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The FDA label for the amyloid antibody aducanumab (Aduhelm) started off exceedingly broad, basically including anyone with Alzheimer’s disease, but was subsequently narrowed to to patients with mild cognitive impairment (MCI) or mild dementia due to Alzheimer disease (AD). Should, though, the label be even more restrictive to mirror the populations studied in the two still unpublished trials of the drug, EMERGE and ENGAGE?  Or should CMS consider restricting coverage for aducanumab to populations meeting trial eligibility criteria and requiring additional evidence on clinical outcomes in groups excluded from the trials?

In today’s podcast, we talk with Tim Anderson and Marco Canevelli, the authors of two recent articles published about the real world eligibility of aducanumab:

Tim Anderson was first author of a JAMA research letter that found that more than 92% of Medicare beneficiaries with Alzheimer’s Dementia and 85% of those with MCI would have been excluded in the clinical trials of aducanumab based on their age or comorbid conditions.

Marco was first author of a JAGS letter to the editor that systematically applied the EMERGE and ENGAGE exclusions to 911 patients with cognitive complaints who went to A geriatric outpatient unit in Milan (Italy). Only six patients (i.e., 0.66%) of these patients would potentially be candidates to aducanumab.

For more podcasts on aducanumab, check out these two:

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

Alex: This is Alex Smith.

Eric: And Alex, who do we have with us today?

Alex: Today we have some far-flung guests. We have Marco Canevelli, who is a neurologist and research associate at the Sapienza University in Rome, Italy, joining us. Welcome to the GeriPal Podcast, Marco.

Marco: Thank you. Good morning, everyone.

Alex: And we have Tim Anderson, who’s a general internist and researcher in the Division of General Medicine at Beth Israel Deaconess Medical Center in Harvard Med School. Welcome to the GeriPal Podcast, Tim.

Tim: Thanks for having me, Alex and Eric.

Eric: And we’re going to be talking about two articles that just got published not too long ago. Tim’s article in JAMA. Was it JAMA IM? I believe, on the representativeness of participants enrolled in clinical trials on Aducanumab, my favorite topic, and also Marco’s article on Real World Eligibility for Aducanumab, basically looking at the two trials for Aducanumab, do the population study look like the populations that we’re potentially going to give this drug to? We’re going to talk a lot about other things as well, but before we do, you have a topic? Not a topic, we have a topic. Do you have a song request? I’m used to noon Podcast. This is a 8:00 AM Podcast-

Alex: It’s early for us. We had to start really early so we could do this with Marco in Italy.

Eric: It was JAMA, right, Tim?

Tim: It was JAMA.

Eric: Do you got a song request for Alex?

Tim: I do. I was hoping to hear I Can See Clearly Now. We’re talking about a drug for which there’s been a lot of clouding and a lot of shadowing. And I think both Marco and I have been interested in trying to see more clearly about Aducanumab, and that’s the inspiration for this song request.

Alex: Nice link. I’ll also mention that Tim actually had some even better song requests that I couldn’t quite pull off in the time that we had. Tim, you want to just say what those other requests were?

Tim: So my first choice was All About the Benjamins. I think also apropro for the topic. Though, I realize hip hop may not be quite so well suited for your acoustic guitar. [laughter]

Alex: That would be a good one. All right. Well, here’s a little bit of, I Can See Clearly Now.

Alex: (Singing).

Alex: So optimistic.

Eric: Tim, is that why you picked this song? Because Aducanumab or Aduhelm is such an effective drug that it’s giving hope for a cure for Alzheimer’s disease?

Tim: I’ll bite my tongue at the answer to that one. But I think it’s, if nothing else worth celebrating the optimism of folks paying close attention to drug approvals, as we are not the first guests on the GeriPal Podcast, I think to be talking about Aducanumab. So, I’ll be optimistic on transparency through GeriPal.

Eric: Well, since Tim mentioned it, for all the guests, we’re going to be talking with Aducanumab. And for all of our listeners, we have had two Podcasts on it already, one with Gil Rabinovici on amyloid, all things amyloid, including amyloid Aducanumab at amyloid PET scans that was from April, and another one with Aaron Kesselheim, and Jason Karlawish on the approval process and what Aducanumab is, and what went wrong with the approval process. And that was from July 29th of this year. And today we’re going to talk about, okay, now, what does it look like in real world practice? And that’s a why I love these two articles in JAGS and JAMA. Marco, can I turn to you first? First of all, how are things going in Rome right now, in Italy, with COVID?

Marco: Yeah. Fortunately, are definitely better than some months ago and last year, especially so things in Rome were relatively better than the rest of the country since the beginning of the pandemic fortunately. But now, there is a very high vaccination rate, so things are definitely better. So, thanks.

Eric: That’s good to hear.

Marco: Yeah.

Eric: Yeah. Happy to hear that.

Marco: Also patients attending our outpatient services are now increasing in numbers. So, also the dementia care and support is now definitely more closer to our standards before the pandemic.

Eric: And, what does your clinical practice look like?

Marco: Yeah, I work in a outpatient memory clinic. In Italy, we call memory clinics a center for dementias and cognitive disorders. And, I spend most of my clinical activities with patients with mild cognitive impairment and dementia. Yeah.

Eric: So, is that how you got interested in looking at the real world eligibility for Aducanumab?

Marco: I was always been attracted by these enormous gaps between the populations that are enrolled in clinical trials, in research protocols and the patients that I daily encounter in my daily practice. And, it’s something that I had already addressed with some geriatric colleagues. I work a lot with geriatricians and less with neurologists. I am a typical neurologist, I think. And so, we explore for example, the reporting of important variables in research protocols, such as age, sex, comorbidities or concomitant treatments that are something that represent the main part of my daily activities, and this information is almost completely missing in the research records from clinical trials. And, this may generate what is known as the evidence-based medicine issue in the care for the people. So, we treat with drugs and intervention, people that are completely different from those that were enrolled in in research protocols. So, disease is an enormous problem to me.

Eric: And how about you, Tim? How’d you get interested this as a subject.

Tim: So, I’m a primary care doc when not playing around with large data sets. And I, amongst almost all new drugs, if there ends up being a commercial on it sooner or later, it’s a conversation that I have with one patient or another. And Aducanumab felt like one of these things that was getting so much news coverage that trying to understand even those early questions that I’m one likely to get for patients. And often, it’s healthy folks who do not have dementia, who are just saying, “Sometimes I forget a name, should I be on this drug?” Is almost how people enter into primary care. I will say that similar to Marco, this question about the gap between who is studied and who gets a medicine, is something that probably pre-dates my interest in Aducanumab. It’s something I’ve had the fortune to study when it comes to the use of things like antihypertensives in older adults and other disease states, and often finding that trials aren’t entirely representative of our patients, but that not all trials are the same. There may be very, very different reasons that certain trials exclude certain folks compared to others. And so, it’s a growing topic of fascination, both to reflect how we talk to patients, but also sometimes how we train our, our students and our residents and the folks who are with us in the clinic.

Eric: Okay. Maybe we can step back, why are trials not representative? What are the reasons that when you create these studies that you may create a study that is not representative of the patient population that you actually are hoping it to give it to?

Alex: You mean from the drug company’s perspective?

Eric: I think from the general perspective, maybe we can list some potential reasons.

Marco: I think that this is somehow reasonable from the point of view of the companies. For example, Alzheimer’s disease is extremely heterogeneous in terms of biological mechanisms, in terms of cognitive trajectories over time. So, you need to apply some strict criteria to modernize the samples. It’s something that I may understand, of course. For example, you need to identify those patients that have amyloid burden at the PET scan or have a specific cognitive profile.

Eric: Great. So, if you have a drug that takes away amyloid, you should probably focused on those with amyloid in the brain. Important thing that the FDA left out early on, I think in their labeling. They should probably read the study a little closer. So, great. So, if you’re going to give a drug for acute coronary syndrome, you should probably include just those people with acute coronary syndrome. If you’re going to give a drug that takes away amyloid focus on amyloid. What are some other reasons?

Tim: I need to think another big one that is understandable and common are these large safety risks. So, if we know a drug might promote bleeding or might promote something along those lines, in an explanatory trial, you might not want to include people who have conditions or take medicines really prone to bleeding which is, I think relevant to Aducanumab. That also though I think becomes important if the drugs are talking about are ones that are used by a large amount of the population. It’s one thing I think if you’re excluding a drug 1% of people take, and another thing when we’re talking about medicines that 20% or 30% of older adults take.

Eric: Great. And, I’m going to put my Ken Covinsky cap on age. I often see age as a factor to exclude people from trials. I think Emerge and Engage the two trials for Aducanumab excluded people who are older than age 85. Why exclude older adults? It seems like that’s a population that may get this drug.

Marco: Yeah. I don’t have the explanation for you. Of course, almost all trials adopt upper age limits. So, this is not just Emerge and Engage, and why we encounter a lot of patients age more than 85 years in our daily practice. So, of course there is the burden of comorbidities. There are also some more difficulties at reaching the clinical sites or the research site for taking the intervention, but we have to include all people or the old, also to have real evidence based medicine interventions. Yeah.

Tim: Yeah. I think that perhaps there are certain diseases where certain age ranges make sense because of competing risks of other causes of morbidity and mortality. But in this case, particularly when studying dementia or when studying any disease that is particularly prevalent amongst older adults, putting an old age cap makes little scientific sense that I can rationale. I can see, I think they also put a minimum age of 50 cap, which made a little more sense in that if you have dementia under age 50, it may not be Alzheimer’s or maybe a specific variant, but I can’t think of reason to say that a 85-year-old is different than an 84-year-old with dementia.

Eric: All right. So, it sounds like there are some reasonable scientific reasons to have good inclusion exclusion criteria, and there are some that maybe don’t make a whole lot of sense, and some that you’re potentially using to really show a benefit and minimize harms. What does it look like then when it gets transferred to the real world? Tim, I’m going to start off with your article in JAMA, Research Letter, September 9th. And what did you do?

Tim: So, we tried to take a pretty simple approach of asking the question of, amongst patients with Medicare in the United States, which is most older adults, how often do the patients who have a diagnosis of dementia or of mild cognitive impairment, have one or more of the different exclusion criteria from the two trials for Aducanumab? And, we did this using insurance claims, which is not perfect, but it’s not a bad estimate in that, to know that you need an exclusion criteria, a doctor must have diagnosed you with that criteria. And so, we looked at all the different criteria that the companies had posted as their exclusion criteria publicly and applied those to about three million or so Medicare beneficiaries who had a diagnosis of dementia in the US in 2018. Finding that only about 10% would’ve met trial inclusion criteria with the remaining 90% meeting one. But in most cases, more like two, three, and sometimes four or more different exclusion criteria including some of the things we talked about, like being over 85, but perhaps I think most commonly having other comorbidities or being on medications that would’ve excluded them out from being in the Aducanumab trials.

Eric: That’s a lot. So, nine out of 10 would be excluded from these trials. What were the big exclusion one, reasons again?

Tim: So, the biggest we found, one was pre-existing heart disease or cardiovascular disease, which is a challenging one, because obviously that’s a very common syndrome in old age. And also, there’s a lot of links between dementia, cardiovascular disease. So, it’s a tricky one. The other ones we found were chronic kidney disease and having conditions for which people usually get blood thinner. So, conditions like atrial fibrillation or history of blood clots or certain types of heart problems for which people are on blood thinners regularly

Eric: And, in the trial Emerge and Engage, so those are the two trials looking at Aducanumab, they excluded folks who were on anticoagulation. So, medications like warfarin or strong antiplatelet agents. Is that right?

Tim: Correct. The way it’s at least publicly written on the ClinicalTrials websites is if you were on a full dose aspirin, then that would be an exclusion criteria. Baby aspirin was allowed, but anything stronger than that.

Eric: What are the practical implications of your findings?

Tim: Well, I think the reason we were so focused on Medicare specifically is as Medicare is now in a decision in the United States of deciding what the confines of paying for this medicine are? They’re likely to be the big payer who decides whether this is worth the investment. And the FDA who approved the drug in the United States put no limits related to these exclusion criteria. They’ve proved them for anyone with cognitive impairment or mild dementia. And so, we hope that both clinicians will read these findings, but also that honestly Medicare will think about these findings when they decide what are the bounds of what they’re feeling will feel comfortable to pay with, to pay for Aducanumab. What are those scenarios? And there is a history of Medicare occasionally requiring either additional evidence to be generated for them to cover drugs fully or requiring that the only time they’ll pay for the drug is if folks are enrolled in certain sort of studies, so that if we are going to give the drugs to people who were not in these trials, we’re at least getting data to understand if that’s helpful or hurtful rather than just doing it blindly.

Eric: All right. So, what I’m reading about AMA right now is that it really should be prescribed by folks who have expertise in dementia, neurologists, geriatricians, and the like potentially specific centers. So Tim, your article is great, but maybe real world application, we have to look at the eligibility of these drugs in those specific centers. Marco, is that what you did?

Marco: Yeah. And, that is even lower than what estimated by Tim. Yeah, I read with great interest the paper in JAMA by Tim. Congratulations on this. And, we had a similar idea, I think that was to apply the eligibility criteria that were adopted in the Emerge and Engage trials on clinical population. And so, we considered a representative sample of patients that were almost 900 patients referred to a geriatric outpatient unit in in a university hospital in Milan, with my friend and colleague, Matt [inaudible], and all these patients had a cognitive complaint. And so, we sequentially applied all the inclusion exclusion criteria. So, the age limits, the education, the need for a former caregiver paying attention to the patient, the clinical condition of MCI or mild ID with mini-mental state combination not lower than 24. So, all the eligibility criteria.

Marco: And so, we found that just six patients out of the 911 that were considered the beginning resulted as potentially eligible to receive Aducanumab if this eligibility criteria were applied. So, there was less than 1% of the overall population, and most of patients were excluded because of the age limit, because of the low educational level, because they were living alone. So, they didn’t have a caregiver because of comorbidities, because they had known Alzheimer’s disease dementia of a higher severity. So, we created a flow chart where at each step, a lot of patients were excluded. So, we remained with just six patients, it was. And what I think that was even more, I say dangerous, is the gap between the number of eligible patients that would be obtained if the FDA indication are applied to this population, because the number is definitely higher. The FDA doesn’t explicitly include some exclusion criteria for age or comorbidities, or even for the PET scan, of course. So, the number of eligible patients becomes extremely higher. It’s nearly 35%. So, there is a gap between 1% and 35% that may be dangerous in regular practice.

Eric: I want to ask, what the hell FDA? But, why is it still the label for Aducanumab, given both of your studies, these huge exclusion criteria, why is the label so broad?

Marco: It’s hard to express my opinion on this, or it’s extremely easy, but I am also surprised by the fact that the amyloid [inaudible] is not mentioned while it is one of the main entry criteria in the trials. And also there is a conditional, of course, I’m Italian, I’m not a native English speaking, but there is a “should be” used in NCI patients and mild [inaudible] patients. So theoretically, I can use this drug, even in patients with a more severe cognitive and functional impairment. So, there is a huge gap between the registration trials and the indications. Yeah.

Eric: Yeah.

Tim: And, I’ll just add that I’m a little surprised that the FDA, or to be honest, the manufacturer hasn’t thought about requesting a change in their labeling, which is what happened in the initial labeling, that it was not limited to folks with mild disease, but initially labeled for everyone. And in part after a lot of public discussion, it felt they changed that label down to the trial studied in terms of inclusion population. I think I wouldn’t expect the age limits and things to end up making it into the FDA, but certain especially safety concerns about other conditions. And those pieces just feel like something that naturally is often in FDA labeling when it comes to other new drugs, certainly something we see with new cancer drugs, new heart drugs, where chronic kidneys disease and things like that are all the time in the FDA label, as at a minimum used with caution, at a maximum don’t use until we have further research. So, I think it’s a drastic change in labeling compared to other new therapeutics.

Eric: Which is interesting, like ARIA-H, so the big side effect that we see with Aducanumab is aria and specifically, basically micro brain bleeds. And my understanding is that based on previous trials of anti-amyloid antibodies found out that potentially as a safety signal with anticoagulants, and new studies are excluding patients specifically who are on anticoagulants, antithrombotics. Why not include that, since we have data that, “Hey, there is a safety concern. We’re going to exclude these patients from the trials. Why not include that as a contraindication, either of you?

Alex: I don’t know how FDA makes these decisions. There’s so many decisions that we could question from approval of Aducanumab on. Yeah, it’s a good question, but I don’t know that we know what they’re thinking.

Marco: Maybe there is the need or the ambition of targeting all the entire ad population. And so, they don’t explicitly mention exclusion or inclusion criteria, but I don’t know.

Alex: Marco, you are in Italy, of course in Rome, and Italy is not beholden to whatever the FDA says or does. So, do you have your own FDA equivalent there? And, what is the approval process like there?

Marco: Yeah, so since I think November, 2020, Aducanumab is also under review at the EMA is the European Medicine Agency, following a standard procedure. So, Aducanumab is not under accelerated approval procedure, like in the US for the FDA. And usually, there is a very high concordance between these entities, FDA and the EMA. So, the majority of drugs that are approved by the FDA at the end are also approved by the EMA, but there are some differences in the validation of surrogate or intermediate endpoint, and also the two assessment are conducted at different times, so there are also other evidence that may be provided by the manufacturer, Biogen in this case. And so, we are extremely curious about this because then EMA should approve the drug, and then the results an Italian agency for the drug that should assess this-

Alex: Right. They could come up with their own exclusion criteria, which they could mirror the FDA, which is very generous exclusion criteria, or they could mirror what they did in the original studies in Engage and Emerge.

Marco: Yeah. It has to replicate somehow the eligibility criteria that were adopted in the registration trials, of course. Yeah.

Alex: And Tim and Eric, I’m not sure if you’re following the CMS process. My understanding is the Centers for Medicare and Medicaid who will decide on whether to approve Aducanumab for under part B Medicare prescribing, because it’s an infusion and not like a pill that you’d have under part D, they won’t make a decision until sometime early in 2022 is what I heard. Have you heard anything different?

Tim: That’s my understanding as well. And I know there’s been an open comment period that I believe is still open this month, though it may be closing in which colleagues have submitted essentially requests for this exact consideration, as well as, I think there’s a request from all interested parties from patient groups to sponsors. And so, it’s certainly an area that folks who feel passionately about this, can directly comment to the FDA and the idea of their processes that they’re trying to take in all of those stakeholder groups to make the coverage determination. And I think some of the most interesting literature out there comes from policy in journals like Health Affairs, talking about all the creative ways the CMS could approve Aducanumab, either in only certain populations or only with certain strings attached. And so, my hope is that, if it is covered, it’ll be covered with an eye towards generating data, sooner than the 10 year window that the FDA asked for additional data from the manufacturer.

Alex: Yeah.

Eric: And I guess the one caveat too, is I’m pretty sure Medicaid will actually need to cover that because they have to cover all FDA approved drugs. So, that may be a separate process. Tim, do you know anything about that?

Tim: I will confess to not being a very wise expert when it comes to Medicaid coverage. I think you’re right in terms of there being a direct requirement about coverage approval, but I don’t know whether there’s ways for that to be limited in certain forms. I think the challenge there is Medicaid, at a state level has a fixed budget. So, if they have to cover it and there’s a lot of demand, that can mean they have to cut what they’ll cover in other fields of medicine.

Eric: Yeah. It’s good that they have to make that choice on a drug that if it works, it works barely at all. Still big if.

Alex: And Tim, you mentioned that there’s an open comment period to CMS, and I just wanted to note that the American Geriatric Society wrote a terrific letter. Eric, I think you may have been involved in this, is that right? The drafting of that letter.

Eric: Minimally.

Alex: Minimally, but to some extent. And one point that they bring up in their letter which we’ll include a link to it in the show notes to this Podcast, is really the lack of representativeness by race and ethnicity in the Engage in Emerge trials. And we’ve talked about this a little bit on our prior Podcast, what did they have? Something like six, I’m seeing Eric nod, six black participants.

Eric: So in the high dose Emerge study, so the only group that showed a difference, there were six black participants who identified as black in that study. So, really all of this for… I think it’s one of the biggest issues right now in dementia research is issues about representativeness, not just on inclusion, exclusion criteria, but the diversity of subjects.

Alex: Right. Yeah. There’s a real potential here, for Aducanumab approval and prescribing to exacerbate existing disparities in Alzheimer’s disease, dementia care. And that, we know that blacks and African-Americans are disproportionately affected by Alzheimer’s disease, and that the approval… And one of the things that AGS encourages CMS to do is to monitor the disparities in uptake and use of Aducanumab over time, and to provide supportive services to people who are living with Alzheimer’s disease who are prescribed Aducanumab, and specifically their language is that CMS must require longitudinal data collection in order to ensure that CMS understands how Aducanumab is being prescribed and administered in the real world, here’s the title of our Podcast, e.g to understand who is getting the product.

Alex: This is particularly important, given lack of trial data from the following patient populations, underrepresented, disproportionately affected, and understudied populations, e.g black people living with Alzheimer’s disease, and people living with Alzheimer’s disease who are excluded from phase three clinical trials, including people over the age of 85, as we’ve discussed, patients with other concurrent or previous neurologic pathophysiology, and people who were on anticoagulation therapy. So, I think judging by the way things are going, my sense is CMS will probably approve it in some form, and it may be a limited form as Tim was talking about earlier, and that it is essential that we monitor post-approval, who is getting the drug, what the impacts are, and hopefully what the outcomes are of prescribing Aducanumab.

Eric: Yeah, and I think that the danger here is people are also using the diversity angle to try to get CMS to fully approve this drug, that it would worsen disparities in care if they don’t get this covered because of the sheer cost. Who can afford, not just $56,000 a year for the drug, but add on another $50,000 a year for MRIs and PET scans and everything else that you need to do to get this drug. So, you run a risk of worsening disparities by not approving this drug. With that said, it’s a drug that if it works, it barely works. And there’s a really good chance that it doesn’t work at all, and if you look at the trials. So, there’s a really fabulous JAMA Neurology paper by Jennifer Manley and Maria Glymour, that goes over the approval. What Aducanumab’s approval reveals about Alzheimer’s disease research, and specifically they talk about only 0.6% of the people in the Aducanumab trials identified as black, 3% Hispanic 0.03% as American-Indian, or Alaskan native, and 0.03% as native Hawaiian or Pacific Islander. That’s terrible. And I think the problem is that a lot of where these studies occur, occur in memory centers in big places where a lot of the people who go there are white and wealthy.

Tim: Yeah. And I think this is a challenge. I think this gets mentioned in Maria and Jennifer’s article as well, but the NIH is able to say, “We have certain requirements when it comes to recruitment by age and by diversity.” And certainly, they’ve made a stronger push to be inclusive, but the NIH is not who funds new drug trials. Generally, the NIH is funding the initial thing that leads to the discovery of Aducanumab in the first place. And so, industry really gets to choose. And just like you said, they’re choosing by convenience of who comes into memory centers. And, if you haven’t essentially fixed the health equity access question, when it comes to who can access high quality neurologists, folks like Marco, then you haven’t been able to even start to recruit people to those trials. And, that becomes a bigger question that I’m not sure if the government can regulate how industry selects people, but I think that the attention to the initial just access to care gets overlooked quite a bit.

Alex: And Marco, in Italy, I’m sure there are issues with people living in very rural areas, not having access to specialized Alzheimer’s disease centers, where they have the capability to infuse and monitor people prescribed Aducanumab.

Marco: Yeah. There is this issue of diversity also of course in Europe and it’s a multicultural population. And so, there is the risk that for example, international migrants or people composing ethnic minorities will be excluded from the access to these treatments, for example, most of the measures and tests that have been adopted in Emerge and Engage, have been developed in Western contexts. So, they do not support a culture sensitive cognitive assessment. So, this may underestimate or overestimate the cognitive performance of patients. And of course, another risk implication of the approval of Aducanumab is that will increase the in inequalities in the access due to diagnosis and treatment because only the patients that have access to the highly specialized services that have frequent contacts with their GPs at least in Italy, will have access to a biomarker based diagnosis of Alzheimer’s disease, because for example, in Italy, not all the dementia facilities have a PET scan available.

Marco: And so this is, I think, one implication that there is not debate on this. If Aducanumab is approved in Europe, this will automatically translate into the clinical practice, a biomarkers based diagnosis of Alzheimer’s disease. And, we should know and we should remember that the clinical validation of this biomarkers is not completed. There is a real world problem, also in this area of research, because biomarkers should be validated in real world population of patients. And there are very few data that confirm that their validity of these biomarkers. So the accuracy to distinguish between AD and non-AD dementia is high also in real world population of patients. But the availability of disease modifying treatments of course, will render this biological based diagnosis of Alzheimer disease immediately available, immediately valid. And this is danger I think.

Eric: Yeah, so many things about that is dangerous, including the fact that we’re now using a surrogate marker, which is amyloid in the brain, as the reason to approve a drug, because reminder, FDA did not approve this based on the meaningful clinical findings of either Emerge or Engage. They base it on, “Hey, it reduces amyloid in the brain. So, that’s good enough for us to approve this drug, through an accelerated pathway.”

Marco: Yeah. There results are nice viewpoint on JAMA Neurology I think by Vincent Planche on the use of surrogate endpoint and amyloid load as a surrogate endpoint, is another methodological issues that should be addressed, because… Yeah.

Eric: Yeah. Okay. Tim, a question for you. Zooming out, beyond Aducanumab. So, this is not just a problem with Aducanumab. This is a problem with every drug, and Marco does a good job of bringing that back in, is that this is a problem of not even NIH. This is drug company sponsored trials creating these inclusion exclusion criteria to really enrich the base, but also for real scientific of reasons, you don’t want too much heterogeneity in your sample. If you’re going to study a drug to reduce amyloid, people should probably have amyloid in their brain. How do we fix this moving forward? Do you have any ideas?

Tim: So, I think that there is maybe a challenge between the need for explanatory trials or those really closely knit, small population, initial trials that may only have these hyper selected populations, and then the need for what often gets called pragmatic or almost real world trials. And, I think unfortunately, the discourse of drug approval is we have to approve things as fast as possible. And so, we get impatient. And initially, we were as sometimes doctors impatient, but now seems to be the FDA as well to not wait for those studies. I don’t think it necessarily makes sense to have exclusion criteria for every new drug that we have, but it does make sense to have staggered trials where you start in certain populations, if that’s working well, then you expand out. But that’s something that you have to really think about, like how we regulate drug approvals, and really say that either we’re going to make a conscious decision that when we approve it, we’re going to only go with studied groups.

Tim: We’re only going to go with studied groups and groups for which at least we’re not likely to harm them. And then maybe that last bar is those high risk people. I think weighing risk and benefits in unstudied groups is that important piece. The risk and benefit in an 86-year-old versus an 84-year-old is probably not that different. The risk can benefit in somebody on two anticoagulants versus somebody on nothing is probably quite a bit different. And so, I wonder if there’s a way to more develop that framework for doctors as well as the FDA to be able to quickly synthesize who these trials apply to. Unfortunately, it feels like rarely is there something we teach in medical education.

Eric: Yeah. I think potentially also thinking about it, new standard for medical journals is that, I don’t think it’s enough just to say, “I’m going to exclude these folks and here are my exclusions,” but why? Why did you include these folks? Why did you exclude these conditions like anticoagulation? Why did you do that? Greater than 85, why did you do that? Why does your sample include mostly just white people? Actually, addressing those… It could be in the supplement, but somewhere for us to figure out, what was the reason behind this exclusion?

Marco: Yeah. And also maybe a minimum core of information should be always provided in terms, for example, which is the proportion of patients that had diabetes? Which is the main comorbidities? Maybe in the supplementary material, of course, so that the clinician can somehow compare the population of the trial and the population that is encountering in the daily practice. For example, how many drugs, the mean number of drugs that the patients enrolled in the trial were taking. So the number, not the categories, so maybe for drugs. Okay. So, they can somehow try to understand their clinical complexity and compare with my population.

Eric: Yeah. Maybe that should be in the FDA label, where you actually see, this is the pie chart of what looks like for comorbidities in general, and this is the pie chart of what we’re including in this trial, or this is the percent of people that would be included 1% for Marco’s trial. 10% for Tim’s analysis. So you get a sense of like, maybe this is not generalizable to the patients that I care for.

Tim: I don’t see why these have to be separate studies that Marco and I do. Why can’t it be baked into the FDA approval documents as you said, or actually in that table, one is just another column of, this is the population of Alzheimer’s in the countries that we did our trial in, or something.

Eric: But wouldn’t it be great to have a table one, given that these studies are not even published yet? We’ve had three Podcasts on the subject. There’s been more editorials on Aducanumab-

Alex: The more we Podcast, the less likely they are to publish. [laughter]

Marco: So, stop Podcasts. [laughter]

Eric: Well, I want to thank both Marco and Tim for joining us on this Podcast. Before we end, Alex, do you want to give us a little bit more?

Alex: Yeah. Because, things are so bright and cheery.

Eric: Yeah.

Alex: I think I’m starting to understand this song was selected with a bit of irony.

Alex: (Singing)

Eric: I feel like that’s going to be the song at the Biogen Investor Conference. [laughter]

Alex: Although in the news, Biogen’s not doing so great. We have institutions like MGH and others who are not prescribing it. We’ll see.

Eric: Yeah. I think the problem that we’re going to see now is all of the other amyloid antibodies coming out. If they’ve approved Aduhelm, there’s no a reason not to improve all of these others that really have not shown to make a meaningful clinical difference, but they can reduce amyloid burden in the brain. It’s a logical fallacy not to approve them.

Alex: It’s all about the Benjamins.

Eric: All about the Benjamins. Tim and Marco, thank you for joining us.

Alex: One of these days, I will rap. [laughter]

Tim: I will wait for it. Every AGS, I’ll look for it, Alex. [laughter]

Eric: Thank you Archstone Foundation for your continued support. And to all of our listeners, thank you for supporting the GeriPal Podcast. Bye, everybody.

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