the approval of aduhelm, quit. One of them, Aaron Kesselheim (who we have on our podcast today) described it as “the worst drug approval decision in recent U.S. history” in his resignation letter. Then the FDA had to revise the label one month after publishing it because the original didn’t even come close to looking like the population in which treatment was initiated in clinical trials. Then, wait for it, after a firestorm of criticism the FDA’s commissioner had to ask for an independent investigation to look into the interactions between Biogen representatives and FDA members. And now CMS is deciding if and how to cover Aduhelm, a drug that will cost at least $56,000 a year per patient not incluiding the doctor’s visits, amyloid PET scans, and frequent MRIs that will be necessary to monitor for side effects.

On today’s podcast we talk all about aducanumab with Aaron Kesselheim, Professor of Medicine at Harvard Medical School and previous member of that now famous FDA advisory committee, as well as Jason Karlawish, Professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania Perelman School of Medicine.

I’d love to point you to the journal articles for the two phase III trials on aducanumab, but as of yet, they are unpublished (this should tell you a little about the faith Biogen has on its drug data), so I’ll leave you with these resources instead:

  • CMS’s request for public comment for their National Coverage Determination analysis to determine whether Medicare should cover the drug and any other monoclonal antibodies directed at amyloid

The last one is particularly important as whether you are for or against the coverage of aducanumab, your voice matters. There is a letter being circulated by physicians who care for people with Alzheimer’s Disease urging CMS not to cover aducanumab given the limited clinical evidence for benefit, known harms, and exorbitant cost. You can find the letter here. If you would like to sign the letter, you can add your name by clicking this link.

Eric: Welcome to the GeriPal podcast. This is Eric Widera.

Alex: This is Alex Smith.

Eric: And, Alex, I am very excited today. We’re going to be talking about aducanumab or Aduhelm with two national experts on the subject. Who do we have with us today, Alex?

Alex: Just to be clear, Eric’s been talking about aducanumab on every single podcast we’ve recorded since it was approved. We’re delighted to welcome today Aaron Kesselheim, who is an internist, who is a professor at Harvard Medical School, who is a lawyer, who runs a program on the intersection of law and regulation for clinical therapeutics. He was also on the FDA advisory committee that recommended against approval of aducanumab and then resigned six weeks ago and says he hasn’t heard the end of it since then. Welcome to the GeriPal podcast, Aaron.

Aaron: Thank you, both. It is a pleasure to be here and to talk about these issues.

Alex: And we’re delighted to welcome back Jason Karlawish, who is a physician and writer. We had him on our podcast about his book on the history of Alzheimer’s disease. He’s a professor at the University of Pennsylvania School of Medicine and is co-director of the Penn Memory Center and is a self-described reluctant prescriber of aducanumab. Welcome back to the GeriPal podcast, Jason.

Jason: It’s great to be back, Alex and Eric. Sorry it had to be under these circumstances.

Eric: Well, we’ll have a link to our past podcast with Jason and to his book on the show notes. And we also did a podcast with Gil Rabinovici on amyloid PET scans and aducanumab. So, we’re going to dive into aducanumab in full today, but before we do, Aaron, do you have a song request for Alex?

Aaron: I do. As an homage to where I grew up in New Jersey, and it turns out where Jason also grew up, in New Jersey. Jason, I’m from Cherry Hill, New Jersey. Where are you from?

Jason: Oh, wow. I’m a little more north. Ramsey, New Jersey. Bergen County. A little more north on the Garden State Parkway.

Aaron: All right. Well, so, somewhere in between us was where Bruce Springsteen is from. And so, we’re requesting Born to Run.

Alex: All right. Great choice. I love The Boss. I slowed this down and I don’t have a full band, so this is my acoustic version.

Alex: (singing).

Eric: Excellent job. Have you guys been to a concert by Bruce? I heard they’re amazing.

Aaron: A lot. For sure.

Alex: Yeah. You kind of have to, as a New Jerseyan, right?

Aaron: That’s right.

Alex: I mean, I saw him like three years ago. He’s still stage-diving. That’s amazing.

Jason: Successful aging.

Alex: Hey, Eric, did we mention that we’re now sponsored by Biogen?

Jason: You’re probably the last of their efforts to throw some coin around to try and pump this business model.

Eric: Well, let’s dive into this topic. Let’s just kind of think about it broad. I’m going to assume some of our listeners have not even heard of aducanumab or Aduhelm. Jason, what the heck is it? And why should we care?

Jason: Aducanumab is a drug manufactured to use an antibody to target amyloid in the brain of a human. The theory is that if you can remove amyloid, particularly oligomers seems to be the target that that drug particularly seemed to target, that that would affect one of the underlying pathologies that’s well-associated with Alzheimer’s disease, dementia, namely elevated amyloid, the presence of amyloid plaques, along with, of course, tangles of tau protein. It’s one of a number of therapies of a similar model that’s been tested in humans.

Jason: And this particular drug made it all the way to Phase 3, two identical Phase 3 studies, ENGAGE and EMERGE, which were halted on a futility analysis. More data came in. More analyses were done. One study popped out to have a effect on drug greater than placebo. The other did not. The rest is history, namely the companies decided to still pursue an application to FDA. We’ll talk more, but it seems like FDA was as encouraging as the company was, if not even more. And a review occurred in November of last year that Aaron was present at, I witnessed, which resulted in a decision that was nearly unanimous to say the drug was not safe and effective based on standard approval regulations to decide.

Jason: Time passed. And on June 7th, the FDA issued a decision that said that the drug will be approved, but they used a different set of regulations that had not been discussed prior: the accelerated approval regulations. And here we are today with the drug available. There’s more to say obviously about those events, but that’s the drug. So, aducanumab was transformed in a rather dark baptism, I think, from aducanumab into Aduhelm for the treatment of Alzheimer’s disease.

Eric: And, Jason. So, let’s talk about some of the clinical data too. Aaron jump on in. Aducanumab or Aduhelm is really good… is this a question at all about whether how good is it at treating, I think with Gil Rabinovici said is mouseheimer’s. Being able to take away amyloid plaques from the brain, does it do a really good job of that?

Jason: Oh, we’ve been treating mice successfully with antiamyloid therapeutics since the turn of the century. In fact, that was the breakthrough study in mice that even made the national news, it was so provocative. Since then, these drugs in the class have been pretty good at removing amyloid. In fact, with respect to aducanumab, the 2016 front cover of Nature depicted a brain with and without amyloid. And the story was aducanumab’s ability, in an early phase study, to remove amyloid. So, that’s been well-described for this particular drug for at least four or five years. No surprise there. We knew that.

Jason: The question was the degree to which this removal of amyloid translated into improvements and/or stabilization in the health and well-being of our patient’s brain. And I think there, I’m of the view that more study is/was/still is needed of this drug. And simply put, this drug is not ready to be given to patients with a prescription, but to be given to subjects having reviewed an informed consent form. I still think the drug needs more study.

Jason: I’m of the view that there may be something here. We can talk more what that may be and why, but the removal of amyloid was not a surprise. We knew that for five years. The issue was the degree that that translates into benefit for patients. And that, I think, is still in equipoise.

Aaron: And if I could take you back to the glory days of November, 2020, which is when we had the advisory committee meeting, the discussion at the advisory committee was not about the amyloid and aducanumab’s effect on amyloid. In fact, the FDA told the advisory committee that there wasn’t a debate over whether or not aducanumab reduced amyloid. And I think the advisory committee had actually voted that that was the case. But the whole discussion at the advisory committee was about the effect of aducanumab on cognitive function. And what the advisory committee found, nearly unanimously, was that there was no convincing evidence that it had any effect on cognitive function.

Aaron: And then six months later, the FDA approves the drug based on the effect on amyloid. It kind of switches the entire premise on which the approval was made. And so, the drug follows this so-called Thunder Road from thinking about the effect on cognitive function to being approved on the basis of amyloid, which, again, wasn’t even in discussion at the advisory committee.

Alex: Let’s see how many Bruce Springsteen references we can work in here during the next hour. [laughter]

Jason: Yeah, well, if it isn’t Bruce Springsteen, it’ll be John Le Carre novels or some other story of sort of what just happened and who knew what, when, pick your espionage and/or whatever stories because I think that’s event number one, that in the Alzheimer’s field… when I went to bed on the evening of June 6, the idea of reducing amyloid as a surrogate measure, the way we reduce LDL with a drug, was a provocative hypothesis in need of further testing. By the evening of June 7th, it was clinical practice. And that was not because of a breakthrough study; it was because of this imperious decision by the FDA.

Jason: And as Aaron points out, the way they dismissed that topic in November and never reconvened the advisory board or any discussion of this regulatory approach is blow number one of several blows against the reputation of the FDA and has raised real concerns about the process that the FDA engaged in. And accusations, for example, that… well, claims by, say, Alfred Sandrock at Biogen, the head of research and development, that science proceeds in public discussion and debate. I totally agree with Dr. Sandrock, but there was no public discussion or debate of the particular approval that was given. That’s exactly what Aaron said. And I think that it raises real concerns about what FDA’s decisions are, their decision-making, and casts a real pall on this particular decision as well.

Eric: Yeah. So, Jason is referring to an article that just came out today from Biogen saying that there’s a lot of misinformation out there and misunderstanding, and that’s not how scientific debate should work, which is also interesting I find because how many Phase 3 randomized controlled trials have been published to date?

Jason: Of aducanumab?

Eric: Of aducanumab? None. So, that’s usually how I think about scientific discussion, is actually through this traditional route. And we still don’t have a publication.

Eric: Aaron, I’m going to turn to you. How common is it that A, the FDA advisory committee universally, unanimously said basically no to this, and that basically FDA goes down this different path without actually involving an advisory committee moving forward?

Aaron: Yeah. I think the sort of statistics say that the FDA… the FDA doesn’t have to agree with its advisory committee. And I think the FDA doesn’t agree with its advisory committee maybe about 20%, 25% of the time. But usually when the FDA doesn’t agree with the advisory committee, it actually isn’t in the direction of putting more restrictions than the advisory committee recommends. And this was the completely other direction. And it also usually isn’t disagreeing with a unanimous advisory committee. So, I do think that those two considerations, the fact that it was unanimous and the fact that the FDA approved the drug over the recommendation of it make this a relatively unique decision. And since then, I think that there were other-

Jason: What about, Aaron, then going and using a different set of regulations too?

Aaron: Yeah. And so, another major issue is this idea that it switched the premise on which it was approving the drug from thinking about the effect on cognitive function to the impact on amyloid, at the 11th hour. That is also relatively unheard of.

Aaron: And I think that one of the more unique things also about the advisory committee itself is, I’ve been to sort of half a dozen or so of them as a member of the advisory committee since 2015, usually there’s some kind of controversy where the FDA says, “Well, we think this,” and the company says, “Well, we think this.” And you can see where the points of difference were. At this advisory committee, the FDA and the company came in almost sort of in line with each other. And they both said, “Look, we think this drug should be approved. Don’t you think it should be approved, advisory committee?” And I think the advisory committee pushed back against that and said, “No, actually. We don’t think that there is convincing evidence.” So, I think that dynamic was also questionable. And since then, there’s been some reporting about off-the-record, off-the-books meetings between the FDA and the company that occurred before the advisory committee. Maybe they were doing a little bit of dancing in the dark, so to speak.

Jason: Number two?

Aaron: So, I think all of these things are important parts of the process that deserve further investigation.

Jason: Yeah. I mean, just to add to Aaron’s point, Billy Dunn says to Aaron and his colleagues on November, “The discussion of amyloid as a surrogate is off the table. Not a topic.” You can find that in the transcript. I have an essay in Nature Reviews Neurology where we quote page and verse. But it turns out actually in June of 2020, conversations between FDA and Biogen were on just that topic.

Jason: And number two, when Aaron and his colleagues heard the presentation in November, which he’s described, the FDA’s statistician, Tristan Massie, had issued a detailed report critical of the standard approval. And there was never a discussion of that report. Minimal discussion of that report. Tristan himself certainly never presented. Moreover, moreover, since the decision, FDA has issued memos that describe, real-time memos prior to the decision, the internal discussions. And in addition, Pam Belluck of the New York Times earlier this week published a more detailed investigation. And it turns out FDA was deeply divided, that some in FDA wanted standard approval; others opposed standard and accelerated; and still others viewed accelerated approval as a sort of compromise in some sense. So, you had three different competing opinions in there.

Jason: And then to add to the intrigue, the need for congressional hearings quite frankly, the need for the Office of Inspector General, Janet Woodcock, the acting commissioner, essentially, as best as I can tell, says, “I was not really following this. I was busy with Operation Warp Speed and other things.” And my response to that, if I was in the Senate or the House would be, “Alzheimer’s is one of the top killers, prevalent disease, costly, arguably sort of the COVID of long-term care. And you were not at all apprised of this decision that would be earth-shattering?” I have to say at least she at least dropped the ball on this one. But anyway, I don’t want to make it about Janet Woodcock. The process that has unfolded at FDA has multiple moments where it just raises real questions of the question, what’s going on at FDA?

Eric: So, maybe we can talk about that, but before we do, maybe we can just actually talk about the data. So, we mentioned that this drug, Aduhelm, aducanumab, removes amyloid. So, they’re using a surrogate marker. We’re saying it does that well. Should amyloid be a surrogate marker for clinical benefit?

Jason: No.

Eric: Why not?

Jason: Because the data that describe the reduction of amyloid and its relationship to clinical course are still a work in progress, both when done in experiments, like Aduhelm and other drugs, number one.

Jason: And number two, amyloid accumulation occurs up to 10 years prior to symptomatic onset. By the time symptoms are occurring, amyloid accumulation essentially has peaked out. And so, the idea that reduction of an alteration to amyloid is like the CD4 count, if you will, of HIV, reduce it, the patient does better, or LDL. Pick your… you start to sort of leap across metaphors or stories that just don’t hold up anymore.

Jason: The missing actor in all of this is another biomarker, namely tau. And we can talk more about that.

Eric: Aaron, what do you think about that?

Aaron: Yeah. I mean, I think this is the essential question, is the drug was approved as being under accelerated approval on the theory that the reduction in amyloid plaque was reasonably likely to translate into clinical benefit. And I think that fundamentally, the issue is, is there reasonable likelihood that that’s going to happen? And I think that there is a lot of debate right now and not a lot of clarity about what changing amyloid does and what the point of it has.

Aaron: There’s been a long history of drugs that have targeted amyloid. Now, some of those drugs haven’t removed it as well as aducanumab does, some of those, but the history of drugs targeting amyloid has led to a lot of drugs that don’t change cognitive function, and some drugs even make cognitive function worse. Maybe it’s the case that aducanumab is totally different from that history, but I think that it is incumbent on Biogen to demonstrate that in a clinical trial or at least provide some suggestion that that’s the case.

Aaron: In the results that we have from the aducanumab studies, which, by the way, as Jason said, were closed on futility after 18 months or so of therapy in a lot of patients in there, there doesn’t appear to be that kind of a effect where you see a clear relationship between changes in amyloid plaque and effect on cognitive function, for which there was none in the trials, when you pull the trials together.

Eric: And I find it’s a little bit of a double-talk when I hear FDA or Biogen talk about it. They say, “You’ve got to ignore all of those past fail anti-amyloid studies because they didn’t work like this drug, but, hey, we have lots of evidence that amyloid actually is a reasonable surrogate marker based on past studies.” So, which one is it?

Jason: Yeah. They’re sort of robbing a scientific Peter to pay Paul.

Aaron: It’s a brilliant disguise, so to speak. [laughter]

Jason: Indeed.

Alex: There you go.

Jason: So, I think without getting too in the weeds here with the science, but, I mean, let’s do that. Yeah. If you look at folks with, particularly MCI, and 75% of the subjects of the ENGAGE and EMERGE study had mild cognitive impairment. So-

Eric: ENGAGE and EMERGE, those were the two Phase 3-

Jason: Phase 3 study.

Eric: … randomized controlled trials that were stopped early based on a futility analysis.

Jason: Right. And then reanalyzed when more data came in. One popped out. That would be Emerge and Engage remained negative.

Eric: And only in the high-dose group.

Jason: 75% of the subjects had MCI, inefficiencies in cognition, and all had to have elevated amyloid. If you look at individuals with mild cognitive impairment, my colleague, David Wolk, has published this recently, and there are other data in the literature, MCI, elevated amyloid, trivial to no tau, they are very stable people over time: minimal change in cognition, minimal transition to mild stage dementia. It’s only when you put tau in the mix and start to show tau scan measures that correspond to Braak Stage 3 spread of tau pathology in the temporal lobe that you start to see change over time in these individuals. And indeed, the latest sets of studies now have made an emphasis on, you have to have elevated amyloid and evidence of tau spread in order to get the drug to be tested. And indeed, many of us thought that the next study that should be done with aducanumab was just that. They didn’t have tau tracer available when they started the studies a couple years ago, ENGAGE and EMERGE, and only later did they add tau tracer.

Jason: So, you’ll see this data that they put out where they have like 15 subjects who had tau scans in the Phase 3 trials. And they report data out from that. 15 subjects with tau scans, you could use those, their first names, for a wordless learning tasks to test whether they’ve transitioned to dementia. My point being, it just wasn’t a study that was designed in a way that I think now we think these studies need to be designed to establish, do these drugs make a difference or do we need to move on to a different mechanism. And I think that makes the field so furious.

Jason: And I will say, and then I’ll take a drink of tea, amongst the crowd in the Alzheimer’s field that I hang out with, I have not been able to find folks, other than those who are in the sort of clinical-trial world who’ve been very public even before approval, who viewed this approval as the breakthrough. Most of them just slap their foreheads and say, “I can’t believe this happened.” Many of them won’t speak about it because politics, et cetera. But I will say people who I deeply respect just shake their heads and say, “This was a bridge too far, too soon.” And they are really angry about what’s happened. These are people who are well-respected trialists, folks in the drug discovery world, folks at Alzheimer’s centers. And so, yeah. A bridge too far, too soon is the way you might want to describe this one. I’m jumping to film metaphors there.

Eric: Okay. What about the argument that you need a first-in-class before you have a best-in-class drug? So, you need to get-

Jason: This is like dog rating?

Eric: … that first drug out there before you get the drugs that actually work because that’s what I hear from… I haven’t heard one person say, “This is a breakthrough.” Even the people who are supporters, like, I listened to a lot. Dr. Salloway is another. Nobody is saying, “This is an amazing drug that is just going to have huge clinical impact.” It’s all, “You know, maybe it works a little bit.”

Jason: Yeah. So, Aaron, I’m sorry, I got to-

Eric: But you need that first drug out there. That’s what the Alzheimer’s Association is saying.

Jason: Yeah. This is this innovation. And in Sandrock’s letter to the field to tell us all to behave, the head of research and development at Biogen, Alfred Sandrock, his letter to the world today, his closing point is that this will spur innovation. And he is absolutely correct. It has already spurred a host of VC, venture capital, and others coming forward with various ways to test amyloid. But that’s a business argument; that is not a scientific argument, “spurring innovation.”

Jason: And Congress, to its credit, has been pouring money into Alzheimer’s research. We are getting our grants funded. We are getting our research done in this space. We did not need the approval of this drug to pump us as a stimulus package for Biogen and other VC firms to continue our research. And I find that innovation argument a business argument; that is not a scientific argument. It is not a public health argument. And I reject it as part of the discussion as to justify the approval of this drug for therapeutic.

Aaron: I feel like that’s right. I think that the argument isn’t about how well the drug works because it might be the drug, it doesn’t appear to have much effect. And I think the issue is that the drug doesn’t work at all. There isn’t good evidence right now that the drug works. It might work. Who knows? But we don’t know. And that’s not the basis on which we approve drugs. We approve drugs when there is some evidence, some convincing evidence, that the drug works. And right now, we don’t have that.

Aaron: And I think the innovation argument is a good one. There’s a whole bunch of other drugs that reduce amyloid. And most of them were now going to go into larger clinical trials to try to test what effect that drug would have on actual cognitive function. And now, those trials won’t happen. These drugs are now… Eli Lilly has indicated that they’re just going to bring those drugs to the market. And that’s not actually innovation; that’s hurting innovation because now, we won’t actually know what these drugs actually do.

Jason: Well, if you take innovation as the venture capital view of innovation, it’s beautiful. I mean, the money is flowing. And I’ve heard that crowd and those who surround them clucking that this is revolutionary.

Jason: But Aaron’s point, let me reiterate it because it’s so important. So, in May of 2020, in the New England Journal of Medicine, investigators reported the results of an Eli Lilly-sponsored study of a drug called donanemab. There were provocative data on an anti-amyloid, donanemab, in individuals with tau and amyloid, remember what I said earlier, that there may be a signal here going on clinically. The abstract of the article in the New England Journal of Medicine in May of 2021 concludes further study is needed to validate these clinical findings.

Jason: In June of 2021, less than a month and a half later, Eli Lilly says, “We’re going to go ahead and look for approval.” And I can’t fault a company for doing that because their regulators said, “I’m lowering the evidentiary bar.” And from the perspective of a board of directors and shareholders, it’s like, well, sure. Go for it. But from the perspective of public health and patient care and science, that’s throwing away evidentiary standards. And so, this is a real problem. This is not just about aducanumab now.

Eric: Well, I want to go back to November, Aaron. You’re in this FDA advisory committee. You’re being presented basically the data from Biogen and FDA saying, “Hey, this drug is great. Don’t look at the pooled analysis because you can’t pool these two identical studies. Look at EMERGE. And hey, we’re seeing this clinical benefit on the high-dose group. And we should look at this plus the phase 1b study.” How convincing was it? Was this a clear absolutely, no, come on? What was going through your head when you were seeing this data?

Aaron: Maybe I would say I was on fire.

Aaron: I mean, I think that basically, the idea that we should only focus on the one positive trial and not focus on the identically designed trial that was negative is not really the sort of right way to think about the evidence.

Aaron: And so, you have two trials. The two trials were identically designed. And they were pooled. And when they were pooled together, they were found to be futile. When they were then subsequently reanalyzed separately, they found this signal in the high-dose arm in one of the trials. And I think that it’s impossible to evaluate that study without also looking at the other study, the negative study, where, in fact, the placebo patients did better than the aducanumab patients, although that result wasn’t statistically significant. So, yeah. I mean, I think that the idea that, well, let’s discount the negative trial and let’s only focus on the positive trial just isn’t the way that you’re supposed to analyze studies.

Aaron: And I think that the people on the advisory committees said, as a group, I think each of us came to this conclusion individually because we’re all separate individuals that came to this and didn’t talk about it ahead of time, said, “That doesn’t make sense. And if you’re going to approve a drug, you need something that you can look to and be confident in that the drug actually works. And we don’t have that. We have two conflicting studies. And what we need is we need more research to try to figure out if this drug actually works or not.”

Alex: There are so many things we could talk about. I want to make sure that we get to a couple of topics. One is pricing. $56,000 a year.

Jason: Per patient.

Alex: Plus the cost of scans, monitoring. This is going to potentially break Medicare, if they approve it.

Alex: We had a meeting. I’m part of the California Technology Assessment Forum, which is a division of the Institute for Clinical Effectiveness Research run by Steve Pearson. They met last week. I’m normally on the panel. I wasn’t because I was on vacation and also because I sang a song that many of our listeners are familiar with about aducanumab. And Steve Pearson, the director, called me and said, “I don’t know if you can be an impartial member after you sang that song about aducanumab.” Anyway, they voted 15 to zero that the evidence that aducanumab plus supportive care is superior to supportive care alone was not there. It’s not there. And then the value is not there.

Alex: And the pricing, if anything, should be less than $10,000. And here it is priced at $56,000. How did that happen? How can a poor man stand such times and live?

Aaron: Well, I would say that this is truly a story that is born in the USA because we allow drug companies in the US to charge whatever price they want for drugs. And we are alone in the industrialized world in doing that. In most places around the industrialized world, they have a process called health technology assessment after a drug is approved in which they evaluate the value, the clinical benefits that the drug offers. And then they go through a process of negotiating a price, a fair price, with the manufacturer. And for drugs that offer a lot of value, that price might still be quite high, but for drugs that don’t offer any value, the drug is usually priced at the level of comparable drugs or at the level of the clinical benefits that it offers. And so, since we don’t have that in this country, that allows Biogen to declare any price that it wants for the drug. And that’s why that’s the situation that we have.

Aaron: And then, of course, we have to talk about coverage of that price by insurers. And there are some insurers, like Medicaid, certain drugs in Medicare, where we automatically cover every FDA-approved drug at its price or at sort of a price with a guaranteed discount on it. And so, we have this situation in the US that is alone in the world, where once a drug gets FDA approval, a drug company announces its price, that drug then becomes available. Now-

Eric: Aaron, can I ask you a quick question?

Aaron: Yeah.

Eric: How much is Biogen’s hands a little bit tied? Because this is an infusion. It’s an infusion that A, we don’t even works and has side effects. So, if you’re trying to get physicians to prescribe it, you can’t use evidence, but maybe incentives, for example, getting additional money to infuse this drug in your clinic and this additional money that they get per infusion. Because they wouldn’t make a lot if it was priced at $1,000 a year, but at $56,000 a year a physician actually may make a decent income prescribing or giving this drug, or an infusion center would.

Aaron: Yeah. Well, I mean, I think that that’s an important issue too, is the conflicts or the conflicts of interest that it puts some physicians into because the way that we reimburse infusion drugs through Medicare is that we give physicians a percentage of the cost of the drug to infuse the product. And in the context of oncology drugs, there are studies that show that [inaudible 00:32:30] to prescribe costly oncology drugs. And so, I think this just goes back to our drug payment system, where we don’t really have a lot of rules or regulations that ensure that drugs are priced fairly and are priced in line with the benefits that they provide.

Jason: Two points. It is a biologic and biologics are expensive to make, but, again, let’s just have an open conversation about how costly this thing is to make. By the way, also a dog may start barking any minute now.

Jason: The other point, I want to build on what Aaron just said, this drug, because it’s an infusion, is actually prescribed, reimbursed not under Part D, but under Part B. And under Part B, it means, as Aaron points out, providers get a percent of the total cost. Now, it’s 6%, but it’s actually… I just got educated that it’s more about 4%.

Jason: So, the point is that there’s a dark irony here of this drug, namely it fulfills, back to sort of only in America, et cetera. It fulfills one of the dark ironies of the American healthcare system, which is if a disease doesn’t have a business model, it can’t fully be seen as a disease, namely diagnosed and treated. And Alzheimer’s has been haunted by that. And by a business model, what I mean is a healthcare system has to at least break even on diagnosis and care or at least make a little money. And if you can break even or at least make a little money, especially if it’s a big, common disease, you can diagnose and treat patients. If you can’t, you struggle. And that’s been the case, certainly, for Alzheimer’s, as I think all of us as clinicians know. Certainly, I can say it at our memory center. We live off of cross-subsidies from research and philanthropy.

Jason: Well, you’re right. I mean, the sad irony here is this $56,000 a year with a 4% profit stands to be a wacky stimulus package for the care of patients with Alzheimer’s. And I don’t find that at all appetizing; I find that to be an indictment of our system. But I will say, even the most rueful critics… even the most clear critics of this decision will ruefully admit, excuse me, ruefully admit that this will actually be a win-win for the memory centers because it will start to bring funds in to pay for what we’ve always wanted to do.

Alex: Yeah. Let’s talk about that because, Jason, you are the director of the Penn Memory Center. We have Mount Sinai, we have Cleveland Clinic saying they are not going to administer this drug.

Eric: I think Sinai said “yet.”

Alex: Yet. Okay.

Jason: Yeah. Sinai’s waiting for the Office of Inspector General.

Jason: So, my colleagues and I very much allow each of us as providers to make the decisions we want to make to practice medicine we want to make. Having said that, we’ve not arrived at any collective decision different than what we decided a few weeks ago, which is let’s get the system going to make this drug available.

Jason: And from the perspective of a memory center, this is a choice. It’s out there. The system has produced it. I have to have some faith and trust in the system. And for this particular disease, a disease of autonomy, I have to do everything I can to respect my patient’s autonomy. And if, after learning about the uncertainties of the benefit, frankly, the potential, I won’t use the “S” word, but the trust-damaging events that led to the approval, et cetera, if someone’s still wants to take the drug who’s within the eligibility criteria, I’m a reluctant prescriber, but I kind of view folks who come to the Memory Center as a kind of person that are looking for things.

Eric: So, how would they get it paid for? Because-

Jason: We will see what their insurance will cover. I mean, that’s part of the missing calculus here.

Jason: … which is when a prescription’s handed in, will it be reimbursed.

Eric: When we’re thinking about CMS, what do we know right now about whether or not Medicare will cover this? Do they have any options for limiting the use of this drug? Or they’re in it for the 50 to 100 billion dollars that it’s going to cost?

Aaron: Right. So, Medicare Part B usually covers all FDA-approved drugs. And they cover about 80% of the cost and leaves 20% of the cost to patients, some of whom have their own insurance program, some of whom might qualify for Medicaid or other subsidies to cover that cost, some of whom we’re going to have to pay for that out of pocket. But the 80% of that is going to come out of Medicare Part B, our tax dollars.

Aaron: Medicare has a process called a national coverage determination in which they can evaluate their coverage criteria. They usually don’t use those coverage determinations for drugs. They usually use them for surgeries or expensive procedures, but they have announced that they are going to apply this national coverage determination process to aducanumab to determine what they’re going to do with it. And so, nine months from now, we’ll get a decision.

Aaron: They may say, for example, that they’re going to require an attestation of a diagnosis of Alzheimer’s, of early Alzheimer’s disease, as opposed to later stages. They might require a PET scan or some other imaging modality to guarantee that the patient has amyloid plaques. So, they might put restrictions or some restrictions on who could get the product, but I think it’s very unlikely that Medicare is going to not cover the drug. And then we’re going to be left with this question.

Aaron: And I think this is one area where Jason and I differ. I don’t think that I would recommend… I would not recommend the drug outside of a clinical trial right now for a patient who came to my primary care clinic because I don’t think that there is good evidence that the drug works. And I think that there are concerns about the drug safety and concerns about the financial considerations that a patient will have to go through. And maybe it’s better for that patient to consider other supportive care or other ways that they can use their funds.

Alex: Supportive care. Let’s talk about that for a second. Chris Langston, who is the president and CEO of Archstone Foundation, which funds GeriPal, full disclosure, in addition to Biogen. Oh, no, sorry, not Biogen. [laughter] But he wrote a blog post saying that they should mandate collaborative care.

Alex: We have a history going back, like decades, showing that collaborative care, comprehensive dementia care, human touch-centered care, let’s call it, is really effective for outcomes related to patients, with outcomes related to caregivers in the setting of dementia. Can we mandate that in addition to aducanumab that there must be payment for supportive collaborative care services for all people who are prescribed? Eric, you want to jump in?

Eric: Yeah. And I think in addition, it’s if you’re going to be infusing this, you also have to offer that kind of… it can’t just be the infusion; it has to be associated with-

Jason: Well, so, here’s the dark irony, as I was saying, which is folks will say, “Well, now that the revenue we’re going to get here is going to finally pay for the services we need,” what Chris Langston says should have been there, and I agree with him, before aducanumab, because, of course, we need to have support staff, staff who can help monitor for the side effects. We need to be able to have the time to educate the patient and family about the risks of the drug, the need potentially for ApoE testing. We need to maybe help them have access via transportation to come in for the scans, et cetera. Again, I’m not saying any of this with great celebratory rhetoric. I’m saying the dark irony here is that the revenue from the drug is viewed as a way to finally staff up memory centers to deliver the care that we know, as you have said, Alex Smith, works.

Jason: To even just add to the anger I sometimes feel over this, alternating with regret and whatnot, or sometimes you just got to laugh, is the National Academy of Sciences issued a report, full disclosure I was on the committee, looking at collaborative care models and concluding that the evidence was good enough to get them out there, though further research was needed to support “their wide dissemination.” And the shocking thing is the quality of the evidence supporting them was far better than the quality of the evidence that got FDA approval for aducanumab.

Alex: Exactly.

Jason: And yet, we were, of course, using a standard that required for wide dissemination. If you don’t cry, you’re going to… if you don’t laugh, you’re going to cry, excuse me. When you see within the same calendar, 12-month period, proven things that, well, wait, it’s good, but we need more evidence. And then this drug is out there and everyone’s all happy because it’s going to cost $56,000 a year and the venture capital’s going to flow, et cetera. And it is just all about business. And Janet Woodcock said, “There’s a more powerful force out there than Medicare. She’s dead. And that’s the marketplace.” And she said that. She’s on record saying-

Alex: There’s a darkness on the edge of town.

Jason: There is.

Eric: Well, I could continue on this discussion.

Alex: We could go forever.

Eric: Yeah. Forever. Real quick. So, lightning.

Alex: Lightning round.

Eric: You guys have a magic wand. You can make one change. One thing that happens from here going forward. What would you do with that magic wand? It could be around the inquiries around this. It could be about CMS. But you can only have one thing. Jason, what’s your one thing?

Jason: Oh, I struggle because do I want to go specific to this or the more general problem? But I’m going to be the co-director of the Memory Center here. Reverse the decision and call for the rapid execution of the confirmatory Phase 3 trial with design features to finally establish does this drug actually clinical course of the disease.

Eric: Oh good use. Aaron.

Aaron: Yeah. That sounds like a great… I support that idea, if we had truly had a magic wand. Since we don’t, I mean, I think that the best we can hope for is that the investigations will uncover ways that we can try to make sure that that problematic processes and decisions like this are restrained because I do, I think that the FDA is an incredibly important public health agency. It makes the right decision most of the time and makes a lot of important decisions. And so, it’s really important that we figure out, when there are these kinds of problematic decisions, what happens so that it doesn’t affect the trust that people have in other decisions that the FDA makes and that we can try to make better decisions in similar circumstances in the future.

Eric: Maybe go back to the glory days of the FDA.

Aaron: That’s right. Waiting on a sunny day.

Jason: Indeed.

Eric: Hey, Alex, before we go through all the Springsteen songs, do you want to get us a little bit more of Born to Run?

Alex: (singing).

Eric: Jason, Aaron, big thank you for joining us for this podcast.

Jason: Thank you, guys, for doing this. It’s really important. And I really appreciate you giving it the time.

Aaron: Thanks a lot. It’s been a lot of fun

Eric: And thank you for actually putting yourself out there and being vocal about your thoughts on this drug, the FDA, and everything else. I really encourage all of our listeners. CMS is open for comments right now on aducanumab, Aduhelm. We’ll have a link to that on our show notes too, but I really encourage you to make your voice heard. If you feel passionate, either way about this drug, because others are, and they generally have a lot more money than us.

Eric: Thank you to all our listeners. Thank you, Archstone Foundation for your continued support. Goodnight, everybody.

Alex: Good night.

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