If this was simply a matter of making the drug available for informed consumers willing and able to pay for it out of pocket, I wouldn't be as concerned.
If we're going to have Medicare and private insurance companies pay $56K/year per patient for a drug that may not have positive effects that outweigh the risk of side effects, that's a major problem.
Limiting access to experimental drugs is a difficult question. I know someone who has a different poorly-understood disease (not Alzheimer's, I'm being deliberately vague to avoid debates) who managed to get enrolled in a clinical trial for an experimental treatment. She responded fantastically well to the drug, as did a small number of other patients in the study. On average, however, the response to the drug was poor.
She and several other responders have now found each other online and are trying multiple avenues to get back on the drug. They're getting desperate enough that they're pooling funds to order a custom synthesis from another country and have it analyzed for purity by a 3rd party lab. I'm terrified to think of the risks they're incurring, but they're so desperate to return to remission that they'd rather take the risks than continue to suffer. It must feel unthinkably unfair to be given a glimpse of remission, only to be forbidden to continue to buy the drug because it didn't work on a majority of patients.
In their case, it's likely that the disease has multiple causative factors and the drug in question only treats one specific cause. Without stratifying trials by these yet to be determined different causes, it's difficult for trials to show efficacy on large populations. I wonder if Alzheimer's disease could be similar, in that certain subsets of patients respond to the drug but the average patient will not.
>> If we're going to have Medicare and private insurance companies pay $56K/year per patient for a drug that may not have positive effects that outweigh the risk of side effects, that's a major problem.
The usual story for why we allow patenting of drugs and high prices is that development is very costly - particularly the cost of doing trials. If they're going to allow this on the market without trials that show efficacy, the least they can do would be to allow generics at low prices while we're doing the efficacy testing on the general public ;-) </sarcasm>
> If we're going to have Medicare and private insurance companies pay $56K/year per patient for a drug that may not have positive effects that outweigh the risk of side effects, that's a major problem.
Hmm, what if we added a new phase where it's approved but can only be sold at a low, regulated price? Then if/when it is proven effective, they can transition to charging more.
Without getting into whether it's actually a good idea, in theory the high prices are meant to be a reward that makes it worthwhile to invest in drug development. Delaying the reward would still allow that incentive but keep it tied to actually creating drugs that work while still allowing patients earlier access.
The risk with that is that it creates a ‘perverse’ incentive for the FDA to not fully approve drugs because the approved drugs might shoot up in price 1000x the moment they exit the ‘purgatory approval’, and granting the official approval might kill some people who can afford the purgatory price, but not the fully approved official one.
That then would create the ‘perverse’ incentive for poorer people who are dying of major diseases to sign up for any and all trials possible to lock in prices, regardless of relevance, and make things much, much worse for themselves due to misuse. Richer people would not do that since they can pay the full price without locking the old price in, so this risks converting the sick and poor people already battered by life into lab rats.
If you instead don’t enforce the requirement to actually take the drugs to lock in the price, then everyone signs up for everything and your drug companies will stop making any new drugs.
Amyloid plaques seem to be correlated with lots of things--they seem to be a general response to damage to the brain.
Almost all of the evidence seems to point that amyloid plaques are not causative with Alzheimer's.
The fact that every single drug (including this one!) targeting amyloid plaques (some of which are actually effective at reducing amyloid plaques) has failed to do anything for Alzheimer's suggests that amyloid plaques are the WRONG target.
Mean drug effect is possibly a bad metric to measure. If the distribution is bimodal, or has very high variance, the FDA could take that into account when approving a drug.
I believe SSRIs often vary in effectiveness, for example; some people are just very good responders. Fortunately, their mean effectiveness is high enough.
I think we can improve access to experimental and unapproved drugs while still protecting consumers from malicious marketing of these drugs or sabotaging the current drug approval process.
Hopefully, eventually we'll be able to figure out why a drug works for one person but not for the next so that we can get pinpointed approvals for just that subpopulation.
So the solution to the problem of doctors and medicine makers not being able to figure out what's gonna be safe and effective for whom is to just tell the patient to try to figure that out on their own?
The solution to doctors and medicine makers not being able to figure out if it's safe and effective is to let patients make choices as to what they can put in their own bodies.
This seems like cherry-picking. Quackery doesn't care about regulation (for example, hydroxychloroquine is prescription-only in the US), and shady hucksters abound in all industries (including ours; look at all the meaningless "threat intelligence" hype).
You could also just as easily look at the situation where poultry practices banned in Europe are the norm everywhere in the single-hand-countable poultry producers in the US, or the "regulation" they apply to tobacco products (which kill 7x more than opiates in the USA). It's a farce.
The FDA isn't doing what they ostensibly exist to do, and they are doing a whole bunch of stuff they're not. It's the worst of both worlds.
The supplements market is quite tiny ($36bn) compared to the "unregulated market for pharmaceuticals" that most people mean by that phrase ($150bn+).
For me and many, many others, that market serves us far better than the regulated one.
You're cherry-picking supplements quackery and hucksterism out of the 6x larger "unregulated drugs" market on Earth, which exists despite insanely harsh penalties prohibiting it. It would likely be much larger if not illegal.
I'm not sure I understand your argument. The supplements market is an even bigger fraction of the pharmaceuticals market than I thought, so I'm even more convinced of my point now. But, again: the literal point of the supplements market is to function the way you suggest the pharmaceuticals market should. I think that we should rather regulate the remaining $36B in supplements out of existence.
The supplement industry has some problems. But it also has a few things going for it. It's far cheaper, and the only people that have been harmed from it made a choice to take that risk.
I don't know anyone personally who's life has been screwed up by supplements. But I do know two people personally whose lives were wrecked for years because of FDA regulations.
Not to mention the absurdity that was restricting the j&j and AZ vaccines.
We can have both an approval process and an end to the prescription system. We almost do already with prescriptions for off-label uses being common, although that turns every doctor into a drug dealer.
The approval process would then be a regulation on advertising, rather than a regulation on what is banned and what is not.
I think the FDA was in a difficult spot. There have been no new Alzheimers drugs in decades and patients are desperate for treatments. There is reason to believe that beta amyloid blockers need to be given in the earliest stages of Alzheimers (when diagnosis is difficult) to have any impact on cognitive decline. The trials did not focus on early stage patients, so there may be positive impacts if it can be given early enough.
Great! So let's figure out a way to make this study happen so that the drug can be given effectively (if it does indeed work) rather than have a blanket approval of a drug that lacks any proof of efficacy at all.
That a drug hasn't been approved for a treatment in years is no reason to approve one that doesn't work.
> So let's figure out a way to make this study happen so that the drug can be given effectively (if it does indeed work) rather than have a blanket approval of a drug that lacks any proof of efficacy at all.
It isn't a blanket approval, but it does sound way too generous in terms. From the linked article:
> The agency seems to have approved it based on its demonstrated ability to clear beta-amyloid, and is asking Biogen to run a confirmatory trial to show efficacy.
> They will be absolutely overjoyed to do that, of course, because the whole time that’s going, they will be selling the first drug that (in theory) targets the etiology of Alzheimer’s. The backed-up demand is going to be gigantic, and Biogen is going to make enormous amounts of money. They have nine years, as it turns out, to get this trial done, and I feel safe in predicting that it’s going to take alllll niiiiine loooong sloooow years to get this done.
I guess the thinking is that it could take years to know whether it's working or not through an RCT. I believe they are currently allowed 9 years by FDA to show efficacy. If the side effects aren't significant why not let people in need try it?
The side effects are significant. It comes with some risk of brain bleeds and a high risk of cerebral oedema in patients who have APOe4.
This is an important genetic profile for those who understand Alzheimer’s, as homozygotes for APOe4 are 12x more likely to develop Alzheimer’s.
This is a cop out decision by the FDA. Efficacy can be determined by a RCT - instead a decision was made which supports biogen’s share price
Coming soon: insurance companies refusing to cover this because efficacy has not been demonstrated and stories of impassioned family members fighting against evil insurance companies in order to cover "the medicine their love one desperately needs".
But i would expect that the cost of these medicines are quite a bit lower. After all water is pretty cheap. Most of them are just placebo's, but then again placebo's really do work.
An absolutely shocking decision, which will have immense negative consequences for healthcare and healthcare costs far into the future. A license to turn false hope into profit margins and commissions for snake oil salesmen.
I had a quick look at what various special interest "non profits" had to say about this:
Alzheimer's Association -> very positive, basically an advert (https://www.alz.org/get-involved-now/new-day). " A new type of Alzheimer’s treatment, aducanumab addresses the disease in a way that has never been done before. This therapy slows progression of the disease, rather than only addressing symptoms."
Alzheimer's Foundation of America -> much more measured (https://alzfdn.org/alzheimers-foundation-of-america-statemen...) "We are hopeful that it will improve the quality of life for individuals living with Alzheimer’s disease and their caregivers. Patient access and affordability to all of those in need is of significant importance."
Alzheimer's Association transparency page claims that they received under $300k from Biogen in 2020 and that <2% of their revenue is from biotech - I feel like they are either selling themselves a bit too cheaply or being a bit dishonest. Their whole website feels weirdly corporate as well.
> I suppose only things that definitely cause harm, because otherwise why not just ask for the same deal that Biogen got, and go out and prove efficacy while you turn a profit?
In a sense, this is how it's sort of always worked. The approval process is about protecting investors. If a drug is good it's usually pretty obvious. When it's not obvious, efficacy in a more abstract sense must account for cost, which is out of the FDA's jurisdiction.
The real problem with its organization is that it is, as you're saying, Medicare's procurement agent. But it is not empowered to consider cost.
> Adding pricing to its concerns would make what is already a nightmare process even worse.
TBH, I believe that is a huge root cause problem with our health care system. We need to stop pretending that money is infinite, and measure the cost against the benefit (in this case, little or none) when deciding whether Medicare/insurance companies should pay for a treatment.
Perhaps this shouldn't be the responsibility of the FDA, but SOMEWHERE there should exist a process that says, "OK, this drug increases lifespan on average by 1 week, but costs $10,000 a month in treatment, sorry we're not going to cover it."
The MHRA decides which drugs are safe and effective and for which diagnoses.
Then NICE decides which of those drugs are available on the public health system (NHS) by evaluating £/quality-adjusted life year. I don’t see why Medicare should be any different.
If it’s not available on the public health system you can still pay for it yourself or via private insurance provided it’s licensed by the MHRA.
Only a few short years ago, the eminently sensible idea of offering end of life planning (making a will, recording end of life medical desires) was demonized/weaponized as “death panels”.
What you’re saying seems sensible, but my cynicism…
Not for nothing, but, despite all the airtime this issue gets, my understanding is that pharmaceuticals are a pretty small component of health care spending; like, if you zeroed it out, you'd get less than a grocery store discount.
I disagree. See https://www.politifact.com/factchecks/2019/feb/22/amy-klobuc... (drug costs come between 15-17% of total spending). And given how you can divvy up spending (drugs, facilities, doctors, nurses, admin staff, overhead, etc.), one sixth of total spending seems like a very large amount.
And, it's especially the case that for certain individuals (this page also made the top of HN today, https://www.goodrx.com/blog/most-expensive-drugs-period/) that drug costs are a gargantuan, total-lifetime-salary kind of expenditure.
Considering their own advisory committee advised against approving the drug because of the lack of evidence that it works, the FDA doesn't really judge the medical evidence very well!
Given the studies showing higher rates of chronic infections in Alzheimer's patients (like herpes viruses and periodontal disease), why aren't there more trials like this:
>Anti-viral therapy in Alzheimer's disease will investigate the efficacy of treating patients with mild Alzheimer's disease with the U.S.A marketed generic anti-viral drug Valtrex (valacyclovir, 500mg oral tablet). Valacyclovir, titrated to 4 grams per day, repurposed to treat Alzheimer's disease, will be compared to matching placebo in the treatment of 130 mild AD patients (65 valacyclovir, 65 placebo) who test positive for herpes simplex virus-1 (HSV1) or herpes simplex virus-2 (HSV2). The study will be a randomized, double-blind, 18-month Phase II proof of concept trial.
I understand beta-amyloid is still the most likely cause of the disease, but given how lackluster the results of targeting beta-amyloid have been, why can't alternative hypotheses be investigated more fully?
It's just a lucky coincidence that the industry colludes to not test generics (or falsify studies claiming they are ineffective, as was done with hydroxychlorquine) so they can continue to develop on-patent $56k per year drugs to sell.
Biogen's stock performance yesterday was disturbing given the efficacy questions... This market feels whack. Anyone interested in a potentially more effective Alzheimer's AND Parkinson's drug might be interested in Annovis Bio: https://www.biospace.com/article/annovis-bio-shows-alzheimer...
Given better results, it's a sign the plaque theory is wrong...
Oh, Biogen's now guaranteed to make loads of money before the efficacy question comes back to bite them, because the FDA's approval greenlights them to sell it before the efficacy can be firmly resolved (i.e., they come out with their subsequent trial data which, if history is any indication, is pretty likely to say it doesn't work).
If it's been shown to reduce plaque but not been shown to improve outcomes, is that positive evidence that it won't improve outcomes? Or is it more that noticing plaque reduction is fast while noticing outcome improvements would take a while? In other words, is this a case of "it's shown not to be efficacious, so wtf approval?" or is this more a case of "jury's out, so release it in the meantime"?
Important context is that all interventions that have assumed amyloid to be causal for Alzheimer's have failed to show material clinical improvement.
So the bar is really much higher than "did remove plaque" and the prior should be this wasn't going to improve clinical response. The fact that it didn't and was still approved is a complete abdication of what the FDA preaches. It's rare to see a uniform response from those that report on drug dev. but it has been unequivocal - the FDA needs to get its shit together.
AFAIK there is no reliable non-invasive procedure to determine the amount of plaques in the brain. So it will be difficult to make hard statements about the effect of potential drugs on the plaques.
Also we are not really very interested in the effect on plaques, we are interested in things like cognitive behavior which are a lot easier to measure.
> Or is it more that noticing plaque reduction is fast while noticing outcome improvements would take a while?
This statement is true, but the trial will have gone on long enough to note whether or not both plaque reduction and outcome improvements happen, because plaque reduction isn't considered sufficient evidence for outcome improvement, despite some attempts to force the FDA otherwise. (Although I guess the FDA has kind of caved in at this point, given that it's conditionally approving this on the basis of plaque reduction despite seeing no outcome improvement.)
I am no expert, but my understanding (referenced obliquely in the article) is that this is not the first drug to target reducing the amyloid beta plaque, that does not show positive results. This is raising the question of whether it's treating a side-effect of the disease, rather than actually treating the disease. In other words, it's not all that surprising anymore that a drug targeting the plaque, does not work well.
Could you perhaps change the title?
I have read several articles about it but I could not remember its name. It will probably get more views if you include "Alzheimer" in the title.
If the FDA views its role as evaluating for harms only and not efficacy, then this isn't itself necessarily a contradiction.
That doesn't change the fact that this approval is deeply disheartening and tells us the FDA is cool with any random product claims so long as they don't actively hurt people.
But, hey, for all those folks who glory in the good ol' days when men were men and radium was a cure-all, the good news is at this rate we'll be back to snake oil and patent medicine in no time!
I strongly recommend making Derek's "In The Pipeline" column a regular read, because he provides the information that answers your question.
First, there are the number of people who would take the thing. Alzheimer's is terrible, but I think many more people would take a COVID-19 vaccine than have Alzheimer's. A drug that causes problems in 0.1% of people is treated differently when the population size is 29.8 million[0] people of advanced age vs. 7.8 billion people[1] of all ages.
Second, the FDA has more than one advisory committee[2]. Which makes sense; I don't expect the world expert on CPAP and BiPAP machines to also be the world export on COVID-19 vaccines.
Medicare could decide not to cover it, but that's unlikely. The story here is regulatory capture. The enormous and ever-growing profits of pharma give them equally enormous resources to throw at buying regulators and congressmen.
The -mab suffix means it's a "monoclonal antibody," or a lab-made protein that specifically targets a certain antigen (for example, an antigen found on a cancer cells).
As per the other commenter, but also they have a 10 year development pipeline and 10 years ago some major rockstars started hitting the market (ipilumimab, traztuzumab ) which are anti cancer ones but many others also). These were essentially the second generation of these drugs, the first gen sort of came out in the late 90s/early 2000s (ie Bevacizumab, infliximab ) and proved so versatile that they’ve spawned whole industries.
The particular advantage is that a drug company can generate an antibody, clonally produce it, and demonstrate efficacy but no one else can claim the same efficacy because any other drug company is going to have an antibody that binds slightly differently and so has a different efficacy. (Ie so a generic here is called a bio similar antibody).
There have even been bio similar that have had the opposite effect to the desired one (by for example acting as a receptor agonist rather than an antagonist)
So the drug has been shown to reduce these amyloid plaques, but the trials have not conclusively demonstrated any effect on patient outcomes. The author then claims it should be effectively banned for this reason. Why shouldn't someone be allowed to take it if they want to?
Most of the patients this could be prescribed to are on Medicare. At $56k per patient and 5.5 million patients that's $308Billion. Oh and the drug causes edema in the brain in 40% of patients who are APOE e4 carriers which will be overrepresented in the patient population. That edema lead to confusion and patient falls. The scientific advisory board voted 10:0 with one abstention against approval. I'd just as soon not pay for something that doesn't work and in some cases causes harm.
So then isn't the issue medicare reimbursement, not FDA approval?
To be honest, this, along with several other things over the last year, has reinforced my perception that drug regulation in general is a failure and that the FDA needs to move away from an approval role (that is, approving the availability of the drug) to a truth-in-labeling role (that is, is this drug what the seller says it is).
How do you handle any medical claims by the manufacturer? Few consumers will be able to determine independently whether or not such claims are justified.
How should consumers judge the quality of the research into this drug?
> Why shouldn't someone be allowed to take it if they want to?
It's not entirely an issue of freedom. It's also about whether or not taxpayers have to pay Medicare to provide it.
By some estimates, 1 in 9 people over the age of 65 have some degree of Alzheimer's. The cost of the drug is estimated at $56K per year.
If we, the taxpayers, are now on the hook to pay $56K/year for up to 1 in 9 elderly people in the country for a drug that may not actually work and has some serious side effects, that's not good at all. Given the data we have, there's a significant probability that we'd be paying $56K/year to make these patients worse on average given the risk of serious side effects of the drug with negligible appreciable upside. That's a major problem.
It might be possible for Medicare to deny this drug due to lack of efficacy, but that sounds like a political nightmare.
There's a history of drugs that reduced amyloid plaques, perhaps with even better efficiency than aducanumab (I don't recall exact details) yet still failed to demonstrate any effect on patient outcomes.
The commentary that the trials haven't "conclusively demonstrated any effect" is an understatement. Recall that one of the trials outright failed the endpoint, and the attempt to reconcile that with the other trial smells strongly of statistical hogwash. The advisory committee rejected it wholesale, with not a single vote in favor and only one vote not in disfavor (i.e., abstention).
My understanding is that aducanumab has shown the greatest efficacy of any beta amyloid blocker (at reducing beta amyloid, with the least side effects. It definitely has side effects (brain swelling in 40%), but other Beta amyloid blockers have proven largely intolerable.
> Why shouldn't someone be allowed to take it if they want to?
That's the standard libertarian argument and we have an actual A/B experiment that shows what happens.
People used to be able to market any old thing (such as "snake oil") to cure whatever they wanted to say. A regime was built up over time (culminating in 1963) that you had to demonstrate both safety and efficacy in order to sell a drug, and you could only describe the drug in ways you had demonstrated (which included manufacturing).
In 1994 Orrin Hatch (he of copyright maximization and senator from a state with a lot of "natural" scammers") got a law passed to say that anything "natural" was exempt from any FDA rules and sellers could say whatever they want. And as a result unlocked a huge snake oil business that preys on people when they are feeling most vulnerable. Fortunately most of those things are harmless nonsense but sadly not all.
If you decide there is no need to prove efficacy than nobody would spend time on it. And thus drug had its trials halted because nobody was being cured (not only do you not want to spend money on them, but it's unethical to expose people to side effects of a drug that doesn't help them.
The FDA is saying that even though it's unethical to do in a trial it's OK to do in the market.
There should be a step between banning and approval.
If you look at the history of hiv/aids drug approval it's pretty clear that there is significant harm that can be done by banning unapproved drugs.
At the same time, removing the requirement to show efficacy to be approved is also quite obviously bad for the reasons outlined in the article.
Why can't the company be allowed to provisionally sell the drug with the warning that the FDA has evaluated the drug as "unproven efficacy" until such a time as the follow up studies are completed?
They could sell them as supplements but then they wouldn't be legally able to claim efficacy or be billed as medicine. They can't make nearly as much money without FDA approval.
Good chuckle, but he's missing another tack to this. Saying it's purely based on safety and not efficacy makes it equivalent to the dietary supplement market is missing a key point. And that's the potential upside. Taking a moonshot on curing Alzheimers is far more worthy than taking a moonshot on curing varicose veins. As the Boomers start to hit their twilight years, we're going to have an absolute epidemic of Alzheimers patients and exactly zero chance of treating any of them with anything but palliatives. If Aducanumab has a 3% chance of success, then by all means we have to try. And if Biogen gets rich off of a flop, at least it will encourage more pharmas to get in on the action.
But the pharmaceutical companies have tried several times to get an Alzheimer's drug that work. Being the first one to get an approved drug is a license to print money to the tunes of tens or hundreds of billions of dollars--enough to cover the costs of development. The reason why we haven't had any yet is because they don't work.
Why should Biogen's probably-doesn't-work Alzheimer's drug get a pass that the dozen or more attempts that showed similarly bad results didn't get? Note in particular that the assessments of everyone who looked at Biogen's statistical claims here is that those claims are not substantiated by statistics.
They have failed to prove efficacy in a trial. Why believe it has a 3% chance of working? Do you think arbitrary chemicals have a 3% chance of curing some disease, even when it has yet to be shown? There’s absolutely no reason to believe this.
It's not a random drug. It's proven to reduce plaques. The phase 3 trials were inconclusive in proving that it improved patient outcomes which is certainly a bad sign but it's absolutely possible that future trials would show different results. I'm not saying the FDA is definitely right. I'm admittedly out of my depth on this topic. All I'm saying is this blog glossed over the severity of the problem they are trying to solve.
Dementia is absolutely terrifying. My parents have already told me to euthanize them if it ever happens to them. I'd absolutely let them try this unproven therapy before doing that.
This is an epistemologically leaky argument. The goal of an Alzheimer’s drug is not to reduce amyloid plaques, it’s to treat Alzheimer’s. There is, as of now, no evidence that it does so. Giving people false hope of treating a horrible disease does actually seem more unethical than not giving them the treatment at all.
I get it, I'm just saying it's not like they're selling essential oils or healing crystals. Reducing plaques could at least plausibly have some benefit. And I'm not arguing necessarily that the FDA are therefore justified, I'm just saying it's not fair to compare this to diet supplements. I was pointed to some other posts by this same guy about how bearish he is on amyloid plaque reduction as a plausible therapy which would have been useful context.
> I get it, I'm just saying it's not like they're selling essential oils or healing crystals.
You might have more of an argument here if this drug was only going to cost as much as essential oils or healing crystals, ironically. Would you suggest somebody go into debt for treatment with this product? It's likely to be quite expensive.
Alternative medicine typically has no chance because it's made from ingredients like food that are already proven safe and not obviously effective through centuries of use and thus unlikely to have much effect on anything. Here's a drug that was so dangerous it had to go through clinical trials to prove it was safe, so it's potentially more potent - at something.
If we're going to have Medicare and private insurance companies pay $56K/year per patient for a drug that may not have positive effects that outweigh the risk of side effects, that's a major problem.
Limiting access to experimental drugs is a difficult question. I know someone who has a different poorly-understood disease (not Alzheimer's, I'm being deliberately vague to avoid debates) who managed to get enrolled in a clinical trial for an experimental treatment. She responded fantastically well to the drug, as did a small number of other patients in the study. On average, however, the response to the drug was poor.
She and several other responders have now found each other online and are trying multiple avenues to get back on the drug. They're getting desperate enough that they're pooling funds to order a custom synthesis from another country and have it analyzed for purity by a 3rd party lab. I'm terrified to think of the risks they're incurring, but they're so desperate to return to remission that they'd rather take the risks than continue to suffer. It must feel unthinkably unfair to be given a glimpse of remission, only to be forbidden to continue to buy the drug because it didn't work on a majority of patients.
In their case, it's likely that the disease has multiple causative factors and the drug in question only treats one specific cause. Without stratifying trials by these yet to be determined different causes, it's difficult for trials to show efficacy on large populations. I wonder if Alzheimer's disease could be similar, in that certain subsets of patients respond to the drug but the average patient will not.