For reasons that will soon become apparent, I would like to share with you a joke I heard back at medical school. I will remind you that this was in Belgrade, Serbia in the early 2000s, but the joke would apply to any Serbian institution of higher education, or indeed any place anywhere in the world that uses oral exams [Note: I have heard these called viva voce in the US, which is a bafflingly cheerful-sounding name for a rather traumatic ordeal. ] to determine the final grade. Please also bear in mind that I am not the best at telling jokes.

Anyway, here it is. A not very well prepared student comes in for his Anatomy 1 exam with a rather erratic professor (the joke had the actual name, which I am sure changed from time to time and from school to school). While sitting in front of the office waiting for his turn, a teaching assistant (again, named) approaches him. “Look”, the TA says, “I know he can be tough but for 100 euros things would go a lot easier for both of you. I’m going into his office now so if you have enough with you I can pass it on.” It so happened that the student did have a fresh 100 euro bill with him, which he gave to the TA, who then knocked on the door, spent a few minutes in the office, then came out with a smile and a nod. With newly boosted confidence, the student did better than he could have hoped for and got a 7 (on a 5 to 10 scale). Beaming with pride for his academic savvy and mental fortitude, he winks at the TA hanging around in the hallway. The TA winks back.

So when the time came for Anatomy 2 ⊕ [Note: Technically, there was no “Amatomy 1” and “Anatomy 2” but rather a mid-oral exam you had to do after the first two semesters where you got drilled about everything but the central nervous system, followed by the final oral exam in which everything was in play. Fun times. ] , our student was even more confident and less prepared, and by now you should know where this is going. Same professor, same hallway, same TA coming in with an offer for the privilege to pay a 100 euro lubrication fee. Alas, the professor was in a foul mood that day and flunks the student within 10 minutes. Crestfallen, the student slouches out of the office and sees the TA. “So sorry about that”, says the TA while handing him back the 100 euros, “but you were so bad that there was no chance he could let you pass.”

The joke, if you can call it that, is that the professor was psychotic but not corrupt, and that the TA was playing a game of chance. If it works it works, if not, well, there is always the money-back guarantee. It is as close as you can get to a victimless scam.

A phone call my wife received this morning reminded me of the scheme. It was from someone presenting as staff from the Johns Hopkins billing department. Apparently, there was a balance past due, back from November of last year. This was only a courtesy call, you see, but would you like to pay now or set up a payment plan, to avoid it being sent for collection?

Between the six of us we get about two dozen Explanations of Benefit each quarter. I may not be diligent about looking at every line item, but if there is one thing our insurance company helpfully provides even without logging in to the portal and opening the PDF it is the amount owed. Now, if my wife and I were inundated with work the way we usually were something could have slipped through the cracks, but I was on paternity leave with more time than usual to deal with the overhead of living in the United States so I was pretty sure there was nothing we could have received from insurance that we would have missed.

Except for a pile of snail mail on our dining room table, which I collect about once per week. And there, in an envelope addressed to my wife, was an account statement from Hopkins dated last week — due early next month — that said that we did indeed owe just shy over half a grand for hospital services rendered last November.

This was the first we had ever heard about owing for these particular services, rendered in an in-network facility, performed by in-network physicians. And was that not a curious sequence of events, an early morning phone call urgently asking you for money you didn’t even know you owed until, at best, just the week before? I didn’t want that particular loose thread hanging over me on Tax Day of all days so there I was, HRA card in hand, ready to settle the balance online, until my wife who is as wise in the ways of health insurance and billing as she is in the ways of shopping asked me to cross-check the Hopkins statement with the insurance EOB before I did anything rash.

What a good thing I did, as they did not match. If you are lucky enough not to have to deal with American health care, this is how billing works: hospitals have a list price for their services which they pull out of thin air. Insurance companies have their own opinion about what those services are worth, and a hospital being “in-network” means that they have agreed on the insurance company’s price while “forgiving” the rest. On the hospital bill this will be the “insurance adjustment”. Well, the adjustment our insurance said they negotiated and what was shown in the Hopkins statement differed by exactly the amount Hopkins was now asking from us, which as an in-network hospital they were not allowed to do.

So now it was me on the phone calling the Hopkins billing department, asking about the charge, the person on the other end of the line checking — on a 15-minute muzak hold — what was going on, not finding out, promising a call back in 5 to 7 business days and not to worry about the collection because we will get to the bottom of this mysterious error (if it is an error at all, let’s wait and see) that the hospital made, happens very rarely, practically never, always in the hospital’s favor. I look forward to receiving a voicemail, 5 to 7 business days from today, telling me that the magnanimous Hopkins billing department staff has forgiven all our transgressions and that our balance was zero.

Back when there was such a thing as guidance on conflicts of interest for federal employees, it was drilled into and onto us that even semblance of impropriety, what social network warriors would tag as not a good look, was to be avoided at all costs. It does not matter if you did or did not mean to pick this contractor because your spouse works there — they may be the best company in the world for the job for all we care — you should not be involved in the decision. I agree with this now-antiquated viewpoint and propose extending it to scammy behavior or large corporations. It doesn’t matter whether you used a fake charge on a late bill to threaten collection while offering a quick solution with the express intent to defraud or if an unfortunate series of events led to only the appearance of a scam: it is not a good look. One that, unlike our fictional teaching assistant’s, can and does have real victims.

Per Tanner Greer, China is all-in on leading the new industrial revolution, which will of course first be a revolution in science and technology. My only insight into the tech part is that Chinese companies now make the most innovative earphones and the most electric cars, and from reading Apple in China I have a vague sense that they were contract manufacturers in those fields first, then perfected the craft and outdid their former employers.

Most relevant to the world is what they [Note: But who are “they”? CCP leadership which sets the tone, startups and conglomerates which do the actual legwork, or the provincial bosses who act as intermediaries? I won’t even pretend to know. ] have done and will do with renewable energy, batteries, quantum computing and the like. The most relevant to me is what they are doing with biomedical research, particularly in cell & gene therapy. And as the field progresses from discovery to manufacturing — both research-grade and commercial — to clinical trials and actual practice so does the extent of their involvement.

On the discovery side, Chinese authors have already overtaken their American counterparts in the number of papers in top scientific journals. A crude metric for sure — and let’s not get into the whole peer review debate — but it is a measure of general lab activity. Determining whether China overtaking the US is a direct or indirect result of American sinophobia or evidence that the sinophobia was justified I will leave as an exercise for the reader.

In manufacturing, China is in the “let us do your work for you” stage. Not a week goes by that I don’t get an email from a China-based CDMO [Note: Contract Development and Manufacturing Organization, which just to make things confusing is often shortened even further to Contract Manufacturing Organization, or CMO, which means so many different things within the same field (Chief Medical/Manufacturing/Marketing Officer, anyone?) that it has become ridiculous. ] and WuXi Biologics — headquarters in Shanghai — is among the top 5 companies of that type in the world. These companies specialize in being taught how to do things and then doing them at scale, picking up a few things about process development and optimization on the way. Why the US would not want CDMOs from China was so obvious that the bill forbidding federally funded entities from contracting with them sped through Congress, though not after being revised to not explicitly mention WuXi by name.

“They” are not taking the same approach with clinical trials: a wise decision on their part, since the only thing they could have possibly learned from American trialists was inefficiency and bloat. No, the big push is for investigator-initiated trials which can speed up approvals — they only require local oversight, not a national FDA-equivalent to give their blessing — and get cell & gene treatments to patients within weeks, provided of course that they are manufactured in China.

An eternity ago I wrote about two different types of trials, ones meant to introduce new treatments and others meant to establish guidelines and prune less effective therapies. I argued that the regulatory burden for the two should be different, since the latter — Set 2 as I called them — are clearly less risky and carry less uncertainty. We have of course already experienced the world of unregulated trials of new therapies, and it was not pretty. With its IIT push, China is speeding them up further. The risks are clear, but who benefits?

Top of mind are the patients who will get effective treatments sooner. The invisible graveyard will shrink! But of course most treatments won’t work and most patients who take part in IITs and their family members will have spent much time, some even money, to get false hope. A much larger proportion of the beneficiaries will be companies that hit a false positive, and in single-center IITs of small sample size there will be many of those. They will of course be willfully ignorant of the fact that their high response rate in a 10-patient single-arm open-label trial was spurious, but will instead get just enough conviction to pass on the asset to the greater fool. And so will the roulette wheel keep spinning, fueled by financialization that somehow ends up being the root cause of most of the world’s current ills.

I fully expect the American biotech establishment to learn the wrong lesson from Chinese IITs and instead of feeling relief that someone else is taking on the foolish risk be pressured into copying them. Here is to the steadfast box-checkers and blank faces whom I trust to put on the brakes.

A lovely early afternoon tea and French pastries spoiled because of chatter from a nearby table — in Serbian! — about “quantum medicine”. I don’t care if University of Chicago conned someone into funding research on it, the whole field is Scientology-level bullshit.

• Raghuveer Parthasarathy: Space mirrors, solar panels, fools, and their money.

A few months ago I noted that the one of the main reasons biotech was not like tech was its almost unlimited freedom do bullshit. Well, people are able to raise money by BS in other areas as well, as this article shows, but an order of magnitude less because most investors are able to do back of the envelope calculations.

• Bryan Vartabedian: The Measure of Everything.

A take on Goodhart’s Law as applied to medicine, this time through the lens of instrumentalisation. If any of these articles tickle you and you haven’t yet read Zen and the Art of Motorcyle Maintenance, please do so now. Ted Gioia recently wrote about the book and its legacy. As an occasional note-taker I am in the minority club of Lila fans as well, though both of Pirsig’s books are due for a re-read.

• James Olds: The Chronology Problem.

The point is in the subtitle: “how our bias towards recency in scientific discovery hurts our understanding”. It rings true, and even reminded me of the 26 years it took for CRISPR/Cas systems to travel the path from an oddity to a gene editing platform, until I realized that those 26 years were not spent idling as this review in Cell describes in detail. So, the (lack of) developments in theoretical biology would be a much better example.

• Phil Price: Ted Williams and Me.

Ted Williams was, apparently, a base-ball player about whom John Updike had this to say: “For me, Williams is the classic ballplayer of the game on a hot August weekday, before a small crowd, when the only thing at stake is the tissue-thin difference between a thing done well and a thing done ill.” This applies to any profession you can imagine, and indeed things outside of one’s professional life. People who have the inner drive to do things well even in the absence of stakes could unkindly be called “perfectionists”, but let’s remember that they are the ones who keep the wheels of civilization in motion, in opposition to the hordes of blankfaces, lazy asses and morons.

Proactive vs Reactive DDAVP: The Clamp Finally Faces an RCT from Joel Topf is a perfectly good hyponatremia article if you are into that sort of thing, but what got me interested was the preamble:

Note: This was one of my first posts on Roon.com If you are an American physician who likes to chat about medicine, you should sing up.

Roon.com is “a community for physicians to connect, share knowledge, and shape the future of medicine.” A walled garden for physicians? Made and funded mostly by ex-Pinterest people? Sign me up!

The titular “it” is enshitification, particularly of the “let’s digitize everything” type.

Next year will be a full decade since my initial board certification in oncology, and with that comes another set of multiple choice questions for quarterly completion. We can debate whether ABIM’s MOC scheme is fair — I think not — but still being the law of the land, it led me to think about board prep for the first time since 2018, when I completed my hematology boards.

Being an over-preparer (as people who finish medical school tend to be), I started looking into the size and cost of ASCO-SEP [Note: “ASCO” is the American Society of Clinical Oncology. “SEP” stands for “Self-Evaluation Program”. “ASCO-SEP” was something oncology fellowship programs gave to their trainees free of charge some time during their second or third year of fellowship to get them ready for the board exam. This was less from the goodness of their hearts and more because fellowships were graded — and to the best of my knowledge still are — on the percent of their graduates who pass the boards on the first attempt. A rate lower than around 80% would raise all sorts of flags and could lead to audits, suspensions and even closures. So, mid and low-tier programs would overselect on good test takers during fellowship match season, with interesting consequences (the discussion of which is better left for some other time). ] and was dismayed to learn that it is no longer a physicial book published every 3 or so years which one could use as a reference, doorstop or paper weight long after passing the boards, but rather a 12-month digital subscription with no option for a print copy. You would think that ditching print would lead to all sorts of dematerialization efficiencies — no typesetting, no printing, storage, etc — that could potentially lower the price and make it more affordable for everyone. Alas, if there were any efficiencies to begin with, they didn’t trickle down to the end-user: the cost of subscription for members if $550. And did I mention it was only for a year? Enshittification in action.

ASCO’s quirky sibling is ASH, the American Society of Hematology, which publishes ASH-SAP. [Note: “SAP” is for “Self-Assessment Program”, and the fact that they chose different acronyms for the same thing tells you much about the world of medicine. ] It is a smaller organization with fewer members yet it managed to put out a print copy for $60 over the digital-only offering — a more than fair price for a textbook. This is not the first time ASH has been on the right side of history.

So if anyone knows anyone in the ASCO leadership, please nudge them over to the ASH approach. Maybe you can mention ASH-SAP explicitly and let mimetic forces do their magic. And if you can influence decisions at ASH, whatever you do don’t highlight that ASCO-SEP is digital-only and please don’t talk about efficiencies, lockup and similar matters lest hematologists get any wrong ideas.

• Aaron Cheng: On the emotional weight of a life in medicine. Thoughts of a newly-mintend hematologist which act as a good counterbalance to the popular fictional accounts. Feel free to peruse the few pre-2017 posts from the Infinite Regress archive for my own thoughts from that period.
• Fred Vogelstein: Enveda’s drugs from plants will turn pharma upside down. This is what Ruxandra Teslo warned us about a few months back.
• Joseph Howlett for Quanta Magazine: The Man Who Stole Infinity. On Georg Cantor, plagiarist. It does cause one to become more cynical, as we keep discovering that high-profile scientists built their reputiations on the backs of people with more scrupules and less need for attention. Taleb’s minority rule applied to sociopaths.
• Adam Mastroianni: The one science reform we can all agree on, but we’re too cowardly to do. It is to abolish for-profit scientific publishers, and I am all for it. But, people being people, I do not have high hopes that this prisoners’ dilemma will have a positive outcome.

• Derek Lowe: The Best Ideas Are Not Always Enough.

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.

• Adam Kroetsch: Why clinical trials are inefficient. And why it matters.

An overly long article ⊕ [Note: ᔥNintil ] with which I don’t completely agree ⊕ [Note: 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.

• Ruxandra Teslo: A response to Dario Amodei on AI & clinical trials.

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.

• Alex Tabarrok: If you have the right to die, you should have the right to try!

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.

• Rebecca Robbins and Gina Kolata for the NYT: Grail’s Cancer Detection Test Fails in Major Study. Some of my earliest tweets — now protected, so apologies for linking if you haven’t already followed me — were about Grail and why their project to screen healthy people for early signs of cancer would likely fail. Nine years and billions of dollars later…
• Peter Bonate: Drugs Explained. A layperson’s primer on drug development from a pharmacologist, available on GitHub.
• Colin Gorrie: How far back in time can you understand English?. One thousand years of the English language in one blog post.
• Joel Hawksley: How I built Timeframe, our family e-paper dashboard. It was quite the journey, interrupted by the Boulder County Marshall Fire which burned down more than a thousand buildings in late 2021. “On the night of December 31–January 1, heavy snowfall put an end to the fire.”
• ConchCat: I accidentally ate lunch with a cult. The cult in question is Twelve Tribes, accused of exploiting its followers as free labor, along with assorted abuses of women and children. But the sandwiches were good!

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" [Note: 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. ⊕ [Note: 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.