Gravity Falls (2012–2016) is the king of our household, but if there were ever a contender to replace Dipper and Mable it could only be Over the Garden Wall (2014). Well, November 3–7 were the 10-year anniversary of it coming out on Cartoon Network, and there is a stop motion short voiced by the original cast to commemorate. It’s been a busy few weeks so I only saw it now, but it made my day (and will quite possibly be the highlight of my week). (ᔥwaxy.org)
A friend raved about Anora (2024) and I’ve never heard of the movie until this morning. Earlier this week I quizzed my kids about actors and actresses and all they knew were YouTubers. Either movies are dying as a pop-cultural phenomenon or I am completely out of the loop. Quite possibly both.
I am at ACR Convergence all weekend, but here are some quick shots:
Here is a good list of pragmatic trials (on X) that a national institute serious about the health of the public may want to sponsor and/or run. There are many such open questions in oncology as well, and don’t get me started on diagnosing every deep venous thrombosis for hereditary thrombophilia.
I recently spoke at an event dedicated to “making clinical trials faster” in the US. Mine was the first talk of the day, so I wanted to set up a framework of thinking about clinical trials that would be useful for further discussion. The attempt was a resounding failure at the level of the talks that followed — more on the specifics of that below — but I still think it’s a good framework so I’ll turn my 5-minute talk into a few paragraphs here in the hopes that more people start looking at the problem from that perspective.
The problem with “making clinical trials faster” is that clinical trials are two very different things with very different purposes to the point that we should probably use a different phrase for one of them. And you can optimize for one or the other, but not both. I am a fan of the mental technique where you figure out the edges of a jigsaw puzzle first — identify the rare extremes — in order to find the more generalizable truth that is somewhere on the spectrum. Here we have the opposite problem: we live in and try to optimize for the middling hodgepodge whereas the two extremes would have been preferable.
These are the two extremes:
Set 1 trials are Phase 1, 2 and 3 trials regulated by the FDA with 20-page informed consent forms, lengthy approval processes, strict safety and data monitoring procedures, and costs up the wazoo. The costs are OK since they lead to “value creation” for the economy, of course, but they also contribute to rising cost of health care. And they are especially OK in cases where they are covered by the Sponsor, either a multi-billion-dollar “big pharma” conglomerate or a well-funded biotech. The pembrolizumab KEYNOTE trials are a typical examples but there are too many to count. KEYNOTE-001 in particular is a good example of “speeding up” these types of trials (it was a phase 1 study that lead to accelerated approvals for two indications).
Set 2 trials are “pragmatic” Phase 3 trials that are IND-exempt are they use drugs in their approved indications and should have short, 1-page consent forms, minimal regulatory oversight, and trial procedures integrated into the standard of care to the level that most if not all costs should be covered by medical insurance. And medical insurance companies should be particularly interested in these trials, as they help optimize care and remove ineffective drugs and devices from the market, if not literally then at least by the virtue of physicians not using them any more. As such they are “value-destructive”: imagine a potentially billion-dollar blockbuster drug being found to be no better than a $2-per-dose generic. The RECOVERY trial is the best example of this kind of a trial, leading to quick establishment of standard of care in severe Covid-19. RECOVERY was wholly done in the United Kingdom, and examples of Set 2 trials in the US of A are few and far between.
The outcome of making Set 1 trials faster is more new drugs and devices on the market, including the hypothetical miracle cures that the burdensome FDA approval process is keeping away from patients, leading to large invisible graveyards (for that hypothesis, consider me a skeptic). The outcome of making Set 2 trials faster is fewer ineffective drugs and devices in use. They are the yin and the yang of drug development, creating harmony when they are in sync: new drugs come in, bad ones go out. But at the same time they are diametrically opposed, so it should be no wonder that the tradeoffs required to make one or the other set faster are different.
Of course, clinical trial infrastructure in the US is wholly dedicated to Set 1 trials. This is what the FDA was set up to do, what IRBs are primed for, what the entire ecosystem knows how to do, from clinical research coordinators doing the administrative work at the trial site, to the pharmacovigilance staff monitoring safety, to the administrative and budget offices of universities managing the contracts. But the two sets share the same ecosystem, and all the money being pumped into it by Set 1 makes Set 2 trials nearly impossible: who wants to pay that kind of money for something that could potentially destroy the value of a drug?
And this is my fear for the “make clinical trials faster” project: it will have cheerleaders from both the Set 1 and Set 2 crowd. But there is only one set of tradeoffs to be made, and if I had to bet I would bet that the Set 1 tradeoffs will win if for nothing else then for the major lobbying potential of the pharmaceutical industry. The system is already out of balance, and it wouldn’t take much to tip it completely into disaster territory where so many new but marginally effective drugs overflow clinical practice and it becomes a competition for the best door-to-door salespeople to persuade doctors that their marginal drug is (marginally) better than the other guy’s marginal drug. And if you want to compare the two drugs head-to-head in a Set 2 trial, well, you are out of luck because the regulatory energy of activation and the cost of paying for a trial database and the research coordinator and the data manager is so high that you can’t even… But of course, this is not a hypothetical disaster scenario, this is just modern medicine.
So I gave my 5-minute talk and what followed was a near-perfect encapsulation of Set 1 and Set 2 people talking over each other’s heads. On one hand we should make informed consent forms shorter (Set 2). On the other, let’s use “real-world evidence” to find new indications for drugs and speed up their approval (Set 1). Let’s ease up the monitoring requirements for trials (Set 2). But also do human challenge trials (Set 1). And so on, and so forth.
My gut instinct is to optimize the system for Set 2 trials and to untangle the FDA’s relationship for them. As much as some would like to shoehorn additional responsibility to an already overburdened federal agency, FDA has no place regulating clinical practice. Now, there is another set of federal institutions that have National Health in their name that could maybe lead the way for pragmatic trials, but they too mostly fund small Phase 1–2 studies of marginal drugs whose only distinction is that they came from an academic lab rather than the pharmaceutical industry (and this is because, of course, Phase 3 trials are too expensive to run on a federal budget).
But let’s leave that discussion for a different time.
What else?
I love and hate Maggie Appleton’s website at the same time. I mean, just look at it. But then the last essay went up almost 2 years ago, and “loose, unopinionated notes” come out at a rate of one every other month.
“Digital gardens” may not the best of metaphors. A garden left on its own will keep growing and may turn into something beautiful. A blog without new articles becomes a museum or, worse yet, a mausoleum with its own flesh-eating aliens.
📚 Finished reading: Meditations for Mortals by Oliver Burkeman and I can’t say I’ve learned too much. The book was for the most part a validation of my approach to blogging which has in turn been my approach to life in general: do not be afraid of half-assing when the alternative is no ass at all.
Here is a brief anecdote that may help contextualize some recent developments, in particular why anyone black, or brown, or uneducated, or poor may have preferred Trump over Harris.
Two apartments ago, a bit before Covid, we were living in a 2-bedroom apartment in Northwest DC that was absolutely gargantuan by European standards but must have seemed cramped for a family of five-plus-a-house-guest to our neighbors. One neighbor in particular, let’s call her Alice, seemed unusually interested in the goings on of our household: the foreign accents, the visiting grandparents, so many children. So she made a point to, whenever we bumped into each other in the hallway, gather as much information as possible, and give a few bits about herself in return.
Alice worked for a federal agency, you see, and as a hard-core democrat was trying to minimize the chaos that the orange man — this was during the first Trump administration — and his peons spewed on the people. Now the agency in question was healthcare-adjacent so my wife and I, both being physicians, knew that the problems ran deeper than the president and his appointees, but that is not the point of the story.
The point is this: with every interaction, Alice would highlight that we were not US citizens, then highlight some more that we had visiting family members who also were not citizens and who may or may not be in the country legally (they were all, of course, visiting on a tourist visa as they have been in more than a decade since we moved from Serbia), then apologize for what Trump was doing to the immigrants and aren’t we all lucky that DC is a town of welcoming democrats and can you please let her know if we needed any help with anything, at which point Alice would — unironically — wink.
It’s hard for me to say what felt more insulting, the sly and not so sly insinuations that we were there illegally, the entitlement that we must be best of friends because we were immigrants, or the expectation of gratitude to all the democrats for “fighting on our behalf” when there was no fighting to be had. And this is before we even had our green cards, staying on a combination of work and (this is my favorite name for a bureaucratic invention) Alien of extraordinary ability visas. I can only imagine how much worse the feeling would have been if we were citizens with the unfortunate property of having an unusual accent or unconventional (for upper-middle-class-non-hispanic-whites) housing arrangements.
To be clear, I have no idea what Alice’s intentions were. I am pretty sure she didn’t want to insult anyone, and that her thoughts and feelings were true. And it is often the case that someone can feel insulted for reasons completely within their control: a slight sense of shame that you weren’t living up to someone’s arbitrary standards, annoyance that you are spending hours on immigration paperwork when others don’t have to yet feel as welcome, outrage that anyone would give even a hint of a suggestion that you are a family of Anne Franks looking for an attic. All internal and within your own control, but not any less true. Humans being humans.
This was all before Covid-19. After March 2020 our hallway conversations turned into talks about masks, vaccines, and how everyone was grateful to have doctors in the building. About a year into the pandemic another neighbor ran out of their antipsychotic medications and started setting small fires and hitting random hallway doors with baseballs bats so we were soon out — the benefits of renting — but we stayed on good terms with Alice. Still, those first few impressions stuck, and majority of our interactions are only first impressions without the benefit of a pandemic to deepen a relationship.
One of the defining properties of America is, I’ve learned over the years, the tendency to go all-in. People don’t just go on a hike or two a year, they buy hiking gear, download hiking apps, plan out routes and become hikers. They don’t go out for a jog when the weather is nice and they feel like it, they train for a marathon. They don’t enjoy a night out at a restaurant, they rate and review and call themselves “foodies”. They don’t just like their work, they do it on evenings and weekends and holidays too. That is how you get to the highest GDP of any developed country, I guess, but there is also some subtlety lost and the democrats who were all-in on immigration have lost that subtlety and unintentionally — I hope — fanned the flames of indignation across the board. So not only were those pro-immigration efforts insufficient to overcome the feelings about the economy, they may have even hurt.