Experts Have Resigned from an FDA Committee over Alzheimer's Drug Approval

https://www.npr.org/2021/06/11/1005567149/3-experts-have-resigned-from-an-fda-committee-over-alzheimers-drug-approval

by busymom0 • 5 years ago

319 146 5 years ago

JadeNB• 5 years ago

This is from June—it's interesting, but is there some particular reason to resurface it now? Has there been some recent development?

lowkey_• 5 years ago

Personally, I don't remember seeing this in June. It doesn't seem that there's a recent development, but it seems important and interesting enough that it's worth posting.

busymom06• 5 years ago

Seemed relevant as I saw it was referenced in another recent news from couple weeks ago where “Two senior FDA vaccine regulators are stepping down: Marion Gruber, director of the FDA’s Office of Vaccines Research & Review, and deputy director Phil Krause will exit the agency.”

https://www.cnbc.com/2021/08/31/two-senior-fda-vaccine-regul...

datavirtue• 5 years ago

"patients' copayments for the drug could cost around $11,500 annually."

For drugs like this the drug company pays the patients' total out of pocket (co-payment) in full on the first infusion. The patient never has anything to pay in this case...if they have insurance.

whoknowswhat112• 5 years ago

This is actually how they manipulate / overcharge on pricing. Because the person paying is not the person getting, they can charge anything, and there is HUGE pressure to proscribe still.

If instead they even required patients to still cover out of pocket portion, prices would need to be way lower.

You see this overseas. People pay out of pocket. I was in a fair number of developing countries, it's actually a bit nuts for westerners. The process to get for example things like basic antibiotics is near over the counter. Other items are INSANELY cheap. And accessibility (if you have USD) is good.

rootbear2• 5 years ago

My sister, who is on Medicare, is paying over USD 10,000 a year for her cancer drugs (ALK-positive lung cancer). That's out of her pocket.

mcguire2• 5 years ago

What are "drugs like this", and why is the drug company paying for it?

macintux2• 5 years ago

209-comment thread at the time: https://news.ycombinator.com/item?id=27472107

busymom06• 5 years ago

Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 71 (32.0%) were affected by a postmarket safety event. Postmarket safety events were more frequent among biologics, therapeutics indicated for the treatment of psychiatric disease, those receiving accelerated approval, and those with near–regulatory deadline approval. From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%)”

https://jamanetwork.com/journals/jama/fullarticle/2625319

qwerty456127• 5 years ago

By the way, I've got a question to whoever is into the Alzheimer research: I have recently heard Alzheimer symptoms instantly disappear shortly before the patient's death - people regain their sane mind in full (or close to) capacity but then die in just about a day. Is this true or a myth? Were there at least some such cases documented credibly?

gameswithgo• 5 years ago

Alzheimer patients have moments, brief, at random times, where lucidity seems to be there for a bit. This could certainly happen in the moments before or day before dying, and for family this might seem meaningful when it happens. But there is not any kind of connection between the things. Patients just get worse over time until they die.

merpnderp• 5 years ago

Not sure why you're being downvoted. I spent years visiting family in Alzheimers wards and this was my experience too. Some days patients would have a brief moment of clarity, but usually it was just the typical symptoms.

For instance the sister for a famous (for the state) news reporter would seem to come out of it a bit to talk about her sister, but mostly she just walked along the walls, tracking the trim with her fingers and mumbling to herself.

TedDoesntTalk• 5 years ago

Is this true or a myth?

It is a nice myth to pull at your heart strings

burning_hamster2• 5 years ago

Your cynicism is misplaced as terminal lucidity is, in fact, a well documented phenomenon.

https://en.wikipedia.org/wiki/Terminal_lucidity

whoknowswhat112• 5 years ago

Do you have a citation? I had someone who passed away at home who had a period of greater clarity relatively shortly before they passed. Many things I think could have contributed - but it didn't seem like a myth.

CivBase2• 5 years ago

My grandmother passed away a few years ago. Her Alzheimer's had gotten very severe, although technically she died with the disease not of it. Her symptoms definitely did not diappear shortly before her death.

However, she did have a moment a few months before where her symptoms seemed to completely vanished for a couple hours after a doctor flushed out her Alzheimer's meds. Unfortunately I was not there, but my mom said she was suddenly completely attentive and remembered everything like her old self during that time. I don't know if it was coincidence, related to the meds, or if the flushing process did something (I'm told it was intense). I wouldn't be surprised if other patients have experienced similar things, but I don't think it's related to death.

ianhawes• 5 years ago

My grandfather had a similar fate. Roughly 4 months before his death, my uncle was taking care of him for a week while my grandmother was traveling. My uncle had, for the longest time, been adamant that the medication had made his dementia worse. Unbeknownst to the rest of the family, he stopped administering the dementia meds for the week that he was caring for him.

It was bizarre interacting with him during this lucidity. He was able to do most physical things without assistance (he still had a bad hip) and you could engage with him in conversation. He knew who I was without prompting, something he hadn’t been able to do for about 4 years. He knew all his children and grandchildren. He also shared stories from his middle years, something he had stopped doing during the early stages.

It wore off though, in about a week or so he began to have the brain fog set in. His doctor was also not too happy to hear about the withdrawal.

The only person who seemed disturbed and worried about this moment of lucidity was his caretaker, who had worked with dozens of elderly folks with memory issues prior. She said it almost always happened before a sudden decline. She was right, about 3 weeks later he became very ill and then died within a few months.

nunb• 5 years ago

could you tell us a bit more about the flushing process and what these meds were? if they were anti-anxiety & anti-depression meds, then perhaps they could have had the effect of unsedating a person?

burning_hamster2• 5 years ago

Terminal lucidity is a fairly well documented but not very well understood phenomenon.

Here are a few review papers I could dig up in a couple of minutes:

2019: https://juniperpublishers.com/pmcij/PMCIJ.MS.ID.555601.php

2017: https://sciendo.com/article/10.1515/cpp-2017-0003

2011: https://pubmed.ncbi.nlm.nih.gov/21764150/

2009: https://pubmed.ncbi.nlm.nih.gov/20010032/ (with focus on dementia)

Scientific American blog post: https://blogs.scientificamerican.com/bering-in-mind/one-last...

rootbear2• 5 years ago

Neither my grandmother, who died of a stroke that was probably related to her late stage Alzheimer's, nor my father, who died of severe Alzheimer's, experienced terminal lucidity. But it seems to be a real phenomenon, and worthy of study.

tapoxi• 5 years ago

The company behind this drug - Biogen - was also dumb enough to hold an international conference in downtown Boston during the beginning of the pandemic, and spread COVID throughout the state.

encryptluks22• 5 years ago

That had their drug approved by the same FDA that you suddenly trust in that regard.

EamonnMR• 5 years ago

People where still working in offices and going to school then. Heck, I was at Pax East just before that went down. We where concerned about Corona, talked about it, but we still went along with tons of others.

macintux2• 5 years ago

Still, you’d think a medical company would be a bit more sensitive to the topic. Other conferences had already been canceled.

And in fact it may have had a massive impact.

Between 205,000 and 300,000 coronavirus cases across the U.S. can be traced back to the Boston conference, say the scientists, whose findings were published in the journal Science on Thursday.

https://www.cbsnews.com/news/boston-biogen-medical-conferenc...

mountainriver• 5 years ago

Rick Doblin had recently brought this up as the FDA forced his MDMA research to have a 2nd phase 3 trail even though they had stellar results in phase 2 and 3.

Such an odd contrast as they passed a drug which had a number of failed studies and only one marginally successful one.

fighterpilot5• 5 years ago

odd contrast

It probably makes more sense if we view the FDA not as a monolith but a collection of lots of individuals, some of which don't communicate or work together directly.

zepto9• 5 years ago

Not really. You’d expect an organization like the FDA to be policy based.

jcims• 5 years ago

This is true everywhere though, isn't it? It's all just people. Government, families, companies, research labs, law enforcement, universities, religions, political parties, movements, etc.

As a result all of our laws, relationships, products, theories, judgement, pedagogy, spirituality and platforms are composed and interpreted by a dizzying array of perspectives and values. Our brains can't handle the combinatorics, so we just personify them and anyone we associate with them is just a fragment of the whole.

refurb2• 5 years ago

Two phase 3 are standard. And I assume Rick was going after full approval not conditional as per the Alzheimer’s drug?

s1artibartfast7• 5 years ago

Two well controlled studies are required, so it really comes down to how the Phase 2 was structured and powered to see if it can count as the 2nd study.

derbOac• 5 years ago

There are many odd contrasts with the FDA.

For example, why are they even involved in a discussion of booster doses of the Pfizer vaccine when they've given it full approval? Shouldn't that be at the discretion of physicians or other prescribers?

Why isn't acyclovir available over the counter?

Why has cannabis been treated as a mortally dangerous substance?

Why have miracle berries inexplicably classified as an illegal undeclared sweetener (https://www.theatlantic.com/health/archive/2014/05/can-mirac..., https://en.wikipedia.org/wiki/Miraculin#cite_note-Atlantic-2...)?

I think the role of the FDA has expanded much too far.

s1artibartfast7• 5 years ago

Boosters are at the discretion of doctors

hellbannedguy• 5 years ago

There's still a bit of ethics in some people.

Now--I wish the FDA would revisit approval data on every anti-depressant since Prozac, and including Prozac.

Irving Kirch was the first to look at all the drug trials, and not just cherry pick. His study is in Lancet.

https://www.psychologytoday.com/us/blog/psych-unseen/201802/...

eli• 5 years ago

This was a few months ago. Congress is now investigating the FDA approval of Aduhelm.

encryptluks22• 5 years ago

And likely will cover themselves as the corruption is widespread.

MeinBlutIstBlau2• 5 years ago

Not to be a little harsh here, but is it really all that bad? People with alzheimers are basically knocking on deaths door. They aren't even themselves anymore when it gets real bad. They constantly are in a state of of "who are you people being nice to me?" with friends and family. It's like getting upset over a risky drug for cancer patients in stage 4. It's not like in the grand scheme of morality it's going to do much if any harm. And unfortunately, some people need to be test subjects.

busymom06• 5 years ago

I think giving false hope is definitely bad. Also the price of the drug alone (regardless of who covers it) is ridiculous for something which is useless.

MeinBlutIstBlau2• 5 years ago

If you're expressly told before taking it the same information we know now, is it false hope? Also isn't praying to a god false hope? Rolling dice in Vegas...false hope?

Everything in life is a gamble. How you interpret the results is you own undoing.

toast0• 5 years ago

I think this is a legitimate question.

In my mind, there are two main issues. The first is what other alternatives would be overlooked because of an approved treatment, including further research.

The other issue is money. These medicines cost a lot of money, and it there's no improvement it's a waste of resources not only for the patient, but also for the insurance pool they're in. If it's something that's not expensive, go nuts, but thousands of dollars to move the metric but not the symptoms doesn't make sense to me.

dannyw• 5 years ago

With that logic, if you're being DDoS'd, might as well as start piping /dev/random to /.bash_history. It gives hope!

javagram• 5 years ago

The drug is extremely expensive, it’s a vast waste of money if it doesn’t work and millions are prescribed it.

Running another trial makes sense if “test subjects” are needed but giving the drug general availability when the previous trial failed and was actually stopped because of failure doesn’t make much sense to me.

rocqua• 5 years ago

I recall from a previous HN article, there is a _lot_ of controversy in the Alzheimer research area. Specifically about whether the amyloid plaque in Alzheimer actually is the root cause of Alzheimer. With the dissenting opinion being that the plaque is actually just a symptom.

As I recall, the claim (by the dissenters) in the article was that big names in research had staked their reputation on the plaque theory. Those big names were claimed to use their weight to suppress any research into alternative theories. The article then stated that the little bit of research into alternative explanation seemed promising, and that there were trials on removing plaque that did not seem to cure Alzheimer.

This news about a controversion FDA approval feels like it is related to this controversy. And to my mind, it strengths the case for 'plaque does not cause Alzheimer'.

ajkjk• 5 years ago

My understanding from having a few friends / family members in the field is that no on believes amyloid plaques are the cause anymore -- as you said -- but also that there isn't actually much controversy about this. So it's not that alternative theories are being suppressed, really, but that that's a media spin you might have picked up somewhere.

JamesBarney• 5 years ago

I think few people believe amyloid plaques are the sole cause but there is still quite a bit of evidence that amyloid is heavily involved in Alzheimer's. Genetically almost all of the genes associated with Alzheimers have to do with the productions or cleaning up of amyloid beta.

oldgradstudent• 5 years ago

Yet, this drug was approved solely on it's ability to reduce amyloid plaque, without any cognitive effects.

fabian2k• 5 years ago

Already 20 years ago there were serious discussions whether the fibrils were actually responsible, or maybe instead some toxic intermediates might be the cause. As far as I understand the case against fibrils as the main cause only got stronger, and the mainstream view among scientists is that it is quite likely that there is more going on there and the fibrils alone are not the full explanation.

hirvi742• 5 years ago

I wonder how the amyloid plaques not being thought to be the cause of Alzheimers will affect the research of CTE (one of the many other tauopathies.)

For what it is worth, there seems to be a lot of internal debate around the causes, symptoms, and treatments of CTE. In fact, there are debates as to whether CTE is a distinct tauopathy or even exists at all (at least in the form the public understands it).

someguydave• 5 years ago

plenty of therapies only treat symptoms

OneTimePetes• 5 years ago

But symptom treatment is not good enough with this, as even removing the plaque, does not prevent-repair the damage. In this case, the symptoms would just shift to another set of symptoms

wongarsu• 5 years ago

Sure, but you have to treat the symptoms you actually care about. Lowering a fever doesn't make your nose less runny.

If amyloid plaques are just a symptom, then it's much less obvious that treating them will have positive effects on the symptoms you actually care about.

shkkmo• 5 years ago

The facts here paint a pretty different picture. 10 of the 11 scientists on the panel voted "no" and the last member voted "uncertain". These no votes were precisely because the only "successful" study of the drug only showed plaque reduction and failed to show any direct improvement in Alzheimers outcomes.

To me that indicates that this isn't a controversy between scientists, but an example of corruption / regulatory capture. Biogen spent a bunch of money researching a drug based on an unproven theory. When their results were very poor, the FDA allowed them to switch to accelerated approval, then ignored their unanimous panel of experts to grant that approval. This allows Biogen to sell an extremely expensive drug and recoup some of their loses before the ongoing studies required under accelerated approval further undermine the drug's claims of effectiveness.

jmartrican• 5 years ago

Just finished reading a book where the Sackler family manipulated the FDA into allowing Oxycontin to be released. My regards for the FDA is pretty low right now. If the consumers of pharama can't trust the FDA, then this might end up hurting the big pharma, because the people will think twice before taking some meds.... i know do.

irthomasthomas• 5 years ago

I've read a few books recently that referred to Alzheimer's as type 3 diabetes, since the root cause appears to be insulin resistance. https://en.wikipedia.org/wiki/Type_3_diabetes

ABetaMale2• 5 years ago

I've spent about the last two months reading the scientific literature on Alzheimer's, and while there is some dissent, the amyloid hypothesis is currently by far the dominant one, and for good reason IMO. The below is adapted from a comment I wrote on Aug 20 on the ACX Substack:

---

It is natural to ask: "sure, we see amyloid-β plaques with Alzheimer's Disease, but could there be a confounder, rather than amyloid-β being the cause?" However, we have strong evidence that it's the cause.

In fact, in a subset of cases, we have smoking gun evidence that amyloid is the cause: certain mutations or duplications of the APP (amyloid precursor protein), PS1 & PS2 (presenilin 1 & presenilin 2, parts of the enzyme γ-secretase involved in cleaving APP to make amyloid-β) genes guarantee that one gets Alzheimer's, and typically quite early (between the age of 30 and 60 for the onset of clinical symptoms). We have mapped out the structure and function of the corresponding proteins extremely well, and we know how, functionally, those specific mutations affect the behavior of those proteins: either to increase total amyloid-β production, or to increase production of the specific peptide (amyloid-β 42) implicated in Alzheimer's Disease. [1] I am not aware of another plausible effect of those mutations besides this one, and the mutations guarantee you get Alzheimer's Disease.

Now, this represents approximately 1% of Alzheimer's cases, the so-called autosomal dominant variety, so it's a priori conceivable that the other cases have a different cause. In the remaining cases, we have evidence consistent with an impairment of amyloid clearance mechanisms, however that evidence is more circumstantial and in some cases compatible with other hypotheses. But the disease looks like exactly the same disease as the 1% of cases in which we have smoking gun evidence of amyloid being the cause: we still see the same progression of amyloid-β, followed by a progression of hyperphosphorylated tau, followed by neurodegeneration and cognitive decline, and with the same sequence of brain regions and cognitive symptoms.

Suppose there are two bank robberies. In the first, we have smoking gun evidence of the culprit: a video camera showing a guy getting out of his car, with a clear image of his face and the license plate, and then of him walking into the bank, pointing a gun at the teller, the teller handing over a bag of cash, and him walking out with that bag of cash. In the second: we also have footage of the same guy and the same license plate at the scene of the crime, but an occlusion prevents clear footage of the exact moment of the robbery. However, the robbery occurred in the same town and on the same day, and eyewitness reports are that the robbery was conducted in basically the same manner. In that case, is there much question as to the identity of the robber?

As for the track record of amyloid-targeting therapy for Alzheimer's, I think it's fair to say that it's been less successful than hoped for but that also:

1) There has been a mixture of benefit and no effect; rather than the mixture of benefit, no effect, and harm which you'd expect to see if the drugs really were useless. For example:

A) The recent phase 2 trial of the similar drug donanemab showed success in its primary endpoint of reducing cognitive decline, by 32% (p = 0.04). [2]

B) The recent phase 2b trial of another similar drug lecanemab had promising results, although it didn't pass its primary endpoint, arguably due to a needlessly convoluted Bayesian statistical analysis. It showed reductions in cognitive decline of 26%, 30%, or 47% (p = 0.125, 0,034, or 0.017), depending on endpoint. [3]

C) With respect to aducanumab [4], the first phase 3 trial, EMERGE, passed its primary endpoint and all pre-designated secondary cognitive endpoints, with p-values for the high dose arm between 0.0006 and 0.0493 (0.0120 on the primary endpoint), and effect sizes ranging from an 18% slowdown to a 40% slowdown in cognitive decline (22% on the primary endpoint).

The second phase 3 trial, ENGAGE, did not show statistically significant benefits on any pre-designated endpoints, but the effect sizes still ranged from -3% to 18% (-2% on the primary endpoint). So given only pre-designated endpoints, we have two trials, one of which showed a clear benefit, and the other of which showed no effect, or very slight benefit if we give some weight to pre-designated secondary endpoints. From a Bayesian perspective, this has to be seen as weak evidence of benefit.

Lastly, both trials showed a substantial and significant (p < 0.001 in EMERGE, p < 0.01 in ENGAGE) reduction in phosphorylated tau, a neuropathology both regionally and chronologically highly correlated with volume loss and cognitive decline in Alzheimer's Disease.

2) The amyloid cascade hypothesis offers explanations for past failures of amyloid-targeting therapy, for example poor target specificity (some therapies such as semagacestat were not proven to engage amyloid in the first place, and were also known to produce other toxic effects unrelated to reduction in amyloid), deficient screening of participants (in some cases, patients were selected only for cognitive symptoms and not for the presence of amyloid, thereby reducing statistical power), and not intervening early enough (no one believes amyloid is the main proximate cause of neurodegeneration, so if you intervene late, it might be too late to prevent the cascade of problems it's believed to cause).

By contrast, I'm not aware of alternative hypotheses which even offer a story which can account for the known facts, such as the aforementioned evidence in the APP and PS1/PS2 genes.

For those interested in learning more, a good starting point for the current state of the science is [5]. A more up-to-date and comprehensive review paper is [6].

[1] Haass et al (2012). Trafficking and proteolytic processing of APP. https://doi.org/10.1101/cshperspect.a006270

[2] Mintun et al (2021). Donanemab in Early Alzheimer’s Disease. https://doi.org/10.1056/nejmoa2100708

[3] Swanson et al (2021). A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. https://doi.org/10.1186/s13195-021-00813-8

[4] Petersen et al (2019). EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease. https://investors.biogen.com/static-files/ddd45672-9c7e-4c99...

[5] Selkoe and Hardy (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. https://doi.org/10.15252/emmm.201606210

[6] Long and Holtzman (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. https://doi.org/10.1016/j.cell.2019.09.001

c618b9b695c42• 5 years ago

I am in pharma, though not tied to Alzheimer's research.

A narrative of this-one-theory-being-kept-down-by-the-man is attractive, but a bit thin in practice. The amount we do not know about anything in biology (especially the brain) is staggering. Few researchers are willing to make definitive statements owing to our ignorance in the space. Biological research is the closest one can come to direct manifestation of Murphy's Law.

Many are invested in the amyloid hypothesis, but only because it is the most compelling target to date. Everyone knows the emperor has no clothes. If/when better evidence comes to light, the field would move accordingly. Until that time, pharma companies will keep throwing billions of dollars at abeta hoping that their compound will have an effect where others have failed.

Edit: corrected typo pointed out from below

tdeck2• 5 years ago

I remember a study from a few years ago that showed a compelling link between gum disease and Alzheimer's. What happened to that hypothesis? Has it gained any more traction?

zzt123• 5 years ago

When you say that the amount we do now know is staggering, do you mean the amount we do not know? The rest of your post suggests the latter, which is somewhat an antonym of what was actually written.

Root_Denied• 5 years ago

If/when better evidence comes to light, the field would move accordingly.

This is a bit of an idealistic view.

It's entirely possible for large players within a given system to pick and choose winners, specifically in where they direct funding. This isn't the same thing as actively platforming against a particular path, just funding the one that they see as most promising.

I think the argument here revolves not around the "gerontologists hate this one trick that big pharma doesn't want you to know" but rather than there's some small number of people making decisions based on their own biases with regard to research directions and there's a dissenting group that would like to see broader research done before committing the finite available resources to just that one path.

btilly• 5 years ago

You have argued for why we shouldn't be suppressing alternative hypotheses. But you haven't provided good evidence that this hasn't happened.

However a series of high profile articles and editorials have said that we have. For the latest example, read https://www.scientificamerican.com/article/alzheimers-inc-wh....

Given that, I will continue to believe that this area of science absolutely have acted in a non-scientific way.

mcguire2• 5 years ago

Technically, I believe the claim by dissenters is...

"As NPR's Jon Hamilton has reported:

"This drug has generated all kinds of excitement because it is the first approved drug that does more than just relieve the symptoms of Alzheimer's. This drug actually affects an underlying disease process by reducing the amount of sticky amyloid plaque that builds up in the brain. The catch is that removing this plaque may not actually help patients avoid memory loss and thinking problems. One big study showed that it did. Another showed that it didn't.""

In other words, the drug works against what may be a symptom of the disease, but hasn't reliably been shown to do anything for the actual problem.

Science is hard.

Oh, and by the way,

"The drug will be administered through infusions every four weeks, resulting in a yearly cost of about $56,000, the companies said. That's the list price, which doesn't necessarily reflect the out-of-pocket costs for someone who has insurance and/or Medicare. Preliminary estimates suggest patients' copayments for the drug could cost around $11,500 annually."

sgent• 5 years ago

Also it causes brain bleeds in about 40% of patients, and was only tested on those with mild disease. Again, showing no improvement of progression or symptoms, but a reduction in plaque.

arc-in-space• 5 years ago

...But not over stalling the mRNA vaccines for half a year

rossdavidh• 5 years ago

Another industry expert, with much the same opinion: https://www.science.org/content/blog-post/open-floodgates

xibalba• 5 years ago

I heard a theory on some podcast that the ulterior motive here may be to try to incentivize more R&D into Alzheimer's pharma. This approval is thus a green light signal.

DebtDeflation• 5 years ago

We may very well see a repeat of this situation in the next couple days when the FDA considers a different Advisory Committee's recommendation on the Covid vaccine boosters. There is speculation that the FDA may ignore the recommendation to limit boosters to 65+ and those with risk of severe disease and instead approve it for a broader population. At the end of the day, the Advisory Committee is just that - a committee that advises and the FDA is not bound by that recommendation. It seems a bit disingenuous of the committee members to expect the broader FDA to just rubber stamp their recommendation, particularly when it was a split decision.

setgree2• 5 years ago

Scott Alexander's "Adumbrations Of Aducanumab" is essential reading on this subject IMO [0].

He makes an interesting point that when the FDA approves a drug, it means that Medicare is automatically on the hook to pay for it, and that a more sensible system might decouple approval and mandated reimbursement by having multiple levels of approval (e.g. 1 star = this is probably safe, 2 stars = it's definitely safe, 3 = there's weak/controversial evidence for efficacy, 4 stars = it is safe and it works, etc.).

But it's interesting to me that we hear about FDA scientists resigning when a panel is too permissive, but not when it's too restrictive. Can we chalk this up to something about the kind of people the FDA recruits? I can recall just one instance of an FDA official pushing the institution to go faster, and that was when the doctor's wife died of cancer [1].

[0] https://astralcodexten.substack.com/p/adumbrations-of-aducan...

[1] https://www.nytimes.com/2016/01/03/us/politics/fda-regulator...

Brakenshire3• 5 years ago

We do have to make drug discovery vastly more efficient, but we want to make it more efficient at making useful drugs available, not just making drugs available. If you decouple availability from effectiveness then drug companies will just market unproven drugs to people who are desperate or who don't know any better. Or even if the drug companies do nothing people will just start taking drugs on the basis of recommendations from Facebook.

Maybe that means building randomized trials into treatment in a much more regular way (like with the Covid RECOVERY trials, where any doctor could enroll patients with a web form, and source the candidate treatment from the local pharmacy), which vastly reduces cost for treatments already on the market with other indications. And perhaps altering the balance of risk for patients with life-threatening or terminal diseases.

civilized2• 5 years ago

One reason your proposal isn't happening today might be because we don't want tons of doctors choosing to enroll in these "field" randomized trials, if they might be experimentally treating people with drugs that aren't safe. We want to know about safety first before unleashing on the world, even in a randomized trial context. And since the FDA bundles verification of safety and efficacy together, so we can't do your proposal without unbundling them.

Now, imagine that after safety is verified to a 1 or 2-star level, we don't make the drug approved for general use, but doctors can freely enroll in randomized trials as you proposed? That way we're getting the efficacy data quickly but safely.

Maybe a minor point, but we do have to unbundle safety from efficacy in some sense to get off the ground here. The question is, what exactly is allowed to happen after safety is established but efficacy is not yet established?

Sanguinaire• 5 years ago

The problem here is letting drug companies market to the uneducated general public - there is a good reason why that practice is banned in most countries.

themacguffinman7• 5 years ago

If you decouple availability from effectiveness then drug companies will just market unproven drugs to people who are desperate or who don't know any better. Or even if the drug companies do nothing people will just start taking drugs on the basis of recommendations from Facebook.

But this already happens for certain treatments. The FDA already regulates a separate category with loose efficacy requirements for dietary supplements and herbal remedies. These medically irrelevant treatments are immensely popular, they're just forbidden from marketing specific medical claims and being actually toxic. People still end up taking FDA approved treatments like Ivermectin for non-FDA-approved purposes based on Facebook recommendations.

Why do we always have to make people's choices for them? They're grown adults capable of making their own decisions and their own mistakes. If they want to ignore the science and the credibility of the FDA process, they should be free to do so.

cameronh90• 5 years ago

In the UK, as I understand it, we have:

MHRA: approval for marketing and sale within the UK

NICE: analyse cost/benefit ratio and safety profile for use within NHS (which is then approved by the NHS CCGs)

jeherr• 5 years ago

In regards to the panel being too restrictive or permissive, I think you have to look at the possible motivations for why. If you have a drug candidate that seems safe and effective, what possible motivation could the panel have for rejecting it? The pharma company gets their drug to market, patients get new and better drugs. The incentives are aligned so the issue with being too restrictive is a debate about how risky we should be approving new drugs.

On the other hand for a drug that’s safe but maybe not effective, there’s a lot of money to be made off of people willing to do anything to prolong their time with their loved ones who have been diagnosed with Alzheimer’s. Aside from that, the FDA can hurt it’s reputation by approving drugs that just don’t work too frequently and be accused of being in the pockets of the pharma companies. There’s a stronger possibility of corruption affecting the decision, and whether that corruption is real or perceived doesn’t matter much for public trust.

usefulcat• 5 years ago

Perhaps we need a third level of FDA approval. In addition to 'approved' and 'not approved', we could have 'safe but not demonstrated to be effective'. Drugs in the third category would be legal to prescribe but Medicare and insurance companies would not be required to pay for them.

Although in practice I guess this would probably not be very different from 'not approved', in which case it seems right for the FDA to reject ineffective drugs.

In any case, one thing we definitely do not want is to incentivize the creation of ineffective drugs, especially expensive ones.

dougmwne4• 5 years ago

What on earth would be the point of that? Why should we encourage the development of new snake oil? Why encourage drug companies, which currently must provide evidence their drugs work, to pivot into snake oil? Do you think we are an enlightened people immune from the snake oil our ancestors used to fall for? Recent pandemic events would beg to differ!

AshamedCaptain• 5 years ago

If there's weak evidence for the effectiveness of a drug, then most likely the drug has no effect at all. Let's remember that crap such as homeopathy would rank as 3 stars on your proposed system.

Our current research/science publishing system is not well suited to evaluating very small effects. Not that there may any system well suited to that.

dougmwne4• 5 years ago

Precisely. If I want to create weak evidence for a drug, I can just run a few dozen studies and statistics will take care of the rest. Drugs with real, but very small effects are also not very useful as they aren't going to move the needle much, and certainly not as much as the quite powerful placebo effect.

mchusma• 5 years ago

Here here. People at the FDA should be resigning over them banning the COVID vaccine for kids under 12, for example. But we don't see behavior like that.

It's just a sign that the FDA is so horribly broken, it probably can't be recovered.

One note that I think would be important is that we should stop using the term "approved" or "not approved" and instead used "banned" or "not banned", as this is a more clear way to describe the situation. For example, in Sep 2020, it was completely obvious that taking a covid vaccine if you were elderly was dramatically better than waiting for COVID. But you could not, because the government said no. It didn't matter how informed you were, how much your doctor would agree, the answer was no. You go to jail if you try to take it. That should be called "banned".

danzk• 5 years ago

Government programs need to be able to negotiate drug prices to get a fair deal before subsidising them.

Whenever a trade deal comes up between the US and Australia, they always want to kill our PBS system that negotiates lower drug prices with pharmaceutical companies.

s1artibartfast7• 5 years ago

Great read, thanks!

refurb2• 5 years ago

The FDA does have that option and is doing it for this drug. It’s called a “National Coverage Determination”

https://www.cms.gov/newsroom/press-releases/cms-opens-nation...

"Today, the Centers for Medicare & Medicaid Services (CMS) is opening a National Coverage Determination (NCD) analysis, a process that will allow the agency to carefully review and determine whether Medicare will establish a national Medicare coverage policy for monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s disease."

alexfromapex• 5 years ago

Will there be any criminal charges? They could've been paid off and then all that happens is they resign?

busymom06• 5 years ago

I think you are misunderstanding the resignations. They resigned because they didn't agree with the approval.

The latest exit comes from Dr. Aaron Kesselheim, a professor at Harvard Medical School who is also director of the Program On Regulation, Therapeutics, And Law at Brigham and Women's Hospital. He said the FDA is greenlighting Aduhelm despite not having enough proof that the drug will help Alzheimer's patients.

georgewsinger• 5 years ago

I wish we could "resign" the FDA from telling us which drugs we can and cannot experiment with under threat of imprisonment.

Factorium• 5 years ago

Given the extreme wealth and aging condition of baby boomers, I feel like we are going to see a lot of money dumped into for-profit drugs and health services designed to 'counter' their normal mechanisms of aging.

You could argue that society-wide COVID lockdowns and forced vaccinations, in reaction to a virus which is really only driving excess deaths in that generation, would never have been supported if that cohort was smaller or less influential.

m0zg2• 5 years ago

People at FDA are working real hard for their post-FDA do-nothing six figure paychecks and board seats. It's great to see, however, that not everyone is just cynically milking the system like that.

busymom06• 5 years ago

Unfortunately the good people are resigning and leaving (like in this case) so the worse people stick around. Both the previous fda heads are now on the board of Pfizer and moderna.

m0zg2• 5 years ago

The current ones will be on the same boards as well.

xyzzy21• 5 years ago

FDA, CDC, NIH, etc. are all 100% captured!

https://en.wikipedia.org/wiki/Regulatory_capture

This kind of story is all too common. These are NOT scientific or medical organizations anymore because of how corrupt they are.

Experts Have Resigned from an FDA Committee over Alzheimer's Drug Approval

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