Today I learned, thanks to a leaked email from Vinay Prasad to his staff, ⊕ I also learned that Prasad puts a double space after each period which is inexcusable in 2025 when we all use variable fonts on our electronic devices, not a fixed width-font typewriter. Whatever his high school typing teacher told him, he should drop the habit.that FDA’s CBER does actual bench research. This is pure stupidity on my part, as it is right there in the name: Center for Biologics Evaluation and Research. Silly me. They have a page dedicated to describing the work of their 65 principal investigators, and it seems to be at least on par in topics and rigor to the work done at the NIH Intramural Research Program though the latter if of course bigger.

Prasad’s email boils down to this: CBER research staff has strayed from its mission, which is primarily regulatory. We will look at work performed and planned and cut that which is not in line with the mission. He invokes sunken cost fallacy by name, so one would assume work in progress will also be cut, maybe even things completed that haven’t yet been written up — why spend hours formatting a manuscript when you could be reviewing IND Investigational New Drug applications and BLAs Biologics License Application, and let me use this sidebar to note how infuriating it is that one acronym includes the word “application” in it and the other doesn’t, forcing one to resort to clumsy phrases such as the one to the left. I supposed you could write “BLAs and IND applications” but that is listing them out of sequence. instead? And we certainly shouldn’t abuse the privilege of conducting research without having to apply for grants by just padding our CVs with insignificant work that will never be cited, which is another thing Prasad rises against.

My initial reaction was “damn right” but then I realized that regulatory review is just another price scientists-at-heart pay in order to do the work they want, similar to teaching in academia and low pay with no opportunity for outside activities at the NIH IRP. I suppose that eliminating the opportunity for self-directed research — which is what Prasad proposes instead of, let’s say, cutting it down to 10–20% of one’s time — would select for a certain type of a person (I imagine a box-checking blankface) but is that what we want? Is that what Prasad wants?

The tedious and unappreciated work of regulatory review is the price some scientists are willing to pay in order to perform research. Giving scientists the opportunity to do the work that’s meaningful to them is the price the FDA may have to pay to get good people to perform regulatory review. Any important scientific contributions that arise from this concession should be seen as an unexpected gift, not a requirement for staying employed as a reviewer.

• Tom Forsyth on Mastodon: “Recent discussion about the perils of doors in gamedev reminded me of a bug caused by a door in a game you may have heard of called Half Life 2.” Parallels in biology immediately come to mind.
• David Roberts on Blue Sky: “In an era filled with tech dipshits who never developed emotionally past the age of 13 & use their wealth to become odious monsters … listen to Steve Wozniak.” We are where we are in big part because there weren’t enough Steve Wonziaks in key industries when it mattered. Or rather, because they by definition bowed out and gave the sociopaths free space to roam.
• Ruxandra Teslo on X: “We should do smth abt this.” The “this” is the threat of clinical trial infrastructure being flooded by the biotech equivalent of AI slop. And many misguided people think that this is a good thing!
• Joe Janizek on Substack: The birth of Advanced Radiology. Or: radiology as chess. Radiology and pathology are the few areas of medicine in which AI may be produce immediate benefit.
• Nassim Taleb on Substack: Medical Mistakes with Probability, 2. Why the benefit of statins in people with barely elevated cholesterol and no other risk factors is grossly overestimated. Note that this constitutes most of the market for statins! My cynical take: Now that they are all out of patent I don’t think anyone would complain about cutting back.

• Niko McCarty: Here are 30 great essays about biology. They are indeed great, and it even includes one where I gave a modest and unattributed contribution (you will be able to guess which one). To this I would add William Kaelin’s Publish houses of brick, not mansions of straw, cited many times on this blog (most recently just last month).
• Jason Locasale: My latest article in The National Review on what 60 Minutes got wrong about Harvard and the biomedical research industrial complex, and why the deeper issues in science can’t be fixed by throwing more money at broken institutions. Here is the article, which I agreed with directionally but had so many “I know this person and let me tell you what they are truly like” moments that I thought there had to be a backstory to this insider-ish scoop. And indeed there was, as noted in responses to Michael Eisen’s tweet. So much drama, and all it does is make it easier for people to shrug their shoulders, say that it’s complicated, and defer to higher authorities (i.e., Harvard).
• Nassim Taleb: I believe this paper addresses, even solves, the most relevant statistical problem of the century, including the replication crisis & the fake results in publication. No false modesty here. Papers like this make me think that frequentist statistics are fine for the lab where you can truly do the same experiment over and over, but when it comes to clinical trials you can never cross the same river twice and we should all be Bayesians.
• Christopher Hooks: I sincerely believe that anyone pushing this should be shot. I agree in spirit. Whoever made this AI abomination should study Hayao Miyazaki and his work.

Last year, Nassim Taleb was on a podcast with Joe Walker. It became “controversial” in some circles because of some things he said about negative probabilities and quantum mechanics — ha ha, look at Taleb, barging into the wrong lane again — but the highlight for me was what he said about the world of startups and venture capital:

TALEB: No, no, the mechanism. They don’t make their money, venture capitalists, they don’t make money by waiting for the company to really become successful. They make their money by hyping up an idea, by getting new investors and then cashing in as they’re bringing in new investors. I mean, it’s plain: look at how many extremely wealthy technology entrepreneurs are floating around while not having ever made a penny in net income. You see? So the income for venture capital comes from a greater fool approach.

WALKER: Okay, so a Ponzi kind of dynamic?

TALEB: Not necessarily Ponzi, because you’re selling hope, you package an idea, it looks good, so you sell it to someone, and then they have a second round, a third round. They keep [doing] rounds so you can progressively cash in.

WALKER: Got it.

TALEB: It’s not based on your real sales. Or your real cash flow. Particularly in an environment of low interest rates, where there was no penalty for playing that game.

WALKER: Do you think there’s any skill in VC?

TALEB: They have skills, but most of their skills are in packaging. Not in …

WALKER: Not for the things people think.

TALEB: Exactly. Packaging, because they’re trying to sell it to another person. It’s a beauty contest.

Of course, these dynamics continue to be in play beyond the private equity stage, reigned in somewhat by financial market rules or what is left of them. Assuming what Taleb said was correct — and if you disagree you may as well skip reading (or better yet, drop a comment below because I would love to see the arguments against Taleb’s thesis) — the VC-backed startup model is uniquely ill-suited to funding drup development, and I would wager that many of the issues lamented over substack articles and policy papers can be traced back directly to its rise.

Of course, this blog being what it is you will not get graphs showing the parallel increase in sheer number of biotech startups, the cost of clinical trials, and the millions of dollars spent per sucsessful drug (by whatever definition you chose), with a few thousand words on why this particular correlation does imply causation. If you have enough time to make such a graph, please share. Instead, here are three reasons I came about by the way of armchair research for why biotech is not tech:

1. Larger freedom to bullshit (than tech)
2. Harder to test against reality (than tech)
3. Less end-user price sensitivity (than in tech)

The first two apply to many non-tech fields: social sciences, philosophy, interpretive dance, etc, and in those two ways it is tech, by which I mean both software and engineering (though software is somewhat more malleable) that is unique. What sets anything related to medicine apart is that sick people and their families are willing to spend unlimited amounts of money to get their health back, or even to just squeeze out a few more good months out of a dire prognosis. This is as true for America’s hyper-capitalist health care “system” as it is for any “socialized medicine” country whose citizens still find ways to collect money via online fundraiser or SMS services to send their loved ones abroad for life saving therapies and stem cell scams alike.

Freedom to bullshit is particularly large in cutting-edge fields, which are exactly the places where we wound now go to startups instead of established players to sow the seeds. The data is more likely to be confidential, not yet peer-reviewed or even presented at a conference. Uncertainty is always higher here, and this is why the professional sociopathic bullshitters will have an edge: earnestness may get you a miss congeniality prize but you will never get the crown.

Testing biotech against reality can only be done — for now — in clinical trials, and those are notoriously slow, expensive, and easy to explain away in case of negative results (see the case of Sarepta). A failed rocket launch is a failed launch: we will have learned more for the next one but can’t pretend we’ve reached orbit. It is also severely supply-constrained: there are only so many clinical trialists around, running clinical trials is not their day job, and those who find clinical research interesting are likely to jump ship and transition to industry further limiting supply. This is the area with most room for improvement and kudos to Ruxandra Teslo and Willy Chertman for making the case for clinical trial abundance, but there is a major headwind to their efforts:

Good health has no price or a variant thereof exists as a phrase in many, maybe most, world languages. Let’s not go into why that is (economist Robin Hanson has some interesting ideas), because my interest is in the outcome: the health care ouroboros. ⊕ Not to be confused with the ouroboreos What is that, you ask? It is the curious phenomenon of economists explaining that Americans pay more for health care than anyone else in the world because they subsidize the world’s drug development, while at the same time pointing to high costs of health care as a reason for why clinical trials in America cost so much! Truthfully, this would not be a problem if it didn’t directly contribute to item number 2, leading to an unsustainable positive feedback loop when it comes to price, and a negative one when it comes to actual working drugs making their way to patients.

So let’s review the proposed interaction between the three factors that has led to our current drug development quagmire. Bullshitters are attracted to the American medical honey pot. If there was money to be made in interpretive dance they would have chosen that, but alas it is health care that both has large amounts of money sloshing around and gives them enough freedom to perform their hijinks. The particularly outworldly bullshitters in other fields can only do this up to a point — Elizabeth Holmes hit a well when it came time to produce actual lab results — but in drug development reality is slow to come by and can be explained away, as noted above. If Liz had chosen therapy instead of diagnostics she could have avoided the anklet!

But so what? How does this prevent working drugs from coming to market? Well, it is more than anything a beauty contest: the better story wins, unrestrained by reality which is difficulty to know anyway because clinical trials are what they are. So, an otherwise sucessful drug is out-competed for clinical trials sites which can only run a certain number of trials at a time, until it is eventually dropped in the absence of a bullshitting champion. Who knows how many good drugs now languish in order for the likes of Sarepta to prosper? And this not because of any failure of structure-based drug design compared to screening, but because its rise as a drug development method came about at the same time as the field became more and more financialized.

I would like to highlight the last paragraph as an indication of me changing my mind about something, which is a rare occurrence. Two years ago almost to the day I wrote that no one was hiding miracle cures, mostly as defence of the FDA requiring clinical trials instead of “real-world data” for commercial approval of drugs. I still hide behind the final sentiment, but not behind the statement that there are no drugs that exist now which may be truly world-changing whose development is being held back by clinical trial regulation. I worry now that this indeed may be the case. The next step in bringing them to patients should not, however, be to loosen the criteria for market approval, but for getting them into trials as quickly as possible. And good luck doing that without breaking the vicious cycle of health care-trial-health care costs.

• Ruxandra Teslo: What will it take for AI to change drug discovery?. Producing boatloads of hypotheses won’t be enough, and would even set the field back. Good stuff. Again, China is eating America’s lunch here so something better change, and soon, but it is unlikely LLMs will be of immediate help.
• Chris Arnade: Asian style materialism. And if you think, well, maybe it is time for one civilization to sunset so that another one will rise, observations like Arnade’s should make you pause. The culture there seems rather bleak. And I consider him a rather impartial observer.
• Sarah Kliff for the NYT: The ‘Worst Test in Medicine’ is Driving America’s High C-Section Rate. It is about fetal HR monitoring, a particularly salient topic right now. It seems to be the Swan-Ganz catheter of obstetrics, thankfully much less invasive.
• Anish Koka on X: In the wake of the hubbub on novel promising gene therapy approval for Huntington’s disease, this video on the Sarepta debacle is a must watch. Can’t be… I am sure that everything was on the up-and-up.

Where are all the trillion dollar biotechs? asked Lada Nuzhna in her rarely updated blog. I will paste only the conclusion but the entire post is thoughtful and well-documented:

Drug development, like any other industry, is greedy - it addresses the most tractable diseases with the biggest outcomes first. Genetic targets, clear biomarkers, and one-pathway wins gave rise to the biotech boom of the 70 and 90s, when recombinant insulin, monoclonal antibodies, and early gene therapies created a sense of an endless frontier. Unlike with other industries, reinvesting capital from those early wins back into the ecosystem didn’t accelerate industry’s progress – we’ve been on a reverse trend for a while now. Today, remaining problems resist the very playbook this industry was built on.

Most industries have eras when progress stalls before a new paradigm unlocks scale again. Electricity needed transmission grids, computers needed operating systems, and aviation needed jet engines. For biotech, whether the shift will come from new modalities, new regulatory frameworks, or entirely new ways to validate efficacy in humans is not yet clear, but we can, perhaps, outline the boundaries within that future will exist: manufacturing and trials should get cheaper with each run, regulations should become more adaptive, approval frameworks should increase and not decrease in variance, and new therapeutic modalities should focus on unlocking new biology, not just producing slightly better iterations on problems we already know how to solve. Until those new paradigms take hold, building a trillion-dollar biotech will remain caught in Lewis Carroll’s logic: running as fast as we can just to stay in place, and twice as fast to make any real progress.

Note that “trillion-dollar biotech” is (hopefully) just shorthand for a company that produces truly world-changing drugs, and is rewarded accordingly by the all-knowing all-seeing Mr Market to reach a trillion-plus valuation. But if you put dollars first and benefit to humanity second, would that not perhaps contribute to these Alice in Wonderland dynamics? Maybe it’s the gold-digging approach to this decades-long gold rush that caused the shovels to become so expensive, maybe even more valuable than hitting gold. More than that: hitting gold — i.e., developing an effective drug — in this topsy-turvy world can even get you punished.

As Kyla Scanlon stated so succinctly, it is a casino economy now. In biotech it isn’t just now but from its very inception, as I have recently learned, and surely there are downstream effects in this approach to drug development. Again, Nuzhna’s blog post is exceptionally well-written and researched but maybe just maybe the problem deserves to be reframed?

• June 25, 2024: Inside the controversy over FDA’s recent gene therapy approval
• July 18, 2025: Analysts demand transparency after Sarepta’s roundabout disclosure of 3rd patient death
• July 18, 2025: FDA Requests Sarepta Therapeutics Suspend Distribution of Elevidys and Places Clinical Trials on Hold for Multiple Gene Therapy Products Following 3 Deaths
• July 30, 2025: Prasad Resigns From Top FDA Post Amid Fallout Over Sarepta Dispute.
• August 7, 2025: The Sarepta Scandal: Laura Loomer, Vinay Prasad, and the history of pharma’s latest attempt to reassert control at Trump’s FDA
• November 3, 2025: Sarepta’s Duchenne confirmatory trial fails, but biotech will ask FDA for full approval anyway

All this for drugs that cost millions of dollars per dose from a company with $2B in revenue. Neutral people in the know have their opinions too. Know me by my enemies indeed.

The story of the United States Food and Drug Administration is a story of mismatches.

Mismatch one: cramming both food and drugs regulation into a single agency. Humans have been making food since the beginning of time — it is in fact one of our defining characteristics — and while the methods have become more and more intricate and our definition of food wider and wider to now include some decidedly unfood-like substances it is not a field where people expect too much experimentation and adding risk to production yields absolutely no reward to the end user. Drugs as used now — aspirin aside — are a modern invention. We learned about DNA less than a century ago and cell & gene therapy weren’t even an idea until late into the 20th century. An eye-blink, compared to food. And when it comes to production, risk is very much encouraged for those who need the drugs, particularly for rare diseases without approved therapies.

That is the second mismatch, one within the Drug section of the FDA: generic drugs that have been used for decades are more like food, unapproved, experimental treatments are quite the opposite. This is a source of constant tension that leaves much room for improvement. To be clear: Europe is worse. EMA requires drugs tested at any stage to be manufactured in a fully audited manufacturing facility; FDA allows for “phase-appropriate GMP compliance”. This still requires major investment, lest you leave yourself exposed to the whims of a random audit.

The third mismatch, one written up in STAT this morning, is one of management. Regulation of food and established drugs requires a certain mindset and personality type; regulation of experimental drugs is something else entirely. There is a paradox here: while most of FDA’s work is focused on the first two — it is the baseline activity absolutely essential for proper functioning of society — the focus of the public is mostly on the third. Unless, of course, something goes wrong which it amazingly rarely does considering the amounts of food consumed in this country. But the culture has been determined by this baseline activity, and I imagine people going to work at the FDA self-selected for that kind of culture: steady, stable, contemplative, detail-oriented and intentionally boring.

Which is to say, I am not at all surprised about reactions like this, where I can absolutely see both sides of the story and in fact agree with both. But the tie-breaker is this: the steady-as-she-goes leadership of what should be the leading edge of innovation has led to the US getting further and further behind China all while its taxpayers are bankrolling said innovation. This state of affairs is untenable and all the policy memos in the world won’t help unless this root mismatch is resolved.

If you figure out a way to do it — and do it with urgency — that does not involve breaking up the FDA into at least two pieces, do let me know.

• Nassim Taleb breaks with Russ Roberts. I learned about EconTalk from Taleb, after he wrote it was the only podcast worth participating in as a guest. The two haven’t had any public exchanges in two years so this was not much of a surprise. I continued listening to EconTalk, though with mixed feelings.
• A podcast on AI and medical progress. It is four hours long and I have no time to listen but I may run the transcript through an LLM to get a summary and a false sense of knowledge and understanding.
• Where are the Mozarts of our time? On one hand I agree that too much of the “top talent” is “wasted on writing algorithms to move trades a quarter of a thousandth of a millisecond faster.” On the other hand, isn’t Lin Manuel Miranda the Mozart of our time?
• Why are doctors less respected? Because “optimizing performance” and “curing disease” are two different things entirely, and you can’t do both while also acting as the nanny nagging about car seats, guns in the household and other matters which have much to do with well-being but nothing with disease.
• What happened to Harvard? This is so confirmatory of everyone’s worst fears about the Ivy League schools that I remain skeptical.

• Adam Cifu: Goodharts Law and Medical School Admissions. A significant contributor to scientific slop is “research output” as requirement for fellowship, residency, and even medical school admissions. And yes, I am also a fan of the law.
• Paul Teirstein for WSJ: The Gatekeeper Driving Doctors From Medicine. On board certification, which now seems to have some powerful enemies so consider me conflicted.
• Jonathan D. Cohen and Isaac Rose-Berman for NYT: Gambling. Investing. Gaming. There’s No Difference Anymore. “There should be a line of separation,” Alexander Hamilton [wrote] in 1792, “between respectable stockholders … and mere unprincipled Gamblers.” As a side note, it is incredible how much sports betting has exploded in the 15 years I’ve been in the US. One of many ways America is looking more and more like Serbia, where seedy gambling outposts are now more common than grocery stores.
• Brian Potter: More on US Pedestrian Deaths. An update of a previously linked-to post, which raises more questions than answers. Allow me to be somewhat conspiratorial: could worse hospital care combined with increasing organ donation contribute to this increase? There have been 3,200 more pedestrian deaths in 2023 compared to 2009 and 8,393 more deceased donor donations according to OPTN. And then there is this.