Though it could certainly inspire such a study.

Sure, but someone needs to fund, organize, and conduct the study. If you're not at a research hospital it's not as easy for a one off case to generate a study.

This is a fairly innocuous change the doctor should be organizing on their own to publish a pilot study. In terms of funding very little would be required since you’re just making a small adjustment to when an existing drug regimen is happening which you already isn’t a controlled factor requiring FDA oversight or anything.

Even simple studies are expensive and difficult. You need IRB approval, data collection and organization, staff to do those things. It seems simple from the outside but making it happen takes time, effort, and money which then means also applying for grants which is a process in and of itself.

It's no wonder biology hasn't even entered into the punch-card phase.

When I did my bio undergrad I was keenly aware our bodies are just scaled up molecular machines. I was hoping for a future where we'd grow MHC-neutral clonal bodies for organ harvesting.

Nope. We're in the stone age.

Move fast and break things in human medicine means unethical researchers maim and kill people, often marginalized people. Nazis, Japanese experimenting on prisoners, Tuskegee airmen syphilis experiments, Cincinnati radiation experiments and many others stand as testament to what ambitious unethical scientists will do to further their knowledge and career. Thus we have strict guardrails that slow down how we do things.

I am close with a few folks in medical research and the broken nature of the system and sheer amount of red tape has broken their dreams. It is impossible to get anything done.

There is a difference between "reasonable guardrails" and suffocating progress until it's nearly impossible barring Herculean efforts by multibillion dollar entities. It cannot be understated how badly the current bureaucracy has destroyed medical progress.

We are seeing the same problem with nuclear overregulation result in worse outcomes and more deaths for people globally.

There is real suffering and a human cost, measurable in lives, to slowing down progress - just as there is one for reckless progress.

I don’t disagree but the guy below you wants to grow human shells and try head transplants.

Transplant a few heads and suddenly you never get invited to another Christmas party

2017

https://nationalpost.com/health/worlds-first-human-head-tran...

I maybe wouldn’t put this on my LinkedIn

This is why we can't have nice things. I don't (mostly) doubt that poster's good intentions, but it takes only a few people with undirected ideas and flexible morals or empathy to necessitate strict rules around medical research.

good! old, dinosaur like systems need to be forgotten already.

We've been able to clone mammals for 30 years and haven't acted on it. We're still toying with molecular systems beyond the limit of detection.

Clone humans. Cut off their brain stem during development. Turn off cephalization signals for good measure. Scale it up to industrial scale.

Research problems solved.

We'd have every study at our fingertips. We'd have organs and tissue and blood for everyone.

We could possibly even do whole head transplants and cure all non-blood, non-brain cancers.

But we're playing in the sand.

You might be surprised at how little of the body still functions without brain function, well, some bits of the brain, including basic homeostasis and immune system function.

We're not at all trying.

If you toss out the old rule book and provide unlimited funding, it can be made to work.

Yeah, sure. There are probably going to be only a few tens of thousands "unknown unknowns" side-effects but hey, who cares? We will figure them out, we are out of the stone age cave now!

This comment, more than any other, has sold me on the value of red tape in medical research.

Our genome is a machine, from the nucleotides to the packing, to the enzyme activity, to the metabolic flux.

Our bodies are bigger machines made of lots of little machines.

Our minds or conscious egos or "souls" are the neurotransmitter and activation activity of the connectome and all of its cells and synaptic weights and metabolic activity. They're our lived experiences for as long as our brains can function. Minds experience and produce wonderful things.

If you divorce the body from the mind, there is no "person". Just a very complicated machine. A very valuable machine full of parts.

A human body in a vegetative state is not a person. It's a dormant machine. People may have emotional attachment to that vestige, but it is no longer capable of being a person. It is not a person.

We use brain dead humans for organ transplant all the time. If you understand the premise, then it isn't that far-fetched that we might grow vegetative humans in a lab for medical use and research.

Bodies that never have brains can never become persons. They're no different from plants.

My guess is that you're either a dev or an orthopaedic surgeon, well-versed in managing the machinistic aspects of systems, but with little motivation to go beyond them.

There is decent experimental evidence to demonstrate that we are more than gene expression and the machine analogy you insist on is not a good one for understanding biological systems - see work by Michael Levin, as example.

There is a wider paradigmatic shift underway that moves from thinking about parts to processes. This refocus on relations rather than objects is very important and, for biological systems, points to a fundamentally social/collective aspect to their nature.

The machine metaphor also fails when you can no longer explain how the machine works. This is true in many areas of medicine (e.g. anasthesia) and, while we continue to believe (sometimes with enormous zeal) in the concepts that helped us in the past, we cling to them at the cost of building better understanding.

What you say isn't "wrong", but it is too limited to be a useful guide in asking new questions about things like immunotherapy treatments.

It's almost as if your undergrad biology gave you just enough information to make assumptions that aren't true?

The medical journals are filled with studies that "should have worked" and didn't.

Heck, there are a ton of studies that "should have worked" that were harmful.

So much for "we're just scaled up molecular machines".

If a study like this needs a complicated IRB approval or extra data collection vs what’s already being collected for health records, you’re doing it wrong and the process has become more important than the problem you’re trying to solve.

  > the process has become more important than the problem you’re trying to solve.

This holds true in almost every professional field for which life is on the line. Medicine, class 3 electronics, aviation.

We have a word for this, which roughly translates to "rule of paperwork". Bureaucracy.

And I think there is a reason why the bureaucracy exists in these cases. "Move fast and break things" doesn't work very well there.

What happens if your study clearly hurts people? What happens if your study clearly helps people? You find out in the first few weeks, what do you do? How do you ensure you collected enough of a sample of a general population to make your study representative? How do you ensure your patients properly consented to the study (past shameful human experiments aside, you likely need many institutions participating, so you can't control everything yourself).

Do I keep going or is the IRB approval process clearer now? There is a reason it exists.

I think once again - when the process becomes the metric it’s insane. What time things are being administered is already random and not regulated or organized. “What if it hurts” isn’t relevant for something like this because the reasoning is that the baseline is that “when” doesn’t matter, you’re still giving the same dosage. “What if it clearly helps?” What if. Then you publish a paper or give a talk at a conference and try to better mobile the medical community. Or see if the administrators are willing to help scale this up further.

> How do you ensure you collected enough of a sample of a general population to make your study representative?

You don’t need to. This would be a pilot study to check whether there’s maybe a there there before you do it larger scale to measure predictive power at population level.

> Do I keep going or is the IRB approval process clearer now? There is a reason it exists.

I think you’re completely failing to engage with the argument that this particular case about time shifting delivery of a drug should not need meaningful IRB engagement other than “I’d like to change the time I deliver the drug for 2 more patients because we had one patient respond positively and this isn’t believed to be a factor” “ok cool yup”.

You’ve jumped from no IRB to full IRB without considering the context of the problem being solved which is why I said when the process becomes the goal vs the problem you’re trying to solve - you’re imaging the worst and most complicated situations possible for a case that would never demand it.

You are approaching things from software development perspective of "what's the worst that can happen? I rollback". In the topic discussed, you cannot rollback. While you might have a reasonable suspicion that changing the time will improve some outcomes in most, you cannot be sure that it won't greatly reduce positive outcomes in many. The IRB is often in place not to stop positive outcomes, but to reduce negative ones.

No I'm not. I'm pointing out the time of administration literally is already under the discretion of the hospital. There's literally no recommendation one way or the other and hospitals administer randomly based on what's convenient for staffing (i.e. not a medical decision). A) there's nothing dangerous about taking something your doing randomly anyway and systematizing it. B) there's no plausible way this is even remotely dangerous.

> The IRB is often in place not to stop positive outcomes, but to reduce negative ones.

Research can literally be IRB exempt if it provides minimal or no risk to patients which is literally what this is. Even if you put this in the "minimal risk" category which would be extreme that's still minimal IRB oversight and approval takes ~1-3 weeks.

You're imagining IRB is something it's not even intended to be and then saying it's a reasonable bottleneck in general because of real problems it prevents and thus justified for this specific experiment (where it wouldn't be relevant).

This is top to bottom a failure to follow up - doctor's are overworked & fail to follow up on potential research results because they act more like mechanics.

We can appreciate that process is important, but at some point you're falling down a slippery slope here, surely?

We're talking about a factor that no one has previously had reason to consider important.

Of course, I don't know hard it truly is to undertake a study. I have to imagine for something like this you could write up a basic study protocol in fairly short order.

Indeed, as any ethicist worth his salt would argue: we don’t want anyone saving lives without proper approval.

Any ethicist worth your salt would presumably have no problem approving experiments that will also cost lives.

There are an endless number of parameters in medicine that can be fiddled with. If an N=1 sample were enough to convince you, all sorts of garbage would meet that pattern.

What a intellectually lazy response.

No, it would be more accurate to say "any ethicist worth his salt would argue: don't make changes that could be harmful based on a hunch"

I think it was a bit tongue in cheek, not so much lazy. Also, considering the kinds of gatekeeping and forced "concerns" I've seen some ethicists push forth just for the sake of showcasing their fixations instead of really looking at costs and benefits, I don't think it's far off the mark on reality to argue that medical ethics is worth considerable scrutiny too, and shouldn't hid behind a mantle of being above criticism.

Or you could consider if there’s reason to believe there’s a causal relationship, if there is you could change your protocol (offer it in the evening as an option), measure the improvement, publish the result and simultaneously improve your patient outcomes and move science forward.

That's why doctors publish case studies all the time -- to inspire larger scale and statistically sound studies.

The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child.

There are many things that are simply uncertain and “untrue until proven otherwise” isn’t an exclusively optimal policy.

It's ok, the strongest defenders of EBM are never going to discover anything worthwhile as they get caught in a loop of "no evidence enough to test" and "no evidence for this because nobody tests it"

Counterpoints: the detractors of this purported loop would likely neither fund the vast amounts of research they’d demand be done nor believe the results if they conflicted with their anecdata. I have yet to see a good faith argument against evidence based method that provides an effective and realistic alternative. Because that would take evidence.

The opposite approach exposes people to a lot of unnecessary and dangerous medical treatment. The evidence based approach has uncovered that stenting doesn't work[1], yet a lot of do something proponents are still installing them at great risk to patients and at great cost to medical systems.

[1] https://lowninstitute.org/stents-dont-work-a-look-back-at-th...

> The razor to use to determine whether something is actually evidenced based under uncertainty is whether you would follow the same policy if it was your own child.

What? This makes no sense. How do you explain anti-vaxxer parents with this perspective? Parents may feel they know best, but feeling and fact have nothing to do with each other.

> It’s not shameful, it’s how evidence based medicine works.

Yeah, but I'll bet nothing happened as an outcome of this. No study, no communication to anyone else. That information probably just withered on the vine.

I did a molecular bio undergrad and had classes with a bunch of pre-med students. They had zero interest in the science, just getting A's. They did care about appearance and money, driving cool cars, and dating hot partners. I know my experience is purely anecdotal and not indicative of all doctors, but I came away from my undergrad experience highly unimpressed with our medical feedstock. The only students in upper level electives that cared were the research-track students.

I talk to my doctors regularly about medicinal chemistry and biochem -- they don't know anything. It's embrassing how little they retain or care.

"Evidence-based" is a really problematic term when it is used to protect bureaucracies and medical managerialism, rather than actually interact with scientific processes in an ethical way. Their anecdote is actually a good example of why evidence-based logic is not the end-all.

So if one person injects themselves with honey and wakes up tomorrow cured from Covid, we should inject everyone with honey? That’s the exact opposite of a scientific process.

Evidence-based medicine is the scientific process. Love seeing the grandstanding on this thread against EBM without a single practical alternate proposal. Instead of complaining, what do you propose instead?

Barry James Marshall

Classic HN reply. No elaboration, explanation, nothing. What exactly am I supposed to have read from your mind?

Since no one wants to explain and you I just got downvoted, Barry James Marshall is ironically an example of EBM and is HIMSELF an active proponent of EBM.

He had a biological hypothesis that the scientific community disagreed with and tested it on himself for a case study to get data. That case study was successful and then became a clinical trial. That trial was replicated and shown to work. He then won a Nobel prize for that work and the risk he took. This is an evidence-based process. EBM doesn’t mean you disregard a N=1, it means you expand N=1 into N=10, then N=100,… before you apply something to the general population. This is loosely how phase-1,2,3,4 trials work in the US.

Dismissing EBM because of Marshall is like dismissing all of math because someone disproved a popular conjecture like the local-to-global conjecture. Sure the community sentiment had it wrong, but the systematic logical approach of Math got it right. In Marshall’s case the community sentiment had it wrong, but the EBM approach eventually got it right. Half this thread doesn’t even know what they are arguing against.

Prof. Barry Marshall is an example of why Evidence-Based Medicine works against community sentiment.

The other commenter already said, ought not to let the information wither on the vine. That's a reasonable take.

Second, "evidence-based X" is largely a euphemism and increased usage under political austerity. In Western society especially in academia by "medicine" we already assume some semblance of applied science, and so "evidence-based medicine" has been well critiqued in medical and other scientific literature, in relation to how institutions like hospital administrators and (austerity) state policies might misuse the term, etc. You are not aware of this issue, so just read some of the literature.

“You are not aware of this issue”

I’m in medical school and very aware, thank you for your condescension. Less important than my practical experience, I also have an academic degree in medical, health, and societal systems alongside my other more technical degrees. And none of my background even matters. This thread is just complaints all the way down with no actual practical solutions being mentioned. Frankly almost everyone in this thread has a fundamental misunderstanding of how the scientific process works in practice and isn’t even ready for a discussion about evidence based medicine. I’m not even a die-hard supporter of EBM, I think it has several apparent failures some of which are in this thread, but I do believe it is the best approach we practically have. I also don’t believe a collection of N=1 anecdotes means we should dismantle everything the past century in medicine has brought.

If you want a real conversation, every other alternative system of medicine has failures far worse than EBM. Which is why you don’t see practical solutions being offered anywhere in this thread just anecdotes and feelings about how the system has failed X or Y.

People don’t understand EBM is a consolidated approach to prevent anecdotal data from a single person destroying the lives of millions. Other non-scientific systems like Ayurvedic medicine are particularly susceptible and fail in multiple ways due to anecdotal data. Any holistic approach to medicine will necessarily include EBM such as an MBE or personalized approach, because holistic approaches cannot generalize research at scale. But nowhere in this entire thread do I see even a single named mention of an alternative or holistic system. Just anecdotes all the way down.

And you still didn’t answer my question. At least explain what an alternative would look like or give me a paper or link to educate my ignorant self. Instead of just saying “read some literature” like a conspiracy theorist and calling me ignorant.

[flagged]

You crossed repeatedly into personal attack in this thread. That's not ok and not allowed here.

If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.

It's great that you're in medical school and very aware, but that doesn't make it ok to break the site guidelines, which you unfortunately did repeatedly in this thread.

If you wouldn't mind reviewing https://news.ycombinator.com/newsguidelines.html and taking the intended spirit of the site more to heart, we'd be grateful.

Sorry, I was definitely snarky in my comments and if I could edit my comments to remove the snark and change the tone I would.

However, your "It's great that you're in medical school and very aware" is very patronizing and pointedly dismissive. Its a superficially polite acknowledgment that feels sarcastic rather than genuinely complimentary. I don't really mind, and I acknowledge the point you're trying to make. But if your goal is to curate a curious discussion and avoid snark you should model it too.

Sorry! You are right.

It's all too easy to fall into, and we do it too. In such cases it's good when people point it out, and I'm happy to take my own medicine.

The fix is to be more mindful of how easily this happens and edit one's comments to err on the side of unsnark. That's what I will do. If you're willing to do that as well, then HN will be better off in both cases.

(I do think it's great that you're in medical school and willing to share some of what you know on HN, but I shouldn't have singled out the "very aware" bit - that was me being passive-aggressive.)

Here’s my anecdote for your anecdote. While there certainly are doctors who care about the flashy lifestyle, I know plenty more who truly care.

Also medicine is an evidence-based practice because fundamentally our knowledge is woefully incomplete. Doctors are basically applied statisticians, the chemistry and biochemistry people are the researchers.

It is not shameful indeed. One never knows what the father had experienced if he had been given the therapy during the day.

The oncologist could have written a paper (there are many single case papers), or started a trial by himself if he was very intrigued. But of course one can’t do that for every above average case.

I have to say, in this particular case there is a very plausible mechanism and the trial would not be that hard. So it is a real shame that nothing was done with this.

Previous rounds of chemo were done on the normal morning infusion schedule and he ended up with a completely depleted immune system and was put in strict quarantine. He also got multiple infections that were life threatening.

This is the reason I started looking into the alternate dosing schedule.

Well the concept is now being studied quite closely. Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced.

https://pmc.ncbi.nlm.nih.gov/articles/PMC9599830/

I'm comfortable calling that shameful. Not on any one in particular, it's a systemic problem that could be reduced with sufficient tenacity and courage to take risks.

There's limited time and a finite supply of doctors and researchers. They can't study everything that's promising all at once, and good ideas fall through the cracks all of the time.

I think this clears a bar of things that are useful and simple to study. Theres basically no effort involved. If it ends up beneficial we just update job postings from 'daytime infusion tech' to 'nighttime infusion tech'. Instant improvement in outcomes. I doubt you even need to clear this in any way to get the study greenlit.

Agreed. Scheduling is patient discretion anyway. It's the lowest bar possible as far as I can tell.

> Had someone taken it seriously thirty years ago it's quite possible that the net amount of suffering that millions of patients have endured since then could have been reduced.

You can only say that with hindsight because of the data over the past 30 years.

What if the data showed the opposite? Then the doctor would have given his patients a worse outcome all on a "hunch".