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Tuesday links, science and medicine

Sunday links, clinical trials edition

Drugs which look great in those cellular machinery flow charts with boxes and arrows pointing every which way, and which may even cure a few genetically monstrous and wholly artificial lab mice, tend to flop where it matters. Lowe links to 11 such examples and writes in more detail about the twelfth.

An overly long article ᔥNintil with which I don’t completely agree For example, Kroetsch describes the role of a site investigator as resembling “that of a glorified data entry clerk - the investigator’s primary responsibility is gathering the data that the drug company needs and sending it to them”. This is incorrect: site investigators usually have clinical research coordinators and data managers to do it for them. But this deserves a post of its own. but which nevertheless provides a good overview of the many things wrong with how clinical trials are being conducted in the US, the biggest one being that they are reinventing the wheel each and every time they are done. The “lean trial” proposal at the end matches my own thinking.

Teslo picks up on the tech bro magical thinking streak in which things you don’t sufficiently understand seem eminantly solveable using the most recent technological developments. Five years ago it was electronic medical records and blockchain, now it’s clinical trials and AI. The article gives the many reasons why things are not that simple. Now, if we all agreed on the set of LLM prompts that would provide an unbiased protocol and informed consent form review thus eliminating as many people from the loop as possible, well, then we may be on to something.

If someone qualifies for euthanasia, should they also not be eligible for every expanded acces, compassionate use, right-to-try scheme imaginable? Obviously: yes. Maybe not so obviously: there is a branch of my subspecialty aptly named desperation oncology which in the vast majority of cases leads to false hope, financial ruin and, worst of all, time misspent in doctors' offices and infusion clinics instead with your loved ones. As a doctor and a human being I am partial to life, so I see state-assisted dying programs like Canada’s MAID as monstrous, but “you’d rather be dead so here, take this drug” is only a half-step above that qualifier and leads to the bad reputation of experimental therapies.

Monday links, science, technology and cults

Where is the Delaware of clinical trials?

I admire the fight for clinical trial abundance, I truly do, but the longer I think about it the more convinced I am that making nips and tucks to federal law and FDA guidance is the wrong way to go about it.

I have been involved in clinical trials for more than a decade and have seen it through the eyes of an investigator, sponsor and IRB member directly, and owing to a few friendships with ex-FDA employees, from the eyes of regulators as well. The common thread between all cases of delay and all frustrated attempts to speed things up were not laws and regulations but humans. The blankfaces and boxcheckers. Those IRB members who prefer the list of possible toxicities in a consent form in table form as opposed to a list, or a list as opposed to a table, and with percentages of expected occurrences instead of qualitative statements of possibility, but can you please explain what does percentages mean in qualitative terms, and is it “toxicity” or “adverse event”, and you should list only true toxicities not hypotheticals, except when we require you to add each potential adverse event — sorry, toxicity — whether it happened in this or other trials or not, and for each round of these changes there is another 3-week turn of the IRB roulette during which a different person may view the edits and give their own two cents — leave their own fingerprint.

And that is only the IRB! Their are personal imprints to be made at every level of clinical trial desing and implementation, between different departments of the Sponsor, “key opinion leaders" Or “KOLs”. The whole KOL ecosystem is worth writing about at length, just not today. sitting on advisory boards, administrators and worriers-in-chief at clinical trial sites, and even, rarely, clinical trial investigators themselves although in the US at least they are the ones least involved in clinical trials. More often than note, the way to leave your fingerprint is by citing a rule or a law or precedent from the FDA or the IRB or some other state-level regulatory agency whether or not said rule, law and/or precendent apply.

To be clear: most people in the clinical trial ecosystem are not like this. But much like airport noise complaints, in which one household accounted for almost 80% of all complaints, it only takes a handful of people to gum up the works and make it appar like the whole system has conspired against smooth trial execution.

So ho do we achieve abundance? Cutting down on the laws that govern trials is an option, and would certainly reduce the degrees of freedom at which blankfaces and boxcheckers operate. But America is a country of min-maxers and I can easily see things going sour with drive-by trials and phase 1 clinics being run out of a storage unit in South Florida. Which operate even now, so just you wait for the walls to come down and the minmaxing trial beast to be unleashed. Chesterton’s fence and all that.

Could we not reduce the number of gummer-uppers in the chain instead? There are plenty of trials that are quick to start, quick to execute, and not even all that costly, largely due to people being reasonable. Can we inject more reasonable people into the ecosystem, if we can’t inject more reason into people who are already there?

This thought brought me to Delaware, the second smallest state of the USA that has 60% of Fortune 500 companies incorporated there owing to the convenience, flexibility and predictability of its corporate law system. To my layperson’s eyes it seems, from the example of Delaware, that its not the law itself that makes the difference but rather who implements it and how — which was on spectacular display earlier this week.

Convenience, flexibility, predictability.

Now clearly the Delaware of clinical trials can’t be Delaware — it is far too small and wouldn’t have enough trial candidates. But California, Texas, Florida and New York could all vie for the spot, each having a population similar to Australia, the phase 1/2 promised land. Texas was the first to make some waves, tiny and of an uncertain direction, but in the ballpark of what would be needed. The only changes that federal law needs are those that would allow the states to compete among themselves in being clinical trial champions.

If that last image made you think of China and its competing provinces, it is for a good reason: the Chinese have been eating everybody’s lunch for the past few years, in large part because of the vicious internal competition elaborated on elsewhere. There are other lessons there, for some other time.

Tuesday links, on science, medicine, technology and a bit of something extra

Why no scientist should hang their hat on a single pet theory, with real-world examples. The same problem haunts the world of biotech even as its denizens claim their superiority at drug development.

About a recent Nature Medicine article which found that LLMs were no better than Google at helping patients diagnose and manage their self-reported maladies. The reasons are those that I suggested two and a half years ago — ChatGPT can give you the correct answer from a properly structured clinical vignette, but the art and science of medicine are transferring the reality in front of you — the patient’s haphazard story, their hodge poge of medical records, the subtle physical exam findings — into something salient. Not saying AI won’t get there at some point, but it clearly still needs work.

Rao has collected 101 (!?) of his best Twitter threads and a few hundred single tweets into a book. A note on the title page says:

This book is LLM-friendly. Point your LLM to venkateshrao.com/twitter-book if you want it to explore it. A full interactive archive, explorable via an AI oracle, is under development.

Living up to his call to be (slightly) monstrous.

Yes, it is a person I hate making a good point, which is that the brutalist architecture of L’Enfant Plaza is out of place so close to the National Mall and should be kept where it belongs. I even prefer the proposed neoclassicist style to what Trump’s ego would want, which I imagine to be a Dubai And even Dubai would be better than what’s in the President’s id. on the Potomac.

Hacked to Pieces? The Effects of Ransomware Attacks on Hospitals and Patients

From American Economic Journal: Economic Policy about the effects of ransomware on patients: ↬Tyler Cowen

Ransomware attacks decrease hospital volume by 17–24 percent during the initial attack week, with recovery occurring within 3 weeks. Among patients already admitted to the hospital when a ransomware attack begins, in-hospital mortality increases by 34–38 percent.

The implication is that the computer systems being down has a huge detrimental effect on patient outcomes. What the abstract doesn’t get into — and I don’t have access to the full article — is how they calculated the in-hospital mortality among the already admitted patients. Many of them will have been discharged early or transferred to other hospitals if stable enough, decreasing the denominator and overestimating mortality. At least I hope that’s the case!

"In China, A.I. Is Finding Deadly Tumors That Doctors Might Miss"

So says this NYT headline (gift link). In reality, and in the article itself:

The tool might also be more useful for trainee doctors than for experienced specialists, said Dr. Diane Simeone, a pancreatic surgeon at the University of California San Diego. Some of the tumors that the tool caught in the Nature Medicine study should have been “super obvious” to well-trained radiologists even without A.I., she said.

But she acknowledged that it could be a valuable backstop for hospitals where specialists are in short supply.

This is based on the data So yes, A.I. is finding deadly tumors that an overworked and/or undertrained doctor might miss. Which is valuable, but a different message altogether from the one that the headline was trying to convey.

Separately, is “in China” becoming the new “in mice”? The link is to a PLOS One blog from 2021. The most recent post there as of the time of my writing this is a scathing and rather unfair review of the science of Pluribus. I refrained from adding it to my feed reader. What assumptions do writers have, and what emotions do they raise in readers, when they report about things happening “in China”? Was it the same with the Soviet Union? Whenever someone fans the flames of mimetic rivalry, I grab my wallet.

📺 The Pitt (2025)

First things first: The Pitt (2025) is miles better than two other era-defining medical shows, ER and House MD. The conceit — one hour per episode, one shift per season — makes for a more realistic pace. The case selection is good, if on the extreme end of any possible presentation. The medical staff personality types are spot on, They are all good, but I would like to highlight the charge nurse and the neuro-atypical first-year resident as commonly encountered phenotypes that TV shows never seem to get right.if not quite representative of the variety of English accents one would hear during rounds. And the battle between administrators and clinicians hit all the right notes, even if having the hospital’s Chief Medical Officer hover over ER staff at all hours of the day would be considered atypical for the role.

Kudos are also due for the use of prosthetics, sometimes quite grizzly, with an abundance of open wounds and mangled extremities. With so much exposed tissue I wondered why no one was wearing a mask during procedures even while, in a mid-season episode, admonishing an anti-mask patient about their beliefs. But that is, of course, another conceit, otherwise we would never be able to tell who was saying what. A more believable move was to have one of the medical students More kudos for making the two students smart, competent and lovable all at once.present for most of the cases, requiring everyone to explain what they were doing at an 8th grade level (our own 8th grader who was watching with us also appreciated this). Granted, the historical reminiscences and calling out different healthcare-related statistics were much less plausible: they reminded me of the most self-important parts of Studio 60 on the Sunset Strip that its then-arch rival 30 Rock so successfully parodied.

Admittedly, it is an unusual hospital. More than 20 ORs and so much house staff with only one attending physician during a day shift sounds… implausible. It does make for great tension-building, and it was no wonder that Noah Wiley’s character — spoiler alert — by the end of the season gets burnt out to a crisp. Another oddity is how competent and unflappable all of the staff were during — another spoiler — a major traumatic event that no one wanted to experience but everyone was prepared for. Color me skeptical that operations would have been that smooth.

Still. As fanciful as they were, ER and the less-remembered Chicago Hope were, to me at least and I suspect to many others of similar age, The less I say about House MD the better. a large part of the draw of medicine. It is good to know that there is a half-decent show out there that may keep the flame going.

A rare day-job update: we have not one but two papers out in the journal Nature Medicine this morning. The first is clinical and the other biomarker data from the same randomized trial, both open access. The last big paper was more than two years ago, and the post-publication feeling hasn’t changed.

Friday links, science and biotech edition, with extended commentary

The case for faster bench-to-bedside-and-back type of research, with which I agree. It is remarkable, however, how each generation interested in biomedical research reinvents the wheel without checking prior art. I would also argue strongly that the (correct) thesis of the essay is not a refutation of the biotech-as-casino hypothesis but rather its confirmation, unless you enlarge “biotech” to include academia and government research but then what are we even doing. Investors have no patience for nuance and view clinical trials as dichotomous regardless of how companies try to present them, and interpreting translational research results requires even more patience and tolerance of ambiguity.

Ginexi has been a program at the NIH for more than two decades, so caveat lector, but many POs are indeed mini-Moseses in their scientific domains. On one hand they perform important and valuable work, on the other the importance of a single human being to the careers of investigators young and old tend to favor those with soft skills of communication more than those of scientific and intellectual rigor. No judgements on my end because I genuinely can’t tell if the alternative would be any better.

Some genuinely good advice on how to write grants in a way to increase the odds of them being funded, with emphasis on accepting the reviewers' comments and suggestions and approaching the grant resubmission as one would an offer to revise and resubmit a scientific manuscript, with much thanking and back-bending. Do keep that in mind when you read the next item.

This is true for most, as there are far too many academic right now for all of them to have soul in the game. However, academia continues to ask for more than it gives back out of too many people, while at the same time putting a negative selection pressure against people who are stubborn, single-minded and thus predisposed to a soul-in-the-game phenotype (see above). The only reason why the system survives at all is that the churn has been too low to fully reveal the tension, but it continues to creep towards the breaking point providing yet another case study of things that happen gradually and then suddenly.