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.

The Medical Journal of Record The New York Times. The link is to a gift article. has an excellent story on Kawasaki disease out today which reminded me of Balkan endemic nephropathy, another rare disease with an unusual and infectious disease-like distribution. ⊕ Note that prevalence and distribution are where the similarities end. Kawasaki disease is a vasculitis (inflammation of the blood vessels) that affects children and young adults. Balkan endemic nephropathy caused your kidneys to shrivel up and stop working, and affected the middle-aged and the elderly. It had no known cause back when I was in medical school (which was — gasp — 20 years ago), but it has since been tied to accidental consumption of a certain plant. Well, accidental in the Balkans but intentional in China, where it was used in some traditional medicines and could cause “Chinese herbs nephropathy”, which was like the Balkan version on speed. Note that I am referring to both BEN and CHN in the past tense, but should probably temper my enthusiasm: even though we know what’s causing them and how to prevent them, their prevalence has decreased but is not zero.

The genetic revolution has been great for many aspects of medicine, but it has also made us a bit lazy. The promise of the late 1990s and the early 2000s has been that we would fine the genetic cause of most diseases, and would be only a step away from solving them. While we certainly found many genetic disorders, most of the are in the ultra-rare category and tied to newly-established diseases that were previously only described as syndromes. The “big” diseases — hypertension, type 2 diabetes mellitus, major depression and the like — are as unknown as ever, their cause described as “multifactorial” which is code for “we don’t know”. Stomach ulcers were also thought to be multifactorial until we found out they were mostly caused by a bacterium. A similar thing seem to be happening with multiple sclerosis, which seems to be caused by a virus, one that was mostly thought to be an unavoidable nuisance but is now a vaccine target.

But haven’t we already discovered all the big bad bugs? I sincerely doubt it. We have trouble identifying even larger organisms Also a gift link, this time to The Washington Post. I’m on a roll today. — there could be hundreds of disease-causing creatures and substances that we don’t yet know about because we can’t see them, can’t grow them, and/or don’t know where to look. And we terrifyingly bad at looking for anything but the obvious — there are parts of our own anatomy that we’ve discovered just recently.

So, I know that we will find the cause of Kawasaki disease and can only hope that it will be soon. I also hope that we will find the one main cause of the obesity epidemic. Add in essential hypertension and psychiatric disorders in there. Much money has been spent on discovering the genetic factors of these diseases. Now that we know that genes play but a small part in most of them, maybe it’s time to reallocate the funds.

Alex Tabarrok gives name to something we’ve all experienced:

Ironically, just as measles can induce immunological amnesia, vaccines can induce social amnesia about the severity of diseases, thereby making society more susceptible to pathogens that they previously were able to resist.

“Vaccine-induced social amnesia” is a good way to describe it. See also: people who ex post claim we never needed covid-19 lockdowns when the truth is in fact the opposite.