The Aducanumab Approval
blogs.sciencemag.org
blogs.sciencemag.org
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.
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>
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.
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.
The problem is that every drug that has targeted amyloid has failed to do jack shit in any cohort--not early, not late, not alien--none of them.
Any rational science system would conclude "The amyloid hypothesis for Alzheimer's is WRONG."
But, no, the bio people just plow on further because amyloid gets published, and funded, and, now, approved.
One day we'll look at this time as the alchemy period of neuro.
"The amyloid hypothesis for Alzheimer's is WRONG."
Amyloid plaques are correlated with Alzheimer. AFAIK it is still an open question if they play a role in the causation of the symptoms.
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.
I believe SSRIs often vary in effectiveness, for example; some people are just very good responders. Fortunately, their mean effectiveness is high enough.
(Not a doctor, etc)
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.
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 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.
Whatever the FDA is supposed to be doing, they're not doing it.
The approval process would then be a regulation on advertising, rather than a regulation on what is banned and what is not.
That a drug hasn't been approved for a treatment in years is no reason to approve one that doesn't work.
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.
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
The private insurance companies won’t be paying for this one. Taxpayers will.
You'd predict that in a few years and after a few billions wasted regulators will wake up to the Phase IV results and withdraw approval.
Imagine how hopeful these families feel right now. I really hope Derek turns out wrong, but I know it's unlikely that he will.
List price is $56,000 per year if you're curious.
Here's a discussion of the various ways of thinking about drug pricing in the U.S. (e.g., Average Wholesale Price (AWP). You can search using the acronyms if you're curious: https://www.rjhealth.com/2019/07/31/drug-pricing-101-reimbur...
(edit) made my comment a bit less confrontational in tone
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.
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 it's 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.
What you’re saying seems sensible, but my cynicism…
> NHE grew 4.6% to $3.8 trillion in 2019, or $11,582 per person, and accounted for 17.7% of Gross Domestic Product (GDP).
> Prescription drug spending increased 5.7% to $369.7 billion in 2019, faster than the 3.8% growth in 2018.
So that is around 10%. Still a pretty high amount of money.
[0] https://www.cms.gov/Research-Statistics-Data-and-Systems/Sta...
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.
https://clinicaltrials.gov/ct2/show/NCT03282916
>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?
Given better results, it's a sign the plaque theory is wrong...
watching social trust be destroyed on this scale in real time is both amazing and deeply disorienting
in the long run, I suppose the feeling goes, we are all dead
my children won't be though
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"?
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.
I, personally, have little hope for that.
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.
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.)
(Though to be fair fish oil apparently has more evidence for its efficacy)
Also the same for several purported treatments for Covid. Efficacy is less important than cost and potential profits.
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!
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.
[0]: https://en.wikipedia.org/wiki/Alzheimer's_disease#cite_note-...
From TFA:
> 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.
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)
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 should consumers judge the quality of the research into this drug?
How should they judge potential side-effects?
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.
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).
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.
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?
Should this be banned? Absolutely not. Should medicare be forced to pay for it? Also no.
COVID vaccines were the same way. Should they have been banned early on? Absolutely not.
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.
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.
Of particular note is that he, like most practitioners, is of the opinion that the record of unmitigated failure of amyloid blockers is that it means that the theory that reducing amyloid plaques improves outcomes should now be considered discredited. See, e.g., https://blogs.sciencemag.org/pipeline/archives/2019/01/30/an... and https://blogs.sciencemag.org/pipeline/archives/2018/06/12/an...
If the drug reduces plaques, but doesn't cure Alzheimer's, it's not a 'bad sign'. It simply means the drug doesn't work.
P-value hacking over and over again[1] until we finally get a study that shows us that the drug works is not the solution. [2]
[2] Unless the problem we are solving is "We have too much money that we need to spend on snake oil."
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.