Breaking Down Medicare’s Proposed Decision on Aducanumab and Monoclonal Antibody Treatments

Jason Karlawish
Jason Karlawish, MD

On January 11, the Centers for Medicare and Medicaid Services (CMS) announced its much-anticipated coverage proposal for monoclonal antibody treatments that target amyloid for the treatment of Alzheimer’s disease. According to the proposed policy, this class of drugs, which includes aducanumab, also known by the brand name Aduhelm, would be covered for people with Medicare only if they are enrolled in qualifying clinical trials. Dr. Jason Karlawish joins the podcast to discuss the recent proposal, share his reaction to the decision, and tell us how this coverage policy could impact the development of other Alzheimer’s disease treatments in the future.

Guest: Jason Karlawish, MD, co-director, Penn Memory Center, professor of medicine, medical ethics and health policy, and neurology, University of Pennsylvania

Episode Topics

1:48 What’s the difference between the FDA and Centers for Medicare and Medicaid Services?

3:58 What is the purpose of sharing a proposal and allowing public comment after? Is it possible the proposal could change?

9:09 What are your key takeaways from the CMS proposal?

11:58 Who’s being charged the cost of the treatment if it is part of a clinical trial?

18:33 What does this decision, with its focus on research often occurring in major urban medical centers, mean for equity and access?

26:27 What is the future of Alzheimer’s disease research after the CMS decision?

Show Notes

Read the Center for Medicare and Medicaid Services’s press release about the proposed coverage policy, view submitted public comments about the decision, and submit your own comment.

Learn more about Dr. Jason Karlawish’s work and writing at his website.

Listen to our four-part episode series with Dr. Jason Karlawish about his book, The Problem of Alzheimer’s, on our website (episode 1, episode 2, episode 3, episode 4).


Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: In June 2021, the FDA granted accelerated approval for aducanumab, a controversial drug treatment for Alzheimer’s disease. At the time, the FDA provided very little guidance on who could receive treatments. On January 11, the Centers for Medicare and Medicaid Services announced that it would only provide coverage for the treatment when administered as part of a clinical trial, citing a need for more data on patients benefiting from the treatment.Here to discuss aducanumab and the recent medicare decision is Dr. Jason Karlawish. A physician and geriatrician, Dr. Karlawish is a prolific author and writer, having published his most recent book, The Problem of Alzheimer’s, early last year. Since the FDA approval of aducanumab, Dr. Karlawish has written numerous essays and commentaries on the topic and has been a much sought after source for media outlets around the world. Dr. Karlawish is also a professor of medicine, neurology, and medical ethics and health policy at the University of Pennsylvania and co-director of the Penn Memory Center. Dr. Karlawish, welcome back to Dementia Matters.

Dr. Jason Karlawish: It's great to be back, Dr Chin, but you can just call me Jason. I'll call you Nate. (laughs)

Chin: (laughs) And to begin, Jason, when it comes to getting new medications from research to the clinic, what's the difference between the FDA and Centers for Medicare and Medicaid Services?

Karlawish: So they're both parts of the Department of Health and Human Services, and the difference is FDA’s job is to review a drug application put in by industry to decide whether it's safe and effective and CMS’s job is to decide - is a therapy that's been proposed for us to cover reasonable and necessary. So safe and effective, FDA. CMS, reasonable and necessary. So typically, as day follows night, you know, CMS coverage follows FDA approval because FDA says the drug is safe and effective and, kind of obvious, it's probably reasonable and necessary - particularly if you stick to the label of who's the drug indicated for. I think the problem that happened obviously with aducanumab when it became Aduhelm is it wasn't approved as safe and effective and it put CMS in a bind.

Chin: But this isn't the first time, of course, that the FDA and Medicare haven't agreed on something. And in your book you actually talk about something also related to Alzheimer's with the amyloid PET scan.

Karlawish: Right.

Chin: And while we're not going to talk about that today though it isn't - this isn't the first time that there's been a disagreement.

Karlawish: That's right. We've been here before and the before in the Alzheimer's field was when Lilly had approved - FDA approval for its amyloid imaging agent and Medicare declined to cover it citing a lack of evidence that the scan produced health benefits. So there the decision was to not cover it. In the case of the decision that occurred just last week, the decision was we'll cover it but you have to be in a clinical trial to study whether the drug in fact is beneficial. CMS had three choices: non-coverage, coverage with evidence development, or just coverage - like you know we'll pay for it - and they chose that middle-ground evidence development.

Chin: And so when they release this proposed national coverage determination - so often refer to NCD - this memo. Now the key word here is proposed because really, it's not final and it allows for thirty days of open public comment. What is the purpose of sharing a proposal knowing that it's not final and then allowing for public comment? Is it possible they could change their mind? And who actually writes in for public comment?

Karlawish: Well, the public does. (laughs) All of us. Americans do, Americans do. And indeed, back to amyloid imaging with Amyvid Lilly tracer, that's what happened. There was further commentary and discussion and eventually actually CMS did do a coverage with evidence development for amyloid imaging as you know - the IDEAS study and IDEAS too. So my point about that is that CMS I think shows that… Look, this is political, and I don't mean political like in a dismissive way - “Oh, that's just politics”. I mean politics for what politics is, which is the exercise of power and persuasion and that's what's going on here. Organizations that have power and have the ability to persuade are engaging in exercising their power and persuasion. And I would argue, actually, CMS is probably really trying on the persuasion side. Namely, let's put this out - our power - we can do this. They have statutory authority to do coverage with development but we'll give you - and again the statute requires this - 30 days for comment. We’ll hear those comments. Let's have some back and forth conversations, and there are conversations going on - I know this - between key organizations and CMS to say what is the next logical step here. But I think what CMS did was, let's put out the most extreme - and that is the word extreme - coverage of evidence development requirement, namely a randomized controlled trial, see how people respond to it with the comments that are coming in - and there are now some 200 comments on the website as of yesterday - and then after that we'll take a look and see if we're going to revise this in any way. So this is a process, this is not done, but my hunch is they will stick with some sort of coverage with evidence development, I'd be shocked if they said, “Oh, we were wrong. We'll pay for it.” I just don't think that's going to happen.

Chin: Can anyone write in during this thirty day period?

Karlawish: Yeah. Yeah, yeah, yeah, it's just - go to the website. It's a totally publicly accessible website. You enter your name, contact, and put your comment in and there are plenty of comments there.

Chin: And so okay, now that we've explained the process piece of this, you know, what are your key takeaways from the actual memo that CMS released?

Karlawish: I do want to make one point about what CMS is doing which I think it's very interesting to juxtapose what FDA did. So CMS, in July, asked for public comments around questions they had around this drug in clinical practice. And they got those public comments, they reviewed them, and they wrote their draft coverage of evidence development idea and now they're asking for more public comments. And the comments are public - you can go read them. CMS made clear in their proposal that they issued on January 11th - we read those comments. And they coded them like, what do they say, are they favorable, are they not, etc. I mean it's not just, “Hey write what you want, but no one will ever hear what you said and we're not going to read it.” I think that's very interesting compared to what FDA did. FDA said, “Oh we listen to the public too. We listen to people with Alzheimer's.” And Billy Dunn at FDA was very clear that they listened to the patient community and they said the patient voice was very influential in our decision to grant accelerated approval. So when - how did they hear the patient voice? Well apparently, in January of 2021, they held a listening session - as it was - called with patients and advocates and this was apparently was convened by the Alzheimer Association. My colleagues and I and my group have written to the FDA to say, “Could you please tell us - release the agenda, the attendees, and any key findings and outcomes that came from that meeting?” And the answer was, “We have no agenda. We have no outcomes. We have no list of attendees.” And the answer they make is it's patients sharing personal stories and in the interest of confidentiality - you know I think that is hiding behind confidentiality. At least tell us, was there a report issued? What were the questions discussed? So I find that kind of listening session, which no one hears, that we're told was key to result in the decision for accelerated approval, to be really anti-democratic and a botch in process. And I do applaud CMS for saying, “Look, public comment! It's on the website. You can read everyone's comments. We're going to read the comments.” I think that there's real important differences there in this sort of process of regulatory science and the regulations of insurance that I want to point out.

Chin: So it seems like CMS is much more transparent and methodical about what they're doing leading up to this decision. How is this process different from the CMS compared to the FDA?

Karlawish: I will say CMS compared to FDA has been more transparent and methodical with respect to soliciting public views, reviewing them, and responding to them. And in contrast I think FDA's listening session that occurred in January 2021 frankly was not a listening session because no one heard it other than the people that were in the room.

Chin: So now that you've explained these processes and the differences, what are your key takeaways from the CMS proposal?

Karlawish: Well, the key takeaway from CMS is they're essentially trying to tidy up, I think, what FDA's mistakes were. Namely, you know, FDA approved a drug under accelerated approval, clearly acknowledging that the drug is not safe and effective. It has an effect on a biomarker that may translate into clinical efficacy but another study is needed to prove that and FDA is mandating Biogen do that. Now usually you should think that that trial should be up and running and going with a timeline of when the data are going to come in before you grant accelerated approval. That, of course, is not the case. Biogen has yet to even get that study launched. They may get a protocol out in the next few months. So essentially FDA handed CMS a bit of a challenge, which is here's a drug that's not safe and effective, you have to decide whether it's reasonable and necessary for a very vast patient population. The drug has documented risks, real risks that were detected in the meticulous setting of a clinical trials world. Now we want to put it out into a clinical practice and we're not sure it works. And I think CMS said this is just not going to be something we should widely cover. We need to get more evidence that it's actually safe and effective. and indeed the crux of their decision was given the known risks and the lack of evidence of benefit ,this drug needs more study. And so that's what they've proposed which is - we will pay for the drug and the necessary imaging to determine someone has elevated amyloid if the person is enrolled in a randomized and controlled trial that is designed to show the drug produces clinically meaningful benefit. And in addition, the trial should have a design and recruitment strategies, etc, that give a reasonable likelihood that the patient population is representative of a patient population of persons with Alzheimer's disease in the United States - meaning the diversity in terms of ethnicity, race gender, et cetera.

Chin: And so that's what they mean by coverage with evidence development?

Karlawish: That's right, that's right. We will cover the drug, we'll pay for it, but it has to be in the context of getting some evidence and in this case, evidence meant a randomized controlled trial. And you can go to CMS's website and they have a whole page devoted to coverage with evidence development, and you can see there are a variety of different therapeutics and some diagnostics that are under coverage with evidence development - some stem cell therapies, et cetera, that they're asking… that they are saying we'll pay for it but it has to be in the context of some sort of study. So this is not without precedent. It's not common that they do it, but they've done it before as they've done with amyloid imaging for example.

Chin: And so this is kind of a nuanced question but, when you say coverage - in general when we think about CMS covering medications and treatments they are in essence paying a healthcare system for providing care - but in this regard coverage is actually for a research randomized controlled trial, so who is CMS actually paying? And who's being charged the costs of that drug initially?

Karlawish: That's a little outside my wheelhouse but you're touching on a very interesting issue, which is - I think CMS is going to need to clarify this - which is the copay that surrounds the drug is, of course, paid for by the patient. So, you know, if you write me a prescription for  Aduhelm, I'll get a copay and I'll pay for it. But if you write me a prescription for Aduhelm in the clinical trial, I might be getting Aduhelm or placebo, so am I going to pay a copay on a placebo? And I kind of have to get my head around that. I realize, well if you're in equipoise about whether it's better than placebo, fine. But I think at least psychologically, I think you're have a hard time convincing a patient and a family member - give us a copay for what might be placebo in a clinical trial. Usually people don't pay to be in research, I guess that's my point. In other words we don't say to people, give me a couple thousand dollars a year to be in my research study. In fact, we pay them - which we should because research is work. It's labor and you should pay people to do work, not not pay them. I don't think we pay people enough to be in research. I think they're just going to have to tidy that issue up about the copay and probably cover the copay is what they'll have to do. I mean the American taxpayers paying for what Biogen should have been doing all along, so let's face it I mean that's the problem here. (laughs)

Chin: And I'm glad you answered it that way because I had so many questions when this comes up. You know, who pays for the visits? Who pays for the placebo? There are blood draws. You mentioned an amyloid scan but what about MRI scans and the staff time to work on the actual clinical trial. It doesn't sound like CMS will pay for those things. That's still going to fall under a grant which ends up being taxpayers because it's through the NIH. Is that sound…

Karlawish: Or well, they say - they talk about NIH can hand us a study to do this but I don't see why, for example, Biogen couldn't say, ‘Hey we'll do this study’. In fact Biogen is going to do this study. Namely they're mandated to by FDA and they said in December of last year, just a month ago, that they're going to release the design of the study that's the confirmatory trial. I had a conversation with someone from Biogen last week and - you know, no surprise, still working on it. No details to come. You know, well, I'm sure they're working on it, but I'm sure there were details I could've heard but he didn't want to tell me and that's fine. Like so be it, whatever. Look, this is a process. This is going to work itself out. You know, there will be a trial done by someone, or not. I mean, maybe no one will have the gumption to say, ‘I don't want to spend the money on this,’ because frankly, that's what most major insurers so far have said. I mean most of the CMS contractors who administer CMS benefits such as the Blue Cross and Blue Shield plans, et cetera. They've said, we're not paying for this. The Veterans Administration has said that. And it's quite possible people say, look, you know this is just not working and so let's just wait for the other drugs to finish their phase three trials, the other drugs meaning the other monoclonal antibodies.

Chin: And actually that's perfect segue because, does this decision apply to these future potential drugs, these other monoclonal antibodies that are being studied?

Karlawish: It does because the decision is not CMS coverage of Aduhelm. It's interesting CMS asked for people to comment on coverage for monoclonal antibodies for the treatment of Alzheimer's, obviously one of which is Aduhelm because it's the one that's FDA approved as of June 7th of 2021. But the coverage of evidence development applies to all monoclonal antibodies. Now, of course, there's only one out there as we said. And in their memorandum - which you can go online and read - they reviewed all the data on monoclonal antibodies, you know gantenerumab, solanezumab, canumab, etc, and that informed their decision. Now one of the criticisms, therefore, of what CMS did was - well now, wait a minute, what if one of those other drugs comes out and see an FDA has said this drug is safe and effective. This drug has some meaningful clinical benefit. Well, I guess my response would be, I would think CMS would go back and say well we should re-review that new data because they review the data that are out there which is the only data that are there. They can't fantasize about future data. You know, so I have the hunch they would re-review and say, well, based on these new data, here's our new decision around coverage. We’ll cover it. We still want evidence, but maybe the evidence they would ask for at that point… Let's say company X produces a drug that in phase three shows clear benefit. You could imagine CMS saying, Okay we still want evidence, but it's about safety. In other words, we'll pay for the drug, open label use, but we want someone in a registry to better understand safety issues. Because in wide clinical practice - as you and I both know - in clinical trials drugs have risks. In wide clinical practice, they generally are riskier because people have more diseases. There's a sloppier use than in clinical trials etc. So I don't buy the argument that this will stifle the development of the class of drugs. I buy the argument that it’s based on the data now and the one drug that's available. This is what we'll do. If more data comes in, we'll re-review it and we'll change the decision. 

Chin: So then how does this impact patients - not research participants - patients currently receiving the medication in a clinic environment and the physicians who are prescribing aducanumab in their clinics?

Karlawish: Well, right now I think only about 200 patients, I’m guessing, have gotten the drug because Biogen reported sales of three hundred thousand last quarter. If you figure out given the price of the drug and what per vial, that's just a few hundred people at most who have gotten the drug. And indeed that's been the case. So what this means is if you want to take the drug now, there needs to be a trial and you're going to have to find a trial site and get into the trial site. And of course this is a challenge. This will limit access. I totally agree with Harry Johns, president and CEO of the Alzheimer Association, that this will limit access to people who can get to a study site and that has been an ongoing challenge and problem for access to research for decades in America, absolutely.

Chin: Well, actually that's the next one I wanted to talk about because the Alzheimer's Association did release a pretty powerful statement saying that equity and access are important issues. It's particularly important when it comes to clinical research because having underrepresented people truly represented will lead to adequate and reliable data when it comes to actual therapies out in the public. And doing this where now you'd have to be at an academic research center for the most part could limit that access. So what is your response, then, to that kind of rebuttal to the CMS decision? 

Karlawish: Well, there's two equity issues that are being blended in to the Association's response to this CMS's proposal. One is what you've said which is access to clinical trials. That - as I said - has been an issue for decades, including the trials ENGAGE and EMERGE trials that Biogen did with aducanumab. I mean there were a handful - literally you could count them - of individuals of color in that study, in those studies. Now a company has no obligation to assure diversity in their trials, but Medicare, being a public servant has, I think, a greater warrant to say, we want evidence and we need evidence about how this drug works in the American people. So I applaud them for saying the studies that we’ll do need to be able to get a representative population. So I have a little challenge with, you know, the Association's criticism which is well, you know, then this will be part of the solution which is adequately fund the study and make the effort to make it diverse. The other aspect of equity though is, well, by not making this drug available in clinical practice, it further enhances the inequities of that - of treatment of underrepresented, underserved communities in America. And I guess when I follow that logic I say, so what you're saying is is that a drug that has not been shown to be safe and effective, that carries real risks, a large copay, is the solution to the inequities that have existed for decades in diagnostics and therapeutics and Alzheimer's disease? I find that staggering. I don't - I can't walk my way into that and say, yeah I see what you're saying, you're right. We need to approve, you know under accelerated approval, risky intravenous infused drugs to be able to improve the diagnostics of persons of color in America. I find that shocking. I think we could improve the diagnostics of underrepresented communities in America and access to good care by creating a network of memory centers, adequately staffed and funded. We don't need a questionably effective risky drug to do that. In fact, I find that to be somewhat rude.

Chin: Do you think it's harder though, not just the long underserved communities based on race but also geographic location. And so those in rural parts of the country, it's harder to get to an academic center and do infusions every two weeks.

Karlawish: It's harder to get access to a memory center, never mind aduhelm. If we walked the clock back to 2019, access to memory centers were limited to institutions that had some sort of general research operation because research, frankly, was the cross-subsidy that keeps most memory centers going. I mean, in my book I narrate the one memory center I could find that was not academic and or a clinical trial shop was Memory Cares in Asheville, North Carolina, and the way Dr. Peggy Noel got that going was - charge Medicare what we can, charge the caregiver a separate fee for caregiver education and training, and then go out and raise money as best we can amongst the community of Asheville. And you know by - and she's lucky, and she'll tell you, I'm lucky to have succeeded. So you know this is not about Aduhelm. This is about America's lack of will to spend the necessary resources to create an infrastructure of long-term care services and supports for older adults with disabling cognitive impairments. That it has to be a conversation about Aduhelm shows you how we're over reliant on the biopharma industry for innovations and improvements in care in America.

Chin: So what do you say to your patients in clinic who are hoping for a new therapy, that have been sort of waiting for something like aducanumab prior to the FDA approval? While it's not a cure but having something, some form of meaningful treatment. So given this back and forth with the FDA and CMS, what do you say now - after this or let's say after April 11th when the final decision comes out - what do you tell patients who are looking for something beyond the two drugs that we have since 2003?

Karlawish: I am optimistic that something is going to break, something's going to work. Aduhelm may work. It actually may work and if there is a study of Aduhelm to fulfill the CMS requirements or even the FDA's requirements for Aduhelm, our center, for example, is very interested in looking at that protocol and I think the odds are we would do it because I think the drug may work. So too some of the other monoclonal antibodies that are out there. I disagree with the notion that there's been no progress. There's absolutely been no new therapeutic until about nine months ago - that is absolutely correct - or six months ago, but if you look at the progress in the last few years with respect to biomarker identification, target engagement, things are looking pretty encouraging. And in some sense aducanumab has been a bad bump on the road that has revealed some of the faults in our system. So you know, it's encouraging that folks who are in our clinical trials at our site are still in the trials keen to continue. Many of them actually when faced with the decision, gee, I could take this drug that's available if it becomes available clinically - which right now it might not because of the coverage of evidence development - versus stay in the clinical trial I'm in, most have said I'm going to stay in the clinical trial.

Chin: And one of the key aspects of all of this has been clinically meaningful outcome and that's of course being debated. And so as a physician treating people who are experiencing cognitive changes - some of which are due to Alzheimer's disease - how do you define clinically meaningful outcome in regards to therapy, not necessarily medication, just in general clinically meaningful outcome?

Karlawish: Yeah. The problem of dementia is disability - disabling cognitive impairments - and disability means troubles with day-to-day function. And so I am in the camp that says, show me the drug has an effect upon the decline in function seen in persons with Alzheimer's disease, dementia and that's the conversation to have. So in that sense I find some of these scales that mix together cognition and function into a metric scale, it kind of hides the bottom line which is how am I doing in my daily life. How's my mom, my dad, my partner, doing in their daily life? I think the use of the clinical dementia rating - the CDR - as a metric measure, one of the problems has been it really is an ordinal measure. Point five, one, two, three you know, one, whatever - how are you? A, B, C, D. And it really should be how many people move from point five to one or one to two. I think the use of the sum of boxes score and then a statistical test to see if that difference between the two sum boxes scores is significant is starting to dilute the ability to see whether this means anything to patients, and I think that was one of the controversies that surrounded even the positive result that was seen. I always get confused which one was positive but whatever, EMERGE or whatever it was. And even worse there, it was a relative ratio to yield a 20% difference, not an absolute difference, and so, you know, it's disappointing. But this has been a problem that's haunted the Alzheimer's field for a while, which is cardiovascular disease, most other diseases of aging, the ways we talk about benefit are very coherent - death, hip fracture, stroke, heart attack. There's zero one events, either you have it or you didn't. People know what they mean. In our field, we struggle with translating our benefits, the way we talk about benefit in a research setting, into clinical practice. 

Chin: Well then to end, Jason, going forward after April 11th, how does the Alzheimer's disease research field pivot? What does the future look like for 2022 and 2023?

Karlawish: Little ambiguous. We'll see. I do hope - I really hope that the FDA decision doesn't set a precedent for more accelerated approvals of monoclonal antibodies. Unfortunately, if we look at what they've done with the therapies for muscular dystrophy - you know, Exondys and Vyondys and Amondys - these were therapies all approved under accelerated approval. It's a little frightening the data that got those drugs into clinical practice. They didn't make it into the media because Duchenne isn't a big common disease, although the drugs are very expensive. If past performance predicts future behavior, we're in for a wild ride with FDA here. I hope that FDA has learned a lesson from the events of the last six months, that this shift that they've made in their behavior as a regulatory agency to be far more deferential to innovation and the marketplace is a shift they need to walk back from. Maybe under the new FDA commissioner, Dr Caliph, we’ll see that, but we'll see.

Chin: Well, as always this has been a very interesting conversation. Thank you, Jason, for your perspective on this recent development withCMS proposal. Thank you very much.

Karlawish: Thank you, Nate. Great to be here.

Outro: Thanks for listening to Dementia Matters. Be sure to follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you get your podcasts to be notified about upcoming episodes. You can also listen to our show by asking your smart speaker to play the Dementia Matters podcast. And please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. 

Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers.

This episode of Dementia Matters was produced by Rebecca Wasieleski and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions.

To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at You can also follow our Facebook page at Wisconsin Alzheimer’s Disease Research Center and our Twitter @wisconsinadrc. If you have any questions or comments, email us at Thanks for listening.