If you are an American, the country’s best decade was whenever you were a teenager, says The Washington Post. Compare and contrast to Serbia, whose best decade is more dependent on your politics and can be anything from the 1340s to the 1960s. My teenage years were, of course, not so glorious.
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.
Breaking my “no politics until November” promise to self in order to quote today’s Stratechery update:
[The] Democrats gave up the enviable position of being the default choice for people who didn’t want to think about politics at all.
And this is exactly what has been bothering me since 2016. I spent my whole childhood and young adulthood in a country (Serbia) where you had no choice but to think about politics, and a big part of coming to the US was not having to think about it too hard. Alas, instead of the Balkans becoming westernized the West has been balkanized.
If there had been a webpage monitoring the progress of the actual moonshot in the 1960s, it would have said stuff like “we built a rocket” and “we figured out how to get the landing module back to the ship.” In 1969, it would have just said, “hello, we landed on the moon.” It would not have said, “we are working to establish the evidence base on multilevel interventions to increase the rates of moon landings.”
This is Adam Mastroianni skewering the “science moonshot” initiatives, and rightfully so. If all we have to show for them are 2,000 papers full of mealy-mouthed prose, it was a ground shot at best.
📚 Finished reading: The Will to Battle by Ada Palmer, who continues to mix enlightenment philosophy, history and some dark, dark humor to produce an artifact from the 25th century that may answer some question we have in the 21st. I am at once sad and relieved that there is only one book left in the series.
Here are a few facts we should all be able to agree on:
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.
There are inherent utopian assumptions about our ability to create a better world. The arrogance of those assumptions consistently produces a world of unforeseen consequences.
This comes from an Orthodox priest, but may as well have been written by Nassim Taleb. Effective Altruists and those adjacent should take note.
📚 Finished reading: Seven Surrenders by Ada Palmer. The only thing I have to add to my initial impressions is that I have promptly picked up the third Terra Ignota book. If you don’t think you like sci-fi but have interest in history, philosophy or religion, these may be the sci-fi books for you.
Gee thanks, Siri.
📚 Currently reading: Seven Surrenders by Ada Palmer and holy smokes is this good. After only a day of reading I am half-way in, and even the most macabre plot points from Part 1 have been paying off handsomely. I can’t wait to see what miracles the rest of the book brings.