Most likely the approval process which included running several studies cost them $100 million. It is not that they gave $100 million to the FDA. Running studies are very expensive, you have to pay doctors, administrators, supporting staff etc.
I'm a doctor and have been peripherally involved in several large clinical trials. I could believe that a multi year study involving many rounds of expensive investigations (eg screening MRIs in, say, the recent aducanumab study) could cost tens of millions of dollars, as this paper found (https://pubmed.ncbi.nlm.nih.gov/30264133/) - "Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million"
However Scott seems to be:
a) referring specifically to an 'FDA application fee', rather than the cost of running a trial and
b) talking about a relatively straightforward trial with short term clinical endpoints
so I'm going to assume he either misplaced a decimal point or is just mistaken. Happy to be corrected!
I believe he's referring to the cost of the trials combined with the fees.
Though I think I disagree with scott for a seperate reason.
The FDA tends to do a "he who pays for the trial gets the use patent" thing.
Before they ran a pair of full clinical trials to prove it worked as a sleeping medication a bunch of doctors might have had a hunch it had that effect due to patient reports but the evidence base was poor.
Just like patents encourage people to reveal their designs, drug patents and clinical use patents incentivise companies to pay to run the big clinical trials that would otherwise never get run which generate all the nice neat tables of effects, side effects and contraindications.
When you know that a drug is good for [use] becuase you've got the summary in front of you from a bunch of clinical trials it's hard to imagine a world where you don't know that information or only have a hunch about that.
It is kinda stupid for the FDA to not just routinely inspect substances approved in Europe and Japan for one's with a reasonably acceptable evidence base rather than waiting for companies to jump through symbolic hoops.
If something is expensive to create, we have a separate IP system for establishing temporary monopolies, which at least in theory can be tuned to produce economically efficient outcomes (e.g. protection that eventually expires by default). FDA approval has no such characteristic. There are problems with the IP system we have as well, but they are probably made worse by trying to also use the FDA to incentivize companies to do studies.
She sounds like a deeply pragmatic woman whose intensely committed to getting shit done.
She’s interested in saving babies and found allies to accomplish that goal. Shitting on the FDA would make things worse.
She could’ve written a libertarian blog or become a policy wonk but she focused on visible outcomes.
I think there’s a lesson to be learned here about the mentality of implementors versus wonks. Maybe she’s too short term and institutionally minded for this crowd but it’s a valuable perspective.
I think it depends on the level at which you want to get things done.
If you're a medical researcher, then you just have to accept the rules as the reality at which you operate in, regardless of how arbitrary and counterproductive they are. If the FDA mandated that double blind trials literally require everyone involved to be blindfolded, the only question to ask would be "what brand of sleep mask has FDA approval?"
If you're trying to operate at a political level and reform the system, then questioning the rules is exactly the kind of thing you should be doing.
It's a "game player" vs "game designer" distinction - they're two very different ways to approach the world, and while they can overlap you can't really be both at the same time.
Also, it was a speech she gave after winning an award for the work. Using a platform like that to drag anyone who was involved in the thing you're getting the award for is just ... not a thing that's done outside the confines of the internet.
It's not a normal thing to do, but it's been done. My favorite example is John Taylor Gatto's "The Psychopathic Schoolteacher," which was his acceptance speech for New York's Teacher of the Year award. https://www.naturalchild.org/articles/guest/john_gatto.html
From what I understand, companies live in fear of retribution from the FDA. Mary Ruwart writes about this in her book "Death by Regulation" providing a first hand account from her time inside the pharma industry. I suspect one of the reasons the AstraZeneca vaccine wasn't approved in January was retribution for a mistake AstraZeneca made in failing to immediately notify the FDA about a pause in the Phase III trial.
For academic researchers it's a different story, but they also have to work with the FDA too (for instance with trial design) if they want whatever they are working on to have a chance of getting approved. The FDA also provides funding to researchers, as we saw in Scott's last post, and grants compassionate use applications, etc etc.
Finally, researchers can be part of FDA advisory committees. I'm not sure if that is paid, but it is prestigious.
So I'm pretty sure fear of retribution is a factor when researchers are talking publicly about the FDA.
The EMA approved AstraZeneca vaccine but when the reports about blood clots came in, half of European national regulators suspended its use. EMA quickly reviewed the case and maintained that benefits overweight risks and suspension was not justified. The EU even sued AstraZeneca for missing deliveries at the same time deciding not to use AZ vaccine. They donated the remaining AZ vaccines to third-world countries but they come with short expiry dates and a lot of bad reputation that are increasing anti-vax sentiments.
For what it is worth, it seems that a stronger EMA would have been more beneficial for the EU. Similarly, without strong FDA I suspect that doctors and general people would have more doubts about the safety and efficacy of their medicines.
Re the EMA: its becuase the EU is a lot looser than the US. The EMA is more advice to state regulators.
From someone who used to work with the EMA they were saying brexit probably had a bad effect on its effectiveness as the UK beaurcrats played a non-trivial role in getting the various state regulators to keep calm.
EMA takes longer to approve drugs than the FDA, on average (see https://www.pmda.go.jp/files/000204615.pdf, slide 6). This could be a result of understaffing though rather than then being more strict. They have a different model than the FDA where they contract out a lot of the reviewing to private firms which some people say is better.
From talking to someone who works in drug trials, its also sometimes like the student who did the assignment and handed it in 2 days after it was assigned.... a month later watching one of their classmates who left it till the night before swearing about how it's "totally unfair" and an impossible deadline.
Sometimes they know that behind a story of delay is someone who kept screwing up and taking months to do a few days worth of tasks.
> I have no idea how you can write "they usually carry out their mandate well" in one place and then, in your main post, just go ahead and repeat your original belief—backed by an example you know is wrong—that the FDA does stupid and destructive things on practically a daily basis.
Which is a really bad thing for Kevin to be confused about, because if he’d read the next paragraph of Scott’s post, he’d read all about how Scott reached the conclusion because he anticipated this criticism and basically held the readers’ hand through the thought process.
> My problem is: doing anything in medicine is illegal until you clear a giant hurdle. To clear the hurdle, you have to pay millions (sometimes billions) of dollars, fill in thousands of pages of forms, conduct a bunch of studies that can be sabotaged for reasons like “this drug is too good so it would be unethical to have a control group”, and wait approximately ten years. You have to clear this hurdle to do anything, even the most obviously correct actions. Everything starts out illegal, and then a tiny set of possible actions is exempted from the general illegality. The easiest name for this hurdle is “the FDA”, since they’re the agency charged with enforcing it.
Meaning either Kevin drum conveniently stopped attentively reading at exactly the point where Scott’s post would provide the most fodder for his pro-FDA position, or he specifically cherrypicked that quote despite knowing that Scott fully addresses the concern immediately after the quoted section. (Note, my quotation from Scott is followed up by him reiterating the same point with specific examples for about 8 paragraphs, so there’s no way Drum could have had a microstroke or something and missed that specific paragraph.) In conclusion, Kevin is either a deliberately deceitful huckster or just a straight up moron and this piece has provided all the evidence I need to conclude that I don’t actually have to read anything else he has written in the past or will write in the future.
But I have to say, the most baffling part of Kevin's piece is when he "defends" the FDA by insisting that we start the clock of when we knew Omegaven was effective from when the company that makes it applied for authorization. Like “the FDA doesn’t actively go out and do it’s job proactively seeking new, useful medicines to help through the approval process so Americans can get prompt access to useful new drugs. Instead, they sit on their hands, even while getting a constant flow of emergency use requests, until someone pays the millions of dollars to make the adequate sacrifice to Moloch to get through their Kafkaesque approval process before they’ll even begin thinking about whether maybe they should form an exploratory committee to consider whether to process the paperwork which will begin the approval process” is some kind of ringing endorsement of the FDA.
> In conclusion, Kevin is either a deliberately deceitful huckster or just a straight up moron and this piece has provided all the evidence I need to conclude that I don’t actually have to read anything else he has written in the past or will write in the future.
Gotta say I oppose this mentality, except insofar as you don't *have* to read anything. If writing one dumb thing is enough to banish someone's posts to the shadow realm forever, you either have to apply that heuristic very selectively or end up with an incredibly cautious stable of writers.
This isn't a problem of dumbness. It's a problem of either fantastically implausibly bad reading comprehension or literally trying to actively deceive his readers. You can rule thinkers out when they're actively trying to make their readers dumber. But in the spirit of glasnost, if there's anything of his that you think would make me rule him back in, I'll read it and I promise to give it a fair hearing.
I... have exactly the same thing I said above to say to that. I didn't think he was dumb, just that I think one bad take shouldn't rule someone out forevermore
I've never read the guy, so I have no recommendations. I just think the approach you're putting forth here is mistaken in principle
Again, if this was a bad take in the sense that I think it was an honest mistake, I would 100% agree with you. (I'm a huge fan of Robin Hanson, despite my thinking that a lot of the points raised by his critics are valid, for exactly this reason.) But if the quote mining that Kevin did really was a result of a good-faith mistake of the kind which we should forgive... I'm sorry but that requires some deeply implausible assumptions. And even if we are to assume incompetence and not malice, we still need to assume *a lot* of incompetence to get what Kevin actually wrote. If we have that level of incompetence, then I wouldn't rule out Kevin on the grounds that he's actively trying to make me dumber, I'd just do it on the grounds that I have more reading material than I have reading time and I can do much better than someone that bad at basic reading comprehension.
Lots of people get hung up on one thing they read in some essay or post or article or book, and it so colors how they read the rest that they miss a lot of important detail. I imagine that's what happened to Drum in this article.
I think sticking someone with a "burn notice" is justifiable for deceit (as opposed to being honestly wrong). Fact-checking a fraud can get quite difficult, and cross-correlation of deceit is much higher than ignorance (if someone knows very little number theory, they may still know a lot about biology; if someone lies about number theory, they're probably also willing to lie about biology).
(The main exception I'd make is that high-stakes deceit doesn't generalise especially well to low-stakes deceit. Most people have a threshold of stakes where they feel comfortable lying; if someone lies to avoid going to jail, they're probably willing to lie to avoid dying - or to avoid going to jail for something else - but they won't *necessarily* lie for money or attention.)
I think you hit the nail on the head, especially with regard to Kevin Drum. This is not the first time I have read a blogger responding to Kevin about some claim that comes down to "Ok, KD is either an amazingly bad reader, deceitful, or so deep in motivated reasoning that he doesn't even know if what he says makes sense." This has been going on for years and years, at least going back to 2009.
I am honestly a little confused about why so many people call Kevin Drum their favorite blogger, unless that is a euphemism for something.
"I want a world where if there is a $250 version of a drug, and a $10 version of the same drug, people are allowed to choose the $10 version even though the manufacturer did not give the FDA $100 million dollars."
Everybody wants that world. So how come generics aren't more widely prescribed? "Sure, I could give you a script for the fancy new drug the pharma rep tried selling me on, or I could write a prescription for the fifty-year old version that is now out of patent so there are three cheaper versions on the market". Why doesn't this happen?
But the thing is, we are living in an imperfect world, and *if* you get the world where:
- everybody from NBC News to random bloggers know that the babies are much less likely to die on fish-oil based fluids
- FDA doesn’t hold up approval for an additional five months arguing about the wording of the warning label
- ketamine eventually gets approved for use as a depression treatment
- if everyone knows COVID vaccines are safe and effective, then the government will have approved COVID vaccines as safe and effective
That is *also* the world where Aduhelm gets approved, because the drug company doesn't want to wrangle with the FDA over the warning label and pressure from patient advocacy groups who are grasping at straws works and everyone from NBC to random bloggers are saying it's a breakthrough miracle drug and the government relies on the pharma lobbyists telling them it's safe and effective.
It's the world where Dr. Ogu's Natural Herbal Remedies for epilepsy to AIDS get approved for the same reasons.
It's the world we used to have, before in the USA the 1906 Pure Food and Drug Act was passed, where the role of the FDA was limited to "there isn't any actual poison like arsenic in this item (anymore)" enforcement.
If it contains terra alba, barites, talc, chrome yellow, or other mineral substance or poisonous color or flavor, or other ingredient deleterious or detrimental to health, or any vinous, malt or spirituous liquor or compound or narcotic drug."
I do like the bit about poisonous substances in confectionary, don't you? Ah, the wonderful world where you could merrily put poison in sweets before the meddling and interfering hand of government intervened to retard you!
The pendulum swings wildly from extreme to extreme, and yes there should be a moderate mid-point, but when you have evil fools selling Miracle Mineral cures for autism, and parents so desperate for a 'cure' that they will torture their children, and people going on Amazon to give positive reviews of the product, I find it hard to say we're over-regulated.
Indeed, we face a complicated tradeoff of bad things, and the argument is largely about what the right point on the tradeoff would be. There is no practical point in the space of possible tradeoffs where we don't sometimes get approved medicines that have terrible side-effects, or drugs that are only marginally better than a sugar pill. There is also no practical point where we don't sometimes delay the availability of lifesaving or genuinely helpful drugs. (We can avoid the first by banning all new drugs, and the second by abolishing the FDA, but short of that, both errors will be made sometimes.)
ISTM that one fairly easy improvement we could make would be to use other countries approvals/experience to allow drugs in the US. Something like "if it's approved in the UK/EU/Japan/etc., and has been on the market a couple years there, it's approved in the US as well unless the FDA makes an explicit case to keep it out." Or "you can buy/prescribe things that have gone through safety but not efficacy trials under these conditions...."
I expect there are more ways to improve the tradeoff we're making, but I don't have great confidence about that--this is a place where all choices have painful costs associated with them. OTOH, Scott is speaking from experience as a practicing psychiatrist and has run into several cases in his practice where FDA policies seem to be making things worse. Probably we should pay attention to that, even if we're not sure exactly where the optimal tradeoff point is.
"painful costs". Yes, but who gets to make the decision about what painful costs are to be borne? That's the problem: it's not deciding between risks, it's *who* decides. If you think regulation is a good thing, then you think that the government is better at deciding who should bear what risks. Do they have a better incentive or better information than the individual who is making the decision for their own risk?
Well said — people think so strangely about this topic. "Once upon a time, candy very rarely had bad stuff in it, therefore there is no such thing as over-regulation" really seemed like a good argument to at least two people in this thread, apparently?!
Deisach contributed several specific examples with evidence, historical context with a link to learn more, and several well formed arguments. That’s great!
If we’re discussing the FDA, the historical context of why the FDA was established and what law established it is interesting. As is the example of the sort of bad thing that might be encouraged by the FDA’s abolition.
It wasn’t exactly a powerful and fully sourced peer reviewed journal article on the topic. But it’s perfectly good! And it started a few other conversations
> and what arguments?
short and unsatisfying arguments can still be arguments
I don't agree. I don't see any well-formed arguments; all I see is "yeah but with NO regulation, you could sell poison", and this is so obvious and well-covered that it doesn't really need examples and evidence — or mentioning. The question is, as always, how *much* regulation we need *now*; the situation with confectionery in 1906 is essentially irrelevant.
Well indeed, WC, that is a question we must all ask ourselves at some point in our lives. "Who am I, where do I come from, where am I going?" as the British Army patrol asked Kevin McAleer.
1. I am Thirteen Ways Of Looking At A WC
2. I am ragweed pollen on the breeze, and the solar UV index is moderately high.
3. I am he as you are he as you are me/And we are all together
An orbiting pendulum looks like it's simply swinging from any given point, and yet in actuality (and in spite of appearances), at no point in its orbit does the bob actually approach the happy point it is orbiting.
I'd be more sympathetic to Scott's position if we lived in a world where miracle drugs like imatinib were being developed every year*. But drug development is very, very, very hard. Your pre-test probability should be that most novel pharmaceutical interventions will not significantly outperform current standard-of-care + placebo. Given that landscape, the mandate and ethos of the FDA makes quite a bit of sense. The public (and the American healthcare system) is much more at risk from being victimized by ineffective and/or harmful treatments than having genuinely transformative medications delayed or withheld.
*(I'll grant Scott's point that the particular mandate/ethos was a very bad fit for development of COVID vaccines, which are the rare intervention with an enormous effect size)
The asymmetry I'm assuming is that for a given indication, a vast majority of pharmaceutical compounds won't work better than placebo. So if you have a marketplace flooded with Placebo Plus products with no meaningful regulatory restraint or oversight, you dilute the number of people getting effective treatment, you increase financial toxicity to the healthcare system, and you are exposing people to a wide range of tail-risk side effects.
Robin Hanson's work indicates that a whole lot of medicine is no better than a placebo. But the effect of this is just to waste money. If lots of people buy placebos that do nothing, and people with rare conditions (like those infants or the guy that lost his intestine) that can actually be improved by drugs get those drugs, it sounds like a net plus.
Leaving aside the ethics of constructing a society that caters to a small cohort of the information elite, only a tiny fraction of people have the time, expertise, and disposable income to evaluate the evidence base of candidate pharmaceuticals and conduct autologous n of 1 trials - and that fraction would turn to '0' if you deregulated the space and allowed shoddy, biased, and outright fraudulent research results to proliferate.
If you want evidence of that, you need to look no further than 2020. Many of the people who would describe themselves as 'diligent about [biomedical literacy and research]' went head-over-heels for a whole variety of placebo-equivalent antiviral candidates. There was so much clinical and biomedical data - much of it shoddy, unreliable, and non-replicable - that people's empirical apparatuses were swamped.
Imagine that, but for every indication and disease. How would a person with a life-threatening condition decide which drugs to try, in what combination, and in what order? How would insurers decide what was reimbursable? How would doctors be able to decide what was safe and effective to prescribe patients? How would the system bear the costs of this flood of products? Aducanumab alone had the potential to bankrupt Medicare, and that's just one shoddy monoclonal antibody.
Actually I think doctors all over the world were doign the same thing. Nobody knew what would help with covid, so they threw anything that might help at it--zinc, HQC, azithromycin, ivermectin, vitamin D. I think this always happens with a new disease. Eventually, people found some stuff that seems to work and switched over.
I go back and forth on this. It's definitely hard with the FDA involved. But it's weird how often drugs approved for one indication randomly help with another (eg fluvoxamine, an antidepressant that seems to also treat COVID - or ketamine, an anaesthetic that seems to also cure depression - or any of the substances mentioned at https://slatestarcodex.com/2014/07/17/psychotropic-base-rates-the-argument-from-antibiotics/). I'm not really sure what to make of this.
I'd love to see good data on the success rates for drug repurposing (and by success, I mean statistically significant differences in clinically meaningful outcomes in large double blind RCTs). I suspect the number is quite low, and that number is likely an underestimate given how much of the denominator would be hidden / unpublished.
I agree that many drugs have off-target activity that we don't always anticipate or understand. But I'm much more skeptical that the off-target activity is clinically meaningful, or if it is clinically meaningful, that it would outperform current standard-of-care.
Derek Lowe has had faint praise for drug repurposing, that may be worth reading. Here's one, though he mentions it in passing in a few other posts that I don't have the attention to find at the moment.
This is interesting, thanks for the link! It mostly aligns with my priors but he does bring up a few good examples (like thalidomide) where very high-signal off target effects were effectively repurposed within the same drug class.
I mean Covid drug repurposing didn’t seem to go great? A lot of drugs were identified and given to a lot of people. Azithromycin hydroxychloroquine remdesivir and a bunch a others, and i guess ivermectin although I can’t say if that one works or not.
combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients).
Going with 1.11
The pharmacies steadily dispensed an average of 383,685 prescriptions for hydroxychloroquine (HCQ) per month, and 1839 prescriptions for chloroquine (CQ) per month. However, from February to March, prescriptions for hydroxychloroquine jumped by 86.2%—from 367,346 to 683,999. Prescriptions for chloroquine jumped from 2346 to 6066—an increase of 158.6%. Among those patients given hydroxychloroquine, the number who were simultaneously prescribed azithromycin jumped from 8,885 in February, to 101,681 in March—a 1044% increase.
(I am now going to pull numbers out of my colon, and I don’t expect this to have really any relation to actual hcq deaths. I probably misinterpreted at least two of my sources somehow)
Assuming of 300k given hcq, the case/hospitalization and hospitalization/death ratio for the general population are the same as for that group (which there are no grounds at all to make), 300k* 600k deaths / 35M ~~= 5.1k deaths. 11% increase = 500 deaths. If it’s 75k like another source suggests, 125 ish. Which is quite a few, but not exactly at the scale of the vaccines being delayed. (But I would submit again that the fda process being very strict may have pushed the drug companies to have actually good development processes and those with to the top)
I believe the drugs that were useful were the steroids, which is much less an experiment than the others.
I think both. Huge amounts of time and treasure and genuine genius have gone into treatments that looked great until the clinical trial, where it turned out they didn't do any good. But also stuff that works can be impossible to get approval for because it can't be patented and producing the evidence that it works sufficient to get approval costs hundreds of millions of dollars.
> Given that landscape, the mandate and ethos of the FDA makes quite a bit of sense.
There seems to have been ample evidence to the contrary for the fish oil. It wasn't even a "new" drug. Something that has a proven safety record in other jurisdictions shouldn't have to overcome the same hurdles as a truly new drug.
The pendulum has never swung back to the old days you bring up. Even though we could rely on third-part certification like Underwriters Lab, fraud laws for false claims, and Hanson's would-have-been-banned stores.
I don't find it hard to say we're over-regulated. Here, I'll say it. "We're over-regulated". The counter to your "merrily put poison in sweets" claim is the requirement that manufacturers of industrial alcohol merrily put poison into their products. I've seen an estimate that, since prohibition, 10,000 people have been killed by this government requirement.
Essentially, your claim is that individual action in the marketplace is insufficient to solve problems of unhealthy foods. Perhaps that's the case, but it doesn't explain why the government has been encouraging people to eat unhealthy foods (too many carbs, because "eating fat gives you heart disease", when that's exactly backwards) for most of my lifetime.
So, do you suppose there could be some possible middle-ground between allowing people to put poison in candy and preventing people from using a treatment that's known to work and approved in many other countries?
This is like the dumb internet argument style where anyone who proposes less government is accused of wanting to move to Somalia, while anyone who proposes more government is accused of wanting to move to North Korea.
Is there a middle ground between having a forest fire burn down your entire forest and not having it burn down any part of the forest?
Part of the problem is that you're thinking this decision can be made by itself: that we have a knob which can control the amount of regulation of substances, and that we just tell our politicians where we want the knob to be set, and them and all the other politicians put in their setting, the average gets taken, and that's the setting.
Firstly, most people are dumbshits, as I'm sure you've noticed. Second, we never send our best and brightest to govern us. In fact, the best and brightest are too smart to want to be politicians. Third, once you give a politician power, they never want to give it up, so the knob only gets turned in the direction of more control, and only rarely less control. Fourth, political power is fungible. You may think you're giving a politician the power to keep us safe from unsafe substances, but what if they trade it to another politician (who has promised to eliminate unsafe substances from the market) in exchange for the power to benefit an evil corporation?
Your case would be more powerful if you offered examples of times, probably more than we know, the FDA put the kibosh on as yet to be known harmful therapies. I keep a quote handy I fall back on occasion: Thomas Chalmers, the famous medical researcher, once wrote, “One only has to review the graveyard of discarded therapies to discover how many patients have benefitted by being randomized to a control group.” Not quite apples to apples to your response above, but it's close to the spirit.
Also, I don't follow your two-track description of the FDA. The first, "stupid," and the second, THe FDA is a product of the charter organizing committees set forth for them: slow, deliberate, and overly cautious. The latter doesn't validate the former. If you didnt imply that, I misread your intent—apologies for the misinterpretation.
The most radical FDA reform proposal I've heard is that the FDA should use its current system to check if drugs are safe, but be laissez-faire about whether or not they're effective. The safety checking is (as far as I know) relatively quick and easy and not usually most of a delay (though I would have to double-check this before asserting it officially). I think this is kind of like what they do with vitamins/supplements right now, which are cheap, numerous, easy-to-get, often ineffective, but safe enough that if you dared someone to take a randomly chosen Whole Foods product I think only the most over-cautious people would have any qualms.
Overall, I like that idea, but implementation is going to have to resolve the issue of "safe" not being binary.
To pick and extreme example, chemotherapy drugs are literally poison, but they're net benefits to patients with certain forms of cancer because undertreated cancer is worse for the patient than the chemotherapy drugs. You're probably going to want some kind of backup process where some standard of evidence of benefit can be used to get approval despite known or likely hazards of the drug. The tricky part is to stop the acceptable level of risk for basic certification and the standard of proof of effectiveness for approval despite risk from drifting to the point you're effectively back to the current system.
Indeed. And sometimes how we think about risk is just weirdly broken or mis-calibrated (the reaction to the super rare AZ or J&J vaccine-associated blood clots, for example). Certain people get all weird about me taking medicine that ups my risk of blood clots and breast cancer, when realistically the risks are comparable to the average female baseline risk (which is higher than the normal rate for a male), and they also significantly reduce my risks of falling victim to other things, like prostate cancer, alongside the positive effects which I want. If I were to get certain surgeries, some doctors would force me off my medications for weeks leading up to it because of that fear of blood clots, despite the risk not actually being high (cis women on birth control are at significantly higher risk and generally doctors won't force you to stop that before surgery) and going off the medications being quite unpleasant in and of itself.
You can't really consider them in isolation though. We ought to accept a drug that prevents 10,000 fatal heart attacks a year even if it causes a dozen liver failure each year too. I mean, the FDA didn't accept the first beta blocker historically and Europe did but they shouldn't have accepted such a risky drug without proof of efficacy. Of course, an easy solution is to be open to safe drugs bit stringent with dangerous ones.
Tier 1: Drugs that have proven reasonably safe can be manufactured and sold, but can't be marketed with claims of curing disease, and won't be covered by insurance.
Tier 2 is drugs that are also proven effective. That's the only tier we have now.
Now watch as the cost of a drug is multiplied by a factor of ten the day it's moved from Tier 1 to Tier 2, because insurance is paying so they can charge $100 / bottle for what was formerly $10/bottle over the counter.
I feel like at this level, though, it wouldn’t resolve a bunch of the fundamental objections. Ketamine, to take one of your frequent examples, doesn’t seem like it meets this bar: you say it causes “acute distorted cognition for the next few hours” at clinical doses, and it has lots of potential harms at recreational doses. That doesn’t seem like a level of safe that we’d be happy to have it sold over the counter at Whole Foods, which presumably would move it into the “must show effectiveness” track and we’re back where we started.
That’s not to say that the FDA is the right answer, but lots of medications have some bad effects that trade off against their good effects, so just evaluating safety without an eye to effectiveness seems like it doesn’t actually result in lots of medications meeting the bar.
The FDA would be more useful and believable if they restricted themselves to an advisory role. Then you would have insurance companies saying "Sorry, we don't pay for this because the FDA advises against it." but people could still get the compound they believe helps them.
When I take a drug to treat my diabetes, or blood pressure, or some other chronic condition, or even cancer -- then yeah, I want to be pretty damn sure it's effective, not just safe. Leaving my conditions untreated is *not* safe.
Of course! So why do you trust the government to do what you should be doing? What would happen if they failed to ensure that your medicine is effective, like they failed us by telling us that fat is bad for you? What mechanism is in place to correct their failure? If a private company created medicine that was not effective, they would probably go out of business. How might the FDA "go out of business" given that they are reliant on politician goodwill, not customer goodwill?
> So why do you trust the government to do what you should be doing?
Whom should I trust instead ? Every snake-oil salesman who comes my way ?
Look at it this way. The last time you rode in an elevator, did you stop to consider the probability of it crashing to the ground, burying you deep in the elevator shaft ? Did you check the local reviews for the construction company who built the elevator before getting into it ?
If you trust "the government" -- or rather, the teams of engineers and scientists whom the government either employs, or forces to pass standardized test -- to maintain your elevator, then why not medicine ?
Who should you trust? Walgreen's. Kinney's. Rite Aid. CVS. They should be the ones testing for safety because unlike any government agency, they compete with each other and will HAPPILY test their competitor's product and gleefully point out anything that isn't safe.
I trust the elevator company because they will lose everything if any one of their elevator crashes to the ground because of incompetence on their part.
Why do you trust the government? Who is monitoring them? Not CVS. Not Walgreen's. Not Kinney's. Because none of them have any interest in catching the government's errors, because all that will do is cause everybody to stop buying from their local pharmacy.
If you ask me to predict the future, I will ask you what incentives people have. CVS, Walgreen's, Rite-Aid have good incentives, the FDA has bad incentives.
Basically that they should approve for safety and effectiveness, but not clinical utility. And have explicit tiers available for measured effectiveness (biomarkers / symptoms / survival etc).
Sure, but that opens the door to homeopathic-style treatments. Is it safe? Of course, there's not enough of anything in this to do anything good, bad or indifferent. Is it effective? Well, if you don't have anything really wrong with you and it triggers the placebo effect, sure. If you do have something really wrong with you, um, yeah.
But hey, at least it's a lot cheaper than Aduhelm at $56,000 per year! Which is something approved as safe but not effective:
"Why does this drug cost so much?
There are millions of people and their families who want a new Alzheimers treatment. Any Alzheimers treatment.
"We have established a price for Aduhelm that reflects the overall value this treatment brings to patients, caregivers and society -- and one that will enable continuous innovation," wrote Biogen's CEO Michel Vounatsos in a letter announcing the approval.
The nonprofit Institute for Clinical and Economic Review, which scrutinizes drug prices, argues that because the drug has not been proven to be effective, a more reasonable and cost-effective price would be much lower -- maybe as low as $3,000. That's far from the $56,000 Biogen will charge.
The impossible problem.
More than 120,000 Americans die from Alzheimer's each year, making it among the leading causes of death in the US.
But treatment of the disease has been stuck for years, and the FDA had not approved a new drug to treat this disease since 2003."
The bargain is not "how many thalidomides is one omegaven worth", it's "how many aduhelms is one omegaven worth".
Omniscience is not available to anyone, even someone who works for the government. It is only through trial and experimentation that we know anything. The FDA's remit in verifying effectiveness is very problematic. It should only be testing for safety. It is up to other parties to determine effectiveness.
In the US, you can buy homeopathic remedies and herbal medicines and such over the counter. And you can go to a chiropracter or accupucturist or naturopath for your cancer. So maybe this would be a terrible world, but it woudl be the terrible world we already live in, at least in the US.
Still don't have an answer to the question of "how many patients does this (lack of approval for the fish oil formula) impact every year." I am betting that it is under 1k and probably under a hundred, not the tens of thousands originally given.
FDA-employed researcher who is a partner of a family member, enormously paraphrased: "the article correctly described the FDA's difficulty with too fast/too slow on drugs, but noted that the 'F' part of FDA doesn't have a similar issue, mainly because it doesn't approve foods before they can be sold as food; if something appears to be making people ill, it’s super fast and super easy to get authorization and budget to study/ban it, but for foods which no one has thought to test yet and which are only on the radar on priors like the one I'm currently working on, it took a year to set up protocols and it will be at minimum a year before any results of anything are to be looked at".
I disagree with your assessment that you're "basically correct" when you're off by a factor of 2-4 in the detail that serves as the crux of the point. You're right that this is an example of the FDA being overly restrictive on a drug that ought to be widely available, but there is an absolutely massive difference between an organization that delays new drug releases by 5 years compared to 20 years.
I agree I came on way too strong originally, but I think there's some leeway in when you date from. Omegaven was invented in 1991, there was a WSJ article about it being a miracle drug in 2006 ( https://www.wsj.com/articles/SB116338867216321332 ), there were studies confirming it in 2011, it was well-known in the libertarian blogosphere by 2014, and it got approved in 2018. Which of those is the starting point for saying the FDA was "delaying"? In a default-yes medical regimen, I think people would have started using it around the WSJ article in 2006, so maybe 12 years earlier.
One of the questions I was thinking about when reading your initial article was: Assuming we can only work with the single lever of FDA restrictiveness, how many Omegavens is one Thalidomide worth? The number of years the FDA delayed Omegaven strongly influences my answer to that question (as does the rate at which the FDA encounters "Omegavens" and "Thalidomides" in the wild). That's what I mean when i say that the particular detail you were most incorrect on is an essential one, and being off by a factor of 2 is a large one.
Very good point, I apologize for implying otherwise.
It seems to me, however, that Scott is arguing for a standard wherein the FDA would have gotten Thalidomide wrong. In this case, it would have been by adopting a European approved drug, but it probably would have also approved it in its own channels by only looking for first-order safety effects as opposed to inter-generational ones (perhaps he believes we ought to have stricter safety standards for researching drugs given to pregnant women?). I do suspect that on net this tradeoff would be worth it; that the cost of Thalidomides would be more than made up for by easier drug access and accelerated research.
The history as I have heard it is that prior to the thalidomide scandal, the FDA checked only for safety; after it, it started checking for effectiveness as well, ("Kefauver-Harris Drug Amendments"), even though the safety check caught thalidomide.
The first COVID vaccines passed the safety check in, IIRC, May 2020. The rest of the delay was effectiveness.
How many people died between May 2020 and whatever month in 2021 you choose to mark for the "general availability" of the vaccine, and why shouldn't we lay those deaths at the feet of the FDA? Somebody's got to go to jail.
I think overall it would still be worth it if some thalidomides got through, but see my response to Brad above - I don't think there's any need to compromise safety here.
Any clock should probably start with when it was approved for use in EU. Off label applications are allowed in US even when they haven't been "proven" to be effective. Simple reciprocity could have avoided the entire fiasco.
But Scott could have written the exact same paragraph, with exactly the same amount of outrage, only replacing '20' with '10.' This means he's basically right and just needs to make a minor correction.
Consider two different ways someone could be off by a factor of 2-4.
Example 1: I claim we should do my economic plan because it has a positive NPV of $1B compared to the next best alternative plan with a positive NPV of $0.9B. If it turns out my economic plan actually only had $250-$500M of value, my main point is refuted and I should retract.
Example 2: Imagine I'm going around screaming, we need to stop this serial killer because they've already killed 20 people! And it turns out they had, in fact, only killed 5 to 10. If I'd falsely attributed 10-15 deaths to the serial killer, I should correct that and discontinue saying the false number once I learn the truth. But the main point of stopping the serial killer is very much still in place!
Scott usually operates within a utilitarian-ish framework wherein certain things trade off against others, and therefore are generally examples of type 1. I generally operate within this framework as well, and when doing so being off by a factor of 2 *may* lead to significantly different conclusions!
Yes, Omegaven getting delayed is evidence against the FDA no matter what the duration of the delay is. However, the degree of evidence is proportional to the length of that delay (among some other factors like the magnitude of impact that delaying has). So when you're off by a factor of 2, you've doubled the evidence of your example! That should be a big deal.
That evidence against then has to trade off against evidence for: the FDA didn't approve thalidomide in the US largely because they deemed European approval insufficient. Its rules provide some protection, the question is whether the cost of that protection is too high. If you fudge the evidence by a factor of 2, that can significantly shift the answer.
>"I want a world where if Europeans have been giving fish oil based nutrient fluids to babies for years, and everybody from NBC News to random bloggers know that the babies are much less likely to die on fish-oil based fluids, and all the studies that have been done confirm it, you are allowed to give those babies the fish oil based fluids without waiting another five years for an FDA approval."
Isnt the problem in this case that it was not as clear cut as you are trying to make out, based on https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671012/ , it seems like there was actual opposition from within the medical community, not the FDA, and that along with a lack of support from the drug company was the reasons things took so long. Ie Gura calls out
`The fact that we demonstrated that IV soybean oil was detrimental, but IV fish oil was not, created controversy in the medical community. Papers and commentaries were published that suggested that Omegaven caused growth failure, bleeding, and progression of hepatic fibrosis. These criticisms led to us to do more translational and clinical studies.`
This being said it looks we got a pretty positive paper in Nature in 2011, https://www.nature.com/articles/jp2010182 , after which point it seems like education more that the FDA was the problem. Do we have any recorded cases of doctors who wanted to use Omegaven having any difficulty in acquiring it after this point?
Yes, "lack of support from the drug company" was relevant *in the context of the current system*, where without drug-company-level resources you can't push anything through the difficult FDA approval process. If you make it cost millions of dollars to do something, there will always be someone who resists paying.
There was (bad) opposition from within the medical community, but I don't think it would have passed a simple cost-benefit analysis, and a quick check at Europe, where this had been used for a long time, would have defused it.
In terms of "did doctors have trouble acquiring it" - doctors at hospitals that were willing to do an IND (very complicated FDA related process) did not, but very few hospitals were willing to do that. If you can call making people go through a very complicated process to vote "voter suppression", I think it's fair to call this "drug suppression". Of course you can always just do the complicated thing, but many people won't.
I am not so sure you can so quickly dismiss the opposition within the medical community, even in a world where there is no final FDA hurdle it is still going to take time and money to run the studies required to overturn this opposition if the conventional wisdom is that it was not the lipids.
Its also quite relevant when you are trying to present the narrative that everybody 'knew' for years that this worked and was safe, which doesn't seems to be the case. It reads like there was active opposition in the domain and it took time to do the science to prove them wrong.
Wouldn’t they have done that in this case too? Why couldn’t every hospital have done said paperwork in 2005 and saved all those babies? Maybe doctors themselves are the real ones who, to quote the Twitter thread I posted earlier, “should all be to be sent to The Hague”. Why didn’t the parents just push to ensure that happened? Is a bit of paperwork really that much?
(well it is! It’s a big an impediment)
Because that’s a counterfactual with a lot of distance between it and what we know. Maybe they wouldn’t have quickly! Maybe they would have in 2014 instead of 2018 - better, but 2/3 of the babies would still be dead! Consumer pressure isn’t exactly a great driver of health outcomes in many other areas.
If no doctor can prescribe it without an IND exception, then a parent might be SOL. But if any of them can and some just don't want to, parents can go from one of the doctors who says no to one who says yes, which presumably wouldn't require moving to Boston.
There's a few comparisons of the FDA to "random person on the street". I think this is unfair, because "random person on the street" probably wants to start treating everything with ivermectin, or ban masks because they cause irreparable damage to oxygen intake. The comparison you're actually making is "random person with a graduate degree on the internet". I think this would be a reasonable target, and one that is hopefully attainable by a bureaucracy full of graduate degrees.
The FDA is supposed to decide that a drug is safe and effective. What the median person thinks about invermectin matters when the median person thinks ivermectin *is effective*.
Not to mention that bad judgment cabout a drug treatment is going to be correlated with bad judgment about drugs in general. If you were governed by random people without graduate degrees it would certainly matter if they had bad judgment about drugs, even if they weren't prescribing treatments for you.
All his examples are places where highly educated people on the internet have come to conclusions that the FDA hasn't, but then he characterizes them as "random people on the street". That was my point.
I think the average person on the street hasn't heard of ivermectin and is totally fine with wearing masks (other than the inconvenience of it), but I guess this just depends on the streets you're walking on. I think ordinary people are more likely to have no opinion than the wrong opinion on most issues.
I'd say Ivermectin is actually the textbook case study for Scott's argument. At this point it doesn't actually matter if ivermectin works or not. I know an ivermectin advocate who, by the way, is an engineer at Google and highly qualified. Conversations about it with him go roughly like this:
Him: Hey, there's this great treatment for COVID. Here's a load of links to interviews with doctors and studies and other evidence suggesting that it is indeed, really great, at least when used as a prophylactic. Also it's been around for decades and is known to be totally safe even in high doses.
Other person: wow that's great news so how do I get myself some?
Him: You can't, it's not an approved drug so doctors won't prescribe it.
Other person: That sounds crazy, if there's so much evidence it works why isn't it approved?
Him: Because the legal basis for emergency approval of the vaccines rests on there being no available treatment for COVID. If drug agencies approved ivermectin, they would have to revoke the authorization of the vaccination programme. Also don't try searching YouTube for it, all the evidence is being erased.
Other person: what, why?!?!
Him: because the FDA hasn't approved it and tech firms think any medical ideas unapproved by regulators are dangerous.
Other person: ohhhhh.....
Note that the takeaway is invariant to whether ivermectin actually works or not. Governments and their regulators have got themselves into a position where they have so publicly and so strongly committed to vaccines as the One True Solution to COVID that they cannot approve any other treatment, regardless of what it is or how well it works. Nor can they admit to the possible existence of such treatments (would undermine their own authority) nor even obtain useful data about those treatments, because they only accept evidence that's very expensive to gather and nobody will fund such studies when they know that it won't be approved for political reasons anyway. And during all this the public health and media classes (which includes journal editors) are busy trying to cleanse all communication channels of any information that might undermine the vaccine rollout.
That sort of Kafka-esque catch 22 gets noticed and is the sort of thing public health agencies seem to specialize in creating.
Note: all the people making these terrible and stupid decisions have at least graduate degrees and often more. I'm in agreement with the sibling comment by WC. I'd much rather be ruled by a mix of people, many of whom do not have degrees, than a credentialed class. Consider that by the telling of their own journal editors, half or more than half of what professors publish is wrong. Those professors are then teaching those wrong things to their students, and those students then go into the world with a childish attitude that the teacher is always right, thus dealing double damage to society: not only are their heads pumped full of wrong beliefs but they've been inured into a culture in which criticism of professors is totally taboo.
One of the dangerous things about credentials, and being told for years that you are smart in general, is that you start to believe that you can solve all sorts of problems, and that if you can't that must mean you aren't smart. Both are huge incentives to try and force your rule on people and never admit that you are wrong, while making sure no one else does either.
I'm confused. Aren't there all sorts of treatments for covid that have been approved, ranging from regeneron and remdesivir to dexamethasone and the like? And can't you find all the information on studies involving ivermectin in the usual places? (i.e., not YouTube, but preprint servers and so on)
I'd say the usual place to find out about studies on a very timely and important topic would be the media, not pre-print servers that hardly anyone knows about. At least, the media they seem happy to write stories on the basis of pre-prints normally.
Good point about remdesivir. Perhaps the issue is that those drugs have also been approved under emergency use authorizations? I never got deep into the treatments side of things myself, but I have a vague feeling the original claim was something like "if there's a pre-approved / known safe drug treatment then the EUA for the vaccine would be revoked". If all treatments are considered to be as experimental as the vaccine then that presumably wouldn't apply.
As ivermectin is off-patent no pharma company is submitting evidence to the FDA that it's safe for use with COVID, because that new use case isn't patentable. This comes back to Scott's point about how safety and effectiveness should be unbundled. There's no argument I'm aware of that ivermectin is dangerous, but apparently that didn't stop it getting sinkholed.
I think you might have responded to the wrong post, but I will take a whack at your question from the perspective of mine.
Once you have assumed the right to force other people to do what you want (hereafter "rule") based on your credentials and general smarty-ness, there is a large cost associated with being wrong, or even just not entirely correct.
The main cost there is that people no longer feel the need to listen to you; you stop getting to rule. That's no fun, if only from an endowment effect angle.
Another cost is that there are people competing with you for rulership, and they will not be satisfied with saying "Well, you were largely correct, just a bit wrong in the particulars." These people might even be logically on your team, in so far as they want broadly the same things you do, but they all are definitely NOT on your team because they want one particular same thing you do: to rule. Thus any weakness they can demonstrate in your smartyness might well cost you your rule, so you need to never be wrong.
A third cost, that keeps you stuck in the "I am always right, always" dynamic, is that people want you to rule specifically because you will think for them. If you hedge and say "Well, on the one hand, there is X Y and Z to think about, but on the other you have A, B and C. You are going to have to weigh the costs and benefits and decide what is right for you," you are going to lose subjects. People HATE that shit. When I worked in industry and consulting some years ago, that was the number one take away: never show uncertainty. People don't go to smart people for advice or leadership to be told "Well, that's a tough choice, it depends." They go to smart people to be told "Ok, this is what you have to do, and it will fix all your problems."
If it turns out that something else fixes the problems too, well, that's called a competitor, and unless you can credibly blame not coming up with it yourself on your petitioner, as the smart person you had better come out against it and smash it into the ground, lest your supplicants go to that guru instead.
So from the official rulering smart people, there can be only their proposed solution: vaccination. Treatments don't do it, otherwise why not just let everyone who doesn't want to get vaccinated just get sick, get treated, and hey presto, now they are vaccinated too?
Throw in the accusation from e.g. Bret Weinstein that all the non-vaccine approaches like treatment need to either be emergency only or smashed into the ground because the emergency vaccine pass only works if there isn't an available treatment, and you get a decent explanation of why discussion of ivermectin is verboten. The pharmaceutical money doesn't want to see a super cheap solution to the problem, and the rulers don't want to see a solution that is different from their solution. Plus, who wants to let a good crisis go to waste all because it turns out a cheap and safe medicine can take care of it?
I rather expect this sort of logic is what drives the meme that vaccines are going to end COVID, or have any chance of doing so, despite exactly 1 virus being ended by vaccination, and corona viruses being very far away from smallpox. If politicians were to say "We just need you to get a vaccine and then another every fall for the rest of your life to make sure you are pretty unlikely to get COVID or spread it," people would be a lot less excited. Making COVID extinct gets very close to the ideal of "Make this problem not have happened" people are looking for in a leader, but if that is off the table the rulers seem a lot less appealing.
Now I'm confused about what you're replying to. I was just, in that comment, replying to the claim that the FDA *needs* to deny ivermectin in order to keep the vaccines approved, because, as I point out, the FDA *has* approved other treatments.
I'm not trying to engage in some major defense of how the FDA actually does things. I think there are all sorts of ways it can and should be improved.
In this particular comment I was trying to debunk the false claims in the comment I was replying to, and in my top level comment I was just pointing out that Scott shows "highly educated people can come to better decisions than the FDA" but then claims "the FDA does worse than a random person off the street", and I was saying that there's a big gap between those two claims.
Fair point. I dug up the language from the relevant law (search for "(3)that there is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition;" at https://www.law.cornell.edu/uscode/text/21/360bbb-3 )
Looking at remdesivir at the FDA's site, that was approved proper in Nov of 2020, specifically for treatment of COVID that requires hospitalization, and apparently can only be given in a hospital. All the others are still under emergency approval (EUA). That might be the key fact, that a treatment requiring hospitalization is not an adequate alternative to a vaccine, but at home treatments might be? Or the FDA just decided no one was going to check their work and force them to un-authorize the vaccine so late in the game, so didn't worry so much after last fall? I dunno.
The difference between the FDA and the random person on the street is that the random person on the street doesn't try to force their decisions on other people so much, and generally say "I dunno" if pressed. The FDA has a habit of forcing their choices on others by default. Besides, the group "random people off the street" does likely include "ACX readers and other miscellaneous smart people".
In part though, I am inclined to agree with you, Kenny, because I suspect that the behavior of the FDA is pretty closely to what the average person on the street thinks: we can be made totally safe and there are no trade offs between safety and health. At some point the average believe, or median perhaps, seems to have moved in that direction.
Right. I don't fully follow how the remdesivir approval hasn't caused the vaccines to become unauthorized. Unless there are other clauses that modify the one you quoted, the language doesn't seem to have any get-out clauses in it: remdesivir would be "approved and available" for "treating such disease".
Perhaps the disconnect here is that my friend is right about what the law says, and the law is simply being ignored along with everything else? That would certainly align with my priors on everything else COVID/public health related. The rules are super strict right up until they're not.
When I stop at a traffic light these days, I ask myself "Why am I doing what the government wants me to do, when I or any other fool can see that there are no cars and perhaps more importantly no policemen in sight?"
I didn't used to ask this question. Compliance was the default. Now it has become at issue.
The medical establishment has dug themselves a very deep hole. I don't know how they can escape. We may need a new organization to address widespread diseases.
Some medical professionals believe that ivermectin is a life-saving drug which has cured COVID-19 in otherwise terminal cases. But you (a "random person on the internet") should feel free to disagree with them.
"I think this is unfair, because "random person on the street" probably wants to start treating everything with ivermectin, or ban masks because they cause irreparable damage to oxygen intake"
That seems unlikely to me. What evidence are you basing this claim on?
Thank you for tackling this complex and vital topic. One question to contend with is who stands to lose if the FDA's mandate was unbundled as you suggested in your first post.
Yes and no. Lowering the barriers to entry would increase competition (not necessarily on the same drug, but via different drugs), and pharma spends similar amounts marketing to R&D anyway IIRC.
Increasing the number of players could potentially also weaken the pharma industry's regulatory capture (if enough of them opt out of bribing politicians), which would also endanger their profit margins.
Profit margins aren't the same thing as profits. Looser standards means larger market size, so a smaller slice of a larger pie can still mean a larger overall slice.
Begining to believe in something like: "libertarianism is inevitable if it's correct." In other words, if libertarianism really works, we should expect it to just arise naturally, on its own. If you need some state actors to force the state of the world into libertarianism, we should expect random perturbations to eventually knock it out of libertarianism.
So then you ask, ok, but what would it look like if the world fell into libertarianism? Certainly it wouldn't' be 'large crowds voting for limited government and consistently keeping an eye on politicians and being aware of all the ways people come into power over states' - i think it's more likely that it would be 'the dissolution of states ability to function and the general breakdown of state reputation, period'.
So rather than imaging a world where we shut down the FDA and let drug research go and then people make their own risk/reward decisions, it's easier to imagine this playing out the way uber played out: it's not like people voted against taxi medallions. Someone just started breaking the law, and once they made enough money, it wasn't really political feasible to stop them. Now replace uber with a bunch of decentralized autonomous networks, and, well...
I disagree. Uber is a car service, NOT a taxi. The hallmark of a taxi is that it can be hailed on the street, and Ubers can't. You could ALWAYS call a car service and car services were NOT required to have a taxi license.
> If you need some state actors to force the state of the world into libertarianism, we should expect random perturbations to eventually knock it out of libertarianism.
I'm under the impression that it used to be much more libertarian and already fell out of it. I.e. the patent medicine era, with some effective medicines, some merely ineffective, and of course radium-containing energy drinks, infant soothers with opium, curing people via radio, supplements with ground-up mummies in them (!) (also used as paint), the works.
And in countries all over the place people didn't like it and passed regulations about it. For better or worse. So I think that's an important question (and it's relevant to many areas beyond drug regulation).
Worth noting that we have such things today too, Steve Jobs famously spent a long time worshipping at that altar. Various kinds of alternative medicines are wildly popular. I don't see medical regulators banning acupuncture anytime soon, do you?
IOW the quack doctors from the patent medicine may seem to have disappeared, but did they really? Or did they just change what they were selling in ways that are evolved to evade our BS detectors?
To roughly quote Terry Pratchett in "Feet of Clay": Humans have a design flaw; inside each of their heads is a little space upon which is written "Kings... what a good idea!"
Now that you mention it, I wonder if that is what Pratchett had in mind as inspiration. The book is about golems, after all. (And a simply fantastic read, by the way. Probably top 3 of his novels.)
What's going to happen is that states will draw back their 10th A power and start writing laws that conflict with federal government law, AND (more to the point) back them up by defending "transgressors" against the federal government. I mean, there's no law which lets the federal government ignore the Constitutional strictures, and the Supreme Court would have a hard time ruling against a US state that was actively encouraging its citizens to ignore unConstitutional laws.
For example, Larry Sharpe suggests that sales of any product which is produced and sold entirely in one state should not be subject to a federal income tax. Any state could proclaim this, and defend the state's resident against any efforts by the feds to acquire the taxes they claim.
So? No reason why the states cannot violate the Constitution. It's not like the federal government has any idea what it says, so they wouldn't be consulting it to see if what a state is doing complies with or violates the Constitution.
I think engaging with Drum & his community might be kicking the hornet's nest of a highly sneery community whose mostly uninterested in hearing/discussing opposing viewpoints. Unclear upside with visible downside. That's a reasonable opinion to have.
Don't you think the whole "Scott is one of my heroes. It hurts to see him tested this way" might be a little melodramatic? Scott is not Christ, my comment isn't Satan, and this Substack isn't 40 days in the desert.
But Scott *is* Christ. "Christ" is not a person, it's a role. That's why he's *Jesus* [the] Christ. Like Trump the President or Biden the President or Alexander the President.
His intellectual rigour is highly variable. He puts out a lot of partisan fluff, but he also does enough quality think-pieces that a lot of people forget or forgive the former. Especially people who are in the same general segment of the ideological landscape (technocratic center-left) as Drum.
The thing Drum probably gets the most credit for is popularizing the lead-crime hypothesis: he wrote a series of articles explaining and summarizing the evidence for it and the proposed mechanisms for it, which got picked up and discussed by a bunch of other bloggers and opinion writers.
Is the lead-crime hypothesis an example of his rigor? Pinker wrote a scholarly tome about violence a few years ago and didn't think to mention it at all.
It does seem like he was wrong about lead & crime, but as far as criminology goes it's one of the most reasonable mistakes a commentator has made on it, which puts him above most.
Drum is actually pretty great, has debunked a lot of bad science, and is one of the people most responsible for getting the lead-crime hypothesis into public knowledge. I admit I don't read him regularly and only see him when a lot of people are missing him, so I might only be seeing his best work.
I would like to point out how remarkable it is that these articles, over the last few days, have cumulatively generated tens of thousands of words of criticism about how awful the FDA is and you haven't even said anything about pharma companies manipulating the science to win approval while the FDA haplessly signs off on it.
Perhaps that point has been argued to death and it's super boring to keep talking about, but just for completeness it's worth mentioning the Alzheimer's drug is the lite form of a different FDA badness controversy. The deluxe version is that the FDA has also corruptly and incompetently approved drugs it shouldn't have.
So, we can't even say it's worth it to slow the pace of drug development to an expensive mind numbing crawl because at least when the FDA approves something we can be certain it's solid. We don't have that assurance either.
I mean both run-of-the-mill bribery like naked exchanges of cash for approval (seemingly rare), but also more nuanced ethical eyebrow raising like pharma companies directly funding about 50% of their budget and also regulatory capture concerns.
There's a lot more in Ben Goodacre's book, which I don't have handy.
Yeah, I think the current system is something like "the FDA sets a very high bar for efficacy, pharma companies cheat to meet it, the FDA brings the bar higher, pharma companies cheat even more", and so on.
I realize that "it's easy to cheat" and "they're very strict" seem like opposite problems, but I think there's actually a weird sense in which they contribute to each other. A lot of FDA approvals are something like:
- There's some drug that obviously should exist but doesn't because the FDA is too strict
- This becomes a big embarrassment
- Some pharma company proposes a drug that fills the gap
- The FDA lets it through to end their embarrassment
This is what happened with ketamine. We knew ketamine treated depression really effectively. Nobody was willing to get it through the FDA because it was off-patent and they couldn't make money off it. Some pharma company finally applied for an approval for esketamine, a patentable chemical which is very much like ketamine and would let the FDA look on top of the ketamine situation. The esketamine (surprisingly to everyone including me) didn't seem to work very well, but it was so embarrassing not having ketamine be available that the FDA gave up and let them use it.
I don't know if this is at all common, but it's one of the examples I'm personally most familiar with.
I guess a problem is, approval or not, shouldn’t those trials happen anyway for off parent drugs? Even if some docs are allows to prescribe it, their resistance in the omegaven saga and many others means most won’t. And then you’ll still need a series of trials to really prove it works so everyone uses it. Can the expense of trials be reduced? Can doctors do their own trials - but reading the omegaven story the FDA at least encouraged trials a little while every other entity ignored the possibility. Is there anyone with reasons to do trials on generics?
Might be less than 100MM if your “trials” are based on prescriptions that are already happening, I.e. you don’t need to pay for the prescriptions but just provide doctors with a randomization placebo blinding tool for drugs they’re already prescribing? Idfk. If you’re loosening prescription restrictions one should track and maybe randomize them
For me this is a classic “half an argument”. You’ve successfully shown that there are lots of problems with the FDA. What you haven’t yet done is show that any possible alternative would be better.
In particular, the situation I fear is that drug vendors, unrestricted by an FDA, would peddle many ineffective drugs, and it would make everyone’s life much harder. I’ve never seen a good argument that suggests the market would be able to fix this problem.
I mean like the 19th century, when snake oil was a real product, not just a metaphor. (In fact, the problem wasn't even the snake oil, which is dubious Chinese medicine. The problem was the many knock-offs of snake oil.)
You seem to be imagining that drug advertisements in a non-FDA would would dutifully report the results of high-quality trials. I don't think that's how marketing works. I don't think it's how marketing would work in a world of unregulated or less-regulated medicine.
The classic model of a market involves a buyer and a seller who are both fully cognisant of their own needs and of the features of the product being sold. Where that doesn't hold (e.g. patients lack medical knowledge), there is no way, even in theory, for a market to be effective. Now, there are many mechanisms that can make up for this problem. One is regulation (think FDA). Another is consumer education (I can't see how this could work). Another is third-party certification (think Cochrane Approved). Another is chains of intermediaries (think doctor recommendations). All of these have been suggested; so far as I can see, none of them look like they will convincingly solve the problem.
Again, that sounds naive. Pressure from investors to have meticulous disclosure? The pressure you get from investors, by definition, is to make more money. All I'm suggesting would happen is something that already happens: drug companies would try to maximise the apparent benefits of their drugs. And now there would be no FDA to stop them. Think of the prescription opioid crisis of the 2010s.
If the FDA disappeared in a puff of smoke, of course, the rest of the medical establishment would adapt, change its practices, develop new approaches to working out which drugs are safe and effective and which aren't. What I'm saying is, there has never been an advanced medical system on earth that doesn't have something like an FDA. So what's being proposed here is pretty new. Maybe it could work. But I don't think I've ever seen a realistic proposal for what the new mechanisms or institutions would look like. If Scott has some ideas, I'll be reading them with interest.
But you seemed to be suggesting that this was just a really trivial problem, and of course people will choose the best drugs. That's incorrect. It's not trivial.
Once again, something that you think would be simple doesn’t seem simple to me. Here are two reasons: (1) Handing medical regulation over to the existing tort system would mean that questions of medical research would have to be decided in court. Courts historically refuse to do that. It’s not inconceivable that you’d have a medical court to decide issues of effectiveness, but it would have to be a new institution. And that’s what I’m asking for: the other half of the argument. What would this medical court look like, and why would it perform better than the current system?
(2) Most of the issues around the licensing of drugs involve probabilities. Drugs usually have side effects; many new drugs are effective for some people. The question that the FDA asks is how bad/frequent are the side effects; and does this drug help more/fewer people than the current standard. Neither of these questions are easily amenable to tort cases. Even class actions would struggle (e.g. the drug vendor admits the drug will kill 5% of patients; in reality it kills 8%; who are the victims who deserve compensation?). Again, these questions aren’t insoluble, they’re just difficult. I’d want to see some attempt at answering them and quantifying them before I’d think a big change in the current system would be a good idea.
>The probability a priori that the FDA is literally the best of all possible worlds is actually infinitesimal.
This is literally true, but useless as a source of insight. It's improbable that the current FDA is the best of all possible worlds because it's improbable that *any specific situation* is the best of all possible worlds.
This has nothing to do with the FDA specifically, it has to do with the fact that you really need to be asking about a range: "is the FDA a lot closer to the best of all possible worlds than the nontrivial FDA alternatives?" That one isn't improbable.
You are acting as one of those Internet literalists who thinks "that isn't literally accurate" means something when he's ignoring connotation and context.
"You need to show that some alternative is better" in this context doesn't literally mean that you can show that *any alternative* is better. There's probably some better variation on the FDA which is nearly the same as the existing FDA but with a trivial change. That doesn't count. What it means is that you need to show that some substantially different alternative to the FDA is better.
They would peddle lots of ineffective drugs. And people consume lots of ineffective medicine right now (that's a focus of Robin Hanson's research). It's a question of cost/benefit. You internalize the cost of buying an ineffective medicine, as well as the benefit of an effective one. The FDA does not have much upside from you not losing your intestine because you got access to a drug that's actually good.
It's easy to point out problems, because almost nothing is perfect and most organizations only occasionally "pretty good" on a Pareto-optimal basis. So how about if someone describes a pathway for new legislation that would direct FDA to take some of the good steps described here? There would be at least two parts: (1) What changes should be made, and (2) What's the practical path to making those changes. IMHO, pretty much anything else is pretty much "Someone else do the hard work." I mean, if you want to just complain about something FDA, take a look at the QC and inspection regime for imported generic drugs.
Two very simple options would be to go back to the 1960's FDA that didn't test effectiveness, and to allow anyone to sell with approval from one of a few agencies, such as EMA or the Japanese one.
Of course it isn't. People with a moat around their product due to expensive FDA approval would lose out! Pecuniary externalities prevent Pareto optimality. Did you mean Kaldor-Hicks efficiency?
I want a world where the drug company will accept the FDA's desired wording on the warning label and distribute the lifesaving drug while they try to convince the FDA to temper down the warning in the meantime. Or was that not an option?
I'm relying entirely on the content in Scott's link to the original story, entitled "The FDA almost killed me":
"Even though the FDA had granted Enyvio Priority Review Status, for the next five months the FDA kept John (and undoubtedly many others) suffering as they debated the wording for the warning label...The FDA wanted to put a warning about the possibility of a severe allergic reaction on the label...A warning about allergic reactions would make Entyvio look less safe, something that the company rightly took objection to..."
"Another possible reason for the delay might be related to the fact that the FDA claimed that Entyvio put patients at risk for progressive multifocal leukoencephalopathy (PML)...The company disputed this...but the FDA wasn’t convinced. In the end, the FDA decided to include a warning about PML on the label and require post-market surveillance."
I too would like this. But I think it's like "instead of declaring war, why not just have dictators give up their weapons of mass destruction peacefully", or "instead of resisting arrest, how about people just surrender to the police, or even better, never do anything suspicious to begin with". Might be great if it worked, but it's easier to determine what the government demands than to turn people into angels who always follow all demands no matter how extreme.
I think that "instead of resisting arrest, how about people just surrender to the police and let the criminal justice system sort it out" is our actual system, which, despite the inequities of the criminal justice system, probably works better than the alternative.
To clarify, I think that the drug company's action here is part and parcel of the problematic system (within which the FDA is the implementing actor). If one thinks drug companies are evil, one would say they knew a too-strict warning label would permanently taint the drug and lower profits in the long run, so they held out. If one thinks drug companies are great, just substitute "lower drug acceptance and cause unneeded deaths" for "lower profits" in the previous sentence.
Every time some process seems to go especially badly in the United States one should check how the same problem played out in Canada. In this case I wonder how long it took them to approve the fish oil variant treatment...
"Silenor brand paid a $100 million FDA application fee" and "even though the manufacturer did not give the FDA $100 million dollars." - PDUFA fees are closer to $3M. Clinical programs can run in the hundreds+ of million dollars, but that money isn't going to the FDA.
" only to be frustrated by repeated questions about the drug's sustained subjective sleep maintenance efficacy in non-elderly adults with primary insomnia"
Looking at that line, this seems to raise a good question about the efficacy of the drug and if the company couldn't or wouldn't answer it, no wonder it took so long to get approval. If I'm a thirty-five year old insomniac and I get prescribed this drug and it works for a while then stops working, I want to know about that and not "well if you were eighty with hypertension it would knock you out for months!"
"Nevertheless, executives could raise their champagne glasses this morning as the developer's share price (SOMX) shot up 80 percent on the news."
"Somaxon has spent $108m on R&D in the last six years as it has pushed the drug towards the market and the next thing it is likely to do is ask investors for some more cash to help finish the job, capitalising on its two-and-a-half year high share price. With $4m left in the bank the company needs to top up the coffers quick smart to give it a fighting chance of sealing a decent commercialisation deal.
However, Silenor will be competing against some very entrenched products, like Dainippon Sumitomo’s Lunesta and multiple generic versions of Sanofi-Aventis’ Ambien, which was generating sales of $2.5bn a year before it lost patent protection in 2007.
Despite the huge amounts of money thrown at Lunesta by its former owner, Sepracor, the drug is probably more famous for its hugely expensive marketing campaigns than commercial success – sales reached $736m last year – and many have concluded that the insomnia market is only for the brave.
Combine this with the fact that the active ingredient in Silenor is available generically, and not all observers are expecting the drug to be the next insomnia blockbuster."
No wonder they want to charge $250 a go for a prescription. And no wonder they want to try and make sure they're the only one licenced for this use.
And perhaps this is why the makers of Sinequan decided to market it as an antidepressant and not a sleep aid - too much competition, not enough profit in the insomnia market, but there's always room for another antidepressant as people regularly cycle through all the alternatives to try and find one that works for them.
I see that doxepin was approved in the USA in 1969, so again this sounds like another example of "take an old medication, give it a slight spin, brand it as new and charge full whack for it". Doxepin-as-Sinequan was already established so doxepin-as-Silenor was a new branding by a different company (Pfizer were manufacturing Sinequan).
Sinequan seems to have been discontinued since 2006? Presumably because it was so cheap and generic that it wasn't enough of a cash cow?
There's a couple common proposed solutions to this problem:
1) Radical deregulation (abolish the FDA)
2) Radical change in government to make it more efficient
Regarding (1) - we have some experience from where geographically and historically regulations are less enforced.
The issue with (1) is that people respond to incentives. And there are two incentives here - the incentive to act in a framework of rationality for the greater good, and the incentive to make money.
In the past, the market for cure-alls was was very lucrative (they sold energy drinks that contained real radium, among other things). No doubt many salesman genuinely believed in the effectiveness of their products, so they were making money and doing good at the same time. You see a similar thing with the supplement industry today.
For a modern day example, in Ukraine today you can be upsold ineffective alternative-medicine treatments when you go to routine dental visits.
To strongman radical deregulation a bit, I think it could work out well for people like us who are maybe a bit more able and willing to vet in detail all medical treatment we receive. And, in practice, many people may become distrustful of the health-care-services market (just like people would be distrustful of the stock market if it was full of scams) and avoid purchasing health care at all or only purchase services from a few big gatekeepers (perhaps big hospital systems like Kaiser).
While the last point might resemble the old system in certain ways, it avoids some of the perils of centralization and central-points-of-failure. And if you kept non-profit status and a monthly subscription model, that avoids many of the obvious adverse financial incentives.
You might see a concerted marketing push to lure people people away from evidence-based systems to higher-margin ones though (which would have more money available to buy ads). And hospital systems don't currently pay for drug trials - if that remained up to the drug companies themselves, there are still obvious adverse incentives there.
Ok, on to point (2), radical change in government. This is an increasingly popular position on the modern right and I think more politically realistic than (1). We need a CEO / monarch / whatever word you want to use in place of "dictator". After all, corporations are more efficient, right? Except for all the ones that aren't because they are monopolistic and can afford not to be or never become big to begin with. But let's ignore those for a second.
Again, let's look at the incentives. Of course there's the basic one - staying in power because they don't want to be killed or go to jail forever. And of course the desire to make money. But there's also the intrinsic motivation of technocratic health care reform.
You can look at dictatorships all over the world and see how they do, on average. And you can also look at the group of people such a person is likely to be selected from, in the US. Do they seem particularly interested in technocratic health care reform? What is the likely outcome here? Do they even show close to the level of intelligence and self-restraint as autocrats like Orban? (Who as far as I know, isn't known for his health care policies.)
There's may be an option (3), which is find a specific incremental reform that seems to be the most valuable, and try to build support for it among the public / institutions / and/or political class, which is where currently where change comes from. But that's not exciting.
I want to clarify the Ukraine example - I'm talking about mixing evidence-based and not-evidence-based-but-presented-as-evidence-based treatments together, where they look the same and the distinction isn't obvious to the consumer (and of course the not-evidence based products provide their own marketing material that makes this easy for the providers). So, something that's not directly analogous to how alternative medicine works in the US.
The not-evidence-based ones of course present their own evidence but don't have the proper level of rigor, so the consumer would have to vet the rigor of the scientific study and the trustworthiness of the data, or find a reliable third party source in an online environment where there is a big financial incentive for the producer to make sure their message is heard better (and it's also cheaper to write articles mindlessly promoting something that properly evaluating it).
I don't speak Ukrainian so I can't say if these sites exist. I can say based on other markets that even review sites can be easily created and gamed or cut deals with manufacturers if there's money in it, look at the mattress industry in the US.
Let's assume the FDA, and the regulatory system it is part of, is uniquely bad in the ways Scott outline, and either stops many useful medications from being developed, or delays them by decades.
Why doesn't the other 95% of the world develop those medications?
Or do they, and we never hear about it? If so, what great, banned in USA, cures are out there?
I don't think the thesis is that the FDA is *uniquely* horrible. A quick googling suggests that the EU, Britain, Japan, and South Korea all have drug approval processes that are conceptually similar to that used in the US. There are incremental improvements over the FDA in many of these countries, but none of them sound like libertarian paradises (or libertarian dystopias, depending on how you feel about laissez faire).
One of the bigger differences, which seems like low-hanging fruit for incremental FDA reform, is that many of these countries allow some form of expedited review based on existing data for drugs approved by other countries with similar standards. This is especially a factor for the EU, where individual countries have their own approval processes (and Germany in particular seems relatively lenient) and the central EU agency providing a bridge for expedited EU-wide approval once one or more member states have approved.
Another factor is that the US is unique in being a large, rich country with strong patent protection and little in the way of price-fixing for prescription drugs. The FDA can get away with being more expensive and time-consuming to deal with than the rest of the developed world because potential profits from selling prescription drugs are much more heavily concentrated in the US than your 5% figure suggests.
Germany is very lenient; for some reason, Germans are extremely fond of homeopathy and biodynamic cures and the rest of it, and such cures (which are often laughed to scorn on here) get prescribed by ordinary doctors and paid for by medical insurance plans:
I'm very happy to buy German cosmetic brands that are all vegan biodynamic etc. etc. etc. (e.g the Weleda brand or Dr. Hauschka - the rose cream is expensive but great for mature skin https://www.drh.ie/face/28-rose-day-cream.html) but I would not go for medical treatments of the same nature.
According to this article in German from 2019 [1], of 40 billion € paid for medical remedies by public health insurance, homeopathic remedies only accounted for 20 million €. While I don't like that, either, it's essentially negligible in comparison (0.05% of the total).
The overall market is much bigger, but it's presumably paid for by private insurance or out of pocket. I don't endorse spending one's own money on homeopathy, either, but would certainly not advocate for forbidding that.
I wonder what fraction of hte homeopathic remedies are prescribed to people when the doctor just thinks they don't need any medicine but they'll complain if they don't get something.
The US is 24% of the GWP (nominal, since that's what matters to multinationals), and probably about 40-50% of the available money extractable by pharma (developing world uses less pharmaceuticals, and is extremely willing to revoke patents if significant profiteering takes place). "95%" is a bit of an exaggeration.
The main reason the US is the main source of pharma is that nearly everywhere else has state run medical systems that very heavily restrict what you can charge for a medicine, either legislatively/regulatorily setting the price or being the sole purchaser and so effectively setting the price that way. In effect, US consumers pay for the large majority of the development of all new drugs. Not all, some still happens in other parts of the world, but it is very heavily weighted towards the US.
Developing a drug or medical device outside the US then trying to sell it inside the US to make back the costs just adds the hurdles of learning a foreign legal and regulatory system, not to mention language, to the normal FDA hurdles.
Adding to that, it isn't obvious that the FDA is a lot worse than the regulatory agencies of other countries or regions, although not accepting the work of the EU or Japanese (or others) regulatory agencies is odd. I have heard complaints from other countries that sound a lot like the usual FDA issues.
(Which shows that the FDA forcing pre-registration of clinical trials massively improved the published data by eliminating undetectable p-hacking.)
Without a barrier similar to the FDA's mandate to evaluate efficacy, who will actually force drug companies to do good science instead of 'looks good' science? Bad science is better for business because it is far less likely to fail your drug.
No, you can't simply handwave the practical issues with demonstrating malfeasance by establishing an incentive for 'sniffing out torts'. A lack of incentive isn't the biggest problem with relying on torts; it's the inability to detect p-hacking after the fact. If a study isn't pre-registered, p-hacking is completely non-detectable.
I also doubt very much that most p-hacking would be legally fraud. Running ten endpoints and publishing the three most promising and interesting ones really isn't 'lying about what your drug does' by the layman's sense of the word 'lying'. It's statistical malfeasance, but probably not legal malfeasance.
I'm also incredibly skeptical of the idea that the FDA's high standard of proof made drug studies worse that they would be without it. Good studies are harder and more expensive than bad ones, and without some incentive to do good ones I expect very few good ones to be done.
Well, the US is already extremely litigious society. Maybe it is good in certain aspects as it ensures better consumer rights but generally I think that we can solve more conflicts without involving courts.
The FDA could give a seal of approval to only those companies which do such pre-registered trials, but it's still legal to buy drugs without the seal. So uncertain low-information consumers can look for the seal, and desperate people who don't want to die can take their chances.
Yeah, something like that might work. I like the similar idea Scott mentioned about a 1-5 star ranking for drugs with variable prescribability (though it's complex enough that I worry about how it would end up working in practice and public opinion.)
As Scott discussed in the original post, you can still have an agency tasked with "determine if a drug works according to an agreed-upon criteria". The idea is to decouple that from "determine if a drug is safe" and "decide whether it's legal to use a drug" and (maybe) from "decide whether insurance companies should be required to provide the drug". The fish oil story goes very differently if the doctors only needed approval from the "Drug Safety Administration" and the "Drug effectiveness administration" was out of the picture.
Right, but... what's going to incentivize pharma companies dumping millions of dollars on good, well-designed trials? They can probably get 90% of the profit by just proving safety and then advertizing well.
"In 2013, NBC ran an article called Drug Treatment Omegaven That Could Save Infant Lives Not Yet Approved By FDA. In 2014, libertarian blogs were using it as an example of excessive FDA delay"
In other words, two institutions that are highly motivated to report that there's a miracle cure being held up by the FDA said, guess what, there's a miracle cure being held up by the FDA. I would not call that very convincing evidence that objective observers were of the belief that something might be going on here.
My argument is that (1) lots of people were asserting Omegaven was great long before the FDA approved it, and (2) those people were right.
I was using the links to prove (1). For (2), see the UpToDate quote in my last article, the Dr. Gura piece, the 2011 study, and (last but not least) the fact that the FDA did eventually approve it.
But you don’t think it’s relevant that the “lots of people” were, at least in the beginning, highly motivated to tell that story? If we look through their archives, don’t you think we’ll find that both NBC and those blogs have cried wolf on this topic?
Problems like this are not unique to the FDA. I venture to say that all government agencies and many private businesses eventually fall victim to massive inefficiencies. Parkinson's Law provides a decent explanation of how this can happen. Basically as an agency gets larger the needs of the members of the organization (getting promoted, gaining prestige, not getting blamed for anything etc.) are at odds with the needs of the public the agency allegedly serves. I used to work with the IRS. In my current career I deal with the FCC and FAA regularly and I can assure you that these organizations are as difficult deal with as the FDA. While they don't (usually) kill people they do ruin their lives.
In a perfect world when a private business becomes inefficient, it falls victim to a more efficient competitor. Government agencies however seem to last forever.
I think that it is useful to have a rigorous process for drugs that will be used for decades by tens of millions of people.
But if babies are dying now or there is a raging pandemic then it makes no sense to follow this process. I know it’s wild but maybe the FDA could have a “compassionate use” exception for drugs that anecdotally clearly seem to help patients but where we don’t have RCT studies, and “emergency use approval” for vaccines when there is a raging pandemic.
… sarcasm off: I am guessing that by and large the FDA does “err on the side of caution”. It may well be that if there is a lever in the FDA to make the process lighter weight then someone should make it 5-10% lighter but I don’t think it should go all the way to the max. Drugs are really really hard to evaluate and the average person or doctor really can’t tell if they work or not. This is not a situation that the free market would work well in. Ideally there should be a cost/benefit/profit/damage analysis that ensures the process is tailored to (1) the benefit per patient of the drug works vs (2) the potential harms to the patient if it is unsafe or doesn’t work (which can also harm) but also societal aspects such as the total cost of the drug to the system, which is also proportional to the profit of the manufacturer and their ability to fund the process.
A drug that will be used by tens of millions and will make billions of dollars in profit should be subjected to a higher standard than a drug that will only be used by few patients for a rare condition. I don’t know if this is or isn’t the case now.
This reminds me of restaurants in Albuquerque. In the old days anybody could open an Mexican food stand, and taco trucks roamed the streets. Then the restaurant association got the city to require licensing, fees, inspections - things that larger restaurants, esp chains, had no trouble meeting, but drove the mom and pop places out of business. Now if you want a breakfast burrito you buy it out of the trunk of someone's 72 Chevy, with exponentially greater health risks. My favorite part, however, is how the restaurant association is always complaining to the press about too much regulation.
As someone who doesn't live in the USA, I want to emphasise that the choice isn't "FDA or snake oil", the debate is much more complicated than that. There are lots of different systems around the world that face the exact same challenges as the FDA but respond in different ways:
According to this article, the FDA is the most expensive (for both the government and for the drug companies) and takes significantly longer than most other equivalent agencies. Now, paying more for worse service seems like a general problem with the American healthcare system, but it does suggest that changes could be made without worsening the quality of healthcare - a shorter and less expensive application process would be a great start - you'd have access to more drugs at a lower cost!
I think it’s worth noting that the FDA is probably more expensive in part because so much more drug development happens here. And the FDA takes longer to approve drugs, certainly, but probably because the drugs often get developed in the US for approval at the FDA first, and then the evidence is already collected for other trials. I’m not so sure we can just “take that trade off” as we’re in a different situation. In terms of costs, we likely do overspend, as you say that is a general characteristic of US healthcare - but I’m not sure we can change speed just by switching to other systems - and also US personnel and all other costs are just higher than other countries due to higher incomes. And the us FDA does not appear to take significantly longer than similar agencies here, as it has the second lowest mean approval time (333 day) higher than Japan and UK (311 and 230). I don’t
And as my above comment about roxadustat shows - when other health systems try to fast track the FDA approval, they may screw up. Here, China fast tracked approval and got a “historic” approval on a drug before the US - but after the FDA “capriciously” delayed and delayed and delayed, it came out that they had incorrectly performed a the safety analysis on a trial and the advisory committee voted to not approve on grounds of risk benefit not favorable. https://astralcodexten.substack.com/p/contra-drum-on-the-fish-oil-story/comments#comment-2571594
In the story about vedolizumab (Entyvio) I would also blame the drug company for not advising the patient that their stock is nearing expiration and since the approval is taking longer than expected, he should ask for compassionate use which would have been granted.
In really this was probably a big company with poor communication between departments and most likely no one really cared or even knew that the batch is expiring until they finally received the approval.
Another thing is that initial expiry dates are often very arbitrary. The regulator requires studies to justify longer storage times. Sometimes they can be proved by accelerated aging (higher temperature, humidity) and extrapolating this data. In case of products stored in the fridge (2°C-8°C) it's probably harder and the most common way is simply to store the product and see how it deteriorates. Initial batches have short expiry dates but after one or two years more data comes in and usually the expiry dates can be made longer. It is very likely that the batch they couldn't give to the patient for legal reasons was actually good.
The FDA screws up every hour of every day, in the same way our hypothetical False Data Administration screws up every hour of every day. Not because they’re constantly making stupid, minor mistakes. But because their whole mandate / philosophy / modus operandi is mistaken.
which, to be fair, does sound different from
Every single thing the FDA does is like this. Every single hour of every single day the FDA does things exactly this stupid and destructive.
... but I get it. You are angry and the FDA may fulfil its mandate pretty well but it's still the face of the bureaucratic apparatus kicking you in the groin...
That being said. Why is the FDA set up the way it is? Is not ultimately a reflexion of how risk adverse and uneducated (when it comes to probas/stats) the population is? Or at least how responsive the political system is to such population?
The FDA isn't some anomaly within the US Government. This is the administrative state - this is how our government functions (it's the culmination of the New Deal State). (This post is an excellent example of Conquest's First Law of Politics though).
The criticisms are valid, but talk about missing the forest for the tree. You can't change the way the FDA works without changing the function of the government.
I’m assuming you’re approaching this from the reactionary perspective?
If so, then why are the relatively absolutist or dictatorial states that have good technological development - Singapore, China, etc - not much better about drug safety and approvals?
Also, . We became aware that the primary cardiovascular safety analyses included post-hoc changes to the stratification factors,” Enrique Conterno, CEO of FibroGen, said in a press release. “It is important to emphasize that this does not impact our conclusion regarding the comparability, with respect to cardiovascular safety of roxadustat to epoetin-alfa in dialysis-dependent (DD) patients and to placebo in non-dialysis dependent (NDD) patients.”
Based on the analysis, however, “we cannot conclude that roxadustat reduces the risk of (or is superior to) MACE+ in dialysis, and MACE and MACE+ in incident dialysis compared to epoetin-alfa,” Conterno said in the release.
The Institute for Clinical and Economic Review also released a report stating there was insufficient data to show that the HIF-PH inhibitor provided a health benefit over currently available anemia drugs, such as Aranesp (Amgen Inc.).
I think it's fairly obvious why China would be bad at this (https://en.wikipedia.org/wiki/Lysenkoism). I certainly wouldn't defend the Chinese regime's rigorous devotion to any objective facts.
Singapore is a better question. I worked on a project with the Monetary Authority of Singapore for a year or two and my impression is that many of their more technical government agencies are set up to work like the ones in the US.
Note that I'm not saying that the administrative state is bad - I'd rather have the FDA making these decisions than Congress or the actual Executive Branch. You just can't criticize it for being itself. The administrative state does indeed function like the administrative state! Amazing discovery.
I think taking the Chinese market as an example of "wonder drugs" would indeed be dodgy, after all this is the same market that needed their government to crack down on people putting melamine into raw milk to boost protein content, leading to contaminated infant formula as well as other food products:
Not to be pointing fingers at the Chinese as the sole persons ever to do shit like this, people *everywhere* will and do adulterate food products in order to increase their profit margin. Things like this are why we have institutions like the FDA and comparable regulatory bodies in the first place.
Letter from the American Academy of Pediatrics calling for the FDA to use cost/benefit/common sense to speed up approval of the vaccine for under 12 children,
Would this work though? The benefits for kids under 12 (or under 4 or under 18) for a Covid vaccine are pretty close to zero (at least the first order benefits, maybe would help old people, but that's not obvious given how little it seems to spread among children). The costs of other vaccines to children are definitely non-zero (all treatments have some side effects).
It's almost certain, given the extreme changes in outcomes for Covid by age, that the vaccine wouldn't pass cost/benefit below a certain age (not certain where that age is).
Yes, this is very low. The 350 is for 18 and under and it's not clear how many died with Covid vs from Covid (estimates have been as low as 0 for from Covid).
The broader pointer stands. As you go further down the age range, the benefits get and less, while there are still some costs. At some age level, the lines are going to cross.
"Since the approval of earlier monoclonal antibody drugs such as Remicade and Humira, scientists learned that in the long term some patients can develop allergic reactions to treatment. The FDA wanted to put a warning about the possibility of a severe allergic reaction on the label. The problem was that the drug had been designed specifically to avoid the allergic reaction rejection problems that occurred with Remicade and Humira, drugs which did not contain such a warning. A warning about allergic reactions would make Entyvio look less safe, something that the company rightly took objection to."
Because I *am* that bitch, I went to have a look about the warning of side-effects that the FDA imposed upon the makers of Entyvio, in particular the allergic reaction ones.
Given that within the story itself, John had suffered allergic reactions ("That all changed suddenly and unexpectedly in 2005 when his throat closed up after his injection. Unfortunately, as happens to many long-term Remicade patients, his body had developed an immune response to the drug. In response doctors switched him to a similar monoclonal antibody drug, Humira. However by 2013 his immune system had started rejecting the Humira as well"), and that once someone has already shown such reactions to medication, they are somewhat more likely to have similar reactions to other medication, I think that the FDA were considering all the "Johns" out there who would want to go on to the new wonder-drug Entyvio.
So what is this warning? From the company's own website:
"Infusion-related and serious allergic reactions can happen while you are receiving ENTYVIO or several hours after treatment. You may need treatment if you have an allergic reaction. Tell your healthcare provider or get immediate medical help if you get any of these symptoms during or after an infusion of ENTYVIO: rash, itching, swelling of your lips, tongue, throat or face, shortness of breath or trouble breathing, wheezing, dizziness, feeling hot, or palpitations (feel like your heart is racing)."
We're left with two possibilities here:
(1) The above is a lie, forced upon the makers of the drug by the FDA in order to get approval. However, surely the drug company would go to court over being forced to put a false, and very damaging, claim on their label? Those who know better, can advise me; maybe they feel that going up against the FDA is too difficult and will cause too much trouble down the line and that they would lose their case regardless
(2) The above is true, and the drug company did not want to put it on the label because (a) not being monsters, they felt their drug was safe enough and wouldn't kill patients above the ordinary acceptable level of risk and (b) a warning like that would put people off, and after sinking so much money and time into developing the drug and getting it licenced, they needed to recoup all that, and they couldn't sell the maximum amount if doctors and patients thought it was dangerous.
Talking about how things are approved in Europe, it seems that in 2020 the EU approved Entyvio:
Ah, but look here: it seems the heartless Europeans *also* insisted on warnings about allergic reactions:
"Special warnings and special precautions for use
Intravenous vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions, including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering intravenous vedolizumab. Observe patients during infusion and until the infusion is complete.
Infusion-related reactions and Hypersensitivity Reactions
In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity. If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks."
This kind of "before you take it, make sure your doctor is prepared to manage anaphylaxis" is *somewhat* different to the story as posted about "this *perfectly safe* drug which *didn't* stimulate the same allergic reactions was held up by the FDA who almost killed me".
Or maybe I'm reading this all wrong, and it's not a case of a desperate patient, a drug company wanting to get a new drug on the market as fast as possible, and a regulatory body trying to be responsible but perhaps being over-cautious?
And if the FDA was bad for dragging its heels from 2013 to "five and a half years later", which would bring us up to 2018-2019, what do you say about the EU which also took from 2013 ("Takeda Pharmaceuticals filed the paperwork for approval with the European Medicines Agency on March 7th, 2013 and filed with the FDA on June 21st, 2013") until 2020 to approve it?
Also that John applied in 2013, didn't get it until 2014 (which is not too bad a delay) and the story then pivots to the solemn "but by then it was too late":
"It wasn’t until September 2014 that John got the drug. By that time John was in precarious health. Although he now had the drug in his system, it was too late to help. In January 2015 his doctor sent him to the ER where he stayed in an ICU for several days fighting an infection. John had to have two major surgeries that ultimately removed his large intestine altogether. "
But once again we are in the world of "what if?" By the account in this story, John has been suffering from this disease since he was nine, two other therapies eventually failed (as they were expected to do) because of natural resistance of the immune system building up, and he was so bad that his doctor wanted urgently to go for this new drug.
Had he gotten it in 2013 would he still have ended up in hospital? WE DON'T KNOW. He might have done anyway, given that he was in such poor health by that time. He might have developed an allergic reaction to the drug. There are a lot of "maybes" and "could have happened". So the fact that he got the drug, didn't have a bad reaction, and is still alive and presumably more well than he would have been is the HAPPY ending to this tale.
So it's a great clickbait headline, but I don't think it's quite true to say "The FDA nearly killed me".
"Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier (see section 4.8). Vedolizumab treatment is not to be initiated in patients with active, severe infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment."
So why did I pluck out that plum? Because once again, the story as presented tells us:
"In January 2015 his doctor sent him to the ER where he stayed in an ICU for several days fighting an infection. John had to have two major surgeries that ultimately removed his large intestine altogether. "
But increased susceptibility to infection is a known risk of the disease! It wasn't "because I was denied access to the drug" that it happened. And it could have happened even had he been put on Entyvio - see the part about "withholding treatment if the patient develops an infection while on vedolizumab".
So yes, I understand the story from John's side and from his supporter's side; it's a lovely journalistic human-interest story complete with eyeball-grabbing headline, but it's maybe not entirely the whole of the matter. And nobody is lying, I'm not accusing anyone of faking or inventing or the like. What I want to point out is that, when people are sick and desperate, they easily formulate a narrative of "this will cure me" and any opposition, therefore, is "they will kill me if they don't let me have this".
People try all manner of things once severely ill. Haven't we previously discussed over-medicalisation in American medicine, where families try to keep elderly or very sick family members on life-support and expensive treatments past the point of doing any good?
It's very probable the FDA needs a kick in the pants to make it change the length of time it takes to approve drugs. But please take "they denied me this miracle cure" stories with some caution; yes, some of them will end up with "and Entyvio works wonders" but some are also "that's why I went to Mexico for laetrile treatment".
I don't know anything outside this post about the Entyvio saga, but the claim made was not that the risk doesn't exist or isn't serious, but that all these TNF-alpha inhibitor drugs carry the risk of escalating allergic reactions (I had it happen on Enbrel and Humira), which can even include anaphylaxis, but the FDA wanted the warning on only this one, making it look more dangerous than the others when that would be very misleading. Which seems like a fair thing to object to - they should all have the warning.
To order contact lenses in Canada you pick a vendor website, pick your brand of contact lenses, dial in your prescription, enter payment info and shipping address, and hit the Buy button.
In the USA there is a weird additional step where you must enter the contact information of the Licensed Official Person who wrote you the prescription. Your order is delayed for at least one business day while a human at the vendor must call your Offical Person's office in order to manually confirm that you have a valid prescription and entered it correctly.
This additional step is costly: it adds friction, leading to abandoned carts; means the vendor must employ qualified Speakers-To-Offical-Persons; and (as I discovered) means your Official Person gets a chance to phone and harangue you for your disloyalty in trying to buy your lenses from an online vendor instead of their shop.
If there are offsetting benefits of this approach they are a mystery. I'm curious what terrible problems this system averts and why these problems don't seem to happen in Canada. I suspect there may be no good answer if things kind of evolved this way rather than being the outcome of some careful consideration of policy alternatives.
Someone in an earlier thread mentioned that in some states it is illegal to pump your own gas, and residents of such states are happy to make up reasons on the spot for why it would be crazy to let things work any other way.
"Someone in an earlier thread mentioned that in some states it is illegal to pump your own gas, and residents of such states are happy to make up reasons on the spot for why it would be crazy to let things work any other way."
*And why none of those reasons seem to explain why everything seems to be just fine in the other 48 states.
There is an in principle very simple way to reform DFA: require them to design their procedures to produce net of cost benefits. What is the text of the law? I don't know, especially given the fact that the ways news is reported a horrible side effect of a new drug gets more space than the wonderful main effects of a new drug. But clearly "DFA-good"/"FDA-bad" is a totally silly way to discuss reform of DFA or any regulatory system.
Covid vaccines are an excellent example. Using the "FDA" as a euphemism for the entire regulatory environment around vaccine development and production. The "FDA" killed more people during the covid pandemic than they saved during their entire existence. Challenge trials could have been completed with dozens of vaccine candidates by May 2020 (almost all vaccine candidates turned out to have worked, and certainly would have been worth the trade of of other risks in the nursing home population ). The most vulnerable 3 million people (mostly nursing home residents). accounting for half of all deaths, could have been vaccinated in June or July 2020, this population would serve as a large safety study for the next most vulnerable, ect.
This would mean the first batch of vaccines being rolled out would be subunit, then killed virus and adenovirus, as MRNA vaccines were not at the time as rapidly scalable due to lack of supply of precursors. Subunit vaccines grown in e coli, on the other hand, can be cultured using materials from any supermarket. Killed virus/adenovirus needs a scaling step that takes 2 extra months growing Vero cells.
> I worry that people are going to assume I got lucky, that maybe I’ve been spouting a bunch of crap about “the FDA needs to approve drug X! the FDA needs to approve drug Y!” for years, and most of those drugs were unsafe or ineffective, but just by coincidence I got this one right and now I’ll never shut up about it.
No, I worry that you're counting the hits and ignoring the misses. To paint a full picture, you'd need to count the number of cases when:
1). The drug is safe and effective and yet the FDA takes years to approve it -- you've already done this part.
2). The drug is safe and effective and the FDA approves it in a timely manner -- I understand that your contention is that this never happens, but "never" is a high bar to clear.
3). The drug is dangerous and deadly (to a large enough percentage of the population), and the FDA spends years studying and then fails to approve it.
4). The drug is dangerous and deadly and yet the FDA approves it anyway.
5, 6). Same as (3) and (4), but for perfectly safe drugs that are no more effective than the placebo.
Regarding COVID vaccines, yes, they are still not fully FDA-approved... but, to be fair, they shouldn't be. The vaccines have been out for less than a year, and there's still a good chance that taking the vaccine would make your precious fingers fall off a year later. Granted, in this case specifically the possibility of this happening is slim to none, but "the average guy on the street" has no capacity to judge this for himself for every single drug. I mean, I am the average guy, and I don't have this capacity, so I should know. When I take a fully FDA-approved drug, I can do so without worrying too much about any unexpected side-effects; I can even be reasonably sure that my doctor is correct when he says there'd be no harmful drug interactions. *That's* what FDA approval means, and it's a good thing.
AFAIK the COVID vaccines are approved for emergency use, which is also a good thing. The FDA is saying, "look, we are not our usual 99% sure that your fingers won't fall off, but it's still better than dying of COVID, so go ahead and take the vaccine". I don't see what's wrong with that.
Agreed - I was waiting for Scott to address the times the FDA may have correctly identified unsafe drugs that the 'average guy on the street' would have thought were safe and useful.
It all started with no FDA, and people having the freedom to consume whatever they want. A bunch of people consume a "miracle herb" and go blind.
Common consensus directs the government to introduce the FDA, which in time thwarts the introduction of potentially life-saving cures. The people and online bloggers grow disillusioned, and want the FDA to loosen up and let unverified drugs flood the market with a cautionary "We've not officially approved this, and this won't be covered by insurance".
Out of the 1000 such drugs that flood the market, one of them makes hundreds of people go blind.
Again, the government decides that no drugs unapproved by the FDA can be sold.
I don't think weakening of the FDA can be a long term solution. We need ways to comprehensively test drugs ten times as fast for much, much cheaper. Although fantastical, this is the only long term solution I can think of.
Now here's a truly novel suggestion: How about FDA legislation designed to allow normal adults to stick their own necks out and use non-FDA approved drugs and devices if they so choose !!! Is government my master or my servant ???
Your motte and bailey are switched, and the "FDA is designed [...]" is a straw man. Scott is not is saying that the FDA is designed with the purpose of delaying life-saving drugs, and if he was, that would be much worse imo than the other statement. He's saying that the FDA is designed in such a way that it has such effect; yes, that "every single hour [etc]" (obvious hyperbole of "most of the work they do is more harmful than positive"). I see no hiding the ball.
I think there's a fairly straightforward way to regulate the FDA process. Give all FDA employees a 10% raise, and then make 20% of their paycheck dependent on how well they meet a quantifiable cost/benefit standard. So if they end up something like a factor of 10 or a standard deviation away from the performance goal they get 0% on the 20% adjustable paycheck portion
If it is not in the FDA's immediate control to come close to the standard that they now have a strong personal incentive to match, this will still immediately create a powerful lobby of knowledgeable individuals in favour of changing whatever needs to be changed to make it possible
Lets say the other perverse incentives still win out. If nothing satisfactory is happening within a year Congress puts out a tender for bids for the FDA 2.0. Lets say they accept 3 bids and these companies set up a shadow FDA that proposes certain processes and 'approves' drugs and generally gives their own version of whatever the FDA is doing. After another year the regulating board that is judging the FDA's performance can assess the bidding companies on their own cost/benefit rating and Congress then has the option of choosing one of the bidders to succeed the FDA, giving a generous severance to whoever doesn't get brought on from the original FDA
Alternatively, one of the FDA 2.0 companies could be chosen to operate in parallel to the FDA with the power to approve things provisionally and with less final authority than the FDA. This option would allow more fast tracking without any risk to the reputation of FDA 1.0
Three applicable mental models here to reconcile "everyone in FDA is smart and good" and "overall FDA has negative consequences":
(1) Systems. FDA is a system with a goal "approve (only) good drugs". If the goal itself has inherent problem, no individual agent has to act in bad faith or stupidly in order for the system to act in a problematic way. Donella Meadows' book here is a wonderful primer.
(2) Binary classification. Ultimately, approving (only) good drugs is a binary classification problem. You want to classify the good drugs as approved, and the bad ones as not approved. False positive (FP) here would be approving a bad drug, false negative (FN) is not approving a good drug. Absent of an oracle that is 100% accurate, any binary classification has to choose whether they prefer false positives or false negatives. You cannot reduce false negatives to zero without having some false positives.
(3) Defaults and do no harm. In this case, FDA prefers false negatives over false positives, the same way that the justice system does. This probably follows "primum non nocere" and has the burden of proof on the intervention. It probably makes sense given the Lindy effect of drug :shrugs:?
Until the pro FDA crowd provides some replicable Randomized Controlled Studies demonstrating BOTH the safety and the efficacy of the FDA I will treat them like any other kook touting they have a cure for cancer.
I'd also like to live in the world where the fact that ketamine treats severe chronic treatment resistant depression is well known, because it saved my life. I'd really like to live in a world in which it was well known early enough to have saved the lives of several friends of mine who took themselves out of the game the hard way.
But I'm a known zealot on the ketamine question, so I'll just leave it all at that.
Every story you hear from people working at the FDA is "People who bitch about the FDA don't understand how hard the job is! The leopards require round-the-clock monitoring to ensure they're always in peak physical condition. That's right, leopards, plural. Assholes never think about that, do you? We have to have a backup leopard on standby at all times, to replace the leopard if it's ever in less than peak physical condition. And then there's all the behind-the-scenes work. Never mind the special vitamins, we have to have our own leopard breeding program because the market sure isn't going to provide one."
Every time someone complains about trying to save lives and getting mauled by the leopard, hordes of commentators come out of the woodwork to mock them: "Didn't you see the 'BEWARE OF THE LEOPARD' sign? It's your own stupid fault!"
Every time someone actually does (finally) get allowed to save lives, they always thank the heroic FDA employees who valiantly fought the leopard at great professional risk.
Whether somebody ends up in the pro-FDA blogosphere or the anti-FDA blogosphere turns on the question of whether, when they hear a story like "Heroic FDA Employees Fight Off Leopard After It Only Killed A Few Hundred Or Thousand People", they immediately wonder why there even is a leopard or why someone would need to fight it.
People buy snake oil cures and use homeopathic remedies for cancer now, in the world with the FDA behaving as Scott describes.
Typo thread: "the Silenor brand [paid] a $100 million FDA application fee for approval as a sleeping pill"
Addressing the claim rather than the typo, is this actually true?
Does it really cost $100 million to submit an application for a sleeping pill?
This seems ... implausible.
Most likely the approval process which included running several studies cost them $100 million. It is not that they gave $100 million to the FDA. Running studies are very expensive, you have to pay doctors, administrators, supporting staff etc.
I'm a doctor and have been peripherally involved in several large clinical trials. I could believe that a multi year study involving many rounds of expensive investigations (eg screening MRIs in, say, the recent aducanumab study) could cost tens of millions of dollars, as this paper found (https://pubmed.ncbi.nlm.nih.gov/30264133/) - "Trials designed with placebo or active drug comparators had an estimated mean cost of $35.1 million (95% CI, $25.4 million-$44.8 million"
However Scott seems to be:
a) referring specifically to an 'FDA application fee', rather than the cost of running a trial and
b) talking about a relatively straightforward trial with short term clinical endpoints
so I'm going to assume he either misplaced a decimal point or is just mistaken. Happy to be corrected!
I believe he's referring to the cost of the trials combined with the fees.
Though I think I disagree with scott for a seperate reason.
The FDA tends to do a "he who pays for the trial gets the use patent" thing.
Before they ran a pair of full clinical trials to prove it worked as a sleeping medication a bunch of doctors might have had a hunch it had that effect due to patient reports but the evidence base was poor.
Just like patents encourage people to reveal their designs, drug patents and clinical use patents incentivise companies to pay to run the big clinical trials that would otherwise never get run which generate all the nice neat tables of effects, side effects and contraindications.
When you know that a drug is good for [use] becuase you've got the summary in front of you from a bunch of clinical trials it's hard to imagine a world where you don't know that information or only have a hunch about that.
It is kinda stupid for the FDA to not just routinely inspect substances approved in Europe and Japan for one's with a reasonably acceptable evidence base rather than waiting for companies to jump through symbolic hoops.
If something is expensive to create, we have a separate IP system for establishing temporary monopolies, which at least in theory can be tuned to produce economically efficient outcomes (e.g. protection that eventually expires by default). FDA approval has no such characteristic. There are problems with the IP system we have as well, but they are probably made worse by trying to also use the FDA to incentivize companies to do studies.
Another typo: "$100 million dollars" doesn't need both the "$" and the "dollars"
The NBC article is available on Archive.org: https://web.archive.org/web/20130612022529/http://rockcenter.nbcnews.com/_news/2013/06/07/18833434-drug-treatment-omegaven-that-could-save-infants-lives-not-yet-approved-by-fda
Thanks, I've added the correct link into my essay.
When I read what Gura said about the FDA, my immediate thought was, 'stockholm syndrome'.
But, another possibility is, how dare any one who is engaged in pharmacology research criticise the FDA, or even engage in faint praise?
I'm sure it does happen, but yeah, I had a similar thought.
She sounds like a deeply pragmatic woman whose intensely committed to getting shit done.
She’s interested in saving babies and found allies to accomplish that goal. Shitting on the FDA would make things worse.
She could’ve written a libertarian blog or become a policy wonk but she focused on visible outcomes.
I think there’s a lesson to be learned here about the mentality of implementors versus wonks. Maybe she’s too short term and institutionally minded for this crowd but it’s a valuable perspective.
I think it depends on the level at which you want to get things done.
If you're a medical researcher, then you just have to accept the rules as the reality at which you operate in, regardless of how arbitrary and counterproductive they are. If the FDA mandated that double blind trials literally require everyone involved to be blindfolded, the only question to ask would be "what brand of sleep mask has FDA approval?"
If you're trying to operate at a political level and reform the system, then questioning the rules is exactly the kind of thing you should be doing.
It's a "game player" vs "game designer" distinction - they're two very different ways to approach the world, and while they can overlap you can't really be both at the same time.
Also, it was a speech she gave after winning an award for the work. Using a platform like that to drag anyone who was involved in the thing you're getting the award for is just ... not a thing that's done outside the confines of the internet.
It's not a normal thing to do, but it's been done. My favorite example is John Taylor Gatto's "The Psychopathic Schoolteacher," which was his acceptance speech for New York's Teacher of the Year award. https://www.naturalchild.org/articles/guest/john_gatto.html
From what I understand, companies live in fear of retribution from the FDA. Mary Ruwart writes about this in her book "Death by Regulation" providing a first hand account from her time inside the pharma industry. I suspect one of the reasons the AstraZeneca vaccine wasn't approved in January was retribution for a mistake AstraZeneca made in failing to immediately notify the FDA about a pause in the Phase III trial.
For academic researchers it's a different story, but they also have to work with the FDA too (for instance with trial design) if they want whatever they are working on to have a chance of getting approved. The FDA also provides funding to researchers, as we saw in Scott's last post, and grants compassionate use applications, etc etc.
Finally, researchers can be part of FDA advisory committees. I'm not sure if that is paid, but it is prestigious.
So I'm pretty sure fear of retribution is a factor when researchers are talking publicly about the FDA.
The EMA approved AstraZeneca vaccine but when the reports about blood clots came in, half of European national regulators suspended its use. EMA quickly reviewed the case and maintained that benefits overweight risks and suspension was not justified. The EU even sued AstraZeneca for missing deliveries at the same time deciding not to use AZ vaccine. They donated the remaining AZ vaccines to third-world countries but they come with short expiry dates and a lot of bad reputation that are increasing anti-vax sentiments.
For what it is worth, it seems that a stronger EMA would have been more beneficial for the EU. Similarly, without strong FDA I suspect that doctors and general people would have more doubts about the safety and efficacy of their medicines.
Re the EMA: its becuase the EU is a lot looser than the US. The EMA is more advice to state regulators.
From someone who used to work with the EMA they were saying brexit probably had a bad effect on its effectiveness as the UK beaurcrats played a non-trivial role in getting the various state regulators to keep calm.
That's definitely true. EMA was based in London before. Many EU countries have lax standards and they also want to assert their independence.
EMA takes longer to approve drugs than the FDA, on average (see https://www.pmda.go.jp/files/000204615.pdf, slide 6). This could be a result of understaffing though rather than then being more strict. They have a different model than the FDA where they contract out a lot of the reviewing to private firms which some people say is better.
All the vaccines have a similar blood clotting risk.
https://twitter.com/moreisdifferent/status/1421475970062557184?s=20
I have written about the AZ ban in the EU over clotting. It was a mistake and lives were lost as a result:
https://moreisdifferent.substack.com/p/europes-reckless-precaution
This feels more like "fish don't notice the water" to me, tbh.
From talking to someone who works in drug trials, its also sometimes like the student who did the assignment and handed it in 2 days after it was assigned.... a month later watching one of their classmates who left it till the night before swearing about how it's "totally unfair" and an impossible deadline.
Sometimes they know that behind a story of delay is someone who kept screwing up and taking months to do a few days worth of tasks.
Kevin writes:
> I have no idea how you can write "they usually carry out their mandate well" in one place and then, in your main post, just go ahead and repeat your original belief—backed by an example you know is wrong—that the FDA does stupid and destructive things on practically a daily basis.
Which is a really bad thing for Kevin to be confused about, because if he’d read the next paragraph of Scott’s post, he’d read all about how Scott reached the conclusion because he anticipated this criticism and basically held the readers’ hand through the thought process.
> My problem is: doing anything in medicine is illegal until you clear a giant hurdle. To clear the hurdle, you have to pay millions (sometimes billions) of dollars, fill in thousands of pages of forms, conduct a bunch of studies that can be sabotaged for reasons like “this drug is too good so it would be unethical to have a control group”, and wait approximately ten years. You have to clear this hurdle to do anything, even the most obviously correct actions. Everything starts out illegal, and then a tiny set of possible actions is exempted from the general illegality. The easiest name for this hurdle is “the FDA”, since they’re the agency charged with enforcing it.
Meaning either Kevin drum conveniently stopped attentively reading at exactly the point where Scott’s post would provide the most fodder for his pro-FDA position, or he specifically cherrypicked that quote despite knowing that Scott fully addresses the concern immediately after the quoted section. (Note, my quotation from Scott is followed up by him reiterating the same point with specific examples for about 8 paragraphs, so there’s no way Drum could have had a microstroke or something and missed that specific paragraph.) In conclusion, Kevin is either a deliberately deceitful huckster or just a straight up moron and this piece has provided all the evidence I need to conclude that I don’t actually have to read anything else he has written in the past or will write in the future.
But I have to say, the most baffling part of Kevin's piece is when he "defends" the FDA by insisting that we start the clock of when we knew Omegaven was effective from when the company that makes it applied for authorization. Like “the FDA doesn’t actively go out and do it’s job proactively seeking new, useful medicines to help through the approval process so Americans can get prompt access to useful new drugs. Instead, they sit on their hands, even while getting a constant flow of emergency use requests, until someone pays the millions of dollars to make the adequate sacrifice to Moloch to get through their Kafkaesque approval process before they’ll even begin thinking about whether maybe they should form an exploratory committee to consider whether to process the paperwork which will begin the approval process” is some kind of ringing endorsement of the FDA.
> In conclusion, Kevin is either a deliberately deceitful huckster or just a straight up moron and this piece has provided all the evidence I need to conclude that I don’t actually have to read anything else he has written in the past or will write in the future.
Gotta say I oppose this mentality, except insofar as you don't *have* to read anything. If writing one dumb thing is enough to banish someone's posts to the shadow realm forever, you either have to apply that heuristic very selectively or end up with an incredibly cautious stable of writers.
https://www.lesswrong.com/posts/u8GMcpEN9Z6aQiCvp/rule-thinkers-in-not-out
As they say! You might be selecting against some of the very traits that make someone worth reading here, by pruning anyone who sticks their neck out
This isn't a problem of dumbness. It's a problem of either fantastically implausibly bad reading comprehension or literally trying to actively deceive his readers. You can rule thinkers out when they're actively trying to make their readers dumber. But in the spirit of glasnost, if there's anything of his that you think would make me rule him back in, I'll read it and I promise to give it a fair hearing.
I... have exactly the same thing I said above to say to that. I didn't think he was dumb, just that I think one bad take shouldn't rule someone out forevermore
I've never read the guy, so I have no recommendations. I just think the approach you're putting forth here is mistaken in principle
Again, if this was a bad take in the sense that I think it was an honest mistake, I would 100% agree with you. (I'm a huge fan of Robin Hanson, despite my thinking that a lot of the points raised by his critics are valid, for exactly this reason.) But if the quote mining that Kevin did really was a result of a good-faith mistake of the kind which we should forgive... I'm sorry but that requires some deeply implausible assumptions. And even if we are to assume incompetence and not malice, we still need to assume *a lot* of incompetence to get what Kevin actually wrote. If we have that level of incompetence, then I wouldn't rule out Kevin on the grounds that he's actively trying to make me dumber, I'd just do it on the grounds that I have more reading material than I have reading time and I can do much better than someone that bad at basic reading comprehension.
Lots of people get hung up on one thing they read in some essay or post or article or book, and it so colors how they read the rest that they miss a lot of important detail. I imagine that's what happened to Drum in this article.
I think sticking someone with a "burn notice" is justifiable for deceit (as opposed to being honestly wrong). Fact-checking a fraud can get quite difficult, and cross-correlation of deceit is much higher than ignorance (if someone knows very little number theory, they may still know a lot about biology; if someone lies about number theory, they're probably also willing to lie about biology).
(The main exception I'd make is that high-stakes deceit doesn't generalise especially well to low-stakes deceit. Most people have a threshold of stakes where they feel comfortable lying; if someone lies to avoid going to jail, they're probably willing to lie to avoid dying - or to avoid going to jail for something else - but they won't *necessarily* lie for money or attention.)
Especially since, as I was amused to note, there are people in the comments to Kevin's blog who say exactly the same thing about Scott.
I think you hit the nail on the head, especially with regard to Kevin Drum. This is not the first time I have read a blogger responding to Kevin about some claim that comes down to "Ok, KD is either an amazingly bad reader, deceitful, or so deep in motivated reasoning that he doesn't even know if what he says makes sense." This has been going on for years and years, at least going back to 2009.
I am honestly a little confused about why so many people call Kevin Drum their favorite blogger, unless that is a euphemism for something.
"I want a world where if there is a $250 version of a drug, and a $10 version of the same drug, people are allowed to choose the $10 version even though the manufacturer did not give the FDA $100 million dollars."
Everybody wants that world. So how come generics aren't more widely prescribed? "Sure, I could give you a script for the fancy new drug the pharma rep tried selling me on, or I could write a prescription for the fifty-year old version that is now out of patent so there are three cheaper versions on the market". Why doesn't this happen?
But the thing is, we are living in an imperfect world, and *if* you get the world where:
- everybody from NBC News to random bloggers know that the babies are much less likely to die on fish-oil based fluids
- FDA doesn’t hold up approval for an additional five months arguing about the wording of the warning label
- ketamine eventually gets approved for use as a depression treatment
- if everyone knows COVID vaccines are safe and effective, then the government will have approved COVID vaccines as safe and effective
That is *also* the world where Aduhelm gets approved, because the drug company doesn't want to wrangle with the FDA over the warning label and pressure from patient advocacy groups who are grasping at straws works and everyone from NBC to random bloggers are saying it's a breakthrough miracle drug and the government relies on the pharma lobbyists telling them it's safe and effective.
It's the world where Dr. Ogu's Natural Herbal Remedies for epilepsy to AIDS get approved for the same reasons.
It's the world we used to have, before in the USA the 1906 Pure Food and Drug Act was passed, where the role of the FDA was limited to "there isn't any actual poison like arsenic in this item (anymore)" enforcement.
https://en.wikisource.org/wiki/Pure_Food_and_Drug_Act_of_1906
"In the case of confectionery:
If it contains terra alba, barites, talc, chrome yellow, or other mineral substance or poisonous color or flavor, or other ingredient deleterious or detrimental to health, or any vinous, malt or spirituous liquor or compound or narcotic drug."
I do like the bit about poisonous substances in confectionary, don't you? Ah, the wonderful world where you could merrily put poison in sweets before the meddling and interfering hand of government intervened to retard you!
The pendulum swings wildly from extreme to extreme, and yes there should be a moderate mid-point, but when you have evil fools selling Miracle Mineral cures for autism, and parents so desperate for a 'cure' that they will torture their children, and people going on Amazon to give positive reviews of the product, I find it hard to say we're over-regulated.
https://www.amazon.com/hz/reviews-render/lighthouse/B074Q254HB?filterByKeyword=mms&pageNumber=1
Bad things are created by government action. If you are unwilling to acknowledge that, you should be ignored.
Indeed, we face a complicated tradeoff of bad things, and the argument is largely about what the right point on the tradeoff would be. There is no practical point in the space of possible tradeoffs where we don't sometimes get approved medicines that have terrible side-effects, or drugs that are only marginally better than a sugar pill. There is also no practical point where we don't sometimes delay the availability of lifesaving or genuinely helpful drugs. (We can avoid the first by banning all new drugs, and the second by abolishing the FDA, but short of that, both errors will be made sometimes.)
ISTM that one fairly easy improvement we could make would be to use other countries approvals/experience to allow drugs in the US. Something like "if it's approved in the UK/EU/Japan/etc., and has been on the market a couple years there, it's approved in the US as well unless the FDA makes an explicit case to keep it out." Or "you can buy/prescribe things that have gone through safety but not efficacy trials under these conditions...."
I expect there are more ways to improve the tradeoff we're making, but I don't have great confidence about that--this is a place where all choices have painful costs associated with them. OTOH, Scott is speaking from experience as a practicing psychiatrist and has run into several cases in his practice where FDA policies seem to be making things worse. Probably we should pay attention to that, even if we're not sure exactly where the optimal tradeoff point is.
"painful costs". Yes, but who gets to make the decision about what painful costs are to be borne? That's the problem: it's not deciding between risks, it's *who* decides. If you think regulation is a good thing, then you think that the government is better at deciding who should bear what risks. Do they have a better incentive or better information than the individual who is making the decision for their own risk?
Well said — people think so strangely about this topic. "Once upon a time, candy very rarely had bad stuff in it, therefore there is no such thing as over-regulation" really seemed like a good argument to at least two people in this thread, apparently?!
Deisach contributed several specific examples with evidence, historical context with a link to learn more, and several well formed arguments. That’s great!
If we’re discussing the FDA, the historical context of why the FDA was established and what law established it is interesting. As is the example of the sort of bad thing that might be encouraged by the FDA’s abolition.
It wasn’t exactly a powerful and fully sourced peer reviewed journal article on the topic. But it’s perfectly good! And it started a few other conversations
> and what arguments?
short and unsatisfying arguments can still be arguments
I have to agree with you there, WC; things have never been the same since they took the alcohol out of gripe water:
https://www.medicinenet.com/why_is_gripe_water_banned/article.htm
I was reared on the old-fashioned formulation and look out I turned out! 😁
I don't agree. I don't see any well-formed arguments; all I see is "yeah but with NO regulation, you could sell poison", and this is so obvious and well-covered that it doesn't really need examples and evidence — or mentioning. The question is, as always, how *much* regulation we need *now*; the situation with confectionery in 1906 is essentially irrelevant.
Cool. Here’s a real well formed argument by me. https://astralcodexten.substack.com/p/contra-drum-on-the-fish-oil-story/comments#comment-2571594
Nobody’s really taken a look at it, sadly. Wanna take a crack at disagreeing with it?
"What are you contributing here? "
Well indeed, WC, that is a question we must all ask ourselves at some point in our lives. "Who am I, where do I come from, where am I going?" as the British Army patrol asked Kevin McAleer.
1. I am Thirteen Ways Of Looking At A WC
2. I am ragweed pollen on the breeze, and the solar UV index is moderately high.
3. I am he as you are he as you are me/And we are all together
4. I am the guttersnipe's guffaw at your somewhat unfortunate initials https://en.wiktionary.org/wiki/water_closet
13. Ceci n'est pas treize
6. I am the head of the spear in battle
Who can say, WC, who can say? To quote Philip Larkin:
"Ah, solving that question
Brings the priest and the doctor
In their long coats
Running over the fields."
An orbiting pendulum looks like it's simply swinging from any given point, and yet in actuality (and in spite of appearances), at no point in its orbit does the bob actually approach the happy point it is orbiting.
I'd be more sympathetic to Scott's position if we lived in a world where miracle drugs like imatinib were being developed every year*. But drug development is very, very, very hard. Your pre-test probability should be that most novel pharmaceutical interventions will not significantly outperform current standard-of-care + placebo. Given that landscape, the mandate and ethos of the FDA makes quite a bit of sense. The public (and the American healthcare system) is much more at risk from being victimized by ineffective and/or harmful treatments than having genuinely transformative medications delayed or withheld.
*(I'll grant Scott's point that the particular mandate/ethos was a very bad fit for development of COVID vaccines, which are the rare intervention with an enormous effect size)
The asymmetry I'm assuming is that for a given indication, a vast majority of pharmaceutical compounds won't work better than placebo. So if you have a marketplace flooded with Placebo Plus products with no meaningful regulatory restraint or oversight, you dilute the number of people getting effective treatment, you increase financial toxicity to the healthcare system, and you are exposing people to a wide range of tail-risk side effects.
Robin Hanson's work indicates that a whole lot of medicine is no better than a placebo. But the effect of this is just to waste money. If lots of people buy placebos that do nothing, and people with rare conditions (like those infants or the guy that lost his intestine) that can actually be improved by drugs get those drugs, it sounds like a net plus.
Leaving aside the ethics of constructing a society that caters to a small cohort of the information elite, only a tiny fraction of people have the time, expertise, and disposable income to evaluate the evidence base of candidate pharmaceuticals and conduct autologous n of 1 trials - and that fraction would turn to '0' if you deregulated the space and allowed shoddy, biased, and outright fraudulent research results to proliferate.
If you want evidence of that, you need to look no further than 2020. Many of the people who would describe themselves as 'diligent about [biomedical literacy and research]' went head-over-heels for a whole variety of placebo-equivalent antiviral candidates. There was so much clinical and biomedical data - much of it shoddy, unreliable, and non-replicable - that people's empirical apparatuses were swamped.
Imagine that, but for every indication and disease. How would a person with a life-threatening condition decide which drugs to try, in what combination, and in what order? How would insurers decide what was reimbursable? How would doctors be able to decide what was safe and effective to prescribe patients? How would the system bear the costs of this flood of products? Aducanumab alone had the potential to bankrupt Medicare, and that's just one shoddy monoclonal antibody.
Actually I think doctors all over the world were doign the same thing. Nobody knew what would help with covid, so they threw anything that might help at it--zinc, HQC, azithromycin, ivermectin, vitamin D. I think this always happens with a new disease. Eventually, people found some stuff that seems to work and switched over.
"But drug development is very, very, very hard"
I go back and forth on this. It's definitely hard with the FDA involved. But it's weird how often drugs approved for one indication randomly help with another (eg fluvoxamine, an antidepressant that seems to also treat COVID - or ketamine, an anaesthetic that seems to also cure depression - or any of the substances mentioned at https://slatestarcodex.com/2014/07/17/psychotropic-base-rates-the-argument-from-antibiotics/). I'm not really sure what to make of this.
I'd love to see good data on the success rates for drug repurposing (and by success, I mean statistically significant differences in clinically meaningful outcomes in large double blind RCTs). I suspect the number is quite low, and that number is likely an underestimate given how much of the denominator would be hidden / unpublished.
I agree that many drugs have off-target activity that we don't always anticipate or understand. But I'm much more skeptical that the off-target activity is clinically meaningful, or if it is clinically meaningful, that it would outperform current standard-of-care.
Derek Lowe has had faint praise for drug repurposing, that may be worth reading. Here's one, though he mentions it in passing in a few other posts that I don't have the attention to find at the moment.
https://blogs.sciencemag.org/pipeline/archives/2020/09/11/drug-repurposing-how-often-does-it-work
This is interesting, thanks for the link! It mostly aligns with my priors but he does bring up a few good examples (like thalidomide) where very high-signal off target effects were effectively repurposed within the same drug class.
I mean Covid drug repurposing didn’t seem to go great? A lot of drugs were identified and given to a lot of people. Azithromycin hydroxychloroquine remdesivir and a bunch a others, and i guess ivermectin although I can’t say if that one works or not.
(And they didn’t work, and hcq specifically made things worse?)
https://www.nature.com/articles/s41467-021-22446-z
combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients).
Going with 1.11
The pharmacies steadily dispensed an average of 383,685 prescriptions for hydroxychloroquine (HCQ) per month, and 1839 prescriptions for chloroquine (CQ) per month. However, from February to March, prescriptions for hydroxychloroquine jumped by 86.2%—from 367,346 to 683,999. Prescriptions for chloroquine jumped from 2346 to 6066—an increase of 158.6%. Among those patients given hydroxychloroquine, the number who were simultaneously prescribed azithromycin jumped from 8,885 in February, to 101,681 in March—a 1044% increase.
https://www.contagionlive.com/view/hydroxychloroquine-chloroquine-prescriptions-covid-19-us
(I am now going to pull numbers out of my colon, and I don’t expect this to have really any relation to actual hcq deaths. I probably misinterpreted at least two of my sources somehow)
Assuming of 300k given hcq, the case/hospitalization and hospitalization/death ratio for the general population are the same as for that group (which there are no grounds at all to make), 300k* 600k deaths / 35M ~~= 5.1k deaths. 11% increase = 500 deaths. If it’s 75k like another source suggests, 125 ish. Which is quite a few, but not exactly at the scale of the vaccines being delayed. (But I would submit again that the fda process being very strict may have pushed the drug companies to have actually good development processes and those with to the top)
I believe the drugs that were useful were the steroids, which is much less an experiment than the others.
Is drug development really hard? Or is it really hard to develop a drug that has a no-kidding-sure-fire $1BB+ market?
I think both. Huge amounts of time and treasure and genuine genius have gone into treatments that looked great until the clinical trial, where it turned out they didn't do any good. But also stuff that works can be impossible to get approval for because it can't be patented and producing the evidence that it works sufficient to get approval costs hundreds of millions of dollars.
> Given that landscape, the mandate and ethos of the FDA makes quite a bit of sense.
There seems to have been ample evidence to the contrary for the fish oil. It wasn't even a "new" drug. Something that has a proven safety record in other jurisdictions shouldn't have to overcome the same hurdles as a truly new drug.
The pendulum has never swung back to the old days you bring up. Even though we could rely on third-part certification like Underwriters Lab, fraud laws for false claims, and Hanson's would-have-been-banned stores.
I don't find it hard to say we're over-regulated. Here, I'll say it. "We're over-regulated". The counter to your "merrily put poison in sweets" claim is the requirement that manufacturers of industrial alcohol merrily put poison into their products. I've seen an estimate that, since prohibition, 10,000 people have been killed by this government requirement.
Essentially, your claim is that individual action in the marketplace is insufficient to solve problems of unhealthy foods. Perhaps that's the case, but it doesn't explain why the government has been encouraging people to eat unhealthy foods (too many carbs, because "eating fat gives you heart disease", when that's exactly backwards) for most of my lifetime.
Indeed, the government has often *heavily subsidized* unhealthy foods!
So, do you suppose there could be some possible middle-ground between allowing people to put poison in candy and preventing people from using a treatment that's known to work and approved in many other countries?
This is like the dumb internet argument style where anyone who proposes less government is accused of wanting to move to Somalia, while anyone who proposes more government is accused of wanting to move to North Korea.
Is there a middle ground between having a forest fire burn down your entire forest and not having it burn down any part of the forest?
Part of the problem is that you're thinking this decision can be made by itself: that we have a knob which can control the amount of regulation of substances, and that we just tell our politicians where we want the knob to be set, and them and all the other politicians put in their setting, the average gets taken, and that's the setting.
Firstly, most people are dumbshits, as I'm sure you've noticed. Second, we never send our best and brightest to govern us. In fact, the best and brightest are too smart to want to be politicians. Third, once you give a politician power, they never want to give it up, so the knob only gets turned in the direction of more control, and only rarely less control. Fourth, political power is fungible. You may think you're giving a politician the power to keep us safe from unsafe substances, but what if they trade it to another politician (who has promised to eliminate unsafe substances from the market) in exchange for the power to benefit an evil corporation?
Scott
Your case would be more powerful if you offered examples of times, probably more than we know, the FDA put the kibosh on as yet to be known harmful therapies. I keep a quote handy I fall back on occasion: Thomas Chalmers, the famous medical researcher, once wrote, “One only has to review the graveyard of discarded therapies to discover how many patients have benefitted by being randomized to a control group.” Not quite apples to apples to your response above, but it's close to the spirit.
Also, I don't follow your two-track description of the FDA. The first, "stupid," and the second, THe FDA is a product of the charter organizing committees set forth for them: slow, deliberate, and overly cautious. The latter doesn't validate the former. If you didnt imply that, I misread your intent—apologies for the misinterpretation.
Brad
The most radical FDA reform proposal I've heard is that the FDA should use its current system to check if drugs are safe, but be laissez-faire about whether or not they're effective. The safety checking is (as far as I know) relatively quick and easy and not usually most of a delay (though I would have to double-check this before asserting it officially). I think this is kind of like what they do with vitamins/supplements right now, which are cheap, numerous, easy-to-get, often ineffective, but safe enough that if you dared someone to take a randomly chosen Whole Foods product I think only the most over-cautious people would have any qualms.
Overall, I like that idea, but implementation is going to have to resolve the issue of "safe" not being binary.
To pick and extreme example, chemotherapy drugs are literally poison, but they're net benefits to patients with certain forms of cancer because undertreated cancer is worse for the patient than the chemotherapy drugs. You're probably going to want some kind of backup process where some standard of evidence of benefit can be used to get approval despite known or likely hazards of the drug. The tricky part is to stop the acceptable level of risk for basic certification and the standard of proof of effectiveness for approval despite risk from drifting to the point you're effectively back to the current system.
Indeed. And sometimes how we think about risk is just weirdly broken or mis-calibrated (the reaction to the super rare AZ or J&J vaccine-associated blood clots, for example). Certain people get all weird about me taking medicine that ups my risk of blood clots and breast cancer, when realistically the risks are comparable to the average female baseline risk (which is higher than the normal rate for a male), and they also significantly reduce my risks of falling victim to other things, like prostate cancer, alongside the positive effects which I want. If I were to get certain surgeries, some doctors would force me off my medications for weeks leading up to it because of that fear of blood clots, despite the risk not actually being high (cis women on birth control are at significantly higher risk and generally doctors won't force you to stop that before surgery) and going off the medications being quite unpleasant in and of itself.
You can't really consider them in isolation though. We ought to accept a drug that prevents 10,000 fatal heart attacks a year even if it causes a dozen liver failure each year too. I mean, the FDA didn't accept the first beta blocker historically and Europe did but they shouldn't have accepted such a risky drug without proof of efficacy. Of course, an easy solution is to be open to safe drugs bit stringent with dangerous ones.
My version is two tier:
Tier 1: Drugs that have proven reasonably safe can be manufactured and sold, but can't be marketed with claims of curing disease, and won't be covered by insurance.
Tier 2 is drugs that are also proven effective. That's the only tier we have now.
Agreed this is a good first draft of a proposal.
:+1:
Now watch as the cost of a drug is multiplied by a factor of ten the day it's moved from Tier 1 to Tier 2, because insurance is paying so they can charge $100 / bottle for what was formerly $10/bottle over the counter.
I feel like at this level, though, it wouldn’t resolve a bunch of the fundamental objections. Ketamine, to take one of your frequent examples, doesn’t seem like it meets this bar: you say it causes “acute distorted cognition for the next few hours” at clinical doses, and it has lots of potential harms at recreational doses. That doesn’t seem like a level of safe that we’d be happy to have it sold over the counter at Whole Foods, which presumably would move it into the “must show effectiveness” track and we’re back where we started.
That’s not to say that the FDA is the right answer, but lots of medications have some bad effects that trade off against their good effects, so just evaluating safety without an eye to effectiveness seems like it doesn’t actually result in lots of medications meeting the bar.
Ketamine is safe, *if* taken at the recommended doses. It is also an addictive drug (US schedule 3)
Addictive drugs would certainly be left out of any such reform in the US.
Though I'll note that alcohol *is* sold freely at Whole Foods.
The FDA would be more useful and believable if they restricted themselves to an advisory role. Then you would have insurance companies saying "Sorry, we don't pay for this because the FDA advises against it." but people could still get the compound they believe helps them.
When I take a drug to treat my diabetes, or blood pressure, or some other chronic condition, or even cancer -- then yeah, I want to be pretty damn sure it's effective, not just safe. Leaving my conditions untreated is *not* safe.
Of course! So why do you trust the government to do what you should be doing? What would happen if they failed to ensure that your medicine is effective, like they failed us by telling us that fat is bad for you? What mechanism is in place to correct their failure? If a private company created medicine that was not effective, they would probably go out of business. How might the FDA "go out of business" given that they are reliant on politician goodwill, not customer goodwill?
> So why do you trust the government to do what you should be doing?
Whom should I trust instead ? Every snake-oil salesman who comes my way ?
Look at it this way. The last time you rode in an elevator, did you stop to consider the probability of it crashing to the ground, burying you deep in the elevator shaft ? Did you check the local reviews for the construction company who built the elevator before getting into it ?
If you trust "the government" -- or rather, the teams of engineers and scientists whom the government either employs, or forces to pass standardized test -- to maintain your elevator, then why not medicine ?
Who should you trust? Walgreen's. Kinney's. Rite Aid. CVS. They should be the ones testing for safety because unlike any government agency, they compete with each other and will HAPPILY test their competitor's product and gleefully point out anything that isn't safe.
I trust the elevator company because they will lose everything if any one of their elevator crashes to the ground because of incompetence on their part.
Why do you trust the government? Who is monitoring them? Not CVS. Not Walgreen's. Not Kinney's. Because none of them have any interest in catching the government's errors, because all that will do is cause everybody to stop buying from their local pharmacy.
If you ask me to predict the future, I will ask you what incentives people have. CVS, Walgreen's, Rite-Aid have good incentives, the FDA has bad incentives.
> I will ask you what incentives people have.
Interesting. Asking that question is exactly why most people I know trust the (Canadian) government more than private companies.
I saw a slightly less radical proposal along the same lines here:
https://www.niskanencenter.org/how-can-the-fda-foster-greater-resilience-in-the-medical-marketplace/
Basically that they should approve for safety and effectiveness, but not clinical utility. And have explicit tiers available for measured effectiveness (biomarkers / symptoms / survival etc).
Sure, but that opens the door to homeopathic-style treatments. Is it safe? Of course, there's not enough of anything in this to do anything good, bad or indifferent. Is it effective? Well, if you don't have anything really wrong with you and it triggers the placebo effect, sure. If you do have something really wrong with you, um, yeah.
But hey, at least it's a lot cheaper than Aduhelm at $56,000 per year! Which is something approved as safe but not effective:
"Why does this drug cost so much?
There are millions of people and their families who want a new Alzheimers treatment. Any Alzheimers treatment.
"We have established a price for Aduhelm that reflects the overall value this treatment brings to patients, caregivers and society -- and one that will enable continuous innovation," wrote Biogen's CEO Michel Vounatsos in a letter announcing the approval.
The nonprofit Institute for Clinical and Economic Review, which scrutinizes drug prices, argues that because the drug has not been proven to be effective, a more reasonable and cost-effective price would be much lower -- maybe as low as $3,000. That's far from the $56,000 Biogen will charge.
The impossible problem.
More than 120,000 Americans die from Alzheimer's each year, making it among the leading causes of death in the US.
But treatment of the disease has been stuck for years, and the FDA had not approved a new drug to treat this disease since 2003."
The bargain is not "how many thalidomides is one omegaven worth", it's "how many aduhelms is one omegaven worth".
Omniscience is not available to anyone, even someone who works for the government. It is only through trial and experimentation that we know anything. The FDA's remit in verifying effectiveness is very problematic. It should only be testing for safety. It is up to other parties to determine effectiveness.
In the US, you can buy homeopathic remedies and herbal medicines and such over the counter. And you can go to a chiropracter or accupucturist or naturopath for your cancer. So maybe this would be a terrible world, but it woudl be the terrible world we already live in, at least in the US.
Still don't have an answer to the question of "how many patients does this (lack of approval for the fish oil formula) impact every year." I am betting that it is under 1k and probably under a hundred, not the tens of thousands originally given.
Still have not been able to find this information, but I admit I was very possibly wrong about that.
FDA-employed researcher who is a partner of a family member, enormously paraphrased: "the article correctly described the FDA's difficulty with too fast/too slow on drugs, but noted that the 'F' part of FDA doesn't have a similar issue, mainly because it doesn't approve foods before they can be sold as food; if something appears to be making people ill, it’s super fast and super easy to get authorization and budget to study/ban it, but for foods which no one has thought to test yet and which are only on the radar on priors like the one I'm currently working on, it took a year to set up protocols and it will be at minimum a year before any results of anything are to be looked at".
I went through a similar analysis as yours on reddit when I first read Kevin's article (https://www.reddit.com/r/slatestarcodex/comments/ozz9je/interesting_criticism_of_the_recent_fda_posts/h83hnn8/).
I disagree with your assessment that you're "basically correct" when you're off by a factor of 2-4 in the detail that serves as the crux of the point. You're right that this is an example of the FDA being overly restrictive on a drug that ought to be widely available, but there is an absolutely massive difference between an organization that delays new drug releases by 5 years compared to 20 years.
I agree I came on way too strong originally, but I think there's some leeway in when you date from. Omegaven was invented in 1991, there was a WSJ article about it being a miracle drug in 2006 ( https://www.wsj.com/articles/SB116338867216321332 ), there were studies confirming it in 2011, it was well-known in the libertarian blogosphere by 2014, and it got approved in 2018. Which of those is the starting point for saying the FDA was "delaying"? In a default-yes medical regimen, I think people would have started using it around the WSJ article in 2006, so maybe 12 years earlier.
One of the questions I was thinking about when reading your initial article was: Assuming we can only work with the single lever of FDA restrictiveness, how many Omegavens is one Thalidomide worth? The number of years the FDA delayed Omegaven strongly influences my answer to that question (as does the rate at which the FDA encounters "Omegavens" and "Thalidomides" in the wild). That's what I mean when i say that the particular detail you were most incorrect on is an essential one, and being off by a factor of 2 is a large one.
To its credit, the FDA didn't approve thalidomide: https://en.wikipedia.org/wiki/Thalidomide_scandal#United_States
Very good point, I apologize for implying otherwise.
It seems to me, however, that Scott is arguing for a standard wherein the FDA would have gotten Thalidomide wrong. In this case, it would have been by adopting a European approved drug, but it probably would have also approved it in its own channels by only looking for first-order safety effects as opposed to inter-generational ones (perhaps he believes we ought to have stricter safety standards for researching drugs given to pregnant women?). I do suspect that on net this tradeoff would be worth it; that the cost of Thalidomides would be more than made up for by easier drug access and accelerated research.
The history as I have heard it is that prior to the thalidomide scandal, the FDA checked only for safety; after it, it started checking for effectiveness as well, ("Kefauver-Harris Drug Amendments"), even though the safety check caught thalidomide.
The first COVID vaccines passed the safety check in, IIRC, May 2020. The rest of the delay was effectiveness.
How many people died between May 2020 and whatever month in 2021 you choose to mark for the "general availability" of the vaccine, and why shouldn't we lay those deaths at the feet of the FDA? Somebody's got to go to jail.
I think overall it would still be worth it if some thalidomides got through, but see my response to Brad above - I don't think there's any need to compromise safety here.
> how many Omegavens is one Thalidomide worth?
That seems like a red herring. Omegaven had a proven safety record in Europe.
Any clock should probably start with when it was approved for use in EU. Off label applications are allowed in US even when they haven't been "proven" to be effective. Simple reciprocity could have avoided the entire fiasco.
This isn't journalism, it's blogging. You don't have to be exactly right the first time, you only need to be willing to correct yourself.
My point was that I believe Scott got it wrong the second time as well when he evaluated his initial take as basically correct.
I do believe Kevin was unnecessarily harsh, since the facts do support Scott's conclusion, but more weakly by a factor of 2-4.
But Scott could have written the exact same paragraph, with exactly the same amount of outrage, only replacing '20' with '10.' This means he's basically right and just needs to make a minor correction.
Consider two different ways someone could be off by a factor of 2-4.
Example 1: I claim we should do my economic plan because it has a positive NPV of $1B compared to the next best alternative plan with a positive NPV of $0.9B. If it turns out my economic plan actually only had $250-$500M of value, my main point is refuted and I should retract.
Example 2: Imagine I'm going around screaming, we need to stop this serial killer because they've already killed 20 people! And it turns out they had, in fact, only killed 5 to 10. If I'd falsely attributed 10-15 deaths to the serial killer, I should correct that and discontinue saying the false number once I learn the truth. But the main point of stopping the serial killer is very much still in place!
Scott's error was very much the later type.
Scott usually operates within a utilitarian-ish framework wherein certain things trade off against others, and therefore are generally examples of type 1. I generally operate within this framework as well, and when doing so being off by a factor of 2 *may* lead to significantly different conclusions!
Yes, Omegaven getting delayed is evidence against the FDA no matter what the duration of the delay is. However, the degree of evidence is proportional to the length of that delay (among some other factors like the magnitude of impact that delaying has). So when you're off by a factor of 2, you've doubled the evidence of your example! That should be a big deal.
That evidence against then has to trade off against evidence for: the FDA didn't approve thalidomide in the US largely because they deemed European approval insufficient. Its rules provide some protection, the question is whether the cost of that protection is too high. If you fudge the evidence by a factor of 2, that can significantly shift the answer.
>"I want a world where if Europeans have been giving fish oil based nutrient fluids to babies for years, and everybody from NBC News to random bloggers know that the babies are much less likely to die on fish-oil based fluids, and all the studies that have been done confirm it, you are allowed to give those babies the fish oil based fluids without waiting another five years for an FDA approval."
Isnt the problem in this case that it was not as clear cut as you are trying to make out, based on https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671012/ , it seems like there was actual opposition from within the medical community, not the FDA, and that along with a lack of support from the drug company was the reasons things took so long. Ie Gura calls out
`The fact that we demonstrated that IV soybean oil was detrimental, but IV fish oil was not, created controversy in the medical community. Papers and commentaries were published that suggested that Omegaven caused growth failure, bleeding, and progression of hepatic fibrosis. These criticisms led to us to do more translational and clinical studies.`
This being said it looks we got a pretty positive paper in Nature in 2011, https://www.nature.com/articles/jp2010182 , after which point it seems like education more that the FDA was the problem. Do we have any recorded cases of doctors who wanted to use Omegaven having any difficulty in acquiring it after this point?
I feel like I addressed this pretty thoroughly.
Yes, "lack of support from the drug company" was relevant *in the context of the current system*, where without drug-company-level resources you can't push anything through the difficult FDA approval process. If you make it cost millions of dollars to do something, there will always be someone who resists paying.
There was (bad) opposition from within the medical community, but I don't think it would have passed a simple cost-benefit analysis, and a quick check at Europe, where this had been used for a long time, would have defused it.
In terms of "did doctors have trouble acquiring it" - doctors at hospitals that were willing to do an IND (very complicated FDA related process) did not, but very few hospitals were willing to do that. If you can call making people go through a very complicated process to vote "voter suppression", I think it's fair to call this "drug suppression". Of course you can always just do the complicated thing, but many people won't.
I am not so sure you can so quickly dismiss the opposition within the medical community, even in a world where there is no final FDA hurdle it is still going to take time and money to run the studies required to overturn this opposition if the conventional wisdom is that it was not the lipids.
Its also quite relevant when you are trying to present the narrative that everybody 'knew' for years that this worked and was safe, which doesn't seems to be the case. It reads like there was active opposition in the domain and it took time to do the science to prove them wrong.
Even if some doctors oppose it, parents who know their children will die without Omegaven would push to ensure they got it.
Wouldn’t they have done that in this case too? Why couldn’t every hospital have done said paperwork in 2005 and saved all those babies? Maybe doctors themselves are the real ones who, to quote the Twitter thread I posted earlier, “should all be to be sent to The Hague”. Why didn’t the parents just push to ensure that happened? Is a bit of paperwork really that much?
(well it is! It’s a big an impediment)
Because that’s a counterfactual with a lot of distance between it and what we know. Maybe they wouldn’t have quickly! Maybe they would have in 2014 instead of 2018 - better, but 2/3 of the babies would still be dead! Consumer pressure isn’t exactly a great driver of health outcomes in many other areas.
If no doctor can prescribe it without an IND exception, then a parent might be SOL. But if any of them can and some just don't want to, parents can go from one of the doctors who says no to one who says yes, which presumably wouldn't require moving to Boston.
There's a few comparisons of the FDA to "random person on the street". I think this is unfair, because "random person on the street" probably wants to start treating everything with ivermectin, or ban masks because they cause irreparable damage to oxygen intake. The comparison you're actually making is "random person with a graduate degree on the internet". I think this would be a reasonable target, and one that is hopefully attainable by a bureaucracy full of graduate degrees.
The FDA is supposed to decide that a drug is safe and effective. What the median person thinks about invermectin matters when the median person thinks ivermectin *is effective*.
Not to mention that bad judgment cabout a drug treatment is going to be correlated with bad judgment about drugs in general. If you were governed by random people without graduate degrees it would certainly matter if they had bad judgment about drugs, even if they weren't prescribing treatments for you.
All his examples are places where highly educated people on the internet have come to conclusions that the FDA hasn't, but then he characterizes them as "random people on the street". That was my point.
I think the average person on the street hasn't heard of ivermectin and is totally fine with wearing masks (other than the inconvenience of it), but I guess this just depends on the streets you're walking on. I think ordinary people are more likely to have no opinion than the wrong opinion on most issues.
I'd say Ivermectin is actually the textbook case study for Scott's argument. At this point it doesn't actually matter if ivermectin works or not. I know an ivermectin advocate who, by the way, is an engineer at Google and highly qualified. Conversations about it with him go roughly like this:
Him: Hey, there's this great treatment for COVID. Here's a load of links to interviews with doctors and studies and other evidence suggesting that it is indeed, really great, at least when used as a prophylactic. Also it's been around for decades and is known to be totally safe even in high doses.
Other person: wow that's great news so how do I get myself some?
Him: You can't, it's not an approved drug so doctors won't prescribe it.
Other person: That sounds crazy, if there's so much evidence it works why isn't it approved?
Him: Because the legal basis for emergency approval of the vaccines rests on there being no available treatment for COVID. If drug agencies approved ivermectin, they would have to revoke the authorization of the vaccination programme. Also don't try searching YouTube for it, all the evidence is being erased.
Other person: what, why?!?!
Him: because the FDA hasn't approved it and tech firms think any medical ideas unapproved by regulators are dangerous.
Other person: ohhhhh.....
Note that the takeaway is invariant to whether ivermectin actually works or not. Governments and their regulators have got themselves into a position where they have so publicly and so strongly committed to vaccines as the One True Solution to COVID that they cannot approve any other treatment, regardless of what it is or how well it works. Nor can they admit to the possible existence of such treatments (would undermine their own authority) nor even obtain useful data about those treatments, because they only accept evidence that's very expensive to gather and nobody will fund such studies when they know that it won't be approved for political reasons anyway. And during all this the public health and media classes (which includes journal editors) are busy trying to cleanse all communication channels of any information that might undermine the vaccine rollout.
That sort of Kafka-esque catch 22 gets noticed and is the sort of thing public health agencies seem to specialize in creating.
Note: all the people making these terrible and stupid decisions have at least graduate degrees and often more. I'm in agreement with the sibling comment by WC. I'd much rather be ruled by a mix of people, many of whom do not have degrees, than a credentialed class. Consider that by the telling of their own journal editors, half or more than half of what professors publish is wrong. Those professors are then teaching those wrong things to their students, and those students then go into the world with a childish attitude that the teacher is always right, thus dealing double damage to society: not only are their heads pumped full of wrong beliefs but they've been inured into a culture in which criticism of professors is totally taboo.
This, right here.
One of the dangerous things about credentials, and being told for years that you are smart in general, is that you start to believe that you can solve all sorts of problems, and that if you can't that must mean you aren't smart. Both are huge incentives to try and force your rule on people and never admit that you are wrong, while making sure no one else does either.
I'm confused. Aren't there all sorts of treatments for covid that have been approved, ranging from regeneron and remdesivir to dexamethasone and the like? And can't you find all the information on studies involving ivermectin in the usual places? (i.e., not YouTube, but preprint servers and so on)
I'd say the usual place to find out about studies on a very timely and important topic would be the media, not pre-print servers that hardly anyone knows about. At least, the media they seem happy to write stories on the basis of pre-prints normally.
Good point about remdesivir. Perhaps the issue is that those drugs have also been approved under emergency use authorizations? I never got deep into the treatments side of things myself, but I have a vague feeling the original claim was something like "if there's a pre-approved / known safe drug treatment then the EUA for the vaccine would be revoked". If all treatments are considered to be as experimental as the vaccine then that presumably wouldn't apply.
As ivermectin is off-patent no pharma company is submitting evidence to the FDA that it's safe for use with COVID, because that new use case isn't patentable. This comes back to Scott's point about how safety and effectiveness should be unbundled. There's no argument I'm aware of that ivermectin is dangerous, but apparently that didn't stop it getting sinkholed.
I think you might have responded to the wrong post, but I will take a whack at your question from the perspective of mine.
Once you have assumed the right to force other people to do what you want (hereafter "rule") based on your credentials and general smarty-ness, there is a large cost associated with being wrong, or even just not entirely correct.
The main cost there is that people no longer feel the need to listen to you; you stop getting to rule. That's no fun, if only from an endowment effect angle.
Another cost is that there are people competing with you for rulership, and they will not be satisfied with saying "Well, you were largely correct, just a bit wrong in the particulars." These people might even be logically on your team, in so far as they want broadly the same things you do, but they all are definitely NOT on your team because they want one particular same thing you do: to rule. Thus any weakness they can demonstrate in your smartyness might well cost you your rule, so you need to never be wrong.
A third cost, that keeps you stuck in the "I am always right, always" dynamic, is that people want you to rule specifically because you will think for them. If you hedge and say "Well, on the one hand, there is X Y and Z to think about, but on the other you have A, B and C. You are going to have to weigh the costs and benefits and decide what is right for you," you are going to lose subjects. People HATE that shit. When I worked in industry and consulting some years ago, that was the number one take away: never show uncertainty. People don't go to smart people for advice or leadership to be told "Well, that's a tough choice, it depends." They go to smart people to be told "Ok, this is what you have to do, and it will fix all your problems."
If it turns out that something else fixes the problems too, well, that's called a competitor, and unless you can credibly blame not coming up with it yourself on your petitioner, as the smart person you had better come out against it and smash it into the ground, lest your supplicants go to that guru instead.
So from the official rulering smart people, there can be only their proposed solution: vaccination. Treatments don't do it, otherwise why not just let everyone who doesn't want to get vaccinated just get sick, get treated, and hey presto, now they are vaccinated too?
Throw in the accusation from e.g. Bret Weinstein that all the non-vaccine approaches like treatment need to either be emergency only or smashed into the ground because the emergency vaccine pass only works if there isn't an available treatment, and you get a decent explanation of why discussion of ivermectin is verboten. The pharmaceutical money doesn't want to see a super cheap solution to the problem, and the rulers don't want to see a solution that is different from their solution. Plus, who wants to let a good crisis go to waste all because it turns out a cheap and safe medicine can take care of it?
I rather expect this sort of logic is what drives the meme that vaccines are going to end COVID, or have any chance of doing so, despite exactly 1 virus being ended by vaccination, and corona viruses being very far away from smallpox. If politicians were to say "We just need you to get a vaccine and then another every fall for the rest of your life to make sure you are pretty unlikely to get COVID or spread it," people would be a lot less excited. Making COVID extinct gets very close to the ideal of "Make this problem not have happened" people are looking for in a leader, but if that is off the table the rulers seem a lot less appealing.
Now I'm confused about what you're replying to. I was just, in that comment, replying to the claim that the FDA *needs* to deny ivermectin in order to keep the vaccines approved, because, as I point out, the FDA *has* approved other treatments.
I'm not trying to engage in some major defense of how the FDA actually does things. I think there are all sorts of ways it can and should be improved.
In this particular comment I was trying to debunk the false claims in the comment I was replying to, and in my top level comment I was just pointing out that Scott shows "highly educated people can come to better decisions than the FDA" but then claims "the FDA does worse than a random person off the street", and I was saying that there's a big gap between those two claims.
Fair point. I dug up the language from the relevant law (search for "(3)that there is no adequate, approved, and available alternative to the product for diagnosing, preventing, or treating such disease or condition;" at https://www.law.cornell.edu/uscode/text/21/360bbb-3 )
Looking at remdesivir at the FDA's site, that was approved proper in Nov of 2020, specifically for treatment of COVID that requires hospitalization, and apparently can only be given in a hospital. All the others are still under emergency approval (EUA). That might be the key fact, that a treatment requiring hospitalization is not an adequate alternative to a vaccine, but at home treatments might be? Or the FDA just decided no one was going to check their work and force them to un-authorize the vaccine so late in the game, so didn't worry so much after last fall? I dunno.
The difference between the FDA and the random person on the street is that the random person on the street doesn't try to force their decisions on other people so much, and generally say "I dunno" if pressed. The FDA has a habit of forcing their choices on others by default. Besides, the group "random people off the street" does likely include "ACX readers and other miscellaneous smart people".
In part though, I am inclined to agree with you, Kenny, because I suspect that the behavior of the FDA is pretty closely to what the average person on the street thinks: we can be made totally safe and there are no trade offs between safety and health. At some point the average believe, or median perhaps, seems to have moved in that direction.
Right. I don't fully follow how the remdesivir approval hasn't caused the vaccines to become unauthorized. Unless there are other clauses that modify the one you quoted, the language doesn't seem to have any get-out clauses in it: remdesivir would be "approved and available" for "treating such disease".
Perhaps the disconnect here is that my friend is right about what the law says, and the law is simply being ignored along with everything else? That would certainly align with my priors on everything else COVID/public health related. The rules are super strict right up until they're not.
When I stop at a traffic light these days, I ask myself "Why am I doing what the government wants me to do, when I or any other fool can see that there are no cars and perhaps more importantly no policemen in sight?"
I didn't used to ask this question. Compliance was the default. Now it has become at issue.
The medical establishment has dug themselves a very deep hole. I don't know how they can escape. We may need a new organization to address widespread diseases.
Some medical professionals believe that ivermectin is a life-saving drug which has cured COVID-19 in otherwise terminal cases. But you (a "random person on the internet") should feel free to disagree with them.
"I think this is unfair, because "random person on the street" probably wants to start treating everything with ivermectin, or ban masks because they cause irreparable damage to oxygen intake"
That seems unlikely to me. What evidence are you basing this claim on?
I am grateful to Drum for inspiring Scott to say more. Scott gives excellent rant, and this one seems right on target.
Thank you for tackling this complex and vital topic. One question to contend with is who stands to lose if the FDA's mandate was unbundled as you suggested in your first post.
The people who've already passed the hurdle and now have monopoly power, like that company mentioned above.
True, although these are the same companies whose ongoing R&D would have a greater return on investment with a different approval mandate.
Yes and no. Lowering the barriers to entry would increase competition (not necessarily on the same drug, but via different drugs), and pharma spends similar amounts marketing to R&D anyway IIRC.
Increasing the number of players could potentially also weaken the pharma industry's regulatory capture (if enough of them opt out of bribing politicians), which would also endanger their profit margins.
Profit margins aren't the same thing as profits. Looser standards means larger market size, so a smaller slice of a larger pie can still mean a larger overall slice.
The FDA mostly.
Begining to believe in something like: "libertarianism is inevitable if it's correct." In other words, if libertarianism really works, we should expect it to just arise naturally, on its own. If you need some state actors to force the state of the world into libertarianism, we should expect random perturbations to eventually knock it out of libertarianism.
So then you ask, ok, but what would it look like if the world fell into libertarianism? Certainly it wouldn't' be 'large crowds voting for limited government and consistently keeping an eye on politicians and being aware of all the ways people come into power over states' - i think it's more likely that it would be 'the dissolution of states ability to function and the general breakdown of state reputation, period'.
So rather than imaging a world where we shut down the FDA and let drug research go and then people make their own risk/reward decisions, it's easier to imagine this playing out the way uber played out: it's not like people voted against taxi medallions. Someone just started breaking the law, and once they made enough money, it wasn't really political feasible to stop them. Now replace uber with a bunch of decentralized autonomous networks, and, well...
"Someone just started breaking the law"
I disagree. Uber is a car service, NOT a taxi. The hallmark of a taxi is that it can be hailed on the street, and Ubers can't. You could ALWAYS call a car service and car services were NOT required to have a taxi license.
> If you need some state actors to force the state of the world into libertarianism, we should expect random perturbations to eventually knock it out of libertarianism.
I'm under the impression that it used to be much more libertarian and already fell out of it. I.e. the patent medicine era, with some effective medicines, some merely ineffective, and of course radium-containing energy drinks, infant soothers with opium, curing people via radio, supplements with ground-up mummies in them (!) (also used as paint), the works.
And in countries all over the place people didn't like it and passed regulations about it. For better or worse. So I think that's an important question (and it's relevant to many areas beyond drug regulation).
Worth noting that we have such things today too, Steve Jobs famously spent a long time worshipping at that altar. Various kinds of alternative medicines are wildly popular. I don't see medical regulators banning acupuncture anytime soon, do you?
IOW the quack doctors from the patent medicine may seem to have disappeared, but did they really? Or did they just change what they were selling in ways that are evolved to evade our BS detectors?
Some homeopathic medicines actually work. Or, rather, some medicines marketed as homeopathic actually work.
To roughly quote Terry Pratchett in "Feet of Clay": Humans have a design flaw; inside each of their heads is a little space upon which is written "Kings... what a good idea!"
The Jews had trouble with that problem. Just read Judges.
Now that you mention it, I wonder if that is what Pratchett had in mind as inspiration. The book is about golems, after all. (And a simply fantastic read, by the way. Probably top 3 of his novels.)
What's going to happen is that states will draw back their 10th A power and start writing laws that conflict with federal government law, AND (more to the point) back them up by defending "transgressors" against the federal government. I mean, there's no law which lets the federal government ignore the Constitutional strictures, and the Supreme Court would have a hard time ruling against a US state that was actively encouraging its citizens to ignore unConstitutional laws.
For example, Larry Sharpe suggests that sales of any product which is produced and sold entirely in one state should not be subject to a federal income tax. Any state could proclaim this, and defend the state's resident against any efforts by the feds to acquire the taxes they claim.
The income tax, specifically, is clearly constitutional - the Sixteenth Amendment overrides the Tenth Amendment.
So? No reason why the states cannot violate the Constitution. It's not like the federal government has any idea what it says, so they wouldn't be consulting it to see if what a state is doing complies with or violates the Constitution.
Except state laws get struck down by SCOTUS fairly frequently for violating the Constitution.
If you're fine with states violating the Constitution, there's no reason to be talking about the Tenth Amendment or any Constitutional text.
Very interesting. Given the states already ignoring federal laws they don’t like, this seems like a plausible approach.
What makes this guy worth responding to? I skimmed his stuff and it looks… light on intellectual rigor and shamelessly partisan?
I think engaging with Drum & his community might be kicking the hornet's nest of a highly sneery community whose mostly uninterested in hearing/discussing opposing viewpoints. Unclear upside with visible downside. That's a reasonable opinion to have.
Don't you think the whole "Scott is one of my heroes. It hurts to see him tested this way" might be a little melodramatic? Scott is not Christ, my comment isn't Satan, and this Substack isn't 40 days in the desert.
But Scott *is* Christ. "Christ" is not a person, it's a role. That's why he's *Jesus* [the] Christ. Like Trump the President or Biden the President or Alexander the President.
His intellectual rigour is highly variable. He puts out a lot of partisan fluff, but he also does enough quality think-pieces that a lot of people forget or forgive the former. Especially people who are in the same general segment of the ideological landscape (technocratic center-left) as Drum.
The thing Drum probably gets the most credit for is popularizing the lead-crime hypothesis: he wrote a series of articles explaining and summarizing the evidence for it and the proposed mechanisms for it, which got picked up and discussed by a bunch of other bloggers and opinion writers.
Is the lead-crime hypothesis an example of his rigor? Pinker wrote a scholarly tome about violence a few years ago and didn't think to mention it at all.
He separately posted an article dismissing it here, which I thought was pretty compelling and in my experience Pinker holds up pretty well (AGI gaffe notwithstanding): https://stevenpinker.com/files/pinker/files/pinker_comments_on_lead_removal_and_declining_crime_0.pdf
So, that further primes me against Drum.
It does seem like he was wrong about lead & crime, but as far as criminology goes it's one of the most reasonable mistakes a commentator has made on it, which puts him above most.
There are a LOT worse commentators out there than Drum, sorry to say, even at mainstream outlets.
Drum is actually pretty great, has debunked a lot of bad science, and is one of the people most responsible for getting the lead-crime hypothesis into public knowledge. I admit I don't read him regularly and only see him when a lot of people are missing him, so I might only be seeing his best work.
You're definitely better calibrated than I in blogosphere personalities.
When I was skimming through his work, I saw pieces like this (and the comments): https://jabberwocking.com/so-what-can-we-do-about-fox-news/ and felt his schtick was more about punditry than engaging with opposing viewpoints.
But I can see how you'd see it as a signal:noise thing.
I would like to point out how remarkable it is that these articles, over the last few days, have cumulatively generated tens of thousands of words of criticism about how awful the FDA is and you haven't even said anything about pharma companies manipulating the science to win approval while the FDA haplessly signs off on it.
Perhaps that point has been argued to death and it's super boring to keep talking about, but just for completeness it's worth mentioning the Alzheimer's drug is the lite form of a different FDA badness controversy. The deluxe version is that the FDA has also corruptly and incompetently approved drugs it shouldn't have.
So, we can't even say it's worth it to slow the pace of drug development to an expensive mind numbing crawl because at least when the FDA approves something we can be certain it's solid. We don't have that assurance either.
What do you mean by "corrupt", here.
I mean both run-of-the-mill bribery like naked exchanges of cash for approval (seemingly rare), but also more nuanced ethical eyebrow raising like pharma companies directly funding about 50% of their budget and also regulatory capture concerns.
There's a lot more in Ben Goodacre's book, which I don't have handy.
Yeah, I think the current system is something like "the FDA sets a very high bar for efficacy, pharma companies cheat to meet it, the FDA brings the bar higher, pharma companies cheat even more", and so on.
I realize that "it's easy to cheat" and "they're very strict" seem like opposite problems, but I think there's actually a weird sense in which they contribute to each other. A lot of FDA approvals are something like:
- There's some drug that obviously should exist but doesn't because the FDA is too strict
- This becomes a big embarrassment
- Some pharma company proposes a drug that fills the gap
- The FDA lets it through to end their embarrassment
This is what happened with ketamine. We knew ketamine treated depression really effectively. Nobody was willing to get it through the FDA because it was off-patent and they couldn't make money off it. Some pharma company finally applied for an approval for esketamine, a patentable chemical which is very much like ketamine and would let the FDA look on top of the ketamine situation. The esketamine (surprisingly to everyone including me) didn't seem to work very well, but it was so embarrassing not having ketamine be available that the FDA gave up and let them use it.
I don't know if this is at all common, but it's one of the examples I'm personally most familiar with.
I guess a problem is, approval or not, shouldn’t those trials happen anyway for off parent drugs? Even if some docs are allows to prescribe it, their resistance in the omegaven saga and many others means most won’t. And then you’ll still need a series of trials to really prove it works so everyone uses it. Can the expense of trials be reduced? Can doctors do their own trials - but reading the omegaven story the FDA at least encouraged trials a little while every other entity ignored the possibility. Is there anyone with reasons to do trials on generics?
Who's going to pay the $100MMs to get it approved?
Might be less than 100MM if your “trials” are based on prescriptions that are already happening, I.e. you don’t need to pay for the prescriptions but just provide doctors with a randomization placebo blinding tool for drugs they’re already prescribing? Idfk. If you’re loosening prescription restrictions one should track and maybe randomize them
For me this is a classic “half an argument”. You’ve successfully shown that there are lots of problems with the FDA. What you haven’t yet done is show that any possible alternative would be better.
In particular, the situation I fear is that drug vendors, unrestricted by an FDA, would peddle many ineffective drugs, and it would make everyone’s life much harder. I’ve never seen a good argument that suggests the market would be able to fix this problem.
I mean like the 19th century, when snake oil was a real product, not just a metaphor. (In fact, the problem wasn't even the snake oil, which is dubious Chinese medicine. The problem was the many knock-offs of snake oil.)
You seem to be imagining that drug advertisements in a non-FDA would would dutifully report the results of high-quality trials. I don't think that's how marketing works. I don't think it's how marketing would work in a world of unregulated or less-regulated medicine.
The classic model of a market involves a buyer and a seller who are both fully cognisant of their own needs and of the features of the product being sold. Where that doesn't hold (e.g. patients lack medical knowledge), there is no way, even in theory, for a market to be effective. Now, there are many mechanisms that can make up for this problem. One is regulation (think FDA). Another is consumer education (I can't see how this could work). Another is third-party certification (think Cochrane Approved). Another is chains of intermediaries (think doctor recommendations). All of these have been suggested; so far as I can see, none of them look like they will convincingly solve the problem.
Again, that sounds naive. Pressure from investors to have meticulous disclosure? The pressure you get from investors, by definition, is to make more money. All I'm suggesting would happen is something that already happens: drug companies would try to maximise the apparent benefits of their drugs. And now there would be no FDA to stop them. Think of the prescription opioid crisis of the 2010s.
If the FDA disappeared in a puff of smoke, of course, the rest of the medical establishment would adapt, change its practices, develop new approaches to working out which drugs are safe and effective and which aren't. What I'm saying is, there has never been an advanced medical system on earth that doesn't have something like an FDA. So what's being proposed here is pretty new. Maybe it could work. But I don't think I've ever seen a realistic proposal for what the new mechanisms or institutions would look like. If Scott has some ideas, I'll be reading them with interest.
But you seemed to be suggesting that this was just a really trivial problem, and of course people will choose the best drugs. That's incorrect. It's not trivial.
Once again, something that you think would be simple doesn’t seem simple to me. Here are two reasons: (1) Handing medical regulation over to the existing tort system would mean that questions of medical research would have to be decided in court. Courts historically refuse to do that. It’s not inconceivable that you’d have a medical court to decide issues of effectiveness, but it would have to be a new institution. And that’s what I’m asking for: the other half of the argument. What would this medical court look like, and why would it perform better than the current system?
(2) Most of the issues around the licensing of drugs involve probabilities. Drugs usually have side effects; many new drugs are effective for some people. The question that the FDA asks is how bad/frequent are the side effects; and does this drug help more/fewer people than the current standard. Neither of these questions are easily amenable to tort cases. Even class actions would struggle (e.g. the drug vendor admits the drug will kill 5% of patients; in reality it kills 8%; who are the victims who deserve compensation?). Again, these questions aren’t insoluble, they’re just difficult. I’d want to see some attempt at answering them and quantifying them before I’d think a big change in the current system would be a good idea.
"What sounds naive is pretending that the FDA is not subject to the sort of public choice problems that every other state-run institution is"
Private choice has problems, too.
>The probability a priori that the FDA is literally the best of all possible worlds is actually infinitesimal.
This is literally true, but useless as a source of insight. It's improbable that the current FDA is the best of all possible worlds because it's improbable that *any specific situation* is the best of all possible worlds.
This has nothing to do with the FDA specifically, it has to do with the fact that you really need to be asking about a range: "is the FDA a lot closer to the best of all possible worlds than the nontrivial FDA alternatives?" That one isn't improbable.
You are acting as one of those Internet literalists who thinks "that isn't literally accurate" means something when he's ignoring connotation and context.
"You need to show that some alternative is better" in this context doesn't literally mean that you can show that *any alternative* is better. There's probably some better variation on the FDA which is nearly the same as the existing FDA but with a trivial change. That doesn't count. What it means is that you need to show that some substantially different alternative to the FDA is better.
This.
C.f. Canada
He has said that is coming
They would peddle lots of ineffective drugs. And people consume lots of ineffective medicine right now (that's a focus of Robin Hanson's research). It's a question of cost/benefit. You internalize the cost of buying an ineffective medicine, as well as the benefit of an effective one. The FDA does not have much upside from you not losing your intestine because you got access to a drug that's actually good.
Except Scott did propose alternatives that would be better.
It's easy to point out problems, because almost nothing is perfect and most organizations only occasionally "pretty good" on a Pareto-optimal basis. So how about if someone describes a pathway for new legislation that would direct FDA to take some of the good steps described here? There would be at least two parts: (1) What changes should be made, and (2) What's the practical path to making those changes. IMHO, pretty much anything else is pretty much "Someone else do the hard work." I mean, if you want to just complain about something FDA, take a look at the QC and inspection regime for imported generic drugs.
Two very simple options would be to go back to the 1960's FDA that didn't test effectiveness, and to allow anyone to sell with approval from one of a few agencies, such as EMA or the Japanese one.
In my world, that, too, is not Pareto-optimal.
Of course it isn't. People with a moat around their product due to expensive FDA approval would lose out! Pecuniary externalities prevent Pareto optimality. Did you mean Kaldor-Hicks efficiency?
I want a world where the drug company will accept the FDA's desired wording on the warning label and distribute the lifesaving drug while they try to convince the FDA to temper down the warning in the meantime. Or was that not an option?
Are you saying you know this story and know that the FDA offered a label on week 1 and the company objected, or is this a guess?
I don't have any trouble imagining the FDA taking 5 months to write the first label, but I have no actual knowledge of this case.
I'm relying entirely on the content in Scott's link to the original story, entitled "The FDA almost killed me":
"Even though the FDA had granted Enyvio Priority Review Status, for the next five months the FDA kept John (and undoubtedly many others) suffering as they debated the wording for the warning label...The FDA wanted to put a warning about the possibility of a severe allergic reaction on the label...A warning about allergic reactions would make Entyvio look less safe, something that the company rightly took objection to..."
"Another possible reason for the delay might be related to the fact that the FDA claimed that Entyvio put patients at risk for progressive multifocal leukoencephalopathy (PML)...The company disputed this...but the FDA wasn’t convinced. In the end, the FDA decided to include a warning about PML on the label and require post-market surveillance."
I too would like this. But I think it's like "instead of declaring war, why not just have dictators give up their weapons of mass destruction peacefully", or "instead of resisting arrest, how about people just surrender to the police, or even better, never do anything suspicious to begin with". Might be great if it worked, but it's easier to determine what the government demands than to turn people into angels who always follow all demands no matter how extreme.
I think that "instead of resisting arrest, how about people just surrender to the police and let the criminal justice system sort it out" is our actual system, which, despite the inequities of the criminal justice system, probably works better than the alternative.
To clarify, I think that the drug company's action here is part and parcel of the problematic system (within which the FDA is the implementing actor). If one thinks drug companies are evil, one would say they knew a too-strict warning label would permanently taint the drug and lower profits in the long run, so they held out. If one thinks drug companies are great, just substitute "lower drug acceptance and cause unneeded deaths" for "lower profits" in the previous sentence.
Every time some process seems to go especially badly in the United States one should check how the same problem played out in Canada. In this case I wonder how long it took them to approve the fish oil variant treatment...
"Silenor brand paid a $100 million FDA application fee" and "even though the manufacturer did not give the FDA $100 million dollars." - PDUFA fees are closer to $3M. Clinical programs can run in the hundreds+ of million dollars, but that money isn't going to the FDA.
I think this is more in the sense of 'paid a blood price,' like sacrificing a cow to an altar or something.
But yes, could be more clearly stated.
My source is https://www.fiercebiotech.com/biotech/somaxon-finally-wins-fda-approval-for-sleep-drug-silenor, which describes their application process as "a financially exhausting quest that has consumed more than $170 million".
I guess it's not fair to call this an "application fee" per se rather than associated costs, so I will change the wording in the post.
" only to be frustrated by repeated questions about the drug's sustained subjective sleep maintenance efficacy in non-elderly adults with primary insomnia"
Looking at that line, this seems to raise a good question about the efficacy of the drug and if the company couldn't or wouldn't answer it, no wonder it took so long to get approval. If I'm a thirty-five year old insomniac and I get prescribed this drug and it works for a while then stops working, I want to know about that and not "well if you were eighty with hypertension it would knock you out for months!"
"Nevertheless, executives could raise their champagne glasses this morning as the developer's share price (SOMX) shot up 80 percent on the news."
And that's our problem of incentives right there.
Some drugs move faster than others; it only took Silenor two years to get approval, which I think is fair enough given the questions raised above:
https://www.evaluate.com/vantage/articles/news/somaxon-wins-approval-silenor-and-hunt-partner-begins
"Somaxon has spent $108m on R&D in the last six years as it has pushed the drug towards the market and the next thing it is likely to do is ask investors for some more cash to help finish the job, capitalising on its two-and-a-half year high share price. With $4m left in the bank the company needs to top up the coffers quick smart to give it a fighting chance of sealing a decent commercialisation deal.
However, Silenor will be competing against some very entrenched products, like Dainippon Sumitomo’s Lunesta and multiple generic versions of Sanofi-Aventis’ Ambien, which was generating sales of $2.5bn a year before it lost patent protection in 2007.
Despite the huge amounts of money thrown at Lunesta by its former owner, Sepracor, the drug is probably more famous for its hugely expensive marketing campaigns than commercial success – sales reached $736m last year – and many have concluded that the insomnia market is only for the brave.
Combine this with the fact that the active ingredient in Silenor is available generically, and not all observers are expecting the drug to be the next insomnia blockbuster."
No wonder they want to charge $250 a go for a prescription. And no wonder they want to try and make sure they're the only one licenced for this use.
And perhaps this is why the makers of Sinequan decided to market it as an antidepressant and not a sleep aid - too much competition, not enough profit in the insomnia market, but there's always room for another antidepressant as people regularly cycle through all the alternatives to try and find one that works for them.
I see that doxepin was approved in the USA in 1969, so again this sounds like another example of "take an old medication, give it a slight spin, brand it as new and charge full whack for it". Doxepin-as-Sinequan was already established so doxepin-as-Silenor was a new branding by a different company (Pfizer were manufacturing Sinequan).
Sinequan seems to have been discontinued since 2006? Presumably because it was so cheap and generic that it wasn't enough of a cash cow?
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=016798
https://www.prescriber.org.uk/2006/04/doxepin-discontinued
There's a couple common proposed solutions to this problem:
1) Radical deregulation (abolish the FDA)
2) Radical change in government to make it more efficient
Regarding (1) - we have some experience from where geographically and historically regulations are less enforced.
The issue with (1) is that people respond to incentives. And there are two incentives here - the incentive to act in a framework of rationality for the greater good, and the incentive to make money.
In the past, the market for cure-alls was was very lucrative (they sold energy drinks that contained real radium, among other things). No doubt many salesman genuinely believed in the effectiveness of their products, so they were making money and doing good at the same time. You see a similar thing with the supplement industry today.
For a modern day example, in Ukraine today you can be upsold ineffective alternative-medicine treatments when you go to routine dental visits.
To strongman radical deregulation a bit, I think it could work out well for people like us who are maybe a bit more able and willing to vet in detail all medical treatment we receive. And, in practice, many people may become distrustful of the health-care-services market (just like people would be distrustful of the stock market if it was full of scams) and avoid purchasing health care at all or only purchase services from a few big gatekeepers (perhaps big hospital systems like Kaiser).
While the last point might resemble the old system in certain ways, it avoids some of the perils of centralization and central-points-of-failure. And if you kept non-profit status and a monthly subscription model, that avoids many of the obvious adverse financial incentives.
You might see a concerted marketing push to lure people people away from evidence-based systems to higher-margin ones though (which would have more money available to buy ads). And hospital systems don't currently pay for drug trials - if that remained up to the drug companies themselves, there are still obvious adverse incentives there.
Ok, on to point (2), radical change in government. This is an increasingly popular position on the modern right and I think more politically realistic than (1). We need a CEO / monarch / whatever word you want to use in place of "dictator". After all, corporations are more efficient, right? Except for all the ones that aren't because they are monopolistic and can afford not to be or never become big to begin with. But let's ignore those for a second.
Again, let's look at the incentives. Of course there's the basic one - staying in power because they don't want to be killed or go to jail forever. And of course the desire to make money. But there's also the intrinsic motivation of technocratic health care reform.
You can look at dictatorships all over the world and see how they do, on average. And you can also look at the group of people such a person is likely to be selected from, in the US. Do they seem particularly interested in technocratic health care reform? What is the likely outcome here? Do they even show close to the level of intelligence and self-restraint as autocrats like Orban? (Who as far as I know, isn't known for his health care policies.)
There's may be an option (3), which is find a specific incremental reform that seems to be the most valuable, and try to build support for it among the public / institutions / and/or political class, which is where currently where change comes from. But that's not exciting.
I want to clarify the Ukraine example - I'm talking about mixing evidence-based and not-evidence-based-but-presented-as-evidence-based treatments together, where they look the same and the distinction isn't obvious to the consumer (and of course the not-evidence based products provide their own marketing material that makes this easy for the providers). So, something that's not directly analogous to how alternative medicine works in the US.
The not-evidence-based ones of course present their own evidence but don't have the proper level of rigor, so the consumer would have to vet the rigor of the scientific study and the trustworthiness of the data, or find a reliable third party source in an online environment where there is a big financial incentive for the producer to make sure their message is heard better (and it's also cheaper to write articles mindlessly promoting something that properly evaluating it).
I don't speak Ukrainian so I can't say if these sites exist. I can say based on other markets that even review sites can be easily created and gamed or cut deals with manufacturers if there's money in it, look at the mattress industry in the US.
Here is a big question I never see discussed:
Let's assume the FDA, and the regulatory system it is part of, is uniquely bad in the ways Scott outline, and either stops many useful medications from being developed, or delays them by decades.
Why doesn't the other 95% of the world develop those medications?
Or do they, and we never hear about it? If so, what great, banned in USA, cures are out there?
I don't think the thesis is that the FDA is *uniquely* horrible. A quick googling suggests that the EU, Britain, Japan, and South Korea all have drug approval processes that are conceptually similar to that used in the US. There are incremental improvements over the FDA in many of these countries, but none of them sound like libertarian paradises (or libertarian dystopias, depending on how you feel about laissez faire).
One of the bigger differences, which seems like low-hanging fruit for incremental FDA reform, is that many of these countries allow some form of expedited review based on existing data for drugs approved by other countries with similar standards. This is especially a factor for the EU, where individual countries have their own approval processes (and Germany in particular seems relatively lenient) and the central EU agency providing a bridge for expedited EU-wide approval once one or more member states have approved.
Another factor is that the US is unique in being a large, rich country with strong patent protection and little in the way of price-fixing for prescription drugs. The FDA can get away with being more expensive and time-consuming to deal with than the rest of the developed world because potential profits from selling prescription drugs are much more heavily concentrated in the US than your 5% figure suggests.
Germany is very lenient; for some reason, Germans are extremely fond of homeopathy and biodynamic cures and the rest of it, and such cures (which are often laughed to scorn on here) get prescribed by ordinary doctors and paid for by medical insurance plans:
https://undark.org/2020/03/16/homeopathy-globuli-germany/
I'm very happy to buy German cosmetic brands that are all vegan biodynamic etc. etc. etc. (e.g the Weleda brand or Dr. Hauschka - the rose cream is expensive but great for mature skin https://www.drh.ie/face/28-rose-day-cream.html) but I would not go for medical treatments of the same nature.
According to this article in German from 2019 [1], of 40 billion € paid for medical remedies by public health insurance, homeopathic remedies only accounted for 20 million €. While I don't like that, either, it's essentially negligible in comparison (0.05% of the total).
The overall market is much bigger, but it's presumably paid for by private insurance or out of pocket. I don't endorse spending one's own money on homeopathy, either, but would certainly not advocate for forbidding that.
[1] https://www.aerzteblatt.de/nachrichten/106083/Spahn-will-Homoeopathie-auf-Kassenkosten-nicht-antasten
I wonder what fraction of hte homeopathic remedies are prescribed to people when the doctor just thinks they don't need any medicine but they'll complain if they don't get something.
Did you not read the post above? Omegaven was approved in Europe but not the US this whole time!
I would also advise you to read his post on "Russian chemistry".
Link: https://slatestarcodex.com/2014/08/16/an-iron-curtain-has-descended-upon-psychopharmacology/
Sure, but that is one isolated drug.
If this is a systemic problem, there should be hundreds of similar drugs in use steroids the world.
And maybe there is. This is what I'm asking.
Scott's post on the different drugs in different countries is about just that.
The US is 24% of the GWP (nominal, since that's what matters to multinationals), and probably about 40-50% of the available money extractable by pharma (developing world uses less pharmaceuticals, and is extremely willing to revoke patents if significant profiteering takes place). "95%" is a bit of an exaggeration.
The main reason the US is the main source of pharma is that nearly everywhere else has state run medical systems that very heavily restrict what you can charge for a medicine, either legislatively/regulatorily setting the price or being the sole purchaser and so effectively setting the price that way. In effect, US consumers pay for the large majority of the development of all new drugs. Not all, some still happens in other parts of the world, but it is very heavily weighted towards the US.
Developing a drug or medical device outside the US then trying to sell it inside the US to make back the costs just adds the hurdles of learning a foreign legal and regulatory system, not to mention language, to the normal FDA hurdles.
Adding to that, it isn't obvious that the FDA is a lot worse than the regulatory agencies of other countries or regions, although not accepting the work of the EU or Japanese (or others) regulatory agencies is odd. I have heard complaints from other countries that sound a lot like the usual FDA issues.
The best argument in favor of the FDA's mandate is this famous graph: https://journals.plos.org/plosone/article/figure?id=10.1371/journal.pone.0132382.g001
(Which shows that the FDA forcing pre-registration of clinical trials massively improved the published data by eliminating undetectable p-hacking.)
Without a barrier similar to the FDA's mandate to evaluate efficacy, who will actually force drug companies to do good science instead of 'looks good' science? Bad science is better for business because it is far less likely to fail your drug.
No, you can't simply handwave the practical issues with demonstrating malfeasance by establishing an incentive for 'sniffing out torts'. A lack of incentive isn't the biggest problem with relying on torts; it's the inability to detect p-hacking after the fact. If a study isn't pre-registered, p-hacking is completely non-detectable.
I also doubt very much that most p-hacking would be legally fraud. Running ten endpoints and publishing the three most promising and interesting ones really isn't 'lying about what your drug does' by the layman's sense of the word 'lying'. It's statistical malfeasance, but probably not legal malfeasance.
I'm also incredibly skeptical of the idea that the FDA's high standard of proof made drug studies worse that they would be without it. Good studies are harder and more expensive than bad ones, and without some incentive to do good ones I expect very few good ones to be done.
Well, the US is already extremely litigious society. Maybe it is good in certain aspects as it ensures better consumer rights but generally I think that we can solve more conflicts without involving courts.
The FDA could give a seal of approval to only those companies which do such pre-registered trials, but it's still legal to buy drugs without the seal. So uncertain low-information consumers can look for the seal, and desperate people who don't want to die can take their chances.
Yeah, something like that might work. I like the similar idea Scott mentioned about a 1-5 star ranking for drugs with variable prescribability (though it's complex enough that I worry about how it would end up working in practice and public opinion.)
As Scott discussed in the original post, you can still have an agency tasked with "determine if a drug works according to an agreed-upon criteria". The idea is to decouple that from "determine if a drug is safe" and "decide whether it's legal to use a drug" and (maybe) from "decide whether insurance companies should be required to provide the drug". The fish oil story goes very differently if the doctors only needed approval from the "Drug Safety Administration" and the "Drug effectiveness administration" was out of the picture.
Right, but... what's going to incentivize pharma companies dumping millions of dollars on good, well-designed trials? They can probably get 90% of the profit by just proving safety and then advertizing well.
Maybe? If insurance only covers "proved-effective" drugs then I'd imagine most sales would still require proving effectiveness.
Also not central but "good, well-designed trials" feels possibly generous...
"In 2013, NBC ran an article called Drug Treatment Omegaven That Could Save Infant Lives Not Yet Approved By FDA. In 2014, libertarian blogs were using it as an example of excessive FDA delay"
In other words, two institutions that are highly motivated to report that there's a miracle cure being held up by the FDA said, guess what, there's a miracle cure being held up by the FDA. I would not call that very convincing evidence that objective observers were of the belief that something might be going on here.
My argument is that (1) lots of people were asserting Omegaven was great long before the FDA approved it, and (2) those people were right.
I was using the links to prove (1). For (2), see the UpToDate quote in my last article, the Dr. Gura piece, the 2011 study, and (last but not least) the fact that the FDA did eventually approve it.
But you don’t think it’s relevant that the “lots of people” were, at least in the beginning, highly motivated to tell that story? If we look through their archives, don’t you think we’ll find that both NBC and those blogs have cried wolf on this topic?
Problems like this are not unique to the FDA. I venture to say that all government agencies and many private businesses eventually fall victim to massive inefficiencies. Parkinson's Law provides a decent explanation of how this can happen. Basically as an agency gets larger the needs of the members of the organization (getting promoted, gaining prestige, not getting blamed for anything etc.) are at odds with the needs of the public the agency allegedly serves. I used to work with the IRS. In my current career I deal with the FCC and FAA regularly and I can assure you that these organizations are as difficult deal with as the FDA. While they don't (usually) kill people they do ruin their lives.
In a perfect world when a private business becomes inefficient, it falls victim to a more efficient competitor. Government agencies however seem to last forever.
I think that it is useful to have a rigorous process for drugs that will be used for decades by tens of millions of people.
But if babies are dying now or there is a raging pandemic then it makes no sense to follow this process. I know it’s wild but maybe the FDA could have a “compassionate use” exception for drugs that anecdotally clearly seem to help patients but where we don’t have RCT studies, and “emergency use approval” for vaccines when there is a raging pandemic.
… sarcasm off: I am guessing that by and large the FDA does “err on the side of caution”. It may well be that if there is a lever in the FDA to make the process lighter weight then someone should make it 5-10% lighter but I don’t think it should go all the way to the max. Drugs are really really hard to evaluate and the average person or doctor really can’t tell if they work or not. This is not a situation that the free market would work well in. Ideally there should be a cost/benefit/profit/damage analysis that ensures the process is tailored to (1) the benefit per patient of the drug works vs (2) the potential harms to the patient if it is unsafe or doesn’t work (which can also harm) but also societal aspects such as the total cost of the drug to the system, which is also proportional to the profit of the manufacturer and their ability to fund the process.
A drug that will be used by tens of millions and will make billions of dollars in profit should be subjected to a higher standard than a drug that will only be used by few patients for a rare condition. I don’t know if this is or isn’t the case now.
Yes yes and yes
This reminds me of restaurants in Albuquerque. In the old days anybody could open an Mexican food stand, and taco trucks roamed the streets. Then the restaurant association got the city to require licensing, fees, inspections - things that larger restaurants, esp chains, had no trouble meeting, but drove the mom and pop places out of business. Now if you want a breakfast burrito you buy it out of the trunk of someone's 72 Chevy, with exponentially greater health risks. My favorite part, however, is how the restaurant association is always complaining to the press about too much regulation.
As someone who doesn't live in the USA, I want to emphasise that the choice isn't "FDA or snake oil", the debate is much more complicated than that. There are lots of different systems around the world that face the exact same challenges as the FDA but respond in different ways:
https://www.nature.com/articles/nrd.2017.135#affil-auth (rather short, but a good start)
According to this article, the FDA is the most expensive (for both the government and for the drug companies) and takes significantly longer than most other equivalent agencies. Now, paying more for worse service seems like a general problem with the American healthcare system, but it does suggest that changes could be made without worsening the quality of healthcare - a shorter and less expensive application process would be a great start - you'd have access to more drugs at a lower cost!
I think it’s worth noting that the FDA is probably more expensive in part because so much more drug development happens here. And the FDA takes longer to approve drugs, certainly, but probably because the drugs often get developed in the US for approval at the FDA first, and then the evidence is already collected for other trials. I’m not so sure we can just “take that trade off” as we’re in a different situation. In terms of costs, we likely do overspend, as you say that is a general characteristic of US healthcare - but I’m not sure we can change speed just by switching to other systems - and also US personnel and all other costs are just higher than other countries due to higher incomes. And the us FDA does not appear to take significantly longer than similar agencies here, as it has the second lowest mean approval time (333 day) higher than Japan and UK (311 and 230). I don’t
And as my above comment about roxadustat shows - when other health systems try to fast track the FDA approval, they may screw up. Here, China fast tracked approval and got a “historic” approval on a drug before the US - but after the FDA “capriciously” delayed and delayed and delayed, it came out that they had incorrectly performed a the safety analysis on a trial and the advisory committee voted to not approve on grounds of risk benefit not favorable. https://astralcodexten.substack.com/p/contra-drum-on-the-fish-oil-story/comments#comment-2571594
In the story about vedolizumab (Entyvio) I would also blame the drug company for not advising the patient that their stock is nearing expiration and since the approval is taking longer than expected, he should ask for compassionate use which would have been granted.
In really this was probably a big company with poor communication between departments and most likely no one really cared or even knew that the batch is expiring until they finally received the approval.
Another thing is that initial expiry dates are often very arbitrary. The regulator requires studies to justify longer storage times. Sometimes they can be proved by accelerated aging (higher temperature, humidity) and extrapolating this data. In case of products stored in the fridge (2°C-8°C) it's probably harder and the most common way is simply to store the product and see how it deteriorates. Initial batches have short expiry dates but after one or two years more data comes in and usually the expiry dates can be made longer. It is very likely that the batch they couldn't give to the patient for legal reasons was actually good.
The FDA screws up every hour of every day, in the same way our hypothetical False Data Administration screws up every hour of every day. Not because they’re constantly making stupid, minor mistakes. But because their whole mandate / philosophy / modus operandi is mistaken.
which, to be fair, does sound different from
Every single thing the FDA does is like this. Every single hour of every single day the FDA does things exactly this stupid and destructive.
... but I get it. You are angry and the FDA may fulfil its mandate pretty well but it's still the face of the bureaucratic apparatus kicking you in the groin...
That being said. Why is the FDA set up the way it is? Is not ultimately a reflexion of how risk adverse and uneducated (when it comes to probas/stats) the population is? Or at least how responsive the political system is to such population?
If that's the case, there's no solution...
The FDA isn't some anomaly within the US Government. This is the administrative state - this is how our government functions (it's the culmination of the New Deal State). (This post is an excellent example of Conquest's First Law of Politics though).
The criticisms are valid, but talk about missing the forest for the tree. You can't change the way the FDA works without changing the function of the government.
I’m assuming you’re approaching this from the reactionary perspective?
If so, then why are the relatively absolutist or dictatorial states that have good technological development - Singapore, China, etc - not much better about drug safety and approvals?
In terms of approval speed - https://www.sciencedirect.com/science/article/pii/S0149291820303362 - China tends to be worse than the US, this review finding a 2 year average delay compared to US or Europe.
And here is an article how China leapfrogged US and EU regulators in approving some drugs on a fast tracked rolling clinical trial basis - https://www.mercatus.org/bridge/commentary/how-chinas-drug-approval-agency-outpacing-international-counterparts - and impugns the FDA’s slowness. one of those drugs was roxadustat, which they link here - https://www.wsj.com/articles/big-pharma-wins-drug-approval-in-china-ahead-of-west-for-first-time-11545137592 . So wow, Chinese consumers have had access to a wonder drug for years that we haven’t! What’s the catch? Apparently, the risk benefit profile has problems - the (us) FDA advisory committee voted 13-1 and 12-2 in two votes
to not approve roxadustat https://www.astrazeneca.com/media-centre/press-releases/2021/status-on-us-fda-advisory-committee-for-roxadustat.html (this adcomm review was called “capricious” by this site - https://www.fiercepharma.com/marketing/capricious-fda-spooks-fibrogen-astrazeneca-last-minute-roxadustat-adcom-cuing-another - lol).
Whoops
Also, . We became aware that the primary cardiovascular safety analyses included post-hoc changes to the stratification factors,” Enrique Conterno, CEO of FibroGen, said in a press release. “It is important to emphasize that this does not impact our conclusion regarding the comparability, with respect to cardiovascular safety of roxadustat to epoetin-alfa in dialysis-dependent (DD) patients and to placebo in non-dialysis dependent (NDD) patients.”
Based on the analysis, however, “we cannot conclude that roxadustat reduces the risk of (or is superior to) MACE+ in dialysis, and MACE and MACE+ in incident dialysis compared to epoetin-alfa,” Conterno said in the release.
The Institute for Clinical and Economic Review also released a report stating there was insufficient data to show that the HIF-PH inhibitor provided a health benefit over currently available anemia drugs, such as Aranesp (Amgen Inc.).
From https://www.healio.com/news/nephrology/20210716/fda-panel-does-not-recommend-approval-of-roxadustat-for-anemia. Not sure it’s so clear that a more lenient FDA is better! Roxadustat apparently also lead to higher overall mortality.
I think it's fairly obvious why China would be bad at this (https://en.wikipedia.org/wiki/Lysenkoism). I certainly wouldn't defend the Chinese regime's rigorous devotion to any objective facts.
Singapore is a better question. I worked on a project with the Monetary Authority of Singapore for a year or two and my impression is that many of their more technical government agencies are set up to work like the ones in the US.
Note that I'm not saying that the administrative state is bad - I'd rather have the FDA making these decisions than Congress or the actual Executive Branch. You just can't criticize it for being itself. The administrative state does indeed function like the administrative state! Amazing discovery.
I think taking the Chinese market as an example of "wonder drugs" would indeed be dodgy, after all this is the same market that needed their government to crack down on people putting melamine into raw milk to boost protein content, leading to contaminated infant formula as well as other food products:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799451/
Not to be pointing fingers at the Chinese as the sole persons ever to do shit like this, people *everywhere* will and do adulterate food products in order to increase their profit margin. Things like this are why we have institutions like the FDA and comparable regulatory bodies in the first place.
Yeah. So I am unhappy with the idea promoted by most readers and Scott here that “just make the fda do fda things less!”
Obviously the FDA needs serious changes but ... what changes?
Letter from the American Academy of Pediatrics calling for the FDA to use cost/benefit/common sense to speed up approval of the vaccine for under 12 children,
https://downloads.aap.org/DOFA/AAP%20Letter%20to%20FDA%20on%20Timeline%20for%20Authorization%20of%20COVID-19%20Vaccine%20for%20Children_08_05_21.pdf
Would this work though? The benefits for kids under 12 (or under 4 or under 18) for a Covid vaccine are pretty close to zero (at least the first order benefits, maybe would help old people, but that's not obvious given how little it seems to spread among children). The costs of other vaccines to children are definitely non-zero (all treatments have some side effects).
https://twitter.com/justin_hart/status/1421937708713189376
It's almost certain, given the extreme changes in outcomes for Covid by age, that the vaccine wouldn't pass cost/benefit below a certain age (not certain where that age is).
The case/death rate for kids was 0.00%-0.03% and the percent of deaths that were in kids was 0.00%-0.25% (with kids as 15% of cases). His link reports 350 deaths in kids. (This is https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/children-and-covid-19-state-level-data-report/)
Yes, this is very low. The 350 is for 18 and under and it's not clear how many died with Covid vs from Covid (estimates have been as low as 0 for from Covid).
The broader pointer stands. As you go further down the age range, the benefits get and less, while there are still some costs. At some age level, the lines are going to cross.
Good chart here: https://www.facebook.com/DrCharlesLaing/posts/2873618672850969
An unvaccinated child still has less risk than anyone else that's been vaccinated
I mean 2 in 1k to 1 in 10k for a 30yo is still probably worth it.
"Since the approval of earlier monoclonal antibody drugs such as Remicade and Humira, scientists learned that in the long term some patients can develop allergic reactions to treatment. The FDA wanted to put a warning about the possibility of a severe allergic reaction on the label. The problem was that the drug had been designed specifically to avoid the allergic reaction rejection problems that occurred with Remicade and Humira, drugs which did not contain such a warning. A warning about allergic reactions would make Entyvio look less safe, something that the company rightly took objection to."
Because I *am* that bitch, I went to have a look about the warning of side-effects that the FDA imposed upon the makers of Entyvio, in particular the allergic reaction ones.
Given that within the story itself, John had suffered allergic reactions ("That all changed suddenly and unexpectedly in 2005 when his throat closed up after his injection. Unfortunately, as happens to many long-term Remicade patients, his body had developed an immune response to the drug. In response doctors switched him to a similar monoclonal antibody drug, Humira. However by 2013 his immune system had started rejecting the Humira as well"), and that once someone has already shown such reactions to medication, they are somewhat more likely to have similar reactions to other medication, I think that the FDA were considering all the "Johns" out there who would want to go on to the new wonder-drug Entyvio.
So what is this warning? From the company's own website:
https://www.entyvio.com/vedolizumab
"Infusion-related and serious allergic reactions can happen while you are receiving ENTYVIO or several hours after treatment. You may need treatment if you have an allergic reaction. Tell your healthcare provider or get immediate medical help if you get any of these symptoms during or after an infusion of ENTYVIO: rash, itching, swelling of your lips, tongue, throat or face, shortness of breath or trouble breathing, wheezing, dizziness, feeling hot, or palpitations (feel like your heart is racing)."
We're left with two possibilities here:
(1) The above is a lie, forced upon the makers of the drug by the FDA in order to get approval. However, surely the drug company would go to court over being forced to put a false, and very damaging, claim on their label? Those who know better, can advise me; maybe they feel that going up against the FDA is too difficult and will cause too much trouble down the line and that they would lose their case regardless
(2) The above is true, and the drug company did not want to put it on the label because (a) not being monsters, they felt their drug was safe enough and wouldn't kill patients above the ordinary acceptable level of risk and (b) a warning like that would put people off, and after sinking so much money and time into developing the drug and getting it licenced, they needed to recoup all that, and they couldn't sell the maximum amount if doctors and patients thought it was dangerous.
Talking about how things are approved in Europe, it seems that in 2020 the EU approved Entyvio:
https://www.takeda.com/newsroom/newsreleases/2020/european-commission-approves-subcutaneous-entyvio-for-use-as-maintenance-therapy-in-ulcerative-colitis-or-crohns-disease/
Ah, but look here: it seems the heartless Europeans *also* insisted on warnings about allergic reactions:
"Special warnings and special precautions for use
Intravenous vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions, including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering intravenous vedolizumab. Observe patients during infusion and until the infusion is complete.
Infusion-related reactions and Hypersensitivity Reactions
In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity. If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks."
This kind of "before you take it, make sure your doctor is prepared to manage anaphylaxis" is *somewhat* different to the story as posted about "this *perfectly safe* drug which *didn't* stimulate the same allergic reactions was held up by the FDA who almost killed me".
Or maybe I'm reading this all wrong, and it's not a case of a desperate patient, a drug company wanting to get a new drug on the market as fast as possible, and a regulatory body trying to be responsible but perhaps being over-cautious?
And if the FDA was bad for dragging its heels from 2013 to "five and a half years later", which would bring us up to 2018-2019, what do you say about the EU which also took from 2013 ("Takeda Pharmaceuticals filed the paperwork for approval with the European Medicines Agency on March 7th, 2013 and filed with the FDA on June 21st, 2013") until 2020 to approve it?
Also that John applied in 2013, didn't get it until 2014 (which is not too bad a delay) and the story then pivots to the solemn "but by then it was too late":
"It wasn’t until September 2014 that John got the drug. By that time John was in precarious health. Although he now had the drug in his system, it was too late to help. In January 2015 his doctor sent him to the ER where he stayed in an ICU for several days fighting an infection. John had to have two major surgeries that ultimately removed his large intestine altogether. "
But once again we are in the world of "what if?" By the account in this story, John has been suffering from this disease since he was nine, two other therapies eventually failed (as they were expected to do) because of natural resistance of the immune system building up, and he was so bad that his doctor wanted urgently to go for this new drug.
Had he gotten it in 2013 would he still have ended up in hospital? WE DON'T KNOW. He might have done anyway, given that he was in such poor health by that time. He might have developed an allergic reaction to the drug. There are a lot of "maybes" and "could have happened". So the fact that he got the drug, didn't have a bad reaction, and is still alive and presumably more well than he would have been is the HAPPY ending to this tale.
So it's a great clickbait headline, but I don't think it's quite true to say "The FDA nearly killed me".
Since too much is never enough, here's another extract from the EU version of the information pamphlet on vedolizumab/Entyvio:
https://www.ema.europa.eu/en/documents/product-information/entyvio-epar-product-information_en.pdf
"Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier (see section 4.8). Vedolizumab treatment is not to be initiated in patients with active, severe infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment."
So why did I pluck out that plum? Because once again, the story as presented tells us:
"In January 2015 his doctor sent him to the ER where he stayed in an ICU for several days fighting an infection. John had to have two major surgeries that ultimately removed his large intestine altogether. "
But increased susceptibility to infection is a known risk of the disease! It wasn't "because I was denied access to the drug" that it happened. And it could have happened even had he been put on Entyvio - see the part about "withholding treatment if the patient develops an infection while on vedolizumab".
So yes, I understand the story from John's side and from his supporter's side; it's a lovely journalistic human-interest story complete with eyeball-grabbing headline, but it's maybe not entirely the whole of the matter. And nobody is lying, I'm not accusing anyone of faking or inventing or the like. What I want to point out is that, when people are sick and desperate, they easily formulate a narrative of "this will cure me" and any opposition, therefore, is "they will kill me if they don't let me have this".
People try all manner of things once severely ill. Haven't we previously discussed over-medicalisation in American medicine, where families try to keep elderly or very sick family members on life-support and expensive treatments past the point of doing any good?
It's very probable the FDA needs a kick in the pants to make it change the length of time it takes to approve drugs. But please take "they denied me this miracle cure" stories with some caution; yes, some of them will end up with "and Entyvio works wonders" but some are also "that's why I went to Mexico for laetrile treatment".
I don't know anything outside this post about the Entyvio saga, but the claim made was not that the risk doesn't exist or isn't serious, but that all these TNF-alpha inhibitor drugs carry the risk of escalating allergic reactions (I had it happen on Enbrel and Humira), which can even include anaphylaxis, but the FDA wanted the warning on only this one, making it look more dangerous than the others when that would be very misleading. Which seems like a fair thing to object to - they should all have the warning.
Your analogy only works if you are actually calling for the abolition of the FDA.
To order contact lenses in Canada you pick a vendor website, pick your brand of contact lenses, dial in your prescription, enter payment info and shipping address, and hit the Buy button.
In the USA there is a weird additional step where you must enter the contact information of the Licensed Official Person who wrote you the prescription. Your order is delayed for at least one business day while a human at the vendor must call your Offical Person's office in order to manually confirm that you have a valid prescription and entered it correctly.
This additional step is costly: it adds friction, leading to abandoned carts; means the vendor must employ qualified Speakers-To-Offical-Persons; and (as I discovered) means your Official Person gets a chance to phone and harangue you for your disloyalty in trying to buy your lenses from an online vendor instead of their shop.
If there are offsetting benefits of this approach they are a mystery. I'm curious what terrible problems this system averts and why these problems don't seem to happen in Canada. I suspect there may be no good answer if things kind of evolved this way rather than being the outcome of some careful consideration of policy alternatives.
Someone in an earlier thread mentioned that in some states it is illegal to pump your own gas, and residents of such states are happy to make up reasons on the spot for why it would be crazy to let things work any other way.
"Someone in an earlier thread mentioned that in some states it is illegal to pump your own gas, and residents of such states are happy to make up reasons on the spot for why it would be crazy to let things work any other way."
*And why none of those reasons seem to explain why everything seems to be just fine in the other 48 states.
There is an in principle very simple way to reform DFA: require them to design their procedures to produce net of cost benefits. What is the text of the law? I don't know, especially given the fact that the ways news is reported a horrible side effect of a new drug gets more space than the wonderful main effects of a new drug. But clearly "DFA-good"/"FDA-bad" is a totally silly way to discuss reform of DFA or any regulatory system.
Covid vaccines are an excellent example. Using the "FDA" as a euphemism for the entire regulatory environment around vaccine development and production. The "FDA" killed more people during the covid pandemic than they saved during their entire existence. Challenge trials could have been completed with dozens of vaccine candidates by May 2020 (almost all vaccine candidates turned out to have worked, and certainly would have been worth the trade of of other risks in the nursing home population ). The most vulnerable 3 million people (mostly nursing home residents). accounting for half of all deaths, could have been vaccinated in June or July 2020, this population would serve as a large safety study for the next most vulnerable, ect.
This would mean the first batch of vaccines being rolled out would be subunit, then killed virus and adenovirus, as MRNA vaccines were not at the time as rapidly scalable due to lack of supply of precursors. Subunit vaccines grown in e coli, on the other hand, can be cultured using materials from any supermarket. Killed virus/adenovirus needs a scaling step that takes 2 extra months growing Vero cells.
> I worry that people are going to assume I got lucky, that maybe I’ve been spouting a bunch of crap about “the FDA needs to approve drug X! the FDA needs to approve drug Y!” for years, and most of those drugs were unsafe or ineffective, but just by coincidence I got this one right and now I’ll never shut up about it.
No, I worry that you're counting the hits and ignoring the misses. To paint a full picture, you'd need to count the number of cases when:
1). The drug is safe and effective and yet the FDA takes years to approve it -- you've already done this part.
2). The drug is safe and effective and the FDA approves it in a timely manner -- I understand that your contention is that this never happens, but "never" is a high bar to clear.
3). The drug is dangerous and deadly (to a large enough percentage of the population), and the FDA spends years studying and then fails to approve it.
4). The drug is dangerous and deadly and yet the FDA approves it anyway.
5, 6). Same as (3) and (4), but for perfectly safe drugs that are no more effective than the placebo.
Regarding COVID vaccines, yes, they are still not fully FDA-approved... but, to be fair, they shouldn't be. The vaccines have been out for less than a year, and there's still a good chance that taking the vaccine would make your precious fingers fall off a year later. Granted, in this case specifically the possibility of this happening is slim to none, but "the average guy on the street" has no capacity to judge this for himself for every single drug. I mean, I am the average guy, and I don't have this capacity, so I should know. When I take a fully FDA-approved drug, I can do so without worrying too much about any unexpected side-effects; I can even be reasonably sure that my doctor is correct when he says there'd be no harmful drug interactions. *That's* what FDA approval means, and it's a good thing.
AFAIK the COVID vaccines are approved for emergency use, which is also a good thing. The FDA is saying, "look, we are not our usual 99% sure that your fingers won't fall off, but it's still better than dying of COVID, so go ahead and take the vaccine". I don't see what's wrong with that.
Agreed - I was waiting for Scott to address the times the FDA may have correctly identified unsafe drugs that the 'average guy on the street' would have thought were safe and useful.
I feel that this is the pendulum in motion again.
It all started with no FDA, and people having the freedom to consume whatever they want. A bunch of people consume a "miracle herb" and go blind.
Common consensus directs the government to introduce the FDA, which in time thwarts the introduction of potentially life-saving cures. The people and online bloggers grow disillusioned, and want the FDA to loosen up and let unverified drugs flood the market with a cautionary "We've not officially approved this, and this won't be covered by insurance".
Out of the 1000 such drugs that flood the market, one of them makes hundreds of people go blind.
Again, the government decides that no drugs unapproved by the FDA can be sold.
I don't think weakening of the FDA can be a long term solution. We need ways to comprehensively test drugs ten times as fast for much, much cheaper. Although fantastical, this is the only long term solution I can think of.
Now here's a truly novel suggestion: How about FDA legislation designed to allow normal adults to stick their own necks out and use non-FDA approved drugs and devices if they so choose !!! Is government my master or my servant ???
https://i.imgflip.com/5j3a40.jpg
Your motte and bailey are switched, and the "FDA is designed [...]" is a straw man. Scott is not is saying that the FDA is designed with the purpose of delaying life-saving drugs, and if he was, that would be much worse imo than the other statement. He's saying that the FDA is designed in such a way that it has such effect; yes, that "every single hour [etc]" (obvious hyperbole of "most of the work they do is more harmful than positive"). I see no hiding the ball.
I think there's a fairly straightforward way to regulate the FDA process. Give all FDA employees a 10% raise, and then make 20% of their paycheck dependent on how well they meet a quantifiable cost/benefit standard. So if they end up something like a factor of 10 or a standard deviation away from the performance goal they get 0% on the 20% adjustable paycheck portion
If it is not in the FDA's immediate control to come close to the standard that they now have a strong personal incentive to match, this will still immediately create a powerful lobby of knowledgeable individuals in favour of changing whatever needs to be changed to make it possible
Lets say the other perverse incentives still win out. If nothing satisfactory is happening within a year Congress puts out a tender for bids for the FDA 2.0. Lets say they accept 3 bids and these companies set up a shadow FDA that proposes certain processes and 'approves' drugs and generally gives their own version of whatever the FDA is doing. After another year the regulating board that is judging the FDA's performance can assess the bidding companies on their own cost/benefit rating and Congress then has the option of choosing one of the bidders to succeed the FDA, giving a generous severance to whoever doesn't get brought on from the original FDA
Alternatively, one of the FDA 2.0 companies could be chosen to operate in parallel to the FDA with the power to approve things provisionally and with less final authority than the FDA. This option would allow more fast tracking without any risk to the reputation of FDA 1.0
Three applicable mental models here to reconcile "everyone in FDA is smart and good" and "overall FDA has negative consequences":
(1) Systems. FDA is a system with a goal "approve (only) good drugs". If the goal itself has inherent problem, no individual agent has to act in bad faith or stupidly in order for the system to act in a problematic way. Donella Meadows' book here is a wonderful primer.
(2) Binary classification. Ultimately, approving (only) good drugs is a binary classification problem. You want to classify the good drugs as approved, and the bad ones as not approved. False positive (FP) here would be approving a bad drug, false negative (FN) is not approving a good drug. Absent of an oracle that is 100% accurate, any binary classification has to choose whether they prefer false positives or false negatives. You cannot reduce false negatives to zero without having some false positives.
(3) Defaults and do no harm. In this case, FDA prefers false negatives over false positives, the same way that the justice system does. This probably follows "primum non nocere" and has the burden of proof on the intervention. It probably makes sense given the Lindy effect of drug :shrugs:?
Until the pro FDA crowd provides some replicable Randomized Controlled Studies demonstrating BOTH the safety and the efficacy of the FDA I will treat them like any other kook touting they have a cure for cancer.
We need a land value tax, goddamn this is horrible. So many monopolies destroy so much.
I'd also like to live in the world where the fact that ketamine treats severe chronic treatment resistant depression is well known, because it saved my life. I'd really like to live in a world in which it was well known early enough to have saved the lives of several friends of mine who took themselves out of the game the hard way.
But I'm a known zealot on the ketamine question, so I'll just leave it all at that.
Every story you hear from people working at the FDA is "People who bitch about the FDA don't understand how hard the job is! The leopards require round-the-clock monitoring to ensure they're always in peak physical condition. That's right, leopards, plural. Assholes never think about that, do you? We have to have a backup leopard on standby at all times, to replace the leopard if it's ever in less than peak physical condition. And then there's all the behind-the-scenes work. Never mind the special vitamins, we have to have our own leopard breeding program because the market sure isn't going to provide one."
Every time someone complains about trying to save lives and getting mauled by the leopard, hordes of commentators come out of the woodwork to mock them: "Didn't you see the 'BEWARE OF THE LEOPARD' sign? It's your own stupid fault!"
Every time someone actually does (finally) get allowed to save lives, they always thank the heroic FDA employees who valiantly fought the leopard at great professional risk.
Whether somebody ends up in the pro-FDA blogosphere or the anti-FDA blogosphere turns on the question of whether, when they hear a story like "Heroic FDA Employees Fight Off Leopard After It Only Killed A Few Hundred Or Thousand People", they immediately wonder why there even is a leopard or why someone would need to fight it.