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TRANSCRIPT – Breakthrough or Breakdown: Should the FDA Have Approved the New Alzheimer’s Drug?

[Transcript created by voice recognition]

Danielle Pacia, The Hastings Center Hello and welcome to Breakthrough or Breakdown. Should the FDA have approved the new Alzheimer’s drug, a Hastings Center conversation? We are pleased to be joined by doctors Aaron S. Kesselheim, Jason Karlawish and Mildred Solomon. Both audience members will not be audible or visible during the webinar. We do hope for a strong audience participation. So please do ask questions and type them into the Q&A box at the bottom of your screen. We aren’t using the chat function, just the Q&A one. This webinar is being recorded and will be available on the Hastings Center website later today. It’s the 11th webinar the Hastings Center has sponsored since twenty twenty all on emerging ethical issues and health and health research. You can locate all of these on the Hastings Center website, thehastingscenter.org. Now, I would like to introduce Mildred Solomon, president of the Hastings Center, who will be leading us in this discussion.

Mildred Solomon, The Hastings Center Hello, everybody. Thank you, Dani. There are six hundred of you participating in this event and we thank you for joining us. A couple of weeks ago, the Food and Drug Administration made a decision to approve a new Alzheimer’s drug, as you can imagine. Also known by its brand name, Aduhelm, how the FDA chose not to approve Adhelm under their usual pathway because they acknowledged that the trials had not provided strong enough evidence of clinical benefit, but they did give it approval under their accelerated approval pathway. This is a special pathway that enables the FDA to approve drugs which show impact on a surrogate endpoint or a biomarker. In this case, the biomarker was the prevalence of amyloid plaque in the brain, which has been thought to be, though not proven to be, associated with cognitive impairment. Biomarkers are used rather than clinical improvements in disease or medical condition, because such trials usually would have to run longer to detect a clinical benefit. The FDA asserted that it wasn’t certain, but that it was reasonably likely that reductions in amyloid plaque could slow the progression of cognitive impairment and therefore how might demonstrate clinical benefit in future trials. Algae is the first drug approved for cognitive impairment in the last 18 years, the Alzheimer’s Association has hailed it as, quote, a new era in Alzheimer’s treatment and research, a new era. They see it as a new age and they believe it’s going to lead to a string of powerful new tools in the fight against the condition. On the other hand, numerous scientists, clinicians, bioethicists and policymakers have serious concerns about the drug’s efficacy, its side effects and the possible negative social, scientific and financial consequences of its approval. Perhaps most important is that in November 20 twenty, the FDA’s own advisory committee unanimously arrived at the conclusion that the clinical trials provided no convincing evidence of efficacy. Now such advisory committee findings are most often determinative, but the FDA went ahead with approval anyway. And in response, three committee members, one of whom is with us today, resigned in protest. Although the key dispute has been over the question of efficacy, the expected annual price tag, which has been set by Biogen, the drug maker, has added fuel to this fiery protest. Biogen has set an annual price tag of about fifty six thousand dollars, representing an annual cost to Medicare of anywhere between twenty nine and one hundred billion dollars, depending on the number of patients who take it occur. And in addition, there’s going to be costs for patients, for copays and for imaging studies that are required to screen for both eligibility and side effects. It’s been pointed out that at this price, the nation would be paying more for this questionably effective drug than the entire budget for NASA, our national space exploration program. In preparing this event, the Hastings Center sought, as we always do, to include people known to have contrasting views. We invited the FDA and the Alzheimer’s Association to send a representative to join our panel. Both organizations declined our invitation. We are, however, honored to have two outstanding experts here with us today, Aaron Kesselheim is a professor of medicine at Harvard Medical School and in the division of Pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston. He is both a physician and a lawyer, and he is a, well, world renowned expert in ethics and health policy related to drug development. Dr. Kesselheim was one of the three members of the FDA advisory committee who resigned over the FDA’s decision. Dr. Jason Karlawish, which is the Hastings fellow. He is a professor of medicine and a neurologist at the University of Pennsylvania’s Perelman School of Medicine, where he co directs the pen memory center. Dr. Karlawish is an expert in the care of people with Alzheimer’s disease, and he’s recently published a highly praised book, The Problem of Alzheimer’s How Science, Culture and Politics Turned a Rare Disease into a Crisis and what we can do about it. Welcome to you both. I’m going to start with you, Dr. Kesselheim , because first I want our audience to know as much as possible about the clinical trials themselves, that about the advisory committee findings and why you felt it was important to resign. And then I’m going to turn to you, Dr. Karlawish. Wish to help patients and family members in our audience make sense of their personal options. I think our audience will want your advice. Is this a drug that they should ask for? And then we’re going to open it up to those of you in the audience. Dani is going to be collecting your questions. You can write your questions into the Q&A function at any time, and she’ll be going through those. We’re not using the chat function, so make sure you use the Q&A. So let’s begin, Aaron. My understanding is that Biogen ran two different clinical trials. Would you describe the trials and what they found?

Aaron S. Kesselheim Sure, Dr. Solomon, thank you for inviting me to this to this panel, and I’m excited for the conversation over the next hour. So the essential controversy here relating to the two pivotal trials that Biogen organized to test the efficacy of addiction AMAP. And I want to say, first off, that, you know, that Biogen should be commended for organizing two large trials, testing the clinical effects of the drug. The you know, when we win FDA approves drugs, it approves drugs on the basis of the idea that there is substantial evidence of effectiveness from adequate and well controlled trials. And to try to meet that standard, Biogen organized to do two trials, basically with the same design. And these trials were intended to test the progression of the progression of of the clinical symptoms that patients with early Alzheimer’s disease and evidence of amyloid plaques on on on pet imaging had over the course of a number of months of their of their getting after. Meanwhile, getting treatment with without Academi at two different dosing levels and with a placebo. So the Biogen organized these two different trials and the controversy arose because Biogen had a predetermined stopping rule for these trials, a rule where the trials would be analyzed together and determine whether or not it appeared that the drug was futile and was not providing any benefit. And what happened was, was that when Biogen’s data safety monitoring board evaluated the trials together for futility, it showed that there was no evidence, no hope that the drug would would show benefit. And so Biogen publicly announced that it was stopping the trials for futility. And then the controversy arose because Biogen then as well as a little bit more data rolled in from the wrapping up of the trials, Biogen then looked back at the trials individually and found that in one of the trials in one of the arms, it appeared as if there was a statistically significant reduction in the progress of patients in their in their Alzheimer’s disease course in that in that trial.

Mildred Solomon, The Hastings Center Measured by a slowing of their cognitive decline, the pace of cognitive decline

Aaron S. Kesselheim measured by a very slight slowing in the pace of their cognitive decline. So the measurement that they use to determine the cognitive decline was a clinical measurement called the RSV, or CDR sum of boxes, which is a widely used scale in the field that measures cognitive decline on a on a scale of one zero to 18 points. And what they found was in the high dose arm of one of the two trials that patients decline in their CDR sum of boxes slowed by by about 20 percent or two point three nine points on this on the CDR sum of boxes scale over the course of 18 months of therapy.

Mildred Solomon, The Hastings Center Well, 20 percent reduction sounds like it’s not tiny.

Aaron S. Kesselheim Well, 20 percent reduction is not tiny, but the actual reduction, the sort of absolute reduction was only point three nine on the scale, which was almost imperceptible to the patients in the family members themselves. What was observable based on the based on the application of this on the boxes scale.

Mildred Solomon, The Hastings Center And they were so the FDA and its own public statements that I’ve read have said that they agreed with the advisory committee that this wasn’t strong enough proof of efficacy, even this even in this small subgroup where where this change was seen.

Aaron S. Kesselheim Well, actually, so what? So the FDA. So when we met as an advisory committee back in November, the FDA stated flat out that any statistically significant change in CDARS some the boxes they would consider to be clinically meaningful, they didn’t care how small the some of the boxes change was. The controversy at the advisory committee was the fact that what happened was that after Biogen identified this this statistically significant change in the high dose arm of one of the two trials, Biogen and the FDA worked together to reanalyze the two different studies and try to understand why the one study failed and was wrong and why the other study that showed the positive effect was right. And then what they did was they presented that information to the advisory committee and asked the advisory committee if we thought that that the that the totality of the evidence that was presented showed that it looked like there was a clinical benefit for this drug. And our response as an advisory committee, which was near unanimous, was that it did not appear that there was convincing evidence. In fact, there was one one statistically significant arm of one trial and one negative trial. And both of those together suggested that we don’t really know if this drug works. And the right thing to do would be to study it in a further and to try to provide a clearer answer as to whether or not this drug actually affects cognitive function. Because we didn’t think that we didn’t think that the evidence to that point was was was convincing that it did that because you had the one positive and one negative trial. And, you know, and and in addition to that, of course, there were a whole bunch of side effects that were associated with the drug during the trials. And for that reason, we weren’t as an advisory committee. We were not convinced by the you know, that that the drug showed a clear effectiveness.

Mildred Solomon, The Hastings Center And in a public statement, I think I think it was in The New York Times. The Center for Drug Evaluation Research said that the way we recommended approval, not because of clinical benefit, but under the accelerated pathway, because we saw a reduction in the biomarker and a reduction in amyloid plaques. So they seem to have agreed with you that there wasn’t enough evidence about efficacy.

Aaron S. Kesselheim Well, so at the at the advisory committee meeting itself, it seemed pretty clear that the FDA and Biogen were both pushing for treatment, that they did think that there was evidence of clinical benefit. And so what happened was, was that after the advisory committee voted nearly unanimously that there wasn’t, the FDA then came back and approved the drug in June on the basis of its effect on visible amyloid plaques. And in fact, the drug does appear to reduce visible amyloid plaques pretty clearly. And I think the issue is, is that it’s not really clear what that means, that there is a lot of uncertainty in the field about whether changing amyloid plaques, even in patients with early Alzheimer’s disease, is meaningful in altering the course of the disease. But they didn’t actually. I mean, when we talked about that at the advisory committee, they explicitly excluded discussion of amyloid plaque as a surrogate for clinical effect. They said, look, we’re not looking at the amyloid plaque. We’re focusing on the actual clinical benefit. And so what it appeared was that after the advisory committee voted against it, the FDA switched course on its on its comments and instead approved the drug on the basis that it changes amyloid plaque and isn’t just not making any claims about whether or not it clearly changes cognitive function, but are saying we think that the fact that it changes amyloid plaques means that it’s reasonably likely to affect amyloid, to affect your to affect your cognitive function. But, you know, as we pointed out in these trials, you know, that that followed patients for 18 months that have already been run. You’ve got one trial that shows that it doesn’t actually do that. And one trial that shows that it does do that to allow it to is very small to a very small degree. So I don’t know on what basis the FDA is making this claim that this drug will have a reasonable likelihood that it will affect cognitive function, because we already have two trials actually testing the drug on its cognitive function. And and everyone seemed to agree at the advisory committee that it wasn’t it wasn’t a very convincing effect.

Mildred Solomon, The Hastings Center So at the bottom line, what what were the main reason or reasons that you decided to resign?

Aaron S. Kesselheim Well, I decided to resign because I felt like as an advisory committee member that I was I was very concerned about the process and the the way that the advisory committee was set up. You know, usually advisory committees are set up where the the FDA presents one side or one point of view and the company presents a different point of view. And you can see where the controversy was in this case. The advisory committee was set up where it seemed like the FDA and the company were in full agreement about what should happen. And they were looking to the advisory committee to kind of give it a sort of a validation. It wasn’t really clear what the controversy was. And then when we had presented our view that were there wasn’t convincing evidence that this drug works to, then, you know, after that switch and switched perspectives and switched the premise on which they were evaluating the drug and then approved the drug in a totally different premise that they presented to the advisory committee, made me concerned that they weren’t using the advisory committees as they should, as truly sort of independent expert views on on a on an important and an important issue. Now, of course, you know, the FDA doesn’t have to agree with the advisory committee or follow the advisory committee’s recommendations, but they should, at least in sort of respect the process enough to make sure that the advisory committee is is providing important insight. That is then that where there’s that a process for implementing that insight. And if there is a difference of opinion that the FDA decides to go against that insight, then some clear explanation as to why they did that or so I felt like. So I felt like I I resigned to try to bring attention to what I thought was the way that the FDA was getting away from, you know, using advisory committees to the extent that they are supposed to be used in order to provide support and trust for the FDA’s making independent decisions about about the drugs that they’re reviewing. So that was so I think that that night I brought I think I you know, I resigned not only to bring attention to what I thought was an extremely problematic approval, but also. To to bring attention to the process leading to that approval, which I also thought was very problematic.

Mildred Solomon, The Hastings Center Thank you, Dr.Karlawish I want to focus on your advice for patients and also for clinicians who may be inundated with requests for this drug. But before I do, I want to give you a chance to respond to the issues that Aaron and I have been talking about, what the FDA’s ruling was. Is there anything you want to underscore or highlight in terms of this process?

Jason Karlawish Sure. And again, thank you, Mildred, for organizing this gathering. And greetings, everyone, from North Korea to New York, where I’m in a cabin on a bit of a holiday.

Mildred Solomon, The Hastings Center And thank you for doing it during your vacation.

Jason Karlawish And unlike Dr. Kessler, I’m a bit underdressed, if you will, compared to my colleague. But greetings from my from the Adirondacks. I on the morning of June 7th, if you would ask me, is amyloid beta amyloid an adequate surrogate for the treatment of persons with mild cognitive impairment or mild stage dementia due to Alzheimer’s disease? I would have said that that’s a provocative hypothesis. That is the source of urgent study and needs more study. But by the evening of June 7th, it had become clinical practice and it became clinical practice because by fiat, essentially a divided FDA transformed that into clinical practice, namely that you could use a beta amyloid measure together without a kinematic to treat a patient. Aaron’s nicely outline the events. I’ll just reiterate that many in the field share the same shock that I felt the transformation of the amyloid hypothesis into clinical practice by regulatory fiat from a divided FDA. We would only learn in the weeks to follow that actually FDA was divided. And number two, we were very disturbed and I say we colleagues, et cetera. I’ll speak now, though, for myself that the November hearing was about standard approval. Safe and effective was the questionnaire and his colleagues had to answer. There had been no discussion of accelerated approval. As Aaron points out, it was actually summarily rejected by Billie Dunn as as a topic of interest. And and yet, of course, that was the regulatory basis was accelerated approval with no discussion, an advisory board and really no discussion in the field. The field was very keen that we want to see. We still want to see a surrogate approach to treating this disease much like hypertension, diabetes, other chronic progressive diseases that unfold relentlessly and slowly over time. But we know we knew. We still know that. To do that, we need really good initial studies that validate a surrogate. And the studies that Biogen conducted simply didn’t give us the strength of evidence to make that claim. Like past studies say, with the drug that came to be known as Lipitor, really established the cholesterol hypothesis. And so the field now is divided and disappointed and we find ourselves now in this very difficult situation. So your question to me was what will I tell my patients? Now I’m on record as saying I won’t prescribe it. I wrote that and published that in state news a week or two before the decision. My message was to FDA. They chose not to listen to me. And and so and so now it’s in clinical practice. And so let me be frank and candid. I will prescribe it, but I’m a reluctant prescriber. And why would I do that? Well, you know, this is a disease that relentlessly chips away at a person’s self-determination and autonomy. That’s why it’s a disease, I think, meaning that’s the suffering it causes. And as a practitioner who focuses on the care of persons with Alzheimer’s disease and other disorders that cause dementia, I have a real commitment to doing everything I can to preserve, protect and defend their autonomy. And so now that the FDA, I have to respect the system as much as I am now. I’m worried about the system has made this drug available. If after educating a patient and their family, especially the diad at least, of the drugs, uncertainty’s of benefit, not just the uncertainties of benefit, the risks, additional considerations, etc. If someone chooses to take it, I will write a prescription. But I am a reluctant prescriber.

Mildred Solomon, The Hastings Center So saying more about the risks and the side effects and what your argument would be against prescribing it?

Jason Karlawish Well, you know, the risks to me, the risks to, you know, look, I am an internist and, you know, I’m used to risky drugs when I used to practice general internal medicine. But risky drugs are, of course, balanced against benefits. And to me, the starter concern I have here is that this is a drug that should not be available because I write a prescription for it, but it should be available because I hand someone an informed consent form to consider being in a clinical trial for it. And I think the drug needs additional study to firmly established it because the benefit is uncertain. I’m in equipoise as to whether this drug is effective and I would be very enthusiastic about having someone in a clinical trial to study it. But I’m unenthusiastic about writing a prescription to give it to someone in what amounts to an end of one clinical trial. But again, if someone says, well, I’ll take that on certain benefit because at least some folks thought it was worth approval, it got FDA imprimatur, right, Dr. Cross? It does, yes. But then they need to know about those risks of micro hemorrhages in micro edema, which can be detected by MRI detail it. I’m not trying to be light about it, but I think it’s a well done, well monitored prescribing. You know, those risks can be detected before they become devastating. I think there’s concern about wide prescribing, given folks in clinical trials are generally quite healthy. They’re, of course, well monitored, et cetera. But again, I can tolerate a risky drug if I know it’s got some benefit. But this one, I don’t know if that’s been established. I know that that has not been established. And indeed, to wrap up, the FDA knows it’s not been established because they want to confirmatory trial conducted as part of their approval. And Biogen has nine years with which to get those data.

Mildred Solomon, The Hastings Center Isn’t that an awfully long time? They’re allowing them to wait until 20, 30 to report the results of another trial at nine years of experience with this, you know, with the side effects and all that is that was that is that a usual time timeline?

Jason Karlawish I’ll let Aaron weigh in on the sort of regulatory conditions around accelerated approvals, validation studies. I will say, just as a clinician, that’s an awfully long time. But er and you may have thoughts about what the regs say about how much time you’ve got to get the data back once you’re out there on accelerated approval.

Aaron S. Kesselheim Well, I think, unfortunately, the regs don’t say anything, and that, I think is part of the problem here is that I wish the regs did actually say something about how long if you do approve something by accelerator approval, how long we should expect a follow up clinical trial to be. I think, first of all, if you approve something on accelerator approval, you should go into the process with the confirmatory trial already organized and already underway at the time the drug is approved, meaning you are anticipating accelerated approval earlier in the process. And that way you can get the trial started and underway so that you can have results earlier, so that you can actually have more of a chance of recruiting patients into it, because it’s it’s hard to recruit patients into a placebo controlled trial, on the one hand, when they could just go next door and get the drug in usual clinical practice. And so these, I think, are all changes that we could make on a policy level to the accelerated approval pathway to try to ensure that the pathway is still available for drugs to which it’s reasonably applied. But still, you know that we can expect benefit results in a reasonable timeframe. I think, unfortunately, with past experience, with accelerated approval drugs, a lot of you know, a lot of those drugs take many years before there are confirmatory trials. Those confirmatory trials are oftentimes still subpar in the way that they’re organized. And then in some cases, the FDA doesn’t act on drugs with negative confirmatory trials to take either the drug or the indication off the market. And that’s a problem.

Jason Karlawish What are the thing I am telling my patients and their family members one on one as well as in our pet memory center, communications on the economy is the story, the story that we’re talking about now. And you said, well, you know, why tell them that story. What’s the point of it? That’s not you know, I think, though, that people need to know where the process that put a drug in front of them. And in the case of this drug, the process is erroneous, nicely detailed and elsewhere. And I won’t repeat it raises real concerns about how this drug now is before you patient to be taken. And I think people need to think about that when they reflect on whether they want to take the drug. Because I think, you know, Aaron used a very important word, which is trust. I think we have to have trust in the FDA that their decisions are decisions we can live with, that the system worked. I kind of think of it like a court. You may not like the outcome, but you can live with it because everyone get treated fairly by the rules or correctly and fairly correctly. And I think the concern that’s arisen here and why I support Janet Woodcock call for an OIG investigation, is this real concern about the process actually work or has it broken down? Is this a one off? You know, mistakes were made and they accumulated. And almost what’s becoming kind of a tragic dark comedy or is this reflect a new way things are happening at FDA? There are other drugs in the pipeline that could get this kind of approval now. So this is not this is very concerning in the field. And I think the American public ought to be concerned as well.

Mildred Solomon, The Hastings Center Jason, do you I really I’m interested that you framed this really as a kind of informed consent response that, you know, you’re encouraging families to understand how this process happened and how it may have broken down. I wonder if you would also agree that there’s an obligation or at least it would be a good thing for. Referring physicians to talk about the impact on the patient in the family, not only of whether the drug works or doesn’t work, but that pets, a PET scan will be needed to determine whether they have plaque that they will need to be monitored for brain imaging. To that, 40 percent of the people who received this drug during the Biogen trials had brain swelling or brain bleeding. And that’s a very high percentage. And that seems to me that the financial impact, the inconvenience, impact and the risk of brain side effects are part of that informed consent package.

Jason Karlawish Of course, there are some dark ironies to this. You know, one, because this drug is out there. It very well may make it easier to do amyloid imaging in order to help someone arrive at a better understanding of the cause of their mild cognitive impairment. Now, I say dark irony because. It’s sad that now a diagnostic test could be available for folks because of questionably beneficial drug of great expense has been put out on availability. And I say this because many in the field, when I chat with them, say, well, you know. Shouldn’t have happened, but I guess it’s win win because now we can get access to diagnostics and the four percent that’s earned from the prescribing of this drug will bring some funds flow into memory centers, which have been basically impoverished since their creation. So maybe we’ll finally get the the necessary support staff to provide patient and family education about the risks, the benefits, the hassles of the drug, et cetera, the monitoring help for transportation to come in. And you listen to all this and, you know, of course, you want to build your memory center, right? I mean, my memory center provides patient and family education that’s still valuable and part of care. Just as much as I had a home should be part of care because a donor gave us millions of dollars to pay for our social work team. If we had to rely on clinical billing to support our memory center, we would fire that staff within a month because we couldn’t cover their salaries. And there is a dark irony that it takes a questionably beneficial drug. To bring in the revenue, to finally get memory centers up and functioning, and I haven’t directly answer to your question, but I think folks need to know this is part of a larger conversation in America about how a big, vast and problematic disease is being treated, which is essentially what this reveals is that a disease in America isn’t really a fully a disease until it has a business. And much of that business model relies on the pharmaceutical industry. I like to prescribe drugs at work. I personally and in my own family have met family members who are alive because of pharmaceuticals. But there’s also these dark ironies that the story about a kinematic is unfolding and revealing to us,

Mildred Solomon, The Hastings Center let me provide a little more context and you correct me if I’m wrong, Dr. Karlawish or Dr. Kesselheim , but just so people understand, Medicare was not paying for PET scans to detect an absolute right because there was nothing that could be done. So there was no point in doing the diagnostic imaging if we didn’t if if there was nothing to be done now. Yeah, no. It’s what you were meaning about irony is right. Excuse me. What you’re meaning about irony is that by approving this questionable drug through this accelerated pathway now, Medicare can no longer say there’s nothing to be done and now they will be obliged to provide for these PET scans.

Jason Karlawish That is exactly right. You have linked A to B to C to arrive at D or whatever however you want to. That is exactly right. And again, I my colleagues and I couldn’t wait for the day when we did have an effective drug and we could be able to give people a biomarker based diagnosis to really say to them, you are you do have Alzheimer’s or you do not, you know, and this is what your future is. And so let’s make plans and get treatment going, you know, but but this is not the it is unfolding in a way that just. Yes, it’s very frustrating, though. The story of why amyloid imaging wasn’t approved is a fascinating story, again, about the failure to build memory centers to adequately use that test in a responsible way.

Mildred Solomon, The Hastings Center Yeah, there’s so much to discuss here, and I know the clock is ticking, and that’s why Dani has helpfully shown back up to to remind us that we have six hundred people aching to ask questions. So, Dani, tell us what you what you’ve got.

Danielle Pacia, The Hastings Center People are being so generous in the Q&A function. We’ve gotten a lot of questions, I think a common theme of a lot of the questions coming in is a lot of people just want the panelists to expand on the internal investigation happening at the FDA right now and also related questions. That’s more of a clarification question on what exactly does the FDA stand to gain by approving this drug?

Mildred Solomon, The Hastings Center OK, thanks. I think that’s a question for both of you. But maybe we’ll start with Aaron.

Aaron S. Kesselheim Sure. So so basically what happened is last week, Janet Woodcock, who is the acting director of the FDA, requested that the OIG look into there was an excellent report in stat news that detailed some conversations, informal conversations between one of the FDA reviewers and Biogen early in the process. And those are those kinds of interactions, arguably should be more transparent and clear about them. And so what Dr. Woodcock is asked is, is whether or not the IG wants to investigate those interactions. I would suggest that instead, all aspects of this approval process should be investigated from the relationship, the sort of long term relationship between the FDA and Biogen early in the process to reanalyze the data and to come up with explanations as to why the one trial was the positive and correct trial and the other trial was a negative and incorrect trial. Again, it is important for FDA and sponsors to talk with each other, but that level of detailed collaboration is almost unprecedented. So I think it’s important to investigate the process there. It’s important to investigate the process leading up to the advisory committee, why certain things were chosen to be discussed there, why certain things were not chosen to be discussed, how the FDA switched gears after the advisory committee, how the FDA arrived at the extremely broad initial labeling that that approved the drug for all people with all all all types of Alzheimer’s disease, even people with severe Alzheimer’s disease, where you would not expect this kind of treatment to be useful. And and why why the company was given nine years involved. I think all of those different steps in the process should be the subject of more complete investigation, because, as I said, you know, I like I like to think that the FDA makes the right decision most of the time. And the FDA fulfills an extremely important public health function in this country, in the world. And and so when there is a decision that is as problematic as this one is, we need to try to better understand how it became, how it was arrived at so that we can try to prevent similar bad decisions in the future, but also try to enhance that trust that that people need to have in the FDA’s decision making.

Mildred Solomon, The Hastings Center Jason, anything you’d add to that in terms of the integrity of the FDA in the process,

Jason Karlawish like in summer is spot on? I’m concerned that Janet Woodcock’s call is very narrow. The relationships between selected members of FDA and Biogen look into that. Is that OK or not great? Otherwise, that’s not enough and detailed the things that need to be looked into. Fortunately, at least two congressional committees are interested, and I do hope those committees meet. You could argue, though, that that just sort of will now overly politicize this. But this needs to be figured out. As Aaron has detailed,

Mildred Solomon, The Hastings Center there’s there’s a lot to be investigated about this decision in the process that was undertaken. But it also raises the question of the trustworthiness of the FDA in our times. The structural issues, for example, the decision to I don’t think many of the people in our audience may not know that FDA receives user fees that are extremely important to their budget from industry. If I’m if I had again and I know that you’re the expert on this, Jason knows a lot more about it than I do. But there are structural issues here. If we were really going to take a big lens on not only this particular process, but the way Congress and our society has decided to constrain what is was originally seen and I hope is still seen this before, the foremost regulatory agency with the highest integrity of trying to keep unsafe things off our streets in the world, but now is dependent upon user fees from industry and also that we’ve chosen to evaluate them by the number of approvals they make and the speed with which they make those approvals. So I imagine there are you know, if we really wanted to have a big lens on this, we would be seeing a thorough investigation of this decision, but opening up the whole set of questions about the role of regulation and safety and effectiveness in our society. And what institutions, how institutions should be structured to safeguard those goals? OK.

Jason Karlawish By the way, I noticed in the chat the question several people asking some important new questions about the drug and its risks aren’t. The Penn Memory Center has put together a webpage with the Q and A summary about the drug that we’ve been updating. So if you go to pen memory Synagog P and Memory Center Dog, you click on the out of Khanabad page and we’ve done our best to kind of summarize what’s known and what’s not known. Just lay out the facts as best as we can gather them.

Aaron S. Kesselheim Unfortunately, there is a lot of misperceptions about the drug since it’s been approved in the statements about the drug, in the popular press and other and other places, saying that the drug is, you know, is a treatment for Alzheimer’s disease. And and again, the FDA didn’t even approve it, is that it approved it on the basis of lowering lowering of plaque. And so I think that the that the clarity around that is is really important. And the FDA and Biogen should be doing a much taking a much more active role in trying to dispel some of those misperceptions

Jason Karlawish of Alzheimer’s field was, you know, what’s our cholesterol? What’s our hemoglobin, A1, C, cholesterol, heart disease, hemoglobin, diabetes. Treat that. And, you know, you’re treating the patient’s disease, OK? And that’s a very I don’t contest that theory. These data, this trial, this drug was not the set of data to enter into that new biomarker based world.

Mildred Solomon, The Hastings Center Can you can you help our audience understand the set of studies that have been done? Because my understanding is that if you look at the set of studies about amyloid plaque, that some people can have high amounts of plaque and no cognitive impairment and very little plaque and lots of cognitive impairment. Is that true? Is that true?

Jason Karlawish Yeah. So the the website I mentioned somewhere just popped out of the question is penn memory center, pennmemorycenter.org

Mildred Solomon, The Hastings Center Penn as PENN

Jason Karlawish memory center dog. Yep. So. The EMP, there have been multiple drugs studied that target amyloid, one of the two pathologic markers of Alzheimer’s disease, and many of the drugs have shown an effect on amyloid, meaning by effect on amyloid. They reduce it, they alter the levels, et cetera. None have shown that it clearly translates into a clear, obvious effect on disease course. But let me now get nuance in a way that I think is very important. The totality of the drugs is a disappointment. That is absolutely true. But in the last several years and at a camp as part of the story, we’re beginning to see that depending on the kind of drug and how it goes after amyloid without getting into nuance, it’s not just cleaning up amyloid like a vacuum cleaner cleans up the dog hair. There’s nuances about how to do this, number one. And number two, the kind of patient that receives the drug in terms of where they’re at, in the pathologies of the disease, we’re beginning to see signals that maybe we are able to affect the natural history of the disease. And there are promising drugs and I can’t remember still remains in that list. But the study designs are still being nuanced. And I don’t I say the word nuance. That’s probably not the right word. They’re still being worked out. And let me make a point that I think is really important. I’m guilty of a line that I regret I used in my writings in the last 20 years, there’s been no treatment for Alzheimer’s disease. And when you start with that premise, you create that sense of what we’ve got to do something zero progress in 20 years, that that statement is factually correct. But it is superficial because the last several years we’ve seen real progress with better understanding where someone’s at, specifically in the pathologic course of the disease and when therefore a drug might be the right drug to target and measure its response. And that’s why this decision by FDA is so frustrating, because it throws almost sand in the gears of that progress we were making and creates this. It really disrupts that. And that’s, I think, why many of my colleagues feel very frustrated that we were really making good progress. And then this happened and and. Well, we’ll just move along as best we can, I suppose.

Mildred Solomon, The Hastings Center So you’re concerned about what it will mean for science and being able to do true progress. But you also.

Jason Karlawish Well, let me give you one example. So in May of 2020 in the New England Journal of Medicine, colleagues from Eli Lilly published a report of their drug tinana map for the treatment of Alzheimer’s disease. Phase two study. Well, design some very interesting aspects of the design, very vangard use of both amyloid and tau imaging. My point is this progress, very interesting set of signals and the conclusion of the abstract of that New England Journal of Medicine paper was further research is necessary to validate and confirm these benefits. And the field was very excited to see that further research done. And then in June, after FDA decision, Eli Lilly said, we’re applying for we’re going to probably apply for export accelerated approval, and I can’t fault a company for doing what companies do. If the regulators are changing the standards for what it takes to get a drug to market. What we’re going to go and I can’t fault a company for being a company in America. But my point is, is will we will they do this study they said they were going to do or not? I mean, we’ll find out. And as Aaron points out, we have to figure out what happened with this decision because not just an animal, but laquinimod get near a are all in the works and could now be popped out into clinical practice without the studies that are needed to show. Is this the drug I should prescribe for my patients?

Mildred Solomon, The Hastings Center How can we hold the FDA accountable for making sure those follow up studies get done?

Aaron S. Kesselheim And yeah, so that’s that’s a big question. And again, I think this points back to the rules around accelerated approval and things that need to change around. The rules are accelerated approval to try to better ensure that those that those follow up trials are done and done in a timely fashion and done it with high quality. I think that unfortunately, too often with accelerated approval, those those trials aren’t done. But but I think there are steps you can take. So and I mentioned some of them earlier, but you can make sure that the trials are already underway or are set up to go before you approve the drug, which means, by the way, that you don’t change gears and just decide to approve the drug on accelerated approval at the 11th hour of a long drug approval process. You know, you make sure that there are that the trials are done at a high level of rigor and that the endpoints are reasonable endpoints. And then if the trials are not done after a certain period of time, then there are consequences to to not having the trials done after a certain period of time. And if the trials are negative, then the drug gets removed or the indication gets automatically removed for the market. None of those things currently happen. And as a result, you get things like what happened with this. There was a muscular dystrophy drug that was approved on accelerated approval back in 2016 on the basis of increasing muscle dystrophin levels in extremely small amount. And the FDA was like, well, they’ll do an accelerated approval. They’ll have a confirmatory trial that’ll be done. And four years later, the FDA put out an expression of concern that the accelerated approval trial, the confirmatory trial, hadn’t yet begun. And so, you know, in those circumstances, what do you do? And I think that that part of the process of learning from this episode is going to be thinking about the accelerated approval process and how to ensure that it’s fairly implemented.

Mildred Solomon, The Hastings Center It almost seems like it could be a hack in the sense that if you can’t show efficacy but you can show something with a biomarker, you then you can get to approval that way and not really have to ever prove efficacy. It’s almost I mean, is that too strong a word?

Jason Karlawish Well, I’ll walk back from her back, but it it almost like it becomes a compromised position and it shouldn’t be that sort of well, you know, we couldn’t really agree on standard prevail. So let’s just give it accelerated. One of the aspects of accelerated approval that is part of the regs and was certainly in the statements that FDA issued was this is a bad disease. There’s no treatments. Patients are desperate and you put that together and that gives you the sort of social cultural warrant to use these accelerated approval regulations, which were which were written in the in the beginning of the AIDS era when we need to get drugs into bodies. And I get that sentiment. I think it’s part of the equation. Let’s not deny it. But I think another word needs to be talked about here. In addition to trust and the desire, in addition to desperation, the desire for hope. And that’s the word trust. And again, I go back to you. If I was at FDA, if I was Janet Woodcock, I would say, does the American people trust the FDA? And if there’s even a doubt about the answer to that question, then she needs to repair that trust because trust is like porcelain. It’s easily cracked. But once it’s cracked, it’s hard to repair.

Mildred Solomon, The Hastings Center Dani, what else are you seeing,

Danielle Pacia, The Hastings Center getting a lot of questions about precedent, whether or not this was an anomaly, so specifically people have asked, is it normal for the FDA to totally ignore advisory committees? And is this one incident in a continuation of several approvals from weak evidence?

Aaron S. Kesselheim So I would say some of the statistics indicate that the FDA agrees with the advisory committee about three quarters of the time. However, when the FDA disagrees with the advisory committee, it’s usually disagreeing in a more conservative way such that the advisory committee recommends approval and the FDA says, well, we’ll approve it. But we also want to make sure that these you know, there’s a special safety restriction on the drug for an extra X, Y or Z or something like that. Also, it is also relatively unusual that the FDA disagrees with an advisory committee that was nearly as unanimous as that was as unanimous as our as our committee was. So I think that both of those things make this a bit of an outlier and whether or not it is a precedent or setting for some kind of example for how things are going to go in the future, we’ll see. I think it does set precedents. First of all, as Jason pointed out, it sets precedents for how the FDA is going to treat other Alzheimer’s drugs. And as you know, as you pointed out, there is now no basis for the FDA to deny approval for these other drugs in the pipeline that also change amyloid levels without understanding how they how they actually work on clinical practice. And I think it sets precedent for other diseases as well to to try to make the claim that, well, we also have to sort of biomarkers that we’ve been studying that we don’t have agreement around and we have drugs that may affect those biomarkers without knowing if they actually affect the disease. Why can’t our drug get the same treatment as as the Alzheimer’s drugs got? So I think that it sets precedent in that sense as well.

Jason Karlawish Aaron, I’m curious how often in your experience or what either in your role on the committee or just in your scholarship around FDA? Have they asked an advisory committee? Body of evidence safe is standard approval. OK, thank you, advisory committee, but then go off and use different regs to make a decision. Is that something that happens or is that was that unusual?

Aaron S. Kesselheim Yeah, I’ve never I’ve never heard of that before.

Jason Karlawish So this was unusual. Was unusual because they won against their advisory board. Rech that’s 20 percent of the time they have done that and they can do that. And but typically they go against the advisory board when they advise board says approve it, but they say, no, we don’t. But then they also went and did. We gave you one set of regs and questions, but we’re actually going to now think about it on a different set of regs and different set of evidence. So it’s really unusual. And I guess the point. But what irks me about this is you’re at FDA on the evening of June 7th, the evening, June six, and you say we’re about ready to announce a drug that the advisory board wasn’t asked to rule on it, weigh in on it. We’re divided within our agency about what we should do. They were divided in three different views in the agency. This is a first in its kind drug. There’s not clear consensus in the field that this is the biomarker with which to treat. I would have said, you know, maybe we should put the brakes on this and go back and at least have an advisory board hearing it to see how this plays out there. But that didn’t happen. And here we are.

Mildred Solomon, The Hastings Center One last question from the audience, Dani.

Danielle Pacia, The Hastings Center So we had a quick question just about how would you respond to patients who say that they actually want this drug available to them now? And maybe this is more of a question directed towards Dr. Prokosch. What would you say to your patients that,

Jason Karlawish again, I cannot I am not going to let my patients be the the the crucible upon which this fight is fought? OK, they have to live with this disease. All disease is bad. This disease is uniquely bad. If someone has mild cognitive impairment, meaning inefficiencies in cognition caused by Alzheimer’s or mild stage dementia caused by Alzheimer’s disease, and they learn, they listen to everything that we’ve talked about today, read the materials we and others have created. If after all that, they say, I’m taking the drug, you know, I cannot fault them for making that decision in matters of taste. There’s no disputing that.

Aaron S. Kesselheim I guess I would push back a little bit on that and I would. So I take care of patients in a primary care clinic as well. I would not recommend this drug and I wouldn’t administer it because I don’t think that the drug has sufficient evidence that it works. And I think it has all kinds of risks, both bodily and financial. And so if a patient comes into my office and says, you know, Dr. Kessler, I want this drug no matter what you say, and I know that it’s available on the market, so prescribe it for me. I would probably tell them to try to find another provider to do that, because there’s not because I don’t I don’t feel like I could. I could.

Jason Karlawish I hear you. And I hear you. I hear you. I do. I guess I’m there to be the other provider, you know, and maybe it’s because I work at a memory center. And the typical new patient story is a family that spent about a year trying to get a straight answer for why did my mom has a memory problem? And I guess, you know, I admit it’s an unusual place I work at in that sense. But if they’ve made it in there and whatnot, I don’t know.

Mildred Solomon, The Hastings Center It’s Jason. I no, not Jason. Not to jump on you is on top of Aaron. But I think you’re emphasizing the end game of your conversation with parents, with patients and their families, what you would ultimately do based on your respect for their autonomy and their journey. But I would I think our audience, we have a whole bunch of questions about this, wants to hear what the what your views are about, why it may not be the right thing for them to do.

Jason Karlawish So I did the right thing to do would be to find a clinical trial, the drug, and be enrolled in a clinical trial where you’re doing you’re doing two things. You’re getting well monitored. You’re getting good data about whether it’s affecting you benefit as well as harm. And you’re contributing to the thing that and this is what’s so sad. The folks who are all these clinical trials, they say to me, I can’t believe this happened. I was in these trials. I tried to make this drug a possibility and this is what happened. And they actually kind of feel angry. I really gave my blood, sweat and time for this study. And now this is what it’s all come to. And it’s interesting. Well, I’m going to take it because I’ve been in the trials. I know what it’s like. I’ve tolerated the drug, but I did all this work. And this is what you’ve given me. Yeah. Is there an answer back to the system? And, you know,

Mildred Solomon, The Hastings Center anyway, OK, we only have two minutes left. I want to thank both of you so much for doing this and especially doing it. Dr. Karlawish on your vacation and both of you on short notice. I want to thank the people who have joined us and these great questions. I want to say the Hastings Center has a blog where there is a very compelling essay about why I wouldn’t want my mother to take this drug. I’m going to see that we put that on our home page. If you want to read some more about this. And just to summarize, we’ve talked about ethical problems, I think at three levels. We’ve talked about the social impacts of this approval. Has it is it eroding our trust in the in the FDA? We didn’t get a chance to talk about some other social impacts like costs to the taxpayer of the increased burdens that are going to fall on Medicare. So there’s a lot of social impacts we could continue discussing. The other social impact is perhaps an erosion in our ability to do the science as well. Then a second level I’ve heard through this hour is clinical impacts for the patient. There were a lot of questions I don’t think we got a chance to answer completely that this is risky drug, 40 percent did have brain swelling and brain bleeding. And so they have to have brain images. They have to be able to go into a high tech place to get those images and then family impacts, especially in terms of false expectations and also in terms of cost, because it won’t only be Medicare that’s paying for this. There will be co-pays and there’ll be costs for those imaging studies. So I think we’d really you know, it’s a complex been a very complex story. I hope that the hour has helped us all make better decisions for ourselves and our loved ones. As the time approaches to confront cognitive impairment that unfortunately many of us are going to face in our lifetimes. Longit longevity is great, but it comes with a cost and often that’s some period of time with frailty and dementia. For decades, the Hastings Center has been focusing on improving end of life care and enhancing quality of life for the growing number of elderly in. Aging societies around the world, and I hope today’s program adds to our mutual understanding of those challenges. Thank you all very much.

Jason Karlawish Thank you. Thanks so much, guys, for organizing this virtual event. Good to see him and Dr. Jason.

Danielle Pacia, The Hastings Center Thank you all for joining us today. We encourage you to please, please, please continue this discussion online using the hashtag Breakthru, break down a video. This recording will be available shortly www.thehastingscenter.org, thanks so much again and have a great rest of your day.

Mildred Solomon, The Hastings Center Thanks, Dani.

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