The emotional trial of clinical trials: like online dating with death risk
jakeseliger.com
jakeseliger.com
This was very different. The author is describing a mad scramble to get enrolled in a phase 1 clinical trial, and discussing the scramble as a life-or-death critical choice. Even ignoring the question of whether or not you're in the control arm, these kinds of trials have no guarantee of much of anything. It's even possible the drug itself might hurt you, because that's exactly what they're looking for in phase 1. Per the clinical trial registration for PDL1V:
> Part C will use the dose found in Parts A and B to find out how safe SGN-PDL1V is and if it works to treat solid tumor cancers.
(emphasis mine)
I don't know if the author knows this, but I can't imagine the stress of not being well-informed about the purpose of an experiment like this. And those doctors who are telling him things like "SGNTV had successfully shrunk a lot of tumors" is so maddening, if they didn't follow that with "...but we don't know what it will do in humans, because it's a phase 1 trial". It's not at all clear that they did, because of things like this:
> If I was given SGNTV, I’d have three systemic lines of therapy and be ineligible for PDL1V. And the same in reverse. Sophie’s Choice!
and later:
> A downside of all these phase 1b studies is that there’s little published data, which makes comparisons difficult. Oncologists almost never give numbers: “We dosed 10 patients, and the disease control rate in phase 1a was 50%.” Instead, they’ll be vague, but they’ll also indicate why they think their top trials are their top trials.
If true, this is so, so, so irresponsible. Tell people that you don't know the answer! The control could easily be better than the drug! Don't give them false hope!
So agonizing.
I should probably clarify that point; oncologists are often dealing with small numbers and a lot of uncertainty. I'm also not sure how much they're supposed to say—I don't see the NDAs or other docs they sign with drug companies. That said, if they see tumors shrink in at least some patients, that's pretty good.
I also have recurrent and metastatic squamous cell carcinoma originating in the tongue. A lot of these 1b and even 2 trials are being tested in multiple cancer types. Something can work pretty well in lung but not head and neck, or vice-versa.
They will say they don't know the answer, but I prefer having some guidance. "Good" and "bad" are also relative, particularly for what I have, which is nearly always fatal. Is SGNTV good, cause it shrinks some people's tumors, or bad, cause of all those side effects? The answer is both.
It's still useful IMO to run sanity checks on what you're told. For example, one onc said that I should try a trial very similar to this one: https://www.oncnursingnews.com/view/lenvatinib-plus-pembroli..., or one like it, that had already failed. When I checked to see what research had been published, I was baffled by the rec. I checked w/ my oncologist at UCSD, and she was also like: "I would probably not rank that trial highly."
I mean, that's all they have to go on, so it's all they can say. But it's a long way from any sort of proof, and they really should only be saying "we don't know, and you're taking part in an experiment to find out".
What you're saying about oncologists sounds quite plausible to me...there are sadly a lot of doctors who don't understand science, and it's sort of a fundamental feature of medicine that the people involved want very badly to believe in whatever they're doing. This can/does lead to people making bold claims on thin evidence.
That said, I do hope it works out for you, and I wish you the best. It's a selfless thing to take part in a clinical trial, and even more so when the stakes are so high.
Edit: regarding the pembro+lenvatinib trial article you linked (LEAP), it's not the only one that showed similar results (PFS benefit, but no OS). The CLEAR trial was similar: https://www.youtube.com/watch?v=CsN0mskqUyU
Edit 2: also, I want to add that nothing I said above was meant to imply that they should hide data, just that they should make it clear what the odds are in a phase 1 trial situation.
This is probably partly due to the history of medicine. It's not like engineering, which is fundamentally the practice of applied science. Medicine came from a very different path, basically like voodoo or witchcraft, and has been struggling to become more scientific. Many fields of medicine are fundamentally unscientific, such as chiropractic.
Also, doctors (mostly) aren't scientists or researchers at all: they're basically what non-medical engineers and scientists would consider "technicians". They use tools and knowledge the scientists and engineers have found or made, and apply them to individual problems (i.e. patients).
Of course, it doesn't help at all that the systems doctors work on (human bodies) are ridiculously complex, and themselves not at all a product of engineering. And on top of that, every human is somewhat different, so things that work on one don't work on others.
Personally, I think the entire field of western medicine, though it's still better than the ridiculously unscientific forms of traditional medicine it competes with, needs some work to improve its scientific foundations.
I think this is a fundamental misunderstanding of what doctors are communicating. Of course they can communicate medical consensus, but they can also communicate personal opinion, as fallable as it may be. It is a human interaction.
“Bess and I have learned not to wait. The healthcare system often moves slowly, and it’s good to be agentic. Insufficient agency is how people die while waiting for some indifferent bureaucrat to get back to them, or for some other bureaucratic process to spin up before the rapidly dividing cancer cells spin someone down”
So many little statements in that article ring true but I felt this deep in my core. Your notes about the onc being on vacation resurrected a little taste of the bile I had in my heart for the infuriating pace of everything.
I got to a point of deep, seething hatred for it all until one day my wife’s surgeon broke down crying on the phone. That little glimmer of humanity in what felt like a giant broken machine made me take a moment of pause and consider that some of the seeming indifference and immunity to the urgency might be self-protection. I have no idea what it’s like to work in a field where progress is so slow and the stakes are so high.
I wish you the best and thank you so much for sharing your journey so vividly. I think it really may be useful for those that find themselves in that same crucible.
And then after all of this you need to go to the next patient, smile, and do your best to make them feel comfortable and completely confident in everything you say, all the while they [understandably] see their or their loved one's case as the single most important thing in the world. If you want to create a tech solution for something, it would definitely be the paperwork. But it's mired in a million rules, regulations, and restrictions that alone probably make any sort of effort to streamline it probably unworkable if not unlawful.
The challenge is maintaining that empathy in the face of an incredibly callous system.
I do think that more often than not, the doctors appear uncaring because they're under a very similar feeling that you experienced - but all the time. If they don't build emotional barriers, they wouldn't be able to cope. I feel this is doubly true for areas like oncology where death is a much more regular occurrence and can happen even when everyone has done everything right.
I cannot fathom the feeling of having to see people wither away, to see family after family lose their loved ones. Any doctor who doesn't learn to completely distance themselves from it all is probably not going to last.
It doesn't excuse the doctors for not being direct about the choices at play: you are trying to get into an experiment where there's a 50% chance you'll get the same treatment you'd get anyway (one hopes -- it's what is supposed to happen, but some trials have been less-than-ethical), or a 50% chance you'll get a drug that might well be worse than the control.
Particularly for phase 1 trials, that last part needs to be emphasized. You're not doing it to survive. You're doing it because it's the ultimate altruism -- using your own life to find an answer that might help the next patient.
Patients absolutely enroll in ph1 trials because they want to live, and doctors enroll them because they want them to live too.
A lot of time and money goes into picking drugs that companies and doctors think will perform better than the stand of care. That's the whole reason the trial exists. It exists because there is a plausible argument it will be better than the alternative.
If the currently-available treatments mean I'm going to die, "try something that might kill me or cure me" is absolutely a thing I would consider "to save my life".
Unfortunately, by the time most people reach the "no hope" stage, the disease has processed to the point where no intervention would help.
Conversely most interventions work best at the "early detection" phase. Which (ironically) is when you're best off with proven stuff, not new experimental stuff.
This catch-22 is precisely why its so hard to get improvements in this field.
Hell, I'd go so far as to say that the oncologists who are saying this stuff probably think they're doing the right thing, and are just trying to give desperate people something to hang on to. It's difficult. But it's still necessary to make it clear what these trials are.
I don't think what you want is compatible with early stage trials.
Them not knowing the answer is well established before any conversation takes place. It's the whole point. OP isn't looking at trials that are close to being approved. They're hunting around for anything that might do anything. The super experimental stuff.
If you are taking a commercial medicine, the first place to check is the "prescribing information", which is publicly available and has all of the trial data, adverse events, efficacy, toxicology, interactions, ect. I highly recommend everyone read for any drug they take. They are usually clear and accessible, and where they are complex, that is a starting point for a informed conversation with your doctor.
It is essentially reading the user manual for the drug you are taking.
To a first approximation, about half of drug candidates fail in each phase of development (i.e. 50% drop off in every phase, from 1 to 3). Naïvely, then, about 80% of compounds tested in phase 1 will fail to become drugs.
I also don't why you think the doctor was giving false hope, or being less than candid. I think it is pretty clear that the author knows phase 1 studies are not well characterized and or proven effective.
Second: regardless of what the author understands or does not, the quotes about oncologists pointing to their favorite trial, and the like, are not OK. The only valid answer is "we don't know", because literally every drug candidate in a phase 1 trial has some claim to plausibility outside of humans, yet most fail.
However, they should be clear on what is option vs established consensus
But do those opinions have any scientific basis? If there isn’t any evidence of efficacy yet, then should a doctor say there is because it’s his or her opinion?
However, rat studies, theory, experience, ect are all evidence.
If you are navigating uncharted territory, your should listen to the opinion of your local guide. "I don't like that drug because every one of my patients that took it died horrible deaths" might not mean much statistically, but if there isn't any other data, I would want to know. Same if my doctor thinks a treatment is crazy and will never succeed.
My experience with people working through a serious medical condition at the end of their life is - people are wildly trying to be informed, about themselves, the condition, the health care system, make good decisions, and...
...it is all just happening to you. You're in a wildly careening metal shopping cart, being banged up while bouncing down a long hill surrounded by speeding traffic, and no matter which way you lean, you're not quite steering.
Seeing this, I wish there were ways people could prepare for this, short of having to lose people in their life, or personally enroll in medical school.
I don't think anyone wants to plan for this stuff. I guess the ones who do have had a few close calls, or lived it vicariously, or really love the ones they'll outlive and are planning mostly for them.
I wish you the best, and it makes me want to work even harder to hear about the challenges we still face.
If you are an inmate, or a patient you're just happy once you're out, and don't want to spend more of the time to fix.
And if you're a free or healthy person, why devote time to something that will likely not concern you? (It might some day, but few people are reflecting enough to realize this.)
Respect to the authors for writing this. It will, in time, make a big difference as other people read - like compound interest that accrues slowly but steadily.
I wish them all the best, hopefully one of the drug will work, and there will be some kind good way forward!
The amount of parties which can have some interest in keeping a broken part of the medical system broken is staggering, it can extend from researchers to doctors to insurers to the government to institutions to businesses to the patients themselves and their families AT THE SAME TIME just because of the sheer amount of money that gets thrown around even if the actual medicine is nonsense. Reforms risk fucking with the money and you DO NOT fuck with the money!
Why prisoners must be able to vote or you cannot claim to have a democracy
The amount of money at stake in our acute healthcare system is huge.
You can easily walk away from the article thinking clinical trials were a way to get cures to the public without having to go through all that messy trial stuff, and it's infuriatingly broken. It's not. It's people who are lucky to have time and energy to pursue long shots through a system that's not designed as a health care market.
This is where I strongly disagree. There's a movement out there that of you have a death sentence in form of a disease hanging over you, you should be allowed to try all kinds of I trialled medicine. But currently, in most cases, you're not allowed to.
Then there's the issue about data sharing among hospitals. Are you really suggesting, when you mention that the system is not broken, that this is working well? I wasn't able to get a doctor look at JPEGs of X-rays, because the hospital IT system only accepts DICOM files, and he's only allowed to look at what passed through the hospital IT system. WTF?!
There are all kinds of startups out there who's mission it is to fix this infrastructure, which just shows how broken the system is!
> It's people who are lucky to have time and energy to pursue long shots through a system that's not designed as a health care market.
You somehow imply that if you have the money, you should be ok with having to deal with mentioned brokenness (like have your assistant talk to the hospital nurse and have them play convert-a-DICOM before you speak to the doctor). I can't agree to that. I see zero reasons why a system "not designed as a health care market" should be broken like this; having a better system in place would massively help scientists to produce research faster since less time is lost with admin, data wrangling etc. The fact that rich people can get some use out of this system isn't proof that the current state is an acceptable one.