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Comment by jseliger | Hacker News Reader

In my view, patients should have a "right to try," which is part of fundamental freedom—and this is particularly true for palliative-stage patients without a route to a cure anyway. They are risking essentially nothing.

The FDA is too slow and that's costing lives: https://marginalrevolution.com/marginalrevolution/2021/08/th.... The issue is personal for me, too, because I have a squamous cell carcinoma (SCC) recurrence in the tongue, and the treatment that is most likely to cure it is still stuck in clinical trials. In other words, there's a reasonable shot I perish because the FDA is slow, in which case I'll wind up in the "invisible graveyard" that Tabarrok discusses.

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They had this debate in China recently and the problem was conflict of interest (lots of pricey snake oil for dying patients who can come up with the money). The market has to be regulated even for dying people, if only to prevent scams.

Did the Chinese government ultimately regulate the market to protect people and prevent this kind of corruption?

The regulation is approval by a governmental agency through clinical trials

IIRC it did, though the cynic in me would suggest that by “this kind of corruption” what it prevents is the kind of corruption that government officials don't benefit from.

I trust the Chinese government less than I trust my own with regard to doing the right thing (just because it is the right thing or indeed at all), and that is a pretty low bar…

This wiki article is probably the best place to start:

https://en.m.wikipedia.org/wiki/Death_of_Wei_Zexi

Then there was some movement on the issue in 2019:

https://www.bloomberg.com/news/features/2019-12-10/cancer-tr...

I’m not sure where they ended up due to COVID happening next.

Perhaps the patients should be allowed to use experimental treatments only under the condition that it is offered for free; the upside for the company is that if it works, they get the evidence of efficacy.

This should be the solution. If they’re trials for an unproven solution, why should they pay anything at all. I’m any case, it should be the other way around; it’s the companies who should pay the person for subjecting them to something very likely to be dangerous and painful.

In any case, I agree with the sentiment here. People should have the right to choose.

> the upside for the company is that if it works, they get the evidence of efficacy.

They don't, though. They need a control group.

And that is why you shouldn't be able to ask for the experimental treatment... You should be able to ask to be part of a trial of the experimental treatment.

Remember that if 10 treatments are being tried at once, you can divide the pool of participants so that only a smallish percentage are part of the control group.

...I think that's basically how it works? If the company is running a trial, you can enroll in the trial. AFAIK being in a trial is free for participants.

Of course, there are any number of reasons someone may be rejected from the trial. If that happens, the company isn't going to just freely give them the drug anyway, because it wouldn't provide scientifically valid data. Also, no one would enroll in a trial (which carries the potential of getting the placebo) if they could get the treatment outside the trial.

The drug itself might be paid for, as well as tests under the scope of the study (which might be narrow), but services to administer the drug, and tests or treatment for effects not in the scope of the study, aren't always covered. Or, in the stupidest cases, approval gets bogged down by the drug company, patient, or administering clinic/practitioner trying to get the patient's insurance to cover whatever's not covered by the trial for so long that the patient no longer qualifies (or is dead) by the time insurance relents and agrees to pay.

I have no better words: that is evil.

Can you clarify why that is evil? Are you referring to the use of control groups or the division of the test group into several overlapping trial compounds?

I bet it's control groups.

The FDA thinks similarly. In late 2021, they canceled trials of Paxlovid because it was immoral to have a control group. They did not then _waive the trial requirement_, meaning Paxlovid was both too proven to deny but too unproven to be administered.

Having a control group, but specifically in a study only given to terminally ill patients. Leave the control group to a subsequent study after effectiveness has been established in terminally ill patients.

I understand control groups in general, those are fine. But this is specifically in trials where people are pinning their last hopes out of desperation on some medicine and some random drop of the dice seals their fate.

I agree with you in principle, but where do you draw the line for terminally ill? 100% terminal? in what time frame? 99% terminal? 90%? 50%?

I'd imagine that somebody who has, say, a 10% chance to die in 3 month, is also quite desperate.

(a) some random drop of the dice already sealed their fate. If anything, being admitted to an experimental group and then clustered into control or not, is the DM giving a second roll of the dice.

(b) most therapies don't improve prognosis in terminal cases and some make it worse. We don't know which beforehand. In the cases where the therapy makes it worse, was it therefore immoral to not put more people in the control group?

I'd argue the lack of knowledge makes it a wash morally. If we knew beforehand whether the therapy would be effective, we wouldn't need the control group, but we also wouldn't need the study.

They can then apply to launch formal clinical trials with a control group. This initial evidence of efficacy is of-course anecdotal evidence with more traceability.

I think it’s common practice to give life saving treatment to the control group after there is some measure of confidence that the drug works.

Not always. In some cases, like rabies, the control group is 100% rate of death.

It is not. There are known treatment protocols with a reasonable (25%-ish) survival rate. There is also strong evidence that some people simply develop antibodies for it, and survive it without a vaccination or any treatment at all. It is rare, but definitely possible.

The people who have already died to-date of your terminal illness aren't a good enough control group to tell that your cure works? This is the absurdity of frequentist statistics. If you can't tell the difference between recovering from the treatment and recovering by natural luck, then either the treatment is barely effective at all, or the doctor had no basis to tell you in the first place that you had a terminal illness.

That is correct, the people that have already died are unable to act as effective controls. To establish the medicine causes the disease to go away, you have to use something like a randomized trial. Otherwise, causation is not established. It’s a very difficult problem and a lot of smart people have try to come up with better systems.

With all due respect, why? This seems fallaciously wrong.

It is rather akin to saying that I can't tell whether seatbelts reduce car-crash fatalities simply by comparing collision fatalities from 1967 seatbelt-lacking car models with otherwise-identical 1968 seatbelt-equipped models; I would need to actually randomly and secretly sabotage a certain percentage of the seatbelts from 1968-model cars, while deliberately ignoring everything I know about prior fatality statistics. Even if every automobile collision without seatbelts was fatal, and every collision after seatbelts became mandatory was survived, even if nothing about the cars or driving conditions had changed, you're implying that it wouldn't provide any evidence of the efficacy of seatbelts, unless we conducted a new trial from scratch with a randomized control group as though we had no prior data?

What is the actual difference, in terms of causal evidence, between someone who died of the same disease before the study officially begins, and someone in the "control group" who dies after the study begins?

Almost nothing about medicine operates nearly as cleanly as that example; that's one of the major challenges with medical science. The seatbelt analogy breaks down in this context because the hypothetical of "Even if every automobile collision without seatbelts was fatal, and every collision after seatbelts became mandatory was survived, even if nothing about the cars or driving conditions had changed" doesn't reflect medical reality (and in the rare instances where it does, i.e. when improvement for the test group becomes obvious, immediate, and apparently side-effect free, it can become morally imperative to discontinue the control group).

In medicine, you get confounding factors like change in standard of care year-to-year and facility-to-facility. You almost never get the kind of "clean-room" trials you get in mechanical engineering (and, indeed, the processes to create them would often themselves be unethical). So the best you usually get is trying to reason around (to torture the analogy a bit) "Well we introduced seatbelts three years ago and relative to the year prior to that, fatalities went way down... Oh wait, but COVID also happened the same year we introduced seatbelts and everyone stopped driving" if you compare a current trial to past non-trial standard care as the control group.

Isn't this just the standard challenge of separation of signal and noise that exists in all disciplines, though? It seems that it would be better dealt with by general Bayesian methods than by strict adherence to a controlled-trial process that requires ignoring or even discarding large quantities of data (including every patient who ever had the disease prior to the start of the trial, which for rare diseases, might even be the majority of the data!)

> It seems that it would be better dealt with by general Bayesian methods than by strict adherence to a controlled-trial process that requires ignoring or even discarding large quantities of data

What is the Bayesian prior on "After receiving the COVID vaccination, patient died when they were struck by lightning?"

This is what I mean when I say the 'clean room' practices that are standard for most other fields of science would be considered unethical for medical trials. You can't, generally, lock people in a box for months to eliminate other confounding factors when trialing medicine; the best approach we have, therefore, is to minimize confounding factors by minimizing variables in space, time, &c. Yes, if we could lab-rat humans, keep them in controlled environments perpetually, we could use the previous in-a-box state as a comparison to the current state, probably. That's obviously a non-starter.

(There are some categories of medical research where time-variance has been used; it's just not generally an acceptable signal source, IIUC, for drug and therapy trials. If for no other reason than not nearly enough information has been captured about unrelated past patients to be compared to a current trial because relevant information to monitor was not known when monitoring past patients).

> What is the Bayesian prior on "After receiving the COVID vaccination, patient died when they were struck by lightning?"

Mathematically not difficult to deal with, which is why you intuitively know the answer already, because it's approximately the same way your brain works naturally. The chance of dying when you are struck by lightning is about 10%,[1] which completely overwhelms the chance of the vaccine coincidentally killing you at the same moment by several orders of magnitude; while you could use the this datapoint if you want, Bayesian analysis will still confirm that it has approximately zero evidence supporting (or refuting) that the vaccine causes death, so Bayes' theorem effectively drops that patient out of the analysis. Which is the same thing you'd probably have done intuitively, unless some kind of formal controlled-test study rule prevented you from doing what would normally be the correct procedure. (Or worse, forced you to subject an unvaccinated control-group patient to a lightning strike, just to maintain control...?)

But, since your patient died from the lightning strike rather than surviving it, there is a small signal present that points towards "the vaccine increased the chance of the lightning strike being fatal", which is a postulate that deserves a high initial skepticism until someone can propose a mechanism. But if you notice that multiple people die from lightning strikes after getting vaccinated, such that their lightning-strike survival rate is below the unvaccinated population's, you can start to update on that, and if it keeps happening, it becomes worth your time to investigate a potential mechanistic explanation. Like, the vaccination causing people to be less sweaty somehow.

[1] https://www.britannica.com/one-good-fact/what-are-the-odds-o...

... or the unvaccinated population tends to cluster, for sociopolitical reasons, in a region of the country, where lightning strikes are unusually powerful. IRL confounding factors abound.

Sweatiness is a good example of the sort of thing that would be hard to determine by comparing to past sample groups, since it's a rarely recorded piece of data.

Sure, so you add up those terms in the usual way, which you can do by straightforward factorization and summation, until your sum has diminished to probabilities small enough to round off.

This mathematical procedure is usually called "applied common sense", and if you are attempting to argue that it's impossible, you would in the process be proving that nobody can ever learn anything about anything.

You're still assuming that we know all the terms. We use randomized trials with controls improving out medicines because we almost never have enough information to compare two situationally different groups. In a controlled randomized trial, we can declare what we're testing and what we're measuring up front. The data is just too messy, otherwise. Too many hidden variables and too many possible alternate explanations that weren't measured.

> After receiving the COVID vaccination, patient died when they were struck by lightning?

That is a valid concern and is one of the three known serious adverse events (SAE) experienced during the Moderna covid-19 vaccine testing.

https://www.fda.gov/media/144434/download

> As of December 6, 2020, there were 3 SAEs reported in the vaccine group: a 65-year-old participant with community acquired pneumonia 25 days after vaccination, a 72-year-old participant with arrhythmia after being struck by lightning 28 days after vaccination, and an 87- year-old participant with worsening of chronic bradycardia 45 days after vaccination. On FDA review of the narratives, none of these SAEs are assessed as related. There were no cases of severe COVID-19 reported in the study.

(/s if needed)

Bayesian approaches alone are not enough to establish causality. I say this as someone using bayesian approaches in a causal analysis. Causality is intricately linked to the processes that underly how data is generated. Two different processes can lead to the same probabilistic results.

You don't necessarily need to establish causality in one grand step; it can still be effective to accumulate evidence of causality, even if this evidence cannot distinguish between other competing non-causal explanations.

The process in which a treatment is administered might change the way people behave, changing outcomes. Trials with control groups are easier to justify as having avoided these issues.

If you're interested in learning more, I would recommend learning about Judea Pearl's do-calculus, specifically the backdoor criterion. Although it isn't the end-all of causal analysis, it is a very useful non-experimental approach that will help you develop an appreciation for the benefits of controlled experiments.

As far as seat belts go, that's actually been something discussed a bit in economics. The main concern is if adding seat belts changes how people drive (confounding the actual effects of seat belts). The solution was to measure the protective effect of seat belts on occupants of the passenger seat in collisions involving drunk drivers.

If a disease at a certain well defined stage has a 100% fatality rate after 6 months, why would you need a double blind trial if some patients are still alive 1 year after taking your drug ?

The causality is pretty clear and while you might not claim that it double the life expectancy it would IMHO be immoral not to fast track the approval of that drug.

People who already died are less effective controls than double-blind controls getting a placebo, but they're not ineffective.

Given a treatment with a large effect size like penicillin, a causal link will be very easy to establish even with a suboptimal control group.

They don’t exactly need a control group if the chance of living N weeks is effectively zero. They would need it for something like living N weeks and living N+1 weeks, but any kind of change from an individual expected outcome would be useful signal for maybe more rigorous testing.

> They don't [get evidence of efficacy], though. They need a control group.

This is false. Control groups, preferably in double-blind studies, are an essential part of best practices. However, the bar for what constitutes evidence is much lower than that.

Evidence is any fact that makes a relevant conclusion more or less likely. Evidence need not be conclusive in and of itself. Over time, the cumulative effects of less-strong evidence can form the basis for a reasonable inductive conclusion. Sorry to be trite, but as an example, a person can have evidence that their romantic partner loves them without the use of an identical twin.

Insisting on gold standard medical evidence before allowing someone to undergo life-saving treatment—when the preponderance of the evidence that does exist supports that treatment—is, to be blunt, the very definition of depraved heart murder. It demonstrates a wanton disregard toward human life in the face of the known likelihood that it will result in some number of deaths.

More broadly, however, it is an extremely poor policy, in that this meme both weakens society's critical thinking generally and—among those who see through the elitist charade—significantly weakens the respect of those scientists who make the claim.

> Control groups, preferably in double-blind studies, are an essential part of best practices.

I wouldn't go that far. I think that a paradigm built upon a broader evidence base -- e.g. with far more extensive postmarketing surveillance of drugs -- would be more ethical, of more benefit to society, and ultimately more effective.

Double-blinded studies can miss, can be confounded by placebo effects, can easily be confounded by crooked researchers, and are frequently just plain unethical from first principles. I don't think that they should be considered "essential."

I think all your criticisms of randomized controlled trials (apart from the ethical one) apply to your suggested approach, no?

RCTs are the gold standard for demonstrating efficacy precisely because of the controls. I agree that they're not going to give you enough info about potential side-effects - a thorough monitoring program is definitely necessary for that.

But without RCTs, showing that a drug works would be much harder. How would you weed out the snake oil?

RCTs were not required and were rarely performed prior to 1962, and yet that period from roughly 1940 to 1960 is still today widely known as "the Golden Age of drug development." How did they know, back then, that new drugs work? Simple: They have sufficiently powerful (in a statistical sense) effects in a patient population. Very powerful effects require a very small population -- this applies to ALL drugs that are curative -- whereas moderate effects would require a large population. Reasonably sized safety trials and extensive postmarketing surveillance are entirely sufficient.

> How would you weed out the snake oil?

The current paradigm is "better 10,000 people die of neglect than 1 person die of snake oil or quackery." I'm okay with a little bit of snake oil if it means that more drugs are being introduced more quickly, and I trust practitioners and patients to, more often than not, determine the therapeutic regimens that are right for them.

Those were also small molecule drugs which are relatively simple to produce compared to modern large molecule drugs (biologics such as modern insulin, mrna vaccines, humira, many cancer drugs, etc.)

You might be surprised that the modern processes for true biologicals like peptides and mRNA are actually simpler than the chemical processes for classic drugs. E.g. solid state peptide synthesis. Once you can make a 10 peptide one, you can make a 1000 unit one in an identical way with more iteration.

Compare that to establishing a bespoke chemical process for each drug, or messing with purification of natural biologicals, or fusing antibodies to protein or peptides to grow inside a whole cell.

They should be actually cheap. They aren't because new.

Humira is quite a bit harder to manufacture cleanly than a peptide or mRNA, and still harder than a plain solid state synthesized and folded protein. It requires a lot of post translational modification, which means cellular machinery, which means a whole bacterial cell you now have to grow, feed and remove from the product.

I see! My intuition was that it would be hard to evaluate efficacy without RCTs - I assumed low effect sizes, which I guess is not necessarily true for many drugs.

Agreed that there should be a faster way to trial drugs and get them to market. Though I've heard that the "slowness" of the FDA is actually overstated; not sure how true that claim is.

There is a standard of evidence above guesswork and below controlled trials, that is still useful: you accumulate enough survival rate data of whatever specific terminal condition you're hoping to treat, and compare it to the baseline untreated survival rate, which is already known.

Any statistically significant difference there can then incentivize a drug research company to invest in the (expensive) clinical controlled trial process.

It's strange that people here are actually saying it's better to waste perfectly good research opportunities and watch patients die, than to risk having anything less than perfect evidence of efficacy.

This sounds like the best way to do it.

The company would still need a blinded control group to be able to demonstrate the effectiveness of any treatment.

However patients should be allowed to enroll for free into multiple treatment trials at the same time. For a given number of people and treatments, enrolling in multiple trials simultaneously gives more science output, and more chance of success for the participants, if you assume that ineffective treatments rarely are very harmful.

"However patients should be allowed to enroll for free into multiple treatment trials at the same time."

But this would likely mess up any data, you can get. How can you tie the cure or the bad sideeffects to any drug then?

Apart from that, sure, I think patients should have the right to try anything.

Bad side effects caused by participating in other trials would happen with equal frequencies in the control group.

You just end up with a matrix of treatments. Whatever results you observe from someone undergoing treatments X & Y goes in the "X&Y" box, not the X box and the Y box.

But you would need much more participants in all trials, to make up for all those new combos that you now have to consider.

Also: I can imagine that most of the patients would be eager to engage in all possible treatments. You might not even have a control group that did not participate in the study of the faulty drug X

Then all you get is data about the effectiveness of XY. Would it be any better if only X was tested, but it turned out that that one drug 'X' contained two separate active ingredients, each of which the pharmaceutical company thought would probably be an effective treatment?

That would be the bare minimum in practice. That’s already the case: without premarketing approval (clinical trials), companies are not allowed to charge anything for medicine or medical devices. They’re not even legally allowed to ship them interstate until the premarketing application is accepted.

This is how it already works - this is what a clinical trial is. If you want to include the data point of a medicine working well as admissible, then you better have more than one patient try it at a time. Unless of course your drug is so good at curing patients who are absolutely terminal (like ibrutinib was). But most meds are not that much of a blockbuster. Thus you don’t know if a single patient survived if it’s because this medicine was very effective or if it was just as good as any other available treatment regimen.

>This is how it already works - this is what a clinical trial is.

That's not at all how clinical trials work. If and when someone decides to advance a drug to the next stage of development, it's done because they think there's a sufficiently profitable market at the end of the road. So lots of extremely promising drugs stall out if the numbers don't make sense. Furthermore, the trial enrollment process itself is cumbersome and often your only entrypoint is email "trials@pharmacompany.com" and hope you can a response and can navigate their arbitrary screening process. Speaking of screening: trials are full of exclusion criteria. They can get copy-pasted between trial protocols and often have no real reason excluding you. What's the washout period for your last line of chemo? Ever had any kind of immunotherapy? &c &c From the point of view of whoever is trying to get a drug approved it's better to be safe than sorry wrt any kind of uncertainty in a patient's medical status or treatment history. But that means that there might be a drug that looks extremely promising from previous trials but the only current trial excludes you for a small reason.

I assume they meant that clinical trials are already free for the patient, as suggested by the comment they were responding to.

They're free but not accessible, it's a universe away from compassionate use access wrt practical availability.

The problem with clinical trials is that they are looking for specific patients, though. And they will exclude patients that introduce confounding variables. Some studies exclude patients that are closest to death because they will interfere with the trial as well.

Meh, why not just let some people get fleeced...?

"Sorry, you can't buy cars privately any more -- you need a gov't agency to make sure you don't get screwed. You cannot fend for yourself, right?"

I know the reason, and it’s a doozy. Send me $5 and I’ll let you in on the secret.

Would you feel the same if they got an "experimental treatment" from some quack who ended up giving them a highly dangerous chemical which resulted in a slow and extremely painful death? Because that is 100% what is going to happen when you remove all regulations for experimental medicine.

Similarly, you already cannot buy all cars privately anymore. Business-to-consumer is highly regulated (that's what the Federal Motor Vehicle Safety Standards are for, but home-built cars also need to pass several inspections before they are allowed on the road.

No, not really. That's life... you're taking a risk.

Taking a risk just driving a car, I don't get why you can't take a risk with a medicine.

I was going to make this point. People at EOL by default often have estates, investments, retirement accounts. In other words huge chunks of money/wealth that unscrupulous people may wish to get their hands on. Combine that with the desperation of a dying person and you have the perfect condition to create a very profitable scammer market for worthless treatments.

This also harms eveyone because all the money pouring into a treatment that was a scam from day one is oppertunitu y lost.

I think the argument is to loosen the regulation on human trials, not to drop all regulation on drug companies. They should still have to prove that they’re doing legitimate research and have had some success before opening it up to humans who are terminally ill. They should still be legally culpable for negligence and fraud.

Keep in mind that it's not the pharma companies that are the only, or even most notorious, scammers that would benefit. Families of the dying one are a major risk factor. The difficult[0] truth is, plenty of families would accelerate the demise of a terminally ill or elderly[1] if it were possible. Like with euthanasia, any elective experimental treatment that carries increased risk of death, could become something the patients get pressured or manipulated into by their families.

[0] - The situations can be ethically and emotionally complex, so I'm not passing any generalized judgement, other that this is something a person might be concerned about when contemplating the possibility of ending up in this situation in the future.

[1] - Arguably the same thing, but that's another topic.

> This also harms eveyone because all the money pouring into a treatment that was a scam from day one is oppertunitu y lost.

You guys remember Theranos? When Safeway announced their deal with Theranos in 2012, a bunch of companies working in blood diagnostics folded because they couldn’t raise money or because their investors clawed back entire rounds.

A couple of friends had just raised a series B round to commercialize their surface plasmon resonance blood testing device, which would have actually done what Theranos promised with onsite blood testing (except with proper blood draw, not a finger prick). They were getting the product ready for golden standard testing with a CRO when investors decided it wasn’t worth trying to compete with a Theranos already in the pocket of major pharmacies and pulled the series B funding.

Patents ended up getting sold to some patent troll shortly before the news broke that Theranos was a scam.

The people who funded Theranos weren’t even desperate, just greedy. Imagine what fingers they’ll put on the scales when they’re actually staring death right in the face? It’ll be a disaster.

As a general principle, any set of circumstances which results in net increased influence of people who are demonstrably amoral with regard to the public welfare, should have as many barriers as possible put up to obstruct the success of such people.

Bad money chases out good, increasing the fraction of money in bad hands by billions or tens of billions is going to have a palpable effect on the stability of the world.

There are tradeoffs here, but the current approach seems to protect people's inheritances better than people's lives.

Selling straight up snake oil is still fraud, and letting money be thrown at overhyped but ineffective treatments is a smaller tragedy than forcing people to die when treatments exist.

Which is why there needs to be a process to approve experimental drugs as at least scientifically plausible.

There's a difference between something that works at least in a petri dish or mice, and something with no plausible mechanism of action like homoeopathy.

If they can come up with the money then who cares?

It would be a much better case for regulating if there were some external payer.

Their parents and/or kids come up with money. It is basically theft. If you are ok with theft, fine, otherwise we shouldn’t exempt it just because of the false hope it provides.

That seems like a claims and marketing issue, which is entirely separate from merely producing a drug and selling it when asked. I think it's fine that the FDA regulates advertising, I don't think it's fine that they act as gatekeepers to pharmaceutical products.

This is a very weak excuse. If preventing scams is the main concern then old people should also be banned from purchasing real estate, timeshares, large donations, perhaps even giftcards in certain quantities.

You can't have freedom without some chance of people making bad choices.

Dad asks me for a lot of money to help him buy a time share, I’ll feel ok saying no.

Dad asks me for a lot of money for a snake oil cure that might prevent him from dying from bile duct cancer in a month or two…how am I going to say no to that?

"No dad, it's a scam; there's no evidence, 100 people have taken it with no success, etc."

I have a severely disabled dad and have had this convo.

You'll find out that when your dad has just a few weeks to live, those conversations will get harder.

??? What? I don't think so? Literally experiencing this right now...

Ahhh. This answers a question I've had: I'm in the USA and one of my senators has been banging the drum for allowing patients access to experimental drugs for a few years. I have wondered why this was an issue for him. Maybe I'm cynical but this and easy PR win for him seems like good reasons why.

I guess it would depend on the reason for denial to a patient. If it is solely because it isn't regulatory approved yet then that doesn't seem sufficient. If the drug was provided for free from the pharma company it would be a faster path to a human trial which would be a win/win for all involved with the only possible negative for a person who doesn't have anything to lose.

The link you posted has a addendum which links to this: https://astralcodexten.substack.com/p/details-of-the-infant-...

In the more well researched followup by the same person, the author of Astral Codex, we see that the FDA did not block or slow the approval. It was that the manufacturer had no interest in even submitting a application. In fact, the FDA regularly granted usage exemptions, granted a broad exemption for research, and even directly funded one of the first trials even though they are not primarily a funding body.

The actual moral of the story maybe is that we should let third partys submit applications? It seems like there would be little risk of bad outcomes as they still need to do the approval process. It aligns incentives better as the people ultimately at risk can deploy resources comparable to their QoL improvement instead of the expected increased sales volume at current prices. There is a obvious problem that the production process is inextricably linked to the final output so a non-manufacturer has limited control and insight into a core component that introduces the possibility of regression, but it seems relatively doable to develop protocols for handling that if they do not already exist.

edit: To be fair, once the application was submitted it still took 6 years for approval. There are likely large procedural costs in doing the exemptions and testing that make inaction preferable. So, in some sense exemptions and lacking interest in approval may be problems of their own creation, but on net the overall outcome seems fairly reasonable. Actual improvements in procedural matters are likely too nuanced for a random layperson like myself to comment on.

> The actual moral of the story maybe is that we should let third partys submit applications?

The application isn't a single page form, it's hundreds to thousands of pages detailing everything about the clinical trials ranging from the success criteria for each phase, the doctors and hospitals involved in the trials, and even tiny details like how much blood is going to be drawn, when it will be drawn, and how it's going to be tested.

They're impossible to write without the participation of almost everyone involved in the process since a significant part of premarketing approval is quality control of the final drug manufacturing process.

Yes? I meant they should be allowed to run independent clinical trials and then submit for approval.

I also did point out that the integral nature of the manufacturing process is a obvious potential problem. It, however, does not seem like a insurmountable problem. The specifications on sourced components and the quality control processes applied to them is already integral to the drug manufacturing process. This would just move it one level further up where the final drug produced by some existing production process is a “component”. They also already approve drugs for different uses and evaluate existing drugs for new uses, so it does not seem that qualitatively different from some existing approval procedures. I am not sure of the exact details and am not proposing a specific solution, but it certainly does not seem to be a deal breaker.

Not at all in the field, but are there standardized clinical trial "frameworks" that can be used in order to simplify the process ?

Designing clinical trials from scratch is a very difficult and time consuming process so almost all of them are modeled after previous successful trials targeting the same class of medicine - as specific to the new drug as possible.

There's a lot of copy pasting followed by customization - often by "contract research organization" consultants who specialize in different types of clinical trials - but there are no "frameworks" as we would understand it in software engineering.

Patients who are near the palliative-stage can try many drugs in the FDA approval process. The doctor has to get "permission", but that is granted over 99% of the time. IIRC, it mostly involves making sure the doctor has read up on the research, believes it is necessary to save the patient's life, and agrees to report back on the treatment to the FDA.

If there really is a treatment that is significantly better than current treatments, have your doctors talked to you about this? It was codified into law about a decade ago, but that's not so new that they shouldn't be aware of the program.

I understand where you're coming from, but as the parent of someone in the field of pharmaceutical research they have a different view.

First, human beings aren't Guinea pigs. Yes, the FDA is slow - for damn good reasons. We didn't use to do things this way and then we changed it to fix problems. There are reasons things are the way they are and it's very well-understood in the medical field. Medicine is not a move fast and cause pain and suffering kind of field or move fast and kill people kind of field. They're very conservative.

Two, since human beings aren't Guinea pigs when we do do experiments on them with drugs that have been through a very thorough and extensive pipeline already, they're looking for very specific things. This tends to make a very small population of patients eligible for a trial.

Three, trials are expensive. These aren't drugs that have been scaled-out in production. The costs tend to be exceedingly exorbitant. The medical field is very well aware of the inelastic demand for their services and this opens up new avenues for the unscrupulous to prey on people. Like the used to do in the "good ol' days."

Finally, the fact the treatment you would like to pursue is still "stuck" in clinical trials is indicative they're not convinced of the efficacy of the treatment. I can tell you lots of "promising" treatments never make it out of clinical trials. That's the nature of the beast. Most ideas are dead-ends.

My advice? Don't chase unicorns. Sadly, I've watched too many people in my family die while chasing unicorns and getting obsessed with treatments that are in trial. There are always treatments in trial. Live your life and enjoy what time you have to the fullest.

The counter to this is Sam Pelzmann's "Regulation of Pharmaceutical Innovation" https://www.amazon.com/Regulation-Pharmaceutical-Innovation-...

where he shows, with statistics, that moving fast saves more lives than it costs.

Given all the human pain and suffering economists have wrought may I suggest we insist they stay in their own wheelhouse? Also, it's easy to look back, with statistics, and say had we approved a successful drug/treatment earlier then we could have saved lives. That's survivor bias as it ignores all the treatments that were found to be ineffective or worse and what those effects would have been had they been administered to a wider group earlier.

The book deals with that, specifically. It does not ignore treatments found to be ineffective or worse.

My advice to you is that if that's your view, don't take advanced drugs, but get out of my way if I want or need to, and get out of the way of others. You can pursue your path and I will pursue mine.

They say someone who represents themselves in court has a fool for a lawyer. My experience, purely anecdotal by definition, is someone who practices medicine on themselves has a fool for a doctor. I've seen too many people die faster by bucking modern medical practices. But sure. Feel free. Knock yourself out, especially since you know more than the entirety of the medical establishment.

> First, human beings aren't Guinea pigs. Yes, the FDA is slow - for damn good reasons. We didn't use to do things this way and then we changed it to fix problems. There are reasons things are the way they are and it's very well-understood in the medical field. Medicine is not a move fast and cause pain and suffering kind of field or move fast and kill people kind of field. They're very conservative.

The problem with this is that they don't appear to be optimizing for the minimization of harm, which seems very obviously to be what they should be optimizing for. Instead, they're optimizing for the minimization of harm caused by new drugs/treatments/etc., while ignoring the harm caused by disease. It's all well and good to not cause suffering through your actions, but suffering caused by inaction (or slow action) is still very much suffering that's caused by your decisions.

> Instead, they're optimizing for the minimization of harm caused by new drugs/treatments/etc.

Of course they are. From an ethics standpoint they're responsible for the harm caused to you by new drugs/treatments/etc. They're not ethically (or legally - but that's another matter) for nature harming you via the ravages of disease. If you're familiar with the education of anyone in a medical or medical-related environment then you know it's pounded in their heads to do no harm. Medical intervention is to ameliorate, not deteriorate. Medical intervention is not prescribed if it's not known to heal. That's when palliative care is called for.

I will say it again - human beings are not Guinea pigs, especially when they're dying.

> From an ethics standpoint they're responsible for the harm caused to you by new drugs/treatments/etc.

I would argue that from an ethics standpoint they're responsible for the results of their decisions. If they hold a treatment up for an extended period of time because it might have some complications, but with the benefit of hindsight it is clear that it would have saved lots of people who instead died, they bear some responsibility for those deaths.

> If you're familiar with the education of anyone in a medical or medical-related environment then you know it's pounded in their heads to do no harm.

As it should be, but the point is that harm can be done by inaction, not just by action.

Sorry to read about your illness. Without knowing specifics, it is sometimes possible to get access to trial drugs via a compassionate use exemption[0].

You could find out which centers close to you are part of the trial, and contact them about getting access to treatment.

I've previously contacted a drug manufacturers directly to inquire about access via a trial center. This was for a pancreatic cancer drug made by Halozyme. The trial was ultimately halted due to disappointing results.

Please take into account that a drug still in trial may ultimately fail to meet its endpoints, as in the above case.

[0]https://www.fda.gov/news-events/public-health-focus/expanded...

Went through this for an autoimmune condition with extreme nerve pain. Support forums are full of people that say LDN is a fantastic drug and works wonders. I was on opioids begging doctors to let me try LDN so I could get off the opids. All Refused since they weren’t familiar with LDN.

I was finally able to get it online. I no longer take pain medication. Life is basically back to normal.

and the treatment that is most likely to cure it is still stuck in clinical trials.

it seems like you are contradicting yourself. if it's likely to cure, then that would be borne out by the trial? And then it would be rushed for approval. The vast, vast majority of clinal trials for cancer are unsuccessful. A 'successful' drug may add a few months of life vs placebo at a cost of $10k or more per month.

> if it's likely to cure, then that would be borne out by the trial? And then it would be rushed for approval.

I'm not sure you know how long these things take, even when they work well.

Also, the failure to show a positive clinical effect in a trial mean one doesn't exist, especially at the individual level.

On this topic here is an excellent examination of it

https://timharford.com/2020/06/cautionary-tales-the-spreadsh...

I think that patients should be able to choose, but in reality the advantage will be for them only.

Due to the lack of control groups them taking the pill does not make the science go forward (in the sense that it is an indication for the use).

I believe however that they're is a great interest in the stopping effect: the evidence that the treatment is ultimately harmful.

Still, this is a win-win:

- if the patient gets better, good for them. Does not help the pharma company.

- if the patient gets collateral negative effects, too bad for them (but they were very bad anyway). This helps the pharma company.

Coupled with euthanasia, this would be a humanitarian solution for the extremely sick.

I'm a bit puzzled why you couldn't extract useful information even _without_ a control group. Let's say we have a disease that we know that kills you. If you take the treatment and you don't die, we have pretty damn' positive evidence it works. The control group is the... You know... Many other people that don't take the medicine and die.

This is probably a good indication, but you do not know if it is the pill that is making the effect. It may also be the placebo effect.

It may also be that on day 6 you get better (no matter of you took the pill or not), and then worse on day 20, but much worse than without the pill.

Still, this is a statistical wink so to speak (paraphrasing xkcd (https://xkcd.com/552/)).

To be clear: I am all for patients experimenting on themselves when they do not have much to lose (and whenever they please, but they have to take their responsibilities then). Plus euthanasia if the experiment goes south.

IMO opinion this is an even bigger issue with other medications. Doctors shouldn't get to decide that you should live in pain, or be trapped in a prison of your mind.

In our current society, a doctor has the unilateral decision whether to end a patients life (in so far as they are able to thrive in our society). Access to stimulant and opioid medication should be a right for patients with these conditions.

We don't need a doctor to baby us, when they would certainly have access for themselves and their children. The majority of doctors would not give up their career, move in with their parents, or tell their kids that college is not for them.

> They are risking essentially nothing.

In some cases this is true, but people often want to risk their chance of survival with conventional treatments.

Since any unproven treatment has a chance to produce immense suffering, you would need to pair this with a right to end your life too. That isn't right that exists in too many places now.

What treatment is this? Atezolizumab? (I also have recurrent SCC of the tongue.)

Moderna mRNA-4359: https://clinicaltrials.gov/ct2/show/NCT05533697.

BioNTech has a similar treatment that's also been apparently slow to launch Phase III trials.

Right to try is a cruel scam:

https://sciencebasedmedicine.org/the-cruel-sham-of-right-to-...

> So-called “right-to-try” is a cruel sham that holds out the false hope of survival to terminally ill patients and their families. In return, all they have to give up is patient protections and agree to pay to be guinea pigs to test a drug company’s product. The product of an ideology that uses the terminally ill as shields to hide the ideological motives behind the law, which are to hobble the FDA, right-to-try is a terrible idea.

Wild to say this to someone with everything to gain and little to lose. What is the terrible fate you're protecting terminally ill patients from? Is it worse than death?

There are things worse than death. And then there are things that are bad when added to deaths. In the first category might be "scammers who absorb so much cash that they prevent real cures from being researched". In the second might be "people who squander their family's financial future on magic beans in futile attempt to live, but die anyway".

No one would opt into volunteer to be in the second group. But, I can see a lot of, e.g. 50-year-olds, taking a risk thinking they can refill the college-education funds and retirement funds by just working longer than they intended.

I would imagine when dying one of the comforting thoughts is that your estate will continue being able to care for loved ones after you are gone.

I mean, end of life medical care is already incredibly expensive with very, very little benefit in terms of QALYs saved. We do it anyway. I fail to see how this is different, let people fight to live.

No one is arguing people shouldn't be able to fight to live. In fact, the post you are responding to was only talking about if things are "worse than death".

But in general for the larger point, we should make sure that people can fight to live, but that assholes aren't stealing from them by selling magic beans.

You're displaying a serious lack of reading comprehension. End of life care provided by palliative specialists is completely different to "scammers who absorb so much cash that they prevent real cures from being researched" and "people who squander their family's financial future on magic beans in futile attempt to live, but die anyway".

Historically, the protection was against death and destitution of the family when it was discovered that dad dying of consumption had mortgaged the house to the hilt to afford the overpriced opium.

With the modern social safety net, perhaps the traditional protections can be relaxed.

> Is it worse than death?

Sure, why couldn't it be? Maybe it has severe, painful side effects. There's a reason many people with stage 4 cancer and low chance of survival decide not to go back on chemo. Maybe it kills them earlier than expected. Then what?

It's a way for Big Pharma to get cheap research by dangling false hope in front of the desperate.

Of course some here would view that as a positive.

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