> 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.
"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.
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.
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 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?
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.
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.
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 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.
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.
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.
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?
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.
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.
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?
(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.
"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.
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!
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.
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,
"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".
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.
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.
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 ???
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.
Typo thread: "the Silenor brand [paid] a $100 million FDA application fee for approval as a sleeping pill"
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
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?
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.
"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
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
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 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 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?
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.
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.
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...
What makes this guy worth responding to? I skimmed his stuff and it looks… light on intellectual rigor and shamelessly partisan?
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.
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.
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.
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?
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.
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.
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?
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.
"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.
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!
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.
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
"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".
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.
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.
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
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.