Since you're probably going to see this comment - I have a random question: I'm using the sun lamp for 30 minutes when I wake up, at 9 AM. If I instead wake up at 9:30 or 10 or 11, should I do it then instead, or skip those days? Thanks!
Speaking as a sufferer from SAD who has used light boxes in the pas (although rarely these days, as I have found it more effective to adjust my lifestyle to have frequent walks in the sunshine whenever possible):
I would not worry about the exact timing too much. It's not really that finicky and precise of a thing. Remember it's just artificial sunshine; so if you wouldn't be afraid to go to the park on a sunny day at 11 am, you definitely shouldn't be scared to use the sun lamp at 11 am!
In my personal experience light therapy is moderately effective to fight depression, when taken at any time of day. The main reason to do it in the morning is to prevent it from keeping you awake too late at night, because it resets your circadian rhythm.
Think of light therapy like a dose of caffeine---if you take it in the late afternoon or evening, you might end up staying up a lot later than you intend, or sleeping poorly (though unlike caffeine, using the light box early enough in the day will probably actively help you to sleep better in the night). But you probably wouldn't angst about taking your cup of coffee at the exact same hour every morning, unless it is really important for you to have a totally predictable schedule. (This seems not the case for you, if you regularly allow yourself to sleep in.)
You can even use your sun lamp in the late evening if you are having a really severe depressive funk and care more about ending it than going to bed at a reasonable hour (but be aware that getting good sleep is also helpful for treating depression). Or more reasonably, you could turn it on for an hour at 4 pm if you are in a place where the sun sets that early in the wintertime, and you wish it hadn't done that. (Maybe in that case it would be better to use it more as ambient light cheer rather than spending a long time staring into it.)
The risks of light therapy are pretty low, so there is no harm in experimenting and finding out what works for you. So try using it at 11 am, and if it doesn't cause any noticable problems for you, then you're good!
I find it unlikely that explaining to someone that the internet can be used to do something illegal is itself illegal. Then again, I don't know what weird laws the US might have...
I suspect the details are variable based on a whole host of factors know one is quite sure of? After all, there are (or at least have been) states where cannabis is illegal, including medicinally, doctors can't prescribe it, but they are allowed to recommend it.
Many of our weird laws are there to give authorities enough rope to hang anyone they deem hang-worthy. Actually trying to follow all of them would make you feel like Jamie Lannister complaining about how many vows knights have to swear.
This is a side issue, but there really needs to be a single word or short phrase for "we are pretty sure this medical practice works, the existing controlled trials are not good enough, we will never be allowed to conduct the trial because no one will let us have control group". Examples:
- Diphtheria antitoxin in the early 1900s. There is a section in the book The Microbe Hunters about how the initial trial had lower than usual mortality but no control group, but now (written in 1926) we'd never refuse to give a child antitoxin so we can never do a controlled trial. So like, we're pretty sure this works but we'll never know.
- Surgical masks to block spread of disease. See Scott's posts back in March 2020.
- Apparently, Omegaven rather than soy-based competitor.
I suspect there's many others, even excluding obvious ones like "bandage wounds instead of letting people bleed to death".
If everyone is convinced that leeches work, then clearly it would be unethical to not use leeches, so we can't ever gather the evidence we need to stop using leeches, unless we get lucky with some kind of natural experiment where the hospital's shipment of leeches got lost in a hurricane. I think from a utilitarian perspective it is almost always worth it to have a control group even if you have a strong prior for the treatment being better than the control. Especially if the consequence of not having a control group is that it will continue to be illegal for almost anyone to use the treatment. The control group is no worse off than they would be if they weren't in the study, so go ahead and have a soybean oil based control group.
The difference is that leeches, in your hypothesis, are an ineffective treatment that is already deployed across the entire patient population. The picture is very different if the drug or procedure we want to test is something newly-introduced: in cases with massive and obvious effects, the *past* can serve as the "control group" showing what happens with patients who don't get the new drug.
I recall there was some doctor in New York with a case series of HCQ on covid patients that looked like a massive, obvious improvement to the SoC, but then people did RCTs and it didn't work at all. So at least sometimes the biases of a non-randomized sample can make it look like a big effect when it's not.
You could easily do RCTs of parachutes on inanimate objects or squirrels (without killing the squirrels!)
Hardly anything in medicine is as simple as the physics of terminal velocity, though. You probably can't work from first principles and get as strong of a prior for any medical treatment as you'd have for a parachute. Personally I wouldn't trust any drug without an RCT. _maybe_ I'd trust mechanical ventilation without an RCT, but that's iffy (what about damage to the lungs, circumventing all the homeostatic mechanisms for CO2 levels that control the PH of the blood, and doctors getting overly paranoid about SpO2 of 93% when it's not a real problem until SpO2 drops below 85%? How do we know what is the correct SpO2 level to make mechanical ventilation worth the risks, anyway?)
I was assuming you'd drop them off something high e.g. a crane, like they do when testing parachutes on Mythbusters, since it's less expensive and more controlled than a drop from an airplane. But yeah maybe the airplane itself introduces confounding factors that need to be considered for a real world efficacy trial for parachutes...
Also, you're talking about safety trials, but in the Omegaven case what was (and apparently still is) missing is an efficacy trial. In other words, Omegaven has been given to loads of babies safely in Europe and there isn't really any doubt about its safety. The problem we have is that we don't know exactly how effective it is because no one is willing to run a study in which they know some of the babies are going to be denied a parachute.
Several of these are "compassionate use" so they have tiny numbers (e.g. 2 infants) and there's not really enough data to say 'a resounding yes for Omegaven'. It seems to be helping, but even so some adverse effects are recorded.
Good news, I just performed an RCT of parachutes on squirrels, and both groups were fine. I even did a second RCT on mice and both groups were fine. Now it's time to move onto human trials. We're recruiting volunteers, would you be willing to sign up?
:)
Even in the medical context, lots of drugs have worked on mice but not in humans or vice-versa. At some point we either have to do an RCT on humans or we have to assume that they'll work on humans when they worked on the non-human trial.
We've been monitoring this biomarker called "terminal velocity" across species, and it looks like as the size of the species goes up, the terminal velocity also goes up. If we extrapolate that line out to humans, they'll probably go splat. But our parachutes were able to reduce terminal velocity by 95% in all the animal trials, so let's go ahead and try one on a human :)
Squirrels have a terminal velocity of 40km/h, but you can't scale that up to humans. By that nonsensical logic, a blue whale would have a terminal velocity of 700km/h! This is clearly nonsense. Let me write a longform article about how your field is filled with fools and needs to divest itself of the "terminal velocity fallacy" in order to be taken seriously.
I suffer of a chronic disease without any real cure. So quite interested in research. I stop reading studies when it turns out it's a mice study (some are amusing though, like Viagra curing good knows what...)
Viagra was originally heart medication, with erections as a side-effect. It wouldn't surprise me that increasing blood flow generally could be beneficial for all sorts of conditions, particularly anything that's more like wound healing than fighting off an infection.
I agree. People might object that this would enable snake oil salesmen, but people are already allowed to sell unlimited snake oil in the US, without even proving safety, so long as:
1. they call it a "dietary supplement"
2. they use weasel words to describe its effects
3. the substance can be found somewhere in nature
4. the substance has never been investigated as a potential drug.
None of those criteria have anything to do with consumer protection. It would make sense to replace all of them with "just prove it's safe".
N-Acetyl-Cysteine just got taken off the market after half a century of safe use because someone at the FDA noticed that someone was investigating it as a potential drug in 1963.
That's not exactly how it works. There is a large number of "general recognized as safe" (GRAS) ingredients for which no FDA approval is required, roughly because they have been consumed for a long time and nobody has yet noticed anything evil. (Whether the ingredients are "found in nature" is neither here nor there -- plenty of genuine drugs, e.g. taxol or penicillin, are natural products -- it's a question of whether loads of people have actually been eating it for decades.)
That's why you can add salt or gelatin or vitamin C to a supplement for which you claim health benefits but *not* have to submit a drug application. People were eating those ingredients for decades and even centuries before the FDA was formed, and nothing bad was noticed, so it makes little sense to attempt to regulate them now. Although obviously that does *not* guarantee they're harmless, cf. cigarette smoke, in use since the 1600s. Nevertheless, the FDA's ambit by statute doesn't include GRAS ingredients, so caveat emptor and away you go.
You sure do have to include weasel words in your advertisements if you want to claim specific health benefits. You can make generic claims like "good for you" or "healthy!" all you want, but if you say something specific like "lowers your blood pressure" or "cures cancer" then you do need to add a specific disclaimer that says you haven't asked the FDA to evaluate your claims, because people might naively otherwise assume you wouldn't make such claims unless some massive RCT study had been done and the results certified by the FDA. (The fact that this annoys the neutraceutical and alt-medicine Laetrile aficionados is to my mind evidence that they indeed would like to free-ride on the reputation of real pharmaceuticals for rigorous testing. If they thought FDA approval meant nothing to their customers, or wouldn't be otherwise assumed, they wouldn't give a damn about adding the disclaimer.) But having to add disclaimers is separate from being able to use GRAS ingredients.
NAC got taken off the market because by statute any ingredient which first appears in a consumer product as an FDA-approved drug cannot ipso facto be GRAS. In this case, NAC was approved as a drug in the 1960s, before it was used as a supplement, so it can't be GRAS. That the FDA hasn't rigorously enforced any restriction of it until recently doesn't change its legal status, there's no such thing as a "legal easement" where if you get away with a violation of the law long enough, or it's small enough, it becomes technically legal.
Someone could argue NAC should go back on the GRAS list, and I don't doubt many someones have or will, but the way to do that is do the right (expensive) studies and offer persuasive factual evidence, not make an emotional appeal to intuition: "everybody's been doing this for years!" -- yeah, well, people smoked for centuries before someone figured out it gives you lung cancer and heart disease, which is kind of bad.
This article is fantastic. I also note that it uses the "parachute" terminology already - in particular, to argue that many practices which are claimed to be parachutes are not even close to being parachutes.
Honest question - in Science! am I allowed to use natural experiments as a source of data?
EG in 99.9999% (a few famous people lived) all known cases since the dawn of heavier than air flight of falling from great heights and an aircraft in flight *without* a parachute has resulted in death. In our work with parachutes, 99.9999% of our our research subject survived a fall when protected by a parachute avoided death.
Can I use those two collections of data to reason from like a control and not control group? To avoid exactly the silly argument described here that there is no RCT on parachutes?
Presumably one can and should, in those situations, assemble the evidence one can in the absence of RCTs such as retrospective comparative studies, which still could be persuasive if the effect is large enough (as it would be if ifs a moral imperitave to not do RCTs)
I attended a research talk about mitigating the harm of sepsis by activating an enzyme (Heme Oxygenase 1) naturally occurring in the body. The presenter basically claimed it worked miracles, and i found it convincing. Three years later it has not entered common use.
Something similar happened to me, where the FDA did go faster than their normal process, but still nearly killed me in the process. Dan Elton, of the US Transhumanist Party, wrote an article about it:
See also, a whole lot of people who died of COVID in November-December 2020, while the FDA was evaluating clinical trial data (albeit at "warp speed").
Worse than that - scheduling the meeting and getting the right people to look over the reports usually takes much longer. The COVID vaccines got pushed to the front of the line, just like they did for every intermediate approval. Three weeks really is warp speed for the FDA.
What's doubly depressing is we're repeating the exact same mistake with the third-dose booster shots against the Delta variant, and vaccinations for younger children.
Reading your story, it's not "The FDA almost killed me", it's "the lawyers almost killed me" because the pharma company went in for legal wrangling with the FDA over the blackbox warnings which few people ever read:
"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. 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."
Of course the company objected to it, but you can equally say there "if only the company had agreed at the offset, it wouldn't have taken five months of lawyers exchanging letters to get this done".
And if the FDA had let it go on what the company wanted, no pharma company ever wants "possible side-effects" put on warning labels. I have a dog in this fight as my doctor recommended me a medication, gave me the obligatory warning of possible side-effects, reassured me that such was very unlikely then wrote me a prescription.
I read all the warnings on the box, was highly alarmed by the "this is rare but IF it happens you are in deep doo-doo" warning, looked it up online, yes indeed it was a real, rare, but deep doo-doo side effect. "Well, it's rare, I have little to no chance of getting it" says I; I take my first dose of the medication - and I get the starting warning symptoms.
"Okay, not taking any more of this", I say, I tell my doctor why, she tries to talk me round, I refuse, and I get put on a different medication.
And I do firmly believe that, had it not been for the FDA or similar body sticking it out to put the "it's very, very rare BUT" warning on the label I would have squashed my reservations about the initial symptoms because the doctor says it's okay, continued to take the medication, and ended up in deep doo-doo indeed.
While I see your point, that legal wrangling didn't need to happen at the end of the process - as the story points out, the trials and approval process lasts for *years*. A huge part of the extreme slowness of the FDA is that many things that could easily be done in parallel are only done sequentially, and I bet every email between the wrangling lawyers took a full week to get sent, when realistically it could have all been hashed out in a day or two if everyone involved was locked in a conference room.
^ Yeah. I don't think I mentioned this point in my blog post, but should have. The hashing out could have been done long ago.
Deiseach's comment is well taken. I agree 100% -- the more risk information available to the consumer the better. What they should have done is gone back and modified the labels for the older drugs to update them with the new warning info. It seems it was the contrast between the lack of warning on the old drug and the warning on the new drug that the company took objection to more so than the warning itself, although they had a case against that too. Apparently it's hard to update labels, though (?).
I've read varying accounts online of whether the FDA uses rolling reviews but generally speaking they do not. So they don't start crunching numbers on the Phase III trial data until after the application is submitted. I suspect the factory inspections don't occur until after stuff is approved, also, although I don't know.
As another example of how things can be done in parallel, at some point after the initial phase III trial enrollment(s) they allow have doctors to start prescribing it. That is the idea of adaptive licensing, essentially which I summarize here :
That's a very reasonable point in your case, but I don't think it's a reasonable criticism in my case. If other drugs in the class had this risk, but didn't have the warning, and a new drug is SPECIFICALLY designed to avoid this risk, it makes no sense at all to put the warning label on the old drug.
I see a role for the FDA, for all my bitterness I wouldn't necessarily burn it to the ground. But in this fight the pharma company was entirely in the right to insist on no warning label. "If they had stopped protesting something indefensible they could have helped you sooner" is true... but doesn't shift the blame.
What is the actual number of babies that died due to this? Definitely hundreds? (I saw a claim on Twitter it was more like “ten or twenty” than “hundreds or thousands”)
I also question that number. Not because any single life isn't precious, but because it speaks to the profitability of the treatment *and* about the difficulty in finding enough cases for good studies.
Any word on the number requiring liver transplants or otherwise suffering permanent damage? it could be that the larger number is the total number of babies affected rather than the number that died.
A really good question. No system is perfect and if the worst example of this kind of failure mode we can come up with is tens of people dying where we have a treatment that we can’t get over the hurdle of proof of efficacy, then we actually might conclude that we have a pretty good system.
So why were they so sure that "it isn't the lipids"? Because it seems a bit less certainty on that could have helped a lot. Was that a reasonable position? Would the establishment still have the same kind of position in the same kind of situation or has something changed since then?
I would guess it's because biochemically speaking biologically-derived fatty acids are pretty generic, it's just a question of how many carbons you have in the tails, and where exactly the double bonds lie. They're all metabolized in approximately the same way, so far as we know. I think for a long time people just assumed they were essentially all interchangeable, kind of like whether your gasoline contains heptane or octane doesn't matter that much.
The realization that this was not so -- e.g. that unnatural "trans" fatty acids were strangely dangerous, or that it actually makes a difference whether your first double bond is 6 or 3 carbons away from the end (the difference between omega-6 and omega-3 fats) -- seems only recently to have become part of the standard wisdom. I'm not sure anyone has any good mechanistic grasp on *why* this is true, also. The only obvious lesson here is the usual one: biochemistry is absurdly complex and not infrequently counter-intuitive.
Yes, although in this particular case (the infant parental nutrition), the assertion is that it *was* a matter of life and death. That is surprising to me even now -- I would never have suspected that soybean v. fish oil could mean the difference between lethal liver disease and health. I do not doubt empirical observation, but from a theoretical biochemical viewpoint that is seriously weird.
Perhaps it has something to do with neonate liver function, which differs in some important way from adult (or even child) liver function, in which case it's even less surprising that people were surprised by it, didn't expect it. The body of research on how 6-week-old livers work, and how that might differ from how 6-year-old or 60-year-old livers work, is probably amazingly scant.
> The body of research on how 6-week-old livers work, and how that might differ from how 6-year-old or 60-year-old livers work, is probably amazingly scant.
If the differences aren't known, it just raises the question again of why the overconfidence that it wasn't the lipids? Seems like extraordinary hubris to just assume neonatal liver function has no differences. You'd think we'd have learned better than to make assumptions without empirical data by now.
I don't think it's a question of hubris, it's a question of priorities. People are going to be very desperate to try to save a dying newborn, but they have to focus, because you can't try everything all at once, there just isn't time, or the resources. So they have to make some hard choices -- heck, this happens in medicine *all the time,* oncologists and surgeons and their patients make these choices every day -- do we try this or that first? Because once we make this choice, we're committed, there's no do over...
So they maybe say, gee, based on what we know, we think X or Y is more likely than the lipid content of the food. In this case, they turn out to be wrong. But that, too, happens all the time in medicine. Unless you were there, and know what X and Y actually were, and what the reason was for thinking they were more likely to be the issue, it's very hard to second-guess this and be confident they were idiots, as opposed to people who didn't have all the facts we have trying their best.
Even if I agree with everything you just said, the claim wasn't "we think lipids is less likely than X", it was quoted as "we know it's NOT the lipids". These are very different claims.
And even if they turn out to be *correct* that it's not the lipids, that doesn't rule some other compound present in fish oil that makes the difference, so ruling out the fish oil because of the lipids is also jumping to conclusions.
Reading the account in Scott's post they seem to have done tests with soya oil and without soya oil in such formulas, and similar problems happened in both, so they said "well it can't be the lipids since the same adverse results happen even without the soya".
If, for instance, the babies on non-soya formulations had done better, then they would have accepted "okay, the problem is with the soya oil". But of course, it was more complicated than that and not as simple as "replace the soya with fish oil".
I read a little more on this, and the suspicion is that it's a high fraction of polyunsaturated fatty acids, which actually starts to make sense, since each unsaturation is a hiccup in the normal process of beta oxidation of fats, and requires some extra hokey pokey step, and maybe baby livers don't have the latter ability fully developed. But this is just a wild guess.
it's unclear whether the "without soya oil" formulations had much oil at all - it's possible they were testing whether presence of Omega 6 was harmful and missing that the problem was absence of Omega 3; or, more likely, something more complex like the ratios
In the "relative balance" kind of problems, this is definitely true. In the rarer "actual full-blown deficiency, your body is not getting enough to meet requirements" kind of problems, it is not - deficiency of essential fatty acids (a.k.a. "protein poisoning" a.k.a. "rabbit starvation") is the only known form of malnutrition that can kill faster than simply eating nothing.
Curious about PNALD in Europe. This story is a little different than a new discovery of an alternate use for an older drug or something where there isn't already a body of evidence that it works. If Omegaven was already a standard of treatment there, was there a correspondingly lower incidence of PNALD? Might that have been valid data to use along the way?
Yea, for a complete outsider, this seemed weird to me aswell. I had the impression that science is an international endeavour - so wouldn’t studies on outcomes in Europe be valid? The USA babies could be a huge control group for European ones.
Or are confounding factors between continents too large (eg different quality hospitals)? Or is the number of affected babies still too low? Or do the European babies get other problems more often? Something else?
What is missing from the story in this regard? (Perhaps something obvious for someone with knowledge in medical sciences?)
Yes, I get that; but as I understood it the American regulators were apprehensive due to a lack of (good and large enough) studies. Given that different formulas were approved in the different continents - shouldn’t it be easy to write a study comparing the results (and use that to convince regulators)?
Since saying “babies in Europe in this situation survive 4x as often as in America” in a study seems so obvious, I am sure that there is something missing (in my understanding at least - but maybe also in the story).
Not medically related, and nearly forty years out of date, but when I was doing milk powder testing in a creamery co-op lab, it was for export and had to comply with US regulations, and those were more stringent than the at-the-time acceptable ones in Ireland/EU.
So certification and standards did/do differ from one country to the next, and simply saying "it's fine in European country X" doesn't mean it is legally acceptable in the US.
Just to be clear; I never intended to make the argument that regulations/certifications/standards are the same/similar, nor that “it’s fine there” is/should be enough. Moreso I wonder whether the liver disease (or other issues) were actually obviously gone where the alternative treatment were used.
Yes — I was suggesting the same. Not that the European regulations could apply in the US, but that the European market vs. the American market might effectively function as a giant study with a control for children who did and didn't receive Omegaven. It would still need to pass American compliance requirements but might provide a lot more data than the few US trials.
To put it much stronger: shouldn’t there have been a large and obvious difference in PNALD incidence? And wouldn’t that fact alone be evidence much stronger than that of any of the experiments?
I'm about as cowboyish as it is possible to be and still be employable, so of course I thrived at a tech startup and hated working at a giant tech company. The increase in size of companies due to M&A or economies of scale or natural monopolies in tech is probably driving the culture away from cowboyishness.
In the least cowboyish culture I can think of, Japan, for a long time there were giant conglomerates dominating every industry, all headquartered within a few hundred miles of the God-Emperor's palace. In the wild west, there were tons of small businesses far from the reach of centralized authority.
Isn't everywhere in Japan within a few hundred miles of everywhere else, in particular the God-Emperor's palace? I guess you mean "the greater Tokyo area" in which case it makes sense.
It was a derogatory term in Tombstone, AZ, and much of the Old West almost from the start. "Cowboy" basically meant "robber", with a side order of if they were the first settlers in the area and there was *nothing* to steal, they'd set loose some cattle and sit back until they could steal everything the cows had built.
Western novels, movies, etc, rehabilitated the term in roughly the way that "The Dukes of Hazzard" rehabilitated the Battle Flag of the Army of Northern Virginia. And we need *something* that symbolizes the general ideal of disrespecting established authority while still behaving honorably and engaging in productive enterprises on one's own terms. If there's cause for one or two of those terms to go away because of a preexisting and dishnorable usage, that's one thing - if they *keep* getting deprecated then it's going to look like someone is demanding submission to their authority and that all productive enterprises be done on their terms or not at all.
It sounds like your qualm is with how American healthcare law is written, not with how the laws are administered by the FDA.
As an example, who are you more mad at: judges who upheld disparate sentencing guidelines created during the war on drugs, or the legislators who wrote the laws?
My own take: the legislators are the most to blame. The trial judges are most likely often/usually blameless, but appellate judges arguably are not. Disparate sentencing guidelines arguably infringe on the eighth and fourteenth amendments, as well as some states' own constitutions.
Plot twist: some of the legislators who supported those harsher penalties for crack were black congressmen who saw the devastation crack caused in their communities in the 80s. So long as the demand curve slopes downward, harsher penalties = less crack. I don't agree with the drug war, but it's not such an easy mistake that I'd hold it against them.
And I honestly don't know if I could have done any better in their position, with the information I would have had at the time. Nevertheless, they're responsible for the consequences of their actions, including the unintended ones - to some degree that's the price you agree to when you choose to be in charge. Being wrong isn't something we should condemn anyone for, provided it's an honest mistake and people try to learn from them. Sadly this seems to be an unpopular position.
More importantly, all subsequent legislators are responsible for not having fixed the problems caused by previous laws passed.
> Disparate sentencing guidelines arguably infringe on the eighth and fourteenth amendments
Why? As far as I understand, the 14th Amendment forbids unequal treatment based on who you are, not what you do (such as what drug you sell).
What I don't understand about this debate: If powder cocaine and crack have mostly the same effects, but sentencing is much harsher for crack, then why doesn't everyone who sells/uses crack switch to powder cocaine? And are we sure that whatever difference makes people use crack doesn't also justify the harsher penalties (based on the assumption that drug prohibition is justified at all, which I don't think it is)?
crack is stronger and thus probably more dangerous than powder cocaine. It would make sense to have harsher penalties for dealing more dangerous substances.
IANAL, but my understanding is that if you can demonstrate racist intent on the part of lawmakers, then you may be able to claim the disparate impact is in fact a form of unequal treatment based on who you are. Hard to prove, though, just like it's hard to get any results arguing about unequal enforcement of laws against different groups of people.
Disparate impact is part of some anti-discrimination laws such as the Civil Rights Act of 1964. It's less clear to what extent it applies to constitutionality under the 14th Amendment. It looks like it may apply if discriminatory intent is proved, but it's hard to prove.
Thank you for this story of heroes and a system that can be so cruelly imperfect.
I'm glad you plan to write more on this topic in the future, because it's so important, and your analysis of it has been incredibly enlightening. Do you plan to write about the approval process in other countries as examples of ways the FDA can be improved? Or as cautionary tales?
Wait, so the only evidence for the effectiveness of fish oil in treating PNALD is a poorly powered study and a few miracle cure anecdotes? Miracle cure anecdotes are a dime a dozen. You can easily find thousands of them for everything from homeopathy to touching a statue of the Virgin Mary. That doesn't mean homeopathy obviously works or should be approved by the FDA.
"We were confident we were onto something and began to discuss our findings with others at BCH. The response was not what we expected. We were told “Everyone knows it's not the lipids because liver disease happened with them and without them.” Some individuals would even pull me aside to ask “Are the results real?”"
Usually when one scientist is convinced about the miraculous properties of their discovery while everyone else is skeptical, it's everyone else who's right, not the one scientist. I have no opinion on who's right in this case, but I wouldn't be surprised if fish oil turns out to not be very effective at all in treating PNALD.
This is why bleeding and cupping were standard of care for centuries. Hey, we gave it to Patient X and he got better! But Patient Y died! Yeah, well he had [other factor]/[was already at death's door]/[a physician who didn't do it right].
The reason we enforce the unnatural and cumbersome process of double-blind RCT is *because* historically speaking we know it is incredibly easy for human beings to detect "signal" in "noise" and rationalize it with some elegant theory.
> No, it really isn't. Pick a quack therapy that you're sure doesn't work, and Google "(quack therapy name) + testimonials"
No, what you're doing is fishing for an outcome in a sea of noisy data (like p-hacking). What the doctors did was an introduce a specific intervention to a cohort and observing an undeniably large signal. These aren't remotely the same.
Another typo: "... the got ..."
In: "They asked the FDA for permission, filled out the relevant forms, and (to its credit) the got approved within 48 hours."
No. Scott is contrasting with the 10% * 10% * 10% * 10% that precedes it.
Typo: "...in this country. briefly..."
Since you're probably going to see this comment - I have a random question: I'm using the sun lamp for 30 minutes when I wake up, at 9 AM. If I instead wake up at 9:30 or 10 or 11, should I do it then instead, or skip those days? Thanks!
Speaking as a sufferer from SAD who has used light boxes in the pas (although rarely these days, as I have found it more effective to adjust my lifestyle to have frequent walks in the sunshine whenever possible):
I would not worry about the exact timing too much. It's not really that finicky and precise of a thing. Remember it's just artificial sunshine; so if you wouldn't be afraid to go to the park on a sunny day at 11 am, you definitely shouldn't be scared to use the sun lamp at 11 am!
In my personal experience light therapy is moderately effective to fight depression, when taken at any time of day. The main reason to do it in the morning is to prevent it from keeping you awake too late at night, because it resets your circadian rhythm.
Think of light therapy like a dose of caffeine---if you take it in the late afternoon or evening, you might end up staying up a lot later than you intend, or sleeping poorly (though unlike caffeine, using the light box early enough in the day will probably actively help you to sleep better in the night). But you probably wouldn't angst about taking your cup of coffee at the exact same hour every morning, unless it is really important for you to have a totally predictable schedule. (This seems not the case for you, if you regularly allow yourself to sleep in.)
You can even use your sun lamp in the late evening if you are having a really severe depressive funk and care more about ending it than going to bed at a reasonable hour (but be aware that getting good sleep is also helpful for treating depression). Or more reasonably, you could turn it on for an hour at 4 pm if you are in a place where the sun sets that early in the wintertime, and you wish it hadn't done that. (Maybe in that case it would be better to use it more as ambient light cheer rather than spending a long time staring into it.)
The risks of light therapy are pretty low, so there is no harm in experimenting and finding out what works for you. So try using it at 11 am, and if it doesn't cause any noticable problems for you, then you're good!
Oh, I'm just trying it for circadian rhythm reasons, not depression. Thanks for the comment!
"I can’t find good sources about whether the issue is that soybean oil *prevents* the liver problem, or that fish oil solves the liver problem."
There is a word wrong in this sentence, or I fail comprehension. I think "prevents" was intended to be "causes", but I'm not sure.
And, as long as I'm being super pedantic, it's "pejorative", not "perjorative".
Thanks, fixed.
"...decided to do the reasonable thing and walk my patient through the process of ordering it illegally on the Internet."
While this is very cool and right, I'm concerned about the advisability of admitting it publicly
I find it unlikely that explaining to someone that the internet can be used to do something illegal is itself illegal. Then again, I don't know what weird laws the US might have...
I suspect the details are variable based on a whole host of factors know one is quite sure of? After all, there are (or at least have been) states where cannabis is illegal, including medicinally, doctors can't prescribe it, but they are allowed to recommend it.
Many of our weird laws are there to give authorities enough rope to hang anyone they deem hang-worthy. Actually trying to follow all of them would make you feel like Jamie Lannister complaining about how many vows knights have to swear.
Doing it in your capacity as a doctor seems potentially career-ending. Doctors can lose their license without doing anything illegal.
This is a side issue, but there really needs to be a single word or short phrase for "we are pretty sure this medical practice works, the existing controlled trials are not good enough, we will never be allowed to conduct the trial because no one will let us have control group". Examples:
- Diphtheria antitoxin in the early 1900s. There is a section in the book The Microbe Hunters about how the initial trial had lower than usual mortality but no control group, but now (written in 1926) we'd never refuse to give a child antitoxin so we can never do a controlled trial. So like, we're pretty sure this works but we'll never know.
- Surgical masks to block spread of disease. See Scott's posts back in March 2020.
- Apparently, Omegaven rather than soy-based competitor.
I suspect there's many others, even excluding obvious ones like "bandage wounds instead of letting people bleed to death".
How about "the parachute principle" after the famous lack of RCTs on parachutes?
e.g. "this is a parachute drug" or "this is a parachute intervention" or something like that.
I like this phrasing.
Genius!
If everyone is convinced that leeches work, then clearly it would be unethical to not use leeches, so we can't ever gather the evidence we need to stop using leeches, unless we get lucky with some kind of natural experiment where the hospital's shipment of leeches got lost in a hurricane. I think from a utilitarian perspective it is almost always worth it to have a control group even if you have a strong prior for the treatment being better than the control. Especially if the consequence of not having a control group is that it will continue to be illegal for almost anyone to use the treatment. The control group is no worse off than they would be if they weren't in the study, so go ahead and have a soybean oil based control group.
The difference is that leeches, in your hypothesis, are an ineffective treatment that is already deployed across the entire patient population. The picture is very different if the drug or procedure we want to test is something newly-introduced: in cases with massive and obvious effects, the *past* can serve as the "control group" showing what happens with patients who don't get the new drug.
Yes, but does the FDA ever approve things based on massive, obvious improvements compared to the past SoC, without a real RCT?
Well, no, and that's the problem.
I recall there was some doctor in New York with a case series of HCQ on covid patients that looked like a massive, obvious improvement to the SoC, but then people did RCTs and it didn't work at all. So at least sometimes the biases of a non-randomized sample can make it look like a big effect when it's not.
Isn’t this post about the FDA doing just that?
You could easily do RCTs of parachutes on inanimate objects or squirrels (without killing the squirrels!)
Hardly anything in medicine is as simple as the physics of terminal velocity, though. You probably can't work from first principles and get as strong of a prior for any medical treatment as you'd have for a parachute. Personally I wouldn't trust any drug without an RCT. _maybe_ I'd trust mechanical ventilation without an RCT, but that's iffy (what about damage to the lungs, circumventing all the homeostatic mechanisms for CO2 levels that control the PH of the blood, and doctors getting overly paranoid about SpO2 of 93% when it's not a real problem until SpO2 drops below 85%? How do we know what is the correct SpO2 level to make mechanical ventilation worth the risks, anyway?)
I mean you *could* do an RCT on parachutes on inanimate objects, but why would you need to randomize them?
Assumedly to blind the experimenters so they don’t push the things out of the plane differently or something.
I was assuming you'd drop them off something high e.g. a crane, like they do when testing parachutes on Mythbusters, since it's less expensive and more controlled than a drop from an airplane. But yeah maybe the airplane itself introduces confounding factors that need to be considered for a real world efficacy trial for parachutes...
Also, you're talking about safety trials, but in the Omegaven case what was (and apparently still is) missing is an efficacy trial. In other words, Omegaven has been given to loads of babies safely in Europe and there isn't really any doubt about its safety. The problem we have is that we don't know exactly how effective it is because no one is willing to run a study in which they know some of the babies are going to be denied a parachute.
Going by this page, there were 75 studies done on Omegaven, and only 8 of them so far are completed with results:
https://clinicaltrials.gov/ct2/results?intr=Omegaven&recrs=e&age_v=&gndr=&type=&rslt=With&Search=Apply
Several of these are "compassionate use" so they have tiny numbers (e.g. 2 infants) and there's not really enough data to say 'a resounding yes for Omegaven'. It seems to be helping, but even so some adverse effects are recorded.
Looking at those 8, they're all open label, single group assignment studies - in other words, neither randomized nor controlled.
Good news, I just performed an RCT of parachutes on squirrels, and both groups were fine. I even did a second RCT on mice and both groups were fine. Now it's time to move onto human trials. We're recruiting volunteers, would you be willing to sign up?
:)
Even in the medical context, lots of drugs have worked on mice but not in humans or vice-versa. At some point we either have to do an RCT on humans or we have to assume that they'll work on humans when they worked on the non-human trial.
We've been monitoring this biomarker called "terminal velocity" across species, and it looks like as the size of the species goes up, the terminal velocity also goes up. If we extrapolate that line out to humans, they'll probably go splat. But our parachutes were able to reduce terminal velocity by 95% in all the animal trials, so let's go ahead and try one on a human :)
Squirrels have a terminal velocity of 40km/h, but you can't scale that up to humans. By that nonsensical logic, a blue whale would have a terminal velocity of 700km/h! This is clearly nonsense. Let me write a longform article about how your field is filled with fools and needs to divest itself of the "terminal velocity fallacy" in order to be taken seriously.
I think you forgot that you were discussing control groups.
I suffer of a chronic disease without any real cure. So quite interested in research. I stop reading studies when it turns out it's a mice study (some are amusing though, like Viagra curing good knows what...)
Viagra was originally heart medication, with erections as a side-effect. It wouldn't surprise me that increasing blood flow generally could be beneficial for all sorts of conditions, particularly anything that's more like wound healing than fighting off an infection.
Today, only drugs proven safe and effective are FDA legal.
A simple reform would be to legalize drugs when proven safe.
I agree. People might object that this would enable snake oil salesmen, but people are already allowed to sell unlimited snake oil in the US, without even proving safety, so long as:
1. they call it a "dietary supplement"
2. they use weasel words to describe its effects
3. the substance can be found somewhere in nature
4. the substance has never been investigated as a potential drug.
None of those criteria have anything to do with consumer protection. It would make sense to replace all of them with "just prove it's safe".
N-Acetyl-Cysteine just got taken off the market after half a century of safe use because someone at the FDA noticed that someone was investigating it as a potential drug in 1963.
Isn't acetylcysteine simply a drug in the US? It's sold as a OTC medication – not a supplement – where I live.
That's not exactly how it works. There is a large number of "general recognized as safe" (GRAS) ingredients for which no FDA approval is required, roughly because they have been consumed for a long time and nobody has yet noticed anything evil. (Whether the ingredients are "found in nature" is neither here nor there -- plenty of genuine drugs, e.g. taxol or penicillin, are natural products -- it's a question of whether loads of people have actually been eating it for decades.)
That's why you can add salt or gelatin or vitamin C to a supplement for which you claim health benefits but *not* have to submit a drug application. People were eating those ingredients for decades and even centuries before the FDA was formed, and nothing bad was noticed, so it makes little sense to attempt to regulate them now. Although obviously that does *not* guarantee they're harmless, cf. cigarette smoke, in use since the 1600s. Nevertheless, the FDA's ambit by statute doesn't include GRAS ingredients, so caveat emptor and away you go.
You sure do have to include weasel words in your advertisements if you want to claim specific health benefits. You can make generic claims like "good for you" or "healthy!" all you want, but if you say something specific like "lowers your blood pressure" or "cures cancer" then you do need to add a specific disclaimer that says you haven't asked the FDA to evaluate your claims, because people might naively otherwise assume you wouldn't make such claims unless some massive RCT study had been done and the results certified by the FDA. (The fact that this annoys the neutraceutical and alt-medicine Laetrile aficionados is to my mind evidence that they indeed would like to free-ride on the reputation of real pharmaceuticals for rigorous testing. If they thought FDA approval meant nothing to their customers, or wouldn't be otherwise assumed, they wouldn't give a damn about adding the disclaimer.) But having to add disclaimers is separate from being able to use GRAS ingredients.
NAC got taken off the market because by statute any ingredient which first appears in a consumer product as an FDA-approved drug cannot ipso facto be GRAS. In this case, NAC was approved as a drug in the 1960s, before it was used as a supplement, so it can't be GRAS. That the FDA hasn't rigorously enforced any restriction of it until recently doesn't change its legal status, there's no such thing as a "legal easement" where if you get away with a violation of the law long enough, or it's small enough, it becomes technically legal.
Someone could argue NAC should go back on the GRAS list, and I don't doubt many someones have or will, but the way to do that is do the right (expensive) studies and offer persuasive factual evidence, not make an emotional appeal to intuition: "everybody's been doing this for years!" -- yeah, well, people smoked for centuries before someone figured out it gives you lung cancer and heart disease, which is kind of bad.
And there are a ton of randomized trials of parenteral soy vs fish oil in mice!
Almost nothing meets this criterion, though. https://www.cmajopen.ca/content/6/1/E31
There are several RCTs and at least 25 published trials of soy vs something including fish, so you are right in this case
This article is fantastic. I also note that it uses the "parachute" terminology already - in particular, to argue that many practices which are claimed to be parachutes are not even close to being parachutes.
Honest question - in Science! am I allowed to use natural experiments as a source of data?
EG in 99.9999% (a few famous people lived) all known cases since the dawn of heavier than air flight of falling from great heights and an aircraft in flight *without* a parachute has resulted in death. In our work with parachutes, 99.9999% of our our research subject survived a fall when protected by a parachute avoided death.
Can I use those two collections of data to reason from like a control and not control group? To avoid exactly the silly argument described here that there is no RCT on parachutes?
Yes
Presumably one can and should, in those situations, assemble the evidence one can in the absence of RCTs such as retrospective comparative studies, which still could be persuasive if the effect is large enough (as it would be if ifs a moral imperitave to not do RCTs)
Re surgical masks, here are two studies concluding that masks in surgery are not helpful, based on experiment.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493952/pdf/annrcse01509-0009.pdf
https://link.springer.com/article/10.1007/BF01658736
I read only the abstract of the second one, it is behind a paywall.
I'm not sure how convincing these studies are, but it's not true that no controlled trials of surgical face masks have been done.
IIRC, breast milk vs the alternatives.
I attended a research talk about mitigating the harm of sepsis by activating an enzyme (Heme Oxygenase 1) naturally occurring in the body. The presenter basically claimed it worked miracles, and i found it convincing. Three years later it has not entered common use.
Something similar happened to me, where the FDA did go faster than their normal process, but still nearly killed me in the process. Dan Elton, of the US Transhumanist Party, wrote an article about it:
https://moreisdifferent.substack.com/p/the-fda-almost-killed-me
See also, a whole lot of people who died of COVID in November-December 2020, while the FDA was evaluating clinical trial data (albeit at "warp speed").
Warp speed is an FDA euphemism meaning "it took us three weeks to schedule a meeting".
Worse than that - scheduling the meeting and getting the right people to look over the reports usually takes much longer. The COVID vaccines got pushed to the front of the line, just like they did for every intermediate approval. Three weeks really is warp speed for the FDA.
Yeah, I know. The sarcasm is biting in every direction - that comment was like a hydra of snark.
What's doubly depressing is we're repeating the exact same mistake with the third-dose booster shots against the Delta variant, and vaccinations for younger children.
Reading your story, it's not "The FDA almost killed me", it's "the lawyers almost killed me" because the pharma company went in for legal wrangling with the FDA over the blackbox warnings which few people ever read:
"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. 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."
Of course the company objected to it, but you can equally say there "if only the company had agreed at the offset, it wouldn't have taken five months of lawyers exchanging letters to get this done".
And if the FDA had let it go on what the company wanted, no pharma company ever wants "possible side-effects" put on warning labels. I have a dog in this fight as my doctor recommended me a medication, gave me the obligatory warning of possible side-effects, reassured me that such was very unlikely then wrote me a prescription.
I read all the warnings on the box, was highly alarmed by the "this is rare but IF it happens you are in deep doo-doo" warning, looked it up online, yes indeed it was a real, rare, but deep doo-doo side effect. "Well, it's rare, I have little to no chance of getting it" says I; I take my first dose of the medication - and I get the starting warning symptoms.
"Okay, not taking any more of this", I say, I tell my doctor why, she tries to talk me round, I refuse, and I get put on a different medication.
And I do firmly believe that, had it not been for the FDA or similar body sticking it out to put the "it's very, very rare BUT" warning on the label I would have squashed my reservations about the initial symptoms because the doctor says it's okay, continued to take the medication, and ended up in deep doo-doo indeed.
While I see your point, that legal wrangling didn't need to happen at the end of the process - as the story points out, the trials and approval process lasts for *years*. A huge part of the extreme slowness of the FDA is that many things that could easily be done in parallel are only done sequentially, and I bet every email between the wrangling lawyers took a full week to get sent, when realistically it could have all been hashed out in a day or two if everyone involved was locked in a conference room.
^ Yeah. I don't think I mentioned this point in my blog post, but should have. The hashing out could have been done long ago.
Deiseach's comment is well taken. I agree 100% -- the more risk information available to the consumer the better. What they should have done is gone back and modified the labels for the older drugs to update them with the new warning info. It seems it was the contrast between the lack of warning on the old drug and the warning on the new drug that the company took objection to more so than the warning itself, although they had a case against that too. Apparently it's hard to update labels, though (?).
I've read varying accounts online of whether the FDA uses rolling reviews but generally speaking they do not. So they don't start crunching numbers on the Phase III trial data until after the application is submitted. I suspect the factory inspections don't occur until after stuff is approved, also, although I don't know.
As another example of how things can be done in parallel, at some point after the initial phase III trial enrollment(s) they allow have doctors to start prescribing it. That is the idea of adaptive licensing, essentially which I summarize here :
https://moreisdifferent.substack.com/p/a-laundry-list-of-possible-fda-reforms
That's a very reasonable point in your case, but I don't think it's a reasonable criticism in my case. If other drugs in the class had this risk, but didn't have the warning, and a new drug is SPECIFICALLY designed to avoid this risk, it makes no sense at all to put the warning label on the old drug.
I see a role for the FDA, for all my bitterness I wouldn't necessarily burn it to the ground. But in this fight the pharma company was entirely in the right to insist on no warning label. "If they had stopped protesting something indefensible they could have helped you sooner" is true... but doesn't shift the blame.
What is the actual number of babies that died due to this? Definitely hundreds? (I saw a claim on Twitter it was more like “ten or twenty” than “hundreds or thousands”)
I also question that number. Not because any single life isn't precious, but because it speaks to the profitability of the treatment *and* about the difficulty in finding enough cases for good studies.
Any word on the number requiring liver transplants or otherwise suffering permanent damage? it could be that the larger number is the total number of babies affected rather than the number that died.
A really good question. No system is perfect and if the worst example of this kind of failure mode we can come up with is tens of people dying where we have a treatment that we can’t get over the hurdle of proof of efficacy, then we actually might conclude that we have a pretty good system.
So why were they so sure that "it isn't the lipids"? Because it seems a bit less certainty on that could have helped a lot. Was that a reasonable position? Would the establishment still have the same kind of position in the same kind of situation or has something changed since then?
I would guess it's because biochemically speaking biologically-derived fatty acids are pretty generic, it's just a question of how many carbons you have in the tails, and where exactly the double bonds lie. They're all metabolized in approximately the same way, so far as we know. I think for a long time people just assumed they were essentially all interchangeable, kind of like whether your gasoline contains heptane or octane doesn't matter that much.
The realization that this was not so -- e.g. that unnatural "trans" fatty acids were strangely dangerous, or that it actually makes a difference whether your first double bond is 6 or 3 carbons away from the end (the difference between omega-6 and omega-3 fats) -- seems only recently to have become part of the standard wisdom. I'm not sure anyone has any good mechanistic grasp on *why* this is true, also. The only obvious lesson here is the usual one: biochemistry is absurdly complex and not infrequently counter-intuitive.
That said, the omega-3 vs omega-6 differences that are in the news lately are subtle nutritional effects, and not a matter of immediate life or death.
Yes, although in this particular case (the infant parental nutrition), the assertion is that it *was* a matter of life and death. That is surprising to me even now -- I would never have suspected that soybean v. fish oil could mean the difference between lethal liver disease and health. I do not doubt empirical observation, but from a theoretical biochemical viewpoint that is seriously weird.
Perhaps it has something to do with neonate liver function, which differs in some important way from adult (or even child) liver function, in which case it's even less surprising that people were surprised by it, didn't expect it. The body of research on how 6-week-old livers work, and how that might differ from how 6-year-old or 60-year-old livers work, is probably amazingly scant.
> The body of research on how 6-week-old livers work, and how that might differ from how 6-year-old or 60-year-old livers work, is probably amazingly scant.
If the differences aren't known, it just raises the question again of why the overconfidence that it wasn't the lipids? Seems like extraordinary hubris to just assume neonatal liver function has no differences. You'd think we'd have learned better than to make assumptions without empirical data by now.
I don't think it's a question of hubris, it's a question of priorities. People are going to be very desperate to try to save a dying newborn, but they have to focus, because you can't try everything all at once, there just isn't time, or the resources. So they have to make some hard choices -- heck, this happens in medicine *all the time,* oncologists and surgeons and their patients make these choices every day -- do we try this or that first? Because once we make this choice, we're committed, there's no do over...
So they maybe say, gee, based on what we know, we think X or Y is more likely than the lipid content of the food. In this case, they turn out to be wrong. But that, too, happens all the time in medicine. Unless you were there, and know what X and Y actually were, and what the reason was for thinking they were more likely to be the issue, it's very hard to second-guess this and be confident they were idiots, as opposed to people who didn't have all the facts we have trying their best.
Even if I agree with everything you just said, the claim wasn't "we think lipids is less likely than X", it was quoted as "we know it's NOT the lipids". These are very different claims.
And even if they turn out to be *correct* that it's not the lipids, that doesn't rule some other compound present in fish oil that makes the difference, so ruling out the fish oil because of the lipids is also jumping to conclusions.
Reading the account in Scott's post they seem to have done tests with soya oil and without soya oil in such formulas, and similar problems happened in both, so they said "well it can't be the lipids since the same adverse results happen even without the soya".
If, for instance, the babies on non-soya formulations had done better, then they would have accepted "okay, the problem is with the soya oil". But of course, it was more complicated than that and not as simple as "replace the soya with fish oil".
I read a little more on this, and the suspicion is that it's a high fraction of polyunsaturated fatty acids, which actually starts to make sense, since each unsaturation is a hiccup in the normal process of beta oxidation of fats, and requires some extra hokey pokey step, and maybe baby livers don't have the latter ability fully developed. But this is just a wild guess.
it's unclear whether the "without soya oil" formulations had much oil at all - it's possible they were testing whether presence of Omega 6 was harmful and missing that the problem was absence of Omega 3; or, more likely, something more complex like the ratios
In the "relative balance" kind of problems, this is definitely true. In the rarer "actual full-blown deficiency, your body is not getting enough to meet requirements" kind of problems, it is not - deficiency of essential fatty acids (a.k.a. "protein poisoning" a.k.a. "rabbit starvation") is the only known form of malnutrition that can kill faster than simply eating nothing.
Curious about PNALD in Europe. This story is a little different than a new discovery of an alternate use for an older drug or something where there isn't already a body of evidence that it works. If Omegaven was already a standard of treatment there, was there a correspondingly lower incidence of PNALD? Might that have been valid data to use along the way?
That’s my thought as well!
Yea, for a complete outsider, this seemed weird to me aswell. I had the impression that science is an international endeavour - so wouldn’t studies on outcomes in Europe be valid? The USA babies could be a huge control group for European ones.
Or are confounding factors between continents too large (eg different quality hospitals)? Or is the number of affected babies still too low? Or do the European babies get other problems more often? Something else?
What is missing from the story in this regard? (Perhaps something obvious for someone with knowledge in medical sciences?)
Science is the same everywhere. But regulations are different.
Differing approvals in different jurisdictions is about regulations, not science.
Yes, I get that; but as I understood it the American regulators were apprehensive due to a lack of (good and large enough) studies. Given that different formulas were approved in the different continents - shouldn’t it be easy to write a study comparing the results (and use that to convince regulators)?
Since saying “babies in Europe in this situation survive 4x as often as in America” in a study seems so obvious, I am sure that there is something missing (in my understanding at least - but maybe also in the story).
Not medically related, and nearly forty years out of date, but when I was doing milk powder testing in a creamery co-op lab, it was for export and had to comply with US regulations, and those were more stringent than the at-the-time acceptable ones in Ireland/EU.
So certification and standards did/do differ from one country to the next, and simply saying "it's fine in European country X" doesn't mean it is legally acceptable in the US.
Just to be clear; I never intended to make the argument that regulations/certifications/standards are the same/similar, nor that “it’s fine there” is/should be enough. Moreso I wonder whether the liver disease (or other issues) were actually obviously gone where the alternative treatment were used.
Yes — I was suggesting the same. Not that the European regulations could apply in the US, but that the European market vs. the American market might effectively function as a giant study with a control for children who did and didn't receive Omegaven. It would still need to pass American compliance requirements but might provide a lot more data than the few US trials.
To put it much stronger: shouldn’t there have been a large and obvious difference in PNALD incidence? And wouldn’t that fact alone be evidence much stronger than that of any of the experiments?
Cowboy is still mostly a compliment at a certain hard-charging aerospace company, from my experience.
I'm about as cowboyish as it is possible to be and still be employable, so of course I thrived at a tech startup and hated working at a giant tech company. The increase in size of companies due to M&A or economies of scale or natural monopolies in tech is probably driving the culture away from cowboyishness.
In the least cowboyish culture I can think of, Japan, for a long time there were giant conglomerates dominating every industry, all headquartered within a few hundred miles of the God-Emperor's palace. In the wild west, there were tons of small businesses far from the reach of centralized authority.
Isn't everywhere in Japan within a few hundred miles of everywhere else, in particular the God-Emperor's palace? I guess you mean "the greater Tokyo area" in which case it makes sense.
I assure you it is extremely pejorative in finance (at least post 2008...)
It's real fukin bad in trades; cowboys are the clowns that get 95% of the way to saving an hour, and end up adding 3 onto the end of the job.
"Cowboy" is very bad in software engineering. At least my section of the field.
It was a derogatory term in Tombstone, AZ, and much of the Old West almost from the start. "Cowboy" basically meant "robber", with a side order of if they were the first settlers in the area and there was *nothing* to steal, they'd set loose some cattle and sit back until they could steal everything the cows had built.
Western novels, movies, etc, rehabilitated the term in roughly the way that "The Dukes of Hazzard" rehabilitated the Battle Flag of the Army of Northern Virginia. And we need *something* that symbolizes the general ideal of disrespecting established authority while still behaving honorably and engaging in productive enterprises on one's own terms. If there's cause for one or two of those terms to go away because of a preexisting and dishnorable usage, that's one thing - if they *keep* getting deprecated then it's going to look like someone is demanding submission to their authority and that all productive enterprises be done on their terms or not at all.
It sounds like your qualm is with how American healthcare law is written, not with how the laws are administered by the FDA.
As an example, who are you more mad at: judges who upheld disparate sentencing guidelines created during the war on drugs, or the legislators who wrote the laws?
Thank you.
My own take: the legislators are the most to blame. The trial judges are most likely often/usually blameless, but appellate judges arguably are not. Disparate sentencing guidelines arguably infringe on the eighth and fourteenth amendments, as well as some states' own constitutions.
Plot twist: some of the legislators who supported those harsher penalties for crack were black congressmen who saw the devastation crack caused in their communities in the 80s. So long as the demand curve slopes downward, harsher penalties = less crack. I don't agree with the drug war, but it's not such an easy mistake that I'd hold it against them.
And I honestly don't know if I could have done any better in their position, with the information I would have had at the time. Nevertheless, they're responsible for the consequences of their actions, including the unintended ones - to some degree that's the price you agree to when you choose to be in charge. Being wrong isn't something we should condemn anyone for, provided it's an honest mistake and people try to learn from them. Sadly this seems to be an unpopular position.
More importantly, all subsequent legislators are responsible for not having fixed the problems caused by previous laws passed.
> Disparate sentencing guidelines arguably infringe on the eighth and fourteenth amendments
Why? As far as I understand, the 14th Amendment forbids unequal treatment based on who you are, not what you do (such as what drug you sell).
What I don't understand about this debate: If powder cocaine and crack have mostly the same effects, but sentencing is much harsher for crack, then why doesn't everyone who sells/uses crack switch to powder cocaine? And are we sure that whatever difference makes people use crack doesn't also justify the harsher penalties (based on the assumption that drug prohibition is justified at all, which I don't think it is)?
crack is stronger and thus probably more dangerous than powder cocaine. It would make sense to have harsher penalties for dealing more dangerous substances.
IANAL, but my understanding is that if you can demonstrate racist intent on the part of lawmakers, then you may be able to claim the disparate impact is in fact a form of unequal treatment based on who you are. Hard to prove, though, just like it's hard to get any results arguing about unequal enforcement of laws against different groups of people.
Disparate impact is part of some anti-discrimination laws such as the Civil Rights Act of 1964. It's less clear to what extent it applies to constitutionality under the 14th Amendment. It looks like it may apply if discriminatory intent is proved, but it's hard to prove.
True. But FDA is also as dysfunctional as any major federal agency.
You can also take a step back and observe that FDA is created by legislation.
Thank you for this story of heroes and a system that can be so cruelly imperfect.
I'm glad you plan to write more on this topic in the future, because it's so important, and your analysis of it has been incredibly enlightening. Do you plan to write about the approval process in other countries as examples of ways the FDA can be improved? Or as cautionary tales?
Wait, so the only evidence for the effectiveness of fish oil in treating PNALD is a poorly powered study and a few miracle cure anecdotes? Miracle cure anecdotes are a dime a dozen. You can easily find thousands of them for everything from homeopathy to touching a statue of the Virgin Mary. That doesn't mean homeopathy obviously works or should be approved by the FDA.
"We were confident we were onto something and began to discuss our findings with others at BCH. The response was not what we expected. We were told “Everyone knows it's not the lipids because liver disease happened with them and without them.” Some individuals would even pull me aside to ask “Are the results real?”"
Usually when one scientist is convinced about the miraculous properties of their discovery while everyone else is skeptical, it's everyone else who's right, not the one scientist. I have no opinion on who's right in this case, but I wouldn't be surprised if fish oil turns out to not be very effective at all in treating PNALD.
Google “pnald fish oil”
"The parents demanded to be taken out of the control group, and then all their babies got better" seems like fairly strong evidence to me.
It's not like you have much need to worry about the placebo effect with babies.
No, it really isn't. Pick a quack therapy that you're sure doesn't work, and Google "(quack therapy name) + testimonials". Here's the first result I got for homeopathy: https://www.homeopathyschool.com/the-clinic/patienttestimonials/
This is why bleeding and cupping were standard of care for centuries. Hey, we gave it to Patient X and he got better! But Patient Y died! Yeah, well he had [other factor]/[was already at death's door]/[a physician who didn't do it right].
The reason we enforce the unnatural and cumbersome process of double-blind RCT is *because* historically speaking we know it is incredibly easy for human beings to detect "signal" in "noise" and rationalize it with some elegant theory.
> No, it really isn't. Pick a quack therapy that you're sure doesn't work, and Google "(quack therapy name) + testimonials"
No, what you're doing is fishing for an outcome in a sea of noisy data (like p-hacking). What the doctors did was an introduce a specific intervention to a cohort and observing an undeniably large signal. These aren't remotely the same.