[HN Gopher] Experts Have Resigned from an FDA Committee over Alz...
___________________________________________________________________
Experts Have Resigned from an FDA Committee over Alzheimer's Drug
Approval
Author : busymom0
Score : 263 points
Date : 2021-09-22 11:22 UTC (11 hours ago)
(HTM) web link (www.npr.org)
(TXT) w3m dump (www.npr.org)
| alexfromapex wrote:
| Will there be any criminal charges? They could've been paid off
| and then all that happens is they resign?
| busymom0 wrote:
| 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.
| foolzcrow wrote:
| The FDA is compromised by industry hardliners crossing overbfrom
| corp jobs to gov jobs. They sell us out to corps every time.
| JadeNB wrote:
| This is from June--it's interesting, but is there some particular
| reason to resurface it now? Has there been some recent
| development?
| busymom0 wrote:
| 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...
| lowkey_ wrote:
| 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.
| mountainriver wrote:
| 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.
| derbOac wrote:
| 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.
| refurb wrote:
| Two phase 3 are standard. And I assume Rick was going after
| full approval not conditional as per the Alzheimer's drug?
| s1artibartfast wrote:
| 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.
| [deleted]
| fighterpilot wrote:
| > 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.
| jcims wrote:
| 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.
| mycall wrote:
| This is how democracy and quorum works. It is messy,
| definitely, but if we avoid reductionism to explain the
| chaos, typically a good solution will emerge given time.
| Finding which winning singularities to win in is often a
| money making event.
| denton-scratch wrote:
| s/quorum/consensus/
|
| A quorum is the minimum number of members that must be
| present in some body or group for them to be allowed to
| make decisions. The number is given in the group's
| articles of association; there's nothing messy about it.
|
| A "consensus" occurs when enough members of a group or
| body agree with a proposal, that the remainder "consent"
| to that proposal, even if they don't fully agree with it.
| Consensus is messy, partly because the meaning of the
| word is open to dispute; and partly because "consensus"
| doesn't address the case where the group or body is
| irreconcilably split on the issue at hand.
|
| I don't care to address the word "democracy"; that word
| has as many meanings as there are people on the planet.
| zepto wrote:
| Not really. You'd expect an organization like the FDA to be
| policy based.
| kongolongo wrote:
| Policy has to be interpreted and enforced by people and
| that isn't always going to be consistent even with the same
| person let alone the fact that's its never the same person
| or group of people overseeing every decision.
| zepto wrote:
| True, but that doesn't change the calculus. You'd expect
| a policy to set the required standard, and you'd expect a
| review process to identify major deviations.
| kongolongo wrote:
| Policy also has to be flexible when it comes to things
| with as many complexities as medication. Coming up with a
| universal standard for approval is extremely difficult.
| There can be issues both if it's too rigid or too lax.
| The role of policy in most cases such as this is supposed
| to be a guide, not a strict pass or fail for every
| possible criteria. Discretion from the regulators is
| needed to accommodate for cases that don't fit neatly
| into existing policies.
|
| As a comparison, look at how nearly all of the big social
| media platforms all struggle with policy interpretation
| and enforcement around topics such as misinformation or
| hate speech.
| zepto wrote:
| > The role of policy in most cases such as this is
| supposed to be a guide
|
| Sure, so we should be able to see what guidance was
| followed.
|
| > Discretion from the regulators is needed to accommodate
| for cases that don't fit neatly into existing policies.
|
| Discretion doesn't mean policy can be ignored. Discretion
| would be part of the policy, and we should be able to see
| _what_ discretion was used to come to these decisions.
| kongolongo wrote:
| I didn't say discretion means policy can be ignored, it's
| part of the interpretation of policy. Whether or not a
| policy is applicable for specific circumstances is part
| of discretion. It explains why policy is not universally
| applied and appears inconsistent.
|
| Nothing about one drug being denied approval despite
| having more successful trials than another drug alone
| demonstrates that policy was ignored or that it wasn't
| considered.
| zepto wrote:
| > Nothing about one drug being denied approval despite
| having more successful trials than another drug alone
| _demonstrates_ that policy was ignored or that it wasn 't
| considered.
|
| No, it doesn't 'demonstrate' it, but it certainly makes
| it into a candidate explanation that can't be dismissed.
| fighterpilot wrote:
| You expect consistency from the IRS, because that domain is
| easy to fully articulate and constrain inside policy.
|
| You don't expect it in the FDA because the trade-offs
| between safety, efficacy, urgency, clinical/statistical
| significance, and other dimensions are going to be rather
| specific to each silo of expertise/each product, and rather
| difficult to fully prescribe and encode a priori. So out of
| necessity, some amount of discretion and autonomy are going
| to be provided to each group of specialists, and you are
| bound to get inconsistency.
| zepto wrote:
| That doesn't mean there can't be a policy. Drug safety is
| based on science, after all.
| fighterpilot wrote:
| There can be policy, it just can't be as prescriptive as
| you're asking for.
|
| Consider the review process for paper submissions to
| scientific journals. You can't prescribe an exhaustive
| checklist to Nature reviewers and ask them to
| mechanically follow it. You need to give the reviewers
| some autonomy. And with that autonomy will come
| inconsistency.
| zepto wrote:
| > can't be as prescriptive as you're asking for.
|
| What do you think I am asking for?
| [deleted]
| LeifCarrotson wrote:
| All organizations, even ones which are policy based,
| function like an artist's collective at some level - the
| human level. They all employ humans, who have to interpret
| those policies, and can interpret them in favor of or
| against something they personally have an opinion about.
| zepto wrote:
| If the difference is a matter of interpretation, we
| should be able to tell by comparing against the policy.
| cmrdporcupine wrote:
| Sure, you'd expect and demand that, but that's the goal to
| strive towards not the reality of large organizations.
| Which is why permanent pressure and scrutiny is required on
| any government or corporate entity. That's democracy.
|
| But in terms of _analyzing_ these organizations it 's an
| excellent point that we can't assume consistency. They are
| complex and contradictory.
| zepto wrote:
| True but how is that relevant? The point of policy is to
| manage inconsistency. In this case we would expect there
| to _be_ a policy that sets the required standard, and to
| be able to see whether these decisions match the policy
| or not.
| hellbannedguy wrote:
| 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/...
| setgree wrote:
| 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...
| mchusma wrote:
| 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".
| Brakenshire wrote:
| 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.
| themacguffinman wrote:
| > 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.
| heavyset_go wrote:
| > _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._
|
| In the US, supplements must be vitamins or minerals,
| botanical products, amino acids or enzyme products.
|
| Drug companies can't develop a new compound and then try to
| sell it as a supplement unless it meets those requirements,
| which it probably won't, because drug companies rarely
| develop new compounds that are also found in nature or in
| your body already.
| setgree wrote:
| To quote another SA piece, "the categories were made for
| man, not man for the categories"
| https://slatestarcodex.com/2014/11/21/the-categories-
| were-ma...
|
| OP is saying we could change the laws that configure the
| distinction you draw.
| kelnos wrote:
| > _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._
|
| Most people -- including myself -- are unequipped to
| evaluate the science behind most drugs. That supposed to be
| why the FDA exists. I do not want to make my own mistakes
| here, since they can very easily be fatal, or at least have
| long-term consequences. I want a trusted body of experts to
| give me a recommendation that's as well-informed and
| unbiased as possible. The FDA may or may not be as good as
| they should be at being that body, but it is absolutely
| needed.
| Brakenshire wrote:
| One big reason is you're removing the economic incentive to
| produce good evidence. The herbal remedies industry is a
| perfect example, there will be valid treatments there but
| yet the industry is almost entirely medically useless. Some
| of the treatments might be effective for particular
| diseases, at particular doses but no one ever knows. These
| companies have billions in revenue and are vastly
| profitable but they never look for evidence that treatments
| work because people buy the remedies anyway, and a company
| that spent the money to run the trials would be undercut by
| less scrupulous competition. This is not even a market with
| asymmetry of knowledge, it's a market where no one knows
| anything, and the lack of regulation makes sure it
| continues that way.
| themacguffinman wrote:
| There's still an economic incentive for the highest level
| of FDA approval: Medicare and insurance companies _have_
| to cover it and doctors can prescribe it. That ensures a
| high and consistent level of usage across the whole
| country, not just among people with more money than sense
| (usually IMHO; it 's possible that they're just smarter &
| savvier than the notoriously conservative FDA, who knows,
| this is a big reason why taking away choice is bad on
| principle).
|
| I don't think the lack of credible evidence of efficacy
| in the supplement market is for lack of trying. If an
| alternative medicine is actually effective, it just
| becomes medicine that the majority of people can trust
| and use.
| civilized wrote:
| 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?
| Brakenshire wrote:
| I agree, that's well put and I think that could work very
| well.
|
| I think the key would be having clear centralized standards
| for how the trials are conducted, or you could have doctors
| skirting the system and just using it as de-facto
| prescription, and patients being put at risk for
| ineffective treatment without producing any valid evidence.
| civilized wrote:
| Yeah, if the existing system is built on trust of doctors
| who run clinical trials, we have to ask whether that
| trust scales.
|
| If the system were set up so that doctors would have a
| lot to lose if they didn't follow the system, trust could
| work here. We already trust doctors as professionals on
| many other things...
| Sanguinaire wrote:
| 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.
| irrational wrote:
| Is it banned when it isn't the drug companies doing the
| marketing to the uneducated general public? It wasn't the
| drug companies telling uneducated people to use horse
| dewormer to combat Covid. That seems just as dangerous
| (probably more so) as drug companies making claims to the
| general public.
| jeherr wrote:
| 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 wrote:
| 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.
| AshamedCaptain wrote:
| 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.
| cameronh90 wrote:
| 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)
| datavirtue wrote:
| "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.
| whoknowswhat11 wrote:
| 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.
| rootbear wrote:
| 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.
| mcguire wrote:
| What are "drugs like this", and why is the drug company paying
| for it?
| macintux wrote:
| 209-comment thread at the time:
| https://news.ycombinator.com/item?id=27472107
|
| Also related: https://news.ycombinator.com/item?id=27734268,
| https://news.ycombinator.com/item?id=27671127
| busymom0 wrote:
| > 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 wrote:
| 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?
| TedDoesntTalk wrote:
| > Is this true or a myth?
|
| It is a nice myth to pull at your heart strings
| whoknowswhat11 wrote:
| 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.
| burning_hamster wrote:
| Your cynicism is misplaced as terminal lucidity is, in fact,
| a well documented phenomenon.
|
| https://en.wikipedia.org/wiki/Terminal_lucidity
| AdmiralAsshat wrote:
| And an excellent band name for a Progressive Metal band, if
| ever I heard one.
| rootbear wrote:
| 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.
| CivBase wrote:
| 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.
| nunb wrote:
| 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?
| CivBase wrote:
| The flushing process was some kind of medicine which
| induced vomiting. I'm not familiar with the meds, but I
| know they were intended to delay the progression of
| Alzheimer's. Unfortunately, we can't know if it actually
| worked for her because we don't have a control to compare
| to. It's tempting to say they were ineffective given what
| happened, but for all we know things could have been even
| worse.
| ianhawes wrote:
| 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.
| burning_hamster wrote:
| 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...
| gameswithgo wrote:
| 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 wrote:
| 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.
| tapoxi wrote:
| 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.
| encryptluks2 wrote:
| That had their drug approved by the same FDA that you suddenly
| trust in that regard.
| EamonnMR wrote:
| 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.
| macintux wrote:
| 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...
| MeinBlutIstBlau wrote:
| 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.
| javagram wrote:
| 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.
| toast0 wrote:
| 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 wrote:
| With that logic, if you're being DDoS'd, might as well as start
| piping /dev/random to /.bash_history. It gives hope!
| busymom0 wrote:
| 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.
| MeinBlutIstBlau wrote:
| 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.
| busymom0 wrote:
| That's not what's happening here. If someone really wanted,
| they could have gotten the drug under Right to try Act if
| it was life saving drug or something. This instead is FDA
| approving the drug as if it actually works which based on
| current reporting isn't the case.
|
| Also this drug is crazy expensive for something which
| doesn't even work.
| CamperBob2 wrote:
| The fact that money is involved makes it a zero-sum game.
| Money spent on Aduhelm won't be available for other
| therapies that might potentially be more effective.
| rocqua wrote:
| 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'.
| shkkmo wrote:
| 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 wrote:
| 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.
| c618b9b695c4 wrote:
| 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
| Root_Denied wrote:
| >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.
| tdeck wrote:
| 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?
| himinlomax wrote:
| Note that tooth decay and gum disease are strongly linked
| to sugar consumption, high sugar consumption causes
| diabetes, and Alzheimer has been linked with type 2
| diabetes. I don't know how popular this hypothesis is these
| days, but that's a possible link.
| luigibosco wrote:
| Diabetes and Alzheimer's Disease: Mechanisms and
| Nutritional Aspects:
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209735/
|
| While it may be considered andectoal, this fits with what
| i've seen in my family. In my mind and from what i've
| read it seems to be more of a combination of factors -
| diabetes, an APOE gene, toss in a little depression/loss
| of purpose/retirement/isolation, etc
|
| I find the studies with gamma interesting:
| https://www.alzheimers.gov/clinical-trials/gamma-
| induction-a...
|
| I think it would be good to bring more attention to
| noticing when things start to slip, because as things
| progress there can be less openess to trying new
| things/focus on maintaining state.
| ABetaMale wrote:
| [1] is probably the study you're thinking of. There's also
| [2] regarding herpesviridae, among others.
|
| In short, there are good reasons at this point to believe
| that amyloid-b's primary function is as antimicrobial
| peptide, and thus various infections may cause the seeding
| of amyloid-b deposits. These deposits may then persist for
| years beyond any useful benefit, especially if the brain's
| clearance mechanisms are impaired.
|
| Note that, per [2]:
|
| _Importantly, in the antimicrobial protection model,
| neurodegeneration is not mediated by pathogen activities
| that directly kill neurons. Rather, Ab innate immune
| pathways targeting pathogens mediate the AD [Alzheimer 's
| Disease] neuropathogenesis that leads to widespread
| neurodegeneration. Thus, our model is consistent with the
| amyloid cascade hypothesis and overwhelming data showing
| the primacy of Ab in AD pathology._
|
| [1]. Dominy et al (2019). Porphyromonas gingivalis in
| Alzheimer's disease brains: Evidence for disease causation
| and treatment with small-molecule inhibitors.
| https://doi.org/10.1126/sciadv.aau3333
|
| [2]. Eimer et al (2018). Alzheimer's Disease-Associated
| b-Amyloid Is Rapidly Seeded by Herpesviridae to Protect
| against Brain Infection.
| https://doi.org/10.1016/j.neuron.2018.06.030
| tdeck wrote:
| This is such a great reply, thank you!
| zzt123 wrote:
| 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.
| peddling-brink wrote:
| > we do now know
|
| I think should have been "we do not know"
| c618b9b695c4 wrote:
| Bah, yes that was a (now corrected) typo.
|
| When speaking of biology, assume we know less than we
| think.
| btilly wrote:
| 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.
| ajkjk wrote:
| 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 wrote:
| 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.
| fabian2k wrote:
| 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.
| oldgradstudent wrote:
| Yet, this drug was approved solely on it's ability to reduce
| amyloid plaque, without any cognitive effects.
| hirvi74 wrote:
| 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).
| mcguire wrote:
| 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 wrote:
| 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.
| someguydave wrote:
| plenty of therapies only treat symptoms
| wongarsu wrote:
| 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.
| OneTimePetes wrote:
| 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
| hirvi74 wrote:
| I'm no doctor, but I am curious if any research has been
| conducted on whether this treatment would be beneficial for
| preventing AD in people in "at-risk" populations. Perhaps
| it could be used to stop the plaques from forming to begin
| with.
|
| I could see this treatment being something like exercise
| and diet for type-2 diabetes. Exercise and diet may help
| prevent diabetes, but neither will "cure" the condition
| once the point-of-no-return has been crossed. In other
| words, you can turn a cucumber into a pickle, but you can't
| turn a pickle back into a cucumber.
| irthomasthomas wrote:
| 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
| ABetaMale wrote:
| 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-b plaques with
| Alzheimer's Disease, but could there be a confounder, rather
| than amyloid-b 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 g-secretase involved in
| cleaving APP to make amyloid-b) 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-b production, or to increase production
| of the specific peptide (amyloid-b 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-b, 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-Ab 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
| rossdavidh wrote:
| Another industry expert, with much the same opinion:
| https://www.science.org/content/blog-post/open-floodgates
| georgewsinger wrote:
| I wish we could "resign" the FDA from telling us which drugs we
| can and cannot experiment with under threat of imprisonment.
| DebtDeflation wrote:
| 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.
| xibalba wrote:
| 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.
| eli wrote:
| This was a few months ago. Congress is now investigating the FDA
| approval of Aduhelm.
| encryptluks2 wrote:
| And likely will cover themselves as the corruption is
| widespread.
| arc-in-space wrote:
| ...But not over stalling the mRNA vaccines for half a year
| Factorium wrote:
| 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.
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