Contra Drum On The Fish Oil Story

I.

(it's actually more complicated - I posted a shorter version, later corrected it with a longer version based on the account of one of the doctors involved but said it basically supported my shorter version, he also found the longer version and was about to publish an article saying he had debunked my shorter version, then noticed I had seen the same article and thought it supported me, and he thinks I was wrong to believe this)

He writes:

This is headshakingly dense. As a hit on the FDA, his post wasn't right at all — not its basic structure and not anything else about it. He even admits that although Gura criticizes plenty of other actors, the FDA isn't one of them...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. This is why I'm automatically skeptical of anything on the web that's excessively critical of the FDA.

Kevin is one of my favorite bloggers and I usually appreciate his commentary. But in this case, I still think I was right.

Let's go over the exact phrasing I used (at this point I admit I'm more in defending-myself mode than making-an-important-point-about-the-FDA mode). An early version of the post included a false claim that the fish oil helped the nervous system; I later edited it to a correct claim that fish oil helped the liver. Drum quotes the corrected version where I talk about the liver, so I'll use that here. I wrote:

The FDA approved one version of the nutrient fluid, but it caused some problems, especially liver damage.

This is straightforwardly true.

Drawing on European research, some scientists suggested that a version with fish oil would cause less liver damage — but the fish oil version wasn’t FDA-approved.

Also straightforwardly true.

A bunch of babies kept getting liver damage, and everyone knew how to stop it, but if anyone did the FDA would take away their licenses and shut them down.

Am I exaggerating when I say "everyone"? Reading Dr. Gura’s notes, you could imagine a story where this knowledge was limited to a couple of world experts in Boston, and it took them a long time to make a convincing case, and once they did the FDA approved it.

That story would be wrong. 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 - here’s one of them (search for "Bureaucratic Delay Endangers Lives"). Also in 2014, I personally learned about this for the first time, when writing my review of The Perfect Health Diet (I thought the book was generally bad, but it did alert me to this issue and the evidence supporting Omegaven). In 2016, my friend Eliezer Yudkowsky started writing a book about bureaucratic inefficiency that used the FDA failure to approve Omegaven as one of its central cases; in 2017, he published it as Inadequate Equilibria and I reviewed it here, including a mention of the Omegaven story. In January 2018, my friend Kelsey Piper also blogged about the FDA’s failure to approve Omegaven. Finally, in July 2018, the FDA finally approved the drug. I’ve been hearing about this story for so long that I thought I could recite it from memory (I was wrong, which is why I screwed up so many details in the original).

I think this history might be one of the reasons Drum and I interpret this story so differently. Drum hears about Omegaven, checks and sees that it’s FDA approved, and thinks "well, things worked out well in the end, what’s he complaining about?" I heard about it years ago, saw it wasn’t FDA approved, was able to confirm that it was revolutionary and life-saving, thought "well, I guess a lot of people are going to die from not being able to get this", and read a gradual stream of articles over the next few years confirming that babies were still dying. Then, long afterwards, the FDA approved it. I guarantee you this is less fun and more enraging than hearing about it after the fact.

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. One answer to this might be to look at my past work and see if this is true (I don’t think it is). But a better answer might be to remember that, if you believe coronavirus vaccines work, you’re in this same situation right now. That is, the media, general public, scientific community, etc all know that they work and are safe, but the FDA still has not fully approved them. This isn’t an unusual situation to be in! Most of the time, the FDA lags the general consensus of people paying attention, usually by quite a lot. I think people worry that I want the FDA to auto-approve insane drugs nobody knows anything about, whereas I’d honestly be pretty happy if they just showed the same level of common sense as an average member of the general public.

Around 2010, Boston Children’s Hospital found some loophole that let them add fish oil to their nutrient fluid on site, and infants with short bowel syndrome at that one hospital stopped getting liver damage, and the FDA grudgingly agreed to permit it but banned them from distributing their formulation or letting it cross state lines - so for a while if you wanted your baby to get decent treatment for this condition you had to have them spend their infancy in one specific hospital in Massachusetts.

I was wrong in calling this a "loophole" - they filed an IND with the FDA and got permission to do it as a study (although I don’t know if they were really doing it as a study). Otherwise, as far as I can tell this is true. Some other hospitals also got INDs at a later point.

Around 2015 the FDA said that if your doctor applied for a special exemption, they would let you import the fish-oil nutritional fluid from Europe, but you were only able to apply after your baby was getting liver damage, and the FDA might just say no.

I got this from a book and haven’t been able to figure out exactly what it’s referring to - there doesn’t seem to be a corresponding entry in Dr. Gura’s notes. I suspect it’s true, since I find a lot of "compassionate use of Omegaven" studies from around this time, but I can’t find the actual FDA document involved. In any case, if true it slightly exonerates the FDA, so it’s probably not one of my points of contention with Drum.

Finally in 2018 the FDA got around to approving the corrected nutritional fluid and now babies with short bowel syndrome do fine, after twenty years of easily preventable state-mandated damage and death.

More like ten years - six if you want to date from the Hong Kong study, five from the NBC article, four if you want to date from me personally knowing about it - but otherwise true.

So the mistakes I see are - I overestimated how long it took - more like five to ten years than twenty. And I called Boston's unique ability to prescribe it a "loophole", when it was an accepted part of the regular system. I think it’s fair to summarize this (as I did) as "I got some details wrong but it was substantially correct".

So how come Drum (and some other people!) think that the real story proves me wrong?

II.

Drum says it’s because Gura was very positive about the FDA, and even I (when reviewing Gura’s story) mentioned that the FDA seemed to have performed its mandate pretty well here and I was impressed with everyone involved. How is this positive portrayal compatible with my outrage?

I tried really hard to explain this in the original post, but it seems not to have worked. So let's compare this to a situation Drum and I know well: blogging. Imagine there's a censorship board with a mandate to prevent misinformation. We can call them the False Data Administration. Before you publish a news article, blog post, or any other act of reporting/assertion/argument, you need to get FDA approval. FDA approval still takes ten years and $100 million.

And suppose that there's some important story that ought to be broken soon. I'll randomly choose the Flint water lead crisis. Some intrepid reporter discovers high lead levels in Flint’s water system. She can't just report it unapproved, or she would be arrested. She can't immediately apply get FDA approval, because she doesn't have enough money to fund the studies it would take to prove that this isn't misinformation. So she shops around for a few years, trying to find a media company who will sponsor her studies. The whole time, she's checking in with the FDA, and the FDA is giving her helpful advice - "Yeah, try Washington Post, they sometimes fund things like this" - and sometimes they’re even helping her directly. She gets into a couple of fights with the Mayor of Flint about whether she's even allowed to conduct the study there at all, and for a while it seems like she’ll never be able to publish her report, and maybe the FDA helps walk her through this too. But eventually, five years after she learns about the crisis, some funder takes pity on her, the political stars align, she fills out her pile of paperwork, does her study, and submits her article for FDA approval. The FDA takes a few years to think about it, makes the right decision, and approves the article. Ten years after she first discovered the crisis, she is given permission to inform the public, and politicians and other actors can leap into action to solve it (haha, yeah right).

All of the following things are true of this story:

• Everyone at the False Data Administration followed their mandate well. All individual FDA employees performed admirably and deserve our praise.

• In a society where this kind of censorship was accepted and normal, nobody would associate the ten-year delay between discovery and publication with any failure on the FDA's part. They would interpret the problem as "funders didn't fund the study as quickly as they should" or "the Mayor of Flint was obstructionist". All these interpretations would be completely valid.

• The reporter who discovered the crisis would probably end up with a good impression of the FDA. They helped her along every step of the way, gave her money when she needed it, and approved her story in the end. When she accepted an award, her acceptance speech would be just as positive about her FDA as Dr. Gura's was to our FDA.

But, also:

• It took ten years between the discovery of the lead crisis and it being publicized to the world

• Lots of kids died of preventable lead poisoning during that time

• From our perspective, where we haven’t accepted the False Data Administration as natural, this is 100% the fault of the FDA. Not any particular FDA employee making a bad decision. But the general social decision to make everyone wait ten years and pay a bureaucracy hundreds of millions of dollars before they're allowed to publish an article.

If Bizarro-World Scott tried to protest the FDA by saying "hey, the delay between discovery of the Flint lead crisis and publication probably killed lots of kids, and this is the FDA's fault, shouldn't we do something about this?", then Bizarro-World Kevin could publish his same article: "Actually, you'll see the reporter wrote that she was happy with the FDA's actions, and it performed its mandate well in this situation, your story is full of lies". Bizarro-Scott’s story wouldn’t have any particular lies in it. It would just feel like the sort of thing that must be full of lies, because it said bad things about the FDA, whereas a normal person would see the same situation and say good things about the FDA.

I’ve tried to stress, throughout, that the problem I’m trying to address here isn’t that the FDA fails at its mandate or makes bad decisions. It’s that the FDA by design makes it hard to do things that save lives, prevent pandemics, and improve the world. By design, it makes there a several year gap between when everyone including random bloggers knows that something saves lives, and when anyone can actually use it for life-saving.

III.

People keep asking whether I’m saying the FDA should be abolished. Let me deflect that question with a discussion on the indications for use of doxepin hydrochloride.

There’s an antidepressant called Sinequan. It comes in pills of various sizes, starting at 10 mg. It’s not a very good antidepressant, but it does tend to make people very sleepy after they take it. Sinequan is extremely cheap, about $10 per patient per month.

And there’s a sleeping pill called Silenor. It comes in pills of various sizes up to 6 mg. It’s a pretty good sleeping pill, and weirdly enough if you take a high enough dose of it you might also feel less depressed. Silenor is extremely expensive, about $250 per patient per month.

Both Sinequan and Silenor are the exact same chemical, doxepin hydrochloride. Basically any dose of doxepin will make you sleepy, and higher doses also decrease depression. Maximum recommended dose is 300 mg/day, so both the 6 mg Silenor dose and the 10 mg Sinequan dose are nowhere near it.

You might wonder: given that these are the same chemical, why don’t people who need sleeping pills use Sinequan instead of Silenor and save $240/month? The answer is: the FDA has approved the Silenor brand for sleep, but not the Sinequan brand. Nobody really knows if we are supposed to be pretending that the 6 mg vs. 10 mg dose matters (it doesn’t) or whether we’re just supposed to lie back and not trouble ourselves with such questions.

There’s no mystery about how we got into this situation: the Silenor brand paid $100 million to get the FDA to classify them as a sleeping pill, and the Sinequan brand didn’t. This means Silenor has a monopoly on doxepin for sleep, and they know this, so they charge $250/patient/month, ie $3000/year.

At any time, a doctor could just prescribe Sinequan for sleep. In fact, I do this all the time and it works great. But this is an "off label" prescription, and there are various regulations that make off label prescriptions less convenient than the usual type, so most people stick with Silenor, which makes between $10 million and $25 million per year for its parent company.

I want a world where if there is a $250 version of a drug, and a $10 version of the same drug, people are encouraged to get the $10 version even though the manufacturer did not give the FDA $100 million dollars.

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 a study confirms it, you are allowed to give those babies the fish oil based fluids without waiting another five years for an FDA approval.

I want a world where, if a patient is in a race against time to get the treatment that might save their lives, and after a lot of dithering the FDA unanimously agrees that the medicine is safe and effective, it doesn’t hold up approval for an additional five months arguing about the wording of the warning label, by which time the patient telling the story ended up in the ICU, lost his large intestine, and barely survived

I want a world where if everyone knows ketamine is a great depression treatment, if I’ve been blogging about the intricacies of ketamine depression treatment for years - then ketamine eventually gets approved for use as a depression treatment (it still isn’t - if you think it is, you’re probably thinking of esketamine, which is worse and costs 25x as much).

I want a world where, if everyone knows COVID vaccines are safe and effective, if we’re banning YouTube videos saying that COVID vaccines aren’t safe/effective as misinformation, if we’ve banished COVID vaccine safety/effectiveness denialism to the same outer darkness as 9/11 trutherism or Kennedy conspiracy theories - then the government will have approved COVID vaccines as safe and effective.

Does this world require abolishing the FDA? I think it only requires making the FDA no worse than the average guy on the street. I think this is a low bar. If somehow it can’t clear that bar then I guess abolishing it is the only option, but I’m perfectly happy to give it a lot of chances at reform before we go that far, and I still plan to write more about exactly what that reform might look like later. I just wanted to respond to Drum’s article in particular first.

Drum ends with:

This is why I'm automatically skeptical of anything on the web that's excessively critical of the FDA. It's not that I think the FDA is above reproach. It's because of the existence of the "anti-FDA blogosphere" that Alexander mentions. There is indeed an active clique of FDA critics in the blogosphere, mostly of a libertarian bent, who are willing to accept and pass around the most egregious stories imaginable of FDA incompetence. Occasionally they're true, but most often they're very highly exaggerated, like this one. Other times they're little more than urban legends.

There is also an anti-police blogosphere, an anti-Trump blogosphere, and an anti-North-Korea blogosphere. Sometimes people form a blogosphere against a thing because it is bad. One of the people in the anti-FDA blogosphere is that guy who lost his intestine because the FDA delayed his drug for five months arguing about a warning label. People get angry when the FDA almost kills them. Then they write pieces about their anger. I’ve never had the FDA almost kill me personally, but I have had it hobble my efforts to help some really desperate patients who I’ve grown kind of attached to over the years, and yeah, that also makes me angry. If your response is "this comes from an angry person so I can ignore it", I think you will miss a lot of important stories, not just FDA-related ones.

I know anger looks bad, and I try hard not to sound angry, and I think I succeed really amazingly well. You have no idea how non-angry I can sound about malaria killing millions of people, or climate change killing millions of people, or Donald Trump, or Xi Jinping, or all sorts of other terrible things and people. Overall given how enraging the world is, I think I’m doing a really commendable job of not sounding angry all the time. But everyone fails on something and for me it’s this.

Drum continues:

The FDA has plenty of problems, and their critics have performed a useful service by pushing them to improve. That said, the FDA doesn't screw up every hour of every day on practically every useful drug ever presented to them. Even taking normal human frustration into account, that's inexcusable.

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.

(and then sometimes they make some extra stupid minor mistakes, like with aducanumab. But that’s not really my point here)

Maybe a really harsh way to say this would be that Drum feels like it’s unfair to treat this story as a condemnation of the FDA, because it was a perfectly ordinary example of everything going as expected. I think it’s absolutely a condemnation of the FDA, for the same reason.