Frequent Infinite Regress linkee Ruxandra Tesslo wrote an op-ed for The New York Times about why we can’t get new cancer cures. Unsurprising for those who have read her past work, she places the bulk of the blame on the glacial speed by which clinical trials are designed, set up and run, at least in the US. Biotechs are looking at other countries — yes, including China — for their next first-in-human trial. All the cures we need are right there in the lab, you see, it is these darn trials that are too slow, keeping patients away from life-saving medicines. There is a nice n-of-one story about a patient with KRAS-mutated lung cancer who received a RAS inhibitor in a phase 1 trial to set the tone.

Vinay Prasad calls out a few big omissions in Tesslo’s article, and the number one point he brings out is the number one point I have issue with as well: the science is, in fact, lacking. There are no miracle cures locked in a drawer somewhere, not reaching patients because of government bureaucracy or a big pharma conspiracy.

But how can that be, with all the money thrown into cancer research ever since Dick Nixon’s War on Cancer? Well. Though I don’t know this for a fact, I have a strong suspicion that the answer to the curious lack of cancer cures is the same as the answer to that other question no one dares ask: if trials being so slow and expensive is a huge bottleneck, why are they so slow and expensive in the first place? It’s also the reason why a discerning reader of this blog may have noticed that my writing has taken a slight but unexpected anti-market turn.

Financialization, once the great enabler of garage-based startups, has turned every field of American endeavor into a casino and given one too many a bullshitter enough money to choke the competition. Biomedicine is particularly susceptible to bullshit large and small. Even if decently financed, the honest players — of which there are quite a few — have to fight for other limited resources in the ecosystem, from PhDs to do the actual research and clinical trial sites to attention. The result is hyperinflation of trial costs and a veritable bullshit bonanza in the biomedical literature, and this is not even taking into account the more personal motives of academics to fill the field with dreck.

My big fear is that no one is talking about the negative impact of financialization because it is water. Kudos to Tesslo for not talking about billion dollar drugs, but that seems to be the default, even among science journalists. Mr. Market will give you cheaper 4K TVs — surveillance comes for free — what it won’t give you is cancer cures.

A note on the title: I have come to detest The NYT’s two-sentence titles that go out of their way to dumb down the subject matter while piquing people’s interest, but thought it would be fun to write one for a quick post that’s a comment on a NYT article. Promise it won’t happen again.

• Dan Luu: Ed Zitron’s AI prediction track record. Not great. I have linked to Zitron a few times, to articles that were short enough for me to actually read and understand. Most of them were just too long and/or too angry. Fitting that a critique of Zitron’s writing is just as long, though much more even-keel.
• Lilly Lynch: Sympathy for the Devil? Lindsay Clancy, Mercy and Maternal Filicide in History. The less I know about this case the better, but this was some good context.
• Ernie Smith: Wanted: Some Cheap Computing. Issue No. 1 of Smith’s mini-PC newsletter. I am in the market for both a heavy-duty primary machine and some satellite servers, and thanks to the ramapocalypse the latter — and therefore this newsletter — is much more appealing.
• Derek Sivers: Bangalore India hospital flow. Today I learned Sivers was a fan of “executive health checks”. Yikes! As I wrote in a comment to the article:

The human body is not a car. We don’t know how most of it works. There are a handful of labs you should start getting once you hit 40 (or earlier depending on family history), and a few cancer screenings we know work. Anything else is a needless waste of money at best, and a recipe for an iatrogenic disaster if an incidental finding from a whole-body MRI leads to a wild goose chase, biopsies, surgeries, etc. Not to mention the false sense of security these things can give.

• Saloni Dattani: Every disease is a policy failure. A good overview of how far we’ve come in treating many diseases, but also a thoroughly depressing perspective and one that I can’t endorse. It’s like saying “poverty is a policy failure.” No. Poverty and disease are the default state of the human condition. We should celebrate and cherish each step away from them; beating ourselves up over our imperfections in eliminating them is the road to madness.
• Hugh Rienhoff for the FT: Biotech VCs have become like bankers and we might all pay the price. With the above in mind, I think we can agree that financialization of drug development has brought asymmetric returns to the parties involved, and the closer you are to the actual science the further you are from the rewards. The bankers always win.
• Rahul Parikh and Jonathan Mates for Nautilus: The Trouble with Cancer Screening. There is a school of thought which views information as the ultimate good: the more you have the better. Here is a nice example of when that may not be the case. A pox on every doctor who sends out a screening PSA without first discussing it with their patient.

• Gillian Tett for the FT: Welcome to the era of financial candyfloss. ⊕ [Note: Gift link, if you click on time. ] It is the perfect metaphor for American finance: spinning thin and devalued real properties into mounds of tooth-decaying fluff. You know things are bad when it comes not from the Guardian but from a seasoned Financial Times columnist.
• Brett Murphy for USA Today: Rigged. ⊕ [Note: ᔥCorey Doctorow ] An exhaustively sourced, dramatically illustrated, harrowing story about truck drivers working as slave labor, from 2017. If only there were a mechanism by which the richest, most prosperous country in the world could control this and similar excesses of a greedy minority.
• Alice Fleerackers for Nautilus: When Stupid Was a Diagnosis. On the plight of people with intellectual disabilities. In some ways, the 1700s were better to most of them than even now, or rather, they were equally cruel and bad to everyone regardless of their mental prowess. Then came the oh so ironically named Enlightenment.
• David Tuller: Trial By Error: No Benefits for Multidisciplinary Rehabilitation in New ME/CFS Study. “ME/CFS” stands for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and it seems to be the consequence of viruses playing havoc with people’s immune systems, which leads to their autonomous nervous systems being out of whack. Many of you may not remember, but there was a big viral infection going around 5-6 years ago that left everyone exposed all at once, which led to an explosion of these cases in absolute terms, though in terms of percentages it is thankfully still a vanishingly small fraction. Sadly, you can’t rehabilitate your way out of this particular organic problem, and it puts many young and otherwise healthy people out of commission. If only there was a mechanism to fund more basic research.
• Davide Gioia: Wildlife on the Planet Furaha by Gert van Dijk. A book review. The book in question is an alternative evolutionary history, richly illustrated, from a professor of neurology at Leiden University. An instant pre-order for me, and it is coming out next week in the US!

Now that I am back in clinic full-time I have tried and failed to pick up on the more clinical podcasts. Both ASCO and ASH have their podcast series, but they are all so formal and scripted you can see the teleprompter scrolling in front of the speakers’ eyes.

One potentially bright note could have been Cancer Stories, which are spoken versions of Journal of Clinical Oncology’s Art of Oncology article series. Note the past tense; I have a longstanding antipathy towards “narrative medicine”, a mode of fiction in which doctors combine patient stories, or present a single patient’s story anonymously, to make a point. The fallen king of narrative medicine was the neurologist Oliver Sacks, and look at how that turned out. Social media are of course an even more fertile ground for this kind of fakery; I won’t go into the X, Bluesky, Mastodon, TikTok and YouTube accounts that are completely full of it, but there is a lot of content out there and all of it — all of it — is bullshit.

So I was hoping that these stories being published in a peer-reviewed journal would at least be closer to the truth. And I’m not saying they are not, an inch or two closer, with cases not being invented out of whole cloth. What I am saying is that JCO editors are incapable of recognizing AI slop and the very first story I listened to was full of it.

It was disconcerting to hear a professional voice narrate The Liver We Share in the April edition of the podcast. In the story, BU medical student Ryan Wexler writes about his experience as a living donor to his then-fiance now-wife who needed a new liver. Quoth Wexler: “When I learned I was a match, relief arrived not as joy, but as quiet permission to hope.” The hope was justified, for everything went well: “Her recovery, and our journey as a whole, bears little resemblance to the decisive triumph I once imagined. It is quieter, ongoing, and more powerful for it.” Yes, yes, so much quiet. Other empty metaphors and nonsensical turns of phrase abound.

Did Wexler feel bad, I wondered, when the completely credulous host and a great hematologist Mikkael Sekeres — a pre-AI book author I should add — asked him probing questions about his mental state and the specific words he used in the essay? Couldn’t you see through the AI bullshit, Mikkael, I wanted to scream out. He is a bit older than me so maybe there is an age cutoff at which people can no longer detect the slop? At least one of my parents and one in-law don’t have a clue, as they keep forwarding sloppy Instagram links despite my not having an account for more than a decade.

In any case, no, peer review is no protection against bullshit and I will not be exposing myself to any more of it. End of rant.

Derek Lowe is scandalized by the fact that 9 out of 10 drugs that get to a first-in-human trial don’t get approval or, to use some jargon, a clinical failure rate (CFR) of 91% per year. He quotes a recent paper which followed CFR over the last six decades ⊕ [Note: Just to make things confusing, the paper itself calls this percentage “clinical attrition” but Lowe rebrands it to a CFR. Let’s for the sake of consistency stick with the latter, although a pedant may question whether that statistic truly is a rate. ] and noted that it was improved somewhat in the 1970s and 1980s — down to about 80% — but was consistently at or above 88% in every other decade analyzed.

Both the paper and Lowe present this as a Bad Thing. Here is a direct quote from Lowe:

But let’s think about that 91% failure rate for a moment. When I bring this up in presentations, I invite the audience to consider what the auto industry would look like if 91% of new car designs proved unable to roll out of the factory, or if 91% of new airliner models were unable to leave the ground - and if you only found that out after spending all the R&D money to build them at full size and trying to fly them. No cutting-edge restaurant could survive if 91% of its innovative dishes proved inedible or outright poisonous. What other industries operate under these bizarre conditions?

Sounds scary! The paper has a different and a somewhat less alarming spin: see how bad our preclinical testing is if so many of the drug candidates don’t make it to approval for reasons of biology. If there are bad side effects, or the drug doesn’t make it to the targeted tissue, or the liver destroys it too quickly, should we not have picked that up in cell culture or animal testing? Should we not focus our resources on developing more human-relevant preclinical tools, and maybe call them New Approach Methodologies (NAMs)?

At this point in the story I should mention that the paper in question, titled “Need for NAMs: A systematic evidence synthesis revealing over half a century of drug development failure”, was published in NAM Journal. Holy motivated reasoning, Batman.

So now let’s look at the counterfactual: what if the increased CFRs from 1980s to today came by design, from the realization by drug developers that preclinical testing isn’t the greatest at predicting toxicity and is completely useless when it comes to efficacy, so why not just get drugs to clinical as quickly as possible and be as quick in cutting them? My go-to paper outlining this philosophy is one from 2010 which a team from Eli Lilly — as successful at developing drugs as they come — published in Nature Reviews Drug Discovery. To pick out two key points from their above-the-paywall outline:

Reducing late-stage (Phase II and III) attrition rates and cycle times during drug development are among the key requirements for improving R&D productivity.

To achieve the necessary increase in R&D productivity, R&D investments, both financial and intellectual, must be focused on the ‘sweet spot’ of drug discovery and early clinical development, from target selection to clinical proof-of-concept.

Which is to say: since Phase II and especially Phase III trials are an order of magnitude more expensive than Phase Is, let’s quickly do what we must to get drugs into clinic, gather early human data, then make an informed decision. If that makes an arbitrary number go up, so be it.

You can see why the de-emphasis of preclinical efficacy data could have made some lab people unhappy, which I guess is why we now have a journal called NAM. Or was it ‘Nam?

Of course, there are tradeoffs everywhere, and the big tradeoff in the “fail fast” school of drug development is that you are tying your faith, financial and otherwise, to the health care system and contributing to the health care ouroboros. The one where Americans pay so much for health care because drugs are so expensive to develop, and drugs are so expensive to develop because health care in America is generally so expensive. But of course, no one is obligated to run their early-stage trials in the US.

Vinay Prasad asks whether health care is a human right and, using some convoluted mental gymnastics, answers no with a disturbingly LLM-like turn of phrase:

Health care, as it is practiced in 2026 America, is not a human right. It’s a tax penalty on our ignorance and wishful thinking.

This is bullshit, in the classical sense. Not to psychoanalyze Vinay ⊕ [Note: The house style over here at Infinite Regress is to default to last names for any and all persons mentioned. I will on occasion make an exception for friends, which is indeed the case here. ] but this is what years of pandering to your ticket-paying audience will do to you: lose common sense.

To be pedantic, the Universal Declaration of Human Rights specifically mentions the right to health, i.e., a minimum standard of health to which everyone is entitled. The minimum standard in America is prescribed by a single law, EMTALA, which guarantees the right to emergency treatment for those who seek it. It is a floor low enough to qualify as a basement — pathetic for one of the richest nations in the world — but it is nevertheless a floor. Should the minimal standard also involve immunization and the few disease screening programs that are known to be beneficial? Yes! But they are not yet a right in the US. As I’ve noted before, I don’t think it should include the largely superfluous annual “wellness visits”. But if that’s what it takes for immunizations and screening to happen, fine.

But that’s not the bee in Vinay’s bonnet. Rather, he takes issue with the totality of American health care — who doesn’t? — and makes the case for that particular Lovecraftian horror not being a human right. Well, duh.

Cthulhuian or not, there is one good thing about the system: its extraordinarily high ceiling. This is still the place to be for getting the latest and greatest medical treatment, whether in a large academic medical center or a small community hospital, contingent on the doctors in either place knowing what they’re doing. Most stories Americans tell of their exposure to European health care are about how quickly and cheaply minor procedures are performed. Not told are stories of patients with metastatic cancer or autoimmune disease who are waitlisted for getting immunotherapy or other biologics. Or those with debilitating arthritis waiting months for a hip replacement.

With the high ceiling comes some extra girth in the middle, where there are many unnecessary treatments given and diagnostic procedures performed that Vinay rallies against. For good reason! But how you come from Ending Medical Reversal to proclaiming that health care is not a human right is beyond my comprehension.

• Vinay Prasad: The Future of Medicine. Extrapolating the modern tendencies of removing humans from the equation, Prasad (unintentionally?) presents a bleak scenario indeed. For a reality check, here is Cory Doctorow.
• The anonymous Slime Mold Time Mold author: You Can Discover the Drives. An interesting analogy between human drives — from the basics like thirst and hunger to the more complex ones like the need for recognition — and chemical elements.
• Chris Good: Not your keys, not your songs. Remember web3, which tried to be the asbestos we are putting into our technology until “AI” came along? Here is the aftermath of some well-meaning people trying to dabble in it. It did not end well.
• Brett & Kate McKay: How to Recognize and Deal With High-Conflict People. Recognition is important; dealing with them is usually straightforward: flee. And for the times that you can’t — these people need doctors too! — there is some good advice at the bottom.

After 16 years of successfully avoiding Epic*, tomorrow is the day: my provider** training begins. Let’s see how it compares to Cerner, Allscripts et al.

• Fairly certain text behind the link is partially AI-generated, but the illustrations are good!

** Hate hate hate that term.

• Tristan Manalac for Biospace: Amgen’s Tavneos troubles continue as NEJM retracts pivotal publication. First came FDA questions about data integrity. Now the academic authors are confirming the data tampering, though per the now retracted study they did “vouch for the completeness and accuracy of the data, the complete reporting of adverse events, and the adherence of the trial to the protocol. All the authors participated with the sponsor in the design of the trial, the analysis of the data, and the writing of the manuscript.” I wonder if people who sold this rotten pile of garbage to Amgen will offer a refund. So it goes…
• Carl Zimmer and Marco Hernandez for The NYT: This Cell Feeds, Grows and Reproduces. And It’s Manmade. “Dr. Adamala named her creation SpudCell, after its potato-like appearance. Rather than patent it, she and Dr. Endy are organizing a community of scientists to focus on making SpudCells more fully alive and adapting them to new kinds of experiments.” Bravo! Maybe science isn’t a complete lost cause.
• M Auerbach, MY Lim, GM Rodgers, and T DeLoughery for Sensible Medicine: When Normal Isn’t Normal: Non-anemic Iron Deficiency. A very academic group of authors makes a very good case for treating low iron levels in the absence of overt anemia. This is in response to an earlier text which poo-pooed the practice as “overmedicalizing normality”. Adam Cifu from Sensible Medicine proposes randomized controlled trials, though if symptoms of low iron are as diverse as restless leg syndrome, “brain fog” and craving for ice it would be a challenging endpoint to establish. Boy, isn’t medicine hard.
• Titotal (pseud): The best cause will disappoint you: An intro to the optimisers curse. ⊕ [Note: ᔥAndrew Gelman ] Mathematical demonstration of why effective altruists are, at the end of the day, a bunch of bozos. And not just them: America is the land of hyperoptimizers and if Taleb’s Incerto wasn’t a convincing enough case for why that doesn’t end up well in the long run, well, here is a much shorter Substack post that shows one facet of the problem.
• Ed Conway: The Apple-Banana Paradox. On the incredible flattening of banana prices in the last 25 years, and the incoming threat of another fungal infection that could wipe out the current Cavendish banana monoculture. On the other, could this be an opening for a Honeycrisp of bananas? One can hope.