My boss at the NIH was in his late 80s when I started working there, early 90s when I left. There was an obvious physical decline into complete frailty during those four years, but he was as sharp, lucid and stubborn as ever. You don’t get to work into your 90s unless you have it your way, and “the way” became shorter hours in the office with prolonged nap time, sometimes during meetings, while maintaining the final word on anything that happens in the lab.

So, “the mind is willing but the flesh is weak” often came to mind, and until we develop a Futurama-style brain-in-a-box there are limits that biology imposes which can’t be overcome through force of will. You hate to see it, but we will be seeing it more and more often as the Baby Boom generation gets into its sunset years. Not because they’re any more selfish than other generations, mind you (my old boss was of the Silent generation), but rather because they are the most numerous and the biggest beneficiaries of death-delaying medical advancements.

It seems to me that the higher up the person is in the hierarchy and the longer they have worked in the field (my boss spent 60 years at the NIH), the harder it is to imagine anything other than staying on the job until an act of God intervenes. This is exactly what happened; I was gone before then, but there were many in the lab who were left scrambling for a new position, taken by complete surprise that their 90-plus-year-old chief was no longer with us.

So it goes…

Why haven’t biologists cured cancer? asks Ruxandra Teslo in my new-favorite Substack newsletter, and answers with a lengthy analysis of biology, medicine and mathematics. Clinical trial costs inevitably come up, and I know it is a minor point in an otherwise well-reasoned argument but this paragraph stood out as wrong:

Clinical trials, the main avenue through which we can get results on whether drugs work in humans, are getting more expensive. The culprits are so numerous and so scattered across the medical world, that it’s hard to nominate just one: everything from HIPAA rules to Institutional Review Boards (IRBs) contribute to making the clinical trial machine a long and arduous slog.

What happened here is the classical question substitution, switching out a hard question (Why are clinical trials getting more and more expensive?) with an easy one (What is the most annoying issue with clinical trials?). Yes, trials involve red tape, but IRB costs pale in comparison to other payments. Ditto for costs of privacy protection.

If we are picking out likely reasons, I would single out domain-specific inflation fueled by easy zero-interest money flowing from whichever financial direction into the biotech and pharmaceutical industries, leading to many well-coined sponsors competing for a limited — and shrinking! — pool of qualified sites and investigators. It is a pure supply-and-demand mechanic at heart which is, yes, made worse by a high regulatory burden, but that burden does not directly lead to more expensive trials.

There are some indirect effects of too much regulation, and at the very least it may have contributed to more investigators quitting their jobs and decreasing supply. They also contributed to regulatory capture: part of the reason why industry has been overtaking academia for the better part of this century is that it’s better at dealing with dealing with bureaucracy. But again, these costs pale in comparison to direct clinical trial costs.

Another nit I could pick is the author’s very limited view of epigenetics: if more people read C.H. Waddington maybe we could find a better mathematical model to interrogate gene regulatory networks, which are a much more important part of the epigenetic landscape than the reductionists' methylation and the like. But I’d better stop before I get too esoteric.

Here are a few facts we should all be able to agree on:

1. The US has the highest drug prices in the world
2. The US has the highest clinical trial costs in the world
3. American drug R&D is so developed that it subsidizes the rest of the world

The disagreement lies in how these three are connected. If I interpret the Marginal Revolution school of thought correctly, drug prices are high (1) because America subsidizes all R&D (3) while having the highest clinical trial costs (2). So, 3 + 2 → 1 and limiting 1 to make drugs more affordable will lead to a negative feedback loop which would limit 3. This is why people who want to regulate down drug prices are “Supervillains” ⊕ This implies that most drugs approved in the US are (1) life-saving and (2) have no other alternative. My gut reaction, backed by no direct research but some insight in cancer drug effects and mechanism of action, is that this is not the case and that if someone were to perform a rigorous review of approved drugs they would see that most are me-too drugs with marginal benefit. That is not, however, the argument I’m trying to make here which is why it is relegated to the margin. responsible for future deaths of millions of people who won’t be able to benefit from the never-developed drugs.

But of course, if 3 + 2 → 1 were true, there are two more ways to lower 1: limiting the scope of R&D (3) — which wouldn’t be the first time — or, preferably, lowering clinical trial costs (2), which have ballooned out of all proportion thanks to a potent mix of ⊕ To expand on this, on the margin for now and in a separate post later: pre-clinical and phase 1/2 startups get billion-dollar valuations based on but a dream of success, which gets them hundreds of millions of dollars in their accounts, which in turn gets them to spend like drunken sailors on what should be low-single-digit million-dollar trials, which gets you to $>10M phase 1 trial, which borders on clinical trial malpractice. regulatory burden and oodles of money floating around the pharmaceutical/biotech space. The reason for all that money flying around? The promise of high payout guaranteed by unregulated drug prices! So: 1 + 3 → 2.

And if both of those relationships are true, well then there is a positive feedback loop in play, also known as a vicious cycle, and if there is one word that encapsulates the American drug cost landscape “vicious” is better than most.

The problem with high clinical trial costs isn’t only that they serve as an excuse for/lead to high drug prices. They also pose an impossibly high barrier for disconfirmatory trials that could get hastily approved but ultimately ineffective drugs out of the market (see Ending Medical Reversal). Because even in the world of Marginal Revolution’s hyper-accelerated approvals and early access to all, patients and physicians alike would need formal measures of safety and efficacy as a guide, and clinical trials are the ultimate way to do it. So we’d better have a quick-and-dirty way to do those too.

Unless the failure of imagination is mine, and in the Marginal Revolution world it would be an artificial intelligence sifting through “real-world” data for safety and efficacy of the thousands of new medical compounds and procedures blooming in this unregulated Utopia, perhaps even recommended and/or administered by LLMs who would finally bypass those pesky rent-seeking doctors. You have to see item number 6 to believe it. I did a double-take. Then again, maybe I shouldn’t take economists so seriously.

A few links to start off your morning with:

• Looking for the Anti-Mimetic Doctors (Part I)
• Rare Events are Really Common
• Fast Crimes at Lambda School
• How to Age 30 Years in 10 Days

Today I learned about ambroxol, a cold medication available over-the-counter, much like Mucinex and Robitussin, but unlike those two ambroxol may actually work. It’s been available in Europe for almost 50 years and costs around $5 per box, but alas:

You can’t get ambroxol in the U.S. because of the failure of the Food and Drug Administration to grant reciprocal recognition to generic medications approved by its European counterpart, the European Medicines Agency, when they have long been proven safe and effective. To get FDA approval for the sale of ambroxol in the U.S., a drug company would need to sponsor extensive and costly clinical trials. Since it is a generic, as cheap as aspirin, no drug company would bother.

If the drug is that good and that cheap a trial should be neither extensive nor costly — it would certainly be cheaper than the $10 billion the American tax payer gave for Paxlovid, with potentially many more people benefiting. So why not have the NIH run the trial and the FDA approve the drug? Would that not be faster than trying to pass any legislation through the United States Congress?

More generally, I would like economists, politicians and the general public to understand that well-run clinical trials do not have to be complicated and expensive. They are not a limited resource going up in price because of low availability and high demand, requiring us to think of workarounds. In fact, there are more patients than ever, more researchers than ever, and more technology than ever to make them economical and efficient.

Of course, if your notion of a clinical trial is one that includes mountains of paperwork and research bloodwork gathered on the off chance it may someday be needed then yes, it can get pricey. But that is like complaining that pianos are really expensive and unaffordable because the price of a Steinway piano has gone through the roof since the early 1900s. You can play music on a Casio just fine, and if I were an economist I would really want to know why on Earth almost everyone in the pharmaceutical and biotech industry was getting grand pianos instead of electronic keyboards.

(↬Alex Tabarrok, who as an economist interested in drug pricing may want to look into the cost of clinical trials)

The VPZD Show is back after a year-long hiatus and last week’s episode checks a lot of boxes from the Things-I’m-Interested-In list:

• Maintenance of certification (the last time I wrote about it was in September)
• LLMs in medicine (back in March)
• Cancer screening (August and December)
• End-of-life care (which has been a longstanding interest)

The last topic I listed here was what the episode starts with, and is the most poignant part. Recommended.

Always great to see a treatment mature from the lab to clinical trials to a write-up in The Atlantic. This is about post-transplant cyclophosphamide, initially developed at Hopkins for haploidentical (“half-matched”) stem cell transplants, now used even for full matches as it works so well in preventing graft versus host disease. Cheap as chips too, if you can get it (but of course low price and short supply are closely related).

The Paxlovid Phase 3 trial in the vaccinated population showed no difference from placebo. The gamble didn’t pay off, and $10 billion went down the drain instead of funding many, many clinical trials. The best science in the world won’t help if you don’t have the right priorities (and conversely, stamping “science” on your priorities doesn’t make them right).

From the American Journal of Obstetrics and Gynecology:

The high and rising rates of maternal mortality in the United States are a consequence of changes in maternal mortality surveillance, with reliance on the pregnancy checkbox leading to an increase in misclassified maternal deaths. Identifying maternal deaths by requiring mention of pregnancy among the multiple causes of death shows lower, stable maternal mortality rates and declines in maternal deaths from direct obstetrical causes.

Translation: maternal mortality often went undetected, so they changed the way we had to measured it. We don’t like how the new way of measuring is making us look compared to other countries, so we want to change it back. Goodhart wins again. (↬Washington Post)

“Maybe that’s why young people make success. They don’t know enough. Because when you know enough it’s obvious that every idea that you have is no good.”

This was Richard Feynman per the James Gleick biography, and he was correct! Biomedicine is now in this position, as I wrote yesterday.