Thanks for this - I now feel at least 50% more confident in my comment the other day on the monthly links post point out that "a key issue in trial design is that lots of people want to be in a study, and simply lie to the doctors"
In your conclusion, you note this isn't the system you'd like it to be. Is there a description by you or others elsewhere of a possibly superior alternative?
If the core issue is misaligned incentives, could a couple of small tests move the needle without a policy fight?
Example: run an arm where pay is guaranteed for non-serious AEs and there’s a small, fixed “diligence” stipend for timely logs, then compared AE capture, PK/PD outliers, and dropouts to status quo. I'd think reporting would improve when volunteers aren’t worried about losing compensation.
Example: a simple cross-site operational snapshot -- Is dosing order randomized or first-come; what’s the alternate pay policy; how broad are exclusions; how are washouts enforced. Then correlate those knobs with screen-fail rates, AE capture, and protocol deviations. Even a modest, pre-registered audit might show what actually matters.
On reforms, would sponsors/CROs be open to a meaningful day-rate for alternates plus transparent randomized queueing to reduce the “race to screen”? Could contraception language be tuned to mechanism and half-life (ICH/EMA style) with a clear lay rationale? And is there room for a lightweight healthy-volunteer registry via central IRBs or sponsor contracts ---just enough to prevent dual-enrollment and stacked washouts - without waiting on federal law?
Have versions of these have been tried and failed? They seem testable and pleasantly boring -- the best kind of fix.
I'm not sure what you mean by "pay is guaranteed for non-serious AEs." If you mean that participants are guaranteed to be paid for their participation in the study, I don't think that would help much if they're worried about being ruled out of future studies. If you mean that participants would be paid for reporting AEs, that seems like a perverse incentive guaranteed to result in an explosion of AE reports. The people conducting the study don't know the true rate of AEs they're trying to capture (otherwise they wouldn't have to try to study it!) and they have to be careful that they don't set up incentives that result in overshooting the true rate as well as undershooting it.
Oh, I see. I’m not proposing pay-per-AE, just AE-neutral compensation (base pay plus a small fixed compliance stipend regardless of what’s reported) plus a future-eligibility guardrail so routine grade-1/2, expected AEs don’t automatically hurt eligibility unless a clinician flags a real contraindication. Pilot that and track diary timeliness, concordance with labs/PK, and dropouts vs. status quo.
That seems worth testing, but this strikes me as something of a coordination problem. If research participants systematically expect clinics not to be trustworthy to cooperate with (because from their perspective, they're usually not,) then a single clinic guaranteeing that reporting AEs won't hurt eligibility at that clinic may not see much difference, because they're still working with the same participant population, whose expectations are normed on all the other clinics.
If one clinic tests a bunch of variations in procedure, and sees no differences in results, it might be a mistake to conclude that there would be no differences in results if changes were propagated across the whole clinical landscape, and there was enough time for those changes to be reflected in the expectations of participants.
Totally agree on the coordination problem. A single site won’t reset priors. Would it make sense to treat the sponsor/CRO (or a central IRB) as the unit of change and run a staggered multi-site pilot where several clinics adopt AE-neutral pay plus a grade-1/2 eligibility guardrail with a dated, public policy? Start dates randomized by site; evaluate with a simple diff-in-diff on diary timeliness, lab/PK concordance, and dropouts.
To make the commitment credible to volunteers, what about a “portable guarantee” across participating sites, i.e. a benign AE reported at Site A can’t be used to exclude at Sites B/C unless a clinician adjudicates a real contraindication...and implement the same workflow via shared ePRO/payment vendors so it’s visible and consistent?
If that still shows no movement, then the issue likely sits deeper than pay/eligibility fear; if it does, you’ve got a template ready to scale.
I enjoyed this review, it's a pretty niche topic but one I'm familiar with because ~20 years ago I participated in a handful of these types of clinical trials and now I'm helping to plan them.
I've done about a dozen or so Phase 1 trials, and two groups of people I would say you missed in your "who does these trials" sections is:
1) Backpackers, and
2) Foreign students
I think the whole 'no experience required' part attracts less "shady" characters than you seem to have encountered, and more just people who need to make money asap and can't go via the conventional route. I did my trials mostly during COVID in one of the most locked down cities in the world (Melbourne) so that might have contributed.
By contrast I don't think I ever actually encountered personally anyone who seemed all that shady to me. I heard a few stories of people shagging in the bathrooms but beyond that the overall vibe of the people seemed mostly extraverted and friendly.
The whole 'lie at every step of the application process' rings incredibly true though. I have recruited many family members into doing these trials and the one piece of advice I always give is, no matter the question, if it's about having a health problem always say no. They once asked if I had ever smoked, and wanting not to sound too unbelievable I said I had vaped once a few months ago. That was written down as "smoker" for literally years afterwards.
This could just be the fact that you were in Australia? I assume the author was in the US. I would be very surprised if backpackers were a significant portion of this population, as people mostly do not do that kind of urban transit-hopping backpacking in the US in the first place. Students I am sure are a significant component though. If it's at all similar to the population who donates plasma, sites near major universities are likely mostly students and then mostly 'shady characters' at all other sites. But students also likely do not do the cross-country professional research participant who tries to squeeze in as many as possible.
I knew people in college who participated in trials at a company called Pharmaco. My roommate got her wisdom teeth out for free this way.
Pharmaco was located a few thousand feet from the mall and there was a little joke about a path beaten between the two by all the coeds.
Fast forward to being old, and the women I know (only women) who do these things tend to be retired or laid-off and interested in “gigs” of all sorts: the Census, poll work, substitute teaching.
One of my girlfriends, a freelancer, at sixty was also arduously climbing up two flights of stairs to deliver beer and Jell-O cups to kids too lazy to leave their apartments.
Boomer women were hard workers!
Some people, by no means suffering for funds, yet get antsy without any sort of paycheck.
I'm reminded of an interview with Leonard Nimoy's son about his dad's advice that the answer to every question you are asked during an audition interview is "Yes," which went something a little like this:
So, Leonard, we'd love for you to play Crazy Horse in our Custer's Last Stand movie. Can we ask you just a few questions?
Yes.
You know how to ride a horse?
Yes.
And you are of course an expert archer?
Yes.
And you are an expert archer on horseback?
Yes.
And you can shout Sioux curses with a perfect accent while shooting an arrow on horseback at George Armstrong Custer?
Yes.
After all, Dad used to say, they won't start filming for a few weeks, so you can always take lessons.
Perhaps he learned this from his castmate George Takei, who famously claimed before filming of "The Naked Time" that he totally knew how to fence, and then had to quickly run out and take lessons.
Not just in America. The actor who played Kyuzo, the master swordsman of The Seven Samurai, was absolutely terrible with swords. It took a lot of creative editing to make him a master.
My sales guy used to pound that in our head when I was a consultant too, "just say yes, get their money, we can subcontract any capability we don't actually have"
re "Whenever I’ve been tempted to develop a low opinion of their judgment, I’ve had to temper that with the knowledge that many of these people have apparently accumulated much more disposable income in the process than I have."
Sounds a good system to me! They get to study a much more realistic cross-section of the population than they would if nobody lied. It catches all the major problems (ie the ones that they test for and the ones you can't hide). As Douglas Adams said "Any remaining problems are your own."
And, as a bonus, the company is protected against being sued.
And you're providing gainful to people with criminal convictions who otherwise struggle to get jobs.
Maybe we should just adjust our vocabulary and consistently talk about "phase I subjects" instead of "healthy subjects" when referencing these studies. Some experts already do that (though I'm not sure if it's something a reviewer would flag), but I don't think it's filtered into public discourse yet.
It might be even better if we started attaching a few boilerplate words for those new to the topic:
"No side effects were observed in phase I subjects dosed with 5 mg of exampeline (Examplechuck et al., 2025). However, phase I subjects are known to differ from the healthy general population (Examplovich and Chang, 2022)."
It's more the inherent downsides of dishonesty that's the problem here.
1) It punishes honesty and makes society overall more dishonest.
2) Some people don't realize the system is built on dishonesty, and no one quite knows how much dishonesty is happening.
3) The reduced information makes some things much harder to spot. Suppose there was a drug that would have really bad effects if and only if you had taken weed (even if that weed was months ago) Currently, all the participants lie and say they have never touched weed. But if there was accurate data on whether or not they had taken weed, patterns could be spotted.
1. It's not the purpose of drug testing to reform society!
3. Yes, makes the link harder to spot, but that's not your primary concern. If such people have really bad effects it's better to know than have them be honest and be excluded from the trial. If you're going to market a drug what you really want to know is that it won't give any people really bad effects, then once you know it does you can start investigating (or just move on to the next contender drug)
Yes, what I'm wondering here is, how much would these flaws in safety trials cause problems if the US were to switch back to a "safety trials only" system as is often suggested?
Wow, that takes the shine off the whole idea of almost-free money, if 40% of the drugs you're testing will be deemed too dangerous even to be worth a phase two trial.
I mean, think of the awful side effects of so many drugs that actually make it to market, and then consider what might be getting filtered out.
I was hoping for more details of the author's personal experiences (I'm actually not entirely sure if the author has actually tested drugs) and some of the actual effects that he or she might have experienced.
I don't think it's always the side effects that rule a drug out. It might also be that it fails to reach the correct site within the body, or is eliminated too quickly to be of any use.
It can be about poor exposure/pharmacokinetics, not just safety issues.
Safety signals are often not about reported side effects. We can see elevated liver transaminases in the blood, or an EKG signal such as QT prolongation. It would be extraordinarily rare for a patient to die or have permanent damage from a phase I trial. We do a lot of animal toxicity testing first.
Failure in phase II due to poor efficacy (or non-superiority vs the standard of care) is even more common than Ph 1 failure, by the way. Only about 1 in 10 drug candidates will make it from phase I to commercialization.
A delightful accretion of safetyism, the cynic in me is thoroughly amused. But also, it's impressive that even an arrangement this corrupt and perverse could still be be made decently workable with enough effort.
Will the author stay anonymous? Or will the author reveal themselves and vault into the meta-business of teaching folks how to participate in Phase I trials!?
The two people who distrust white doctors reminded me of a Braver Angels discussion with two vax skeptics in 2021. One was white and MAGA, the other was black and BLM. In case you don't recall, Biden had prioritized getting black and old people vaccinated first because they had worse outcomes in aggregate.
The source of the black guy's skepticism emerged when he said "when has the government EVER prioritized the health of black people?"
The bizarre thing is that a lot of times the reference point in articles (which are now on repeat) about black mistrust of the medical establishment, is the Tuskegee syphilis study - which was itself a prioritizing of the health of black people, among whom syphilis was concentrated, at least in the South. However dumb was the worship of the study design later on, to obliviously or callously continue it when treatment was established, the whole thing would not be a millstone around our necks forever and ever if there had been no such original “prioritization”.
re "Do they have any reason to think that ADHD might be associated with an increased risk? I asked, and their answer was, not at all, but better safe than sorry."
Ozempic seems to have somewhat rare but very severe side effects (that include severe depression and suicidal ideation *caused* by the drug) specifically in autistic people, and autism tends to be strongly correlated with ADHD, so there's that.
I kinda feel like you'd rather find that out in a clinical setting than patients at home. But clearly that goes entirely against recruiting only healthy subjects.
The link for “the asshole filter” goes to a copy of another blogger’s post. They disclose that they copied it, but don’t say they had permission to publish a copy. It seems… on brand? Anyway, I think it would be better to link to the original:
I knew sometime who participated in these studies and he said the participants would bite the pills so they knew who was getting placebo or the real thing based on the taste.
One way around this is to put a small amount of denatonium benzoate in both the placebo and the drug capsule, so that both taste very bitter and any taste differences are masked. Is this not being done?
This seems predicated on the assumption that the participants know what the actual study drug ought to taste like in comparison to the placebo, and I don't see why that would be likely to be the case.
That's not to say they might not try, but I don't think it'd be a very reliable method for them to determine which arm they were actually assigned to.
Very interesting read, thanks! I wonder if it would help if there was a country-wide database of people who participated and everyone could participate at most once in life
Yeah that’s the one thing I was seeing that could change the incentives - make the pay higher but have a nationwide tracking system that locks you out from any others for a while.
Phase I = adversarial equilibrium: participants exploit for money, clinics shield from liability, pharma tolerates distortions, yet the system limps forward because downstream filters mop up worst failures.
This is an interesting analysis of why “paying people to do medicine-adjacent things” (eg: compensated donations) can get so much pushback: behind knee-jerk “ick”-type reactions, there’s maybe some sense that the interaction between “people optimizing for getting paid,” the typical mild dysfunction you’d see in any large organization, and the sheer stakes of healthcare, can produce quite the perverse and unanticipated outcome.
Yeah despite knowing rationally that paying people to donate blood is for the best overall, the classist/lived experience (pick one based on your persuasion) side of me istinctively thinks of which kind of person might need quick cash, be free on Wednesday morning etc and recoils at the idea of their blood being in the system
I'm suddenly imagining a dystopia in which these problems are dealt with by drafting participants the way we assign people to jury duty. Of course that would be entirely against medical ethics as we know them, but this is a dystopia. (Whether drafting people to jury duty should be against legal ethics is another question.)
Maybe we could draft people to show up for the first day, but not require them to actually participate? I'm pretty sure that would massively increase the number of people who choose to participate.
Seems a lot less bad than drafting people for actual war, and probably a lot more useful on a global level, too. I'd rather spend a year doing phase 1 trials than a year of being a soldier, so maybe we could offer it as an alternative to draft in countries that have it.
Of course if one country did this sort of draft, all other countries would still benefit from the results, which seems a meaningful practical coordination problem to me (perhaps you restrict this to only your native pharma companies). You'd also get a bunch of very different incentive issues like people pretending to have medical conditions to get out of the draft.
Medical ethics is a scam anyways, we routinely let millions of people die because we are too squeamish about maybe hurting or killing a few (probably volunteering) people through adverse effects, like due to lack of human challenge trials we never found out under which conditions which masks protect you how well from COVID.
Drafting people for war is only done under extreme and very rare conditions, and then only for a small fraction of the population (typically healthy young men). Phase I studies are happening all the time. Nobody's going to accept being drafted and forced to take potentially risky drugs on a regular Tuesday.
Sorry, I probably didn't make this clear enough: I meant I'd prefer doing pharma trials to military draft even in peace time, so I suppose the "nobody" is refuted by existence proof. Assuming you get paid the same amount of money either way, the trial seems a lot less onerous and I couldn't even rule out it being healthier in expectation depending on how physically damaging basic training is.
The US doesn't have permanent draft, but many countries do, some even draft women (Israel comes to mind). Phase 1 trials are also mostly performed on healthy young people, so I don't think there's a large difference there.
Great review, read it with interest. I feel obliged to point out that this is not what an asshole filter is, however:
> Because many research clinics do not actually bother to keep their websites up-to-date, participants are incentivized to [call and ask what's currently available], which applies an asshole filter to clinics’ participant populations. This will be relevant later.
This is a filter for *something* (know-how or initiative) but not being an asshole. The classic asshole filter is someone who says "do not email me" on their website but emails back when someone ignores that request. This means they correspond with people who ignore boundaries.
AFAICT from the post, clinics don't ask people not cal them, and therefore the people who do call are not being selected for assholery.
"Please report your entire medical history, and also if you report anything like the sort of medical history a normal person would have, we won't pay you" is an asshole filter.
You are conflating an EXAMPLE of an asshole filter, with the broader category of:
> "An asshole filter happens when you publicly promulgate a straitened contact boundary and then don't enforce it; or worse, reward the people who transgress it."
I agree (as does Siderea!) that "asshole" isn't a binary condition, and I further submit that "initiative" to one person looks an AWFUL LOT like "asshole" to another.
Interesting read; thanks for sharing information that would be extremely hard to come by in any normal way.
Sounds to me like these Phase I studies should ideally just be eliminated entirely. This review is already taking the position that the later stage actual experimental patients are backstopping any catastrophic side effect risk, and that that's ethical, all of which makes sense to me. So, why not let those people access those potentially effective new drugs earlier? I realize the answer to that question is "everything about the FDA"; I mean ideally speaking: are there good arguments for keeping the Phase I system as it currently is?
Very good review, very honest and too honest to win. Author could have triggered us easily into another "FDA delenda est" but lowered his prospects of winning by staying honest: "How much does this actually matter? Probably not as much as you might think." Love that, big hugs! Glad you made it that far! - Now, WHY does such a truth-loving ADHS-guy take part in those studies, where lying is required? Author denies us even this voyeuristic indulgment. Again: appreciated, but no hugs aka votes.
Agreed. The writer doesn't move on from the mildly interesting and entertaining particulars to larger issues they shed some light on, which would be following the format of most of Scott's essays. In general, I’m puzzled that people who were drawn here by Scott’s posts picked this pretty unScott-like bunch as top 10. It's as though a lot of people just like reading a bunch of detailed facts about a random subject. Personally I do not give a shit about Joan of Arc or what phase 1 clinical trials are like. I'd only enjoy reading about them if the author was quite funny, or so strikingly acute in their descriptions that some paragraphs were little works of art, or used the batch of factoids they present as an entry into an issue that interests me. Maybe I don't have a soul?
Maybe it's possible for people to be drawn here by Scott's posts, but not to expect or want every comment, guest post, or book/not-a-book report to be Scott Lite?
Clearly it is possible. It is still kind of odd. The quality I am pointing to in Scott's essays that is absent in most of these finalists isn't just a stylistic quirk that I wish our essayists were imitating -- it's what's distinctive and great about Scott's pieces.
Different people value different things about Scott's essays. I'd rather not unduly influence voting by sharing my own scores, but I read all the finalists (and most of the review submissions period) prior to selection, and the Joan of Arc one was one of my personal favorites, and I considered it comparably interesting and worthwhile to one of Scott's usual reviews, while clearly not being particularly stylistically similar.
I read a ton of stuff including Scott's writing because I'm a very curious person. I see nothing odd at all about enjoying this essay and others dissimilar to Scott's work.
I'm surprised my grumble stirred as much response as it has. I think I should explain a little better what's on my mind. To put it much less tactfully than I did before: These finalist essays aren't just different in style from Scott's, they are way less good. And I don't mean that they're less good at being Scott essays than Scott's essays are, I mean they are way less good period.
There were 2 essays in among the non- finalists that I thought were extraordinarily sharp, perceptive and well-written. They were in fact not a bit Scott-like. One was called, I think. "The World," and the other called something like, "[person's name,] a Review of a Right Wing Mind." (I just now tried to find them in the list of entries, but it's glitching.) And there are probably some more in the bunch I'd think as highly of, had I read them. I only read and rated about 20. So I could understand if people had picked finalists that were Scott imitators, or if they had picked things that were smart, funny, moving and nuanced in a completely different way. I just have a hard time understanding what it was about the ones that made it to finalist that made them stand out for people.
I probably sounded like a real curmudgeon saying I didn't give a shit about Joan of Arc or participants in clinical trials. But I didn't give a shit what went on in restaurant kitchens either until I read Anthony Bourdain. The authors of Joan of Arc and the present essay could certainly have gotten me interested in their topics, if they had surprised me, or been witty a few times, or laid out some poignant truth in a way that pierced my heart, or found clever ways to convey hard-to-describe things, or stepped way back and pointed out the way the situation's analogous to -- I dunno, Godel's proof, or medieval harvest festivals. BUT: They didn't.
Your take makes perfect sense. I guess I replied to try to explain why many may have voted for the essay and I don't think it is odd: the topic is intrinsically interesting to many, and the writing quality was adequate - it doesn't need to be steller for me to want to read it.
> In general, I’m puzzled that people who were drawn here by Scott’s posts picked this pretty unScott-like bunch as top 10. It's as though a lot of people just like reading a bunch of detailed facts about a random subject.
I liked this review. In a vacuum I might have skipped it, but as the author pointed out, it helps completing the picture, that Scott has started painting with his older posts about clinical trials.
> It's as though a lot of people just like reading a bunch of detailed facts about a random subject
I generally like reading about new facts/perspectives on issues that affect me in some way. And ever since the corona-vaccine-discussions 5 years ago, the topic of clinical trials started to feel more relevant for me.
That being said, this review will probably not become my overall favorite, since it didn't fundamentally alter my perspective on anything, like the 3 winners from last year did.
re "In Phase I clinical trials, the participants are healthy volunteers who’re participating in research for money. There are almost no cases in which volunteer participation is driven by motivations other than money, because the attitudes between research participants and clinicians overwhelmingly tend to be characterized by mutual guarded distrust."
This early general claim about who participates in Phase 1 trials and their motivations is manifestly wrong in oncology and other high-risk disease research.
I was diagnosed earlier this year with a rare, incurable disease that has exactly one FDA-approved frontline treatment and a 100% relapse rate. When relapse comes, the only realistic option is experimental treatment. Patient support groups and physicians strongly encourage clinical trial participation, both to accelerate research for the broader community and because the trials may represent the only hope for patients. The motivations in these cases are obvious and very clearly not financial.
As for the specific claim that Phase 1 trials are healthy volunteers, I used clinicaltrials.gov to spot check the first ten Phase 1 trials returned when searching for my disease. Every one required a confirmed diagnosis and excluded healthy volunteers. I repeated the exercise with ten Phase 1 pancreatic cancer trials and found the same result: healthy volunteers were not permitted in any arm of the studies.
While I agree the current FDA standards for starting dose in a phase 1 oncology trial are too risk-averse, there is some actual benefit in understanding pharmacokinetics and pharmacodynamics at a range of doses, not just your projected efficacious dose range. It isn't all about legal liability.
True. I think this is generally on the pharma/biotech sponsoring the trial, in that the trial protocol does not allow for that, but I don't think there's a hard rule forbidding this. I'm fairly certain I have heard about phase 1 trials where low dose patients were allowed to later join a higher dose group, but I think its pretty rare for trial designs to allow these.
> I was diagnosed earlier this year with a rare, incurable disease that has exactly one FDA-approved frontline treatment and a 100% relapse rate.
Oof, that is rough!
---
I think the review is still valuable even if there are some kinds of Phase I clinical trials that it doesn't apply to; but yeah, in that case it should really give she information about that, and say what it does and doesn't apply to.
Thank you. I work in oncology and felt like I was reading something from a parallel universe. I am very sorry for your misfortune.
Phase I trials for cancer deliberately enroll the polar opposite of healthy patients: only the very sickest patients, the ones whose tumors have progressed through every treatment available and who have no treatment options left, are eligible. It’s pretty much the last step before hospice. The rationale is that these patients have nothing to lose, and, if the drug works, something to gain. (Gleevec very much did happen. Back in the early oughts I interviewed a woman who had been in an early Gleevec trial for a rare GI cancer, and the stories were absolutely Lazarus tier. Of course we’ve all been chasing that high since.)
Depends how you count it. If you're talking annual income, it's low end because you can only do so many trials in a year (places say 3 months since the last one, though I knew people who moved from company to company to circumvent this). But in money per days of your life, it's very rewarding. 15 years ago I did a trial that gave £2k for two weeks on ward (about £3k in today's money)— all tax free.
I didn't want to get a job so I funded my masters degree doing a few clinical trials. This article mirrors a lot of my experience. I had a lot of fun doing the trials, you'd get to chill out all day and have interesting conversations with a wide range of people from all walks of life.
Not all sunshine. One trial they took all the women off of the study because they got too nauseous. It could be hell for neurotics, especially anyone with any tendency towards paranoia. We had one guy leave at 4 in the morning because he thought the nurses were pumping gas through the vents in order to sterilise him.
The participants didn't seem too weird. Few had done a large number of clinical trials, so overall less professionalised than you described. We did talk about trials a fair bit, so a lot of information sharing.
The attitudes did not seem adversarial in the way you describe. There didn't seem to be a culture or assumption of deceiving the staff. My memory is that getting an adverse event sounded like a sweet deal, as you got to go home early on full pay.
I thought they were phase II. But maybe it was 1b. Concerned with refining dose parameters, exploring tolerability and pharmacokinetics, that kind of thing. But not first in human, and for healthy people.
My vague understanding of what made this different from covid challenge trials is that, in the above cases, we do already have a basically satisfactory treatment available for those diseases (but are trying to develop a better treatment, or a vaccine), so any trial participants who get too sick can be cured using known methods - whereas in the case of covid, no such treatment was available during the time when challenge trials would have been most useful.
I guess I'm not sure which of those cases Phase I medical trials are more analogous to. I think somewhere inbetween - if a novel drug has some particularly bad side effect we don't already know about, we don't *necessarily* already have a known treatment for it; however, the chance of getting a novel bad effect from a new drug seems much lower than the chance of... getting covid... from being exposed to covid on purpose.
If we were a sane society, this is how all clinical studies would operate:
1. They make a few hundred doses
2. They ship them to the “International Phase I trials factory” - a stadium-sized facility running 24/7 to inject or dose thousands of paid workers using a sort of “conveyor belt system”.
3. After a short period of waiting for your drug’s turn (not more than a few hours, if even that), anywhere from 10 to 100 workers get the doses and are placed in a secured facility where they are monitored for any side effects.
4. After 24 hours, if no one has significant side effects, one of the “Continental Phase II trials factories” - located next to the biggest airport on each continent - sends out First Class tickets (or Uber vouchers for locals) to Phase II participants, identified in advance through access to the database of all people with a particular disease.
5. After 7 days without any major side effects, all the Phase II trial participants are quickly injected or dosed at the local “conveyor belt” and placed in a secured facility for as long as the Phase II study needs to take place. They are paid very handsomely, have access to great amenities during the stay, can receive visitors, but thanks to being in a secured facility their diet and medicine intake can be strictly controlled to eliminate confounding effects.
6. Once the Phase II participants show any signs of improvement compared to the placebo group, an international Phase III study cohort is emailed a placeholder calendar invite to attend their local “Phase III study conveyor belt”.
7. Naturally, there is an internationally ratified agreement that grants clinical trial facilities sovereign immunity, removing the need to worry about liability of any kind and reducing the participant paperwork to just a few clicks in DocuSign.
Note how everything described above would be trivial to implement with modern technology, with the only impediment being that 99% of humans allow emotions to get in the way of cost-benefit-managed technocracy.
And then you'd end up with drugs which have bizarre undocumented side effects when the patient wasn't standing in line at a conveyor-belt facility for hours before each dose, or otherwise deviates from the Standard Test Environment. Plus researchers abusing their legal immunity - like diplomats who forget how parking lots work, or possibly in far worse ways. https://www.teamfortress.com/tf06_thenakedandthedead/#f=128
Those issues can probably be patched somehow, and it might plausibly still end up as a better system than we currently have, on net, but "emotional" isn't the same as "baseless."
The "safetyism" concerns all seems downstream of our litigiousness, no? These clinics are worried about large civil judgements because someone took an 'experimental drug' and then had a baby with a birth defect.
I wonder if there could be some level of indemnification against civil litigation put in place as a way to help align incentives better.
(This would naturally never become a law because it would expose politicians who voted for it to public backlash when they "sided with big phrama" against honest, hard-working Phase I Clinical Trial participants whose sperm caused birth defects.)
If clinical trial participants were organized as a labor union, individual adverse outcomes could be paid off in the short term from the union's pooled assets, then used as leverage at the next par-rate negotiating session, rather than clogging up the public judicial system.
>Participants in later phases of clinical trials probably are exposed to at least slightly greater risks of side effects and adverse reactions than they would be if Phase I clinical trials didn’t feature perverse incentives against reporting, and filter for a population generally disinclined to do so.
If it's true that later phases are too underpowered to detect safety and tolerability, and Phase 1 participants are disincentivised to report issues, then these side effects could be bumped up to the general population.
Also, why do so many Phase 1 trials select an unusually healthy, tolerant and unallergic participant population? I would expect between animal trials and later phases, Phase 1 wouldn't catch anything useful at all and the results would be totally inapplicable on a diseased(or even general) human population.
Because there are at least three functions of a ph1 trial: screen for big safety issues; make sure that the drug reaches its target and map out how it does so; and see if reaching the target has any measurable effect downstream. Clean participants reduces variability which makes it easier to map out the drug’ course through the body.
If the participants weren't all liars, Im not sure that filtering for immortals would be a great plan either.
What do they think they are doing? "we located the top 0.1% of amazingly healthy people who never have any illnesses or any side effects to any drugs, and they didn't have any side effects to this drug".
Even if you establish this, it wouldn't tell you how likely regular people are to have side effects.
I appreciated this. Short, intelligent, and an interesting perspective on a world I didn't know. Thank you!
It's powerful to realize almost all risks are taken care of by randomization. My takeaway would be to look more closely at differential attrition rates. From this description, it's possible that there are real and serious side effects in 5% of the population which show up as a 5% differential attrition rate.
Is the pharma company not blind to the individual participants, or do the trial labs themselves also suffer the perverse incentives re: not reporting side effects?
Looks like this got posted as its own comment rather than under what it's replying to.
thanks, i'll delete.
Thanks for this - I now feel at least 50% more confident in my comment the other day on the monthly links post point out that "a key issue in trial design is that lots of people want to be in a study, and simply lie to the doctors"
https://www.astralcodexten.com/p/links-for-september-2025/comment/152285966
Interesting.
In your conclusion, you note this isn't the system you'd like it to be. Is there a description by you or others elsewhere of a possibly superior alternative?
I don't think I'd recommend this, but from the viewpoint of getting the best study participants a jury duty model would work better.
If the core issue is misaligned incentives, could a couple of small tests move the needle without a policy fight?
Example: run an arm where pay is guaranteed for non-serious AEs and there’s a small, fixed “diligence” stipend for timely logs, then compared AE capture, PK/PD outliers, and dropouts to status quo. I'd think reporting would improve when volunteers aren’t worried about losing compensation.
Example: a simple cross-site operational snapshot -- Is dosing order randomized or first-come; what’s the alternate pay policy; how broad are exclusions; how are washouts enforced. Then correlate those knobs with screen-fail rates, AE capture, and protocol deviations. Even a modest, pre-registered audit might show what actually matters.
On reforms, would sponsors/CROs be open to a meaningful day-rate for alternates plus transparent randomized queueing to reduce the “race to screen”? Could contraception language be tuned to mechanism and half-life (ICH/EMA style) with a clear lay rationale? And is there room for a lightweight healthy-volunteer registry via central IRBs or sponsor contracts ---just enough to prevent dual-enrollment and stacked washouts - without waiting on federal law?
Have versions of these have been tried and failed? They seem testable and pleasantly boring -- the best kind of fix.
I'm not sure what you mean by "pay is guaranteed for non-serious AEs." If you mean that participants are guaranteed to be paid for their participation in the study, I don't think that would help much if they're worried about being ruled out of future studies. If you mean that participants would be paid for reporting AEs, that seems like a perverse incentive guaranteed to result in an explosion of AE reports. The people conducting the study don't know the true rate of AEs they're trying to capture (otherwise they wouldn't have to try to study it!) and they have to be careful that they don't set up incentives that result in overshooting the true rate as well as undershooting it.
Oh, I see. I’m not proposing pay-per-AE, just AE-neutral compensation (base pay plus a small fixed compliance stipend regardless of what’s reported) plus a future-eligibility guardrail so routine grade-1/2, expected AEs don’t automatically hurt eligibility unless a clinician flags a real contraindication. Pilot that and track diary timeliness, concordance with labs/PK, and dropouts vs. status quo.
That seems worth testing, but this strikes me as something of a coordination problem. If research participants systematically expect clinics not to be trustworthy to cooperate with (because from their perspective, they're usually not,) then a single clinic guaranteeing that reporting AEs won't hurt eligibility at that clinic may not see much difference, because they're still working with the same participant population, whose expectations are normed on all the other clinics.
If one clinic tests a bunch of variations in procedure, and sees no differences in results, it might be a mistake to conclude that there would be no differences in results if changes were propagated across the whole clinical landscape, and there was enough time for those changes to be reflected in the expectations of participants.
Totally agree on the coordination problem. A single site won’t reset priors. Would it make sense to treat the sponsor/CRO (or a central IRB) as the unit of change and run a staggered multi-site pilot where several clinics adopt AE-neutral pay plus a grade-1/2 eligibility guardrail with a dated, public policy? Start dates randomized by site; evaluate with a simple diff-in-diff on diary timeliness, lab/PK concordance, and dropouts.
To make the commitment credible to volunteers, what about a “portable guarantee” across participating sites, i.e. a benign AE reported at Site A can’t be used to exclude at Sites B/C unless a clinician adjudicates a real contraindication...and implement the same workflow via shared ePRO/payment vendors so it’s visible and consistent?
If that still shows no movement, then the issue likely sits deeper than pay/eligibility fear; if it does, you’ve got a template ready to scale.
holy shit, i want sixteen of you in every corporate entity doing anything important
Appreciate it. If you know a sponsor or CRO willing to pilot AE-neutral comp + a light eligibility guardrail, I’ll draft the one-pager.
wrong part of the industry, but i’ll run an eye down my linkedin and see if there’s a possible in
Thanks, happy to DM you the one-pager. If a name pops, I can tailor it for them.
I enjoyed this review, it's a pretty niche topic but one I'm familiar with because ~20 years ago I participated in a handful of these types of clinical trials and now I'm helping to plan them.
I've done about a dozen or so Phase 1 trials, and two groups of people I would say you missed in your "who does these trials" sections is:
1) Backpackers, and
2) Foreign students
I think the whole 'no experience required' part attracts less "shady" characters than you seem to have encountered, and more just people who need to make money asap and can't go via the conventional route. I did my trials mostly during COVID in one of the most locked down cities in the world (Melbourne) so that might have contributed.
By contrast I don't think I ever actually encountered personally anyone who seemed all that shady to me. I heard a few stories of people shagging in the bathrooms but beyond that the overall vibe of the people seemed mostly extraverted and friendly.
The whole 'lie at every step of the application process' rings incredibly true though. I have recruited many family members into doing these trials and the one piece of advice I always give is, no matter the question, if it's about having a health problem always say no. They once asked if I had ever smoked, and wanting not to sound too unbelievable I said I had vaped once a few months ago. That was written down as "smoker" for literally years afterwards.
This could just be the fact that you were in Australia? I assume the author was in the US. I would be very surprised if backpackers were a significant portion of this population, as people mostly do not do that kind of urban transit-hopping backpacking in the US in the first place. Students I am sure are a significant component though. If it's at all similar to the population who donates plasma, sites near major universities are likely mostly students and then mostly 'shady characters' at all other sites. But students also likely do not do the cross-country professional research participant who tries to squeeze in as many as possible.
I knew people in college who participated in trials at a company called Pharmaco. My roommate got her wisdom teeth out for free this way.
Pharmaco was located a few thousand feet from the mall and there was a little joke about a path beaten between the two by all the coeds.
Fast forward to being old, and the women I know (only women) who do these things tend to be retired or laid-off and interested in “gigs” of all sorts: the Census, poll work, substitute teaching.
One of my girlfriends, a freelancer, at sixty was also arduously climbing up two flights of stairs to deliver beer and Jell-O cups to kids too lazy to leave their apartments.
Boomer women were hard workers!
Some people, by no means suffering for funds, yet get antsy without any sort of paycheck.
I'm reminded of an interview with Leonard Nimoy's son about his dad's advice that the answer to every question you are asked during an audition interview is "Yes," which went something a little like this:
So, Leonard, we'd love for you to play Crazy Horse in our Custer's Last Stand movie. Can we ask you just a few questions?
Yes.
You know how to ride a horse?
Yes.
And you are of course an expert archer?
Yes.
And you are an expert archer on horseback?
Yes.
And you can shout Sioux curses with a perfect accent while shooting an arrow on horseback at George Armstrong Custer?
Yes.
After all, Dad used to say, they won't start filming for a few weeks, so you can always take lessons.
Perhaps he learned this from his castmate George Takei, who famously claimed before filming of "The Naked Time" that he totally knew how to fence, and then had to quickly run out and take lessons.
Not just in America. The actor who played Kyuzo, the master swordsman of The Seven Samurai, was absolutely terrible with swords. It took a lot of creative editing to make him a master.
My sales guy used to pound that in our head when I was a consultant too, "just say yes, get their money, we can subcontract any capability we don't actually have"
This was my experience of doing clinical trials in the UK— a lot of South Africans!
re "Whenever I’ve been tempted to develop a low opinion of their judgment, I’ve had to temper that with the knowledge that many of these people have apparently accumulated much more disposable income in the process than I have."
I can't help but feel a little https://xkcd.com/1827/
Obviously true.
But wouldn't it go the other way? If your investments failed, you'd be in more need of participating in clinical trials.
Sounds a good system to me! They get to study a much more realistic cross-section of the population than they would if nobody lied. It catches all the major problems (ie the ones that they test for and the ones you can't hide). As Douglas Adams said "Any remaining problems are your own."
And, as a bonus, the company is protected against being sued.
And you're providing gainful to people with criminal convictions who otherwise struggle to get jobs.
Maybe we should just adjust our vocabulary and consistently talk about "phase I subjects" instead of "healthy subjects" when referencing these studies. Some experts already do that (though I'm not sure if it's something a reviewer would flag), but I don't think it's filtered into public discourse yet.
It might be even better if we started attaching a few boilerplate words for those new to the topic:
"No side effects were observed in phase I subjects dosed with 5 mg of exampeline (Examplechuck et al., 2025). However, phase I subjects are known to differ from the healthy general population (Examplovich and Chang, 2022)."
It's more the inherent downsides of dishonesty that's the problem here.
1) It punishes honesty and makes society overall more dishonest.
2) Some people don't realize the system is built on dishonesty, and no one quite knows how much dishonesty is happening.
3) The reduced information makes some things much harder to spot. Suppose there was a drug that would have really bad effects if and only if you had taken weed (even if that weed was months ago) Currently, all the participants lie and say they have never touched weed. But if there was accurate data on whether or not they had taken weed, patterns could be spotted.
these trials are too small for that, no? without preregistration and blinding it's.... not ideal to try to get these interactions.
1. It's not the purpose of drug testing to reform society!
3. Yes, makes the link harder to spot, but that's not your primary concern. If such people have really bad effects it's better to know than have them be honest and be excluded from the trial. If you're going to market a drug what you really want to know is that it won't give any people really bad effects, then once you know it does you can start investigating (or just move on to the next contender drug)
How common is it for the drug to get rejected at Phase One?
Approximately 40% failure rate
Yes, what I'm wondering here is, how much would these flaws in safety trials cause problems if the US were to switch back to a "safety trials only" system as is often suggested?
Wow, that takes the shine off the whole idea of almost-free money, if 40% of the drugs you're testing will be deemed too dangerous even to be worth a phase two trial.
I mean, think of the awful side effects of so many drugs that actually make it to market, and then consider what might be getting filtered out.
I was hoping for more details of the author's personal experiences (I'm actually not entirely sure if the author has actually tested drugs) and some of the actual effects that he or she might have experienced.
I don't think it's always the side effects that rule a drug out. It might also be that it fails to reach the correct site within the body, or is eliminated too quickly to be of any use.
It can be about poor exposure/pharmacokinetics, not just safety issues.
Safety signals are often not about reported side effects. We can see elevated liver transaminases in the blood, or an EKG signal such as QT prolongation. It would be extraordinarily rare for a patient to die or have permanent damage from a phase I trial. We do a lot of animal toxicity testing first.
Failure in phase II due to poor efficacy (or non-superiority vs the standard of care) is even more common than Ph 1 failure, by the way. Only about 1 in 10 drug candidates will make it from phase I to commercialization.
A delightful accretion of safetyism, the cynic in me is thoroughly amused. But also, it's impressive that even an arrangement this corrupt and perverse could still be be made decently workable with enough effort.
Will the author stay anonymous? Or will the author reveal themselves and vault into the meta-business of teaching folks how to participate in Phase I trials!?
The two people who distrust white doctors reminded me of a Braver Angels discussion with two vax skeptics in 2021. One was white and MAGA, the other was black and BLM. In case you don't recall, Biden had prioritized getting black and old people vaccinated first because they had worse outcomes in aggregate.
The source of the black guy's skepticism emerged when he said "when has the government EVER prioritized the health of black people?"
Damned if you do, damned if you don't.
The bizarre thing is that a lot of times the reference point in articles (which are now on repeat) about black mistrust of the medical establishment, is the Tuskegee syphilis study - which was itself a prioritizing of the health of black people, among whom syphilis was concentrated, at least in the South. However dumb was the worship of the study design later on, to obliviously or callously continue it when treatment was established, the whole thing would not be a millstone around our necks forever and ever if there had been no such original “prioritization”.
re "Do they have any reason to think that ADHD might be associated with an increased risk? I asked, and their answer was, not at all, but better safe than sorry."
Ozempic seems to have somewhat rare but very severe side effects (that include severe depression and suicidal ideation *caused* by the drug) specifically in autistic people, and autism tends to be strongly correlated with ADHD, so there's that.
I kinda feel like you'd rather find that out in a clinical setting than patients at home. But clearly that goes entirely against recruiting only healthy subjects.
Phase 1 explicitly checks that it doesn't hurt otherwise healthy people. The sort of clinical setting you speak of is in subsequent phases.
Do you have a sources for semaglutide's different side effect profile in autistic persons? Also do other GLP-1 modifiers have similar effects?
I've definitely seen at least one, but I can't find it just now, sorry. I'll look some more later.
The link for “the asshole filter” goes to a copy of another blogger’s post. They disclose that they copied it, but don’t say they had permission to publish a copy. It seems… on brand? Anyway, I think it would be better to link to the original:
https://siderea.dreamwidth.org/1209794.html
I knew sometime who participated in these studies and he said the participants would bite the pills so they knew who was getting placebo or the real thing based on the taste.
One way around this is to put a small amount of denatonium benzoate in both the placebo and the drug capsule, so that both taste very bitter and any taste differences are masked. Is this not being done?
This seems predicated on the assumption that the participants know what the actual study drug ought to taste like in comparison to the placebo, and I don't see why that would be likely to be the case.
That's not to say they might not try, but I don't think it'd be a very reliable method for them to determine which arm they were actually assigned to.
Isn't he assuming that the placebo drug is somewhat standardised and participants know the taste of that?
I don't think that part is actually true. I know at least that I've received placebo drugs before which were all completely different from each other.
Perhaps the regulars get enough experience to become placebo connoisseurs.
Phase I trials don't usually have a placebo/control group; everyone is getting the real drug, since the goal is just to see if it's safe.
Very interesting read, thanks! I wonder if it would help if there was a country-wide database of people who participated and everyone could participate at most once in life
Yeah that’s the one thing I was seeing that could change the incentives - make the pay higher but have a nationwide tracking system that locks you out from any others for a while.
Sounds like a guild or trade union, potentially adding whole new layers of meaning to the term "scab."
I think you'd probably very quickly run out of eligible participants, because the vast majority of people wouldn't participate even once.
O1 — Structure
Phase I = safety/tolerability testing, healthy volunteers only, pre-efficacy.
Clinics = liability minimizers; participants = money maximizers.
O2 — Incentive Misalignment
Clinics overload exclusion criteria (“better safe than sorry”).
Honesty → exclusion; lying → access + pay.
Result: honesty systematically punished.
O3 — Participant Profile
Demographic: mostly male, itinerant, anti-authority, fringe investors.
Social: distrustful, contrarian, peer-networked information culture.
Not poor but opportunistic; lump-sum earners with irregular lifestyles.
O4 — Techniques of Evasion
Conceal diagnoses, meds, supplements.
Rotate across sites to bypass washout rules.
Underreport or hide adverse effects.
Share hacks to outsmart staff and maximize inclusion.
O5 — System Outcome
Data inputs skewed: populations cleaner on paper than in reality.
Safety signals muffled by underreporting + dishonest baselines.
Still functional because:
Labs catch acute harms.
Later-phase patient trials filter major risks.
O6 — Meta-State
Equilibrium: neither catastrophic nor pristine.
Science runs on dishonest substrate tolerated as “good enough.”
Cost = eroded validity, hidden risks, gray-zone ethics.
Phase I = adversarial equilibrium: participants exploit for money, clinics shield from liability, pharma tolerates distortions, yet the system limps forward because downstream filters mop up worst failures.
is this an AI summary?
This is an interesting analysis of why “paying people to do medicine-adjacent things” (eg: compensated donations) can get so much pushback: behind knee-jerk “ick”-type reactions, there’s maybe some sense that the interaction between “people optimizing for getting paid,” the typical mild dysfunction you’d see in any large organization, and the sheer stakes of healthcare, can produce quite the perverse and unanticipated outcome.
Yeah despite knowing rationally that paying people to donate blood is for the best overall, the classist/lived experience (pick one based on your persuasion) side of me istinctively thinks of which kind of person might need quick cash, be free on Wednesday morning etc and recoils at the idea of their blood being in the system
I'm suddenly imagining a dystopia in which these problems are dealt with by drafting participants the way we assign people to jury duty. Of course that would be entirely against medical ethics as we know them, but this is a dystopia. (Whether drafting people to jury duty should be against legal ethics is another question.)
Maybe we could draft people to show up for the first day, but not require them to actually participate? I'm pretty sure that would massively increase the number of people who choose to participate.
Seems a lot less bad than drafting people for actual war, and probably a lot more useful on a global level, too. I'd rather spend a year doing phase 1 trials than a year of being a soldier, so maybe we could offer it as an alternative to draft in countries that have it.
Of course if one country did this sort of draft, all other countries would still benefit from the results, which seems a meaningful practical coordination problem to me (perhaps you restrict this to only your native pharma companies). You'd also get a bunch of very different incentive issues like people pretending to have medical conditions to get out of the draft.
Medical ethics is a scam anyways, we routinely let millions of people die because we are too squeamish about maybe hurting or killing a few (probably volunteering) people through adverse effects, like due to lack of human challenge trials we never found out under which conditions which masks protect you how well from COVID.
Drafting people for war is only done under extreme and very rare conditions, and then only for a small fraction of the population (typically healthy young men). Phase I studies are happening all the time. Nobody's going to accept being drafted and forced to take potentially risky drugs on a regular Tuesday.
Sorry, I probably didn't make this clear enough: I meant I'd prefer doing pharma trials to military draft even in peace time, so I suppose the "nobody" is refuted by existence proof. Assuming you get paid the same amount of money either way, the trial seems a lot less onerous and I couldn't even rule out it being healthier in expectation depending on how physically damaging basic training is.
The US doesn't have permanent draft, but many countries do, some even draft women (Israel comes to mind). Phase 1 trials are also mostly performed on healthy young people, so I don't think there's a large difference there.
Great review, read it with interest. I feel obliged to point out that this is not what an asshole filter is, however:
> Because many research clinics do not actually bother to keep their websites up-to-date, participants are incentivized to [call and ask what's currently available], which applies an asshole filter to clinics’ participant populations. This will be relevant later.
This is a filter for *something* (know-how or initiative) but not being an asshole. The classic asshole filter is someone who says "do not email me" on their website but emails back when someone ignores that request. This means they correspond with people who ignore boundaries.
AFAICT from the post, clinics don't ask people not cal them, and therefore the people who do call are not being selected for assholery.
"Please report your entire medical history, and also if you report anything like the sort of medical history a normal person would have, we won't pay you" is an asshole filter.
I agree, but Eudai's point is correct that the part described as an "asshole filter" is not actually one.
You are conflating an EXAMPLE of an asshole filter, with the broader category of:
> "An asshole filter happens when you publicly promulgate a straitened contact boundary and then don't enforce it; or worse, reward the people who transgress it."
https://siderea.dreamwidth.org/1209794.html
I agree (as does Siderea!) that "asshole" isn't a binary condition, and I further submit that "initiative" to one person looks an AWFUL LOT like "asshole" to another.
Interesting read; thanks for sharing information that would be extremely hard to come by in any normal way.
Sounds to me like these Phase I studies should ideally just be eliminated entirely. This review is already taking the position that the later stage actual experimental patients are backstopping any catastrophic side effect risk, and that that's ethical, all of which makes sense to me. So, why not let those people access those potentially effective new drugs earlier? I realize the answer to that question is "everything about the FDA"; I mean ideally speaking: are there good arguments for keeping the Phase I system as it currently is?
I mean you always need a step where you figure out pharmacokinetics as well
Possibly not as it is, but there definitely needs to be a first-in-humans trial which doesn't involve sick people. No amount of animal testing can ever completely replace a human trial. Most - I expect the vast majority - of phase 1 trials are completely uneventful, but sometimes it does go wrong (eg https://www.bbc.co.uk/news/magazine-35766627, https://www.science.org/content/article/what-we-know-so-far-about-clinical-trial-disaster-france)
The author says that the actual medical tests during the study are the backstop. Self-reports are unreliable, but they’re not relying on them.
This sounds like the mirror image of jury duty screenings; both sets of participants are incentivized to lie, but in opposite directions.
Very good review, very honest and too honest to win. Author could have triggered us easily into another "FDA delenda est" but lowered his prospects of winning by staying honest: "How much does this actually matter? Probably not as much as you might think." Love that, big hugs! Glad you made it that far! - Now, WHY does such a truth-loving ADHS-guy take part in those studies, where lying is required? Author denies us even this voyeuristic indulgment. Again: appreciated, but no hugs aka votes.
Agreed. The writer doesn't move on from the mildly interesting and entertaining particulars to larger issues they shed some light on, which would be following the format of most of Scott's essays. In general, I’m puzzled that people who were drawn here by Scott’s posts picked this pretty unScott-like bunch as top 10. It's as though a lot of people just like reading a bunch of detailed facts about a random subject. Personally I do not give a shit about Joan of Arc or what phase 1 clinical trials are like. I'd only enjoy reading about them if the author was quite funny, or so strikingly acute in their descriptions that some paragraphs were little works of art, or used the batch of factoids they present as an entry into an issue that interests me. Maybe I don't have a soul?
Maybe it's possible for people to be drawn here by Scott's posts, but not to expect or want every comment, guest post, or book/not-a-book report to be Scott Lite?
Clearly it is possible. It is still kind of odd. The quality I am pointing to in Scott's essays that is absent in most of these finalists isn't just a stylistic quirk that I wish our essayists were imitating -- it's what's distinctive and great about Scott's pieces.
Different people value different things about Scott's essays. I'd rather not unduly influence voting by sharing my own scores, but I read all the finalists (and most of the review submissions period) prior to selection, and the Joan of Arc one was one of my personal favorites, and I considered it comparably interesting and worthwhile to one of Scott's usual reviews, while clearly not being particularly stylistically similar.
I read a ton of stuff including Scott's writing because I'm a very curious person. I see nothing odd at all about enjoying this essay and others dissimilar to Scott's work.
I'm surprised my grumble stirred as much response as it has. I think I should explain a little better what's on my mind. To put it much less tactfully than I did before: These finalist essays aren't just different in style from Scott's, they are way less good. And I don't mean that they're less good at being Scott essays than Scott's essays are, I mean they are way less good period.
There were 2 essays in among the non- finalists that I thought were extraordinarily sharp, perceptive and well-written. They were in fact not a bit Scott-like. One was called, I think. "The World," and the other called something like, "[person's name,] a Review of a Right Wing Mind." (I just now tried to find them in the list of entries, but it's glitching.) And there are probably some more in the bunch I'd think as highly of, had I read them. I only read and rated about 20. So I could understand if people had picked finalists that were Scott imitators, or if they had picked things that were smart, funny, moving and nuanced in a completely different way. I just have a hard time understanding what it was about the ones that made it to finalist that made them stand out for people.
I probably sounded like a real curmudgeon saying I didn't give a shit about Joan of Arc or participants in clinical trials. But I didn't give a shit what went on in restaurant kitchens either until I read Anthony Bourdain. The authors of Joan of Arc and the present essay could certainly have gotten me interested in their topics, if they had surprised me, or been witty a few times, or laid out some poignant truth in a way that pierced my heart, or found clever ways to convey hard-to-describe things, or stepped way back and pointed out the way the situation's analogous to -- I dunno, Godel's proof, or medieval harvest festivals. BUT: They didn't.
Your take makes perfect sense. I guess I replied to try to explain why many may have voted for the essay and I don't think it is odd: the topic is intrinsically interesting to many, and the writing quality was adequate - it doesn't need to be steller for me to want to read it.
> In general, I’m puzzled that people who were drawn here by Scott’s posts picked this pretty unScott-like bunch as top 10. It's as though a lot of people just like reading a bunch of detailed facts about a random subject.
I liked this review. In a vacuum I might have skipped it, but as the author pointed out, it helps completing the picture, that Scott has started painting with his older posts about clinical trials.
> It's as though a lot of people just like reading a bunch of detailed facts about a random subject
I generally like reading about new facts/perspectives on issues that affect me in some way. And ever since the corona-vaccine-discussions 5 years ago, the topic of clinical trials started to feel more relevant for me.
That being said, this review will probably not become my overall favorite, since it didn't fundamentally alter my perspective on anything, like the 3 winners from last year did.
re "In Phase I clinical trials, the participants are healthy volunteers who’re participating in research for money. There are almost no cases in which volunteer participation is driven by motivations other than money, because the attitudes between research participants and clinicians overwhelmingly tend to be characterized by mutual guarded distrust."
This early general claim about who participates in Phase 1 trials and their motivations is manifestly wrong in oncology and other high-risk disease research.
I was diagnosed earlier this year with a rare, incurable disease that has exactly one FDA-approved frontline treatment and a 100% relapse rate. When relapse comes, the only realistic option is experimental treatment. Patient support groups and physicians strongly encourage clinical trial participation, both to accelerate research for the broader community and because the trials may represent the only hope for patients. The motivations in these cases are obvious and very clearly not financial.
As for the specific claim that Phase 1 trials are healthy volunteers, I used clinicaltrials.gov to spot check the first ten Phase 1 trials returned when searching for my disease. Every one required a confirmed diagnosis and excluded healthy volunteers. I repeated the exercise with ten Phase 1 pancreatic cancer trials and found the same result: healthy volunteers were not permitted in any arm of the studies.
While I agree the current FDA standards for starting dose in a phase 1 oncology trial are too risk-averse, there is some actual benefit in understanding pharmacokinetics and pharmacodynamics at a range of doses, not just your projected efficacious dose range. It isn't all about legal liability.
True. I think this is generally on the pharma/biotech sponsoring the trial, in that the trial protocol does not allow for that, but I don't think there's a hard rule forbidding this. I'm fairly certain I have heard about phase 1 trials where low dose patients were allowed to later join a higher dose group, but I think its pretty rare for trial designs to allow these.
> I was diagnosed earlier this year with a rare, incurable disease that has exactly one FDA-approved frontline treatment and a 100% relapse rate.
Oof, that is rough!
---
I think the review is still valuable even if there are some kinds of Phase I clinical trials that it doesn't apply to; but yeah, in that case it should really give she information about that, and say what it does and doesn't apply to.
Thank you. I work in oncology and felt like I was reading something from a parallel universe. I am very sorry for your misfortune.
Phase I trials for cancer deliberately enroll the polar opposite of healthy patients: only the very sickest patients, the ones whose tumors have progressed through every treatment available and who have no treatment options left, are eligible. It’s pretty much the last step before hospice. The rationale is that these patients have nothing to lose, and, if the drug works, something to gain. (Gleevec very much did happen. Back in the early oughts I interviewed a woman who had been in an early Gleevec trial for a rare GI cancer, and the stories were absolutely Lazarus tier. Of course we’ve all been chasing that high since.)
I'd like to know more about this: "pays on a scale comparable to a regular job".
A regular job a McDonalds? A regular job at Google? What's the range?
Depends how you count it. If you're talking annual income, it's low end because you can only do so many trials in a year (places say 3 months since the last one, though I knew people who moved from company to company to circumvent this). But in money per days of your life, it's very rewarding. 15 years ago I did a trial that gave £2k for two weeks on ward (about £3k in today's money)— all tax free.
Oh man that's nothing. A friend just came back from 2-week trial (plus some follow-ups) and got $13k! I've done some ~$5k
I didn't want to get a job so I funded my masters degree doing a few clinical trials. This article mirrors a lot of my experience. I had a lot of fun doing the trials, you'd get to chill out all day and have interesting conversations with a wide range of people from all walks of life.
Not all sunshine. One trial they took all the women off of the study because they got too nauseous. It could be hell for neurotics, especially anyone with any tendency towards paranoia. We had one guy leave at 4 in the morning because he thought the nurses were pumping gas through the vents in order to sterilise him.
I did several phase II trials in the UK.
The participants didn't seem too weird. Few had done a large number of clinical trials, so overall less professionalised than you described. We did talk about trials a fair bit, so a lot of information sharing.
The attitudes did not seem adversarial in the way you describe. There didn't seem to be a culture or assumption of deceiving the staff. My memory is that getting an adverse event sounded like a sweet deal, as you got to go home early on full pay.
Were they actually Phase II (which I thought generally weren't paid and it would be unusual to do multiple), or is that a typo?
I thought they were phase II. But maybe it was 1b. Concerned with refining dose parameters, exploring tolerability and pharmacokinetics, that kind of thing. But not first in human, and for healthy people.
Probably pk studies then, which run in parallel to the usual 1/2/3 phase trichotomy
Awesome post. It is interesting that this is considered okay whereas human challenge trials are usually a no go.
Nah, human challenge trials are totally a thing, we even have two different accounts of rationalists participating in them (https://eukaryotewritesblog.com/2024/10/21/i-got-dysentery-so-you-dont-have-to/, https://www.vox.com/future-perfect/2019/2/21/18235136/vaccine-malaria-research-trials-volunteers).
My vague understanding of what made this different from covid challenge trials is that, in the above cases, we do already have a basically satisfactory treatment available for those diseases (but are trying to develop a better treatment, or a vaccine), so any trial participants who get too sick can be cured using known methods - whereas in the case of covid, no such treatment was available during the time when challenge trials would have been most useful.
I guess I'm not sure which of those cases Phase I medical trials are more analogous to. I think somewhere inbetween - if a novel drug has some particularly bad side effect we don't already know about, we don't *necessarily* already have a known treatment for it; however, the chance of getting a novel bad effect from a new drug seems much lower than the chance of... getting covid... from being exposed to covid on purpose.
If we were a sane society, this is how all clinical studies would operate:
1. They make a few hundred doses
2. They ship them to the “International Phase I trials factory” - a stadium-sized facility running 24/7 to inject or dose thousands of paid workers using a sort of “conveyor belt system”.
3. After a short period of waiting for your drug’s turn (not more than a few hours, if even that), anywhere from 10 to 100 workers get the doses and are placed in a secured facility where they are monitored for any side effects.
4. After 24 hours, if no one has significant side effects, one of the “Continental Phase II trials factories” - located next to the biggest airport on each continent - sends out First Class tickets (or Uber vouchers for locals) to Phase II participants, identified in advance through access to the database of all people with a particular disease.
5. After 7 days without any major side effects, all the Phase II trial participants are quickly injected or dosed at the local “conveyor belt” and placed in a secured facility for as long as the Phase II study needs to take place. They are paid very handsomely, have access to great amenities during the stay, can receive visitors, but thanks to being in a secured facility their diet and medicine intake can be strictly controlled to eliminate confounding effects.
6. Once the Phase II participants show any signs of improvement compared to the placebo group, an international Phase III study cohort is emailed a placeholder calendar invite to attend their local “Phase III study conveyor belt”.
7. Naturally, there is an internationally ratified agreement that grants clinical trial facilities sovereign immunity, removing the need to worry about liability of any kind and reducing the participant paperwork to just a few clicks in DocuSign.
Note how everything described above would be trivial to implement with modern technology, with the only impediment being that 99% of humans allow emotions to get in the way of cost-benefit-managed technocracy.
And then you'd end up with drugs which have bizarre undocumented side effects when the patient wasn't standing in line at a conveyor-belt facility for hours before each dose, or otherwise deviates from the Standard Test Environment. Plus researchers abusing their legal immunity - like diplomats who forget how parking lots work, or possibly in far worse ways. https://www.teamfortress.com/tf06_thenakedandthedead/#f=128
Those issues can probably be patched somehow, and it might plausibly still end up as a better system than we currently have, on net, but "emotional" isn't the same as "baseless."
yep, it's simply a tragedy how much busywork happens all over the globe because of lack of coordination (which would give us economies of scale)
The "safetyism" concerns all seems downstream of our litigiousness, no? These clinics are worried about large civil judgements because someone took an 'experimental drug' and then had a baby with a birth defect.
I wonder if there could be some level of indemnification against civil litigation put in place as a way to help align incentives better.
(This would naturally never become a law because it would expose politicians who voted for it to public backlash when they "sided with big phrama" against honest, hard-working Phase I Clinical Trial participants whose sperm caused birth defects.)
If clinical trial participants were organized as a labor union, individual adverse outcomes could be paid off in the short term from the union's pooled assets, then used as leverage at the next par-rate negotiating session, rather than clogging up the public judicial system.
>Participants in later phases of clinical trials probably are exposed to at least slightly greater risks of side effects and adverse reactions than they would be if Phase I clinical trials didn’t feature perverse incentives against reporting, and filter for a population generally disinclined to do so.
If it's true that later phases are too underpowered to detect safety and tolerability, and Phase 1 participants are disincentivised to report issues, then these side effects could be bumped up to the general population.
Also, why do so many Phase 1 trials select an unusually healthy, tolerant and unallergic participant population? I would expect between animal trials and later phases, Phase 1 wouldn't catch anything useful at all and the results would be totally inapplicable on a diseased(or even general) human population.
Because there are at least three functions of a ph1 trial: screen for big safety issues; make sure that the drug reaches its target and map out how it does so; and see if reaching the target has any measurable effect downstream. Clean participants reduces variability which makes it easier to map out the drug’ course through the body.
Animal trials don't catch everything; if there *IS* an adverse reaction, young healthy men are generally most likely to recover.
Copying SunKitten's example from above:
https://www.bbc.co.uk/news/magazine-35766627
If the participants weren't all liars, Im not sure that filtering for immortals would be a great plan either.
What do they think they are doing? "we located the top 0.1% of amazingly healthy people who never have any illnesses or any side effects to any drugs, and they didn't have any side effects to this drug".
Even if you establish this, it wouldn't tell you how likely regular people are to have side effects.
it's like testing (side) effects or LD50 or whatever on Keith Richards!
but likely the metabolical difference is small compared to the general population, just the pro testers are very stoic about the side effects
and if it's really bad they drop out anyway
Liked this one a lot.
Reminded me of https://www.theatlantic.com/science/archive/2015/09/life-of-a-professional-guinea-pig/406018 seems not much has changed in 10 years
This seems to be another kind of honesty tax...
https://www.theargumentmag.com/p/the-honesty-tax?triedRedirect=true
I appreciated this. Short, intelligent, and an interesting perspective on a world I didn't know. Thank you!
It's powerful to realize almost all risks are taken care of by randomization. My takeaway would be to look more closely at differential attrition rates. From this description, it's possible that there are real and serious side effects in 5% of the population which show up as a 5% differential attrition rate.
I thought this was an excellent and interesting post.
I like the writing. It is clear and informative. Unlike a lot of prose, it does not fall prey to self indulgenence.
I like the topic. The experience and the incentives of being a phase 1 clinical participant is something I have never come across before.
I like the focus. The lens of inventive structures is such an immensely valuable one to apply to almost any topic.
Kudos!
Is the pharma company not blind to the individual participants, or do the trial labs themselves also suffer the perverse incentives re: not reporting side effects?
better safe than sorry — Amy Gdala