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Alzheimer's, the FDA, and [aducanumab] approval
rndmhero
Registered User regular
Registered User regular
While the FDA approval of a specific medication might seem like an inherently niche topic, the dynamics and implications of this particular drug are wild . Since it overlaps healthcare, science, politics, and the economy, I figured this warranted a discussion of its own.
For full discloser, the OP leans pretty heavily on Dylan Scott's excellent explainer on Vox. However, there has been a ton of coverage on this one through The New York Times, The Washington Post, or I'm sure your preferred outlet of choice.
What is it?
Aducanumab is a monoclonal antibody made by Biogen which targets the Aβ plaques believed to be the causative agent in Alzheimer's disease, a form of dementia that currently effects more than 6 million Americans. Decades of scientific research have not really made meaningful progress on treatments for the disease, and there was an incredible amount of enthusiasm for this drug amongst the patient and advocate communities.
Why is the approval contentious?
Simply put, there's very little data that the drug actually does anything.
There are well-established problems in the scientific process of retrospectively analyzing data for subgroup analysis that was not defined as a prospective, powered endpoint in the initial study. This quality of evidence falls far below what is typically expected for peer review, much less FDA approval. As one internet rando put it, "It's like firing an arrow and then drawing your target around wherever it landed." What's more, the drug showed significant side effects, including brain swelling at high doses.
In November of 2020, the FDA's independent scientific advisory committee voted almost unanimously to reject the application for approval (10 votes against, one abstained).
Despite this, the FDA granted approval to the drug on Monday. What's more, they approved it with essentially no restrictions for use in Alzheimer disease, despite the incredibly narrow subgroup analysis used to justify it.
This has led to a string of resignations by world-renowned health experts from the FDA advisory committee (whose recommendation was ignored):
...as well as widespread condemnation from industry watchdog groups:
Why does this matter?
Apart from the obvious ethical implications of this approval, the financial implications are enormous. Because patients with Alzheimer disease are typically older, the costs of this treatment are likely to be entirely absorbed by Medicare.
Because Medicare does not have a mechanism for refusing or negotiating coverage for FDA-approved drugs, the upper limits of this are staggering:
If only 1 out of every 6 patients with Alzheimer disease receive this drug, the first new drug approved for Alzheimer's in 20 years, the cost would more than double all of the current spending on Medicare Part B drugs combined. If half of them do, that's almost $175 billion annually in mandated spending for a drug that the best experts in the field currently believe does not work.
There's a ton to unpack here, from the perverse financial incentives at every step of the process, the complicated and sometimes deleterious influence that well-intentioned hope and advocacy can have objective scientific review, how absolutely fucked the restrictions on Medicare drug pricing negotiation are, etc. This also follows in the wake of the FDA's Emergency Use Authorization for hydroxychloroquine use in treating COVID last year based largely on political pressure, conspiracy theories, and shoddy preclinical data. The FDA has historically been viewed as an international beacon for rigorous scientific review, but it's hard to see how decisions like this don't continue to erode their credibility in the scientific community, both nationally and around the world.
For full discloser, the OP leans pretty heavily on Dylan Scott's excellent explainer on Vox. However, there has been a ton of coverage on this one through The New York Times, The Washington Post, or I'm sure your preferred outlet of choice.
What is it?
Aducanumab is a monoclonal antibody made by Biogen which targets the Aβ plaques believed to be the causative agent in Alzheimer's disease, a form of dementia that currently effects more than 6 million Americans. Decades of scientific research have not really made meaningful progress on treatments for the disease, and there was an incredible amount of enthusiasm for this drug amongst the patient and advocate communities.
Vox wrote:Alzheimer’s is a terrible disease that robs people of their agency during the final years of their lives and robs families of the loved ones they once knew. The emotional and financial costs are severe. And as the number of Americans over 65 grows, those costs are only expected to increase.
In recent history, the decades-long search for an effective treatment or cure has been driven by what’s known as the amyloid hypothesis, which holds that plaque in the brain found in Alzheimer’s patients is at least in part responsible for the disease and removing that plaque could help relieve the symptoms. Aducanumab, accordingly, targets the amyloid plaque.
Why is the approval contentious?
Simply put, there's very little data that the drug actually does anything.
Vox wrote:Clinical trials of the drug started in 2015 but were halted in March 2019 because it did not appear it would meet the threshold for clinical effectiveness established at the start of the trials. It appeared, in other words, as though the drug didn’t work.
Normally, that would be the end of the story. But an unexpected twist came a few months later when Biogen revealed that, after additional data analysis with the FDA, some patients in one trial had actually seen “better but ultimately mixed results,” as the authors of a Health Affairs post on the controversy put it. Biogen announced it would push ahead with seeking FDA approval in October 2019, with the FDA’s apparent support.
There are well-established problems in the scientific process of retrospectively analyzing data for subgroup analysis that was not defined as a prospective, powered endpoint in the initial study. This quality of evidence falls far below what is typically expected for peer review, much less FDA approval. As one internet rando put it, "It's like firing an arrow and then drawing your target around wherever it landed." What's more, the drug showed significant side effects, including brain swelling at high doses.
In November of 2020, the FDA's independent scientific advisory committee voted almost unanimously to reject the application for approval (10 votes against, one abstained).
The New York Times wrote:A federal panel of medical experts on Friday sharply rejected arguments in support of a closely watched new Alzheimer’s drug, saying the evidence wasn’t persuasive enough for the drug to be approved as the first new Alzheimer’s therapy in nearly two decades.
The nonbinding vote by an advisory panel for the Food and Drug Administration does not mean the agency won’t approve the drug, aducanumab, made by Biogen. But it signals that many experts in the field are not convinced of its effectiveness, another major setback in the long journey to find a treatment for Alzheimer’s that works.
In a seven-hour virtual meeting on Friday, the panel showed pointed skepticism, which contrasted markedly with a presentation by Dr. Billy Dunn, director of the Food and Drug Administration’s office of neuroscience, who said that “the evidence supporting its approval appears strong.”
Overwhelmingly, the panel members disagreed.
Despite this, the FDA granted approval to the drug on Monday. What's more, they approved it with essentially no restrictions for use in Alzheimer disease, despite the incredibly narrow subgroup analysis used to justify it.
This has led to a string of resignations by world-renowned health experts from the FDA advisory committee (whose recommendation was ignored):
The New York Times wrote:In a powerful statement of disagreement with the Food and Drug Administration’s approval of Biogen’s controversial Alzheimer’s drug, three scientists have resigned from the independent committee that advised the agency on the treatment.
“This might be the worst approval decision that the F.D.A. has made that I can remember,” said Dr. Aaron Kesselheim, a professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, who submitted his resignation Thursday after six years on the committee.
He said the agency’s approval of the drug, aducanumab, which is being marketed as Aduhelm, a monthly intravenous infusion that Biogen has priced at $56,000 per year, was wrong “because of so many different factors, starting from the fact that there’s no good evidence that the drug works.”
Two other members of the committee resigned earlier this week, expressing dismay at the approval of the drug despite the committee’s overwhelming rejection of it after reviewing clinical trial data in November.
...as well as widespread condemnation from industry watchdog groups:
The FDA ... has failed in its responsibility to protect patients and families from unproven treatments with known harms.
Why does this matter?
Apart from the obvious ethical implications of this approval, the financial implications are enormous. Because patients with Alzheimer disease are typically older, the costs of this treatment are likely to be entirely absorbed by Medicare.
Vox wrote:Now that aducanumab is approved by the FDA, the issue of coverage falls largely to Medicare; because of the age of the patient population most affected by Alzheimer’s, the federal program is likely to bear the brunt of the drug’s costs.
In practice, if the FDA approves a drug, Medicare will pay for it. Aducanumab would be covered through Medicare Part B, which covers outpatient care, because it is an infusion treatment administered directly by doctors. To be covered by Part B, medical care must be “reasonable and necessary” — a vague standard that has, for medications, historically been mostly synonymous with FDA approval.
Because the drug is covered by Part B, doctors will even have a financial incentive to prescribe it. For prescription drugs, the program pays physicians the average price plus 6 percent, a policy that both Presidents Obama and Trump proposed changing but nevertheless remains in place. Determining which patients would benefit from the drug requires expensive scans, and practices will be able to bill Medicare for those, too.
...
So Biogen is planning to charge $56,000 annually for aducanumab. ICER, which evaluates the estimated value of new drugs, estimates, based on the clinical evidence, that it’s worth more like $8,000; perhaps as little as $2,500.
Because Medicare does not have a mechanism for refusing or negotiating coverage for FDA-approved drugs, the upper limits of this are staggering:
The Washington Post wrote:The Kaiser Family Foundation recently estimated that if 1 million Medicare beneficiaries receive Aduhelm, the total spent in a single year would be $57 billion. Medicare spent $37 billion on all Part B drugs in 2019.
If only 1 out of every 6 patients with Alzheimer disease receive this drug, the first new drug approved for Alzheimer's in 20 years, the cost would more than double all of the current spending on Medicare Part B drugs combined. If half of them do, that's almost $175 billion annually in mandated spending for a drug that the best experts in the field currently believe does not work.
There's a ton to unpack here, from the perverse financial incentives at every step of the process, the complicated and sometimes deleterious influence that well-intentioned hope and advocacy can have objective scientific review, how absolutely fucked the restrictions on Medicare drug pricing negotiation are, etc. This also follows in the wake of the FDA's Emergency Use Authorization for hydroxychloroquine use in treating COVID last year based largely on political pressure, conspiracy theories, and shoddy preclinical data. The FDA has historically been viewed as an international beacon for rigorous scientific review, but it's hard to see how decisions like this don't continue to erode their credibility in the scientific community, both nationally and around the world.
rndmhero on
+15
Posts
I've said before that the US is a third wold country with money, so third world-level corruption (with higher stakes) seems like it should be expected.
Doc: That's right, twenty five years into the future. I've always dreamed on seeing the future, looking beyond my years, seeing the progress of mankind. I'll also be able to see who wins the next twenty-five world series.
I would have thought the purpose was to prevent a bad drug epidemic from sweeping the US.
Yes, prevent the ones that happened there from happening here.
Has there been a bad drug epidemic that swept or is sweeping Europe?
Thalidomide and dirty blood come to mind. Europe doesn't have a stellar history either.
Right.
But Paladin wrote "avoiding a bad drug epidemic that sweeps Europe or China", not "avoiding a bad drug epidemic such as those that sweeps Europe or China", which is a big difference and the reson for my original question.
Secondly, Paladin wrote in the present tense, implying that these epidemics are currently sweeping Europe and China. Can't speak for China, but I'm not aware of such an epidemic in Europe at the moment or recent past. Thus my second question.
Finally, the thalliodomide thing (and other issues) led to the formation of strict regulation on drugs in Europe (as well as in the US). I don't think Europe is worse than the US in regards to drug safety and regulation?
Anyways, this was just me asking for clarification due to unclear communication.
The dirty blood incident (where European drug manufacturers used HIV+ blood to create hemophilia treatments and then didn't pull them, leading to a rash of infections from said treatments) was the mid 80s to 90s. Not nearly as far in the past as you'd like to think.
The thing that's so strange to me is that, despite all this reporting, I have yet to see a convincing explanation for why this was approved. Some people assume corruption somewhere because the decision is so bizarre, but no one has put forward concrete examples or accusations. And this thing's been under a microscope.
The only thing I've heard was that Billy Dunn, the director of the FDA's neuroscience division, has been overtly championing this drug from the outset. Even that, though, appears to be more of a weird desire to usher through the first new Alzheimer's drug in decades rather than any direct (or indirect) financial incentive.
It was using blood products from the States that caused the issue wasn't it? That the UK imported blood from the US to deal with shortages, but whilst the NHS gets blood from healthy donors, the US blood brought was largely from prisons or from people who needed to sell blood for money.
There's currently an inquiry going on as to who knew what and when over here.
Doesn't work might also be down to the way it's administered, I'd be curious to see if this gets struck down whether they partner up with some of the companies doing transport of large biologics across the blood-brain barrier.
Can work but struggles to get to where it needs to in most patients, wouldn't surprise me.
As part of the fast track approval they also have to show something in studies in the next nine years. Which would be a long time spending an unbelievable fuckton of money on something that might do literally nothing.
Could it just be political pressure winning out over scientific opinion? It sounds Iike patients and advocacy groups are pretty happy with this decision.
Speaking as a patient in a niche market, we are often desperate for anything and we are frequently subject to abuse based on our desperation.
They are under duress, essentially.
When the current treatment for Alzheimer's is effectively nothing, any improvement, no matter how slight, will be welcomed by patients and advocacy groups. And they aren't going to be footing the bill for this overpriced drug.
There is a trillion dollar hole in the ground on this plaque hypothesis and someone desperately wants to fill it. Even the National Institutes Of Health got caught up in investing in several extremely expensive failed clinical trials using similar antibodies.
It just happens to also not work. As has been thoroughly established at this point.
This is basically my thinking. And it’s very disappointing, because it’s just going to get hopes up for patients and families only to have them dashed later.
The approval was contingent on a follow up efficacy study. They have eleven years to complete that. I fully expect them to take every last minute of those eleven years.
What I've read said that there were like a couple studies that failed to show improvement, but then they re-examined the data (whatever that means?) and did find some signs of improvement?
That doesn't sound like "throughly established" to me?
I would think that would more be reason to continue with more clinical trials not just throw it on the open market but I'm not the FDA so what do I know, apparently.
I asked one of my more policy-oriented friends, and they said that this is vaguely in line with the gossip on the current acting FDA head Janet Woodcock--that she's a pushover and won't stand up to pressure.
Anyway, it's a legendarily bad decision and a monument to the dysfunction that is American healthcare. The best that can be hoped for is that it at least heightens the contradictions. I wouldn't mind if it also led to some public reappraisal of patient advocacy groups as well. They are not always full of good ideas. They also bear a disturbing relationship with pharma, which has realized that they supply a convenient, sympathetic front to hide behind when lobbying for decisions such as these.
It's a bit accelerationist but as a drug for the elderly, if price is so high it will bankrupt Medicare or if Medicare won't cover it or severely limits it maybe it will push through letting Medicare negotiate prices.
Yeah, to be clear, I don't mean that as a general endorsement of accelerationism or as a reason to be pleased; but, if you're getting accelerated anyway, you might as well hope something comes of it
As I understand it, they tested for one effect, didn't find it, then checked the data for any effect, found one, and said the drug works for that.
The problem is that this is extremely bad science. By pure random chance, most drugs will do something along some metric. What you're supposed to do in these cases is test again for the new thing, not sell your drug to cure the thing you didn't think it was going to cure to begin with, but randomly showed positive results in your trials.
Now, sometimes this other effect is real (viagra on ed instead of heart issues), but then you have to do a new trial to make sure it wasn't pure random chance.
This is correct. Oftentimes it's not that a drug (or whatever your experimental perturbation is) causes an effect that you just didn't anticipate (like Viagra). It's that, statistically, if you run enough enough comparisons, you will eventually identify some type of difference purely by chance. The only way to tell the difference between a real but unanticipated benefit vs statistical noise is to do a separate trial to test that hypothesis.
In this case, they identified some noise in one study that, to my understanding, they couldn't even identify post hoc in the second trial. Rather than telling them to run a study to test the new analysis, which is what the FDA should have done, they approved it without restriction.
The need for a post-marketing study in 9 to 11 years is almost irrelevant here, because 1) the company has the potential to make literally a trillion dollars on the drug by that time, and 2) I suspect independent studies out of academia will have shit all over this long before then.
This seems like a plan that Martin Shkreli would have come up with.
There’s overwhelming evidence of a thing not working, the company saying “but what if it did?”, and the FDA inexplicably saying, “good point, approved.”
Biogen doesn’t have to have even done anything wrong for this to be a train wreck.
The xkcd jellybean comic is basically what's going on. Give me enough data points and a lose enough threshold and I will prove to you that drunk driving is correlated to the length of the longest name of species of bee in the area or something. You're supposed to set a hypothesis up in advance, test, and if that doesn't work and you find something else, then you fucked up when you looked at the data again and are a statistical criminal.
(it's more nuanced than that, but basically finding something you weren't looking for means absolutely nothing. It may be real and it might be worth running another study with that as your hypothesis, but the data you currently have can't show outside of extremely contrived trivial cases)
Any subgroup analysis is the same, incidentally. If your drug doesn't show efficacy at p < 0.05 and you then try it on ten year age bands from 20 to 80 and split by gender, you'd expect to find an effect even if there's none about 40% of the time.
There are at least ten failed clinical trials targeting amyloid beta/plaques now. All withdrawn for lack of efficacy. It’s not just this one.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966425/#!po=0.505051
See table one (open access)
https://blogs.sciencemag.org/pipeline/archives/2021/07/02/the-underside-of-the-aducanumab-approval
https://www.statnews.com/2021/06/29/biogen-fda-alzheimers-drug-approval-aduhelm-project-onyx/
(Paywall)
First reaction: good
Second reaction: Can they do that? Medicare is more or less required to cover anything FDA approved. Maybe the VA, as a prescribing entity, has more leeway.
Medicare has ruled, essentially, that while they can’t outright refuse to cover it, they can limit coverage to patients enrolled in a clinical trial designed to figure out if aduhelm, you know, works.
https://www.statnews.com/2022/01/11/medicare-aduhelm-proposed-decision/?utm_content=bufferf43d3&utm_medium=social&utm_source=twitter&utm_campaign=twitter_organic
You may be thinking, “isn’t that normally the FDAs job?” and yes, yes it is.
https://www.reuters.com/business/healthcare-pharmaceuticals/biogen-discontinue-development-older-alzheimers-drug-aduhelm-2024-01-31/
Hopefully the damage this has done to the FDAs legitimacy is reversible
I feel like this might just throw fuel on the fire that the whole COVID vaccine bullshit started. At the same time, I'm not sure if those people even know this is all going on.
Also I appreciate you necroing this thread to keep us updated. I just have nothing else to add.
Still really expensive, but might actually do some good?
Me personally? Not much.
https://www.science.org/content/blog-post/lecanemab-and-alzheimer-s-more-data
If you accept that the marginal slowing of cognitive decline is real, which you don’t have to given the subjectivity of the measure, there’s still the question of whether that’s actually noticeable in the real world.