The aducanumab approval

by ChristianKl1 min read17th Jun 202115 comments

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As the world knows, the FDA approved Biogen’s anti-amyloid antibody today, surely the first marketed drug whose Phase III trial was stopped for futility. I think this is one of the worst FDA decisions I have ever seen, because – like the advisory committee that reviewed the application, and like the FDA’s own statisticians – I don’t believe that Biogen really demonstrated efficacy. No problem apparently. 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.

[...]

So the FDA has, for expediency’s sake, bought into the amyloid hypothesis although every single attempt to translate that into a beneficial clinical effect has failed. I really, really don’t like the precedent that this sets: what doesn’t get approved, now? 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? I know that this is just the libertarian turn that many people have wished for, but I’m still not sanguine about it. 

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what doesn’t get approved, now?

What doesn't get approved are the things which haven't spent enough money and obeisance to ritual to submit the requests properly, and probably a few things which are actively harmful.

I know that this is just the libertarian turn 

Yeah, I wish it were.  What it really means is that the magical thinking that "FDA approval" is what makes something a "good drug" gets a little more weight, and does nothing to reduce interference or make it cheaper to bring useful things to people who can benefit.

Three experts resign as FDA advisers over approval of Alzheimer’s drug

The approval and explanation riled advisory committee member 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. In a searing resignation letter sent to acting FDA Commissioner Janet Woodcock on Thursday, Kesselheim called the FDA’s decision "probably the worst drug approval decision in recent US history."

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In resigning, he joins neurologists David Knopman of the Mayo Clinic in Minnesota and Joel Perlmutter of Washington University in St. Louis, both of whom also announced resignations this week.

There's one piece here that I don't understand. Why exactly do we expect doctors to prescribe this medication that doesn't work, thereby wasting resources? Is it a situation where we expect patients and patient representatives to demand the medication, due to being scientifically illiterate (or because they are doing Hanson-esque signalling that they care) and then doctor-shopping until they can get it? Or is there some kind of pay-per-treatment incentive that will make doctors want to prescribe it? Or something else?

There is a whole hierarchy of incentives to medical people at different levels in the system. 

At the bottom
1. Free samples
2. Free education. 
3. Cute/good looking drug reps...

The free education comes with a nice meal and convivial company. You just need to sit through the drug company propaganda, which is duly accredited as good for mandatory training hours. What happens if your prescribing fails to conform to the desired profile? You don't get invited to the next "free" training. 

At the top (influential professors):
1. Funding for studies 
2. "Speaking fees". 
3. "Consultancy fees"

As with the lucrative "speaking fees" paid to ex politicians and the highly paid and often made-up jobs provided to ex-politicians and bureaucrats and their families, everyone knows the score. If you make trouble the "speaking fees" and the like dry up. Completely by coincidence of course. 

Or is there some kind of pay-per-treatment incentive that will make doctors want to prescribe it? Or something else?

Given that the treatment is administed intravenously doctors will get money for administrating it to their patients and monitoring the patients so that they don't get too much brain bleeding/swelling. 

Most of that work can be done by a nurse that the doctor employs so the doctor can bill something for which he doesn't have to do much work himself.

Or is there some kind of pay-per-treatment incentive that will make doctors want to prescribe it?

(This isn't a response about this particular drug or its manufacturer.) I think that generally, large pharmaceutical companies tend to use sophisticated methods to convert dollars into willingness-of-doctors-to-prescribe-their-drugs. I'm not talking about explicit kickback schemes (which are not currently legal in most places?) but rather stuff like paying doctors consulting fees etc. and hoping that such payments cause the doctor to prescribe their drug (due to the doctor's expectation that that will influence further payments, or just due to the doctor's human disposition to reciprocate). Plausibly, most doctors who participate in such a thing don't fully recognize that the pharmaceutical company's intention is to influence what they prescribe, and their participations is materialized via cognitive biases rather than by them acting mindfully.

Also, not all doctors are great at interpreting/evaluating research papers/claims (especially when there are lots of conflict-of-interest issues involved).

On one hand, I think the FDA shouldn't be gatekeeping as much as it does. The ideal, I think, would be if they were reduced to an advisory role, where they published an opinion on which drugs are good, and that opinion had some influence on insurers' willingness to pay and doctors' willingness to prescribe, but had no legal force.

However, an Alzheimer's drug is one where, by definition, most of the relevant patient population can't evaluate the evidence themselves. So under a relaxing-standards interpretation, this is a very bad choice for where to relax the requirements first. And under the normal interpretation of what FDA approvals mean, this is just straight-up lying.

I have begun to think that the biggest factor in a drug being approved is drug company sponsorship, and thus the potential for drug company profits. Patentability appears to be a big factor. 

See "regulatory capture". 

Your first link (the one in the "This is a linkpost for ..." intro) is broken. I think it's probably meant to go to https://blogs.sciencemag.org/pipeline/archives/2021/06/08/the-aducanumab-approval .

The best steelman I've heard for the approval is that the FDA just created a multi-billion dollar market for Alzheimer drugs. Once people are paying 50k/year for this drug, other companies will have enormous incentives to try to get a piece of the market, which will create better treatments over the long run. So yes, right now there's gonna be a lot of money wasted on an ineffective treatment, but here the FDA might actually be incentivizing more innovation.

This decision made it harder to bring new Alzheimer drugs to market as one of the people who resigned from the FDA's advisory panel explains on CNN

Companies already knew beforehand that Alzheimer drugs are a multi-billion dollar market.

The fact that the FDA approved the drug based on reducing amyloid beta plaques, suggest that other companies are incentivied to develop drugs that target amyloid beta plaques as well instead of going for something that's actually promising. 

Previous discussion of why targeting amyloid beta plaques likely isn't a good idea can be found at the recent LessWrong post Core Pathways of Aging.

Companies already knew beforehand that Alzheimer drugs are a multi-billion dollar market.

But they didn't know how willing the FDA was to approve placebo-like drugs.

Cassava Sciences, whose Alzheimer drug candidate doesn't target beta amyloid, rose in response to that approval. I doubt that many people will be satisfied enough with this drug to deter signups for new trials.

I don't know what the net effect will be on the development of good drugs, and I doubt that anyone else does either.

placebo-like drugs

The drug isn't just an inert sugar pill. Placebo's don't cause bleeding in more then 10% of the patients. Additionally it does change a metric in the right direction. It's just not a metric that's clinically beneficial.

That suggests that other drugs that also target metrics that aren't clinically benefitial might get approved. 

I doubt that many people will be satisfied enough with this drug to deter signups for new trials.

It results in trials being more work because they now have to make an argument about how their treatment relates to the "state of the art". That might mean having a control group that takes expensive aducanumab.

Crappy drugs that only slow the decline a bit might need an aducanumab comparison, but why would a drug that reverses the decline need that?

See Cassava's trial results.

See also this clinical trial of Bredesen's approach (press release here).