A mural from the rust belt. Obscured by the gas-guzzlers in the bottom left corner is the slogan: “Without Labor Nothing Prospers”. Indeed.

Is a rainy day in the life of a cat really different than any other day?

While assembling slides for the UMBC clinical trials course I’m helping with, I was reminded that Richard Doll and A. Bradford Hill never received the Nobel Prize for medicine despite conclusively showing by the way of a new-fangled method called a prospective cohort study — it was the late 1950s — that tobacco kills. They both did the work in their early middle age and lived into their 90s, so it’s not like they didn’t make it to see their work validated (like, say, Oppenheimer not being there for the confirmation of his black hole theory). Of course, the committee is not infallible — they did hand out the prize to a lobotomist — but the errors of omission are so much worse.

My same slide deck also mentions Barry Marshall and Robin Warren who (deservedly!) won the medical Nobel for another disease pathogenesis discovery: they showed that the helicobacter pylori bacterium — and not stressful living, bad thoughts, lack of dietary milk and butter, or whatnot — is responsible for gastritis. Marshall conclusively proved this by ingesting the bacteria himself back in 1985; the Nobel Committee was impressed enough by this feat of IRB avoidance to hand him and Warren the prize — in 2005, the year of Dr. Doll’s death!

He died in July and the prize was announced in October so I shall refrain from making any inferrences about the cause of death.

Our old neighborhood on Ontario Road, this time last year. Half of these row houses are now but a shell, ready to be converted into flimsy condos. So it goes…

I had a bad reaction to a tweet an X-post ⊕ Let this be the last time I cross out the word “tweet” in reference to posts on X. I actually quite like calling them X-posts, since ex post philosophizing is the most common mode of discourse there.yesterday saying that:

…effective drugs suffer from the silent hero problem that Taleb wrote about in The Black Swan. Many can prevent far worse downstream outcomes (hospitalization, surgeries, chronic pain, early death), but we don’t tend to reward acts of prevention like we do acts of correction. Thus, surgeons are revered and drugs are reviled.

Why would I have a problem with a statement as obvious as that? Yes, humans overvalue procedures and neglect the importance of drugs, especially those with a delayed effect, no matter how large the effect may be. Well, the ellipsis hides the first part, which was agreement to a quoted post which is one of those newfangled blog posts disguised as an X-post so apologies for the long quote:

Drug industry’s [lack of] popularity is thanks to its own success. … If you have a disease for which there is a medicine, you don’t know anything other than the bill at the pharmacy counter.

If you have a disease without a cure, all your faith is put into the drug industry because no one else is coming to help and nothing else matters.

And if you don’t have a disease (yet), you really don’t care other than your fear of the bill you might one day get at the pharmacy counter.

The great irony here is that the pharmaceutical industry doesn’t control what you pay at the pharmacy counter: your insurance plan does.

Followed by a graph that shows plumetting public opinion of the pharmaceutical industry according to Gallup polling, from ~40% positive, 37% negative in 2014 (peak recent positivity) to 18% positive 60% negative in the most recent year, which I presume is 2023 but the image doesn’t say.

This is an example of a reverse-BS sandwich, where three interesting (and perhaps even true) observations are layered in between two nonsensical pieces of dreck.

Let’s start with the middle first. Per the second statement, if you have a disease, and there is a cure, the only thing you “know” is what you have to pay for it at the counter. I would argue that this is only half-true: as a patient, I would also know how I should take the drug (pill, self-injection, infusions at an infusion center, hospitalization, etc), how often and how easily (from a four-times-a-day horse-pill to an ocassional subcutaneous injection), how quickly it works, and what the side effects are. For any particular disease there may be several options, with more convenient and/or less toxic ones costing more; and people may be ready to pay more for the convenience and/or fewer potential side effects. The price difference may not even be that high, like in the case of four-times-daily versus once-daily antibiotics. So there is quite a bit of nuance there, but hey, it’s X: if there needs to be some simplification to make a valid point, that’s OK.

But then after reading the statement that follows I’m not sure if there is any point to be made. It’s an attempt at a dichotomy — separating diseases into those with and without… something. For there are many diseases for which there are medicines, but those medicines are not cures: the terms aren’t interchangeable. And for incurable diseases, the pharmaceutical industry is emphatically not the only place in which people put their faith: see complementary and alternative medicine, support groups, religion. There are many people of different persuasions, motivations, ambitions, and fee schedules who will happily give their support. But lest this is construed as nitpicking I will squint once again and let it pass, assuming that the preceding statement talked about cures, and not medicines in general.

The next statement is absolutely true. Healthy people in general have a hard time imagining what disease is like, and we all know what a financial nightmare American health care can be.

The first sentence is a strong statement of causation: that the pharmaceutical industry is unpopular thanks to — which I interpret as because of — making such good drugs. I’ll attempt to construct the three that follow into supporting arguments:

1. You have a disease for which there is a cure. You take the cure for granted and you don’t like the pharmaceutical industry because you have to pay for their drug.
2. You have a disease for which there is no cure. You don’t like the pharmaceutical industry because you had put all your faith in them because of their past successes (see above), and they have failed you.
3. You don’t have a disease. You don’t like the pharmaceutical industry because you are scared of what may happen to your finances if and when you do get sick.

Do get in touch if I didn’t get this right, but if I did, I’m afraid it’s bad reasoning. It does point to prices as the reason for pharmaceutical industry’s unpopularity, but neglects the price of the vast majority of medicines which are not cures, yet which people take with flimsy or no evidence because of medicalization of normal variability, use of bad surrogate endpoints, and, for terminal diseases like most metastatic cancers, lack of alternatives. The industry isn’t unpopular because it charges to much for life-saving drugs (if anything, it charges too litle), but because it puts out — pushes, even — wimpy drugs that treat nothing in particular.

Yes, if it weren’t for the “silent hero” problem people may be more appreciative of the benefits and the industry may be slightly less unpopular. But make no mistake: the industry as a whole is unpopular because it overweighed the amount of slack it would get riding the coat tails of the many truly miraculous drugs it came out with in the last 20 years, from antiretroviral therapy for HIV, to hepatitis C treatments, immune checkpoint inhibitors, SARS-CoV-2 vaccines, and, most recently, semaglutide (Ozempic).

As for the final statement, well, it’s wrong in two ways: one — the wholesale price sets a ceiling that the patient would pay. Medical insurance could not make the patient pay more for a drug than the drug actually costs. Second, many pharmaceutical companies will be all too happy to cover the entirety of your co-pay for their specialty product, since it is usually significantly less than the margin they get on the agreed-upon price for their drug.

So anyway, I hope you can now see why a simple scroll down the time line is not an easy exercise for me, or really for anyone with more than a passing knowledge of the American drug price problem. There are no purely good participants on any side (even patients, which is a bit of anathema but take a look at the average American’s overflowing medicine cabinet and compare it to that of someone from Europe), and there are very few truly evil parties anywhere (although, yes, some do come to mind). So instead of rapid-fire whataboutist replies, I write articles like this to vent. I hope you don’t mind.

Target-based drug discovery is a waste of time, says a systematic review of 32,000 articles and patents from the last 150 years:

…only 9.4% of small-molecule drugs have been discovered through “target-based” assays. Moreover, the therapeutic effects of even this minimal share cannot be solely attributed and reduced to their purported targets, as they depend on numerous off-target mechanisms unconsciously incorporated by phenotypic observations. The data suggest that reductionist target-based drug discovery may be a cause of the productivity crisis in drug discovery.

So it would seem. And even those drugs initially developed to target a single protein or mutation end up having many more unanticipated effects. Back to the jungle and the ocean depths, then?

(ᔥDerek Lowe)

Patrick McKenzie on X:

I hate to sound intellectually vacuous but choose to get more done. At the relevant margins, get more done. Life : culture / peers will routinely tell you it is OK to get less done and you should politely insist on getting more done. The amount of doneness you get is not fixed.

I have been thinking along these lines ever since reading, some dozen years ago, an article about a particularly successful cystic fibrosis center, whose outcomes were an order of magnitude better than average. This was before any new drugs or promising trials were available, and the only reason why they were so much better was that they did more of everything: more frequent follow-up, more intensive manual therapy, more changes to treatment regimen with subtle changes in condition, less complacency.

Nowhere is this more evident than on the inpatient service. It is incredibly easy to coast with reflexive and defensive medicine, putting out small fires like hospital-acquired infections or patient falls, passing on the buck to the next team, shrugging your shoulders about that 60-year-old with questionable CHF (or is it COPD/asthma) exacerbation who is not following the script and doesn’t seem to be getting any better despite being treated for everything. Patients hang around a bit longer, suffer a bit more iatrogenesis, die a bit sooner, not enough for it to be obvious in any particular case but just enough for the outcomes to be worse in aggregate.

Make no mistake: this is how many (most?) American hospitals operate, for the simple reason that there simply aren’t enough doctors and nurses around for the level of attention sick patients with many active complex disorders deserve. But doing more is the American ethos (see the X-post above); not being able to provide more focused care, we dig into the seemingly infinite supply of more drugs, more procedures, more iatrogenesis to which to expose patients, making their condition all the more complex.

Outside of medicine, this is also the difference you can see in “good” and “bad” (for collaboration) institutions: good ones throw water at embers before they become a fire, communicate more frequently and openly, do not leave documents for review “for after the long weekend”. They do more; or rather, each individual there does more and does not pass on the buck to forces unknown which are beyond their control (and the bigger the institution is, the more numerous and more complacent those forces are; incredible how that works). The not-so-good institutions also do more: of emailing, usually, to tell you that something can’t be done.

So yes, choose to get more done, and also make sure you are doing more of the right thing.

A recent podcast episode and a recent blog post show how screwed up the American drug market is, and in how many different ways.

In his Healthcare Unfiltered interview focused on generic drug shortages, the FDA Commissioner Robert Califf blamed Group Purchasing Organizations for driving down the cost of generic drugs to below what’s economically feasible. The manufacturers don’t have an incentive to shore up their process, the fragile production line fails, and presto, you have a shortage. Which is fine if you are manufacturing a placebo, but in recent years the FDA’s Drug Shortages Database has been ever-growing, and as of today includes potentially currative cancer drugs like cisplatin and carboplatin, many antibiotics, and even some formulations of sugar-water. Not to be confused with placebo.

This all reminds me a bit of my childhood in Serbia back in the mid-1990s, when bread was dirt cheap and never available. But that was too much price regulation. Here, we have too efficient of a market leading to a shortage. Only, I am sure there will be hands raised wanting to tell me that — well, actually — this was a clear example of over regulation, since new factories can’t just pop up too meet the demand and make use of the temporary market inefficiency, being dependent as they are on pesky FDA regulations — like the ones about drugs being safe. If only we could price in the risk of death by sepsis, we’d be in great shape!

So, on one end we have Medicare/Medicaid paying through the nose for brand name drugs because it is forbidden by law from negotiating for a better price, and on the other private GPOs negotiating too well for generics, to the point of extinction, forcing payers to get those expensive brand name drugs. Heads, brand-name pharmaceutical industry wins, tails, payers loose.

It was encouraging to see some movement in the price negotiation area: the comically misnamed Inflation Reduction Act allows for CMS to negotiate the price of some drugs, and the list of those drugs was recently made availalbe. Ideal? Far from it — in an ideal world the federal government would not be involved in any of this; but it’s not the world we live in. This is where the blog post comes in: from Alex Tabarrok, about how we are bad at pricing drugs because of unknown externalities (true!) but also with a side-comment reframing measures the IRA takes allowing nogiation as “price controls”, linking to [a policy paper][10] which suggests yet another set of measure to mitigate the adverse effects of IRA’s proposed solutions to the drug pricing problem. ⊕ Efficient markets for me, but not for thee, as Tabarrok’s writing partner would quip. And so the measures pile up from both the pro- and anti-regulation side. Ad infinitum, I suppose.

See also: better drugs don’t cost more, and a list of a few earnest but misguided attempts at cost control.