But in the [surrogate] end[point], it doesn't even matter
June 9, 2021 6:09 PM   Subscribe

FDA approves Alzheimer's drug Aduhelm (sl arstechnica). The approval is controversial because the FDA admits the drug has not been shown to be effective against Alzheimer's and carries a 40% risk of brain swelling. The approval is based instead on efficacy in reducing plaque and the reasoning that this is likely to have some positive effect.

I'm curious to hear what MeFites in the know think. It appears the controversy is less about the actual details of statistical analysis and more about the approval pathway allowed here and the implications thereof, by essentially side stepping the question of whether the drug works.
posted by ecreeves (39 comments total) 16 users marked this as a favorite
 
I actually saw this earlier today because of this:
Biogen ... has already set the list price for a year’s worth of Aduhelm at $56,000.
I'm sure there are zillions of hyper-expensive drugs, but that's the first time I, personally, have seen a price tag higher than many people earn in a year. Higher than tuition at a number of fine institutions of higher learning.

I am gobsmacked.

I had no idea it was also possibly ineffective.

Thanks for posting this, ecreeves. It's infuriating, but important to know about.
posted by kristi at 6:33 PM on June 9 [20 favorites]


Here's a recent review in Nature about the increasing doubts (and history) of the Amyloid plaque hypothesis for Alzheimer's. There's been significant pushback on the idea that plaques are the key causal element of Alzheimers, rather than a symptom, or part of some constellation of effectors. If the argument is that it reduces plaques, I'm not sure I'd be prepared to take a 50-50 change on brain swelling (or 60k/yr) in return for a small reduction in something with such a poor track record at even correlating with symptoms.
posted by whm at 6:42 PM on June 9 [15 favorites]


Yeah, all the neurologist groups I'm in are shocked, not so much because of the use of a surrogate endpoint, but because the company stopped their trial early saying it didn't work, and are now like "Gotcha! Works after all!"

Here's a good summary:

"Interpretation: One of the trials was trending positive and one trial was null at the time that the sponsor halted the trials for futility. A post hoc analysis by the sponsor claimed that benefit could be seen in a subset of persons in the failed trial who had received all the planned high dose treatments. Other post hoc analyses raised questions about this claim. No evidence was presented to correlate biomarker changes to cognitive benefits.

"Future directions: Our analysis supports the conduct of a third, definitive phase III trial. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proved by clinical trials with divergent outcomes."
posted by basalganglia at 6:43 PM on June 9 [26 favorites]


Hopefully this is not a derail, but for context, targeting metrics rather than outcomes in medicine has led to some painful missteps in history...

Anti-arrhythmia drugs had been on the market for 20 years to control irregular heart rhythm, and doctors were regularly prescribing it to patients who had heart attacks - it was known that patients who had a heart attack tended to suffer arrhythmia related mortality afterwards.

... all this until they ran a study in 1987 (the Cardiac Arrhythmia Suppression Trial) with 1,500 patients that found that patients on the anti-arrhythmia drugs after a heart attack had an 8% mortality rate vs patients on a placebo who had a 3% mortality rate. They even stopped the study prematurely because the study itself had killed 40 patients unnecessarily, and as a result those drugs were either discontinued or else contraindicated in people who had heart attacks.

It's been claimed that it's certain more Americans were killed by anti-arrhythmia drugs than were killed in the Vietnam war - say, 500,000 heart attacks annually in the US, and 1/2 of them were treated with anti-arrhythmia drugs for the next 4 years, with an extra 5% mortality rate per year, that's an extra unnecessary 50,000 deaths per year x 20 years.

The other example I know of is how beta blockers used to be expressly contraindicated in patients with heart failure and considered hazardous for them... the heart is already not pumping enough blood, why would you give them a drug that slows the heart down further, obviously this would make things worse and make them die faster... but it turns out patient survival rates improved with beta blockers, so now it's standard therapy. The doctor who pioneered this therapy was banned from the critical care unit he worked in for trying out this experimental therapy with patients in his care, but as more and more of his patients got better with treatment, it got published in journals and peer reviewed and replicated it has now become the standard of care.
posted by xdvesper at 6:52 PM on June 9 [48 favorites]


I'm in pharmaceutical R&D and work closely with the FDA. Many of my colleagues and I are absolutely floored by this decision. It continues a downward trend for the Neuroscience group that started with the decision to approve Sarepta's first Duchenne's Muscular Dystrophy drug despite no evidence of efficacy. It undermines the FDA's overall reputation for making solid decisions in the interest of protecting public health. As an industry, we'll be picking up the pieces of this approval for years to come. An unmitigated disaster for patients, for caregivers, and for drug research.

Derek Lowe, as usual, has an excellent roundup.
posted by Otherwise at 7:16 PM on June 9 [41 favorites]


It's a FUCKING DISASTER

I can't overstate how much harm this shortsighted decision will cause. Tens of Billions wasted (minimum), thousands of lives destroyed with huge ripple effects across all of medicine and beyond.


e.g.

i) lots of non-cured altzheimers patients who will die having spent lots of cash on a failed treatment - some of whom will have brain swelling and die sooner if they can’t keep on top of their diagnostic scans (which also cost money/resources)

ii) ruining the reputation of the FDA - " You earn public confidence in small drops and you lose it in buckets." gottleib. this isn’t a bucket its a fucking swimming pool.another nail in the coffin of one of the few fiduciary systems left in govt that most people actually believe in. there will also be immense pressure on the EMA and other regulatory bodies, thereby damaging them too.

iii) making it impossible to do new Altzheimer trials since many patients will be given this ineffective medicine and thus cant be enrolled in trials of potentially more effective medicine

iv) everyone who has a "no harm" medicine will use this as a precedent! (see linked article above)

v) emboldening conspiracists across the spectrum:
"the fda was just bought"
"you can't trust science, they don't follow their own rules" (which people will be entitled to say!)

when the world says "big pharma" controls things, the FDA in fact has since the 30’s told big capital to throw away hundreds of billions of REAL dollars in expenses (and trillions in profit) - and tens of thousands of REAL-person-year work by clinicians and scientists. …..because the drugs put before them failed phase III, II I or earlier tests.
if big capital actually ran things like the conspiracists said (like how the natural supplement industry works - no testing AT ALL) , there would be 10,000+ drugs on the market now that aren’t.
but now everyone will point to this decision!

then when the invariable evidence comes out that it doesn't work despite being FDA approved and costing a fortune:

"see! drugs and science don't work. buy my woo/prayer”

vi) further encouraging the weaponizing of patient interest groups to push through un-ready treatments

vii) increased insurance premiums and taxes/debt for everyone!


etc. etc.

I'm livid. If anyone wants me to donate to ANY way to stop this shitshow - law, regulation, lawsuit, fucking coup, sign me up.

tl;dr It's plunged a dagger into the sclerotic but still-beating heart of evidence-based medicine approval and will set us back a fucking century.
posted by lalochezia at 7:21 PM on June 9 [87 favorites]


Usually when they go "Uhhhhh maybe this'll work" it's bad news. Like when they were like uhhhhhh why don't we put a big mesh around the organs? Plaque bad right? So we get rid of it I guess? Maybe that'll do something?? And in this case the only way we'll find out if it works is from people whose ability to consent to anything is on the line if they lose the bet? It doesn't sound great.
posted by bleep at 7:22 PM on June 9


FDA is corrupt. Actions like this will only breed greater mistrust with the authority figures.
posted by asra at 7:23 PM on June 9 [1 favorite]


This was also in the comments of Derek Lowe's summary: Two members of an FDA advisory committee quit after approval of controversial Alzheimer’s drug
posted by JoeZydeco at 7:36 PM on June 9 [19 favorites]


I don’t think it is corruption driven by greed or money, it is the enormous political pressure from patients and their advocates who think this drug does something. No one wants a big fight in congress over why grandma can’t get her memory pills.
posted by interogative mood at 8:43 PM on June 9 [7 favorites]




I'd say odds are good that some Trump leftovers are making money off of investments.
posted by They sucked his brains out! at 8:51 PM on June 9 [5 favorites]


This is, what, the nth study of drugs to treat amyloid plaques, all of the others didn't seem to help (even when they reduced plaques), and the FDA has approved it on the basis that clearing amyloid is a good enough proxy (even though it's never worked before) that they can approve the drug? Do I have that right?
posted by BungaDunga at 8:58 PM on June 9 [8 favorites]


Yeah this is bad. Another level is that one of the only ways to confirm presence of amyloid and officially diagnose Alzheimer’s is a PET scan. PET requires a ton of resources like access to a scanner as well as a nearby facility that can produce radioactive tracers that decay quickly and so is super expensive and difficult to access. Now there’s gonna be a rush on people trying to get PET scans to show they need this drug.

I heard the Alzheimer’s Association was pushing to get this through and likely had an influence on its approval. On its face it looks good for patients and like progress is being made towards a cure but the load on the medical system is gonna ultimately be quite bad.
posted by ghostbikes at 9:00 PM on June 9 [3 favorites]


Also - discussing this with someone else in the field, the study included people with mild cognitive impairment, so more early disease stages, but the approval is also for people with advanced Alzheimer’s. Which wasn’t part of the trial.
posted by ghostbikes at 9:14 PM on June 9 [3 favorites]


Have you seen the homeopathy aisle(s) at your neighborhood pharmacy? This is a terrible decision from the FDA, but it tracks pretty well with where we're at as a society.
posted by ryanrs at 9:15 PM on June 9 [3 favorites]


This watchdog group has been trying to draw attention to aducanumab's vetting for a while; there's the lack of efficacy, how a "prior close collaboration between the FDA and Biogen dangerously compromised the integrity of the FDA’s review" (per director Dr. Michael Carome, director of Public Citizen’s Health Research Group), and the risk of bankrupting the Medicare system:

Becerra Must Take Immediate Action to Address FDA’s Inappropriate Collaboration With Biogen On Alzheimer’s Disease Drug (Public Citizen, April 2021) Secretary of Health and Human Services Xavier Becerra should ask the department’s Office of Inspector General (OIG) to immediately investigate the unprecedented and inappropriate close collaboration between the U.S. Food and Drug Administration (FDA) and Biogen regarding the company’s application for approval of the Alzheimer’s disease drug aducanumab, Public Citizen said today in a letter to Becerra.

Public Citizen warned Becerra of the adverse consequences if the FDA were to approve aducanumab despite the lack of evidence of effectiveness. In addition to providing false hope to millions of Alzheimer’s disease patients and their families, approval of the drug now would pose an unacceptable threat to the financial health of the Medicare program. [...] On Dec. 9, 2020, Public Citizen called on the OIG to launch an investigation of the FDA-Biogen collaboration, but the office replied with a short, pro forma letter signaling that it did not intend to pursue such action.
posted by Iris Gambol at 9:27 PM on June 9 [9 favorites]


Yeah, this stinks to high heaven. I've had alzheimers in my family I want so badly for there to be an effective drug, but I dont want FDA approving ineffective drugs.

I think there was a previously on the blue about a cancer drug.that was highly effective on a very specific cancer, but being marketed more widely. The because they data when average showed medium effectiveness but it meant half the patients getting the drug were receiving zero benefit. Yuck.
posted by CostcoCultist at 10:24 PM on June 9


But here's the thing; when it goes to market Aduhelm [is it just me thinking it sounds like Odin's hat-of-power] will start to bask in the kudos of the placebo effect - it will be as effective as homeopathy which works quite well for this very reason (so don't knock it!). Anecdotes of My Dad's improvement in [or merely slowing decline of] cognitive function will start a cascade:
- families will demand
- docs will prescribe
- pharmacists will fulfill
- public will pay
- most patients will decline anyway
- Biogen sales reps will get bonus
- shareholders will need a bigger handbag for the loot [share-price spiked 50% on Monday]
But the same benefit could be achieved by Big Red Pill Inc., @$5 a day to cover the marketing campaign.
posted by BobTheScientist at 11:02 PM on June 9 [1 favorite]


I'm sure there are zillions of hyper-expensive drugs, but that's the first time I, personally, have seen a price tag higher than many people earn in a year.

Oh boy, venture into the world of monoclonal antibodies (MaB) - any drug that ends with "mab" -basically, a magic bullet, where scientists clone human antibodies and target them at literally anything they like. They are used to treat extremely rare diseases that would otherwise be fatal, however due to being extremely difficult to manufacture and very low sales volumes, the cost per dose is also astronomical. One of the drugs we give out for free (public healthcare) is Eculizumab which comes in at roughly $13,500 per dose for patients who need higher dosages, nearly $750,000 per year.

Wikipedia notes the average treatment plan is $440,000 per year.

Patients need to be on this treatment for the rest of their life.
posted by xdvesper at 3:18 AM on June 10 [5 favorites]


Mabs and other biologics are not just used for rare diseases. Check out Humira and Enbrel that are for used for a range of relatively common autoimmune conditions. I know first hand that enbrel costs $1250 a dose for about $60000 total per year. And it’s worth every penny to me (especially since I’m getting all the benefit and seeing the bill go to insurance). Anyway, the cost of this drug is not so crazy - although the cost benefit ratio may be...
posted by Tandem Affinity at 4:16 AM on June 10 [3 favorites]


Eculizumab and other MaBs for genuinely rare diseases are not really a burden on health system costs despite their high per patient costs. Humira now has much cheaper generic alternatives as well.

This drug is going to be given to many millions of people so that $65 is going to add up real fast.
posted by atrazine at 5:11 AM on June 10 [2 favorites]


Not only is it a horrible medical decision and bad regulatory process, it's a direct cash pipeline from the taxpayer to Biogen. NYT: "Those billions of dollars in anticipated costs are likely to be shouldered largely by Medicare."
posted by CheeseDigestsAll at 5:13 AM on June 10 [4 favorites]


Before my father passed away, we were offered some hope with a just-approved drug. It cost a bundle, but between medicare and the special program offered by the pharmaceutical company, it was affordable for him.

Six months in, my father's doctor decided to take him off the drug because he had learned of several deaths linked to it and it wasn't clear that it was having any effect.

After going off the drug, my father started getting direct mailings from the pharmaceutical company about the drug's benefits and how he should "ask his doctor about it". When we told his doctor about the mailings, the doctor got quite upset and said he'd "have a word" with the pharmaceutical rep at their next meeting. The mailings stopped for a while, but then we got another one just after my father passed away.
posted by RonButNotStupid at 5:32 AM on June 10 [10 favorites]


I don’t think it is corruption driven by greed or money, it is the enormous political pressure from patients and their advocates who think this drug does something. No one wants a big fight in congress over why grandma can’t get her memory pills.

I want to recommend the documentary How to Survive a Plague, about the early days of ACT UP and advocacy for AIDS drugs. Of course, these activists were also dealing with homophobia and people saying that their illness was a punishment from God - a terrible situation - but the film does raise some issues about activists pushing for faster approval of drugs. I mean, what they did was really heroic in a lot of ways and you absolutely see that in the film, but it's also complicated when the meds just aren't there yet.

I have a rare, incurable cancer, and I see this among cancer patients. Some of the drugs that have been approved are lengthening life span by only a few months, yet this gets celebrated in cancer forums. These drugs are insanely expensive, and we are on them for the rest of our lives. I struggle with just how much it costs to keep me alive, but I'm not going to turn down more time. I think the hope we have is that they'll keep us alive long enough for a cure.
posted by FencingGal at 6:16 AM on June 10 [14 favorites]


From health policy professor Harold Pollack: "Angrily contemplating wildly contrast in political economy+financing structures around Aduhelm's rapid approval+proliferation w/political economy+financing structures that force health departments to rely on old fax machines, prevent stockpiling PPE+more."

But I know that messy democracy is better than a bunch of disconnected ivory tower types dictating policy. Don't I?
posted by Mr.Know-it-some at 7:14 AM on June 10 [2 favorites]


the film does raise some issues about activists pushing for faster approval of drugs

IIRC, the documentary adaptation of The Emperor of All Maladies covered breast-cancer patients' push for the accelerated adoption of high-dose chemotherapy in conjunction with stem-cell transplant as a treatment, which is a brutal experience and in the end turned out to be of limited, if any, benefit. They adopted many of the tactics of AIDS activists in the 1980s. You understand quite well the desperation of people (especially from marginalized populations) with terminal illness, but, of course, like all things, capitalism has commandeered it for its own benefit.
posted by praemunire at 8:04 AM on June 10 [4 favorites]


And people don't understand vaccine hesitancy! Pharmaceutical companies are empowered by government regulators to act with complete impunity and to pursue absurd profit above all comprehension. It's a wonder anyone trusts the healthcare system at all.
posted by latkes at 8:07 AM on June 10 [3 favorites]



And people don't understand vaccine hesitancy! Pharmaceutical companies are empowered by government regulators to act with complete impunity and to pursue absurd profit above all comprehension. It's a wonder anyone trusts the healthcare system at all.


Read my comment again.


when the world says "big pharma" controls things, the FDA in fact has since the 30’s told big capital to throw away hundreds of billions of REAL dollars in expenses (and trillions in profit) - and tens of thousands of REAL-person-year work by clinicians and scientists. …..because the drugs put before them failed phase III, II I or earlier tests.
if big capital actually ran things like the conspiracists said (like how the natural supplement industry works - no testing AT ALL) , there would be 10,000+ drugs on the market now that aren’t.
but now everyone will point to this decision!
posted by lalochezia at 8:25 AM on June 10 [8 favorites]


Looking at markers versus looking at patient health is a pet peeve of mine. Cholesterol-lowering agents have had a history of lowering cholesterol and increasing mortality.

This is from the AFCAPS study, a major study at the end of the 1990s which tested the cholesterol-lowering agent lovastatin in the treatment of patients with average total or LDL cholesterol. This greatly increased the range of usage of statins.

This was a big-ass multi-year study.

"A total of 5608 men and 997 women with average TC and LDL-C [. . .] After an average follow-up of 5.2 years . . .

The study was ended early because of the wonderful results.

"Following a review of the second interim analysis (data from 267 participants who had experienced a primary end point event), the Data and Safety Monitoring Board recommended that the trial be stopped early for efficacy."

Lovastain lowered the bad cholesterol!

"Low-density lipoprotein [bad] cholesterol levels were reduced by 25%."

Lovastatin lowered fatal and nonfatal coronary and cardiovascular events!

"For coronary and cardiovascular events (total fatal or nonfatal), treatment with lovastatin resulted in significant (P=.006 and P=.003, respectively) reductions of 25% compared with placebo."

More people died on the drug than on placebo!

"The overall mortality rate was similar in each group, with 80 deaths among participants treated with lovastatin and 77 deaths among participants treated with placebo."

Yes, not statistically significant, but considering the reduction in CV/CHF events, the drug shifted deaths from heart causes to death due to other causes.
posted by dances_with_sneetches at 12:49 PM on June 10 [4 favorites]


As for expensive drugs, the $56,000 per year is nothing. Edited to add: the 2 million dollar price tag is for a one-time treatment.
posted by dances_with_sneetches at 12:52 PM on June 10 [1 favorite]


@ dances_with_sneetches: "As for expensive drugs, the $56,000 per year is nothing." That drug Zolgensma [marketed by Novartis] is weirdly connected with Aduhelm [Biogen], of this thread, because Zolgensma is eating into the profits of Spinraza, Biogen's fabulously expensive treatment for SMA - Spinal Muscular Atrophy. The high price is because the costs of developing any drug from idea to FDA appro are about the same [$2billion and rising is the approx figure] but there are thousands of old folks with Alzheimer's but only 25 tots with SMA - in Ireland; 10x that in UK, 50x that in USA.
posted by BobTheScientist at 1:47 PM on June 10


I'm kind of close to this as my Brother worked on this at Biogen. In talking to him about it he reiterated: "It's not a cure, there is no cure". Which he and I know all too well as our mother and grandmother both passed away due to Alzheimer's related diagnosis.

"It's a step where there have been none for too long." additionally there are parallel trials going on studying other lines - including treating formations of amyloid plaques & tau tangles etc. I'm just not the scientist - he is.

It's just a start that hopefully will continue to build momentum in getting any kind of treatment to offer on the market when at this moment - a diagnosis is a very bleak place to be for the individual and the family.

I'm just trying to offer a different perspective - from someone who has been unfortunately close to this terrible fate. This could be in my future too...
posted by djseafood at 2:07 PM on June 10 [1 favorite]


As for expensive drugs, the $56,000 per year is nothing. Edited to add: the 2 million dollar price tag is for a one-time treatment.

One-time, and turning a near-certain death for a toddler into a life of reasonable quality. It's not like a treatment for psoriasis (which is obviously a very difficult disease to have on several axes, but doesn't tend to kill children).

Nonetheless, it's a deranged system. A significant portion of any drug's "costs" is marketing, which wouldn't even be happening in a sensible world.
posted by praemunire at 2:32 PM on June 10


A significant portion of any drug's "costs" is marketing

And by significant, people should realize pharma spends about as much marketing drugs as they do inventing new ones. Marketing and R&D are funded at similar levels in most pharma companies.
posted by ryanrs at 3:42 PM on June 10


Given the value NICE (the UK government body which decides the drugs the NHS will fund) puts on a quality adjusted life year (£30k), you could actually justify Zolgensma even at that list price.

I think they negotiated a "no win, no fee" arrangement for that one though in which the manufacturer gets paid the full amount only for successful results.
posted by atrazine at 5:28 PM on June 10


That the list price is about the expected QALY gain * threshold isn't a coincidence. If you say the maximum you're willing to pay, they will charge it.

This one drug will force the hands of congress to either change medicare drug pricing or gut the benefit. That it has, as best we are aware, about 0 QALY benefit will probably play a role. At least with the giant cost of hep C treatment there was a huge benefit to the patients. It would have been cost effective for the US government to just buy gilead.
posted by a robot made out of meat at 8:10 PM on June 10 [2 favorites]


The post title is spot on; as several commenters have noted the use of surrogate endpoints has led to the approval of ineffective and even dangerous drugs before. Noted speed limit aficionado and FDA drug reviewer John Nestor warned of the cozy relationship between the FDA and Pharmaceutical companies 50 years ago, and was reassigned away from reviewing drugs in return.
posted by TedW at 6:59 AM on June 11


Medicine: it definitely does something.
posted by turbid dahlia at 3:30 PM on June 13


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