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.
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.
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.
As described here:
Looks exhausting, no? We have come to the Red Queen’s Race stage of the Internet. And as a reminder, this is a dickover.
On my first encounter with Wall Street analysts I also wondered what they were for. Here is Coben’s take:
It is possible some retail investors may follow the research ratings, but in my experience the audience that matters most is the company itself. Management teams appreciate reports seeing their narrative endorsed in a report carrying the logo of a major bank. Flattery takes you a long way in finance, as it does in life.
And in turn management teams may, if the analysis reflects what they believe is the true and right way to talk about the company, prioritize that particular bank to be on the left side, or the upper right corner, or the bottom third paragraph of the second-to-last-page, of the term sheet. And if you have no idea what that last part was supposed to mean, I envy you, truly.
One of my earliest memories of conspiratorial thinking was when I was in 7th grade and flunked a state-wide English language competition. [Note: Worry not, I returned the following year and won 1st place, which was ultimately worth diddly squat except for bragging rights. Oh, and some family lore, for my now-wife’s best friend placed second and apparently told her stories about me. ] Upon return to school, a certain teacher who was generally decent huddled with me and asked me for “the scoop”, meaning for the shenanigans that must have went on for me not to get an awarded. The scoop was that I spent the night before playing something — from the years when it went on the most likely culprit is Quest for Glory: Shadows of Darkness — though of course that’s not what I told him. Which is to say, when Alfie Haaland, the father of Norway’s star centre-forward, Erling, had sarcastically congratulated the referee on England’s victory, I knew exactly where he was coming from.
Good to see that Tyler Cowen’s verbal tick caught Doctorow’s attention:
Today, these Renfields clutch their pearls at the “demonization” of the ultra-rich, calling it “billionaire derangement syndrome.” But the only “billionaire derangement syndrome” that matters is the syndrome that affects billionaires and convinces them that they are above any discipline or rules.
Oh snap.
On how movie stakes have become too high. I agree! Where are this generation’s Harold & Kumar?
On the beginnings and endings of interstate highways. This has been on my mind recently, as I drive up I-25 past the exits to I-70, thinking that, hey, I know exactly where I-70 starts (or ends?): right on the I-695 Baltimore beltway. And to think it goes straight this far out west… Well, except for that little infamous break in Pennsylvania.
“If you literally educate children, care for patients, clean up the environment, or do something like that, you aren’t a looter — but your boss probably is, your boss’s boss definitely is, and you’re part of a dying breed.” No notes there.
Going straight to the quote:
In reality, any program to intentionally add nutrients to nutrient-deprived oceans would be considerably less dangerous than any of these natural analogs. Fires, volcanoes, icebergs and vents just dump crap into the ocean willy-nilly, with no plan, no environmental monitoring, no environmental impact assessment, nothing. Nature does this in precisely the kind of blind, reckless, unthinking way that skeptics fear in people, and even then there’s no evidence of harm.
Let spotting the cognitive error here be an exercise for the Reader.
Hey, I had that exact model back in 2008 and the little guy traveled the world with me back then, from Barcelona and Naples to Bangkok and Kho Samui. Not proud of the fact, but that 1024x600 pixel WSVGA screen is where I first saw Season 4 of The Wire. I even took it with me to the US, so it’s been on as many continents as I have. And wouldn’t you know it, I kept it through all these years, hoping for a good opportunity to resuscitate it. Which is to say: I know what I’m doing this weekend!
I thought my kettle was broken when it beeped at 95°C even though I had set it to boil but then I remembered that we are now mile-high and the water will boil at a lower temperature. I imagine this will cause even more headaches for our family’s baking recipes, but the most immediate concern is how this affects my preferred brewing method.
There is always tweaking to be done, but the gist is: get the water as hot as possible and compensate for lower temperatures by grinding slightly finer (one notch lower on my Baratza Virtuoso grinder) and steeping slightly longer (which is a natural extension of a finer grind but is important for those using an Aeropress or — shudder — a French press). Be prepared for dry air to mess with the bean freshness. Try not to expect too much of light roasts.
This is also more or less what Kagi’s LLM response gave me, [Note: Kagi, unlike free search engines, doesn’t shove half-baked LLM responses down your throat at any opportunity. Rather, it only provides an “AI” response if you end your query with a question mark, which is both simple and delightful. ] the explanation of the physics and chemistry behind it taking three paragraphs instead of three sentences. Which was fine! What was not fine were the actual search results: a depressing line-up of sloppy websites to which I shall not link but which go like this:
Et cetera, et cetera.
Each article was a shockingly long (“Coffee Brewing At High Altitude Explained: What Matters, What Doesn’t”, Read time: 11 minutes) elaboration on the above three points broken up by AI-generated images of coffee setups precariously perched over various mountainous regions. Each homepage was a depressing array of overly glossy thumbnails atop headlines which promise a plethora of affiliate links: “Best Heat Guns for Perfect DIY Coffee Roasting at Home”, “Top Coffee Makers That Keep Every Office Buzzing”, “Master the Basics of Home Roasting: Equipment and Techniques Unveiled”, and so on and so forth for 166 pages, 10 articles on each page, none of them with a publication date because you and I both know they were made in one day, nay, one caffeinated, agentic late-night session.
Would it not be nice if there was an actual indie blog written by a hyper-obsessed coffee aficionado, a fellow high-altitude brewer, or a person really into something? You know, like the old days? If there still are, they are being crowded out by one-man shows who are really good at faking it, at least until you read the first few sentences and, if they’re lucky, click the first link.
Not to poo-pooh on the indie web! I am absolutely certain there are many a cracking post on it about coffee, maybe even some about brewing it at high altitudes. It is just so gosh darn difficult to find. For example, Kagi’s Small Web project — excellent at showing random posts from the indie web — cycled through the same five posts in its “Food” section, only one of which was about coffee (and quite good at that — I am now a subscriber). I would also assume that Kagi’s algorithm would prioritize it over the AI slop if there was indeed information that I needed there but no, link after link it was one sloppy website after another, with a few unanswered forum posts in between.
So maybe this post is now it?
Baby carrots: the Keto Cheetos.
How can an article about actors playing made-up versions of themselves not mention Being John Malkovich? The omission is almost as egregious as the one FT video game writer did to Planescape: Torment. Both of the snubbed works of art came out in 1999, which I can only assume was too far behind the authors’ time horizon, but then if you write about a field for a living shouldn’t you know about its (fairly recent) history?
I am of firm believe that to know a thing is to know its roots. Yes, this can go too far — see the name of this very blog — but most people most of the time don’t go far enough back, the most common knowledge border being their birth year. Which is fine for a blogger, not so great for professional journalists.
Remember when I mentioned paying movers was some of the smartest money you could spend. Well, I should have added paying someone to assemble large IKEA furniture, and then I should have followed that advice. Good lord…