Thank God no. The solution to a clumsy but powerful bureaucracy is not to create an entirely new level of even more powerful bureaucracy and hope that, against all experience, it will be sleek, intelligent, and efficient.
There's a child's rhyme about this, about an old lady who swallowed a spider to catch a fly.
Whilst I agree in principle here, what is being advocated in effect is having a government-funded scheme with no mechanism for controlling costs. Or to put it another way, a way for the cartel of approved manufacturers to take money from tax payers. You need to have a check on that process even if it is additional bureaucracy as the costs are going to be less. Ideally though I guess the check should be democratic rather than bureaucratic.
Yes. The only effective restraint on government is active and informed voters. Asking government to keep an eye on government is deeply silly, and never works. I will say a kind word for federalism, though -- having roughly equipotent goverments keeping an eye on each other has some real value, or used to, back when federalism was taken more seriously. It also gives citizens the ability to vote with their feet.
I'm British. I think we're largely happy with NICE, both the population in general and the doctors. They are slow to react, but the general principle of 'government only pays for cost-effective treatment and cost-effectiveness means price less than "£X/QALY" seems pretty sound.
If you guys had the FDA to say "safe enough to be used", and a NICE equivalent to say "useful enough to pay for centrally", your above problem would be solved.
Glad you like your system. I wouldn't have it if you paid me. The only person I want to decide whether a given drug is useful to me or not is me, and I'm quite happy to pay for it, or buy insurance in advance to cover its cost, in order to have that right. I'm gobsmacked the Brits, historically pretty stout defenders of their personal liberty, are willing to turn over that much authority to Parlaiment. Why not have them arrange your marriages while you're at it, eh?
What system does your insurance company use to decide something is "worth it"? Do they do all their own $/QALY calculations each day? Can you compare one insurance company's "worth it" against another's "worth it" to decide which is more in line with your values?
NICE only determines what standard NHS care will cover.
"I'm quite happy to pay for it, or buy insurance in advance to cover its cost, in order to have that right" would absolutely still be an option.
People often seem to act like the existence of the NHS somehow means that private care and private health insurance don't exist over here, and it simply isn't true (I think Canada is closer to the strawman I keep seeing people attack?) - a more accurate model would be to consider the NHS as Universal Basic Insurance.
Is that the primary goal, though? To do "Science"? Seems to me like it has a relatively large "cost-benefit analysis" role as well, which, as the voting citizens of the country that created the FDA, and who will bear both the costs and benefits of those analyses, I'm not sure it's the "man on the street" unjustly intruding on the FDA's "scientific" jurisdiction. It seems more like the FDA unjustly (and without the relevant expertise) intruding on citizens' implicit demand that their public health agencies serve their best (again, implicit in "best" is some kind of cost/benefit analysis) interests.
Not unless it includes some experiment, and I'm hard-pressed to see what that experiment would be. As an actual real-life scientist, I'm routinely annoyed to see almost anything that involves numerical calculation and/or logic called "science" on the grounds that this is what "science" is. That's mistaking the tools for the task. It's as absurd as saying algebra can be classified as a form of poetry, like Shakespeare, because it (algebra) involves the meaningful arrangement of letters of the English alphabet.
Nothing is a science unless it begins with discovery through experiment. Anything else might reasonably be called philosophy, even natural philosophy, but if there isn't an experiment at the base, it's not science. And for that matter, the use of mathematics is not required: if I hypothesize that it rains every other Tuesday, and conduct the experiment of going outside and returning to drip, or not, on the calendar, I am doing science and my results -- the calendar with rain spots on certain days -- are scientific results, despite the utter absence of math.
I think it’s complicated though. The FDA regulates the trials necessary for scientific investigation of drugs, and in that sense very much participates in the process of drug discovery. They also require complex opinions and decision making from subject matter experts in the scientific fields. So they’re not really “doing science” in the creative sense, but they employ scientists to direct and regulate the process of science (of evaluating and using drugs and other medical interventions). Science in genera is a slippery word and idea anyway
OP also said they lack “the relevant expertise” and I don’t think that’s true - more that they’re misusing it
Sure, they employ scientists, because they need to understand the science, but understanding the science isn't doing science, any more than appreciating poetry is the same as writing the stuff.
I don't think "science" is inherently a slippery word, but a great number of people and interests have made it so because they want to borrow some of the gloss that empirical science in narrow fields has built up for itself over the last few centuries. It's a common form of linguistic corruption.
Perhaps in some general sense, but in the context of this comment about the FDA, it is not the "science" that they are doing - and it is being explicitly contrasted against the "man on the street's" non-scientific "cost/benefit analysis" approach. "Science" defined so broadly that it includes the explicitly political (in a good way), cost/benefit analysis of "gee, maybe we should accelerate approval of a vaccine, given that thousands are dying each day" is meaningless - and worse, if it is "science," then it means that the FDA is not a scientific organization because it's obvious they aren't doing this - by their own admission.
The FDA is not even remotely a scientific organization. It's a regulatory standards-setting body, somewhat akin to NIST or the standards-setting part of the NHTSA or FAA (i.e. without the investigations arm). They are supposed to assess the evidence given to them about new drug efficacy and side-effects, and decide whether to approve or not the proposed use of the drug. Not only do they not do original science, they are not even like a scientific management committee, because they don't propose new areas of research, they don't favor or disfavor this or that line of research, or this or that research spending priority -- they just look at the applications laid before them and make a judgment on it.
I guess you can call them "scientific" in the sense that theyr'e supposed to (1) understand the science they're called upon to judge, so they need to have a background understanding of science, and (2) they are supposed to make their decisions based on a rational assessment of the measured effects -- and not on political, economic, or philosophical grounds.
This is actually not true. The FDA does have a few smallish groups that engage in actual scientific research, often in collaboration with biopharmaceuticals companies. These groups are kept separate from the regulatory function, but I imagine they likely still interact with the regulators. The FDA also hosts seminars delivered by biopharma experts on emerging technologies. Generally, I've found the FDA folks to be quite scientifically knowledgeable, at least within their own specialty. The FDA inspectors are particularly good; they are both feared and respected in the sense that they are quite good at finding legitimate deficiencies.
My point here, the problems at the FDA don't stem from incompetence or poor scientific knowledge. They stem from bad incentives and a flawed system.
Source: I am a co-author on a paper generated from an FDA/biopharma collaboration, and have been involved with plenty of FDA audits.
I think perhaps what you want to say is "that's true in a general way, but there are interesting exceptions -- they have some small groups that actually participate in research. Plus they sponsor seminars and such." That's a very valuable addition, and I thank you for adding it. But I still think a strong general statement needs to be made, because I suspect there are plenty of regular folks who actually think the FDA directs research, and the fact that it doesn't is important.
Thanks for linking to my piece. An interesting problem you bring up in the Axsome story is effectively a public goods provisioning problem: how do we incentivize good trials for generic drugs for repurposing?
Good trials for generic drugs provide the public good of accurate information on a clinical question, and then anyone can use that information.
Some ideas to make this better, ignoring novel drugs to simplify:
1. making clinical trials cheaper per patient. I don't know enough about this to have specific proposals, but it is something I'm eventually going to learn more about. Tentatively: something involving substantial reductions in the power of IRB's and using tech to make multi-site trials easier.
2. prizes for researchers who successfully discover a new use for a generic drug and prove it with a trial. This exists informally, in that a highly cited research trial paper will give you career capital and speaking invites.
3. Something involved prediction markets and clinical trial outcomes? Maybe people who are good predictors of successful drug repurposing should get $$ to choose more drug repurposing candidates?
I've always liked the idea (using the tiered/unbundled FDA Scott describes) + "human challenge trials", that after we do normal trials to establish initial safety (i.e. you don't die when you take it) then we open it up to a "soft approval" where you can legally take it, but you have to sign a really big waiver saying "I KNOW THIS ISN'T FDA APPROVED AND I WON'T SUE" and also "I PROMISE TO BE A PARTICIPANT IN THE ONGOING TRIALS FOR EFFICACY" and then also pay people enough (maybe make Prestigious Advancer of Science Through Clinical Trials a viable career option) to participate.
For 3, part of the problem is that one can’t really make as much money off of generics? Maybe a smaller but significant monetary reward for the company/individuals that pushed through the trial (like 2), maybe per drug prescription, as that more directly replicated the incentive for new drugs and provides the money right to the people who develop them.
I’m not sure the scale works there, you can’t really generate the same amount of money that a very expensive new drug candidate that isn’t genetic would sell, so it’s still very lopsided. I think 1) is the best option, but could mean many different things - it’d be really interesting if a group of doctors could run a multi center trial “themselves” without needing significant funding or backing.
A public body to ... study repurposed generics? It seems like the sort of thing where the problem space (all diseases) times the solution space (all existing drugs) times the space of domain experts (for specific techniques and diseases and drugs and whatever) times people who have the disease and are willing to take it times the people who can administer and run the trial ... is very large, and would be better with some mechanism where more people and companies can participate if they think they have something good. So you’d want big biotechs and small biotechs and individual doctors or researchers and universities and whatever to all be able to do (I don’t know how you both make it compensated and doable at the high standard of a clinical trial but it’s worth thinking about) the sort of repurposing research here. Or maybe federal funding for research in it like public research, paying people to do studies with rewards if they succeed ... but that’s pretty close to wills proposal anyway.
Terrible idea: allow accelerated / less effort repurposing based trials of compounds that passed safety but not efficacy checks in past studies and then were not approved for efficacy
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long
I doubt that when people support restrictions on drugs and stuff, they are thinking of *them* not being allowed to get something they want. They think of other irresponsible or stupid people. I can imagine supporting restrictions on an unsafe drug yet feeling it's an unfair privilege that someone specific gets to choose to circumvent them.
What they are imagining is taking an approved drug in good faith (because it was approved by the FDA and prescribed by a physician) and then having it turn out horribly -- the drug does something terrible that wasn't known ahead of time through carelessness, haste, political/economic influence, et cetera.
You are seeing that play out in real time in the reluctance some people have to get a COVID vaccine because of the speed with which it was approved. There are people who think there may be something screwy about the vaccine, like it has an 80% chance of giving you brain cancer 5 years after you take it, and nobody knows about it yet because 5 years haven't passed since it was invented.
And that is not a completely brain-dead attitude, either. We have plenty of examples of things that were at one time considered reasonable therapies or at least not harmful that proved to have disastrous long-term effects, e.g. smoking was once considered healthy, since it takes decades to develop lung cancer from it and it took people a good long time to realize that.
This attitude about vaccine harms down the line has made me wonder if a poison yet exist that could have serious side effects years down the line from one or two doses.
A sub immediately lethal dose of polonium would do that. Not much exists like that unrelated to oncogenesis (I mean, with critical development periods in pregnancy being one obvious exception).
Cassava contains cyanide. It does not kill you slowly. Cyanide is well excreted by the body. It has even been used at subtoxic doses recreationally(not recommended). Even long term continuous exposure from the environment does not kill you. It can however cause some health issues.
In fact, the process of cooking cassava (and several bean varieties) with the pot lid removed to expel cyanide as well, as washing used on nardoo, acorns and such, can never be 100% effective. That alone should indicate to you that there is not a long term buildup of these toxins.
Well, sure, e.g. the early pioneers in the discovery of nuclear radiation had no idea it could give you cancer decades later[1]. Lead is another poison the harm from which can manifest years to decades later.
"Poison" is a vague term, but prion diseases are an example of this sort of behavior. Exposure to a single small dose of prions causes no immediate effect, but severe to lethal consequences years later. It's obviously not a thing that happens frequently in drug or vaccine development, but I don't think we know enough about prions to absolutely rule it out.
If a doctor prescribes me a drug that I have to pay an arm and a leg for, I'd like to know it works, or at least that it wouldn't kill me. I don't have the time or expertise to hunt down and read scientific papers. The only way I'd know it works to a reasonable confidence and in reasonable time is if a government agency known for high standards approved it.
To be fair, I think they also think about vulnerable populations. If you release a new med, the side effects and negative interactions that end up killing people, will mostly kill people in vulnerable populations - the elderly, people on 10 different meds already, people with compromised health to begin with, etc.
If you're healthy already, you can be correct in thinking that the cost-benefit analysis for you is positive, but that it would be negative for enough people that making it universally available might be negative on the whole.
Even supposing Aducanumab doesn't treat Alzheimer's, if it truly is an anti-amyloid, it should have some beneficial effect. As you wrote earlier, doctors should be allowed to write prescriptions for it (since it seems safe), but insurance shouldn't have to pay for it for AD (since it doesn't seem effective against AD). Under our current system, a drug that might be useful against disease X will be banned forever if it's first tested against disease Y.
But the last ten anti amyloid drugs have not had and beneficial effects, and there’s a long history of misunderstandings or complications in mechanisms of drugs that “absolutely should be beneficial” not being
Technically, that is the situation now. Biogen can legally produce and market it as a remedy for Alzheimer's, and doctors can prescribe it for that condition (or anything else that crosses their minds), but insurance companies are generally under no obligation to pay for it. Nor does Medicare, until the CMS says it must.
What people point out, however, is that the political and market pressure to pay for it will be immense since the FDA approved it (and physicians and families are shortly to be subject to an onslaught of professionally-photographed heartstring-tugging marketing material from Biogen). Furthermore, the funding priorities of Big Pharma may shift, in the sense that the suits are always looking for an easier way to make the next $billion, and now that Biogen has paved a certain path, they may think following that path is easier than plowing another $250 million into Research Team X's kooky idea about what *else* might help with Alzheimer's, and so just possibly a far better therapy might be delayed considerably because it gets starved.
I don't have any brilliant solutions to the rat's nest of competing social, scientific, and economic forces here, but I do feel confident that anyone who fiercely argues the FDA is too damn strict and slow, and ought to let people try shit once it's been proved it isn't very dangerous and might or might not help cannot logically also argue that the FDA should never have approved aducanumab on the mere grounds that it hasn't been proved to help beyond any shadow of reasonable doubt. Those positions are logically incoherent.
Right. I should have written, "Under our current system, a drug that might be useful against disease X will probably remain banned forever if it's first tested against disease Y and fails FDA approval."
Maybe. I don't know, this passes my understanding of the field. I imagine it might depend on why it fails -- if it fails in Phase II (safety), yeah. But if it fails in Phase III (efficacy) I can readily see a big pharma company, after investing umpty $millions in the damn molecule, saying "well let's see if it works on anything else..."
That's right. The problem is that Medicare exists. It shouldn't. The FDA shouldn't stand in the way of anything that's safe. 3rd party payment is the problem.
Drugs are stupid expensive for 2 reasons. 1. Ridiculous barriers to entry
2. 3rd party payment, mostly medicare.
Hell, the copays for most doctors visits for people with insurance cost what the doctor's visit used to cost before HMOs and medicare.
What do you know. It turns out medicine wasnt the one area of the economy where throwing away market forces was a good idea.
Proving effectiveness (to FDA's high standards) doesn't become easier without Medicare. A lot of people here are concerned about the FDA making their lives worse (and sometimes blocking doctors from saving lives) by saying they can't even try a drug that might help.
Well...it would be hard to dump Medicare without a population willing to steel itself to old people getting no medical care, because there *will* be people who fail to properly prepare for old age, not to mention a modest number who did prepare but who suffered from bad luck (the insurance company folded, their investments tanked). Realistically, that's not going to happen.
What might work would be to reform Medicare so it only covers some basic level of care, with better care available through private add-on insurance (which already happens to some extent), and also make it an annual grant to seniors, with which which they can buy insurance on the open market, thus encouraging diversity (all the females can skip coverage for prostate cancer) and competition.
>>, if it truly is an anti-amyloid, it should have some beneficial effect.
No. This doesn't follow at all. 10 anti-amyloid therapies have failed before (I document this in the post Scott linked above). This one failed too. There is in fact /strong/ evidence against it working.
There is strong evidence against aducanumab /by itself/ working against a specific population (old people who already have pretty advanced AD, I assume, because that's what I always see in trials of AD drugs) of one specific neurodegenerative disease. There is stronger evidence that any curing or preventing of Alzheimer's, or of several other neurodegenerative diseases. will have to include a cure or prevention for amyloids.
You should read the Biogen trials. They're /very/ early-stage AD patient with MMSE of "24-30". MMSE scores of 24-30 are basically normal: 20-24 is mild dementia; 25-30 is a normal score.
The idea that the problem is trials just aren't targeting early enough AD patients is a common refrain but it isn't supported here.
>>"There is stronger evidence that any curing or preventing of Alzheimer's, or of several other neurodegenerative diseases. will have to include a cure or prevention for amyloids"
No. There is a wealth of animal data purporting to show this, but absolutely no human clinical trials show this. In fact, there is strong human data against it- large well-funded trials that reduce amyloid burden having absolutely no effect on cognition decline.
You're only looking at drug trials. See the comment below by "Aβ Male" for a summary of some of the evidence that amyloids are a problem. They are junk proteins that build up over time and eventually kill neurons. No one in the field questions this AFAIK. Anything that builds up over time and then kills neurons must be combatted, regardless of what drug trials (which are more complicated than establishing a mechanism, and can fail for many reasons unrelated to whether amyloids contribute to AD) show.
It certainly does, but bear in mind what you have are starting to have here is a competition between pet theories, viz. clearing amyloid will help, clearing amyloid definitely won't -- because the trial didn't (and can't) enroll enough people for long enough to fully test the hypothesis.
AD generally takes years to decades to manifest, and years to decades to kill. An 18-month trial with a modest number of participants and a particular measurement of results is not enough to rule out any benefit at all. It's quite fair to say the benefit has not been proved. It's also quite fair to say the benefit is not likely, based on what we know so far. But you can't say the benefit has been entirely ruled out on the basis of what we know so far. That's why the approval was difficult. That's why reasonable men can disagree on the best action.
We have empirical evidence that amyloids build up and kill neurons. Clinical trials are just one type of evidence, and they aren't designed to prove what you and Will are trying to use them to prove--in this case, that amyloid build-up isn't part of the mechanism behind aging. They are carefully designed only to evaluate whether a particular drug, administered in a particular manner, to a particular population that has developed a particular stage of a particular disease, will produce an effect with a p-value below a chosen cut-off.
In any case, all clinical trials are so similar in their approach that taking 10 clinical trials is not as powerful evidence as looking at 2 or 3 experiments which are truly independent. There's a large number of possible sources of error which most or all clinical trials are subject to, so all the clinical trials in the world still wouldn't provide two independent pieces of evidence.
Again, “drug targets mechanism correctly but it turns out we were wrong about mechanism, even if not fully wrong, enough that the way the drug targets it doesn’t actually help patients” is a somewhat common failure for drugs. “Amyloid important” and “drug remove amyloid” is possible without “drug good”. Why is the failure of all the past drugs in trials - drugs that successfully removed the protein stuff - and then the apparent failure of this one - enough to approve? Should the other ten antibodies will listed have been approved?
The $100 billion/year estimate from my blog post is a high end, and after writing that post, the FDA took a step back and restricted the indication to only early-stage patients. Still, it has the potential to be extremely costly.
Whenever you write about the FDA I can't help but think of the FAA. Drug companies have no incentive to sell dangerous drugs. Just like Boeing doesn't have an incentive to have planes suddenly plummet to the ground killing 100s. Boeing might not but individual Boeing employees certainly do. And not long after we started relaxing regulation those individual employees started to run amok. I don't see why we wouldn't' see the same issue with reduced regulation of Pfizer that we saw with Boeing.
There are a number of reports of safety issues in Boeing planes, with somewhat frequent mass groundings. I had read it had to do with organizational incentives and structure and culture and the ceo changing, idk how much about that is regulations.
The key issue was Boeing being allowed to certify itself. The theory being it would never let planes fall out of the sky. Just like the banks back in 2006 wouldn’t lend all their money to people with no ability to pay it back. Why would they do something so foolish?
“ The FAA delegated to Boeing itself most of the analysis and testing required to certify the MAX as safe to fly. … However, some Boeing ARs complained of heavy pressure from managers to limit safety testing and move quickly through the analyses. One AR who balked at such pressure was removed from the program.”
That's a nice little article. Two things jump out at me as significant factors contributing the problem:
(1) The reduction in authority of the actual engineers in favor of the technical managers, at both Boeing and the FAA.
(2) The decision of Boeing when the problem proved difficult ($$$) to fix by redoing the airframe to let the inherently dangerous behavior of the airframe stand, and "fix it in software" by creating a program to compensate.
Because both of these seem like general modern trends, and generally increasing risks. I can understand why both of them arise: engineering gets more and more complicated, and so people demand more people to whom they can talk in non-gobbledegook -- technical managers -- and they award those people more and more power. It works great in terms of nontechnical people being better able to *understand* what is going on, but it definitely increases the probability of Something Bad happening because the simplifications involved in the technical manager's understanding turned out to be *too* simplified.
The temptation to fix hardware problems in software is also easily understood, since software is cheap and fast and hardware is not, and evil combinations of flawed hardware and buggy software that are just right to cause disaster are ipso facto rare.
But still, they both seem like growing problems, and not easily solved, given the necessarily increasing distance between the frontier of science and technology and the technical competence the average citizen/consumer possesses.
>and evil combinations of flawed hardware and buggy software that are just right to cause disaster are ipso facto rare.
Not the first time it's happened; Therac-25 shot people with lethal radiation beams because of exactly this. Also, cars with auto-engaging out-of-lane prevention (which also prevents driving straight when there is reflective water or a not-in-program arrangement of lines on the road; "possessed by demons" indeed) - although I think that one happened after/around-the-same-time-as the MAX catastrophe.
Yes, and I expect it will happen more in the future. For a long time we kept software out of life-and-death situations, because it was so self-evidently risky. But we are much more accustomed to relying on software these days, and I think the pressure is rising to allow it into more serious situations, because of the immense savings in cost. I'm not sure we have the right set of attitudes and practices for that not to have some significant tragic outcomes, at least until we develop better attitudes and practices.
Ugh, yes. I recently had a Tesla Model S try to stuff me into the side of a tractor trailer on the Autobahn in a construction zone because the car got confused about which set of pavement markings was important. And then I had the passenger turn that shit *off* right fucking now.
When I bought my last car I was musing over some of these add-ons, automatic braking, lane-keeping and stuff, and the salesman (no spring chicken himself) looked at me and said "Dude...seriously, you've been driving 45 years, are you really going to trust the car to do your braking or steering for you?" and I realized he was 100% right. Maybe a person can develop new instincts of when to trust the car and when not to, but I'm too old for that crap. I don't even use the back-up camera much, I just turn and look like I always have, although I'm glad it exists to show me whether there's a cat or kid's tricycle right up against the bumper.
I didn't read that article, but isn't the main problem that the software lacked the redundancy it needed for safety (relying on one sensor instead of the usual standard of two sensors)? Combine that with the fact that pilots were unable to turn the system off (if they even knew it existed) and it was a recipe for disaster.
Depends who you ask. If you ask me, the main problem is the airframe was flawed, did dangerous stuff easily, and that they tried to fix it in software *at all*. Other people, who don't mind putting their lives in the hands of a computer program, will agree with you, and say the problem is that the program was not well designed, or integrated with hardware.
As I understand it, there's already a lot of safety-critical software controlling car behavior (remember all those Toyota unintended acceleration events?). I agree that in general that this is concerning because it's harder to achieve reliability in software than hardware. In this particular case, though, it's a huge error to force the nose down based on a single sensor reading, and this would still be true if it were a hardware circuit forcing the nose down. It's *so* obviously a bad idea that I've been hoping to hear a report explaining how the hell this could have happened without multiple key Boeing employees being grossly incompetent. Even without the regulator doing its job, a flaw this obvious shouldn't slip through.
The pilots were perfectly able to turn the system off. The penultimate Indonesian 737 MAX crew recognized that the automation was about to kill them, in a very slight variation of a common way for automation to kill people in airplanes, so they hit the kill switch that disabled that whole class of automation and flew the plane safely to its destination using the manual backup system. Which is why you never heard of them, or of countless other flight crews doing the same on many other airplanes most of which were not 737 MAXes.
The next Indonesian 737 MAX crew appear to have been clueless buffoons who should never have been allowed to fly an airliner, who in spite of the note from the last crew saying "PS automation is really flaky, don't trust it until it's checked out", never tried to switch to the manual backup.
The Ethiopian 737 MAX crew, appear to have properly recognized the problem, hit the kill switch, and gone over to manual backup controls. Then tried to selectively reactivate part of the automation, and been screwed over because Boeing changed the way the kill switch worked without documenting it. *That* was the unforgivable sin, IMO.
If the idea is that the automation must never ever ever ever fail, get real. Nobody has a clue how to make airliners cheap enough for non-rich you to afford a ticket, without some degree of automation. And nobody has a clue how to make airliners safe enough for you to tolerate them, without human pilots ready to lobotomize the robots and take control. So you make airplanes with lots of automation, because it's much more efficient when it works, and give the human pilots the tools and training and documentation they need to take over when the automation fails
I mean, the MCAS isn't exactly a normal autopilot. Its entire intent was to prevent pilots from inputting dangerous commands i.e. make an airframe safe that is *dangerous to manually pilot* (at least, without specific training, which Boeing wanted to avoid).
Using automation as a failsafe for an untrusted human pilot means you *can't* rely on the human pilot being a failsafe for the untrusted automation - as such, it should be held to a much higher standard than otherwise.
I believe you, but could you clarify something for me: if the pilot has to be there already to take over for the automation failing, why is it cheaper to automate? Can pilots log more hours when they let the plane fly itself as opposed to going manual the whole way? Or are we able to employ a less talented/educated (cheaper) pilot who only has to be capable in a small handful of "automation failed" scenarios and not in the wide away of "operate a plane normally" scenarios?
In the Indonesian case, wasn’t the aircraft also having numerous faults related to airspeed indicators starting on the takeoff roll (before MCAS kicked in)? Also, I thought the report indicated that the captain didn’t think to turn off the auto-trim, but did at least continually flick the trim switch in the yoke, which would override MCAS for a few seconds at a time. This kept them in the air for several minutes, until he handed control to the copilot - without telling him what he’d been doing to keep the aircraft controlled!
The reason Boeing was incentivized to cut corners with MCAS in the first place is that it would have been tremendously expensive to certify and deploy the MAX if they couldn’t pretend it was just a minor update to the existing 737.
The reason it would have been onerously expensive is because the FAA gives the FDA a real run for its money in making innovation insanely slow and costly.
FAA certification of a new aircraft type takes years and hundreds of millions of dollars. Pilots getting a “type rating” in a new aircraft costs the airline low 5 figures each initially, plus must be maintained through ongoing training and currency requirements for each type they fly. Having a mixed type fleet is costly - Southwest flies only 737s precisely for this reason. Type rating don’t really distinguish between “basically the same but for one or two small differences” and “completely different airframes”. A MAX under a new type would be just as different from the 737 NG as an ERJ or an A380.
So Boeing has turned the 737 into basically a ship of Theseus at this point, very little is unchanged since the original 60s design, but Boeing is heavily incentivized to make sure it can stay within the original type certificate, since otherwise they can’t be cost competitive. Airbus does exactly the same thing with the A320.
MCAS is probably not something Boeing would have implemented if the MAX was a clean sheet design (the airplane is basically fine without it, but it doesn’t fly just like an older 737). But the FAA’s onerous certification requirements pushed Boeing into design decisions that were made not for best engineering design, but to maintain apparent commonality.
It seems that the FAA mostly went along with this wink-nudge-its-just-a-737 thing because they fundamentally didn’t believe that treating it as if it was a brand new airplane either, but admitting reality would have forced them to do so, because the only thing that takes more time and money than certifying a new plane is changing any significant FAA rule, no matter how out of sync it is from modern reality.
This is an organization that took >20 years to approve a leaded gasoline replacement for general aviation (an industry where high FAA certification costs mean that basically everyone is flying around with 1950s engine technology)
I think the criticism raised by Charlie (and Kevin Drum, and others) just relies on... an unnatural reading of things? If you think a particular government agency should not exist -- if you think that the function it is supposed to perform is one that should not be performed, and therefore no agency should exist to perform it -- that would to my mind normally be described as you being "against" that government agency, and that is how I would normally someone interpret saying they are "against" a particular agency or that that agency is bad. I don't know why one would read it instead as a comment on the quality of the particular staff? I would normally think of government agencies primarily in terms of their function, not the particular people who happen to be executing that function...
Sure, but my comment generalizes to the case of "the function it is performing is the wrong function and therefore it should perform a different one". You don't have to intend to abolish the FDA to talk in terms of functions rather than the people tasked with those functions.
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us.
I think there's an internally consistent position where the observer doesn't acknowledge that the drugs are being delayed too long, and just objects to the actor breaking the rules. Basically, in this framework whether the treatment works is moot, the objection is just about fairness and/or the morality of rule-following.
(Not supporting this position, in particular; just providing an observation for why most people don't think politicians are heroes when they cut the line, and also the criticism Biden is trying to pre-empt with his statement that he has to wait for FDA approval before taking his booster.)(
Andrew Gelman does a thing where he writes his content and puts them in a queue to post 6 months-ish later. Maybe that's an option foryour less time sensitive pieces.
Sometimes you can understand an acronym even without having it explained (well, at least I can). For example, if you already know "IIRC" ("if I recall correctly"), you can probably understand the sentence "IIUC, photosynthesis converts light energy into chemical energy".
Point. (Though I'm not sure I would have gotten that particular example if you hadn't primed me first.)
But that particular strategy only seems like it would work for stock phrases your audience already expects you to say based on context. If you are trying to promote an idea that is not already widely-talked about, I'm not sure it can help you.
I think he meant 'explain' as in 'explain the joke and how it is supposed to relate to the situation at hand', not just 'say what the acronym stands for.'
The final example about bupropion-dextromethorphan highlights how misguided it is to solely fund clinical trials through the promise of patent-protection. Presumably the government could make a guess at how likely this would be to work, how valuable it would be if it did, and then the government could have people bid on the contract to run a clinical trial.
Does this happen? Does the government, or anyone, fund clinical trials with the condition that anyone can make the drug if it is approved? The Ketamine example fits here too it seems.
Funding agencies and hospitals will occasionally run trials with generic drugs or to figure out specific clinical questions with already approved drugs-- how long should antibiotic X be given? 10 vs 8 days. Etc.
I don't think this happens nearly enough, however.
I'm kind of baffled how you can invoke the "normal knowledge that normal people use" as some kind of accessible source of information when nobody has the first clue how to gather or assess that. Normally among pundits it operationally reduces to "what me and the people I know/read/like think" but that leads straight to the Pauline Kael effect, and some of the unpleasant divisions between "expert opinion" and what vast swathes of regular folks think that we see today on any number of issues.
If nothing else, consider that the "knowledge of normal people" about which we have cared deeply for several centuries is "who should run the country?" and for this purpose we have this vast apparatus of elections, at various levels, terms of various sizes, representation or not, not to mention polling and focus groups and prognostication -- and yet we *still* are routinely surprised by the outcomes, and debate furiously just how genuinely representative they are.
What hope is there of actually discovering what the "knowledge of normal people" actually is on the question of whether Drug X should/should not have been approved, or whether the FDA should be "stricter" or "looser" in general, for various definitions of "strict" or "loose?"
I feel like all you're really saying that's 100% defensible here is that given time, a consensus will emerge, and using the clarity of hindsight we will all be able to say decision Z or T of the FDA was right/wrong or hasty/slow. But noting that hindsight is easier and more accurate than foresight is rather a truism and (barring the invention of time machines) gives no clue on how to improve the situation going forward.
Scott's position is that the consensus often emerges before the FDA makes a decision.
This is not a mechanism that Scott is proposing, it is a standard. If everyone (in the medical community?) already knows that e.g. covid vaccines will be approved for children and the FDA hasn't allowed it yet, then the FDA is moving too slow.
Yes, well, the gist of what I said is that I have very strong a priori doubts that this is true -- that one can empirically measure a reliable "consensus" (among whom? would be the first question) before the FDA makes a decision.
As a rule, people react to events, they do not work proactively to form an opinion on events that have not yet happened yet. Exempli gratia, I doubt except among those most intimately concerned (patients, physicians, researchers) anyone even tried to form an opinion on whether aducanumab should be approved in advance of the event.
And if the "consensus" which we intend to consult is merely among the small community who are intimately engaged ahead of time, because of assorted intersts, but...er...not the *same* small community that is intimately engaged in FDA approval, this (1) does not meet the definition of some broad-based "general commen-sense person" community, and (2) isn't obviously better than what we already have.
Perhaps I should add that I don't doubt a consensus may emerge in some random community or other -- e.g. "all the people I know" -- but as I said at the top, that is a very distinct thing from a general broad-based consensus, and the former should not be mistaken for the latter.
I think the general situation can be 'incentive hacked' from above in a way that simply pressures the experts in the correct direction
Give everyone at the FDA a 10% raise and then make 20% of their paycheck dependent on their performance in terms of a chosen cost to benefit or cautionary principle standard. Something like "10 people's lives are not saved due to overcaution so that 1 person's life is not lost due to lack of caution"
If the FDA is responding to huge overcaution incentives where nobody notices if they don't approve something and good things do not happen and someone loses their job if they do approve something that goes wrong then the large paycheck incentive may fix that and at least might serve as a red flag that the process has problems
At the same time if the FDA is not internally able to approach the quantified goal they themselves will be the ones waving the red flag and identifying what the obstacles are
Who manages the managers? Who watches the watchmen? This just declares an intent to fix things and says “someone’s job will be to make the correct decisions, somehow? And they’ll be responsible for the actual decisions”. It doesn’t fix either the “what is the actual principles we can teach and carry for what to approve and how and when”, and “how does your incentive system not bend when Eric topol says to not rush the vaccine or your expanded approval system (whether or not it really did, doesn’t matter, just the pressure) kills ten black babies in underprivileged communities.”
It would be straightforward enough to be able to assess whether the performance measurement of the FDA was reasonable. We all know that pausing J&J may have saved a few lives and definitely cost, what, thousands? That one at least is pretty bright and easy
One thing the incentive pressure would likely immediately do is cause the FDA to choose a number of other regulatory agencies like the EU's and provisionally or fully approve everything they do because the likelihood is they are overcautious as well. Suddenly the regulatory problem is reduced to whichever agency is the best, assuming the primary problem is in fact overcaution. (I take this almost for granted given the incentives that are at play but I understand that emotionally there is a constituency for allowing 100 or 1000 lives not to be saved so one does not die from undercaution because for some it does feel more wrong for someone to die as opposed to 100 not being saved. What the FDA might do under pressure from a "ok, but here's how far you can go with that" incentive is open up provisional approval that allows people to use drugs that are not fully approved under their own volition and request that the calculation of their performance on not approving that drug yet be suspended since people have at least been given the choice to take their own risk)
Re: your second response below I'd say 20% of someone's paycheck is enough to become the primary incentive in their work. If it doesn't we should hear about just what the problem is because there will at least be an incentive to complain
> It would be straightforward enough to be able to assess whether the performance measurement of the FDA was reasonable
Not really? That sounds somewhat hard. Let’s say the FDA approved all ten Alzheimer’s antibodies right now, but didn’t mandate insurance prescription. And then let’s say they opened a rolling trial option where up to 10k total patients per drug may pay up to $100 each to participate in a trial for drugs that have passed animal safety checks and human safety model checks, to speed up development and use that data for phase three trials, and then this is used for more monoclonal antibodies and also for early likely to fail 3D printed organ test transplants in terminal patients who will die anyway to speed up testing. Should that be rated as Good or Bad by your agency? Is it obvious? Not really
I don’t like the idea of companies regulatory shopping for which of seven agencies with partial mutual recognition of approval is the most generous or corruptible. In some areas that’s fine, but for this one eh. I’d be happy with re using trials and evidence used for other countries if they pass our standards but I’m pretty sure we already do that
20%+ paychecks are not enough to be a primary incentive if, for instance, you will have your agency power taken away if you do the thing, by public backlash. Might also be thinking more of a corporation and less about the actual structures at play in the FDA - who’s making the decisions? Who’s salary so you increase? The political appointed head? Political appointees of all people will have other incentives, and potentially limited ability to fight the careerists if they even want to.
I think 'voting is wonky so we can't learn public opinion about anything' is a bad take.
First of all, in our two-party system, the parties autoamatically re-align themselves so that each side is always capturing about 50% of the population, making the decisions close and hard to call all the time, and there are massive incentives on all sides both to pervert the process of finding out what people want and to misinform people about what they should want. This is probably the hardest version of this problem imagineable, because of the unique circumstances surrounding it.
If you wanted to find out if, say, the majority of people believe that rain is cause by pixies crying when they see a clown get hurt, it would not be at all difficult to get this information. You would do a phone survey with a few hundred or thousand respondents, the outcome wouldn't even be close, and the percentages you get would be very close to accurate.
Those are the two extremes of the easiest possible problem vs the hardest possible problem, but I think that most things you might care to ask about are closer to the crying pixie end than to the voting for president end of the spectrum.
I think it *feels like* the population is really divided on most issues and it's hard to ind out what they really think, precisely because we spend all of our time talking about controversial issues that are tied up with politics and active manipulation. But the vast majority of issues you might ask someone about are not controversial in this way, and on those I think it's not that hard to get a public consensus.
I certainly agree on many issues people *can* be assessed for their understanding and viewpoint pretty easily. But not in the slightest with respect to medicine. People feel *way* more strongly and emotionally about personal health than they do even about who is President. You can take the most rabid Trump-really-won fanatic and the die-hard AOC fanboi and all their political differences will vanish like a pricked balloon if the question before them is how to prevent themselves, a spouse, or a child from snuffing it from a brain tumor, and whether Drug X will do that or not, and whether it should be available, cost what it does, et cetera. Health care is *even more* screwed up with passions and illogic than politics.
""On March 19, 1972, the FDA reassigned Nestor to its Office of Compliance, as part of a reorganization in which Civil Service doctors were replaced as drug approvers by consultants who were often affiliated with commercial companies. Nestor began a grievance proceeding. A review panel determined that senior FDA officials gave "misleading" testimony against Nestor and concluded that Nestor was due an apology and appropriate duties.""
The final decision is made by a bunch of men-on-the-street: a jury. We decided that, even though justice system officials know a lot more about crime, it is too difficult to get rid of their inherent biases, so a group of men-on-the-street does better.
If we take this analogy even further, we could have juries for the FDA. The experts can make their arguments, but the decision would ultimately be decided by a group of men-on-the-street. Random people would get called to make decisions that effect the life and death of their fellow citizens.
While I think that this is interesting, I'm not convinced that it is a good idea. The FDA is often too slow to approve good drugs and the jury system is not exactly known for its speed.
Judges make plenty of decisions in criminal cases, and juries are notorious for not understanding and making somewhat mistaken decisions in trials involving detailed and complex technical evidence or issues. (Judges also do that, but the FDA’s experts are subject matter experts)
I don't think the analogy is especially applicable. The role of a jury is a trier-of-fact. That is, their job is to assess the believability of the witnesses both sides put on, and decide who to believe. The *judge* is the one who decides what the law says, i.e. given this pattern of facts on which the jury agrees, what is the crime (if any) that was committed, and what is the appropriate result?
There's a very decent reason to believe that a panel of average strangers are well positioned to collectively decide whether Witness X is telling the truth or lying. It's a generally-distributed skill, for which there is no known education or technology that could do a better job, it's a collective decision, so individual flakiness is averaged out, and the people involved are very detached from the rest of the judicial process, so they are not influenced by considerations of the sentence, of the effect on other defendants or cases, of the nature of the law, et cetera -- all of which can have powerful effects on lawyers, prosecutors, and judges, the experts in the bowels of the system.
There isn't much that's analogous in the FDA's decisions. A major part of what a criminal trial is about is deciding who's lying, and there is (one hopes!) essentially none of that in the FDA's decision process.
Furthermore, the assumption that would seem to underly this, that an *individual* man on the street has a better judgment of the details than an individual FDA apparatchik, seems dubious a priori and anyway isn't part of Scott's proposal -- I believe he's arguing that some vast consensus, the wisdom of the crowds, so to speak, can exceed the good sense of a much smaller number of FDA experts and bureaucrats.
That is, the key change is to make the number of people who influence the decision much, much bigger. (This may also be the assumption underlying the idea of taking guidance from approvals in other countries -- basically, if the EU and UK and Japan all approve a drug faster than the FDA, maybe the wisdom of the crowds is telling us something.)
Honestly, I think juries are in the wrong place. I'd rather put the "committee of men-on-the-street" as one of the houses of parliament (Congress in the US), where they can tear up criminal overreach at the source.
But many voting age people isn’t informed or smart or strong willed or free of other responsibilities enough to hold all that responsibility - and most of them would agree to some of those - do we should let those chosen nominate someone they know who would serve the position better! Oh wait that’s voting
I was also a bit disappointed in the post and subsequent discussions elsewhere, because the question on what influenced the Aducanumab decision is not really addressed. If the FDA is so risk averse, why authorize this drug and risk reputational damage if it turns out that it doesn't work? Scott kind of gestured at "some decisions will randomly stray from the decision mean in the other direction", but I find this terribly unconvincing, given that the FDA's scientific advisory committee was firm in its rejection. Plus, other bloggers have alleged regulatory capture by big companies, which seems more explanatory.
I feel like a model of how the institution works beside the short and imho simplistic "public perception incentivizes risk aversion" story should be required before condemning an institution so heavily.
> I don’t want to never write posts when I’m angry, because those tend to be the posts people like the most, and I think they get things done in terms of convincing people of important things.
This is a well known phenomenon. Outrage sells. But that doesn't make it good journalism.
IMHO he is ever so slightly distracted by his personal life. I have no proof of this either way except for when people are falling in love their prose may be slightly different. Lingering relentlessly on an idea in order to hash out all the connections might take more effort when the person who might be the love of your life is around. If this is influencing him I think he will figure it out and adjust.
When you say 'outrage sells', I think you're conflating journalism which causes outrage in the reader, and journalism which is written by an outraged journalist.
I think some of the best journalism ever written was almost certainly written by journalists who were outraged by the corruption or cruelty they were investigating. This type of moral outrage is a huge motivator of human beings to work hard and speak passionately on a topic, we should expect it to play a role in situations where people have worked hard and spoke passionately.
I wouldn't want to eliminate it from journalism as I think it would just make journalism even more anodyne and worthless if journalists weren't allowed to talk about things they are outraged by. I think Scott has the right of it when he says to focus on 'edit sober' more in the future, that's all that's needed.
"Then someone finally realized that the jam was caused by a single citizen, one who commuted in the far left lane, driving exactly the speed limit for miles on end."
It distresses me that this was seen as improper behaviour. If the speed limit is too low, raise the speed limit - don't complain about people obeying the law.
Disagree. "Lowest *average* speed you could keep for hours on end" and "lowest speed at which you can find yourself for five minutes without it being a crime" can and should be different things, for the same kind of reason that it is not illegal to make loud noises for five minutes if you have to hammer a particular nail into your kitchen wall one day, but it rightfully is illegal to keep hammering at that wall for hours on end in a way that drives your neighbours mad.
People usually consider the impropriety to be driving in the far *left* lane. The general assumption is (and in a few states the actual law is) that you should always be driving faster than the traffic in the lane to your right, and most people consider that this is a higher-priority rule than driving the speed limit. After all, there may be excellent reasons for temporarily exceeding the speed limit -- you're an ambulance, say, or the interior of your car catches fire while you're in a tunnel -- that even the police and courts will accept, and it seems either dumb to not realize these exist, or antisocial to insist that you yourself are the best judge of whether they apply in whatever situation you're driving in.
I suppose the expectation is "if we don't set a limit, some fool will drive 100mph and crash into everyone, so we want everyone to drive no faster than 70mph, and since everyone drives faster than the limit, to get that we have to set it at 55mph".
But I agree, it makes more sense "set the limit at 70mph and if people drive 100mph crack down on that" then "set the limit at 55mph in the expectation that everyone knows it's 'really' 70mph".
In principle, speed limits serve a useful purpose under all circumstances, because they give the driver unfamiliar with the road an indication of the design specs of the road. If you put a speed limit of 55 on the road, it's saying "the engineers who designed this road designed it so you could drive it at 55 and have enough visibility and time to react to people entering from side streets, go around even blind curves safely at that speed" and so forth. Very useful info.
What annoys people is when the speed limit is clearly set far *below* what the road could handle, e.g. American interstates are generally built to be drive at 85 MPH, and yet the speed limit was generally lowered to 55 in the 70s as part of an idiotic virtue-signaling gesture towards "the Energy Crisis." It took decades for this idiocy to be removed from the rulebooks, so that now you can, for example, drive I-90 through empty stretches of Montana at 90, which is perfectly safe. Not surprisingly, decades of a law that served no practical rational purpose, and which existed as a relic of a stupid fever time in national politics, and as a testament to the difficulty of undoing legislation, gave people a broad contempt for the concept.
In some jurisdictions, as I understand it, they set speed limits rationally, in the sense that they simply monitor the actual speed of drivers and set the speed limit at roughly the typical speed, theorizing that people will in general drive at the fastest speed that is reasonably safe, and that if you average over a large number of people you'll get the community consensus of experienced drivers.
The "handbook" answer for "what to set the speed limit to" is "the 85th percentile of traffic speed"
This is, of course, not appropriate for all roads - residential roads in the US are (typically) set to 25 mph because of pedestrian safety, for example. And for over a generation, the US National maximum speed limit could not be more than 55 MPH, because "fuel efficiency."
Incidentally, as a result of a court case, there must (probably) *be* a speed limit. For a number of years, Montana (IIRC) had a speed limit of "reasonably safe under the circumstances." This was struck as void for vagueness, and now they have a Really High Speed Limit on most roads, and on down from there.
I vaguely recall Nebraska (or maybe Montana) for long years during the reign of the double nickel imposing a "fuel conservation fee" of $10 or so, payble on the spot (but no points, no legal case), if you were above 55 but below the historical limit, in order to continue to qualify for Federal highway funding but not be assholes.
First of all, in the US, the left lane is the passing lane. Unless all lanes are completely filled, you are supposed to only enter it briefly to overtake other cars.
Second of all, to go immediately to the ad absurdum, this logic would condemn anyone who refuses to cooperate with a police state, and excuse anyone who commits any atrocity so long as they are 'following orders'. Sometimes laws are bad, people know they are bad, and they're not getting changed any time soon. Of course they still *should* be changed, and feel free to fight for that, but an immoral action doesn't become moral just because a law says to do it.
If you know the right thing to do, do it. Try to get the law to reflect that, of course, but that's an entirely separate consideration.
Your analogy fails, I think, because a too-low speed limit isn't immoral, merely inconvenient. Besides, unless you had specific knowledge that the speed limit on that stretch of road was improperly set, you should have no reason to think that going the speed limit wasn't the right thing to do.
I'm also guessing that in this specific jurisdiction there is no rule about the left lane being for passing only, since if there was, it would undermine the point of the story. Although in retrospect I am starting to wonder how accurate said story actually is.
Is it immoral to lock someone in a small room for 30 minutes without their consent? Is it less immoral to force 500 people to spend an extra 30 minutes stuck in their car on their daily commute?
I understand that we privilege locking someone in a room by calling it 'false imprisonment' or 'kidnapping' or w/e, and assign 'badness' to it beyond the literal harm done by having to sit in the room. But beyond that, I think the harm done is pretty much the same, making it similarly immoral.
If it was around DC on the VA side of the river, there probably wasn't a rule about the left lane being for passing only; they'd have been pulling people over constantly because the lanes are always filled.
At the time, the speed limit was not set by traffic engineering times, but to enact a "nationwide fuel efficiency mandate" (which has slowly and in piecemeal been reversed in the past roughly 30 years, though the Washington Beltway is still 55 MPH speed limit)
Also, then and now, it is in all the jurisdictions the Beltway passes through (as in the vast majority of the US) to occupy the left lane and not be passing. (The specific wording of the "keep right" laws vary from state to state), but it is rarely enforced.
Ah, I found an article in Wikipedia. The National Maximum Speed Law. Important context which I was missing, thanks.
And he was in fact breaking the law by driving in that manner. OK, that thoroughly changes the nature of the story. Any theories on why he wasn't prosecuted?
Legendarily the parts of the Autobahn where there are no speed limits have *ferocious* enforcement of No passing on the Right / Only Passing On The Left.
When I was much younger I would have, and did, agree with this.
As I got older, and got several times more driving experience, I realized that society depends on informal systems of people working together. Nestor's excuse was "it's easier for me" because he doesn't have to deal with traffic on both sides. This excuse, if applied by everyone, soon forces everyone into the left-hand lane.
I *do* think that speed limit laws should all be changed to be "rational," but Moloch is Moloch, and here we are.
I recommend F.A. Hayek's books "Law Legislation and Liberty" on this topic. Unfortunately I can't remember which of them (mine are in at least three volumes) focuses on the difference between law (what people think should be punished) and legislation (what the state identifies as what should be punished). In the case of a guy driving exactly the speed limit instead of 20 over, the law is definitely being violated to hell and breakfast, while he is following the legislation.
In most places, even cops won't pull you over for going <=10 mph over the speed limit; when I lived around DC that might be a lot closer to 15-20 during heavy traffic. The cops in that case are acting in accordance to the law, which is that going 10 or so over the speed limit is normal and fine, indeed expected.
It is a problem that the idiot legislators don't change the speed limits, but fortunately law tends to lead legislation by quite a bit. Still, following legislation when the law is very different is going to get you social approbation, and well deserved at that.
Oh yes of course! I believe there are around 2 or 3 studies showing memantine is effective both as monotherapy and as an adjunct to stimulants in the treatment of executive function disorders. Anecdotally, it can prevent and maybe even reverse stimulant tolerance. I'm fuzzy on the mechanism here but I understand that this is a well known effect of NMDA antagonists.
So I bought some online, started at 5mg in the morning and titrated up according to FDA guidelines, reaching 10mg BID. I do find that it makes my Adderall stronger. It also helps to quiet the restlessness in my mind, increase motivation (this is the big one for me), and attenuate some of physical side effects of Adderall, such as muscle tension and fast heart rate.
Memantine is also an antagonist at certain acetylcholine receptors, so there is some brain fog when you start, and each time you up the dosage. However, these receptors apparently upregulate quickly, and I indeed found that this side effect disappeared pretty soon.
I've read a lot of reports online from people who tried it for ADHD who said it was a godsend initially and then randomly pooped out on them, so I'm just hoping that doesn't happen to me. I would say I have around 75% confidence that the benefits I experienced weren't placebo.
I think it does, but from what I can tell it's the sort of thing that works really well for some people and not at all for others. You'd have to try it to know for sure, but do remember that it can initially have some very unpleasant side effects, though these typically go away within a week or so.
I do have a few other suggestions that will have effects closer to stimulants though, and are available freely without prescription. One is adrafinil, a prodrug of modafinil. Very stimulant-y but even smoother (less jittery) than amphetamine and methylphenidate due to being more selective for dopamine over norepinephrine, I believe.
Also, there is Sabroxy, a plant extract which contains an alkaloid which is a dopamine reuptake inhibitor. I've found this to be similar to low dose Adderall myself.
Lastly, look into bromantane. This is a Russian drug (it's often referred to as an atypical stimulant) which instead of releasing dopamine, increases its synthesis through several different mechanisms. The advantage of this is one is that its effects persist even after the drug itself has completely left your system.
I would suggest doing a little research on these, and if you're interested, you can find the first two on nootropics depot for relatively reasonable prices.
From a consequentialist perspective, why is it better to let ten guilty men go free rather than convicting one innocent rather than having each kind of error be equally likely?
Since most crimes don't lead to convictions, error parity would seem to imply that most convictions would be false, which seems like it should have some negative consequences? I mean, just look at the problems associated with the distrust of the justice system among US blacks.
Is the distrust of the justice system caused by a high rate of innocent people convicted? So that developments like fingerprints and later DNA evidence would have increased trust?
Sorry, I realize I was a bit unclear. To clarify, I think that (1) high levels of innocent convictions would be likely to lead to distrust & (2) distrust would be likely to lead to problems. The distrust among US blacks is only related to (2).
Because the costs of imprisoning an innocent man are greater than the benefits of imprisoning a guilty man.
Rephrase it as 'why is it better to get punched in the arm 10 times rather than getting stabbed in the stomach once? Shouldn't we want an equal number of each?' The problem is that the two outcomes sound symmetrical, but they're not.
The guilty person may not reoffend, so there may be no harm saved by letting them go. There is guaranteed harm to imprisoning or otherwise punishing an innocent person.
Because the state in punishing the innocent is failing twice: once by failing to punish the guilty party and again by harming the innocent. Since harming the innocent is exactly what a justice system is punishing the guilty for in the first place, yea... that's really bad.
You'd also want to pile on the harms of creating incentives to just punish anyone to close a case when you aren't especially careful.
No... Punishing the guilty is one state, punishing no one is another state, then punishing an innocent is a third state. Distinct states, with increasing amounts of harm, no less.
Because men are (or used to be) inherently suspicious of the government power to imprison (or kill), and the most important features of your criminal justice system are supposed to persuade the citizenry to trust it -- to let it take care of criminals, instead of justice being meted out by vigilantes, committees on public safety, family feuds, private revenge, et cetera.
A key aspect of trusting the system is believing that if it does something drastic, like imprison a man or kill him, it is 100% reliable that he is guilty. Destroying a man who is innocent causes much higher distrust than failing to adequately punish a man who is guilty -- at least, until you reach Afghanistan levels of lawlessness.
Wouldn't letting 9 out of every 10 guilty men go free be likely to encourage reliance on "vigilantes, committees on public safety, family feuds, private revenge, et cetera"? In many American inner cities an enormous number of murders (much less non-fatal shootings) are never solved, and the associates of the victim rely on "self help" via private revenge instead (thus perpetuating feuds).
We already let 9 out of every 10 burglars go free, and probably 9 out of ever 10 rapists, mostly through never reaching the point where we put them on trial in the first place. This hasn't lead to anarchy, vigilantism, etc, because for one crime already committed is water under the bridge and even the victim will usually prefer getting on with their life to going full John Wick, and people expect that the really dangerous criminals will be caught before they cause too much harm.
But for particularly heinous crimes, it's probably better that if we're not going to convict someone we should make that decision as early and quietly as possible, rather than holding a big perp walk and public trial and *then* saying "Not Guilty".
We do let 9 out of 10 guilty men go, given our innocent till proven guilty system and high burden of proof. https://en.wikipedia.org/wiki/Blackstone%27s_ratio#In_current_scholarship. There are 19,141 homicides in 2020 9,576 arrests a few years before that and 6000 murder convictions (ish) in ... 2006. This study, which I’ve only read the abstract of, says Extrapolating to all cases in our dataset, we estimate a slightly smaller rate of 11.6 percent
reviewed the latest research and found that the wrongful conviction rate in capital cases is about 4% according to the best available study to date. This study was published by Samuel Gross and colleagues in 2014. A 2018 study by Charles Loeffler and colleagues reported an overall wrongful conviction rate of about 6% in a general state prison population, with considerable conviction-specific variability (from less than 1% to over 10%). This study provides some support for the previous estimate and reinforces the need for more research focusing on specific crimes and circumstances of conviction. https://innocenceproject.org/research-resources/
Claims a 40% offender self reported false conviction rate for rape (and 20% for murder). That’s ... quite high.
Anyway for murder, with 5% wrongful conviction rate and 75% ish of murderers getting away with it, that’s 4/.05 = 80 guilty men going free for one innocent man being convicted. With 20% and 75%, that’s 20 guilty men free for one innocent man being convicted. So our current system is significantly worse than that, and I’m pretty sure that low commission-1 * conviction rate is true in all areas. It’s also been like this for the entirety of American history, the vast majority of crimes have always not been prosecuted.
To answer your question, no. Such a ratio is common to, as far as I know, every country, - and plenty have less vigilante violence than the US cities do, as do parts of the US. The US has a much lower clearance rate than most countries, partly balanced out by
> Japan maintains near-perfect homicide clearance rates (around 95%, compared with roughly 60% in the United States). This study explored possible explanations for higher homicide clearance rates in Japan than in the United States. Using recent (2000 to 2004) official summary statistics, this study found that Japanese homicides contain a higher proportion of “easy-to-clear” cases, including those with nonfirearm weapons, family member offenders, and child (and not teenager or young adult) victims, than do American homicides. Also the Japanese categorization of homicides in official statistics includes cases favorable to clearance (attempted homicide) and excludes cases unfavorable to clearance (robbery-homicide). These findings suggest caution in attributing Japan's higher homicide clearance rates exclusively to police effectiveness or citizen–police cooperation. Suggestions for future multivariate research are also discussed.
and
To start, critics of the system will say that defendants have no chance of being found innocent if accused of a crime in Japan. I would argue that the infamous 99.3 percent conviction rate is misleading. The Japanese conviction rate must be examined in the context of Japan’s judicial system as a whole. Japan does have an unusually high conviction rate, but the presumption of innocence is maintained throughout trial and judgment. The high conviction rate is largely due to the practice of Japanese prosecutors, who only take on cases after careful examination and when they believe there is enough evidence for conviction. According to 2018 data from the Japanese Ministry of Justice, only 37 percent of the arrest cases were actually taken on by prosecutors. The high conviction rate, therefore, demonstrates the efficiency of the system.
> In Japan, the figure is 700 per year per prosecutor. In the U.S., a rough estimate is that 42% of arrests in felony cases result in prosecution - while in Japan, the figure is only 17.5%.
> . In Japan, 1,800 people were arrested for 1,300 murders, but prosecutors tried only 43%.
Assuming similar wrongful conviction rates, yes, as 60% of murders have suspects not tried, so that’s 60% go free, 5%-10% wrongfully convicted means the ratio (for murders!) is 5-10x innocent free vs guilty convicted for wrong reasons.
> But the opposite is true. In fact, the data indicates that Japanese prosecutors bring charges only when the evidence is overwhelming, and the likelihood of conviction is near absolute, which gives a greater incentive for the accused to confess and aim for a lighter sentence, which, in turn, results in a high rate for confession.
The Japanese criminal justice system, despite retaining the death penalty, is relatively lenient in sentencing by the standard of the United States. Outside capital cases, many of those sentenced to life sentences are paroled within 15 years. Those convicted of less heinous murder and manslaughter are likely to serve less than 10 years. Those convicted of rape will often serve less than two to five years. It is even possible for someone convicted of murder to serve a suspended sentence if the defense successfully argues for mitigating circumstances.
So yes, due to the difficulty of proving crimes and the asymmetry between crime and wrongful punishment, most crimes go unpunished.
Sure would. But try it the other way around: what would the reaction be if 1 out of every 10 men convicted were actually innocent? At least as angry and outraged as in your scenario. So there we have the imbalance: you get outrage if 1 out of every 10 convicted is actually innocent, and also if 9 out of every 10 that is actually guilty goes free. Whether the numbers are 10% and 90%, respectively, should be some other numbers is a matter of detail -- the important fact is they're not 50/50, people are not equally indifferent to the innocent being punished as to the guilty escaping punishment.
I think the reaction would not be as much reliance on "self help" private feuds. It's much harder to feud with the government, and 1 out of 10 is smaller than 9 out of 10.
First off I don't think the saying is about how many of the guilty are convicted vs not convicted, but rather how many guilty go free for every innocent person convicted.
Second, I'd say the question is whether to imprisonment more or less than one innocent man for every 10 guilty man. The system is not a knob you can turn until you are imprisoning precisely 1 innocent per 10 guilty; worse than that, it is not even possible to find out how many innocent men you are convicting. Plus, there are local biases in the system in the form of corrupt officials and sometimes biased juries, even if the law is the same everywhere. Plus, the system's punishments are often out of proportion to the crime, e.g. with people being punished after serving their time by employer discrimination and by questions on various forms like "have you ever been convicted of a crime". In this context, yeah, I'm happier letting a bunch of the guilty to avoid punishing the innocent.
If you permit the innocent to be jailed, you've now made it even easier to weaponize the justice system against political opponents and the powerless. Now you wouldn't even have to go through all the effort of convincing people to criminalize something, you can just fabricate charges and bribe people to jail your target. What's the consequentialist calculation when the people feels there's no justice in society? Hasn't worked out very well in the past...
I've spent the last month and a half buried in the Alzheimer's Disease literature due to a likely case in a family member (and ironically, for this reason I must apologize in advance that I won't have time to engage in a detailed back and forth here). I think the evidence for both the amyloid cascade hypothesis and the efficacy of aducanumab is much stronger than is being characterized by most comments here.
It is natural to ask: "sure, we see amyloid-β plaques with Alzheimer's Disease, but could there be a confounder, rather than amyloid-β 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 γ-secretase involved in cleaving APP to make amyloid-β) 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-β production, or to increase production of the specific peptide (amyloid-β 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-β, 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 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. [2]
B) With respect to aducanumab [3], 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.
Furthermore, the post-hoc analysis, while always to be taken with a large serving of salt, was not done arbitrarily. Rather, they looked specifically at the subpopulations which received higher dosages, an a priori plausible sub-population within which to expect higher efficacy.
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 [4]. A more up-to-date and comprehensive review paper is [5].
[1] Haass et al (2012). Trafficking and proteolytic processing of APP
[2] Mintun et al (2021). Donanemab in Early Alzheimer’s Disease
[3] Cohen et al (2019). EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease
[4] Selkoe and Hardy (2016) The amyloid hypothesis of Alzheimer's disease at 25 years
[5] Long and Holtzman (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
"The one part of this I want to ask about is the “aren’t really any [other] Alzheimers drugs”. There’s galantamine, rivastigmine, donepezil, and maybe some others I’m forgetting. These don’t work very well (or maybe at all). But aducanumab also doesn’t work very well or maybe at all, so why is everyone treating it as so unprecedented?"
Those are cholinesterase inhibitors (NMDA-receptor blockers like memantine are also used against Alzheimer's). The effect on cognition for cholinesterase inhibitors is not very good, NNT around 12, though still better than aducanumab, even if you take biogen's data at face value. However, cholinesterase inhibitors and NMDA-receptor blockers do not treat the underlying disease process of Alzheimer's disease. The hope with anti-amyloid drugs like aducanumab that they would actually be disease-modifying.
> That’s fair. I’ve seen some studies by economists saying that “defensive medicine” and fear of malpractice lawsuits doesn’t seem to raise costs too much in the US - but every doctor I know (including myself) feels like they do.
The studies I have seen were doing some intra-US comparison (e.g., VA vs. non-VA bc VA doctors cannot be as easily sued; or the impact of changes to the rules in Texas) and they do find some limited effects. However, none of these studies have a true counter-factual. VA doctors may themselves be more protected from lawsuits, but they are still in an environment where their colleagues from other institutions have instituted all sorts of "best practices," which they are still socially pressured into performing (I assume non-mormons end up drinking less than they would in New York if they move to Utah; which is still because of the LDS church).
So, the studies falsify the notion that the problem is doctors performing an explicit cost-risk legal analysis and then deciding "defensive medicine" is worth it. They do not falsify a fuzzier idea that medical norms are very heavily influenced by the legal environment, but in a way that responds slowly to changes of incentives and does not respect institutional boundaries. Of course, this hypothesis has the benefit of being hard to falsify, but "long-established legal norms lead to a cultural framework of behaviour that persists when those norms are removed" is a very common pattern in history.
Total non-expert here - isn't there a case that amyloid plaques are a cause and/or symptom of aging, and so drugs that remove them could increase lifespan, even if they don't help with alzheimer's?
About politicians either being privileged by the ability of getting the drugs in advance or heroes for testing them, I think there is a way of making the distinction: how do they think about it themselves? I suspect none of them consider it taking a heroic risk, and therefore that should be our point of view too.
>But the cost-benefit analysis is still heavily in favor of the drug, as it is very safe, molecularly effective, and with no alternatives, in a very widespread and destructive disease. The only cost being some people paying money for a drug that won't help them
I think it's worth pointing out that it's an artifact of our local economic system (maybe not capitalism generally, but the specific model of capitalism plus regulations plus government payments plus etc that governs our health system) that creating a pill that probably costs less than a dollar to manufacture per dose ends up being a tragic $100B boondoggle instead of an interesting novelty.
Because we only know how to value things through the process of supply and demand, we build the entire economy around the maintenance of artificial scarcity in cases where production is cheap and supply could easily be near-limitless, and grant the right to monopoly pricing to all kinds of actors in order to encourage them to keep acting.
I get that we've let the system fall into this situation for a reason - we want to encourage creators to create things, pharmaceuticals especially can be a huge and expensive gamble so you need a big payoff the one in X times it works, etc. But I think it's a deficiency of our system that we provide this incentive by using artificial scarcity to *deny medical treatments that are extremely cheap to administer* to tons of people through outsized pricing.
$1 marginal manufacturing and packaging and transportation cost ignores the substantial development costs, such as opportunity or personell cost paying for tens of thousands of hours of time total from hundreds of highly educated and in demand professionals, drug development chemistry and biology and fooling and science needed for it, bureaucratic cost of even more people to verify it, plus amortizing in the many many many many failures, it’s actually very expensive.
Yes, as I already said, I understand why we have allowed things to develop this way. But...
Ok, think about it this way. Phagecorp requires $50B to pay for all the costs of development and distribution of Altranix, plus a large enough profit to incentivize them to make the drug in the first place and subsidize their other failed projects. Fine, Phagecorp should get $50B, I'm on board. But how do we *get them* that $50B?
The model we're using right now is, they make Altranix pills for $.10 each and sell them for $500 each, they sell 100,000,000 pills to 100,000 patients (treatment is 3 pills a day for a year), and that makes them their $50B. Each of the 100,000 patients is financially crippled by the cost, and there are 10 million patients worldwide who might benefit from Altranix but can't afford it.
Here's a very dumb model that I think would be preferable to that, and there are probably much much better alternative models a domain expert could come up with: The government says 'Ok Phagecorp, you did a good job on Altranix, we're going to hand you a check for $50B right now today. Now the rights to produce Altranix are in the public domain, anyone on the planet can make it, and we're going to start manufacturing it and selling it at cost (maybe $.50 per pill counting distribution costs) to anyone on the planet who needs it.'
Now, the public still pays that initial $50B, which has to come out of taxes instead of insurance premiums (no difference), and Phagecorp still makes the same profit (more actually because they don't have to pay for marketing and defend their patent and etc), but now every patient in the world who needs it can get it for next to nothing.
I think the only sane objection to this is 'We have no a priori way of knowing that Phagecorp deserves $50B instead of $1B or $500B, that type of price discovery is exactly what markets are for in the first place.' I agree that is a strong technical challenge, but given the enormous amount of destruction our current system is causing, and given that I think the government-enforced artificial scarcity model is not finding 'real' prices but rather what lobbyists are able to enforce to begin with, I'm very open to people proposing ways to just estimate this instead, and pay it up front.
I mean isn’t the answer here “the government will pay you $50B*(number of prescriptions per time period)/(pill total useful over ten years)” and then the government does that via Medicare or universal healthcare or whatever? And then there’s your price discovery (number of prescriptions plus whatever Medicare or HMOs or whatever do). And then they still get their 50B that day anyway because of investment and then go off to research more. Which has its problems, including making new clone drugs that are pointless, but is part of the system we have now. For existing generics I’d suggest maybe making it easier (a lot easier) for non pharma entities to run trials? But that doesn’t scale probably. A some % tithe for the runner of a trial proving a generic works per prescription if it works? Prospective contracts with generic manufacturers? Also the whole “prescribing X-clone when you could prescribe X for a fiftieth of the cost” thing seems like an easy target.
Also it’d be really nice to reduce the “costs” of drug development somehow. Taking costs to mean, like, something, whatever, barriers, idk, but without reducing the actual filter on drugs being useful. But no clue how!
That would work if we had universal healthcare and also didn't care about other countries. But we don't and I'd like everyone in the world to have cheap access.
There’s not really a solution to “drugs cost money” aside from insurance and government coverage and cost reduction, aside from “don’t get sick”. Which we should work on - all this FDA stuff has a cost benefit ratio of .001% compared to interventions like “ban adding sugar to food” and “white bread is now illegal, added isolated oils are limited to 3% of food calories” and “every 1% of your customers who are obese / have other health issue that’s diet related is an extra that percent tax on your revenue, with temporary credits on that for demonstrated reductions in calories eaten / better composition of sold food for large chains and, importantly, for large food distributors” and also just big ads of <offensive yet descriptive sequence of words visually describing people of mass and various physical disabilities and life restrictions caused by it> together with an explanation of what causes such things and how to avoid them
That is “somewhat” off topic, but it’s something that is very conceptually simple that would do way more for DALYs than any drug development stuff would. “Universal healthcare” and “all newly developed drugs are now free internationally” are a lot less conceptually simple, and have a much lower benefit. Obviously it’s not gonna happen because nobody wants it, but one can hope.
Anyway why can’t we just mandate existing insurance cover all these drugs (to solve the US problem)? Oh well we did, to an extent ... and if we decouple approval from insurance provision, then well once again run into the problem of people not getting approved drugs that they need access to. “Approval is easy + all drugs are cheap + company gets more money than people voluntarily choose to pay for drug when it’s not stage 2 approved” seems questionable. I guess you could save any monetary reward for after full approval but even then ...you create a massive mess.
" big ads of <offensive yet descriptive sequence of words visually describing people of mass and various physical disabilities and life restrictions caused by it> together with an explanation of what causes such things and how to avoid them"
Do you think that would work on me? I'm here to tell you no. I've been fat all my life, I've tried various diets, most didn't work; I've tried the exercise thing (I can't drive and I've lived places with bad to no public transport so it's been 'walk everywhere') and no pounds dropped off because suddenly I was burning more calories than I consumed; the diet that did work, I got sick a lot more in my life than I ever had before or since, and I fell away from that, and basically my psychology is *fucked*.
So yeah, go right ahead and tell me things that nobody has ever, ever said to me before about how disgusting, ugly, awful, wicked, I am; how I am going to get all these diseases of obesity; how I will go blind and have to have my legs amputated and my kidneys and liver will fail and I will die of heart disease; how I am a lazy parasitic leech on the public. I sure never heard any of that before from the general public, doctors, my family and others!
And I will tell you back: for some people, it might work. The "drop a dress size for Christmas" lot who only have a few excess pounds packed on. The very determined who will get the kick in the pants they need to go on a rigid diet, lose five stone, and keep it off.
But for me? I have fully internalised that I am a useless heap of shit (as someone close once told me) and It. Won't. Work. It will, however, give the people who like to drink, drug, and engage in risky activities but who are just on the right line of the BMI the opportunity to be mean to others. So be it.
I think you're vastly underestimating how conceptually simple 'control what everyone in the country eats' would be. 'Abolish IP protections for pharamceuticals' seems a lot more conceptually simple to me, since IP protections are a made-up thing we have to actively invest huge amounts of money and effort into in order for them to exist in the first place. And 'hand pharmaceutical companies a huge check if they make something useful' also seems conceptually simple.
Let me be a bit more explicit and less snarky in why I think the very core of your idea is absolutely repulsive to me. The following assumes that your idea is possible to implement and would have the desired impact on public health, neither of which I think are certain.
First off, everyone already knows that eating junk food is bad for your health--hell, we even call it "junk food", for Pete's sake!
Second, no one is forcing people to eat junk food. They make the free choice to buy and consume it, with knowledge of the consequences.
Third, the negative impacts are entirely limited to the person who eats the junk food. It's their health that's at stake, not anyone else's. And if you want to say "but insurance, but Medicare!" then that argument generalizes not only to regulating the food you eat, but also mandating a certain amount of exercise, banning any sports that carry a risk of injury, etc. etc. etc.... Having that level of imposition on my life seems like astronomically more of a burden than paying a few dollars more in taxes for statistically higher Medicare payouts.
I want to live in a society where people are free to make decisions for themselves about their own lives, so long as they are not directly harming anyone else.
You also forgot "Government pays cronies 50B$ of money for pill that does nothing. Says "Whoops", then does it again, forever."
You see, you have pretty much described the military industrial complex, with all the problems that government defense contractors cause given to medicine. Defense contracting at least has the fig leaf that the government is the only legitimate market for fighter planes etc., whereas the government itself is only the main market for various drugs because it decides to pay for other people who are the actual market.
Reforming IP laws might be a better solution, or reforming laws on what insurance companies have to cover, or... just about anything else including burning down the entire regulatory regime would probably be better than telling companies "You go ahead and make whatever, and if we think you deserve a giant pile of cash we will give it to you, or not, without any real regard to what actual consumers want." Because doubling down on the government having more control of a system that it is just balls deep in, wrecking everything it touches... that's a lot of "this time will be different!"
Speaking of government spending 50B for a pill that does nothing ... just read a story about Bush’s successful world wide AIDS prevention program. It was preceded by several programs that were funded and that bush “observed were not very successful”. Despite that, he still gave them $500M. To govern, ah...
>creating a pill that probably costs less than a dollar to manufacture per dose ends up being a tragic $100B boondoggle instead of an interesting novelty.
I mean, $100B on the public purse doesn't sound like a tragic boondoggle if it actually fixed Alzheimer's (that's a *lot* of QALYs saved), and Biogen going bust because Biogen did a stupid is no big deal either.
The problem is the $XB on the public purse for something useless.
I think your last point requires a whole lot more evidence to be believable. Sure, everyone knew that Al Capone was a criminal, but also everyone knew that the Central Park Five were guilty, that Airborne was an effective thing to take when you get a cold, and that deoxygenated blood is blue. Everyone knows lots of things that are totally wrong. If you want to claim that everyday reasoning is better than institutional decisionmaking, you can’t just point to a single case where the common people got it right and the institution got it wrong, you need some evidence that that is consistently true over a large body of decisions.
The Central Park Five is a bad example of the point you're trying to make as they still might be guilty of the exact things they were charged with and were almost certainly guilty of other things they were charged with. The comparison with Al Capone is apt in that the fact that someone is guilty doesn't mean that person can be successfully charged with the exact things they are guilty of. (Coerced confessions and over-broad charges don't prove guilt...but also don't prove innocence.)
Bupropion-dextromethorphan: I was curious so I bought some DXM from Dollar Tree (where it is 6x cheaper than at CVS) to see whether it does anything in addition to bupropion, but at least I didn't notice anything. (Apparently DXM has some abuse potential so the register makes an embarrassing loud beep when it is scanned.) Interestingly, it seems like the US is the only country where DXM is sold over-the-counter, so it might end up being slightly less trivial to get around Axsome in other countries.
> But that’s not what happened. Instead, the FDA sent Axsome a letter on July 30 saying that they found “deficiencies” that prevented them from moving forward with the approval. What are those deficiencies? Oh, the FDA doesn’t say. They don’t even give a hint. They just told them to hang tight until August 22.
> I remember the FDA rejected an EpiPen competitor for “certain major deficiencies” without giving more information (at least not to the public). EpiPen took advantage of this to quadruple their prices, although the FDA did eventually approve the competitor a few years later.
I really hope the SEC is taking a good hard look at the trades that happen around FDA members...
The thing that puzzles me about all this discussion is that the problem and solution seems clear and simple, yet Scott hasn't presented it in a clear and simple way.
Simply put, Scott isn't opposed to anyone at the FDA, he just wants some elements of the legal framework around the FDA to be changed. The obvious political slogan: "support FDA reform!"
Specifically, certification of safety needs to be separate from certification of efficacy, so that doctors can prescribe safe drugs even if they aren't proven to work.
The devil's in the details of course, so why not shift the conversation to those details? One issue that jumps to mind is that if a drug is shown to be safe in average healthy people, that doesn't mean it's safe in the sick population it's meant for, so even the safety certification may need to be scoped to a subpopulation.
Want an intern? My previous employers have commended my ability to intuit instructions and take initiative, so you don't need to be too concerned about communicating. I have a few years of experience in research, writing, and editing, mostly for student publications.
If you're interested, email me at t [dot ] amarchana640 [at] gmail [dot] com.
I presume someone else has done this, but I need the exercise; in the spirit of doing things with made-up statistics.
1. The cost of aducanumab to the US health-care system is potentially $100B/year (as per [this](https://denovo.substack.com/p/a-travesty-at-the-fda#footnote-1), because it costs $56k/year per patient, and on approval is mandatorily covered by Medicaid, with the assumption that 1.8 million patients would be treated).
2. According to [a 2008 study](https://pubmed.ncbi.nlm.nih.gov/18362813/) (the highest in [the first link](https://www.nytimes.com/2020/05/11/upshot/virus-price-human-life.html) I managed to find in a cursory googling), "Our base case analyses suggest that plausible lower and upper bounds for a cost-effectiveness decision rule are $183,000 per life-year and $264,000 per life-year, respectively." (incidentally,this means that aducanumab would be a steal at $56k/year if it worked)
In order to be worth it at the above exchange rate, aducanumab would need to save 378,787 lives ($100B/year divided by $264k/year (are years and QALYs fungible in this way? Do we discount actual years somehow, especially given that this medication is likely to be administered near end-of-life?)). If you're more pessimistic about the value of a QALY, it's more like 546,448 lives. If you're _extremely_ pessimistic about it, more like 2,000,000.
If you believe that aducanumab will actually save close to 0 lives, then the answer to
> "So how often do you have to save hundreds of thousands of lives before it’s worth the risk of occasionally also permitting a dud medication that “offers false hope”? _How is this even a question?_"
empirically is "once or twice" if you're an optimist, and "four or five times" if you're a pessimist. It's a question because of the way US medical insurance is structured; specifically the way Medicaid seems to be required to cover anything FDA approved. In this light, it's not implausible or inappropriate to at least ask the question of "are the FDA being to lax".
As I write this, [worldometers says there have been ~640k deaths in the US](https://www.worldometers.info/coronavirus/country/us/) from Coronavirus. Assuming they could _all_ have been prevented by having a maximally lax FDA, how many aducanumabs would have gotten through as a result? If you believe the numbers above, and are a QALY-value optimist, and you think a lax FDA would have let through even two more aducanumab-level drugs, you've just broken even. Under the same assumption, but more such drugs getting through, you've effectively killed more people than you've saved by pushing the FDA lever to "lax".
The more I look at these numbers, the less I agree with Scott's overall position. It really, _really_ seems to be unfair to summarize the situation as "the FDA is incompetent". The real problem is, regardless of the competence of the FDA, their decisions automatically force people to spend money on anything they find in favor. _That's_ the actual problem; take _that_ away and the FDA arguably does no damage. But forcing the FDA to be laxer in the absence of solving the larger problem seems like a _really_ bad idea under the circumstances.
I've forgotten a lot of the history of HMOs, but someone wanting to make an effort post could get a good start by looking up how HMOs reacted to high-dose chemotherapy.
> The HMO bean counters stubbornly refused to look beyond the black letter of their policy rules. The HMO wanted Dr. Billinsley, who was trained and experienced as a cardiac surgeon -- not a thoracic surgeon trained to perform a radical pleurectomy with interoperative chemotherapy or radiation. Obviously, the Stewarts did not need this kind of stress. Now, in addition to dealing with an "incurable" tumor, the Stewarts had to deal with an inflexible, cold and lethargic HMO bureaucracy.
For the case that broke the dam, look to "Overtreated" by Brownlee, starting around page 120:
Setting the stage with emotional appeals:
> "Bill [Peters] took the microphone and said, 'I could give you a lot of statistics about the effectiveness of this treatment protocol, but I think it would be easier to do this with a simple demonstration.' Then he asked the seventy or so breast cancer patients who had accompanied him to the lunch to stand up." ... "'As you look at a woman across the table from you, ask yourself, is the price of this woman's life worth the price of a luxury car?' "
Didn't work:
> ... the publication of clinical trials that would show the treatment wasn't a cure for breast cancer. Even when the evidence was in and it was finally clear that high-dose chemotherapy was no better than standard treatment, some doctors continued to argue that it could benefit some women.
Insurance was forced to pay anyway:
> How is it that a dangerous, highly experimental treatment came to be given to thousands of women before it had been adequately tested? The story ... involves the courts, insurers, hospital administrators, and proselytizing doctors like Bill Peters, as well as the desperate women who were led to believe, by their doctors and the press, that going through the ordeal of a transplant would save them from cancer.
...
> By the time Alice Philipson's first breast cancer patient came to her law office in Berkeley California in 1991, she had learned a thing or two about building a case against health insurers who refused to pay for medical treatments. ... Her new client's name was Ricki ... [who had] an advanced case of breast cancer. When Ricki was first diagnosed three years earlier, she underwent a double mastectomy and chemotherapy. Now the cancer was back, and Ricki was looking to high-dose chemotherapy and a bone marrow transplant as her only hope. But her insurer, a Blue Cross affiliate, did not want to pay for it.
> The company's reluctance was not surprising. The bill for high-dose chemotherapy began at $150,000 and could hit $500,000 if the patient suffered complications. ... Privately, insurers worried that if they agreed to pay for one expensive, experimental procedure, there was no limit to the questionable therapies desperate patients might demand.
...
> [Philipson] bombarded the company with scientific papers and letters from cancer experts saying the procedure was standard practice. ... In the end, the company agreed to pay for Ricki's transplant. Her case was one of the first ever that successfully forced an insurer to pay for a bone marrow transplant for breast cancer. It would not be the last. As Philipson's name circulated among breast cancer support groups, more women came to her, hoping to get their transplants covered by their insurers. Over the next two years, she won three more cases. Then, in 1993, Philipson assisted in a landmark trial that threw open the legal floodgates and forced insurers to begin paying for increasing number of transplants across the country. That year ... Mark Hiepler suyed Health Net on behalf of his sister, Nelene Fox, who has died from her breast cancer while trying to persuade the insurance company to cover a transplant. ... He soon discovered the company doctor who made the decision got a bonus at the end of the year if Health Net saved money. "It sounded terrible" Philipson recalls. ... The [insurer's] defense attorney says 'It's no different from John Deere.' ... The jury comes back and says 'The hell it isn't different.'" ... The jury awarded the Fox family $89 million in damages.
> Ricki didn't live to see the end of the Health Net case. She had survived the transplant, and her cancer had stayed away ... [I]n 1993, it came back more aggressively than ever. She was dead in a matter of weeks. The cure had failed. Philipson was saddened ... but she was too busy with other breast cancer cases to focus on it. Within a year of the Health Net judgment, record numbers of women were filing suit against their insurers. The strategy was always the same. The plaintiffs argued that the insurer was refusing to pay for a treatment was accepted medical practice. Transplant doctors served as expert witnesses, testifying to that effect. Peters himself often served in that capacity, telling the courts, ... "[T]he regiment prescribed is neither experimental nor investigational, as all elements of the treatment as well established and the treatment was over the years proven itself to be an effective cancer therapy."
Much later:
> And the trouble was, high-dose chemotherapy wasn't a cure, even for breast cancer. Alice Philipson knew it by 1995. She had not thought to question the treatment when Ricki died. Medicine, she knew, was an art, and no cure worked every time. But then another former client died, and another. One day, Philipson realized that every woman she knew who had received a transplant was dead. "Nobody got cured," she says. ... "It was a cure that didn't work."
If this thread is still going, does the FDA have “tiers” of how likely a drug is to have some terrible, thalidomide or Vioxx drawback? It seems like monoclonal antibodies should be in “this is extremely likely to be safe” bin. We all make lots of antibodies, chances are, a new monoclonal antibody won’t cause birth defects. Seems speeding their approval would be a net plus.
Is there a word for drugs that are things you already produce, like steroid hormones or dimethyl tryptamine? Seems like these would have fairly predictable effects. Though evolutionary logic implies that they are optimized, they are optimized for people with very different lives. There could be low hanging fruit here. The harms are more or less predictable, and the FDA should approve easily, but not as as easily as yet another Amat.
Other drugs are variations on a theme of some existing drug with well understood pharmakinetics and downsides, THE #MeToo drugs, These seem less certain than the top two classes, though only a methyl group separates terrible methanol from wonderful ethanol.
Then there are things like “this is a variant of a drug with terrible side effects, but great function. We’ve tweaked it to try to make it safer. These are obviously riskier, and the FDA should be really cautious.
As a real example, this year’s flu vaccine antigens will not be put through a decade of testing. They are minor variants of things that have been extensively tested, interacting with well understood (lol, but kinda) physiology.
If the FDA can allow new flu antigens without a Brazilian dollars in testing, maybe there are other pharmaceuticals where this applies? They also have a readily-approved category for medical devices that are “substantially similar” or some such, I forget the wording, to things that are already approved.
Lastly, there are other first world and upper-tier developed-not-wealthy nations. Presumably they differ somewhat in what is approved and when. How does the FDA compare to Euro-FDA, Moscow-FDA, etc? Are drugs usually approved overseas first? How often? Of those that are approved somewhere else, but either approved here later or never, how often do the furriners have to pull the drug because of lack of efficacy or safety?
If other modern countries approve quickly, cheaply, and with few hiccups, that would be strong evidence that the FDA process is severely flawed. If other countries just follow America’s lead, then that does not help much.
"This is an interesting point. We sometimes see politicians “cutting in line” and managing to get advanced drugs that the FDA hasn’t yet made available to the general public. We usually interpret this as unfair privilege, and I think that’s a completely accurate interpretation. But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us."
This seemed pretty obvious to me. I'm surprised this idea didn't come more easily to some people. Perhaps they are more easily influenced by the news slant
This is why it was a good for politicians (Trump etc) to receive the good stuff. It might even speed the equivalent of FDA approval. We aren't yet at the stage where only politicians would benefit, though we are getting there
Some people are more capable, faster, intuitive, and natural with certain modes of thought, and, vice versa, others may have talent in other domains.
I'm glad you're making an effort to be fair and correct
Does the USA Health system have an equivalent of the UK's NICE ? If only for the government-funded parts of the system?
The National Institute for Co-ordinated Experiments? I hope not. ;)
Huzzah for the Lewis reference.
That has been proposed at various points but people called them death panels.
Thank God no. The solution to a clumsy but powerful bureaucracy is not to create an entirely new level of even more powerful bureaucracy and hope that, against all experience, it will be sleek, intelligent, and efficient.
There's a child's rhyme about this, about an old lady who swallowed a spider to catch a fly.
Whilst I agree in principle here, what is being advocated in effect is having a government-funded scheme with no mechanism for controlling costs. Or to put it another way, a way for the cartel of approved manufacturers to take money from tax payers. You need to have a check on that process even if it is additional bureaucracy as the costs are going to be less. Ideally though I guess the check should be democratic rather than bureaucratic.
Yes. The only effective restraint on government is active and informed voters. Asking government to keep an eye on government is deeply silly, and never works. I will say a kind word for federalism, though -- having roughly equipotent goverments keeping an eye on each other has some real value, or used to, back when federalism was taken more seriously. It also gives citizens the ability to vote with their feet.
I'm British. I think we're largely happy with NICE, both the population in general and the doctors. They are slow to react, but the general principle of 'government only pays for cost-effective treatment and cost-effectiveness means price less than "£X/QALY" seems pretty sound.
If you guys had the FDA to say "safe enough to be used", and a NICE equivalent to say "useful enough to pay for centrally", your above problem would be solved.
Glad you like your system. I wouldn't have it if you paid me. The only person I want to decide whether a given drug is useful to me or not is me, and I'm quite happy to pay for it, or buy insurance in advance to cover its cost, in order to have that right. I'm gobsmacked the Brits, historically pretty stout defenders of their personal liberty, are willing to turn over that much authority to Parlaiment. Why not have them arrange your marriages while you're at it, eh?
What system does your insurance company use to decide something is "worth it"? Do they do all their own $/QALY calculations each day? Can you compare one insurance company's "worth it" against another's "worth it" to decide which is more in line with your values?
NICE only determines what standard NHS care will cover.
"I'm quite happy to pay for it, or buy insurance in advance to cover its cost, in order to have that right" would absolutely still be an option.
People often seem to act like the existence of the NHS somehow means that private care and private health insurance don't exist over here, and it simply isn't true (I think Canada is closer to the strawman I keep seeing people attack?) - a more accurate model would be to consider the NHS as Universal Basic Insurance.
Briefly thought Dave Barry was posting on ACX. :(
Dansuul says:
"a scientific organization (which the FDA is)"
Is that the primary goal, though? To do "Science"? Seems to me like it has a relatively large "cost-benefit analysis" role as well, which, as the voting citizens of the country that created the FDA, and who will bear both the costs and benefits of those analyses, I'm not sure it's the "man on the street" unjustly intruding on the FDA's "scientific" jurisdiction. It seems more like the FDA unjustly (and without the relevant expertise) intruding on citizens' implicit demand that their public health agencies serve their best (again, implicit in "best" is some kind of cost/benefit analysis) interests.
Scientific cost benefit analysis is still science, which is a very broad and inclusive term.
Not unless it includes some experiment, and I'm hard-pressed to see what that experiment would be. As an actual real-life scientist, I'm routinely annoyed to see almost anything that involves numerical calculation and/or logic called "science" on the grounds that this is what "science" is. That's mistaking the tools for the task. It's as absurd as saying algebra can be classified as a form of poetry, like Shakespeare, because it (algebra) involves the meaningful arrangement of letters of the English alphabet.
Nothing is a science unless it begins with discovery through experiment. Anything else might reasonably be called philosophy, even natural philosophy, but if there isn't an experiment at the base, it's not science. And for that matter, the use of mathematics is not required: if I hypothesize that it rains every other Tuesday, and conduct the experiment of going outside and returning to drip, or not, on the calendar, I am doing science and my results -- the calendar with rain spots on certain days -- are scientific results, despite the utter absence of math.
</rant>
I think it’s complicated though. The FDA regulates the trials necessary for scientific investigation of drugs, and in that sense very much participates in the process of drug discovery. They also require complex opinions and decision making from subject matter experts in the scientific fields. So they’re not really “doing science” in the creative sense, but they employ scientists to direct and regulate the process of science (of evaluating and using drugs and other medical interventions). Science in genera is a slippery word and idea anyway
OP also said they lack “the relevant expertise” and I don’t think that’s true - more that they’re misusing it
I agree with your below comment - they still require (or should) all the scientific expertise that the real scientists need to do their work
Sure, they employ scientists, because they need to understand the science, but understanding the science isn't doing science, any more than appreciating poetry is the same as writing the stuff.
I don't think "science" is inherently a slippery word, but a great number of people and interests have made it so because they want to borrow some of the gloss that empirical science in narrow fields has built up for itself over the last few centuries. It's a common form of linguistic corruption.
Perhaps in some general sense, but in the context of this comment about the FDA, it is not the "science" that they are doing - and it is being explicitly contrasted against the "man on the street's" non-scientific "cost/benefit analysis" approach. "Science" defined so broadly that it includes the explicitly political (in a good way), cost/benefit analysis of "gee, maybe we should accelerate approval of a vaccine, given that thousands are dying each day" is meaningless - and worse, if it is "science," then it means that the FDA is not a scientific organization because it's obvious they aren't doing this - by their own admission.
The FDA is not even remotely a scientific organization. It's a regulatory standards-setting body, somewhat akin to NIST or the standards-setting part of the NHTSA or FAA (i.e. without the investigations arm). They are supposed to assess the evidence given to them about new drug efficacy and side-effects, and decide whether to approve or not the proposed use of the drug. Not only do they not do original science, they are not even like a scientific management committee, because they don't propose new areas of research, they don't favor or disfavor this or that line of research, or this or that research spending priority -- they just look at the applications laid before them and make a judgment on it.
I guess you can call them "scientific" in the sense that theyr'e supposed to (1) understand the science they're called upon to judge, so they need to have a background understanding of science, and (2) they are supposed to make their decisions based on a rational assessment of the measured effects -- and not on political, economic, or philosophical grounds.
This is actually not true. The FDA does have a few smallish groups that engage in actual scientific research, often in collaboration with biopharmaceuticals companies. These groups are kept separate from the regulatory function, but I imagine they likely still interact with the regulators. The FDA also hosts seminars delivered by biopharma experts on emerging technologies. Generally, I've found the FDA folks to be quite scientifically knowledgeable, at least within their own specialty. The FDA inspectors are particularly good; they are both feared and respected in the sense that they are quite good at finding legitimate deficiencies.
My point here, the problems at the FDA don't stem from incompetence or poor scientific knowledge. They stem from bad incentives and a flawed system.
Source: I am a co-author on a paper generated from an FDA/biopharma collaboration, and have been involved with plenty of FDA audits.
I think perhaps what you want to say is "that's true in a general way, but there are interesting exceptions -- they have some small groups that actually participate in research. Plus they sponsor seminars and such." That's a very valuable addition, and I thank you for adding it. But I still think a strong general statement needs to be made, because I suspect there are plenty of regular folks who actually think the FDA directs research, and the fact that it doesn't is important.
Thanks for linking to my piece. An interesting problem you bring up in the Axsome story is effectively a public goods provisioning problem: how do we incentivize good trials for generic drugs for repurposing?
Good trials for generic drugs provide the public good of accurate information on a clinical question, and then anyone can use that information.
Some ideas to make this better, ignoring novel drugs to simplify:
1. making clinical trials cheaper per patient. I don't know enough about this to have specific proposals, but it is something I'm eventually going to learn more about. Tentatively: something involving substantial reductions in the power of IRB's and using tech to make multi-site trials easier.
2. prizes for researchers who successfully discover a new use for a generic drug and prove it with a trial. This exists informally, in that a highly cited research trial paper will give you career capital and speaking invites.
3. Something involved prediction markets and clinical trial outcomes? Maybe people who are good predictors of successful drug repurposing should get $$ to choose more drug repurposing candidates?
I like your suggestions, especially the prizes.
I've always liked the idea (using the tiered/unbundled FDA Scott describes) + "human challenge trials", that after we do normal trials to establish initial safety (i.e. you don't die when you take it) then we open it up to a "soft approval" where you can legally take it, but you have to sign a really big waiver saying "I KNOW THIS ISN'T FDA APPROVED AND I WON'T SUE" and also "I PROMISE TO BE A PARTICIPANT IN THE ONGOING TRIALS FOR EFFICACY" and then also pay people enough (maybe make Prestigious Advancer of Science Through Clinical Trials a viable career option) to participate.
For 3, part of the problem is that one can’t really make as much money off of generics? Maybe a smaller but significant monetary reward for the company/individuals that pushed through the trial (like 2), maybe per drug prescription, as that more directly replicated the incentive for new drugs and provides the money right to the people who develop them.
I’m not sure the scale works there, you can’t really generate the same amount of money that a very expensive new drug candidate that isn’t genetic would sell, so it’s still very lopsided. I think 1) is the best option, but could mean many different things - it’d be really interesting if a group of doctors could run a multi center trial “themselves” without needing significant funding or backing.
Or you could set up a publix, taxpayer-funded body to do it. Market mechanisms are good at solving a lot of problems but not everything is a nail.
A public body to ... study repurposed generics? It seems like the sort of thing where the problem space (all diseases) times the solution space (all existing drugs) times the space of domain experts (for specific techniques and diseases and drugs and whatever) times people who have the disease and are willing to take it times the people who can administer and run the trial ... is very large, and would be better with some mechanism where more people and companies can participate if they think they have something good. So you’d want big biotechs and small biotechs and individual doctors or researchers and universities and whatever to all be able to do (I don’t know how you both make it compensated and doable at the high standard of a clinical trial but it’s worth thinking about) the sort of repurposing research here. Or maybe federal funding for research in it like public research, paying people to do studies with rewards if they succeed ... but that’s pretty close to wills proposal anyway.
Terrible idea: allow accelerated / less effort repurposing based trials of compounds that passed safety but not efficacy checks in past studies and then were not approved for efficacy
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long
I doubt that when people support restrictions on drugs and stuff, they are thinking of *them* not being allowed to get something they want. They think of other irresponsible or stupid people. I can imagine supporting restrictions on an unsafe drug yet feeling it's an unfair privilege that someone specific gets to choose to circumvent them.
What they are imagining is taking an approved drug in good faith (because it was approved by the FDA and prescribed by a physician) and then having it turn out horribly -- the drug does something terrible that wasn't known ahead of time through carelessness, haste, political/economic influence, et cetera.
You are seeing that play out in real time in the reluctance some people have to get a COVID vaccine because of the speed with which it was approved. There are people who think there may be something screwy about the vaccine, like it has an 80% chance of giving you brain cancer 5 years after you take it, and nobody knows about it yet because 5 years haven't passed since it was invented.
And that is not a completely brain-dead attitude, either. We have plenty of examples of things that were at one time considered reasonable therapies or at least not harmful that proved to have disastrous long-term effects, e.g. smoking was once considered healthy, since it takes decades to develop lung cancer from it and it took people a good long time to realize that.
This attitude about vaccine harms down the line has made me wonder if a poison yet exist that could have serious side effects years down the line from one or two doses.
A sub immediately lethal dose of polonium would do that. Not much exists like that unrelated to oncogenesis (I mean, with critical development periods in pregnancy being one obvious exception).
Improperly prepared foodstuffs. Cassava is the main one here https://en.wikipedia.org/wiki/Cassava#Food_use but there are other food sources, such as nardoo, which if you don't prepare it properly will slowly to rapidly kill you: https://en.wikipedia.org/wiki/Marsilea_drummondii
But I don't think eating them once or twice would hurt you much.
Cassava contains cyanide. It does not kill you slowly. Cyanide is well excreted by the body. It has even been used at subtoxic doses recreationally(not recommended). Even long term continuous exposure from the environment does not kill you. It can however cause some health issues.
In fact, the process of cooking cassava (and several bean varieties) with the pot lid removed to expel cyanide as well, as washing used on nardoo, acorns and such, can never be 100% effective. That alone should indicate to you that there is not a long term buildup of these toxins.
Well, sure, e.g. the early pioneers in the discovery of nuclear radiation had no idea it could give you cancer decades later[1]. Lead is another poison the harm from which can manifest years to decades later.
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[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520298/
"Poison" is a vague term, but prion diseases are an example of this sort of behavior. Exposure to a single small dose of prions causes no immediate effect, but severe to lethal consequences years later. It's obviously not a thing that happens frequently in drug or vaccine development, but I don't think we know enough about prions to absolutely rule it out.
_Great_ example! They're kind of like a biological equivalent of ice nine from Cat's Cradle.
If a doctor prescribes me a drug that I have to pay an arm and a leg for, I'd like to know it works, or at least that it wouldn't kill me. I don't have the time or expertise to hunt down and read scientific papers. The only way I'd know it works to a reasonable confidence and in reasonable time is if a government agency known for high standards approved it.
It doesn't seem like that would require the substances that haven't gotten that seal of approval to be illegal, though?
To be fair, I think they also think about vulnerable populations. If you release a new med, the side effects and negative interactions that end up killing people, will mostly kill people in vulnerable populations - the elderly, people on 10 different meds already, people with compromised health to begin with, etc.
If you're healthy already, you can be correct in thinking that the cost-benefit analysis for you is positive, but that it would be negative for enough people that making it universally available might be negative on the whole.
(I may have expressed myself very badly given the replies I got)
Even supposing Aducanumab doesn't treat Alzheimer's, if it truly is an anti-amyloid, it should have some beneficial effect. As you wrote earlier, doctors should be allowed to write prescriptions for it (since it seems safe), but insurance shouldn't have to pay for it for AD (since it doesn't seem effective against AD). Under our current system, a drug that might be useful against disease X will be banned forever if it's first tested against disease Y.
"Under our current system, a drug that might be useful against disease X will be banned forever if it's first tested against disease Y."
That's not true at all.
https://ashpublications.org/blood/article/111/8/3968/24563/Thalidomide-for-treatment-of-multiple-myeloma-10
It's mostly true, because it's what usually happens.
But the last ten anti amyloid drugs have not had and beneficial effects, and there’s a long history of misunderstandings or complications in mechanisms of drugs that “absolutely should be beneficial” not being
Technically, that is the situation now. Biogen can legally produce and market it as a remedy for Alzheimer's, and doctors can prescribe it for that condition (or anything else that crosses their minds), but insurance companies are generally under no obligation to pay for it. Nor does Medicare, until the CMS says it must.
What people point out, however, is that the political and market pressure to pay for it will be immense since the FDA approved it (and physicians and families are shortly to be subject to an onslaught of professionally-photographed heartstring-tugging marketing material from Biogen). Furthermore, the funding priorities of Big Pharma may shift, in the sense that the suits are always looking for an easier way to make the next $billion, and now that Biogen has paved a certain path, they may think following that path is easier than plowing another $250 million into Research Team X's kooky idea about what *else* might help with Alzheimer's, and so just possibly a far better therapy might be delayed considerably because it gets starved.
I don't have any brilliant solutions to the rat's nest of competing social, scientific, and economic forces here, but I do feel confident that anyone who fiercely argues the FDA is too damn strict and slow, and ought to let people try shit once it's been proved it isn't very dangerous and might or might not help cannot logically also argue that the FDA should never have approved aducanumab on the mere grounds that it hasn't been proved to help beyond any shadow of reasonable doubt. Those positions are logically incoherent.
Right. I should have written, "Under our current system, a drug that might be useful against disease X will probably remain banned forever if it's first tested against disease Y and fails FDA approval."
Maybe. I don't know, this passes my understanding of the field. I imagine it might depend on why it fails -- if it fails in Phase II (safety), yeah. But if it fails in Phase III (efficacy) I can readily see a big pharma company, after investing umpty $millions in the damn molecule, saying "well let's see if it works on anything else..."
That's right. The problem is that Medicare exists. It shouldn't. The FDA shouldn't stand in the way of anything that's safe. 3rd party payment is the problem.
Drugs are stupid expensive for 2 reasons. 1. Ridiculous barriers to entry
2. 3rd party payment, mostly medicare.
Hell, the copays for most doctors visits for people with insurance cost what the doctor's visit used to cost before HMOs and medicare.
What do you know. It turns out medicine wasnt the one area of the economy where throwing away market forces was a good idea.
It's nice to see other people expressing this position. I often feel very lonely here in "perhaps we should try actual free market forces" land.
Proving effectiveness (to FDA's high standards) doesn't become easier without Medicare. A lot of people here are concerned about the FDA making their lives worse (and sometimes blocking doctors from saving lives) by saying they can't even try a drug that might help.
Well...it would be hard to dump Medicare without a population willing to steel itself to old people getting no medical care, because there *will* be people who fail to properly prepare for old age, not to mention a modest number who did prepare but who suffered from bad luck (the insurance company folded, their investments tanked). Realistically, that's not going to happen.
What might work would be to reform Medicare so it only covers some basic level of care, with better care available through private add-on insurance (which already happens to some extent), and also make it an annual grant to seniors, with which which they can buy insurance on the open market, thus encouraging diversity (all the females can skip coverage for prostate cancer) and competition.
>>, if it truly is an anti-amyloid, it should have some beneficial effect.
No. This doesn't follow at all. 10 anti-amyloid therapies have failed before (I document this in the post Scott linked above). This one failed too. There is in fact /strong/ evidence against it working.
There is strong evidence against aducanumab /by itself/ working against a specific population (old people who already have pretty advanced AD, I assume, because that's what I always see in trials of AD drugs) of one specific neurodegenerative disease. There is stronger evidence that any curing or preventing of Alzheimer's, or of several other neurodegenerative diseases. will have to include a cure or prevention for amyloids.
You should read the Biogen trials. They're /very/ early-stage AD patient with MMSE of "24-30". MMSE scores of 24-30 are basically normal: 20-24 is mild dementia; 25-30 is a normal score.
https://investors.biogen.com/static-files/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb
The idea that the problem is trials just aren't targeting early enough AD patients is a common refrain but it isn't supported here.
>>"There is stronger evidence that any curing or preventing of Alzheimer's, or of several other neurodegenerative diseases. will have to include a cure or prevention for amyloids"
No. There is a wealth of animal data purporting to show this, but absolutely no human clinical trials show this. In fact, there is strong human data against it- large well-funded trials that reduce amyloid burden having absolutely no effect on cognition decline.
You're only looking at drug trials. See the comment below by "Aβ Male" for a summary of some of the evidence that amyloids are a problem. They are junk proteins that build up over time and eventually kill neurons. No one in the field questions this AFAIK. Anything that builds up over time and then kills neurons must be combatted, regardless of what drug trials (which are more complicated than establishing a mechanism, and can fail for many reasons unrelated to whether amyloids contribute to AD) show.
No. Empiricism beats pet theories 100% of the time
It certainly does, but bear in mind what you have are starting to have here is a competition between pet theories, viz. clearing amyloid will help, clearing amyloid definitely won't -- because the trial didn't (and can't) enroll enough people for long enough to fully test the hypothesis.
AD generally takes years to decades to manifest, and years to decades to kill. An 18-month trial with a modest number of participants and a particular measurement of results is not enough to rule out any benefit at all. It's quite fair to say the benefit has not been proved. It's also quite fair to say the benefit is not likely, based on what we know so far. But you can't say the benefit has been entirely ruled out on the basis of what we know so far. That's why the approval was difficult. That's why reasonable men can disagree on the best action.
We have empirical evidence that amyloids build up and kill neurons. Clinical trials are just one type of evidence, and they aren't designed to prove what you and Will are trying to use them to prove--in this case, that amyloid build-up isn't part of the mechanism behind aging. They are carefully designed only to evaluate whether a particular drug, administered in a particular manner, to a particular population that has developed a particular stage of a particular disease, will produce an effect with a p-value below a chosen cut-off.
In any case, all clinical trials are so similar in their approach that taking 10 clinical trials is not as powerful evidence as looking at 2 or 3 experiments which are truly independent. There's a large number of possible sources of error which most or all clinical trials are subject to, so all the clinical trials in the world still wouldn't provide two independent pieces of evidence.
Again, “drug targets mechanism correctly but it turns out we were wrong about mechanism, even if not fully wrong, enough that the way the drug targets it doesn’t actually help patients” is a somewhat common failure for drugs. “Amyloid important” and “drug remove amyloid” is possible without “drug good”. Why is the failure of all the past drugs in trials - drugs that successfully removed the protein stuff - and then the apparent failure of this one - enough to approve? Should the other ten antibodies will listed have been approved?
The $100 billion/year estimate from my blog post is a high end, and after writing that post, the FDA took a step back and restricted the indication to only early-stage patients. Still, it has the potential to be extremely costly.
Whenever you write about the FDA I can't help but think of the FAA. Drug companies have no incentive to sell dangerous drugs. Just like Boeing doesn't have an incentive to have planes suddenly plummet to the ground killing 100s. Boeing might not but individual Boeing employees certainly do. And not long after we started relaxing regulation those individual employees started to run amok. I don't see why we wouldn't' see the same issue with reduced regulation of Pfizer that we saw with Boeing.
Can you cite some particular examples of Boeing employees running amok after the regulations relaxed?
Airplanes are the safest form of transportation [1], so it seems weird to me that you're using them as an example of excessively lenient regulation.
[1] https://www.washingtonpost.com/news/wonk/wp/2015/05/14/the-safest-and-deadliest-ways-to-travel/
There are a number of reports of safety issues in Boeing planes, with somewhat frequent mass groundings. I had read it had to do with organizational incentives and structure and culture and the ceo changing, idk how much about that is regulations.
The key issue was Boeing being allowed to certify itself. The theory being it would never let planes fall out of the sky. Just like the banks back in 2006 wouldn’t lend all their money to people with no ability to pay it back. Why would they do something so foolish?
Government bailouts?
“ The FAA delegated to Boeing itself most of the analysis and testing required to certify the MAX as safe to fly. … However, some Boeing ARs complained of heavy pressure from managers to limit safety testing and move quickly through the analyses. One AR who balked at such pressure was removed from the program.”
https://www.seattletimes.com/business/boeing-aerospace/what-led-to-boeings-737-max-crisis-a-qa/
That's a nice little article. Two things jump out at me as significant factors contributing the problem:
(1) The reduction in authority of the actual engineers in favor of the technical managers, at both Boeing and the FAA.
(2) The decision of Boeing when the problem proved difficult ($$$) to fix by redoing the airframe to let the inherently dangerous behavior of the airframe stand, and "fix it in software" by creating a program to compensate.
Because both of these seem like general modern trends, and generally increasing risks. I can understand why both of them arise: engineering gets more and more complicated, and so people demand more people to whom they can talk in non-gobbledegook -- technical managers -- and they award those people more and more power. It works great in terms of nontechnical people being better able to *understand* what is going on, but it definitely increases the probability of Something Bad happening because the simplifications involved in the technical manager's understanding turned out to be *too* simplified.
The temptation to fix hardware problems in software is also easily understood, since software is cheap and fast and hardware is not, and evil combinations of flawed hardware and buggy software that are just right to cause disaster are ipso facto rare.
But still, they both seem like growing problems, and not easily solved, given the necessarily increasing distance between the frontier of science and technology and the technical competence the average citizen/consumer possesses.
>and evil combinations of flawed hardware and buggy software that are just right to cause disaster are ipso facto rare.
Not the first time it's happened; Therac-25 shot people with lethal radiation beams because of exactly this. Also, cars with auto-engaging out-of-lane prevention (which also prevents driving straight when there is reflective water or a not-in-program arrangement of lines on the road; "possessed by demons" indeed) - although I think that one happened after/around-the-same-time-as the MAX catastrophe.
Yes, and I expect it will happen more in the future. For a long time we kept software out of life-and-death situations, because it was so self-evidently risky. But we are much more accustomed to relying on software these days, and I think the pressure is rising to allow it into more serious situations, because of the immense savings in cost. I'm not sure we have the right set of attitudes and practices for that not to have some significant tragic outcomes, at least until we develop better attitudes and practices.
Ugh, yes. I recently had a Tesla Model S try to stuff me into the side of a tractor trailer on the Autobahn in a construction zone because the car got confused about which set of pavement markings was important. And then I had the passenger turn that shit *off* right fucking now.
When I bought my last car I was musing over some of these add-ons, automatic braking, lane-keeping and stuff, and the salesman (no spring chicken himself) looked at me and said "Dude...seriously, you've been driving 45 years, are you really going to trust the car to do your braking or steering for you?" and I realized he was 100% right. Maybe a person can develop new instincts of when to trust the car and when not to, but I'm too old for that crap. I don't even use the back-up camera much, I just turn and look like I always have, although I'm glad it exists to show me whether there's a cat or kid's tricycle right up against the bumper.
I didn't read that article, but isn't the main problem that the software lacked the redundancy it needed for safety (relying on one sensor instead of the usual standard of two sensors)? Combine that with the fact that pilots were unable to turn the system off (if they even knew it existed) and it was a recipe for disaster.
Depends who you ask. If you ask me, the main problem is the airframe was flawed, did dangerous stuff easily, and that they tried to fix it in software *at all*. Other people, who don't mind putting their lives in the hands of a computer program, will agree with you, and say the problem is that the program was not well designed, or integrated with hardware.
As I understand it, there's already a lot of safety-critical software controlling car behavior (remember all those Toyota unintended acceleration events?). I agree that in general that this is concerning because it's harder to achieve reliability in software than hardware. In this particular case, though, it's a huge error to force the nose down based on a single sensor reading, and this would still be true if it were a hardware circuit forcing the nose down. It's *so* obviously a bad idea that I've been hoping to hear a report explaining how the hell this could have happened without multiple key Boeing employees being grossly incompetent. Even without the regulator doing its job, a flaw this obvious shouldn't slip through.
The airframe is stable without MCAS. The system was designed to make the handling more 737NG-like, not to correct any particularly dangerous “flaw”.
The pilots were perfectly able to turn the system off. The penultimate Indonesian 737 MAX crew recognized that the automation was about to kill them, in a very slight variation of a common way for automation to kill people in airplanes, so they hit the kill switch that disabled that whole class of automation and flew the plane safely to its destination using the manual backup system. Which is why you never heard of them, or of countless other flight crews doing the same on many other airplanes most of which were not 737 MAXes.
The next Indonesian 737 MAX crew appear to have been clueless buffoons who should never have been allowed to fly an airliner, who in spite of the note from the last crew saying "PS automation is really flaky, don't trust it until it's checked out", never tried to switch to the manual backup.
The Ethiopian 737 MAX crew, appear to have properly recognized the problem, hit the kill switch, and gone over to manual backup controls. Then tried to selectively reactivate part of the automation, and been screwed over because Boeing changed the way the kill switch worked without documenting it. *That* was the unforgivable sin, IMO.
If the idea is that the automation must never ever ever ever fail, get real. Nobody has a clue how to make airliners cheap enough for non-rich you to afford a ticket, without some degree of automation. And nobody has a clue how to make airliners safe enough for you to tolerate them, without human pilots ready to lobotomize the robots and take control. So you make airplanes with lots of automation, because it's much more efficient when it works, and give the human pilots the tools and training and documentation they need to take over when the automation fails
I mean, the MCAS isn't exactly a normal autopilot. Its entire intent was to prevent pilots from inputting dangerous commands i.e. make an airframe safe that is *dangerous to manually pilot* (at least, without specific training, which Boeing wanted to avoid).
Using automation as a failsafe for an untrusted human pilot means you *can't* rely on the human pilot being a failsafe for the untrusted automation - as such, it should be held to a much higher standard than otherwise.
I believe you, but could you clarify something for me: if the pilot has to be there already to take over for the automation failing, why is it cheaper to automate? Can pilots log more hours when they let the plane fly itself as opposed to going manual the whole way? Or are we able to employ a less talented/educated (cheaper) pilot who only has to be capable in a small handful of "automation failed" scenarios and not in the wide away of "operate a plane normally" scenarios?
In the Indonesian case, wasn’t the aircraft also having numerous faults related to airspeed indicators starting on the takeoff roll (before MCAS kicked in)? Also, I thought the report indicated that the captain didn’t think to turn off the auto-trim, but did at least continually flick the trim switch in the yoke, which would override MCAS for a few seconds at a time. This kept them in the air for several minutes, until he handed control to the copilot - without telling him what he’d been doing to keep the aircraft controlled!
The reason Boeing was incentivized to cut corners with MCAS in the first place is that it would have been tremendously expensive to certify and deploy the MAX if they couldn’t pretend it was just a minor update to the existing 737.
The reason it would have been onerously expensive is because the FAA gives the FDA a real run for its money in making innovation insanely slow and costly.
I'm curious - what corners should the FAA be cutting that they are not presently?
FAA certification of a new aircraft type takes years and hundreds of millions of dollars. Pilots getting a “type rating” in a new aircraft costs the airline low 5 figures each initially, plus must be maintained through ongoing training and currency requirements for each type they fly. Having a mixed type fleet is costly - Southwest flies only 737s precisely for this reason. Type rating don’t really distinguish between “basically the same but for one or two small differences” and “completely different airframes”. A MAX under a new type would be just as different from the 737 NG as an ERJ or an A380.
So Boeing has turned the 737 into basically a ship of Theseus at this point, very little is unchanged since the original 60s design, but Boeing is heavily incentivized to make sure it can stay within the original type certificate, since otherwise they can’t be cost competitive. Airbus does exactly the same thing with the A320.
MCAS is probably not something Boeing would have implemented if the MAX was a clean sheet design (the airplane is basically fine without it, but it doesn’t fly just like an older 737). But the FAA’s onerous certification requirements pushed Boeing into design decisions that were made not for best engineering design, but to maintain apparent commonality.
It seems that the FAA mostly went along with this wink-nudge-its-just-a-737 thing because they fundamentally didn’t believe that treating it as if it was a brand new airplane either, but admitting reality would have forced them to do so, because the only thing that takes more time and money than certifying a new plane is changing any significant FAA rule, no matter how out of sync it is from modern reality.
This is an organization that took >20 years to approve a leaded gasoline replacement for general aviation (an industry where high FAA certification costs mean that basically everyone is flying around with 1950s engine technology)
I think the criticism raised by Charlie (and Kevin Drum, and others) just relies on... an unnatural reading of things? If you think a particular government agency should not exist -- if you think that the function it is supposed to perform is one that should not be performed, and therefore no agency should exist to perform it -- that would to my mind normally be described as you being "against" that government agency, and that is how I would normally someone interpret saying they are "against" a particular agency or that that agency is bad. I don't know why one would read it instead as a comment on the quality of the particular staff? I would normally think of government agencies primarily in terms of their function, not the particular people who happen to be executing that function...
I think Scott would disagree that the FDA shouldn't exist. But some details of the rules it must enforce are problematic.
Sure, but my comment generalizes to the case of "the function it is performing is the wrong function and therefore it should perform a different one". You don't have to intend to abolish the FDA to talk in terms of functions rather than the people tasked with those functions.
> But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us.
I think there's an internally consistent position where the observer doesn't acknowledge that the drugs are being delayed too long, and just objects to the actor breaking the rules. Basically, in this framework whether the treatment works is moot, the objection is just about fairness and/or the morality of rule-following.
(Not supporting this position, in particular; just providing an observation for why most people don't think politicians are heroes when they cut the line, and also the criticism Biden is trying to pre-empt with his statement that he has to wait for FDA approval before taking his booster.)(
I can think of lots of other things we should use politicians for testing with, though. Perhaps as crash test dummies?
Andrew Gelman does a thing where he writes his content and puts them in a queue to post 6 months-ish later. Maybe that's an option foryour less time sensitive pieces.
> "I probably shouldn’t choose an acronym that nobody will understand until I explain it to them"
Is there any other kind?
Sometimes you can understand an acronym even without having it explained (well, at least I can). For example, if you already know "IIRC" ("if I recall correctly"), you can probably understand the sentence "IIUC, photosynthesis converts light energy into chemical energy".
Point. (Though I'm not sure I would have gotten that particular example if you hadn't primed me first.)
But that particular strategy only seems like it would work for stock phrases your audience already expects you to say based on context. If you are trying to promote an idea that is not already widely-talked about, I'm not sure it can help you.
it had take me minute to understand the acronym, and this after the priming, in the wild, i would have no chance at all.
I think he meant 'explain' as in 'explain the joke and how it is supposed to relate to the situation at hand', not just 'say what the acronym stands for.'
The final example about bupropion-dextromethorphan highlights how misguided it is to solely fund clinical trials through the promise of patent-protection. Presumably the government could make a guess at how likely this would be to work, how valuable it would be if it did, and then the government could have people bid on the contract to run a clinical trial.
Does this happen? Does the government, or anyone, fund clinical trials with the condition that anyone can make the drug if it is approved? The Ketamine example fits here too it seems.
Funding agencies and hospitals will occasionally run trials with generic drugs or to figure out specific clinical questions with already approved drugs-- how long should antibiotic X be given? 10 vs 8 days. Etc.
I don't think this happens nearly enough, however.
> a YIMBY analogy by dubbing my position YIMCS (“Yes In My Circulatory System”)
Call it YIMBI: Yes In My Body Innards!
Yes In My BodY! Ok, perhaps overloading the acronym isn't the best plan either.
I'm kind of baffled how you can invoke the "normal knowledge that normal people use" as some kind of accessible source of information when nobody has the first clue how to gather or assess that. Normally among pundits it operationally reduces to "what me and the people I know/read/like think" but that leads straight to the Pauline Kael effect, and some of the unpleasant divisions between "expert opinion" and what vast swathes of regular folks think that we see today on any number of issues.
If nothing else, consider that the "knowledge of normal people" about which we have cared deeply for several centuries is "who should run the country?" and for this purpose we have this vast apparatus of elections, at various levels, terms of various sizes, representation or not, not to mention polling and focus groups and prognostication -- and yet we *still* are routinely surprised by the outcomes, and debate furiously just how genuinely representative they are.
What hope is there of actually discovering what the "knowledge of normal people" actually is on the question of whether Drug X should/should not have been approved, or whether the FDA should be "stricter" or "looser" in general, for various definitions of "strict" or "loose?"
I feel like all you're really saying that's 100% defensible here is that given time, a consensus will emerge, and using the clarity of hindsight we will all be able to say decision Z or T of the FDA was right/wrong or hasty/slow. But noting that hindsight is easier and more accurate than foresight is rather a truism and (barring the invention of time machines) gives no clue on how to improve the situation going forward.
Scott's position is that the consensus often emerges before the FDA makes a decision.
This is not a mechanism that Scott is proposing, it is a standard. If everyone (in the medical community?) already knows that e.g. covid vaccines will be approved for children and the FDA hasn't allowed it yet, then the FDA is moving too slow.
The FDA should be no slower than hindsight.
Yes, well, the gist of what I said is that I have very strong a priori doubts that this is true -- that one can empirically measure a reliable "consensus" (among whom? would be the first question) before the FDA makes a decision.
As a rule, people react to events, they do not work proactively to form an opinion on events that have not yet happened yet. Exempli gratia, I doubt except among those most intimately concerned (patients, physicians, researchers) anyone even tried to form an opinion on whether aducanumab should be approved in advance of the event.
And if the "consensus" which we intend to consult is merely among the small community who are intimately engaged ahead of time, because of assorted intersts, but...er...not the *same* small community that is intimately engaged in FDA approval, this (1) does not meet the definition of some broad-based "general commen-sense person" community, and (2) isn't obviously better than what we already have.
Perhaps I should add that I don't doubt a consensus may emerge in some random community or other -- e.g. "all the people I know" -- but as I said at the top, that is a very distinct thing from a general broad-based consensus, and the former should not be mistaken for the latter.
I think the general situation can be 'incentive hacked' from above in a way that simply pressures the experts in the correct direction
Give everyone at the FDA a 10% raise and then make 20% of their paycheck dependent on their performance in terms of a chosen cost to benefit or cautionary principle standard. Something like "10 people's lives are not saved due to overcaution so that 1 person's life is not lost due to lack of caution"
If the FDA is responding to huge overcaution incentives where nobody notices if they don't approve something and good things do not happen and someone loses their job if they do approve something that goes wrong then the large paycheck incentive may fix that and at least might serve as a red flag that the process has problems
At the same time if the FDA is not internally able to approach the quantified goal they themselves will be the ones waving the red flag and identifying what the obstacles are
Who manages the managers? Who watches the watchmen? This just declares an intent to fix things and says “someone’s job will be to make the correct decisions, somehow? And they’ll be responsible for the actual decisions”. It doesn’t fix either the “what is the actual principles we can teach and carry for what to approve and how and when”, and “how does your incentive system not bend when Eric topol says to not rush the vaccine or your expanded approval system (whether or not it really did, doesn’t matter, just the pressure) kills ten black babies in underprivileged communities.”
It would be straightforward enough to be able to assess whether the performance measurement of the FDA was reasonable. We all know that pausing J&J may have saved a few lives and definitely cost, what, thousands? That one at least is pretty bright and easy
One thing the incentive pressure would likely immediately do is cause the FDA to choose a number of other regulatory agencies like the EU's and provisionally or fully approve everything they do because the likelihood is they are overcautious as well. Suddenly the regulatory problem is reduced to whichever agency is the best, assuming the primary problem is in fact overcaution. (I take this almost for granted given the incentives that are at play but I understand that emotionally there is a constituency for allowing 100 or 1000 lives not to be saved so one does not die from undercaution because for some it does feel more wrong for someone to die as opposed to 100 not being saved. What the FDA might do under pressure from a "ok, but here's how far you can go with that" incentive is open up provisional approval that allows people to use drugs that are not fully approved under their own volition and request that the calculation of their performance on not approving that drug yet be suspended since people have at least been given the choice to take their own risk)
Re: your second response below I'd say 20% of someone's paycheck is enough to become the primary incentive in their work. If it doesn't we should hear about just what the problem is because there will at least be an incentive to complain
> It would be straightforward enough to be able to assess whether the performance measurement of the FDA was reasonable
Not really? That sounds somewhat hard. Let’s say the FDA approved all ten Alzheimer’s antibodies right now, but didn’t mandate insurance prescription. And then let’s say they opened a rolling trial option where up to 10k total patients per drug may pay up to $100 each to participate in a trial for drugs that have passed animal safety checks and human safety model checks, to speed up development and use that data for phase three trials, and then this is used for more monoclonal antibodies and also for early likely to fail 3D printed organ test transplants in terminal patients who will die anyway to speed up testing. Should that be rated as Good or Bad by your agency? Is it obvious? Not really
I don’t like the idea of companies regulatory shopping for which of seven agencies with partial mutual recognition of approval is the most generous or corruptible. In some areas that’s fine, but for this one eh. I’d be happy with re using trials and evidence used for other countries if they pass our standards but I’m pretty sure we already do that
20%+ paychecks are not enough to be a primary incentive if, for instance, you will have your agency power taken away if you do the thing, by public backlash. Might also be thinking more of a corporation and less about the actual structures at play in the FDA - who’s making the decisions? Who’s salary so you increase? The political appointed head? Political appointees of all people will have other incentives, and potentially limited ability to fight the careerists if they even want to.
Also organizational persistence and power and public perception and laws and industry relations probably >>>>> paychecks
I think 'voting is wonky so we can't learn public opinion about anything' is a bad take.
First of all, in our two-party system, the parties autoamatically re-align themselves so that each side is always capturing about 50% of the population, making the decisions close and hard to call all the time, and there are massive incentives on all sides both to pervert the process of finding out what people want and to misinform people about what they should want. This is probably the hardest version of this problem imagineable, because of the unique circumstances surrounding it.
If you wanted to find out if, say, the majority of people believe that rain is cause by pixies crying when they see a clown get hurt, it would not be at all difficult to get this information. You would do a phone survey with a few hundred or thousand respondents, the outcome wouldn't even be close, and the percentages you get would be very close to accurate.
Those are the two extremes of the easiest possible problem vs the hardest possible problem, but I think that most things you might care to ask about are closer to the crying pixie end than to the voting for president end of the spectrum.
I think it *feels like* the population is really divided on most issues and it's hard to ind out what they really think, precisely because we spend all of our time talking about controversial issues that are tied up with politics and active manipulation. But the vast majority of issues you might ask someone about are not controversial in this way, and on those I think it's not that hard to get a public consensus.
I certainly agree on many issues people *can* be assessed for their understanding and viewpoint pretty easily. But not in the slightest with respect to medicine. People feel *way* more strongly and emotionally about personal health than they do even about who is President. You can take the most rabid Trump-really-won fanatic and the die-hard AOC fanboi and all their political differences will vanish like a pricked balloon if the question before them is how to prevent themselves, a spouse, or a child from snuffing it from a brain tumor, and whether Drug X will do that or not, and whether it should be available, cost what it does, et cetera. Health care is *even more* screwed up with passions and illogic than politics.
I find a rather different interpretation of Nestor's shuffle about the FDA on (the ever inerrant) Wikipedia: https://en.wikipedia.org/wiki/John_Nestor ::
""On March 19, 1972, the FDA reassigned Nestor to its Office of Compliance, as part of a reorganization in which Civil Service doctors were replaced as drug approvers by consultants who were often affiliated with commercial companies. Nestor began a grievance proceeding. A review panel determined that senior FDA officials gave "misleading" testimony against Nestor and concluded that Nestor was due an apology and appropriate duties.""
By analogy, consider criminal trials.
The final decision is made by a bunch of men-on-the-street: a jury. We decided that, even though justice system officials know a lot more about crime, it is too difficult to get rid of their inherent biases, so a group of men-on-the-street does better.
If we take this analogy even further, we could have juries for the FDA. The experts can make their arguments, but the decision would ultimately be decided by a group of men-on-the-street. Random people would get called to make decisions that effect the life and death of their fellow citizens.
While I think that this is interesting, I'm not convinced that it is a good idea. The FDA is often too slow to approve good drugs and the jury system is not exactly known for its speed.
Judges make plenty of decisions in criminal cases, and juries are notorious for not understanding and making somewhat mistaken decisions in trials involving detailed and complex technical evidence or issues. (Judges also do that, but the FDA’s experts are subject matter experts)
I don't think the analogy is especially applicable. The role of a jury is a trier-of-fact. That is, their job is to assess the believability of the witnesses both sides put on, and decide who to believe. The *judge* is the one who decides what the law says, i.e. given this pattern of facts on which the jury agrees, what is the crime (if any) that was committed, and what is the appropriate result?
There's a very decent reason to believe that a panel of average strangers are well positioned to collectively decide whether Witness X is telling the truth or lying. It's a generally-distributed skill, for which there is no known education or technology that could do a better job, it's a collective decision, so individual flakiness is averaged out, and the people involved are very detached from the rest of the judicial process, so they are not influenced by considerations of the sentence, of the effect on other defendants or cases, of the nature of the law, et cetera -- all of which can have powerful effects on lawyers, prosecutors, and judges, the experts in the bowels of the system.
There isn't much that's analogous in the FDA's decisions. A major part of what a criminal trial is about is deciding who's lying, and there is (one hopes!) essentially none of that in the FDA's decision process.
Furthermore, the assumption that would seem to underly this, that an *individual* man on the street has a better judgment of the details than an individual FDA apparatchik, seems dubious a priori and anyway isn't part of Scott's proposal -- I believe he's arguing that some vast consensus, the wisdom of the crowds, so to speak, can exceed the good sense of a much smaller number of FDA experts and bureaucrats.
That is, the key change is to make the number of people who influence the decision much, much bigger. (This may also be the assumption underlying the idea of taking guidance from approvals in other countries -- basically, if the EU and UK and Japan all approve a drug faster than the FDA, maybe the wisdom of the crowds is telling us something.)
Honestly, I think juries are in the wrong place. I'd rather put the "committee of men-on-the-street" as one of the houses of parliament (Congress in the US), where they can tear up criminal overreach at the source.
It sounds to me like you're describing Sortition: https://en.wikipedia.org/wiki/Sortition. Examples of Soritition in real life: Taiwan's vTaiwan system (https://www.technologyreview.com/2018/08/21/240284/the-simple-but-ingenious-system-taiwan-uses-to-crowdsource-its-laws/) and Ireland's Citizen's Assembly (https://www.electoral-reform.org.uk/the-irish-abortion-referendum-how-a-citizens-assembly-helped-to-break-years-of-political-deadlock/).
Yes, I am, but putting it in my post seemed like it would require more words.
But many voting age people isn’t informed or smart or strong willed or free of other responsibilities enough to hold all that responsibility - and most of them would agree to some of those - do we should let those chosen nominate someone they know who would serve the position better! Oh wait that’s voting
>But many voting age people isn’t informed or smart or strong willed or free of other responsibilities enough to hold all that responsibility
This applies to politicians as well. (Also to juries, for that matter.)
I was also a bit disappointed in the post and subsequent discussions elsewhere, because the question on what influenced the Aducanumab decision is not really addressed. If the FDA is so risk averse, why authorize this drug and risk reputational damage if it turns out that it doesn't work? Scott kind of gestured at "some decisions will randomly stray from the decision mean in the other direction", but I find this terribly unconvincing, given that the FDA's scientific advisory committee was firm in its rejection. Plus, other bloggers have alleged regulatory capture by big companies, which seems more explanatory.
I feel like a model of how the institution works beside the short and imho simplistic "public perception incentivizes risk aversion" story should be required before condemning an institution so heavily.
I agree. The science is quite clear but exactly how the drug was approved is quite murky: https://www.statnews.com/2021/06/29/biogen-fda-alzheimers-drug-approval-aduhelm-project-onyx/
This brought up a paywall.
> I don’t want to never write posts when I’m angry, because those tend to be the posts people like the most, and I think they get things done in terms of convincing people of important things.
This is a well known phenomenon. Outrage sells. But that doesn't make it good journalism.
IMHO he is ever so slightly distracted by his personal life. I have no proof of this either way except for when people are falling in love their prose may be slightly different. Lingering relentlessly on an idea in order to hash out all the connections might take more effort when the person who might be the love of your life is around. If this is influencing him I think he will figure it out and adjust.
When you say 'outrage sells', I think you're conflating journalism which causes outrage in the reader, and journalism which is written by an outraged journalist.
I think some of the best journalism ever written was almost certainly written by journalists who were outraged by the corruption or cruelty they were investigating. This type of moral outrage is a huge motivator of human beings to work hard and speak passionately on a topic, we should expect it to play a role in situations where people have worked hard and spoke passionately.
I wouldn't want to eliminate it from journalism as I think it would just make journalism even more anodyne and worthless if journalists weren't allowed to talk about things they are outraged by. I think Scott has the right of it when he says to focus on 'edit sober' more in the future, that's all that's needed.
"Then someone finally realized that the jam was caused by a single citizen, one who commuted in the far left lane, driving exactly the speed limit for miles on end."
It distresses me that this was seen as improper behaviour. If the speed limit is too low, raise the speed limit - don't complain about people obeying the law.
Disagree. "Lowest *average* speed you could keep for hours on end" and "lowest speed at which you can find yourself for five minutes without it being a crime" can and should be different things, for the same kind of reason that it is not illegal to make loud noises for five minutes if you have to hammer a particular nail into your kitchen wall one day, but it rightfully is illegal to keep hammering at that wall for hours on end in a way that drives your neighbours mad.
I don't think I disagree with you, but I don't see the relevance.
People usually consider the impropriety to be driving in the far *left* lane. The general assumption is (and in a few states the actual law is) that you should always be driving faster than the traffic in the lane to your right, and most people consider that this is a higher-priority rule than driving the speed limit. After all, there may be excellent reasons for temporarily exceeding the speed limit -- you're an ambulance, say, or the interior of your car catches fire while you're in a tunnel -- that even the police and courts will accept, and it seems either dumb to not realize these exist, or antisocial to insist that you yourself are the best judge of whether they apply in whatever situation you're driving in.
I'm confused by the examples in your final paragraph, but apart from that this explanation sounds reasonable. Thanks.
I suppose the expectation is "if we don't set a limit, some fool will drive 100mph and crash into everyone, so we want everyone to drive no faster than 70mph, and since everyone drives faster than the limit, to get that we have to set it at 55mph".
But I agree, it makes more sense "set the limit at 70mph and if people drive 100mph crack down on that" then "set the limit at 55mph in the expectation that everyone knows it's 'really' 70mph".
In principle, speed limits serve a useful purpose under all circumstances, because they give the driver unfamiliar with the road an indication of the design specs of the road. If you put a speed limit of 55 on the road, it's saying "the engineers who designed this road designed it so you could drive it at 55 and have enough visibility and time to react to people entering from side streets, go around even blind curves safely at that speed" and so forth. Very useful info.
What annoys people is when the speed limit is clearly set far *below* what the road could handle, e.g. American interstates are generally built to be drive at 85 MPH, and yet the speed limit was generally lowered to 55 in the 70s as part of an idiotic virtue-signaling gesture towards "the Energy Crisis." It took decades for this idiocy to be removed from the rulebooks, so that now you can, for example, drive I-90 through empty stretches of Montana at 90, which is perfectly safe. Not surprisingly, decades of a law that served no practical rational purpose, and which existed as a relic of a stupid fever time in national politics, and as a testament to the difficulty of undoing legislation, gave people a broad contempt for the concept.
In some jurisdictions, as I understand it, they set speed limits rationally, in the sense that they simply monitor the actual speed of drivers and set the speed limit at roughly the typical speed, theorizing that people will in general drive at the fastest speed that is reasonably safe, and that if you average over a large number of people you'll get the community consensus of experienced drivers.
The "handbook" answer for "what to set the speed limit to" is "the 85th percentile of traffic speed"
This is, of course, not appropriate for all roads - residential roads in the US are (typically) set to 25 mph because of pedestrian safety, for example. And for over a generation, the US National maximum speed limit could not be more than 55 MPH, because "fuel efficiency."
Incidentally, as a result of a court case, there must (probably) *be* a speed limit. For a number of years, Montana (IIRC) had a speed limit of "reasonably safe under the circumstances." This was struck as void for vagueness, and now they have a Really High Speed Limit on most roads, and on down from there.
I vaguely recall Nebraska (or maybe Montana) for long years during the reign of the double nickel imposing a "fuel conservation fee" of $10 or so, payble on the spot (but no points, no legal case), if you were above 55 but below the historical limit, in order to continue to qualify for Federal highway funding but not be assholes.
First of all, in the US, the left lane is the passing lane. Unless all lanes are completely filled, you are supposed to only enter it briefly to overtake other cars.
Second of all, to go immediately to the ad absurdum, this logic would condemn anyone who refuses to cooperate with a police state, and excuse anyone who commits any atrocity so long as they are 'following orders'. Sometimes laws are bad, people know they are bad, and they're not getting changed any time soon. Of course they still *should* be changed, and feel free to fight for that, but an immoral action doesn't become moral just because a law says to do it.
If you know the right thing to do, do it. Try to get the law to reflect that, of course, but that's an entirely separate consideration.
Your analogy fails, I think, because a too-low speed limit isn't immoral, merely inconvenient. Besides, unless you had specific knowledge that the speed limit on that stretch of road was improperly set, you should have no reason to think that going the speed limit wasn't the right thing to do.
I'm also guessing that in this specific jurisdiction there is no rule about the left lane being for passing only, since if there was, it would undermine the point of the story. Although in retrospect I am starting to wonder how accurate said story actually is.
Is it immoral to lock someone in a small room for 30 minutes without their consent? Is it less immoral to force 500 people to spend an extra 30 minutes stuck in their car on their daily commute?
I understand that we privilege locking someone in a room by calling it 'false imprisonment' or 'kidnapping' or w/e, and assign 'badness' to it beyond the literal harm done by having to sit in the room. But beyond that, I think the harm done is pretty much the same, making it similarly immoral.
Cue discussion of mandatory schooling. :-)
(Would the incremental delay really have been anything like that long?)
If it was around DC on the VA side of the river, there probably wasn't a rule about the left lane being for passing only; they'd have been pulling people over constantly because the lanes are always filled.
At the time, the speed limit was not set by traffic engineering times, but to enact a "nationwide fuel efficiency mandate" (which has slowly and in piecemeal been reversed in the past roughly 30 years, though the Washington Beltway is still 55 MPH speed limit)
Also, then and now, it is in all the jurisdictions the Beltway passes through (as in the vast majority of the US) to occupy the left lane and not be passing. (The specific wording of the "keep right" laws vary from state to state), but it is rarely enforced.
Ah, I found an article in Wikipedia. The National Maximum Speed Law. Important context which I was missing, thanks.
And he was in fact breaking the law by driving in that manner. OK, that thoroughly changes the nature of the story. Any theories on why he wasn't prosecuted?
"Keep right except to pass" laws are almost never enforced; I could make guesses as to why, but that's all they'd be.
Interestingly, Colorado is attempting to do so:
https://www.denverpost.com/2017/11/13/colorado-drivers-should-be-reminded-about-states-left-lane-law/
Note that you can be ticketed for driving in the left lane *even if* you are driving the speed limit, if you are not passing.
Legendarily the parts of the Autobahn where there are no speed limits have *ferocious* enforcement of No passing on the Right / Only Passing On The Left.
When I was much younger I would have, and did, agree with this.
As I got older, and got several times more driving experience, I realized that society depends on informal systems of people working together. Nestor's excuse was "it's easier for me" because he doesn't have to deal with traffic on both sides. This excuse, if applied by everyone, soon forces everyone into the left-hand lane.
I *do* think that speed limit laws should all be changed to be "rational," but Moloch is Moloch, and here we are.
I recommend F.A. Hayek's books "Law Legislation and Liberty" on this topic. Unfortunately I can't remember which of them (mine are in at least three volumes) focuses on the difference between law (what people think should be punished) and legislation (what the state identifies as what should be punished). In the case of a guy driving exactly the speed limit instead of 20 over, the law is definitely being violated to hell and breakfast, while he is following the legislation.
In most places, even cops won't pull you over for going <=10 mph over the speed limit; when I lived around DC that might be a lot closer to 15-20 during heavy traffic. The cops in that case are acting in accordance to the law, which is that going 10 or so over the speed limit is normal and fine, indeed expected.
It is a problem that the idiot legislators don't change the speed limits, but fortunately law tends to lead legislation by quite a bit. Still, following legislation when the law is very different is going to get you social approbation, and well deserved at that.
The Alzheimers drug you're forgetting is memantine, a drug I'm taking right now for my ADHD with great success!
Huh, I'd be curious to hear more about what your experience is like taking it for ADHD!
Oh yes of course! I believe there are around 2 or 3 studies showing memantine is effective both as monotherapy and as an adjunct to stimulants in the treatment of executive function disorders. Anecdotally, it can prevent and maybe even reverse stimulant tolerance. I'm fuzzy on the mechanism here but I understand that this is a well known effect of NMDA antagonists.
So I bought some online, started at 5mg in the morning and titrated up according to FDA guidelines, reaching 10mg BID. I do find that it makes my Adderall stronger. It also helps to quiet the restlessness in my mind, increase motivation (this is the big one for me), and attenuate some of physical side effects of Adderall, such as muscle tension and fast heart rate.
Memantine is also an antagonist at certain acetylcholine receptors, so there is some brain fog when you start, and each time you up the dosage. However, these receptors apparently upregulate quickly, and I indeed found that this side effect disappeared pretty soon.
I've read a lot of reports online from people who tried it for ADHD who said it was a godsend initially and then randomly pooped out on them, so I'm just hoping that doesn't happen to me. I would say I have around 75% confidence that the benefits I experienced weren't placebo.
Thanks, that's incredibly helpful!
Any idea if it works on its own? (I can't get a doctor to prescribe stimulants)
I think it does, but from what I can tell it's the sort of thing that works really well for some people and not at all for others. You'd have to try it to know for sure, but do remember that it can initially have some very unpleasant side effects, though these typically go away within a week or so.
I do have a few other suggestions that will have effects closer to stimulants though, and are available freely without prescription. One is adrafinil, a prodrug of modafinil. Very stimulant-y but even smoother (less jittery) than amphetamine and methylphenidate due to being more selective for dopamine over norepinephrine, I believe.
Also, there is Sabroxy, a plant extract which contains an alkaloid which is a dopamine reuptake inhibitor. I've found this to be similar to low dose Adderall myself.
Lastly, look into bromantane. This is a Russian drug (it's often referred to as an atypical stimulant) which instead of releasing dopamine, increases its synthesis through several different mechanisms. The advantage of this is one is that its effects persist even after the drug itself has completely left your system.
I would suggest doing a little research on these, and if you're interested, you can find the first two on nootropics depot for relatively reasonable prices.
From a consequentialist perspective, why is it better to let ten guilty men go free rather than convicting one innocent rather than having each kind of error be equally likely?
Since most crimes don't lead to convictions, error parity would seem to imply that most convictions would be false, which seems like it should have some negative consequences? I mean, just look at the problems associated with the distrust of the justice system among US blacks.
Is the distrust of the justice system caused by a high rate of innocent people convicted? So that developments like fingerprints and later DNA evidence would have increased trust?
Sorry, I realize I was a bit unclear. To clarify, I think that (1) high levels of innocent convictions would be likely to lead to distrust & (2) distrust would be likely to lead to problems. The distrust among US blacks is only related to (2).
Because the costs of imprisoning an innocent man are greater than the benefits of imprisoning a guilty man.
Rephrase it as 'why is it better to get punched in the arm 10 times rather than getting stabbed in the stomach once? Shouldn't we want an equal number of each?' The problem is that the two outcomes sound symmetrical, but they're not.
What makes it asymmetric?
The guilty person may not reoffend, so there may be no harm saved by letting them go. There is guaranteed harm to imprisoning or otherwise punishing an innocent person.
A lower certainty of punishment increases the amount of additional crimes, not just for that specific offender.
Because the state in punishing the innocent is failing twice: once by failing to punish the guilty party and again by harming the innocent. Since harming the innocent is exactly what a justice system is punishing the guilty for in the first place, yea... that's really bad.
You'd also want to pile on the harms of creating incentives to just punish anyone to close a case when you aren't especially careful.
That sounds like double-counting, since failing to punish the guilty is what's being weighed against punishing the innocent.
No... Punishing the guilty is one state, punishing no one is another state, then punishing an innocent is a third state. Distinct states, with increasing amounts of harm, no less.
Harm to society, not the individuals being punished or not, that is.
Because men are (or used to be) inherently suspicious of the government power to imprison (or kill), and the most important features of your criminal justice system are supposed to persuade the citizenry to trust it -- to let it take care of criminals, instead of justice being meted out by vigilantes, committees on public safety, family feuds, private revenge, et cetera.
A key aspect of trusting the system is believing that if it does something drastic, like imprison a man or kill him, it is 100% reliable that he is guilty. Destroying a man who is innocent causes much higher distrust than failing to adequately punish a man who is guilty -- at least, until you reach Afghanistan levels of lawlessness.
Wouldn't letting 9 out of every 10 guilty men go free be likely to encourage reliance on "vigilantes, committees on public safety, family feuds, private revenge, et cetera"? In many American inner cities an enormous number of murders (much less non-fatal shootings) are never solved, and the associates of the victim rely on "self help" via private revenge instead (thus perpetuating feuds).
We already let 9 out of every 10 burglars go free, and probably 9 out of ever 10 rapists, mostly through never reaching the point where we put them on trial in the first place. This hasn't lead to anarchy, vigilantism, etc, because for one crime already committed is water under the bridge and even the victim will usually prefer getting on with their life to going full John Wick, and people expect that the really dangerous criminals will be caught before they cause too much harm.
But for particularly heinous crimes, it's probably better that if we're not going to convict someone we should make that decision as early and quietly as possible, rather than holding a big perp walk and public trial and *then* saying "Not Guilty".
We do let 9 out of 10 guilty men go, given our innocent till proven guilty system and high burden of proof. https://en.wikipedia.org/wiki/Blackstone%27s_ratio#In_current_scholarship. There are 19,141 homicides in 2020 9,576 arrests a few years before that and 6000 murder convictions (ish) in ... 2006. This study, which I’ve only read the abstract of, says Extrapolating to all cases in our dataset, we estimate a slightly smaller rate of 11.6 percent
reviewed the latest research and found that the wrongful conviction rate in capital cases is about 4% according to the best available study to date. This study was published by Samuel Gross and colleagues in 2014. A 2018 study by Charles Loeffler and colleagues reported an overall wrongful conviction rate of about 6% in a general state prison population, with considerable conviction-specific variability (from less than 1% to over 10%). This study provides some support for the previous estimate and reinforces the need for more research focusing on specific crimes and circumstances of conviction. https://innocenceproject.org/research-resources/
https://link.springer.com/article/10.1007/s10940-018-9381-1?wt_mc=Internal.Event.1.SEM.ArticleAuthorOnlineFirst
Claims a 40% offender self reported false conviction rate for rape (and 20% for murder). That’s ... quite high.
Anyway for murder, with 5% wrongful conviction rate and 75% ish of murderers getting away with it, that’s 4/.05 = 80 guilty men going free for one innocent man being convicted. With 20% and 75%, that’s 20 guilty men free for one innocent man being convicted. So our current system is significantly worse than that, and I’m pretty sure that low commission-1 * conviction rate is true in all areas. It’s also been like this for the entirety of American history, the vast majority of crimes have always not been prosecuted.
To answer your question, no. Such a ratio is common to, as far as I know, every country, - and plenty have less vigilante violence than the US cities do, as do parts of the US. The US has a much lower clearance rate than most countries, partly balanced out by
Is that ratio really found in Japan?
> Japan maintains near-perfect homicide clearance rates (around 95%, compared with roughly 60% in the United States). This study explored possible explanations for higher homicide clearance rates in Japan than in the United States. Using recent (2000 to 2004) official summary statistics, this study found that Japanese homicides contain a higher proportion of “easy-to-clear” cases, including those with nonfirearm weapons, family member offenders, and child (and not teenager or young adult) victims, than do American homicides. Also the Japanese categorization of homicides in official statistics includes cases favorable to clearance (attempted homicide) and excludes cases unfavorable to clearance (robbery-homicide). These findings suggest caution in attributing Japan's higher homicide clearance rates exclusively to police effectiveness or citizen–police cooperation. Suggestions for future multivariate research are also discussed.
and
To start, critics of the system will say that defendants have no chance of being found innocent if accused of a crime in Japan. I would argue that the infamous 99.3 percent conviction rate is misleading. The Japanese conviction rate must be examined in the context of Japan’s judicial system as a whole. Japan does have an unusually high conviction rate, but the presumption of innocence is maintained throughout trial and judgment. The high conviction rate is largely due to the practice of Japanese prosecutors, who only take on cases after careful examination and when they believe there is enough evidence for conviction. According to 2018 data from the Japanese Ministry of Justice, only 37 percent of the arrest cases were actually taken on by prosecutors. The high conviction rate, therefore, demonstrates the efficiency of the system.
> In Japan, the figure is 700 per year per prosecutor. In the U.S., a rough estimate is that 42% of arrests in felony cases result in prosecution - while in Japan, the figure is only 17.5%.
> . In Japan, 1,800 people were arrested for 1,300 murders, but prosecutors tried only 43%.
Assuming similar wrongful conviction rates, yes, as 60% of murders have suspects not tried, so that’s 60% go free, 5%-10% wrongfully convicted means the ratio (for murders!) is 5-10x innocent free vs guilty convicted for wrong reasons.
> But the opposite is true. In fact, the data indicates that Japanese prosecutors bring charges only when the evidence is overwhelming, and the likelihood of conviction is near absolute, which gives a greater incentive for the accused to confess and aim for a lighter sentence, which, in turn, results in a high rate for confession.
The Japanese criminal justice system, despite retaining the death penalty, is relatively lenient in sentencing by the standard of the United States. Outside capital cases, many of those sentenced to life sentences are paroled within 15 years. Those convicted of less heinous murder and manslaughter are likely to serve less than 10 years. Those convicted of rape will often serve less than two to five years. It is even possible for someone convicted of murder to serve a suspended sentence if the defense successfully argues for mitigating circumstances.
So yes, due to the difficulty of proving crimes and the asymmetry between crime and wrongful punishment, most crimes go unpunished.
Er it’s actually 5-10% of the 40% so it’s a factor of 10-20 but these are fermi estimate level guesses anyway
Sure would. But try it the other way around: what would the reaction be if 1 out of every 10 men convicted were actually innocent? At least as angry and outraged as in your scenario. So there we have the imbalance: you get outrage if 1 out of every 10 convicted is actually innocent, and also if 9 out of every 10 that is actually guilty goes free. Whether the numbers are 10% and 90%, respectively, should be some other numbers is a matter of detail -- the important fact is they're not 50/50, people are not equally indifferent to the innocent being punished as to the guilty escaping punishment.
I think the reaction would not be as much reliance on "self help" private feuds. It's much harder to feud with the government, and 1 out of 10 is smaller than 9 out of 10.
First off I don't think the saying is about how many of the guilty are convicted vs not convicted, but rather how many guilty go free for every innocent person convicted.
Second, I'd say the question is whether to imprisonment more or less than one innocent man for every 10 guilty man. The system is not a knob you can turn until you are imprisoning precisely 1 innocent per 10 guilty; worse than that, it is not even possible to find out how many innocent men you are convicting. Plus, there are local biases in the system in the form of corrupt officials and sometimes biased juries, even if the law is the same everywhere. Plus, the system's punishments are often out of proportion to the crime, e.g. with people being punished after serving their time by employer discrimination and by questions on various forms like "have you ever been convicted of a crime". In this context, yeah, I'm happier letting a bunch of the guilty to avoid punishing the innocent.
If you permit the innocent to be jailed, you've now made it even easier to weaponize the justice system against political opponents and the powerless. Now you wouldn't even have to go through all the effort of convincing people to criminalize something, you can just fabricate charges and bribe people to jail your target. What's the consequentialist calculation when the people feels there's no justice in society? Hasn't worked out very well in the past...
What in the past are you referring to?
I've spent the last month and a half buried in the Alzheimer's Disease literature due to a likely case in a family member (and ironically, for this reason I must apologize in advance that I won't have time to engage in a detailed back and forth here). I think the evidence for both the amyloid cascade hypothesis and the efficacy of aducanumab is much stronger than is being characterized by most comments here.
It is natural to ask: "sure, we see amyloid-β plaques with Alzheimer's Disease, but could there be a confounder, rather than amyloid-β 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 γ-secretase involved in cleaving APP to make amyloid-β) 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-β production, or to increase production of the specific peptide (amyloid-β 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-β, 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 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. [2]
B) With respect to aducanumab [3], 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.
Furthermore, the post-hoc analysis, while always to be taken with a large serving of salt, was not done arbitrarily. Rather, they looked specifically at the subpopulations which received higher dosages, an a priori plausible sub-population within which to expect higher efficacy.
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 [4]. A more up-to-date and comprehensive review paper is [5].
[1] Haass et al (2012). Trafficking and proteolytic processing of APP
[2] Mintun et al (2021). Donanemab in Early Alzheimer’s Disease
[3] Cohen et al (2019). EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease
[4] Selkoe and Hardy (2016) The amyloid hypothesis of Alzheimer's disease at 25 years
[5] Long and Holtzman (2019) Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Very nice writeup, thanks.
"The one part of this I want to ask about is the “aren’t really any [other] Alzheimers drugs”. There’s galantamine, rivastigmine, donepezil, and maybe some others I’m forgetting. These don’t work very well (or maybe at all). But aducanumab also doesn’t work very well or maybe at all, so why is everyone treating it as so unprecedented?"
Those are cholinesterase inhibitors (NMDA-receptor blockers like memantine are also used against Alzheimer's). The effect on cognition for cholinesterase inhibitors is not very good, NNT around 12, though still better than aducanumab, even if you take biogen's data at face value. However, cholinesterase inhibitors and NMDA-receptor blockers do not treat the underlying disease process of Alzheimer's disease. The hope with anti-amyloid drugs like aducanumab that they would actually be disease-modifying.
> That’s fair. I’ve seen some studies by economists saying that “defensive medicine” and fear of malpractice lawsuits doesn’t seem to raise costs too much in the US - but every doctor I know (including myself) feels like they do.
The studies I have seen were doing some intra-US comparison (e.g., VA vs. non-VA bc VA doctors cannot be as easily sued; or the impact of changes to the rules in Texas) and they do find some limited effects. However, none of these studies have a true counter-factual. VA doctors may themselves be more protected from lawsuits, but they are still in an environment where their colleagues from other institutions have instituted all sorts of "best practices," which they are still socially pressured into performing (I assume non-mormons end up drinking less than they would in New York if they move to Utah; which is still because of the LDS church).
So, the studies falsify the notion that the problem is doctors performing an explicit cost-risk legal analysis and then deciding "defensive medicine" is worth it. They do not falsify a fuzzier idea that medical norms are very heavily influenced by the legal environment, but in a way that responds slowly to changes of incentives and does not respect institutional boundaries. Of course, this hypothesis has the benefit of being hard to falsify, but "long-established legal norms lead to a cultural framework of behaviour that persists when those norms are removed" is a very common pattern in history.
Total non-expert here - isn't there a case that amyloid plaques are a cause and/or symptom of aging, and so drugs that remove them could increase lifespan, even if they don't help with alzheimer's?
About politicians either being privileged by the ability of getting the drugs in advance or heroes for testing them, I think there is a way of making the distinction: how do they think about it themselves? I suspect none of them consider it taking a heroic risk, and therefore that should be our point of view too.
>But the cost-benefit analysis is still heavily in favor of the drug, as it is very safe, molecularly effective, and with no alternatives, in a very widespread and destructive disease. The only cost being some people paying money for a drug that won't help them
I think it's worth pointing out that it's an artifact of our local economic system (maybe not capitalism generally, but the specific model of capitalism plus regulations plus government payments plus etc that governs our health system) that creating a pill that probably costs less than a dollar to manufacture per dose ends up being a tragic $100B boondoggle instead of an interesting novelty.
Because we only know how to value things through the process of supply and demand, we build the entire economy around the maintenance of artificial scarcity in cases where production is cheap and supply could easily be near-limitless, and grant the right to monopoly pricing to all kinds of actors in order to encourage them to keep acting.
I get that we've let the system fall into this situation for a reason - we want to encourage creators to create things, pharmaceuticals especially can be a huge and expensive gamble so you need a big payoff the one in X times it works, etc. But I think it's a deficiency of our system that we provide this incentive by using artificial scarcity to *deny medical treatments that are extremely cheap to administer* to tons of people through outsized pricing.
$1 marginal manufacturing and packaging and transportation cost ignores the substantial development costs, such as opportunity or personell cost paying for tens of thousands of hours of time total from hundreds of highly educated and in demand professionals, drug development chemistry and biology and fooling and science needed for it, bureaucratic cost of even more people to verify it, plus amortizing in the many many many many failures, it’s actually very expensive.
Yes, as I already said, I understand why we have allowed things to develop this way. But...
Ok, think about it this way. Phagecorp requires $50B to pay for all the costs of development and distribution of Altranix, plus a large enough profit to incentivize them to make the drug in the first place and subsidize their other failed projects. Fine, Phagecorp should get $50B, I'm on board. But how do we *get them* that $50B?
The model we're using right now is, they make Altranix pills for $.10 each and sell them for $500 each, they sell 100,000,000 pills to 100,000 patients (treatment is 3 pills a day for a year), and that makes them their $50B. Each of the 100,000 patients is financially crippled by the cost, and there are 10 million patients worldwide who might benefit from Altranix but can't afford it.
Here's a very dumb model that I think would be preferable to that, and there are probably much much better alternative models a domain expert could come up with: The government says 'Ok Phagecorp, you did a good job on Altranix, we're going to hand you a check for $50B right now today. Now the rights to produce Altranix are in the public domain, anyone on the planet can make it, and we're going to start manufacturing it and selling it at cost (maybe $.50 per pill counting distribution costs) to anyone on the planet who needs it.'
Now, the public still pays that initial $50B, which has to come out of taxes instead of insurance premiums (no difference), and Phagecorp still makes the same profit (more actually because they don't have to pay for marketing and defend their patent and etc), but now every patient in the world who needs it can get it for next to nothing.
I think the only sane objection to this is 'We have no a priori way of knowing that Phagecorp deserves $50B instead of $1B or $500B, that type of price discovery is exactly what markets are for in the first place.' I agree that is a strong technical challenge, but given the enormous amount of destruction our current system is causing, and given that I think the government-enforced artificial scarcity model is not finding 'real' prices but rather what lobbyists are able to enforce to begin with, I'm very open to people proposing ways to just estimate this instead, and pay it up front.
I mean isn’t the answer here “the government will pay you $50B*(number of prescriptions per time period)/(pill total useful over ten years)” and then the government does that via Medicare or universal healthcare or whatever? And then there’s your price discovery (number of prescriptions plus whatever Medicare or HMOs or whatever do). And then they still get their 50B that day anyway because of investment and then go off to research more. Which has its problems, including making new clone drugs that are pointless, but is part of the system we have now. For existing generics I’d suggest maybe making it easier (a lot easier) for non pharma entities to run trials? But that doesn’t scale probably. A some % tithe for the runner of a trial proving a generic works per prescription if it works? Prospective contracts with generic manufacturers? Also the whole “prescribing X-clone when you could prescribe X for a fiftieth of the cost” thing seems like an easy target.
Also it’d be really nice to reduce the “costs” of drug development somehow. Taking costs to mean, like, something, whatever, barriers, idk, but without reducing the actual filter on drugs being useful. But no clue how!
That would work if we had universal healthcare and also didn't care about other countries. But we don't and I'd like everyone in the world to have cheap access.
There’s not really a solution to “drugs cost money” aside from insurance and government coverage and cost reduction, aside from “don’t get sick”. Which we should work on - all this FDA stuff has a cost benefit ratio of .001% compared to interventions like “ban adding sugar to food” and “white bread is now illegal, added isolated oils are limited to 3% of food calories” and “every 1% of your customers who are obese / have other health issue that’s diet related is an extra that percent tax on your revenue, with temporary credits on that for demonstrated reductions in calories eaten / better composition of sold food for large chains and, importantly, for large food distributors” and also just big ads of <offensive yet descriptive sequence of words visually describing people of mass and various physical disabilities and life restrictions caused by it> together with an explanation of what causes such things and how to avoid them
That is “somewhat” off topic, but it’s something that is very conceptually simple that would do way more for DALYs than any drug development stuff would. “Universal healthcare” and “all newly developed drugs are now free internationally” are a lot less conceptually simple, and have a much lower benefit. Obviously it’s not gonna happen because nobody wants it, but one can hope.
Anyway why can’t we just mandate existing insurance cover all these drugs (to solve the US problem)? Oh well we did, to an extent ... and if we decouple approval from insurance provision, then well once again run into the problem of people not getting approved drugs that they need access to. “Approval is easy + all drugs are cheap + company gets more money than people voluntarily choose to pay for drug when it’s not stage 2 approved” seems questionable. I guess you could save any monetary reward for after full approval but even then ...you create a massive mess.
" big ads of <offensive yet descriptive sequence of words visually describing people of mass and various physical disabilities and life restrictions caused by it> together with an explanation of what causes such things and how to avoid them"
Do you think that would work on me? I'm here to tell you no. I've been fat all my life, I've tried various diets, most didn't work; I've tried the exercise thing (I can't drive and I've lived places with bad to no public transport so it's been 'walk everywhere') and no pounds dropped off because suddenly I was burning more calories than I consumed; the diet that did work, I got sick a lot more in my life than I ever had before or since, and I fell away from that, and basically my psychology is *fucked*.
So yeah, go right ahead and tell me things that nobody has ever, ever said to me before about how disgusting, ugly, awful, wicked, I am; how I am going to get all these diseases of obesity; how I will go blind and have to have my legs amputated and my kidneys and liver will fail and I will die of heart disease; how I am a lazy parasitic leech on the public. I sure never heard any of that before from the general public, doctors, my family and others!
And I will tell you back: for some people, it might work. The "drop a dress size for Christmas" lot who only have a few excess pounds packed on. The very determined who will get the kick in the pants they need to go on a rigid diet, lose five stone, and keep it off.
But for me? I have fully internalised that I am a useless heap of shit (as someone close once told me) and It. Won't. Work. It will, however, give the people who like to drink, drug, and engage in risky activities but who are just on the right line of the BMI the opportunity to be mean to others. So be it.
I think you're vastly underestimating how conceptually simple 'control what everyone in the country eats' would be. 'Abolish IP protections for pharamceuticals' seems a lot more conceptually simple to me, since IP protections are a made-up thing we have to actively invest huge amounts of money and effort into in order for them to exist in the first place. And 'hand pharmaceutical companies a huge check if they make something useful' also seems conceptually simple.
Ah, yes; make food taste worse! A wonderful solution to the problem of obesity that will 100% work and has no downsides whatsoever.
Let me be a bit more explicit and less snarky in why I think the very core of your idea is absolutely repulsive to me. The following assumes that your idea is possible to implement and would have the desired impact on public health, neither of which I think are certain.
First off, everyone already knows that eating junk food is bad for your health--hell, we even call it "junk food", for Pete's sake!
Second, no one is forcing people to eat junk food. They make the free choice to buy and consume it, with knowledge of the consequences.
Third, the negative impacts are entirely limited to the person who eats the junk food. It's their health that's at stake, not anyone else's. And if you want to say "but insurance, but Medicare!" then that argument generalizes not only to regulating the food you eat, but also mandating a certain amount of exercise, banning any sports that carry a risk of injury, etc. etc. etc.... Having that level of imposition on my life seems like astronomically more of a burden than paying a few dollars more in taxes for statistically higher Medicare payouts.
I want to live in a society where people are free to make decisions for themselves about their own lives, so long as they are not directly harming anyone else.
You also forgot "Government pays cronies 50B$ of money for pill that does nothing. Says "Whoops", then does it again, forever."
You see, you have pretty much described the military industrial complex, with all the problems that government defense contractors cause given to medicine. Defense contracting at least has the fig leaf that the government is the only legitimate market for fighter planes etc., whereas the government itself is only the main market for various drugs because it decides to pay for other people who are the actual market.
Reforming IP laws might be a better solution, or reforming laws on what insurance companies have to cover, or... just about anything else including burning down the entire regulatory regime would probably be better than telling companies "You go ahead and make whatever, and if we think you deserve a giant pile of cash we will give it to you, or not, without any real regard to what actual consumers want." Because doubling down on the government having more control of a system that it is just balls deep in, wrecking everything it touches... that's a lot of "this time will be different!"
Speaking of government spending 50B for a pill that does nothing ... just read a story about Bush’s successful world wide AIDS prevention program. It was preceded by several programs that were funded and that bush “observed were not very successful”. Despite that, he still gave them $500M. To govern, ah...
Although I agree with you completely, I don't think I've heard anyone propose an alternative system that I strongly expected to work better.
>creating a pill that probably costs less than a dollar to manufacture per dose ends up being a tragic $100B boondoggle instead of an interesting novelty.
I mean, $100B on the public purse doesn't sound like a tragic boondoggle if it actually fixed Alzheimer's (that's a *lot* of QALYs saved), and Biogen going bust because Biogen did a stupid is no big deal either.
The problem is the $XB on the public purse for something useless.
I think your last point requires a whole lot more evidence to be believable. Sure, everyone knew that Al Capone was a criminal, but also everyone knew that the Central Park Five were guilty, that Airborne was an effective thing to take when you get a cold, and that deoxygenated blood is blue. Everyone knows lots of things that are totally wrong. If you want to claim that everyday reasoning is better than institutional decisionmaking, you can’t just point to a single case where the common people got it right and the institution got it wrong, you need some evidence that that is consistently true over a large body of decisions.
The Central Park Five is a bad example of the point you're trying to make as they still might be guilty of the exact things they were charged with and were almost certainly guilty of other things they were charged with. The comparison with Al Capone is apt in that the fact that someone is guilty doesn't mean that person can be successfully charged with the exact things they are guilty of. (Coerced confessions and over-broad charges don't prove guilt...but also don't prove innocence.)
Bupropion-dextromethorphan: I was curious so I bought some DXM from Dollar Tree (where it is 6x cheaper than at CVS) to see whether it does anything in addition to bupropion, but at least I didn't notice anything. (Apparently DXM has some abuse potential so the register makes an embarrassing loud beep when it is scanned.) Interestingly, it seems like the US is the only country where DXM is sold over-the-counter, so it might end up being slightly less trivial to get around Axsome in other countries.
> But that’s not what happened. Instead, the FDA sent Axsome a letter on July 30 saying that they found “deficiencies” that prevented them from moving forward with the approval. What are those deficiencies? Oh, the FDA doesn’t say. They don’t even give a hint. They just told them to hang tight until August 22.
> I remember the FDA rejected an EpiPen competitor for “certain major deficiencies” without giving more information (at least not to the public). EpiPen took advantage of this to quadruple their prices, although the FDA did eventually approve the competitor a few years later.
I really hope the SEC is taking a good hard look at the trades that happen around FDA members...
The thing that puzzles me about all this discussion is that the problem and solution seems clear and simple, yet Scott hasn't presented it in a clear and simple way.
Simply put, Scott isn't opposed to anyone at the FDA, he just wants some elements of the legal framework around the FDA to be changed. The obvious political slogan: "support FDA reform!"
Specifically, certification of safety needs to be separate from certification of efficacy, so that doctors can prescribe safe drugs even if they aren't proven to work.
The devil's in the details of course, so why not shift the conversation to those details? One issue that jumps to mind is that if a drug is shown to be safe in average healthy people, that doesn't mean it's safe in the sick population it's meant for, so even the safety certification may need to be scoped to a subpopulation.
Scott,
Want an intern? My previous employers have commended my ability to intuit instructions and take initiative, so you don't need to be too concerned about communicating. I have a few years of experience in research, writing, and editing, mostly for student publications.
If you're interested, email me at t [dot ] amarchana640 [at] gmail [dot] com.
I presume someone else has done this, but I need the exercise; in the spirit of doing things with made-up statistics.
1. The cost of aducanumab to the US health-care system is potentially $100B/year (as per [this](https://denovo.substack.com/p/a-travesty-at-the-fda#footnote-1), because it costs $56k/year per patient, and on approval is mandatorily covered by Medicaid, with the assumption that 1.8 million patients would be treated).
2. According to [a 2008 study](https://pubmed.ncbi.nlm.nih.gov/18362813/) (the highest in [the first link](https://www.nytimes.com/2020/05/11/upshot/virus-price-human-life.html) I managed to find in a cursory googling), "Our base case analyses suggest that plausible lower and upper bounds for a cost-effectiveness decision rule are $183,000 per life-year and $264,000 per life-year, respectively." (incidentally,this means that aducanumab would be a steal at $56k/year if it worked)
In order to be worth it at the above exchange rate, aducanumab would need to save 378,787 lives ($100B/year divided by $264k/year (are years and QALYs fungible in this way? Do we discount actual years somehow, especially given that this medication is likely to be administered near end-of-life?)). If you're more pessimistic about the value of a QALY, it's more like 546,448 lives. If you're _extremely_ pessimistic about it, more like 2,000,000.
If you believe that aducanumab will actually save close to 0 lives, then the answer to
> "So how often do you have to save hundreds of thousands of lives before it’s worth the risk of occasionally also permitting a dud medication that “offers false hope”? _How is this even a question?_"
> - [Scott A.](https://astralcodexten.substack.com/p/adumbrations-of-aducanumab)
empirically is "once or twice" if you're an optimist, and "four or five times" if you're a pessimist. It's a question because of the way US medical insurance is structured; specifically the way Medicaid seems to be required to cover anything FDA approved. In this light, it's not implausible or inappropriate to at least ask the question of "are the FDA being to lax".
As I write this, [worldometers says there have been ~640k deaths in the US](https://www.worldometers.info/coronavirus/country/us/) from Coronavirus. Assuming they could _all_ have been prevented by having a maximally lax FDA, how many aducanumabs would have gotten through as a result? If you believe the numbers above, and are a QALY-value optimist, and you think a lax FDA would have let through even two more aducanumab-level drugs, you've just broken even. Under the same assumption, but more such drugs getting through, you've effectively killed more people than you've saved by pushing the FDA lever to "lax".
The more I look at these numbers, the less I agree with Scott's overall position. It really, _really_ seems to be unfair to summarize the situation as "the FDA is incompetent". The real problem is, regardless of the competence of the FDA, their decisions automatically force people to spend money on anything they find in favor. _That's_ the actual problem; take _that_ away and the FDA arguably does no damage. But forcing the FDA to be laxer in the absence of solving the larger problem seems like a _really_ bad idea under the circumstances.
I've forgotten a lot of the history of HMOs, but someone wanting to make an effort post could get a good start by looking up how HMOs reacted to high-dose chemotherapy.
By luck, a web search found exactly what I wanted: someone angry (looks like a lawyer) that the HMO *refused* to cover chemotherapy. https://www.worthingtoncaron.com/Patient-Stories/HMO-Thwarts-Treatment-Plan.aspx
> The HMO bean counters stubbornly refused to look beyond the black letter of their policy rules. The HMO wanted Dr. Billinsley, who was trained and experienced as a cardiac surgeon -- not a thoracic surgeon trained to perform a radical pleurectomy with interoperative chemotherapy or radiation. Obviously, the Stewarts did not need this kind of stress. Now, in addition to dealing with an "incurable" tumor, the Stewarts had to deal with an inflexible, cold and lethargic HMO bureaucracy.
Today, the track record of high-dose chemotherapy is probably overall negative. https://blogs.scientificamerican.com/cross-check/cancer-medicine-is-failing-us/
For the case that broke the dam, look to "Overtreated" by Brownlee, starting around page 120:
Setting the stage with emotional appeals:
> "Bill [Peters] took the microphone and said, 'I could give you a lot of statistics about the effectiveness of this treatment protocol, but I think it would be easier to do this with a simple demonstration.' Then he asked the seventy or so breast cancer patients who had accompanied him to the lunch to stand up." ... "'As you look at a woman across the table from you, ask yourself, is the price of this woman's life worth the price of a luxury car?' "
Didn't work:
> ... the publication of clinical trials that would show the treatment wasn't a cure for breast cancer. Even when the evidence was in and it was finally clear that high-dose chemotherapy was no better than standard treatment, some doctors continued to argue that it could benefit some women.
Insurance was forced to pay anyway:
> How is it that a dangerous, highly experimental treatment came to be given to thousands of women before it had been adequately tested? The story ... involves the courts, insurers, hospital administrators, and proselytizing doctors like Bill Peters, as well as the desperate women who were led to believe, by their doctors and the press, that going through the ordeal of a transplant would save them from cancer.
...
> By the time Alice Philipson's first breast cancer patient came to her law office in Berkeley California in 1991, she had learned a thing or two about building a case against health insurers who refused to pay for medical treatments. ... Her new client's name was Ricki ... [who had] an advanced case of breast cancer. When Ricki was first diagnosed three years earlier, she underwent a double mastectomy and chemotherapy. Now the cancer was back, and Ricki was looking to high-dose chemotherapy and a bone marrow transplant as her only hope. But her insurer, a Blue Cross affiliate, did not want to pay for it.
> The company's reluctance was not surprising. The bill for high-dose chemotherapy began at $150,000 and could hit $500,000 if the patient suffered complications. ... Privately, insurers worried that if they agreed to pay for one expensive, experimental procedure, there was no limit to the questionable therapies desperate patients might demand.
...
> [Philipson] bombarded the company with scientific papers and letters from cancer experts saying the procedure was standard practice. ... In the end, the company agreed to pay for Ricki's transplant. Her case was one of the first ever that successfully forced an insurer to pay for a bone marrow transplant for breast cancer. It would not be the last. As Philipson's name circulated among breast cancer support groups, more women came to her, hoping to get their transplants covered by their insurers. Over the next two years, she won three more cases. Then, in 1993, Philipson assisted in a landmark trial that threw open the legal floodgates and forced insurers to begin paying for increasing number of transplants across the country. That year ... Mark Hiepler suyed Health Net on behalf of his sister, Nelene Fox, who has died from her breast cancer while trying to persuade the insurance company to cover a transplant. ... He soon discovered the company doctor who made the decision got a bonus at the end of the year if Health Net saved money. "It sounded terrible" Philipson recalls. ... The [insurer's] defense attorney says 'It's no different from John Deere.' ... The jury comes back and says 'The hell it isn't different.'" ... The jury awarded the Fox family $89 million in damages.
> Ricki didn't live to see the end of the Health Net case. She had survived the transplant, and her cancer had stayed away ... [I]n 1993, it came back more aggressively than ever. She was dead in a matter of weeks. The cure had failed. Philipson was saddened ... but she was too busy with other breast cancer cases to focus on it. Within a year of the Health Net judgment, record numbers of women were filing suit against their insurers. The strategy was always the same. The plaintiffs argued that the insurer was refusing to pay for a treatment was accepted medical practice. Transplant doctors served as expert witnesses, testifying to that effect. Peters himself often served in that capacity, telling the courts, ... "[T]he regiment prescribed is neither experimental nor investigational, as all elements of the treatment as well established and the treatment was over the years proven itself to be an effective cancer therapy."
Much later:
> And the trouble was, high-dose chemotherapy wasn't a cure, even for breast cancer. Alice Philipson knew it by 1995. She had not thought to question the treatment when Ricki died. Medicine, she knew, was an art, and no cure worked every time. But then another former client died, and another. One day, Philipson realized that every woman she knew who had received a transplant was dead. "Nobody got cured," she says. ... "It was a cure that didn't work."
If this thread is still going, does the FDA have “tiers” of how likely a drug is to have some terrible, thalidomide or Vioxx drawback? It seems like monoclonal antibodies should be in “this is extremely likely to be safe” bin. We all make lots of antibodies, chances are, a new monoclonal antibody won’t cause birth defects. Seems speeding their approval would be a net plus.
Is there a word for drugs that are things you already produce, like steroid hormones or dimethyl tryptamine? Seems like these would have fairly predictable effects. Though evolutionary logic implies that they are optimized, they are optimized for people with very different lives. There could be low hanging fruit here. The harms are more or less predictable, and the FDA should approve easily, but not as as easily as yet another Amat.
Other drugs are variations on a theme of some existing drug with well understood pharmakinetics and downsides, THE #MeToo drugs, These seem less certain than the top two classes, though only a methyl group separates terrible methanol from wonderful ethanol.
Then there are things like “this is a variant of a drug with terrible side effects, but great function. We’ve tweaked it to try to make it safer. These are obviously riskier, and the FDA should be really cautious.
As a real example, this year’s flu vaccine antigens will not be put through a decade of testing. They are minor variants of things that have been extensively tested, interacting with well understood (lol, but kinda) physiology.
If the FDA can allow new flu antigens without a Brazilian dollars in testing, maybe there are other pharmaceuticals where this applies? They also have a readily-approved category for medical devices that are “substantially similar” or some such, I forget the wording, to things that are already approved.
Lastly, there are other first world and upper-tier developed-not-wealthy nations. Presumably they differ somewhat in what is approved and when. How does the FDA compare to Euro-FDA, Moscow-FDA, etc? Are drugs usually approved overseas first? How often? Of those that are approved somewhere else, but either approved here later or never, how often do the furriners have to pull the drug because of lack of efficacy or safety?
If other modern countries approve quickly, cheaply, and with few hiccups, that would be strong evidence that the FDA process is severely flawed. If other countries just follow America’s lead, then that does not help much.
"This is an interesting point. We sometimes see politicians “cutting in line” and managing to get advanced drugs that the FDA hasn’t yet made available to the general public. We usually interpret this as unfair privilege, and I think that’s a completely accurate interpretation. But that requires a sort of covert acknowledgment that these drugs are probably being delayed too long - otherwise, these politicians are heroes for taking potentially-dangerous substances and testing them out for the rest of us."
This seemed pretty obvious to me. I'm surprised this idea didn't come more easily to some people. Perhaps they are more easily influenced by the news slant
This is why it was a good for politicians (Trump etc) to receive the good stuff. It might even speed the equivalent of FDA approval. We aren't yet at the stage where only politicians would benefit, though we are getting there
Some people are more capable, faster, intuitive, and natural with certain modes of thought, and, vice versa, others may have talent in other domains.
I'm glad you're making an effort to be fair and correct