[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. ___________________________________________________________________ (page generated 2021-09-22 23:01 UTC)