There seems to be a growing sentiment that FDA delenda est, but if we don't fix the underlying problem that led to this situation, it will just come back.
As the author says, no one ever blames the FDA for the people it failed to save. But approve something without the certainty that it isn't potentially going to kill someone, and there will be hell to your doorstep.
Even if you want the experimental treatment, you cannot get it. Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault. This is sometimes also known as the Copenhagen interpretation of Ethics.
I remember at least three instances in my country where the authorities were forced to allow people to use experimental treatments due to media clamor.
In all three instances, the result was that the treatments were snake oil and people died that might have lived otherwise.
It's easy to say "people who have no other options should get access to experimental treatments" but the problem is that people who have other options want those too, because nobody wants to go through chemotherapy or whatever.
Immunotherapies are still immature but far from snake oil at this stage. They routinely achieve miraculous remissions but also lead to many adverse events. For most late stage tumors, chemotherapy will only, at best, increase life expectancy a bit. In my opinion, the choice is obvious.
Imminotherapies very quickly kill a significant percentage of the people who try them. So it’s a complicated balancing act when someone is likely to die in say 1-2 years but also likely to survive another 6 months.
For people who are likely to die very soon the case is more clear cut, but the people developing these treatments don’t have the resources or infrastructure to try and treat more than a tiny handful of people. Allowing people to pay for such treatments also opens the door for a huge range of bad actors which also costs lives. I am not saying the current system is great, just that there’s a lot more complexity than is obvious on the surface.
I have a good friend who went through Immunotherapy on a Stage 4 lung cancer and had an impressive recovery (all the metastasis tumours disappeared in the scan pictures I've seen). Not cured of course, but has a much longer life expectancy. So I've seen at least one anecdotal evidence that they work.
I'd say that people should be allowed to try whatever treatments they agree to have, in order to save their lives, and also in other cases. One cannot say with a straight face that a woman has sovereignty over her body and thus contraception and abortions should not be banned, and preclude that same woman from getting a treatment that can possibly save her life but has not been approved yet.
It’s unfair to call treatments untested. Medications are tested extensively. The FDA could work with sponsors to come up with a range of risk profiles and expand access.
If the treatment needs to be administrated by a doctor, it demands the resources of the hospital and connected system, for a novel process. It does introduce a real risk factor for the rest of the healthcare provider’s system and the other people counting on it. I don’t see the comparison you’re making at all, really - a novel treatment has completely different context from an abortion.
Talking about immunotherapies feels like oh yes of course it would be worth it…but should you also be able to print out a blog article about holistic medicine and demand the hospital follow that treatment plan for your illness? Should a person insisting their illness be treated with an untested therapy from a disreputable company get a hospital bed instead of you for the same condition because they arrived first?
IMO this seems like something where the burden on the medical system is at least as much of a factor as the risk to the patient.
It took about 40 years to find efficient ways to treat AIDS.
It took about one year to find efficient ways to treat COVID-19.
So, if you have a condition with a few years of life expectancy remaining, maybe it's worth it to wait for some promising scientific results to turn into an approved medicine that will cure you. If you have a few decades (e.g. the normal life expectancy), even more so. If you doctors give you a few months though, maybe the "try anything" approach is a better gamble.
I don't have an issue with people taking magic beans to heal themselves; it's the sellers who knowingly (whole other kettle of fish there) sell snake-oil that are the immoral ones.
My friends mom bought a fancy light for 2000€ that was supposed to cure her cancer. Spoiler: it did not.
Now, that wasn't in the US, and I'm pretty sure the quack device wasn't approved as a medical device. But the fact is that fraudsters will sell their fake medical products to desperate patients who have nothing left to try. These people should rot in jail.
My idea is not about quack medicine. People should be discouraged from using quack medicine, and made abundantly informed that it's guaranteed not to work, while consuming their precious time alive which other treatments might extend.
My idea is about something that has promising results in scientific trials, but may carry unknown risks, and so is not yet approved. The risks may be worth it, because the alternative is a certain and quick death.
The patients should, of course, be also abundantly informed about the risks, the odds of success, etc.
Of course, some people would do things that we would find irrational, no matter how we try to persuade them against that. This may of course be painful to see, but I don't see why should we curtail the free will of an adult in their sane mind, as long as nobody's rights are being infringed. Certain new things always look crazy even though they have merit: see vaccines, blood transfusion, etc.
Just because a treatment doesn’t work doesn’t make it snake oil. Snake oil implies intent to deceive. Untested drugs can be based on a strong theoretical foundation and still not work. I expect the majority of experimental treatments won’t work. We should be trying regardless, not just for the sake of the people taking the treatment, but for the countless people in the future who can benefit from the same treatment when it does works.
Also we should stop patronizing everyone. If someone understands the risk and their doctor agrees, just treat them.
And how do we assess whether "someone understands the risk"? Often, I suspect nobody really "understands" the risk of some minimally-tested, experimental treatment.
Yes, I suppose it could be taken that way. I wasn't intending to argue one way or the other, merely to point out that such an apparently simple condition ("if someone understands...") actually encompasses a huge amount of uncertainty, and so doesn't necessarily represent the "easy answer" that it might at first appear.
Which why in a lot of instances in our lives we are not allowed full personal autonomy. We try to minimize collateral damage as well as self-damage to some extent.
Couldn't this be solved by getting doctors' opinions? If docs says "This person's only chance of survival at the moment is chemotherapy, and it has a good chance of saving their life.", then, refuse the experimental treatment.
But if the docs say "With our current medical knowledge, this person is destined to die within $TIMEFRAME.", then, if the patient consents to try anything, even if it kills them earlier, why not?
To sibling commenters: immunotherapies aren't the only problem. There are a ton of truly evil companies out there pushing therapies that do not work, have never worked, and will never work, because they literally have no possible mechanism to ever do anything. This is a crime, but it's very very hard to prove.
And these companies get very good at gaming the system, because that is their product. They are mechanisms to commit fraud, stealing all their patients' money and all their families' hope. This is a very bad thing. And, no, I am not making any of this up, but I dare not name names here. These companies also tend to be litigious!
The impact of this is extremely severe. First, people die because they choose a truly worthless treatment that can never work, over bad ones that at least had a snowball's chance. Second, people lose faith in The System, because they think that the fraudulent treatments should have worked, so they lose faith in the good ones too. And third, R&D efforts can get redirected away: rare condition X already has a treatment, so let's put our efforts elsewhere (oh wait, no it doesn't, that was fraud, now there will never be a treatment).
We will not untangle the experimental treatments issue until we confront this problem. Just do not think that it is all in "good faith" here, or even "best effort": there is real fraud going on, committed by monsters that know exactly what they are doing to take their profit.
Steve Jobs got into alternative medicine to treat his pancreatic cancer, including trying a fruitarian diet. Since he had a rare form that isn’t as fatal as pancreatic cancer usually is, there’s a chance he could have survived significantly longer if he had instead treated it with traditional, non-experimental medicine.
A simple way to stem most snake oil is to put all payments for snake oil treatments into escrow till the treatment is approved.
Then the snake oil manufacturer can peddle their unapproved treatment to as many people as they like, but they are losing money on every dose unless the treatment turns out to be safe and effective.
Obviously you need a big team of scientists on the approval panel to make sure no snake oil salesmen are faking trial data to get their payday, but that seems solvable.
I love the innovative thinking here but I can easily think of a way to game this system. Snake Oil LLC mounts a PR campaign claiming the governmen is trying to shut them down by delaying approvals so they can't get their money so they can't undercut Big Pharma. If Snake Oil (TM) doesn't work, why have patients ponied up $X billion in fees over the years?
You have enough stories like this (plus there will inevitably be some mistakes by the FDA that will be shown to be proof of government perfidy) and the conspiracy theories will have a field day and fuel a black market.
I mean, this is just a “sufficient misinformation” argument that could be levied against literally any kind of policy. No policy can survive sufficient misinformation.
The point I am making is not a rebuttal to this specific proposal but that any such change will have an attack vector. Hell, the reason we are having this discussion is because of the (unfortunate) case of someone not being served by the current policy. Any new change to the policy will have such cases which will lead to this same discussion.
Creating an equitable drug approval process is a true dilemma.
But at the end of the day, failed treatments still kill people. Some may choose the experimental treatment, and die, over the crappy chemo, which gives them a chance to live. Escrow won’t bring them back.
True. But speeding up the search for a treatment saves many future people.
The ethical tradeoff between definitely saving a life now or probably saving many lives later is an age old problem, but one which society hasn't properly converted into laws and processes in medicine.
If I knew I were going to die, I'd at least want to try something new even if the chances were slim. If it didn't work out, at least it'd be a new data point for those that come after. That means something.
It should be a escrow release when a patient is cured.
This just winds up being cruel. We don't understand a number of diseases, and we don't know how to cure them.
But we can treat symptoms, and sometimes prevent them even if it isn't a cure. It's OK to make Insulin Plus that keeps diabetics alive longer. I have MS, and freaking trust me, I want my non-cure medicine. Without that medicine, my chances of having a very poor quality of life full of discomfort increases pretty dramatically. Lots of things are like this: No real cure, but we make folks lives better by treating symptoms or preventing some damage and things like that.
The only way to not be cruel is to give treatments that work even if they aren't a cure.
Symptoms are used to diagnose, ergo is a treatment of symptoms a cure?
Lets not forget the expansion of the DSM which pretty much incorporates every human being as having a mental health issue or sexual deviancy fetish.
There is no normal in the DSM, so would some medical experts start dialling back on diagnosing new conditions to pad out their careers and income?
That bit about the DSM is a pretty obvious layperson's point of view: It is easy to say that you fit the criteria when you forget that the symptoms need to have negative consequences on your life. And there is 'normal' - normal is a range.
There is a huge difference between being down after a loved one's death and finding yourself feeling that way for no reason or not coping 2 years later.
Considering that - there is no way to answer the last question. That's just a "what if" argument and fails to take into consideration that there is a shortage of mental health experts, and there is absolutely no need for someone to do that sort of thing.
And no, no everyone has a "sexual deviancy fetish", just for the record.
As far as 'treating symptoms'... I have MS. I take medication that slows the disease. If I had fatigue or pain, they would try to treat that too. If it causes depression - which it can - they'd try to treat that. No matter what treatments I get for symptoms, I still have the disease. There is no actual cure.
> That bit about the DSM is a pretty obvious layperson's point of view: It is easy to say that you fit the criteria when you forget that the symptoms need to have negative consequences on your life. And there is 'normal' - normal is a range.
Define normal? Likewise considering the all encompassing vagaries of some words, as noted in legislation, and the lack of detail that exists in descriptions of diagnosis and symptoms, whilst this makes it easier to generate AI's to replace some experts, its not really helping the patient is it?
>And no, no everyone has a "sexual deviancy fetish", just for the record.
Define normal.
> There is no actual cure.
You are uniquely placed to actually find a cure, because I'm reminded of how tolerant (lab) animals are when level 1 of maslows heirachy of needs exists, and I'm also reminded that (lab) animals can not convey information that an owner of a pet or intelligently constructed lab experiment could elucidate.
The phrase "Dont take no for answer" springs to mind, and Thomas Pynchon "If they can get you asking the wrong questions, they don't have to worry about answers.".
Survival of the fittest comes in all shapes and form. I know that copious amounts of histidine a precursor to histamine also causes remyelination of the nervous system, so maybe you have an amino acid lead that might be worth investigating.
> A simple way to stem most snake oil is to put all payments for snake oil treatments into escrow till the treatment is approved.
Even simpler is to prohibit payments for these experimental treatments, but let people who whould die anyway participate in them as long as it is free for them. In return the drug companies could use the outcomes as data points towards their aproval applications.
Why would a drug manufacturer do that? Why would they offeir their advanced but as of yet unaproved drugs for free? It is true it would cost them the manufacturing cost of the drug, but what they get in return is data on how efficient/safe the drug is. Assuming the drug works well they could use that data to prove their case and get approval. And if it is safe and has the desired effect they get their aproval and they could then charge for their drug as usual.
This sets the right incentives for the drug company. If they know they are selling snake oil they would be crazy to offer it for free, especially because all it would do is to prove that it does not work. If they think it can work they gamble with their own money. Which is good because the drug company knows the most about their own drug. The patient in general is not knowledgeable enough to evaluate the chances of an experimental therapy, but the drug company is.
> Even simpler is to prohibit payments for these experimental treatments, but let people who whould die anyway participate in them as long as it is free for them. In return the drug companies could use the outcomes as data points towards their aproval applications.
Hell I'd even approve my tax money to go to those companies which end up saving lives as reward.
> Even simpler is to prohibit payments for these experimental treatments, but let people who whould die anyway participate in them as long as it is free for them. In return the drug companies could use the outcomes as data points towards their aproval applications.
That would never happen for good reason. Drug companies would have every incentive to bias the results towards approval by giving the drugs to detain patients. I’m not exaggerating when I say this might be the worst idea I’ve read in this entire thread.
What do you mean with "by giving the drugs to detain patients"? Is that a typo? I don't see how companies holding on to terminally-ill patients makes the trial results look more favourable. Are you suggesting that companies might not release the bodies of the patients that died during the trial?
> Drug companies would have every incentive to bias the results towards approval by giving the drugs to detain patients.
What do you mean “detain” patients? Remember we are talking about people who have a terminal illness with no known cure. How can drug companies “bias the results”? Obviously I’m not saying we take anything they say as gospel, but in short order these patients are expected to die. If a drug managed to cure them that would be quite hard to falsify don’t you think?
> I’m not exaggerating when I say this might be the worst idea I’ve read in this entire thread.
Well, thank you. I aim to please. Are you sure that you understood the idea well? If you are, could you please explain with more words what is the misbehaviour you are worried the drug companies would commit?
Choosing appropriate patients will lead to longer survival rate unrelated to the drug in question. The whole point of double-blind studies is to avoid this.
> Well, thank you. I aim to please. Are you sure that you understood the idea well? If you are, could you please explain with more words what is the misbehaviour you are worried the drug companies would commit?
I did understood you. You, however, don't seem to understand statistics or economics. Your idea directly incentivizes drug companies to choose patients more likely to make their drugs look better. It is a truly horrible idea.
> Your idea directly incentivizes drug companies to choose patients more likely to make their drugs look better.
Yes. So? The whole patient group in question is destined to die fast. The best we currently can offer them is aleviate their discomfort and help them come to terms with their demise. If the drug company can identify a subgroup who they can possibly save and actually help those that is winning.
> You, however, don't seem to understand statistics or economics.
And you are abrasive and rude. These exclamations don’t add much of anything to the conversation. If there is something particular I am overlooking please adress that instead of speculating about the areas you think I am deficient in. Thank you.
You are aproaching it as if the question we are asking is if this is the best study design. But that is not the question we are asking. There is a patient who we believe is about to die soon. In comes a drug manufacturer and says to the patient: “you do not have to die. I think I have the cure for you”. The patient wants the drug the drug manufacturer is offering. The question is if we are to interject and stop the drug manufacturer giving the patient the drug, and if so under what circumstances.
I am saying: “yes, we should stop the drug manufacturer if the drug is not proven to be effective yet, and he is asking for money for it. There is too much of a chance that the drug manufacturer is a snake oil salesman in disguise and only wants to extract the wealth from the patient and the patient’s family. But if he is honest they can give the drug for free.”
In turn you are saying. “We should stop the drug manufacturer giving the unproven drug to the dying patient even if they are giving it for free, because it is possible that they cherry picked this patient. So though luck dear patient, you must die in the name of scientific rigour. I hope you understand.”
> You are aproaching it as if the question we are asking is if this is the best study design. But that is not the question we are asking. There is a patient who we believe is about to die soon. In comes a drug manufacturer and says to the patient: “you do not have to die. I think I have the cure for you”. The patient wants the drug the drug manufacturer is offering. The question is if we are to interject and stop the drug manufacturer giving the patient the drug, and if so under what circumstances.
This is already largely possible in most states and called "right to try".
> Do I understand you right?
No you seem not to be. Giving away drugs is fine and largely already possible. Choosing patients and then pretending that the data gathered has any reasonable statistical validity when considering general approval of a drug is totally crazy. I think there is essentially zero chance the FDA would ever go for an idea with such overt conflicts of interest so I'm happy your idea will never turn into reality.
> This is already largely possible in most states and called "right to try".
The article’s author is convinced it is not covering them. Do you know otherwise? Perhaps you should let them know. You might save a life.
> Choosing patients and then pretending that the data gathered has any reasonable statistical validity when considering general approval of a drug is totally crazy.
Would like to mention that it is your adition that the drug manufacturer chooses the patients. It was not part of my original comment. And it is not core to the idea.
One can simply imagine a protocol where the manufacturer declares their criteria (what condition, what severity[1]) and how many doses they are able to provide and those “places” get filled up with volunteers. And this of course can be made even more buletproof.
1: and before you point it out, of course if the manufacturer is only willing to test their drug on not-so-bad-but-dying people then they get approval to be used on the same selection.
This plan seems to have excellent incentive alignment and basically mirrors the system in place, but without the need to be approved for clinical trials.
Experimental treatments being available to people with no options (there must be no applicable option with a proven probability of success or this becomes very questionable) could save drug companies millions-billions in the off chance that it proves to be incompatible with human testing or fails to produce the expected effects in humans.
I would take this up a notch or two for patients in a short-range situation that is certainly fatal, opening the door for them to try treatments that have just barely crossed en-vidrio and seem to have acceptable toxicity in mouse models. This would essentially be donating one’s body to science but in a much more useful form, with the side benefit of a slim chance of life extension.
This could benefit humanity by significantly reducing time to market for some drugs and cutting costs on eventual dead-ends.
Of course, for actual efficacy, but you can tell if a treatment has a negative reaction or fails to effect the expected physiology in the expected way with a very small number of samples.
If everyone you give it to dies from reactions, or the expected effects seem to be happening on a physiological level, you don’t know much about efficacy but you do know a lot more about the eventual prospects for an actual clinical trial. It’s basically an extension of en-vidrio testing.
No, that does not set the right incentives. You have completely written off the harm of dangerous or deadly drugs.
The HepC drug Sovaldi brought in around $50B-100B in sales, but probably costs less than $50 to administer. Under your scheme it would make economic sense for a company to kill 1,000,000,000 people testing variants until they chance upon the right one because they incur no costs for administering deadly experiments.
The problem with your scheme is that human lives are valuable. A unsafe drug that causes harm or death is immensely destructive. If we want to be completely reductive, the actuarial value of a human life is around $10,000,000. A unsafe drug could kill the person resulting in a $10M loss to society. Therefore, the company should be required to escrow $10M per person until the treatment is done, paid out proportionally to any potential death or harm in excess of the gold standard treatment. Only then would the incentives be reasonably aligned.
This is obviously a very reductive treatment, but it helps illustrate the problems with unrestricted testing.
> You have completely written off the harm of dangerous or deadly drugs.
I was only talking about testing on people who we know are going to die fast because of their condition, and we do not have a way to save them in any other way. And naturally only with their consent. People who have a ticking clock and therefore willing to try anything.
This is the context the article in question talks about.
I think you forgot to price in the fact that some people live with what is effectively a time limit sometimes counted in months or weeks (like the person from the linked article).
> A simple way to stem most snake oil is to put all payments for snake oil treatments into escrow till the treatment is approved.
I doubt any company anywhere (legitimate or not) would provide drugs under such conditions. It would make much more sense to just focus on getting approval instead.
There's a trivial well-regulated market solution: medical company A registers treatment B with the FDA; patients can try experimental B from A on A's dime: let them out their money where their medicine is.
Exactly, a treatment should be free until approved by FDA.
The team would try to make the treatment an experiment useful for science. They would have no incentives to kill prematurely patients that would otherwise have lived longer. They would work in good faith.
Disclaimer: I actually had had a treatment (surgery) not yet approved, it saved my foot from amputation. This was in Europe.
The doctor was adding me to the long lists of patients he saved. He also trained other doctors to perform the surgery. Eventually the procedure was approved by FDA and in Europe. I'm glad to have contributed.
Before going on that I read all the articles related to my problem (many thanks to sci-hub) and then send a email to the surgeon. He said "I can indeed help you" (best day of my life) I didn't pay anything (only the plane tickets to get where he was)
Before approval it's research, it's an investment. When in developing phase it's normal not to make money.
After approval it's the health insurance or the patient that pay. In countries like Singapore or France the taxes pay so it's "free" (actually it's an "insurance" backed by the govt)
Let's just say I have a personal blacklist of therapeutics companies I will NEVER seriously work for (though I have done a couple things for them that satisfied my conscience), and a few electrical schematics squirreled away should I need to defend myself someday....
Id let people use unaprooved treatments labeling them with big warnings in red that this is not approved and may be snakeoil or something like that. Whoever attempts to hide, remove such labels fined severely, possible jail time. Couple of scandals of unaprooved treatments wreaking havok and very few would risk it afterwards.
Maybe someone should create a throwaway and provide a list of they’re concerned about retribution. People not calling out scum because they are afraid of the consequences of outing criminals makes the world a crappier place for everyone.
Do you have the citations for the three instances where "people died that might have lived otherwise."?
In this person's case, he will not live otherwise, so he has nothing to lose by trying an experimental therapy, although it appears to be too late anyway. Very sad.
> It's easy to say "people who have no other options should get access to experimental treatments" but the problem is that people who have other options want those too, because nobody wants to go through chemotherapy or whatever.
I reserve for myself the right to try to save my own life, even if that means some people who can't handle that responsibility make things worse for themselves. I can't get from, "but other people might hurt themselves" to "therefore you simply have to die, sorry."
No, I think we just have to be straightforward about this; I don't want anybody to purchase snake oil, but that possibility does not move me to eliminate options for myself or my family.
You say this now, but after your son, sister or mother dies after choosing snake oil, you will likely not say "I accept that they chose wrong and that's all there is to it". You will cry bloody murder and blame the system that didn't protect them from the snake oil salesmen, and demand that something be done.
Well, I of course don't know what you personally would do. But some people would do this, and it turns out, actually a lot of the people in that situation would do that. And so something gets done.
This is the same thing as crypto, people "reserving the right to take risks with their own money", and after the money is lost asking why the government didn't protect them. And the same as many other things. Humans suck at accepting the consequences of their own choices.
Nobody has a fetish of taking your choice away from you. People ask for things to be this way, because people are just human.
I agree with your description of reality. That doesn't mean that we have to accept it or say it's ok. It may be politically infeasible for the suggested policy (allowing people to choose treatments even if some people _will_ choose unwisely), or, if enacted, it may be impossible to keep it. But I will continue to advocate for it anyways. I believe in and advocate for _many_ policies that I have close to zero hope will ever be enacted.
I share the same mindset as u and I’ve been told countless times something to the effect of “yea but that’s not realistic” yet I never stop. I’ve often wondered why that is; I assume it’s just some psychological thing/on principle of not simply accepting this thing I perceive as stupid.
Additionally, I think it’s partly me just wanting to spread awareness about <stupid thing> and possibly engage smarter people than me to devise better resolutions/implementations as well.
Wondering if u have any thoughts or I’m just galaxy braining it
IMHO, the solution is not advocacy for policies where people get to choose and take the risk and get whatever results they get. Because there will generally be more people advocating for forced "good" choices.
The solution, I think, is to teach people to understand risk, choices and consequences better. With enough teaching, maybe the advocacy for the forced good will decrease.
Let's say a treatment kills 9 out of 10 people. Maybe those 9 were terminally ill & that's why they died, but maybe the company was just lying and their treatment was doing nothing or killing people more quickly. How do you determine that? When would you shutdown a "death factory"? Would you require mandatory disclosures of the death rate & risks, or could a company hide those facts from prospective patients, only talking about the patients who survived? If they can't show efficacy, should they still be allowed to sell to patients?
I think the ideal of regulation is to try to remove the guesswork & expertise required for the end user to do due diligence. It's not perfect, but at least some minimum level of regulation, such as mandatory efficacy disclosures, would be needed.
I don't fundamentally disagree with you, I just understand why, as a society we may choose a different thing.
One of the reasons my father died of cancer quickly is that he was convinced by a chiropractor/osteopath that he had trouble with his back which could be cured with manipulation.
He was not an idiot, but sick people will make bad choices.
The abstract world of "either I die or I try this experimental treatment" is far more blurry, and there lies the problem, in my very humble opinion.
That is an interesting and relevant point, but it does not apply in case of Jake and others like him -- he has no alternative where he might live.
In my opinion, the FDA ought to be more open to allowing experiments in cases where it is clear the patient is aware of the untested nature of the treatment.
It would result in tragic cases like the three you describe. During COVID-19 it would have resulted in people taking Ivermectin which was ineffective and even harmful.
But during COVID-19 it would also have resulted in determining 6 or more months earlier that the vaccines we made were safe and effective and the number of lives saved in that single instance would have greatly outnumbered the losses from 100 years of experiments.
It's easy to understand the logic of desperate patients who will try anything but it doesn't seem right to allow manufacturers to profit hand over fist selling treatments that may not even do anything, or worse, outright cause harm.
This has been a common complaint for decades. We always want to try rush experimental drugs/procedures that “show promise”.
How often do these drugs, etc turn out to effective? 25 years ago we wanted to rush gene therapy and that didn’t turn out well. Someone died. It probably set back gene therapy:
I think the solution is to invest more into medical research now, then when we, or someone we know, eventually ends up with some horrible disease, (cancer(s), Alzheimer’s, Parkinson’s, etc) we’ll know that we at least we made significant effort, and gave everyone a better chance, rather than settle for a “Hail Mary” drug near the end.
People are, perhaps understandably, very eager to advance at a faster pace, always a faster pace. Nowhere is that more evident than in the case of people facing death regardless, but in addition to the issues you raised (early failures can lead to even worse delays) there are other ethical concerns. Terminally ill people are often understandably desperate, and I would be too in their position, no doubt about it. Their families are desperate, often their doctors are desperate. That doesn't mean that their remaining life doesn't have value though, or that cutting it weeks, months or years short isn't a problem.
I think that's often lost on people, and in a more frightening way, people who are all-to-eager to use the terminally ill as ultimately disposable test subjects for unproven treatments. If it was JUST down to safety then I could see the point to an extent, but as you said efficacy is a big open question too. Of course if you're facing death then you may well want to roll the dice, but the question there too is how well you really understand the odds. The understandable implication in a lot of the discussions around this issue is that if only regulators were a bit faster, people like the author wouldn't die.
The reality is grim though, most of these experimental drugs and therapies are not effective, regardless of whether or not they're safe.
We let people have assisted-suicide for reasons from homelessness to hearing loss, twenty thousand people a year. Why do we respect their self-ownership when they're trying to die but not when they're trying not to die? Why do we get to decide what is and isn't worth the risk?
Because they're trying to die, they're literally getting what they want, guaranteed. Having said that I don't agree with assisted suicide for the reasons you listed. Either way it's not as though people seeking death are being mislead as to the odds, are engaging in desperate reasoning that they'll be the lucky ones who get to live a bit longer.
You offer someone death, they get death.
This is about people desperate for cures and treatments that probably won't work, and may well give them the opposite outcome from what they hope for.
Either way it's not as though people seeking death are being mislead as to the odds, are engaging in desperate reasoning that they'll be the lucky ones who get to live a bit longer
This applies just as much to approved treatments as unapproved, for the same reasons, and has the exact same solutions such as having a third party with no vested interests explain to the patient. In fact it has those problems less than approved treatments because the companies are being paid by the insurance company for the approved treatments but not the experimental ones.
The key is that the approved treatments are proven to have the requisite efficacy, the risks that come with that are an acceptable tradeoff. The unapproved, often largely untested world of early breakthroughs doesn't have that guarantee of potential efficacy, it often JUST has risks.
It may help to not view the options as a binary choice between drugs approved under the current process and any drug not currently approved.
What constitutes the acceptable tradeoff is the heart of the matter. On the one hand, even the current approval process does not always guarantee efficacy (Aduhelm to mention it by name). Medical trials work with considerable uncertainty, and the risk/benefit tradeoff is always a question of probabilities. Even with the current process, there is no certainty or guarantee.
It is possible to take those probabilities and to talk about the expected number needed to treat (NNT) for a medication, the expected side effect profile, how many people might live and how many might die. Things that may sound cold, but that are already routinely done today.
It is hard to know where the tradeoff should be, how much margin of error is the right amount before something is approved, knowing that there is uncertainty even in large trials, but it's not a choice between the totally unapproved and the status quo. (Better yet, we should not model the choice as a single parameter that goes from more choice & more snake oil to less choice & more safety. It's also often possible to improve one aspect of a bureaucracy without it being a zero-sum game.)
I don’t understand your overall point here as this is pretty much how the current system works.
> It is possible to take those probabilities and to talk about the expected number needed to treat (NNT) for a medication, the expected side effect profile, how many people might live and how many might die.
NNT > NNH = efficacy. To calculate these the trials need to be done, which is not the case for experimental therapies as they have undetermined benefits and harms (hence why they’re in trial).
The choice here is between conventional options that have known benefits/harms, however crappy they may be, with something that has unknown values.
Trials are done in multiple phases, with a progressively wider population. There is a point where we consider a drug to still be unproven, but safe enough for human trials.
I think that situations like TFA make a compelling case for selectively broadening access, for some drugs and some pathologies. The characterization of a choice between something proven and something with unknown values is too coarse and not a good model.
Clinical trials are very expensive, drug development as a field tends to move forward with what it thinks will have a chance of making it through. While most new drugs indeed fail (the large majority of them), in diseases with very poor prognosis like OP's cancer, I think we would benefit from still looking at the tradeoff as a decision under uncertainty, instead of a complete unknown. Even with less data than we would otherwise want.
Looking at experimental therapies as completely undetermined leads to a binary choice. There is supporting evidence that allows those therapies to move forward with experimental trials in the first place. The counterfactual of not treating patients with poor prognosis being what it is, my overall point is that treating experimental drugs as total unknowns with benefits and harms that cannot be quantified until the full process is finished is not consistent with the knowledge that, even after all trials are completed, this is still a uncertain statistical result, only with slightly more data than before.
In other words, we are always working with partial unknowns so when the prognosis is bad a larger unknown may be good overall and save lives, even though it wouldn't be acceptable otherwise.
> While most new drugs indeed fail (the large majority of them), in diseases with very poor prognosis like OP's cancer, I think we would benefit from still looking at the tradeoff as a decision under uncertainty, instead of a complete unknown. Even with less data than we would otherwise want.
Which is literally what just happened with osimertinib for NSCLC. It was approved for clinical use and was implemented without any overall survival data.
Safe for clinical trial means the harms are considered safe, has little to no relevance for efficacy.
Once again you’re ignoring the fact that there are (almost) always alternative treatments that have been proven to prolong life.
No one is offering nothing to poor prognosis patients.
From the blog post:
> Monday I’m starting chemotherapy, but that’s almost certainly going to fail, because a CT scan shows four to six new gross tumors, four in my neck and two, possibly, in my lungs.
In someone with such an aggressive disease everything is almost certainly going to fail, experimental or not. Chemotherapy will buy some time. Who knows what an mRNA treatment will do but there’s certainly no (not little, no) evidence that it will be curative.
You're right that there are alternatives, and there is an existing standard of care. I don't think I'm ignoring that. Let me clarify, I am not saying that patients with poor prognosis are being offered nothing. They are being offered standard of care.
I think sticking with standard of care until new drugs have gone through the full, current process may be net negative under the current process, and considering the counterfactual especially for patients with poor prognosis.
Chemoterapy will buy some time with certainty, but in expectations broadening access even slightly means we can gain confidence in the experimental treatments that do work slightly sooner, and that improves the standard of care for everyone. Experimental drugs sometimes do work, and it would be bias to only look at the risks while sweeping aside the potential upside.
Consider what happens a few years from now with the current system and with a system that selectively broadens access in some cases, when the early data seems to support the risk/reward. Even if most new medications fail, the cost of delaying those few therapy that will happen to work is much larger than the risk being paid by the trial population. That's because only a few people participate in trials, but everyone benefits from the results. This is why we have trials at all.
In someone with an aggressive disease such as OP, that person may very likely benefit from having that choice. Today they may choose to buy some time with _relative_ certainty, knowing that chemo has very heavy side effects and that they may not enjoy very much of that remaining time. But they may not choose to try some experimental treatments, even when the risk/reward seems reasonable according to early data, even though that may result in a small chance of success, and certainly data that will help bring therapies quicker to more people.
The benefit of experimental treatment is not just to the individual participating in the experiment. Part of the benefit, that helps justifies the risk, is the idea that a fraction of the treatments will be worthwhile. Slowing down trials is safer in the sense that no one will be responsible for anyone losing their chance at chemo or dying, but it creates the exact kind of invisible deaths in expectation that TFA talks about.
Current standard of care includes experimental therapy. What you are describing is once again how novel cancer treatments are being implemented today.
Furthermore, Step 1 of the NCCN treatment guidelines for these kinds of cancers (i.e. advanced and/or poor responders to conventional chemo) is always that the patient is enrolled in a clinical trial.
In this authors case he does not meet inclusion criteria for the therapies he is listing, both trials require systemic therapy with novel PD-1 inhibitors (aka immune checkpoint inhibitors, immunotherapy) which when they work do so fantastically with little side effects.
Per his description he has not tried any systemic therapy yet.
I’m unclear whether he’s lumping chemo with immunotherapy (often the case by non-domain expert patients) but not even Moderna is interested in going from surgery directly to mRNA.
This isn’t the FDA getting in the way. He hasn’t exhausted good treatment options yet to be eligible for unapproved experimental ones. It would absolutely be detrimental to ignore ICIs in an eligible patient in favor of [insert non-approved experimental therapy with no evidence].
I’ve seen far more advanced metastatic H&N SCC survive for years on ICIs in my clinical practice. We don’t know all the specifics of this case but this isn’t nothing/days/weeks vs mRNA as the author is pitching.
That's fair, I'll admit I didn't check the inclusion criteria in the case of OP.
I'll take your point, and I appreciate the time you took to write a good response, though I've read about enough examples other than the current article that I feel this may be rejecting a wider pattern on the details of the current submission (but maybe I'm wrong, and they all happened to be incorrect for similar reasons).
But I'd like to hear your thoughts on the broader argument of being more aggressive with trials in general. What sticks with me each time this argument comes up, regardless of the particular situation, is this idea that despite some mechanisms for accelerated approvals, we are still far slower than we could be, if we take into account the number of people saved by bringing therapies sooner.
There is a cost to letting people take dangerous medication. I hate the idea of peddling dubious cures to vulnerable people as much as I'm sure you do. It's the counterfactual that makes the argument, the people who do not receive treatment due to delay seems to vastly outnumber the people harmed by experimental treatments.
And the difference seems large enough that it would remain true even if we went much faster. I think that's the strongest objection to the current system.
Please note I am speaking only for the world of oncology as that's my practice focus and what I know best.
> But I'd like to hear your thoughts on the broader argument of being more aggressive with trials in general. What sticks with me each time this argument comes up, regardless of the particular situation, is this idea that despite some mechanisms for accelerated approvals, we are still far slower than we could be, if we take into account the number of people saved by bringing therapies sooner.
Everything in medicine is trade-off. On the extremes we can practice with no regulation and have immediate access to treatments without evidence accepting that many patients will be harmed as many new treatments are inferior or require phase IIIs on the other end and minimize harms but accept that delayed care will itself cause harm.
Current practice is somewhere in the middle, depending on various factors like efficacy, risks/harms, and alternatives many treatments enter practice after phase I/II or used off-label for close indications.
I like where we're currently at for oncology and don't think we need to change much in the process. The bigger hurdle is funneling those R&D $ into high yield research and perhaps making the cost of trials easier (e.g. research alliances, IT infrastructure to simplify multi-center studies and patient recruitment, ?active government involvement).
There's always fine tuning of that balance that can be done and some cases will prove things wrong on either side of the argument but generally speaking I think we're close to where we need to be. Definitely better than when we didn't have the current approval process.
> It's the counterfactual that makes the argument, the people who do not receive treatment due to delay seems to vastly outnumber the people harmed by experimental treatments.
I don't think this is true and I have not seen evidence to support this claim. There is ample evidence of failed treatment options or treatment causing more harm than good. An example I'm well-versed in is HIPEC for advanced ovarian/peritoneal cancers (we've been doing this for years and it turns out it doesn't do much other than excessive morbidity) or Y-90 for HCC/colorectal metastases to the liver (first trials negative and we recently found out "oops we've been underdosing this and measuring non-target dosing to the lungs incorrectly") both of which are for palliative patients with no good alternatives.
Going back to osimertinib as the example, the main criticism of earlier TKIs (same class of drug, and even osimertinib for that matter) was that the promise of limited data (progression free survival rather than overall) led some patients to get TKI therapy rather than platinum based chemo which was standard of care and has proven OS benefit. Except when the OS data came out it was an "oops, OS didn't pan out like PFS" and people were harmed.
That these happen in the current system strongly suggest patients have access to experimental therapies and that we're not being overly stringent, or this data wouldn't exist.
I would also say that a large proportion of the patients I've interacted with that have disseminated disease are on some trial for experimental therapy with the caveat that I've only worked at tertiary care cancer centers. It's really not that hard to get enrolled if you meet criteria. I believe the stories we read of access challenges are largely a vocal minority with challenging circumstances or a misunderstanding of treatment options.
No problem. I appreciate the discussion, it's good for me (and medicine in general) to be challenged on held beliefs as things tend to devolve insidiously in this field.
> Why do we get to decide what is and isn't worth the risk?
It's not their risk to take. Getting a drug to market is a complex process that can be derailed by any number of mistakes ranging from the mundane like improper blood draw during clinical trials to the tragic like accidental deaths that puts public pressure on the FDA to shut it down or spook away investors. Any hiccup in this process can kill it and once a patent expires, the chances of someone bringing that drug to market is almost zero, regardless of its efficacy.
The vast majority of drugs and therapies are developed via private investment and many companies go public before they make even a cent of revenue to fund the clinical trials. Public sentiment is the driving force behind their stock prices because they're literally forbidden from making money until the FDA approves their drug. Lots of them go bankrupt every year before finishing clinical trials or releasing a product and rushing the process is quick ticket there.
Patients don't get to put at risk the decades of good a drug can do because they're desperate and afraid of dying.
I'm not sure removing options from the desperate and dying is a good idea. Those with means will just ignore your concerns and the rest will have _nothing to lose_.
I can't find it anymore, but there was a paper or maybe study looking into the question of healthcare outcomes for just such "people of means." Iirc there was some interesting data which showed being able to afford doctor shopping and concierge service was sometimes correlated with poor outcomes compared to the standard of care overall. I think it makes sense, the patient can demand what they want and then get it, but they're not necessarily armed with the knowledge or perspective to make the informed decision. If they can afford to find a doctor who values a lot of money over anything else though, they can get it, and that might not work out so well for them.
Michael Jackson, Joan Rivers and Lisa-Marie Presley for example would probably all still be alive if they didn't have the money to simply buy the healthcare they wanted, damn the consequences and cost.
> we’ll know that we at least we made significant effort, and gave everyone a better chance, rather than settle for a “Hail Mary” drug near the end.
I think this is a sensible take for someone who is not facing their own imminent mortality. But no matter what we do, the game theory of terminal diagnoses means there will always be incentive to go for a Hail Mary in the end.
The COVID vaccine already had an existing model to work from that was already ready to go and approved in the SARS-COV-1 vaccine nearly a decade earlier.
Did you never experience the situation where someone you care about is making a choice you think is wrong, and you want to protect them from themselves?
I'm not saying this is the right thing to do. I'm just trying to explain how it happens. People don't make good risk judgements in general, and other people think that it is good to do good by force. This is why seat belts are mandatory, smoking is discouraged, drugs are illegal, public companies traded on exchanges are strongly regulated, and so on and so forth.
> Yes probably more people will die
You really don't understand why we choose the option where less people die? We value life, I guess.
Who does the investing? Not "The Market". The incentive isn't to cure but to treat. The Market wants (repeat) customers.
The government? At least, in the US, we've been dismantling the government's ability to do this since at least Reagan. Even our so-called Liberals aren't pushing hard here. You'd have to look to the "fringe" Progressives within the Democratic Party to even come close.
And why? Because "fuck you, I've got mine" may as well be the national motto of the USA at this point.
People will bristle at this, certainly. Look at Biden: he's done so much!
Biden is no FDR. We need a real social safety net in this country. And, yes, we need a "right to try", even if it means waiving malpractice rights in those cases.
> The incentive isn't to cure but to treat. The Market wants (repeat) customers.
I am fed up with this argument.
Compared to a recurring treatment, a cure will:
- destroy the competing recurring treatment
- sell particularly well initially, when you still have the patent, potentially at a high price
- not stop the influx of repeat customers, since as long as people are alive, they will need medicine, and people who are now healthy because you cured them will be more likely to have a well paying job that will pay for expensive drugs
If that argument was true, no one would do vaccines, especially considering that most vaccines are not particularly expensive.
This example is poorly chosen for a different reason explained in my comment.
Alternatively, we can look at novel curative intent therapies for cancer like focal ablation or stereotactic radiation.
The recurring customer alternative of chemo/immunotherapy or the conventional surgical option are at least an order of magnitude more expensive.
You won’t find much novel systemic therapy that’s curative intent because it’s really hard (?impossible) to do, not because the system wants to make more money slowly killing patients.
Agree. I can speak for oncology where the desire is always curative intent treatments. Unfortunately it’s often not possible so we settle for palliative therapy (presumably what GP meant by recurring).
Personally/professionally I think this argument comes from non-experts failing to understand the disease process and therapeutic challenges. I’ve seen no evidence or suggestion in my years of clinical practice that this assertion has a shred of truth behind it.
> If that argument was true, no one would do vaccines, especially considering that most vaccines are not particularly expensive.
While I agree with you this statement does not prove your argument. Vaccines aren’t a good example of funding for curative intent treatments.
The economics behind vaccinations are different as you vaccinate orders of magnitude more patients than would ever get the disease so even if the nefarious assumption is valid the economics may still favor this path.
Wall Street dinged them because Gilead is a one trick pony and the street overestimated revenue, not because Gilead cured HCV rather than just treating it.
Additionally, if their drug didn’t work as well they wouldn’t have gotten away with charging 100k for a course and wouldn’t have made 40B+ in revenue.
> Yee, though, says Gilead isn't filling a hole left from its declining HCV unit. It's merely coming down off a "massive bolus of hundreds of thousands of people who came in during the first two years."
> "The drug is still set to do $8 billion in 2017 and is one of the largest drugs in the world. Not exactly a hole," he said.
The Gilead stock is worth 4x today what it was worth in 2012, before they had the cure. It is better than the average "big-pharma" (ex: Pfizer). The stock plateaued because they couldn't follow up, but before you look at the dip, you should look at the massive raise before it.
Indeed, there's the perverse insensitive to create a repeat customer.
Funnily, an insurance company would push against that, for a final cure. They would like to avoid to pay for repeat treatments.
But the medical insurance in the US is more of a payment scheme, and apparently is not interested in paying less. I bet there is some regulatory loophole, or a government guarantee, that makes it more profitable.
>How often do these drugs, etc turn out to effective?
This is a big point a lot of people ignore. I feel terrible for the author, but if there hasn't been a single drug invented so far that has any real chance of curing him, it's extremely unlikely that this one out of reach drug is going to be the drug that can save his life. I don't really know much about medicine, but I'm pretty sure that progress is usually incremental as well, so you start out with drugs that cure some patients and work from there instead of having some massive breakthrough.
>I think the solution is to invest more into medical research now,
The author is arguing that terminally ill people (with a few months left to live) -- like him -- would be willing participants in trials to help medical research. They already know that mRNA drug or whatever likely won't cure them. It's possible some new scientific knowledge of the drugs' effects can still be gained even when it doesn't cure them.
Given the realistic odds, the primary purpose (from society's perspective) of letting of terminal patients participating in unproven drug trials would be medical research rather than "Hail Mary cures". From the patient's perspective, of course they hope it improves their health.
There's a lot of problems with it, though. Even if advancing medical research was the main goal-- ad hoc use in dying patients provides unclear data. Medical research wants clear inclusion criteria, metrics, reduced statistical noise from similar patients, predeclared outcome measures, and economies of scale in running trials.
We already let terminal patients participate in medical research, but only inviting patients at times and meeting criteria that optimizes the research. Also, only where IRBs have found it to be ethical-- this means not replacing a drug with proven benefit with an experimental treatment with unknown benefit recklessly.
But terminally-ill patients push for inclusion beyond this: to be dosed when there is not an active trial, or to be dosed when they are so sick that the outcome would be difficult to interpret or compare, etc. This isn't for medical research, this is for self-preservation.
>There's a lot of problems with it, though. [...] Medical research wants clear inclusion criteria, [...] , but only inviting patients at times and meeting criteria that optimizes the research [...] But terminally-ill patients push for inclusion beyond this: to be dosed when there is not an active trial, [...]
Your objections are sensible but that's beyond the scope of this author's argument. I'm just taking author's following comment at face value:
">The FDA was loathe to approve initial mRNA human trials, even when those trials would have been full of people like me: those who are facing death sentences anyway."
If it's the drug researchers who don't want the author as a test subject, that's understandable. But he's arguing the _FDA_ shouldn't be the one blocking his participation.
For the situations where there's "no active trial" caused by the FDA not greenlighting the experiments, then of course, the complaint will be that "terminally ill patients want to participate in trials that don't exist". That's sort of a circular argument -- caused by the FDA.
Again, if there's no active trial because the medical researchers themselves are not yet ready, that's understandable. But if the drug scientists are ready but the FDA is not, that's a different issue and it's the focus of the author's essay.
All that said, I don't know how much scientific progress the FDA holds back because of "safety". I'm just trying to explain the author's position.
Excellent explanation, parent is also correct. I think the author’s position is misinformed.
The FDA doesn’t hold back researchers on inclusion/exclusion criteria.
Inclusion for the Moderna trial he linked to:
> Must have primary refractory or acquired secondary resistance to prior immune checkpoint treatments. Primary refractory is defined as prior exposure to anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) antibody for at least 6 weeks but no more than 6 months with demonstration of progression on 2 separate scans at least 4 weeks apart but no more than 12 weeks apart and progression occurring within 6 months after first dose of anti-PD-1 antibody. Acquired secondary resistance must have confirmed objective response or prolonged stable disease (SD) (>6 months), followed by disease progression in the setting of ongoing treatment and confirmed progression on scans at least 4 weeks apart.
Exclusion criteria:
> Participant has received treatment with prohibited medications (that is, concurrent anticancer therapy including other chemotherapy, radiation [local radiation for palliative care is permitted with approval from the Sponsor]…
From the description of the patient’s treatment course it sounds like he had curative intent radiation (given he subsequently had surgery) and would probably not meet this study’s criteria making the limiting factor Moderna not the FDA.
He also doesn’t mention whether he’s starting immunotherapy/checkpoint inhibitors (or his tumor status) and may be lumping immunotherapy with chemotherapy which is a good new treatment option and would typically be offered if eligible. Definitely better than being enrolled in a dose study and in fact is required by Moderna.
> I'm just taking author's following comment at face value
Plenty of mRNA human trials of cancer treatment are in progress. Indeed, as he stated, he wants into two that are underway, but that he is probably too far along for. He wishes that they had been greenlit even earlier and perhaps made their way to be approved drugs that he could just be given by his local doctor.
> For the situations where there's "no active trial" caused by the FDA not greenlighting the experiments,
There's compassionate use exceptions for circumstances like this.
The big thing is, there's two big bars to cross with getting a trial together:
- You probably want to be doing human research in a way that will produce evidence that will convince the FDA to grant you approval. (Hence, drug companies often are nervous that compassionate use will pollute their data).
- The FDA wants to protect human subjects, and if there's a drug that results in 15% survival for a year, vs. 5% for doing nothing and ???% for your new experimental treatment: they want that drug to be tested as part of a protocol that minimizes potential harms, not to randomly replace the 15% survival treatment. Most experimental treatments end up failing.
> Indeed, as he stated, he wants into two that are underway, but that he is probably too far along for.
The author is incorrect on this, he’s not too far along but he does not meet inclusion criteria for either of the studies he cited as both require systemic therapy.
mRNA is not being pitched or tested as a first-line mono therapy by Moderna. I’m not sure why the author is jumping the gun here and ignoring approved systemic treatment options.
I’m ignoring that part because it is nearly impossible to prognosticate prior to initiation of systemic therapy, with the exception of some phenotypes but we don’t have the pathology report in this case.
My point is that he doesn’t even meet the inclusion criteria for these studies, regardless of aggressiveness. This has nothing to do with the FDA, he can’t join the studies because Moderna doesn’t want to study him at this point and not because he won’t survive long enough to enroll.
Whether or not his prognosis statement is correct.
The FDA could create a standard consent form for nonapproved treatment that patients and doctors would sign, which would indemnify the physician from legal repercussions, but they don't, and they bear full blame for that. The AMA would still have its own regulations about the limits of ethical experimentation, with the revocation of a medical license as punishment to serious offenders, and malpractice safeguards could still be there. State laws about gross medical negligence are also an option.
You can get get experimental drugs/treatments that aren’t approved by getting them under the clinical trial for that drug. The question is who pays for it? Cancer treatments are millions of dollars.
> Patients generally do not have to pay extra out-of-pocket costs for treatments studied as part of a trial. Every trial is different, but the clinical trial’s sponsor usually pays for all research-related costs and any special testing.
> Typically, the patient or his or her insurance company is asked to pay for any routine tests, treatments, or procedures that would be required as part of standard cancer treatment. Before you join a clinical trial, you will receive an informed consent document that spells out exactly what you’ll have to pay for and what you won’t.
This can cause all doctors to require it, and this has happened across industries, for example, software and internet platform "terms of service". It is a very bad idea.
For those who are curious, the term was coined on this blog post[1]:
> The Copenhagen Interpretation of quantum mechanics says that you can have a particle spinning clockwise and counterclockwise at the same time – until you look at it, at which point it definitely becomes one or the other. The theory claims that observing reality fundamentally changes it.
> The Copenhagen Interpretation of Ethics says that when you observe or interact with a problem in any way, you can be blamed for it. At the very least, you are to blame for not doing more. Even if you don’t make the problem worse, even if you make it slightly better, the ethical burden of the problem falls on you as soon as you observe it. In particular, if you interact with a problem and benefit from it, you are a complete monster. I don’t subscribe to this school of thought, but it seems pretty popular.
The post provides real life examples of government programs, nonprofits, and individuals being criticized for helping in the “wrong” way.
It interprets telling the vehicle to crash into a barrier rather than hit pedestrians as not placing as much value on protecting passengers. But really, this is just a recognition that the passengers are far more protected in a crash than the pedestrian are when getting hit by the car. Instead of a barrier, it should be a large cliff or something.
So, observing a problem is no more complicated than becoming aware that it exists. That's the only interaction necessary to invoke ethical liability. How does then pretending you didn't observe it release you from anything?
Your guilty conscience will undoubtedly destroy you from within. If you do not repent and request mercy from the great beyonder then surely your next life will be lived in misery as some sort of atomic particle with human awareness and deep dread of your current circumstances.
I can't tell how much of your sarcasm is based on taking me literally. I'm an atheist. I don't believe in an afterlife, and I'm always blown away when people say that without a "fear of God" or fear of hell, no one would act morally. Whenever someone says that, I'm like, well, I guess you want to kill and torture and rape people and you need this dumb framework to stop you from doing that, so thank goodness for religion. But personally I think we all have ethical responsibilities to other living beings, and especially to our own kind, which spring from appreciating the complexity of the world but can be completely attributed to rational, selfish, deductive reasoning and self-preservation, if you really want to get down to it.
Tl;dr you're arguing the fundamentalist POV that ethics can't exist without a God.
> Even if you want the experimental treatment, you cannot get it.
fortunately, Baja California seems to have everything. Or specifically, a different drug approval strategy that is right in the middle of this.
The FDA's main limitation is that it gives a one to one relationship in approvals. A substance is seemingly evaluated for a single narrow ailment. While evaluation process is a threshold of side effects as well as efficacy in treating that single narrow ailment. This process could be expanded to recognize that fulfilling the side effect issue could expand its use in other ways, more easily than whatever semantical distinction of easier the FDA uses now. There could be more possibilities for one to many approvals.
you’re right though, I think this is still limiting as it gets to currently obscure things, liability concerns for the physician if something goes wrong, or what insurance will cover. so its still hit or miss for the patient
> Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault.
If a train is coming with someone pinned to the tracks, and they are begging you to hand them an axe so they can remove their own leg-- knowing they may die from blood loss, do you just do nothing?
Moreover, if a terminal cancer patient wants to commit suicide, they can legally do so on several jurisdictions. Why then, can they not instead opt for this treatment as an alternative to suicide?
There's this overabundance of the need for safety that's overcome society.
It's as if we can't assess tradeoffs anymore.
You see it with the lack of children playing outside - even though random kidnappings are almost a nil risk and that they're more likely to get by a car.
Defective toys. Defective carseats. Millions get recalled for a failed few.
You saw it with masks. You see it with speech, "words are violence".
Everyone wanting the illusion of feeling completely safe.
Uhh, given recalling defective toys or car seats is a pretty straightforward way to prevent further injury, isn’t that a pretty good trade off over knowingly potentially causing more injury just to save money?
How would you feel if your child was injured by a car seat that had a defect the manufacturer completely knew about but refused to recall for the sake of saving money?
You had me to a point. And then you began the usual conservative dog whistles.
"Words are violence"? If you were dox'd, would that be violence? Or your life threatened? Or those you love? Or just people who look or love like you? Where is the line? Wherever you personally believe it should be? No.
Experimental treatments often are very expensive, I believe require a lot of study of the patient and so on ...
It's not like a magical pill(s) you take an go home and live or don't and everyone says "well he consented so he took his chances". The entire process of experimental treatments is hugely expensive.
I think what really drives me crazy is that the FDA approval can limit me taking something.
Put simply, If you believe “my body, my choice” then the current regulatory system is pretty messed up.
To be clear, I’m fine with the FDA existing as a labeling body. Sure label something FDA approved. But don’t limit what we can take because it’s not approved.
Otherwise, you end up with cases like this and many others, where an industry can easily be regulatory captured and ensure competitors are slow or unable to enter the market.
It's a high worth debate, maybe there's a ethics curve.. for most cases you have the normal "don't do harm" but for life threatening you need another board to remove some stops without letting the scams proliferate.
"First do no harm" sounds good on paper, but it fails the trolley problem. It leads you to harmful beliefs like "we should not use the AZ Covid vaccine to save thousands of lives because it might cause one person to die of blood clots".
The problem is that in the real world, it's extremely rarely the case that you can make an intervention that only has benefits, and doesn't have costs, so honestly applying "do no harm" is paralyzing. The medical ethics field understands this, but often the administrators/regulators are way too conservative.
A better model that generalizes without special-casing is "weigh costs and benefits, and be conservative but bounded about unknown risks before making an intervention". In this case the potential downsides are 1) the patient dies which is irrelevant because they are almost certain to die anyway (and they made the informed decision to take this risk), and 2) some reputational damage to the FDA and medical practice if it's seen to be "preying on patients with no other options".
I think 2) is being weighted way higher than it should.
The problem with this model is it requires an understanding of statistics to determine what is ethical and just, and many doctors don't even know how to properly reason about false positives/negatives, let alone the lay public. Yet members of the public aren't willing to forgo their outrage on a subject that they cannot actually conceptualize.
In some sense we are getting the regulators we deserve, not the ones we need; the FDA is probably rationally and correctly evaluating the political risks, media attention, and public backlash around allowing this sort of case.
Thanks, very interesting.. i dont know if it's worth setting up a group to raise statistical understanding or just wait for society to suffer enough to finally learn.
It is (a very rational) approach for administrative workers, who get little credit for getting things better, but are at risk when they can be taken accountable for something terrible.
That way, for example, in Germany, there was a halt on the Astra-Zeneca vaccine after a few cases of thrombosis per million. For comparison, it is one in six for COVID. The halt, most likely, caused many deaths. Yet, these deaths "have happened". If there were a death because an administrative organ didn't take action - the organ would be considered responsible.
For the matter, Pontius Pilate was an administrative worker. And his incentives were aligned accordingly.
In the language of the Trolley Problem, it is doing nothing (no matter how many are there on the tracks) or (even better) finding a way to pass the lever to someone else.
I still think they need another category than what they have now.
My understanding of the current categories of drugs are you have "banned" and "has this specific therapeutic effect that costs billions of dollars to prove".
A category of "this doesn't kill you" in the middle would probably alleviate most of this. Insurance only has to pay for things with proven therapeutic effects, but you can shield people from poison and get a lot more data way cheaper by having his middle category.
The requirement to test for efficacy and not just safety was only added in response to Thalidomide (which disaster had nothing to do with testing for efficacy). So what you're asking for is very not radical.
> Even if you want the experimental treatment, you cannot get it.
Says who? In terminal truly no-option diseases (e.g. glioblastoma multiforme) it’s pretty easy to get access to experimental therapies on compassionate grounds.
The challenge in this particular case brings us to:
> Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault.
This is a false dichotomy. What’s unethical is offering experimental therapy with ?? effect when there are evidence based palliative treatments (e.g. conventional chemotherapy) with proven overall survival benefit.
In cases where an experimental therapy has at least some limited evidence (i.e. suggestion it might work) it’s quickly approved and pushed into clinical pipelines, osimertinib/Tagrisso for lung cancer is a recent example of such a treatment.
No one is advocating or suggesting we just let people die.
>In cases where an experimental therapy has at least some limited evidence (i.e. suggestion it might work) it’s quickly approved and pushed into clinical pipelines, osimertinib/Tagrisso for lung cancer is a recent example of such a treatment.
I think that's the main point of disagreement. There are some encouraging cases where the process works well, and it's fair to point to osimertinib as an example.
But there is a good case to be made (although various blog posts likely state it better than I could in a comment) that the current process introduces enough delay that the opportunity cost is higher than the risk.
Most drugs fail. But getting the drugs that do work to patients even a year earlier may be a much larger benefit than the cost of giving people with serious diseases broader choices, in addition to the current best known standard.
No one is advocating we just let people die, but there's an argument about the cost of delaying therapies and the cost of giving people choices that warrants careful consideration. While proven therapies are good and snake-oil is bad, improving standard of care for everyone historically saves many more lives than sticking with what we know for a longer period of time.
> Most drugs fail. But getting the drugs that do work to patients even a year earlier may be a much larger benefit than the cost of giving people with serious diseases broader choices, in addition to the current best known standard.
This is contradictory. Most drugs fail, how do we identify the efficacious ones other than through trials?
Depending on the anticipated efficacy from early trials as compared to existing ones it will get fast-tracked before the phase II is completed.
Where is the evidence that we’re delaying efficacious therapies where there is no good alternative?
I sound like a broken record right now but this blog post is suggesting we jump to experimental therapies (which would be off label for the author as he does not meet inclusion criteria) before we even have phase I data let alone efficacy, when good validated treatment options exists.
>This is contradictory. Most drugs fail, how do we identify the efficacious ones other than through trials?
One idea is to make trials somewhat less costly by relying more on post-approval monitoring, but there are more subtle critiques of the processes that try to address perceived inefficiencies at the organisation/bureaucratic level rather than just adjusting a single big strict/lenient dial.
Some drugs do not make it to trial at all due to the overwhelming cost of the process. We would identify a larger number of efficacious ones if there were less costly, wider trials. A very expensive approval process results in delays for drugs that do make it to trials, but also causes many candidates to never reach trials.
>Depending on the anticipated efficacy from early trials as compared to existing ones it will get fast-tracked before the phase II is completed.
Part of the argument is that this is good, and we should consider going further in that direction
>Where is the evidence that we’re delaying efficacious therapies where there is no good alternative?
Unfortunately, the best I can point to is a series of blog posts and informal discussions, I'm not aware of any formal published evidence. I remember a blog post on ACX post aducanumab (https://astralcodexten.substack.com/p/adumbrations-of-aducan...). The "FDA delenda est" catchprase leads to several more posts.
I'll admit this is not very compelling. I believe it's worth having that argument, and I'd be happy to be wrong on that one, but all of this is hard to quantify.
(I also want to reaffirm that there are good alternatives, it's a question of whether we could be losing less people than we are losing under the current process, not that there are no current alternatives)
>I sound like a broken record right now but this blog post is suggesting we jump to experimental therapies (which would be off label for the author as he does not meet inclusion criteria) before we even have phase I data let alone efficacy, when good validated treatment options exists.
I'm sorry if I'm repeating myself as well or failing to make a good argument. I think your position is very reasonable. It's a complicated topic and I might not be doing it justice.
> Unfortunately, the best I can point to is a series of blog posts and informal discussions, I'm not aware of any formal published evidence. I remember a blog post on ACX post aducanumab (https://astralcodexten.substack.com/p/adumbrations-of-aducan...). The "FDA delenda est" catchprase leads to several more posts.
I'm a radiologist by training with an interventional oncology component in my practice so I can really only speak to acute care emergencies and cancer with any degree of expertise.
Cancer, heart attacks, strokes, aneurysms are different because there's a time crunch. In these situations FDA approval comes quickly for new medical devices and imaging tests. New aneurysms occlusion devices, stent grafts, and thrombectomy devices are all quickly approved with shortened review processes. Sometimes this has been to our detriment (e.g. early abdominal aortic/EVAR grafts which all leaked and caused disasters when the patient needed re-operation).
In these cases we did exactly what you're suggesting with:
> One idea is to make trials somewhat less costly by relying more on post-approval monitoring
How this translates to other diseases like Alzheimer's is not in my wheelhouse. I assume the process is more strictly adhered to in these cases, but it presumably should be because the potential harm of delaying is seemingly less important unless we're discussing disease-modifying treatments that require early initiation.
In your post the author mentions COVID-19 vaccinations, these were made available before full FDA approval. COVID-19 was highly politicized and the entire process did not follow typical medical procedures. Honestly the evidence that has come out for them isn't very compelling (omicron and later) and largely why most places have dropped vaccination requirements. I'm not sure that this is a good example of the "FDA's failure".
> Even if you want the experimental treatment, you cannot get it. Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault. This is sometimes also known as the Copenhagen interpretation of Ethics.
Most people (myself included) would not agree to that. Experimental treatment should be made possible - at least if there have been promising results with previous studies (animals, small trials etc.). There must be a safeguard, however, to make it impossible to sell false hope to dying people - because they will pay for everything, even if it does more harm than good.
Going on a tangent here: there's a reason medicine is heavily regulated—because of the lessons we've learned the hard way. The same reason law is also heavily regulated. Some of these lessons have become obscured by time, unfortunately. Other lessons may not be fully applicable to the modern state of the field. (I say this as a qualified doctor and lawyer with some appreciation of the history of both fields.)
Are the current regulation regimes perfect? No. Would we be better off without it? I doubt it. Should we try to strike a balance between regulation and innovation? Yes—but doing so is devilishly tricky. No matter what you do, someone somewhere will be unhappy.
> Even if you want the experimental treatment, you cannot get it. Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault. This is sometimes also known as the Copenhagen interpretation of Ethics.
Interesting. Thanks for sharing the "Copenhagen interpretation of Ethics". I've thought many times about this problem, didn't know it had a name.
Comes to mind Dante Alighieri: "The hottest places in Hell are reserved for those who, in a period of moral crisis, maintain their neutrality."
Imo the whole US medical complex needs competition from a small but sophisticated libertarian state without any of the regulations that formed the present system, and I think it will happen. The market demands it, and the world would be better off with some competition. Most likely it will begin with some small nation that sells anti-aging therapies.
There are companies from which you can order bespoke mRNAs. Lead times vary but are in the weeks. Many are abroad. The other components of mRNA vaccines can be assembled by someone with 2 years of biochemical Ph.D. experience. There are no laws against a person assembling and injecting themselves with anything.
I have extra sympathy for the writer of this article, since mRNA vaccines (even if they were a random sequence) are relatively lower risk than many other sorts cancer interventions which are FDA approved. I happen to be an ex-professor, who is a director at a drug company. I know that if I were the unfortunate author of this article, whose heart is in the right place. I would probably be injecting myself with my own janky version of whatever offered hope.
Whether that would actually change my prognosis? Probably not. I can say though that I _would_ and I believe others are entitled to positive freedoms I'd afford myself.
I think it could be ethical to let people try experimental treatments in the context of a phase 1 clinical trial, ensuring that something is learned from the attempt. However, I have also heard that an issue with that constraint is that connecting patients to clinical trials is a huge logistical problem that has not been well-solved.
It actually seems like the kind of problem that could be a good fit for tech: have a registry of clinical trials, make sure it’s widely known and consistently used. I don’t know much about the problem, though, so I don’t know if or whether that’s unrealistic.
This is a very interesting question. Why are medicines regulated federally? As I understand it (and IANAL) doctors, pharmacists and nurses are regulated on a state by state basis.
It would be an extraordinary disaster to kick that regulation back to the states.
Florida would probably outlaw all mRNA technology. Their FDA would refuse to approve any mRNA-based therapies, and so on.
We have seen the disaster that approach can cause in healthcare, insurance, abortion (reproductive health broadly), gay rights, etc. It's insane that we have state by state drivers licensing as an example that is merely highly inconvenient.
It's not a good thing that doctors and nurses are regulated at the state level. It's a horrible thing that contributes to the US healthcare system's vast dysfunction.
The FDA is not bad. The world has never had a shortage of liars, scammers, or snake oil salesmen. The term snake oil itself hearkens back to salesmen who would promise "medicines" to desperate people to con them out of their money.
Allowing trials to be bypassed and allowing people to pay for early access to unproven drugs would bring a flood of such be vendors and be bad for society, bad for medicine, and bad for ethics.
No one is advocating for "pay for access" or a means of bypassing trials that facilitate a "flood of [scammers]", so this is a straw man. You'd have to show why any design for relaxing regulation of trials is necessarily bad in aggregate.
The article even cites a case where the bureaucrats are confident in the safety of a trail drug but unable to approve for political reasons.
Not to mention the FDA allows plenty of snake oil supplements, etc. to be sold, so it's not particularly good at the goal you claim it's optimizing for.
Supplements are regulated as food products as long as the manufacturer doesn't claim they treat or cure anything. The FDA allows them for the same reason they allow fudge brownies or Spam to be sold.
FDA doesn’t regulate supplements as medication but food; however Federal consumer protection laws prevent making false claims.
I imagine allowing terminal non-trial participants access is more than just regulatory red-tape.
If understood one of the authors points it was that allowing non-candidates access could speed up approval. I think that is true, but that would require the same regimented process for administering the trial to ensure quality of data. The same would hold if there was an adverse event as well—patients need to be monitored closely to capture data to provide valuable to the clinical research results.
What I don't understand is why the FDA doesn't automatically rubber stamp approvals on medicine approved in Canada and the European Union. We all know their medicine is good - so why can't I get it?!
Somewhat famously the US not doing this stopped Thalidomide being such a large issue in the US, but of course one example of it failing doesn't mean it is inherently bad policy.
But that’s the problem. No regulatory body has perfect judgement, so they’ll all approve some harmful things and ban some helpful things. If you’re so strict that you don’t allow thalidomide, you’ll also ban stuff like beta blockers for an extra decade, causing 80,000 deaths. The argument in favor of loosening restrictions is that it would reduce overall death and suffering.
If you think the fact that thalidomide, a deadly and basically worthless medication, being successfully blocked by the FDA is an example of a problem, then I'm a bit baffled?
If you think that regulatory bodies make mistakes - then surely you want them checking each other's work?
It's very frustrating to feel you are dying just shy of a breakthrough that can save you. I get that. And the author's contention, that they have a right as a human being to join studies that can potentially save them, is entirely reasonable.
But that's an entire universe apart from rubber stamping medications. We should not give the pharmaceutical industry that much credulity.
If pharmaceuticals have improved the length and quality of our lives, it's because they've been kept on the straight and narrow. This isn't a self regulating industry, they have a desperate base of customers and their "sales people" (doctors) are trusted implicitly - they hold a tremendous amount of power and would abuse it at the drop of a hat.
It used to be regarded as a miracle drug that could be used over the counter in many circumstances, and as they looked into it they discovered it just couldn't be used safely.
That they've narrowed it down to some use case is more of a testament to the thoroughness of the investigation, I'm sure there are many chemicals that could treat leprosy this just happens to be the one we understand how to manufacture and when it is safe to use.
I'm sure it's very meaningful for the people who do take it, but that is what I meant by "basically worthless."
You are obviously deeply and aggressively ignorant about pharmacology. Thalidomide is an effective immunomodulator which is prescribed for multiple conditions beyond just leprosy.
That's true, though I'll note that treatment options seem to have broadened a bit [0]. Thalidomide is effective, but suffers from cost and limited availability (in addition to the teratogenic effects).
I’m saying that the FDA’s strictness cuts both ways. My beta blocker example was not a hypothetical.
Europe approved the use of beta blockers to prevent heart attacks a decade before the US. Although the FDA approved propranolol in the 1960s, and timolol for glaucoma in 1978, they didn’t approve beta blockers for prevention of second heart attacks until the 1980s. This resulted in the deaths of over 80,000 Americans. Amusingly the New York Times article about this approval brags about how many people will be helped by the previously-banned medicine.[1] Nowhere is it pointed out that so many more people could have been saved if the FDA fast-tracked drugs approved in Europe.
It seems that if the Canadian and European regulatory bodies are incompetent or too quick to approve meds, it would show up in some statistics, right? Maybe their life expectancies would be lower or they would have higher rates of certain kinds of deaths. Yet if anything, it’s the US that lags in those areas.
There are tons of examples of the FDA failing to approve things, resulting in Americans dying unnecessarily. A more recent example was Omegaven, an IV nutritional fluid.[1] The FDA took 14 years to approve it, resulting in hundreds of infant deaths. Before its approval, only a few infants at Boston Children’s Hospital managed to get it. The staff there had to get FDA approval to import the fluid from Europe for every infant they wanted to treat, resulting in a lag time of several days. Even though it was clear that Omegaven was much more effective than previous IV nutrition, the FDA’s bureaucratic hurdles prevented it from being adopted sooner.
Maybe part of the reason that the Canadian and UK drug regulators are competent, is because we haven't created a sufficiently large system of incentives to undermine them. Maybe if approving a drug in Canada got you access to the entire world, we would have a very different scenario.
A rubber stamping scheme removes redundancy from the system. Approving drugs faster sounds like a great idea, but there was a reason someone put up that fence you want to tear down, and your arguments haven't addressed it. Furthermore, the fence doesn't need razing to accomplish your goal - I don't see why advocating for the FDA to approve drugs faster should be synonymous with turning them into a rubber stamp.
No one (or at least not me) is contesting the assertion that approving drugs faster may save lives. But I don't want pharmaceutical companies to be able to undermine a single regulatory body and then be able to distribute their drugs everywhere.
There is no reason because it wasn’t a deliberate choice. Different countries created their own standards bodies and didn’t try to coordinate until later. The same thing happened with safety regulations around automobiles and aircraft. Fortunately in those cases, most countries have coordinated and manufacturers can sell the same vehicle in different countries with little extra effort. But for rare diseases with cheap treatments (such as in the case of Omegaven), nobody has the both the resources and the desire to overcome the FDA’s bureaucratic hurdles.
Again, this is a fine argument for making the FDA more effective and for coordinating with international partners, but full of holes as an argument for rubber stamping. And I still don't see why a rubber stamp serves your purposes better.
If you think the UK, European, and Canadian regulators are competent, then you must believe in the possibility of a competent regulator, right? Let's just have one of those, instead of a differently-incompetant regulator who serves as a rubber stamp.
And if we can't, then I'd rather they were too conservative than that they allowed too many drugs on the market.
At this point I don’t know what could change your mind. Your response to any criticism of the FDA or any proposed fix is to say that we need to make the FDA more competent, as if that’s not what people have been trying to do since the FDA was created. Unless you provide details about what would be different from what we’re already doing, you’re just arguing for the status quo.
It’s as if I were pointing out the uselessness of most TSA screening and someone replied that the solution is to make the TSA more competent.
I’d change my mind if there were more examples of harmful drugs in Europe or Canada that the FDA blocked in the US. The thalidomide scandal was over 60 years ago and caused around 4,000 deaths and 6,000 birth defects. You’d need a dozen thalidomide scandals to equal the FDA’s delays in approving beta blockers.
I haven't made the counterclaim to that. That's not the same as saying that the FDA should rubber stamp all European approvals.
Should doctors be able to prescribe drugs approved elsewhere? When we're talking about lifesaving treatment that isn't available in the US, yeah probably there should be some process to do that. I imagine insurance companies will make this next to impossible, but that's not a reflection on your argument, just a shitty reality.
What would convince me that the FDA should rubber stamp European drug approvals? I don't know, but it would be evidence about the structure of the pharmaceutical market and the incentives in place, not a recitation of misses by the FDA.
Your evidence they aren't approving drugs fast enough is convincing, I absolutely buy that a problem exists. But that evidence doesn't address my separate concerns.
Let's say we do go ahead and rubber stamp everything coming out of Europe. What is going to happen?
There's going to be more pressure on European regulators. How are they going to respond to it?
Possibly by being corrupted and subverted and failing open. That would be bad.
The alternative is that they becoming more careful, more plodding, they start taking into account the views of stakeholders the FDA would otherwise have represented, and the process gets gummed up anyway.
I'm sorry if I came off as like, an unreasonable FDA bootlicker or as being callous to the people dying or suffering reduced quality of life due to bureaucratic incompetence, I do think that's terrible.
If what you wanted me to agree with is that doctors should be able to get people drugs that there's excellent reason to believe are safe and effective, regardless of whether the FDA has finished approving them, then yeah, I see how that makes sense.
They approved one drug in under a year in a literal emergency (and it's deeply controversial that they did even that). That doesn't mean they can do that with everything that crosses their desk.
I do buy the author's assertion that people should have right to expose themselves to experimental medicines when it could save their lives though.
Let's say I give you 10 tasks. You're going to have to go back and forth with external stakeholders, and a given task will be blocked much of the time waiting for a response. So you can do each of them concurrently, but it's gunnuh take a year to do each of them.
But the next day I come to you with an 11th task. I tell you this is the only one that matters. I give you full license to blow through your budget, harass people until they get their paperwork done, whatever it takes - this is the only priority. So you get right to work, and with all the blockers cleared you get it done in 6 months.
"Great," I say, "so you can do all them that fast right? And when I come back in 6 months, all of the original 10 tasks will be done?"
But of course they won't be, because you don't have the resources you had before, the external stakeholders aren't as motivated as they were before, and instead of putting all your effort into 1 task you're going to be spreading it across 10.
The external stakeholders in the FDA are extremely motivated to get approval quickly. If this is a resource problem then the case for increasing the budget is clear.
Sure, but they did rubber stamp Fen-phen and Vioxx despite plenty of people within the FDA understanding it should come with a black box warning. The FDA needs a win that's more recent than 1971 if they want to demonstrate their efficacy as regulators.
Because it then becomes a kind of race to the bottom, where all manufacturers will approve medecine in the easiest country, a bit like flag on convenience for ships
They already do that. Having approval and data in another country makes it much easier to get FDA approval. But it's still a lengthy process, costs a lot of money, and often puts you in competition with other options that are approved. There are drugs that have been used for decades in Europe, are perfectly safe and proven to be more effective, and are not available in the USA (and likely the other way around, I'm just aware of specific examples there).
I guess we know that, but why doesn't the EU rubber stamp medicine that's approved in the US? In my opinion it's actually good for there to be independent bodies reviewing things.
Money and politics. Why can someone drive for 6 months in a country with a foreign driver's license but can't get a local license?
I've had this misdiagnosed medical condition for 25 years by multiple doctors. Nothing serious but extremely annoying. There are approved drugs in Europe for decades which are much better than the ones approved in North America. One day the company making the drug that's approved in North America decided to stop making it! You just could not get it. This was the event that finally led to the correct diagnosis for my condition because I was in so much pain I got to see the expert. Turns out my condition has a very simple non-prescription solution and for 25 years I've been taking the wrong meds that happen to alleviate this different condition as well!
So I am good but this condition is not uncommon. What are all the other people that really need this drug in North America doing?
I'm not sure what's the takeaway here. Maybe that efficient/smart organizations generally don't exist. This is just a reflection of human nature.
If you're okay with it, could you expand/name the condition you thought you had, the actual one, and the medication(s)? Never know, might help someone else out
I'm a bit concerned about my privacy but the condition is herpes virus infection of the eye. The similar condition is Thygeson's disease. The drug in question (that I could not get) is called Viroptic which for some reason helps with both conditions (despite them not being related). Thygeson's is thought to be more of an immune system issue.
So if you've been diagnosed with herpes, and anti-virals don't seem to help, maybe you don't have herpes. If you do have herpes of the eye there are good drugs approved in Europe but not in the North America (though there are likely some approved drugs in the US which will still help - it's complicated).
Why can someone drive for 6 months in a country with a foreign driver's license but can't get a local license?
A government issued id, like a driver's license, is often required for various services like opening bank account, a telephone connection, avail some government service etc. Thus a local driver's license can be used for deception by a foreigner who wants to pretend to be a local citizen.
There are many divergent if not contradictory regulatory findings levels and limits between the US Canada and Europe.
eg. Tolerable total cholesterol levels US:200 Euro: 240 (last I checked, these move around quite a bit. In the 70s the US banned Cyclamates as an artificial sweetener, but approved Sacharine while Canada approved Cyclamates and banned Sacharin.
For Glaucoma treatment Europe is "Laser first, drugs second" while the US is Drugs first, laser surgery second.
etc etc.
So all drugs will always be trialed at the most lax country and get approved at a stricter one? Then why make rules because the laxest country will be the one used and in control of approvals
There are "right to try" laws both Federally and in 40+ states. It's unfortunate the author doesn't address those, I'm curious how they interact with his case.
"I do not live in a state with a Right to Try law. Can I still use Right to Try?
"Yes. S.204 makes Right to Try the law of the land. So long as a patient and treatment meet the qualifications of the federal law, Right to Try applies, regardless of whether the patient’s state adopted Right to Try."
A steel-man response would be that assisted suicide is more about pain reduction, whereas experimental drugs could have terrible side effects.
It isn't a convincing argument to me, because possible death avoidance is a higher level of morality to me, but harm reduction is extremely prevalent in medicine as a driving factor.
I think the consideration that an article like this misses is the unintended consequences of speeding a process up / reducing the criteria for review, approval, etc.
I think we can all see incidents of where some oversight process is loosened because of some legitimate desire to help some, but then you learn that the bad / incompetent / exploitative actors come out of the woodwork to test and take advantage of the changing of rules. Not even saying intentionally, but just by sheer numbers, the change you made allowed things that were being held back by (hopefully proper) regulation to now happen.
Anyway, not saying that the FDA and other bodies couldn't move faster -- that is always the case. And there will always be examples of people/cases stuck in the cracks with legitimately sad situations.
But I would hope that people reading such stories think about why there is a process. It's not like the FDA's purpose in life is to stop people from benefitting from new treatments. It's to prevent the flood of bad effects of companies/individuals from being able to say they offer some drug that doesn't work in the way it says it does.
If he's going to die why not give him the option to try medicine that is developed by large players with a good reputation? Weighing historical success into the process seems to make sense to me. Beta programs from Google are usually very functional...
>I think the consideration that an article like this misses is the unintended consequences of speeding a process up / reducing the criteria for review, approval, etc.
In general I feel like the sick should not be held responsible for the unintended consequences of things. The principle that it is better for 10 guilty men to go free than 1 innocent man to be punished applies here as well. How many suicides have happened because it took this long for the use of psychedelics and THC for the treatment of depression and PTSD to be approved (partially, in some places). How many people are suffering today, right now in pain or under the care of doctors they would otherwise leave for poor treatment but the "opioid crisis" has limited their access to the treatments they need? I've faced this problem personally more than once, and while I am sympathetic to the law of unintended consequences, I just can't be convinced that it is the duty of myself or my loved ones to suffer because someone else might abuse something. There is a balancing act to be had for sure, but any borderline case should ALWAYS err on the side of reducing the current actual harm in favor of preventing a nebulous potential future harm.
The author seems to forget that entering a trial doesn't necessarily give you access to the treatment. You have as many chances to be in the control group receiving a placebo.
And as bad, sad and frustrating as it sounds to someone in a desperate situation, it is for the greater good of many more human beings, protecting us from snake oil.
To note, the placebo group is typically getting the best current existing treatment. Rather than nothing. Although in some cases the best treatment is still nothing, which sucks.
It is against medical ethics for the placebo not to be the current standard of care, and experimentally it must be… If you can’t beat the current standard of care then your drug isn’t effective.
Right now he has a 0% chance of survival. If the experimental treatment is at all effective, the probability of not being in the control group multiplied by the probability of effective treatment is greater than 0%.
The probability of a more painful death is also greater than 0%. So it the probability that something could go wrong and cause publicity which would interfere with the testing or approval of the drug and affect other people's access in the future*. There are always tradeoffs.
*this person takes the drug. Two days later they die of a heart attack. Was it caused by the drug? How many resources should be spent to determine that? Should that death be listed in the potential side effects? What if the news story publishes an article and scares people off from the trial? What if it's later proven that the drug had no effect on the heart attack but the distraction from it delayed 10,000 people's access to the drug?
> The author seems to forget that entering a trial doesn't necessarily give you access to the treatment. You have as many chances to be in the control group receiving a placebo.
This is untrue, in this case.
Typically, only some phase 2 and phase 3 trials are randomised; the treatments that the author refers to are at an earlier stage of development and so not in either of these phases. All patients will receive the active therapy.
It's also worth noting that for cancer trials, while new treatments in these later phases may be tested against a placebo, it's never just a placebo - that would be unethical. If the new treatment is an add-on to an existing standard-of-care treatment, then they'll receive the standard-of-care treatment in the placebo group. If it's not an add-on, then it will be tested directly against the standard-of-care. If there isn't an established SoC, it can sometimes be approved without a randomised trial, if the results are good enough.
The greater good argument is repugnant in this case. He is going to die, and deserves an opportunity to do whatever is possible to save himself, including new and little-tested, and likely ineffective treatments. He literally had nothings to lose.
And in this case he would be actively helping humanity as well by being a test case. We would all gain knowledges and information from his treatment, if he could get it.
Regulators are, in general, too sheltered and disconnected from the impact of their actions.
Incentives matter. When you get to make decisions that impact others, but not feel any of the costs associated with that, you do not have the correct incentives. I hope the staff of FDA read this and can’t sleep tonight. We can hope they feel some emotional pain, even if it is only some small subset of the pain they have and continue to cause to others.
I would disagree with this. Regulators that I have worked with in US and EU knew what it meant. Maybe not the most amazing technical people I’ve ever worked with, but they were as competent as any random sample of pharma/tech types. Their jobs is to verify that you have completed all the valid documentation to demonstrate that your drug does what you claim it does. Their opinion on personal emotions are irrelevant. They are supposed to be guideline checkers.
I understand some people are checking boxes, with no space to consider their impact. Please generously reinterpret my point to extend to their management stack and the political establishment that is responsible for the system.
Those who establish, support and tolerate that system should be as directly exposed to its consequences as practicable. It is good for them to see these stories and feel the consequences of their decisions.
The consequences to their actions are that when a doctor prescribes me a medication or when I purchase one off the shelf, I have incredibly high confidence that if I follow the dosage instructions it is safe - safe now, safe in 15 years, not worth further thought on my part. That hasn't been true in most places for most of human history.
The consequences to their actions are that millions of people are saved from the consequences of consuming seemingly promising drugs such as Thalidomide: https://en.wikipedia.org/wiki/Thalidomide
I could sleep just fine knowing that some people looking only at a tiny local example while ignoring the big picture considered me the villain
To the extent that is true, I agree, they should see the positive impact of what they do as well. Your blind faith in the regulatory regime, however, is deeply undeserved. Many approved drugs prove to be dangerous and we can reasonably expect that many effective drugs never make it to market because of bureaucracy.
There is no 100% correct answer here. As soon as you speed up the process, there are still going to be people that just miss out, and then we will have people saying 4 months is too long, it should take 2 months, or let AI approve it, etc. Desperation skews perspective.
The issue with having a standardized approach to people getting experimental drugs is it opens up its own kind of mini-market unless the implication is they would be required to be free by law. And desperation is not the right mindset to make law or rational decisions.
Not trying to sound heartless, its just not as easy as saying "go faster".
Giving someone Treatment X likely means they won't be pursuing Y, whether it be to avoid polypharmacy drug interactions, or simply because the patient prefers X's side effect profile to Y. Y may be the proven treatment, with worse side effects but better efficacy. Even if the doctors inform the patient "X may not work at all and may make it worse", the patient might still choose it.
"What's the harm?" you say. The problem is, without any threshold, there are countless Treatment X. Every single snake oil comes out of the woodwork.
Could you please stop posting unsubstantive comments and flamebait? You've unfortunately been doing it repeatedly, and we've already asked you more than once not to. It's not what this site is for, and destroys what it is for.
Drug policy is larger than this single man. There are trade offs with different approaches here. “There is literally nothing to lose” is simply false. Restrictions against selling whatever to dying patients is because people _will_ take advantage of them and sell snake oil. If you’re okay with that, why not just let people steal from those terminally ill?
My dad recently died. There are always new treatments being studied and some day one of those treatments might actually be able to cure people with the same disease. That day didn’t come early enough for my dad. That sucks but it doesn’t change the fact that drug policy is made for society as a whole and not only for my dad. This isn’t some conspiracy where a cold bureaucracy is letting people die. Sometimes your luck just runs out.
It literally is a conspiracy where a cold bureaucracy is letting people die. That is exactly what is happening.
You appear to think that it is worth letting people die to avoid quack doctors being able to sell them snake oil. I prefer to leave it up to the patient to decide. They are the ones with skin in the game.
Another topic for discussion related to this (and I hope we can be detached enough to discuss the intellectual side of this impersonally):
Even if the drug/treatment method were approved, how much would this cost, would the author even be able to pay for / have the insurance company pay for the treatment?
And by the way, what limits are there on the price of a drug that an insurance company or the government will cough up the money to pay, for one person's extension to life for a couple years?
If someone has a very rare or just very advanced cancer, how much should the rest of us (as individuals paying taxes/premiums/etc) be on the hook for paying for last ditch efforts to prolong that person's life?
These are genuine questions I think are legitimate to ask, if not in polite conversation, then at least at the level of policymaking bodies in govt or insurance companies. I'm sure that people in the UK are quite familiar with this concept or debate.
You cannot just say you'll pay whatever it takes to save someone's life no matter what the circumstances.
3. Accelerated drug approval gets mired in advertising. The general public has no idea how to judge if a drug works or not. Plenty of people believe that homeopathy works. The FDA gets massive pushback when trying to take a drug that is worthless away, because people think it works. This hurts us all and creates an incentive for companies to hide data and deceive customers.
4. The FDA is as fast or faster than the Canadian or EU equivalents. The FDA is not specifically slow, bureaucracy everywhere has become much slower because there are no incentives to be fast but countless incentives to be slow.
5. Lawsuits. It's easy to say "I'm hurting, I'll take anything". But, then, there are rights you cannot give away. If a drug harms you, you will sue. If it kills you, your family will sue. The whole system is bogged down by lawsuits with massive disproportionate payouts. The early biotech companies and scientists involved often cannot deal with even a mistaken lawsuit.
We need a much more comprehensive overhaul of the system, starting with open access laws to all data pertaining to any drugs that are on the market (no manufacturer can keep anything secret for a drug that people take), an FDA that has much more authority and much less industry capture, medical tort reform, to create a system where in exchange it actually makes sense to provide fast tracked approval.
You're missing the part where the FDA has a revolving door with the biggest pharma companies. To think the FDA is some flawed, but impartial, judge of drugs is the key problem. The FDA is controlled by big pharma. No more, no less.
> think how bad it will look that we approved the drug so quickly
The media (both traditional ans social) owns a large chunk of the underlying blame, due to their rush to create simplistic narratives in the wake of anything that "goes wrong" without nuance or examination of tradeoffs.
This quote sounds like self interest in the article, but there is more to it:
> If anything goes wrong,” he argued, “think how bad it will look that we approved the drug so quickly“
People who take an approved drug are relying on the result and authority of a scientific process — across all drugs. Some scary results and people may start to fear the process, which may end up killing more people.
That said I’m sympathetic to his plight and think that he sounds like a candidate for the compassionate use program. Any result would not help approval as who in such a program would volunteer to be randomized into a placebo arm? They’d just plead in a prior human administration disclosure section of any NDA.
(Also, pragmatically, immunotherapy grate nets are customized and extremely expensive. Who will underwrite it? Not the drug company who would have nothing to gain, not the insurance company, and I doubt the patient could afford it).
When a gov org cares about how it will "look" over wether it kills you - you live under tyranny.
A common example why government doesn't solve problems well. Because it's an absolute governing law, there's nowhere else to turn to. This creates an industry of snake oil that preys upon people both as regulated medicine and homeopathic remedies. In practice vertical integration is a requirement for economies of scale. This means all medicines must be created by singular centralized corporations. These corps buy out the regulatory and now we have an incredibly inefficient and locked out market that prevents innovation.
All orgs should be sunset after 20 years by law. Repeal the FDA, replace it.
There's a very easy regulatory solution: Roll the drug approval process back to the way things were done prior to 1962. Back then, safety testing was all that was required. Efficacy testing -- which is difficult, expensive, arguably unethical in itself, and in some cases effectively impossible -- was not required. Drugs cost ~20-50x less to bring to market, and were brought to market faster. Indeed the 40s and 50s are still known as the pharmaceutical industry's "Golden Age." And it wasn't only because of low-hanging fruit.
Pair this paradigm with extensive postmarketing surveillance and periodic reviews for efficacy in a patient population. These could be done at two years, five years, and eight years -- and approval automatically rescinded if safety issues arise or efficacy is close to null.
Give people with fatal diseases a "right to try" drugs that haven't passed safety testing -- and use that data.
generally, insurance companies do require efficacy. many of them have decided not to cover aducanumab for that very reason. though this also gives insurance an additional excuse to deny stratospherically-expensive gene therapies and other life-saving new treatments, since even the most effective new drugs won't have e.g. 10 year survival rates until they're a decade old.
I do think that people should have options, especially when there aren't effective treatments, but it's not exactly simple. In most cases, any treatment you pick has the opportunity cost of other treatments, and for life threatening diseases that opportunity cost might be living. Very few, if any, patients are going to be in a position where they can legitimately evaluate the effectiveness of treatments. In most cases, I don't expect health care providers will be in the position to do that either- even most specialists will be treating a wide variety of conditions, and may have relatively little experience with unusual diseases. Even in the best case, this is assuming that drug companies would actually try to make effective drugs rather than looking for other avenues to sell ineffective drugs (or drugs that were only accidentally effective)- I don't that in today's environment that's at all a reasonable assumption. Ultimately, the information asymmetry is vastly weighted in favor of the drug companies, and the cost is lives.
That's how it works in Mexico. You only need prescription for antibiotics (makes sense as their abuse would create a public problem) and psychologic related drugs (I dont agree with some of them like amitriptyline... ) .
But other than that you can get almost anything even buying it online and get it at home in the next 3 hours.
Yeah, right. They had such advanced cancer medication back then.
> Give people with fatal diseases a "right to try" drugs that haven't passed safety testing -- and use that data.
That data is practically worthless.
I'm in favor of having people try out medication, but it will need to be heavily regulated. And we know what happens to regulation: a party comes along that doesn't like regulation, or gets bribed, and the regulation goes out the window. It's a good way to start another opium crisis.
This is the reflexive response to every common-sense proposal to roll back the regulatory burden.
I'd raise a couple of points in response:
First, Thalidomide was never approved in the USA -- for safety reasons. The mechanisms that were in place at the time did their job.
Second, the response to Thalidomide was overblown and indeed downright hysterical. "Better to let 100,000 people die of neglect than allow one person to suffer an awful drug reaction" is not rational policy.
> That data is practically worthless.
Enough "practically" worthless data, and you get somewhere. It's a matter of quantity. Obtaining "hiqh quality" data is often unethical in medical practice.
A large data set of highly biased, uncontrolled data is still useless. You can't model yourself out of the factors that have not been recorded. And believe me, the data you'll get on patients that try experimental medication will be very, very incomplete.
It also won't be a large dataset. How many people have squamous cell carcinoma between now and the moment of approval and are willing and wealthy enough to buy this particular medicine? 100 seems too much already.
> The mechanisms that were in place at the time did their job.
Barely, according to wikipedia.
> Second, the response to Thalidomide was overblown and indeed downright hysterical. "Better to let 100,000 people die of neglect than allow one person to suffer an awful drug reaction" is not rational policy.
Thalidomide was never going to save 100,000 people. It did cause 2500 birth defects in West Germany alone, though, plus an unknown number of abortions. Given that it was legal in 46 countries, the number of people with birth defects must be well over 10,000. This drug isn't going to save 100,000 people either, certainly not in the period until admission.
> A large data set of highly biased, uncontrolled data is still useless. You can't model yourself out of the factors that have not been recorded. And believe me, the data you'll get on patients that try experimental medication will be very, very incomplete.
There are many safety issues that placebo-controlled and double-blinded studies didn't catch, but postmarketing surveillance later did. Large data sets are more powerful than you give them credit for --- and, moreover, in the real world drugs are not always used the way they are in clinical trial settings. In the real world, people skip doses, double up on doses, drink grapefruit juice, etc.
If you want a full picture of "factors that have not been recorded," you want as large a dataset as possible, as close to real world conditions as possible. It may not be as clean as you'd like, but it'll give you enough to draw every inference.
> How many people have squamous cell carcinoma between now and the moment of approval and are willing and wealthy enough to buy this particular medicine? 100 seems too much already.
When the alternative is to allow the drug to spend a decade or longer in development hell, I'll take poor data and lives potentially saved over "great data" (not really) and a pile of dead bodies.
Besides, when drugs are potentially curative, and the disease otherwise so invariably fatal, even 50 datapoints should be sufficient. This is trivial to model mathematically.
> Barely, according to wikipedia.
Oh come on. Besides, teratogenicity is now an absolutely basic component of safety tests. You don't need the FDA's failed paradigm of extensive efficacy trials to prevent "Thalidomide part II."
> Thalidomide was never going to save 100,000 people.
The exaggerated response to Thalidomide, exemplified in your first comment, has absolutely condemned more than 100,000 people.
> Say you're a runner. In the beginning of your competitive career, you get the most gains by becoming a better runner. And then at some point, you get more gains by shooting (or bribing) the ref.
For those that don’t know, the 1962 change is the Kefauver–Harris Amendment, which was a response to one of, if not the, largest overall global crisis of conscience in the medical field. From Wikipedia: “When first released, thalidomide was promoted for anxiety, trouble sleeping, "tension", and morning sickness.” After some time it became increasing obvious that while it worked, it caused birth defects in pregnant or soon to be pregnant women, with its manufacturers actively trying to quash the information about such cases; again, from Wikipedia: “Use of thalidomide in pregnancy can cause fetal abnormalities such as phocomelia (malformation of the limbs). In males who are taking the medication, contraception is essential if a partner could become pregnant.”
Thalidomide disfigurements were disturbing. Children born with these disfigurements were not linked to Thalidomide until much later. Thalidomide was in fact not allowed a safety regulation by the FDA initially. It wasn’t until the company producing it, Grünenthal, pressured the FDA. You see, the FDA reviewer for the medication was leery about it after some reports had floated over her desk about a possible remote risk that this could potentially cause birth defects. Grünenthal’s international licensee to the US refused to explain multiple papers that linked Thalidomide usage in pregnant women to birth defects.
As it turns out, not only had Grünenthal known about the issue they had actively worked to silence the information, a ploy that worked until a major change in leadership in Germany.
It was denied usage in East Germany.
For a longer documentary on the subject and how it changed medical safety testing, Plainly Difficult has a very good video on it: https://youtu.be/Vi03zz6eCik
(Note: I am explicitly ignoring the context that the Thalidomide development program was run by an actual Nazi who was responsible for unethical and frankly awful experience on unwilling human subjects in concentration camps. If anything, it only amplifies his concern to hide adverse effects, which he did quite successfully until the company was given what can only be considered “A slap in the face”.)
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[ 4.2 ms ] story [ 320 ms ] threadAs the author says, no one ever blames the FDA for the people it failed to save. But approve something without the certainty that it isn't potentially going to kill someone, and there will be hell to your doorstep.
Even if you want the experimental treatment, you cannot get it. Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault. This is sometimes also known as the Copenhagen interpretation of Ethics.
In all three instances, the result was that the treatments were snake oil and people died that might have lived otherwise.
It's easy to say "people who have no other options should get access to experimental treatments" but the problem is that people who have other options want those too, because nobody wants to go through chemotherapy or whatever.
Medical authorities have a shitty job.
For people who are likely to die very soon the case is more clear cut, but the people developing these treatments don’t have the resources or infrastructure to try and treat more than a tiny handful of people. Allowing people to pay for such treatments also opens the door for a huge range of bad actors which also costs lives. I am not saying the current system is great, just that there’s a lot more complexity than is obvious on the surface.
You should be careful not to exclude trials cancelled early when considering how risky trials are.
While PD-1 blockers may cause the immune system to attack another part of a patient's body, we have quite a few ways to treat those autoimmune issues.
They indeed do this and have various avenues for treatments to be approved on expedited timelines.
BTW people picking such experimental treatments would provide important data points.
Talking about immunotherapies feels like oh yes of course it would be worth it…but should you also be able to print out a blog article about holistic medicine and demand the hospital follow that treatment plan for your illness? Should a person insisting their illness be treated with an untested therapy from a disreputable company get a hospital bed instead of you for the same condition because they arrived first?
IMO this seems like something where the burden on the medical system is at least as much of a factor as the risk to the patient.
Screw ‘em
It took about one year to find efficient ways to treat COVID-19.
So, if you have a condition with a few years of life expectancy remaining, maybe it's worth it to wait for some promising scientific results to turn into an approved medicine that will cure you. If you have a few decades (e.g. the normal life expectancy), even more so. If you doctors give you a few months though, maybe the "try anything" approach is a better gamble.
Now, that wasn't in the US, and I'm pretty sure the quack device wasn't approved as a medical device. But the fact is that fraudsters will sell their fake medical products to desperate patients who have nothing left to try. These people should rot in jail.
My idea is not about quack medicine. People should be discouraged from using quack medicine, and made abundantly informed that it's guaranteed not to work, while consuming their precious time alive which other treatments might extend.
My idea is about something that has promising results in scientific trials, but may carry unknown risks, and so is not yet approved. The risks may be worth it, because the alternative is a certain and quick death.
The patients should, of course, be also abundantly informed about the risks, the odds of success, etc.
Of course, some people would do things that we would find irrational, no matter how we try to persuade them against that. This may of course be painful to see, but I don't see why should we curtail the free will of an adult in their sane mind, as long as nobody's rights are being infringed. Certain new things always look crazy even though they have merit: see vaccines, blood transfusion, etc.
Also we should stop patronizing everyone. If someone understands the risk and their doctor agrees, just treat them.
But if the docs say "With our current medical knowledge, this person is destined to die within $TIMEFRAME.", then, if the patient consents to try anything, even if it kills them earlier, why not?
And these companies get very good at gaming the system, because that is their product. They are mechanisms to commit fraud, stealing all their patients' money and all their families' hope. This is a very bad thing. And, no, I am not making any of this up, but I dare not name names here. These companies also tend to be litigious!
The impact of this is extremely severe. First, people die because they choose a truly worthless treatment that can never work, over bad ones that at least had a snowball's chance. Second, people lose faith in The System, because they think that the fraudulent treatments should have worked, so they lose faith in the good ones too. And third, R&D efforts can get redirected away: rare condition X already has a treatment, so let's put our efforts elsewhere (oh wait, no it doesn't, that was fraud, now there will never be a treatment).
We will not untangle the experimental treatments issue until we confront this problem. Just do not think that it is all in "good faith" here, or even "best effort": there is real fraud going on, committed by monsters that know exactly what they are doing to take their profit.
Like Steve Jobs.
Fruit juice kills people.
actual fruit has fiber and you're unlikely to eat enough to cause harm.
Steve Jobs got into alternative medicine to treat his pancreatic cancer, including trying a fruitarian diet. Since he had a rare form that isn’t as fatal as pancreatic cancer usually is, there’s a chance he could have survived significantly longer if he had instead treated it with traditional, non-experimental medicine.
Then the snake oil manufacturer can peddle their unapproved treatment to as many people as they like, but they are losing money on every dose unless the treatment turns out to be safe and effective.
Obviously you need a big team of scientists on the approval panel to make sure no snake oil salesmen are faking trial data to get their payday, but that seems solvable.
You have enough stories like this (plus there will inevitably be some mistakes by the FDA that will be shown to be proof of government perfidy) and the conspiracy theories will have a field day and fuel a black market.
Creating an equitable drug approval process is a true dilemma.
The ethical tradeoff between definitely saving a life now or probably saving many lives later is an age old problem, but one which society hasn't properly converted into laws and processes in medicine.
It should be a escrow release when a patient is cured. Let the science and knowledge speak for itself instead of statistic doing the talking.
The problem is these drugs companies are the stealth chemical weapons development program for the military.
This just winds up being cruel. We don't understand a number of diseases, and we don't know how to cure them.
But we can treat symptoms, and sometimes prevent them even if it isn't a cure. It's OK to make Insulin Plus that keeps diabetics alive longer. I have MS, and freaking trust me, I want my non-cure medicine. Without that medicine, my chances of having a very poor quality of life full of discomfort increases pretty dramatically. Lots of things are like this: No real cure, but we make folks lives better by treating symptoms or preventing some damage and things like that.
The only way to not be cruel is to give treatments that work even if they aren't a cure.
Lets not forget the expansion of the DSM which pretty much incorporates every human being as having a mental health issue or sexual deviancy fetish. There is no normal in the DSM, so would some medical experts start dialling back on diagnosing new conditions to pad out their careers and income?
There is a huge difference between being down after a loved one's death and finding yourself feeling that way for no reason or not coping 2 years later.
Considering that - there is no way to answer the last question. That's just a "what if" argument and fails to take into consideration that there is a shortage of mental health experts, and there is absolutely no need for someone to do that sort of thing.
And no, no everyone has a "sexual deviancy fetish", just for the record.
As far as 'treating symptoms'... I have MS. I take medication that slows the disease. If I had fatigue or pain, they would try to treat that too. If it causes depression - which it can - they'd try to treat that. No matter what treatments I get for symptoms, I still have the disease. There is no actual cure.
Define normal? Likewise considering the all encompassing vagaries of some words, as noted in legislation, and the lack of detail that exists in descriptions of diagnosis and symptoms, whilst this makes it easier to generate AI's to replace some experts, its not really helping the patient is it?
>And no, no everyone has a "sexual deviancy fetish", just for the record.
Define normal.
> There is no actual cure.
You are uniquely placed to actually find a cure, because I'm reminded of how tolerant (lab) animals are when level 1 of maslows heirachy of needs exists, and I'm also reminded that (lab) animals can not convey information that an owner of a pet or intelligently constructed lab experiment could elucidate.
The phrase "Dont take no for answer" springs to mind, and Thomas Pynchon "If they can get you asking the wrong questions, they don't have to worry about answers.".
Survival of the fittest comes in all shapes and form. I know that copious amounts of histidine a precursor to histamine also causes remyelination of the nervous system, so maybe you have an amino acid lead that might be worth investigating.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705972/
Even simpler is to prohibit payments for these experimental treatments, but let people who whould die anyway participate in them as long as it is free for them. In return the drug companies could use the outcomes as data points towards their aproval applications.
Why would a drug manufacturer do that? Why would they offeir their advanced but as of yet unaproved drugs for free? It is true it would cost them the manufacturing cost of the drug, but what they get in return is data on how efficient/safe the drug is. Assuming the drug works well they could use that data to prove their case and get approval. And if it is safe and has the desired effect they get their aproval and they could then charge for their drug as usual.
This sets the right incentives for the drug company. If they know they are selling snake oil they would be crazy to offer it for free, especially because all it would do is to prove that it does not work. If they think it can work they gamble with their own money. Which is good because the drug company knows the most about their own drug. The patient in general is not knowledgeable enough to evaluate the chances of an experimental therapy, but the drug company is.
Hell I'd even approve my tax money to go to those companies which end up saving lives as reward.
That would never happen for good reason. Drug companies would have every incentive to bias the results towards approval by giving the drugs to detain patients. I’m not exaggerating when I say this might be the worst idea I’ve read in this entire thread.
What do you mean “detain” patients? Remember we are talking about people who have a terminal illness with no known cure. How can drug companies “bias the results”? Obviously I’m not saying we take anything they say as gospel, but in short order these patients are expected to die. If a drug managed to cure them that would be quite hard to falsify don’t you think?
> I’m not exaggerating when I say this might be the worst idea I’ve read in this entire thread.
Well, thank you. I aim to please. Are you sure that you understood the idea well? If you are, could you please explain with more words what is the misbehaviour you are worried the drug companies would commit?
I meant to write "certain".
> How can drug companies “bias the results”?
Choosing appropriate patients will lead to longer survival rate unrelated to the drug in question. The whole point of double-blind studies is to avoid this.
> Well, thank you. I aim to please. Are you sure that you understood the idea well? If you are, could you please explain with more words what is the misbehaviour you are worried the drug companies would commit?
I did understood you. You, however, don't seem to understand statistics or economics. Your idea directly incentivizes drug companies to choose patients more likely to make their drugs look better. It is a truly horrible idea.
Yes. So? The whole patient group in question is destined to die fast. The best we currently can offer them is aleviate their discomfort and help them come to terms with their demise. If the drug company can identify a subgroup who they can possibly save and actually help those that is winning.
> You, however, don't seem to understand statistics or economics.
And you are abrasive and rude. These exclamations don’t add much of anything to the conversation. If there is something particular I am overlooking please adress that instead of speculating about the areas you think I am deficient in. Thank you.
You are aproaching it as if the question we are asking is if this is the best study design. But that is not the question we are asking. There is a patient who we believe is about to die soon. In comes a drug manufacturer and says to the patient: “you do not have to die. I think I have the cure for you”. The patient wants the drug the drug manufacturer is offering. The question is if we are to interject and stop the drug manufacturer giving the patient the drug, and if so under what circumstances.
I am saying: “yes, we should stop the drug manufacturer if the drug is not proven to be effective yet, and he is asking for money for it. There is too much of a chance that the drug manufacturer is a snake oil salesman in disguise and only wants to extract the wealth from the patient and the patient’s family. But if he is honest they can give the drug for free.”
In turn you are saying. “We should stop the drug manufacturer giving the unproven drug to the dying patient even if they are giving it for free, because it is possible that they cherry picked this patient. So though luck dear patient, you must die in the name of scientific rigour. I hope you understand.”
Do I understand you right?
This is already largely possible in most states and called "right to try".
> Do I understand you right?
No you seem not to be. Giving away drugs is fine and largely already possible. Choosing patients and then pretending that the data gathered has any reasonable statistical validity when considering general approval of a drug is totally crazy. I think there is essentially zero chance the FDA would ever go for an idea with such overt conflicts of interest so I'm happy your idea will never turn into reality.
The article’s author is convinced it is not covering them. Do you know otherwise? Perhaps you should let them know. You might save a life.
> Choosing patients and then pretending that the data gathered has any reasonable statistical validity when considering general approval of a drug is totally crazy.
Would like to mention that it is your adition that the drug manufacturer chooses the patients. It was not part of my original comment. And it is not core to the idea.
One can simply imagine a protocol where the manufacturer declares their criteria (what condition, what severity[1]) and how many doses they are able to provide and those “places” get filled up with volunteers. And this of course can be made even more buletproof.
1: and before you point it out, of course if the manufacturer is only willing to test their drug on not-so-bad-but-dying people then they get approval to be used on the same selection.
Experimental treatments being available to people with no options (there must be no applicable option with a proven probability of success or this becomes very questionable) could save drug companies millions-billions in the off chance that it proves to be incompatible with human testing or fails to produce the expected effects in humans.
I would take this up a notch or two for patients in a short-range situation that is certainly fatal, opening the door for them to try treatments that have just barely crossed en-vidrio and seem to have acceptable toxicity in mouse models. This would essentially be donating one’s body to science but in a much more useful form, with the side benefit of a slim chance of life extension.
This could benefit humanity by significantly reducing time to market for some drugs and cutting costs on eventual dead-ends.
If everyone you give it to dies from reactions, or the expected effects seem to be happening on a physiological level, you don’t know much about efficacy but you do know a lot more about the eventual prospects for an actual clinical trial. It’s basically an extension of en-vidrio testing.
The HepC drug Sovaldi brought in around $50B-100B in sales, but probably costs less than $50 to administer. Under your scheme it would make economic sense for a company to kill 1,000,000,000 people testing variants until they chance upon the right one because they incur no costs for administering deadly experiments.
The problem with your scheme is that human lives are valuable. A unsafe drug that causes harm or death is immensely destructive. If we want to be completely reductive, the actuarial value of a human life is around $10,000,000. A unsafe drug could kill the person resulting in a $10M loss to society. Therefore, the company should be required to escrow $10M per person until the treatment is done, paid out proportionally to any potential death or harm in excess of the gold standard treatment. Only then would the incentives be reasonably aligned.
This is obviously a very reductive treatment, but it helps illustrate the problems with unrestricted testing.
I was only talking about testing on people who we know are going to die fast because of their condition, and we do not have a way to save them in any other way. And naturally only with their consent. People who have a ticking clock and therefore willing to try anything.
This is the context the article in question talks about.
I doubt any company anywhere (legitimate or not) would provide drugs under such conditions. It would make much more sense to just focus on getting approval instead.
The team would try to make the treatment an experiment useful for science. They would have no incentives to kill prematurely patients that would otherwise have lived longer. They would work in good faith.
Disclaimer: I actually had had a treatment (surgery) not yet approved, it saved my foot from amputation. This was in Europe.
The doctor was adding me to the long lists of patients he saved. He also trained other doctors to perform the surgery. Eventually the procedure was approved by FDA and in Europe. I'm glad to have contributed.
Before going on that I read all the articles related to my problem (many thanks to sci-hub) and then send a email to the surgeon. He said "I can indeed help you" (best day of my life) I didn't pay anything (only the plane tickets to get where he was)
After approval it's the health insurance or the patient that pay. In countries like Singapore or France the taxes pay so it's "free" (actually it's an "insurance" backed by the govt)
Then how do you know it's prevalent?
Let's just say I have a personal blacklist of therapeutics companies I will NEVER seriously work for (though I have done a couple things for them that satisfied my conscience), and a few electrical schematics squirreled away should I need to defend myself someday....
In this person's case, he will not live otherwise, so he has nothing to lose by trying an experimental therapy, although it appears to be too late anyway. Very sad.
I reserve for myself the right to try to save my own life, even if that means some people who can't handle that responsibility make things worse for themselves. I can't get from, "but other people might hurt themselves" to "therefore you simply have to die, sorry."
No, I think we just have to be straightforward about this; I don't want anybody to purchase snake oil, but that possibility does not move me to eliminate options for myself or my family.
Well, I of course don't know what you personally would do. But some people would do this, and it turns out, actually a lot of the people in that situation would do that. And so something gets done.
This is the same thing as crypto, people "reserving the right to take risks with their own money", and after the money is lost asking why the government didn't protect them. And the same as many other things. Humans suck at accepting the consequences of their own choices.
Nobody has a fetish of taking your choice away from you. People ask for things to be this way, because people are just human.
Additionally, I think it’s partly me just wanting to spread awareness about <stupid thing> and possibly engage smarter people than me to devise better resolutions/implementations as well.
Wondering if u have any thoughts or I’m just galaxy braining it
The solution, I think, is to teach people to understand risk, choices and consequences better. With enough teaching, maybe the advocacy for the forced good will decrease.
I think the ideal of regulation is to try to remove the guesswork & expertise required for the end user to do due diligence. It's not perfect, but at least some minimum level of regulation, such as mandatory efficacy disclosures, would be needed.
One of the reasons my father died of cancer quickly is that he was convinced by a chiropractor/osteopath that he had trouble with his back which could be cured with manipulation.
He was not an idiot, but sick people will make bad choices.
The abstract world of "either I die or I try this experimental treatment" is far more blurry, and there lies the problem, in my very humble opinion.
It seems like you're claiming that people who were given medical treatment after media attention weren't down to their last option(s)?
If they were down to their last options, then they made their choice and it didn't work out.
In my opinion, the FDA ought to be more open to allowing experiments in cases where it is clear the patient is aware of the untested nature of the treatment.
It would result in tragic cases like the three you describe. During COVID-19 it would have resulted in people taking Ivermectin which was ineffective and even harmful.
But during COVID-19 it would also have resulted in determining 6 or more months earlier that the vaccines we made were safe and effective and the number of lives saved in that single instance would have greatly outnumbered the losses from 100 years of experiments.
It's easy to understand the logic of desperate patients who will try anything but it doesn't seem right to allow manufacturers to profit hand over fist selling treatments that may not even do anything, or worse, outright cause harm.
So, why can't one go through its own choice of treatment? Disregarding if its a good choice or a bad one.
How often do these drugs, etc turn out to effective? 25 years ago we wanted to rush gene therapy and that didn’t turn out well. Someone died. It probably set back gene therapy:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/
I think the solution is to invest more into medical research now, then when we, or someone we know, eventually ends up with some horrible disease, (cancer(s), Alzheimer’s, Parkinson’s, etc) we’ll know that we at least we made significant effort, and gave everyone a better chance, rather than settle for a “Hail Mary” drug near the end.
I think that's often lost on people, and in a more frightening way, people who are all-to-eager to use the terminally ill as ultimately disposable test subjects for unproven treatments. If it was JUST down to safety then I could see the point to an extent, but as you said efficacy is a big open question too. Of course if you're facing death then you may well want to roll the dice, but the question there too is how well you really understand the odds. The understandable implication in a lot of the discussions around this issue is that if only regulators were a bit faster, people like the author wouldn't die.
The reality is grim though, most of these experimental drugs and therapies are not effective, regardless of whether or not they're safe.
You offer someone death, they get death.
This is about people desperate for cures and treatments that probably won't work, and may well give them the opposite outcome from what they hope for.
There is a difference in kind.
This applies just as much to approved treatments as unapproved, for the same reasons, and has the exact same solutions such as having a third party with no vested interests explain to the patient. In fact it has those problems less than approved treatments because the companies are being paid by the insurance company for the approved treatments but not the experimental ones.
What constitutes the acceptable tradeoff is the heart of the matter. On the one hand, even the current approval process does not always guarantee efficacy (Aduhelm to mention it by name). Medical trials work with considerable uncertainty, and the risk/benefit tradeoff is always a question of probabilities. Even with the current process, there is no certainty or guarantee.
It is possible to take those probabilities and to talk about the expected number needed to treat (NNT) for a medication, the expected side effect profile, how many people might live and how many might die. Things that may sound cold, but that are already routinely done today.
It is hard to know where the tradeoff should be, how much margin of error is the right amount before something is approved, knowing that there is uncertainty even in large trials, but it's not a choice between the totally unapproved and the status quo. (Better yet, we should not model the choice as a single parameter that goes from more choice & more snake oil to less choice & more safety. It's also often possible to improve one aspect of a bureaucracy without it being a zero-sum game.)
> It is possible to take those probabilities and to talk about the expected number needed to treat (NNT) for a medication, the expected side effect profile, how many people might live and how many might die.
NNT > NNH = efficacy. To calculate these the trials need to be done, which is not the case for experimental therapies as they have undetermined benefits and harms (hence why they’re in trial).
The choice here is between conventional options that have known benefits/harms, however crappy they may be, with something that has unknown values.
I think that situations like TFA make a compelling case for selectively broadening access, for some drugs and some pathologies. The characterization of a choice between something proven and something with unknown values is too coarse and not a good model.
Clinical trials are very expensive, drug development as a field tends to move forward with what it thinks will have a chance of making it through. While most new drugs indeed fail (the large majority of them), in diseases with very poor prognosis like OP's cancer, I think we would benefit from still looking at the tradeoff as a decision under uncertainty, instead of a complete unknown. Even with less data than we would otherwise want.
Looking at experimental therapies as completely undetermined leads to a binary choice. There is supporting evidence that allows those therapies to move forward with experimental trials in the first place. The counterfactual of not treating patients with poor prognosis being what it is, my overall point is that treating experimental drugs as total unknowns with benefits and harms that cannot be quantified until the full process is finished is not consistent with the knowledge that, even after all trials are completed, this is still a uncertain statistical result, only with slightly more data than before.
In other words, we are always working with partial unknowns so when the prognosis is bad a larger unknown may be good overall and save lives, even though it wouldn't be acceptable otherwise.
Which is literally what just happened with osimertinib for NSCLC. It was approved for clinical use and was implemented without any overall survival data.
Safe for clinical trial means the harms are considered safe, has little to no relevance for efficacy.
Once again you’re ignoring the fact that there are (almost) always alternative treatments that have been proven to prolong life.
No one is offering nothing to poor prognosis patients.
From the blog post:
> Monday I’m starting chemotherapy, but that’s almost certainly going to fail, because a CT scan shows four to six new gross tumors, four in my neck and two, possibly, in my lungs.
In someone with such an aggressive disease everything is almost certainly going to fail, experimental or not. Chemotherapy will buy some time. Who knows what an mRNA treatment will do but there’s certainly no (not little, no) evidence that it will be curative.
I think sticking with standard of care until new drugs have gone through the full, current process may be net negative under the current process, and considering the counterfactual especially for patients with poor prognosis.
Chemoterapy will buy some time with certainty, but in expectations broadening access even slightly means we can gain confidence in the experimental treatments that do work slightly sooner, and that improves the standard of care for everyone. Experimental drugs sometimes do work, and it would be bias to only look at the risks while sweeping aside the potential upside.
Consider what happens a few years from now with the current system and with a system that selectively broadens access in some cases, when the early data seems to support the risk/reward. Even if most new medications fail, the cost of delaying those few therapy that will happen to work is much larger than the risk being paid by the trial population. That's because only a few people participate in trials, but everyone benefits from the results. This is why we have trials at all.
In someone with an aggressive disease such as OP, that person may very likely benefit from having that choice. Today they may choose to buy some time with _relative_ certainty, knowing that chemo has very heavy side effects and that they may not enjoy very much of that remaining time. But they may not choose to try some experimental treatments, even when the risk/reward seems reasonable according to early data, even though that may result in a small chance of success, and certainly data that will help bring therapies quicker to more people.
The benefit of experimental treatment is not just to the individual participating in the experiment. Part of the benefit, that helps justifies the risk, is the idea that a fraction of the treatments will be worthwhile. Slowing down trials is safer in the sense that no one will be responsible for anyone losing their chance at chemo or dying, but it creates the exact kind of invisible deaths in expectation that TFA talks about.
Furthermore, Step 1 of the NCCN treatment guidelines for these kinds of cancers (i.e. advanced and/or poor responders to conventional chemo) is always that the patient is enrolled in a clinical trial.
In this authors case he does not meet inclusion criteria for the therapies he is listing, both trials require systemic therapy with novel PD-1 inhibitors (aka immune checkpoint inhibitors, immunotherapy) which when they work do so fantastically with little side effects.
Per his description he has not tried any systemic therapy yet.
I’m unclear whether he’s lumping chemo with immunotherapy (often the case by non-domain expert patients) but not even Moderna is interested in going from surgery directly to mRNA.
This isn’t the FDA getting in the way. He hasn’t exhausted good treatment options yet to be eligible for unapproved experimental ones. It would absolutely be detrimental to ignore ICIs in an eligible patient in favor of [insert non-approved experimental therapy with no evidence].
I’ve seen far more advanced metastatic H&N SCC survive for years on ICIs in my clinical practice. We don’t know all the specifics of this case but this isn’t nothing/days/weeks vs mRNA as the author is pitching.
I'll take your point, and I appreciate the time you took to write a good response, though I've read about enough examples other than the current article that I feel this may be rejecting a wider pattern on the details of the current submission (but maybe I'm wrong, and they all happened to be incorrect for similar reasons).
But I'd like to hear your thoughts on the broader argument of being more aggressive with trials in general. What sticks with me each time this argument comes up, regardless of the particular situation, is this idea that despite some mechanisms for accelerated approvals, we are still far slower than we could be, if we take into account the number of people saved by bringing therapies sooner.
There is a cost to letting people take dangerous medication. I hate the idea of peddling dubious cures to vulnerable people as much as I'm sure you do. It's the counterfactual that makes the argument, the people who do not receive treatment due to delay seems to vastly outnumber the people harmed by experimental treatments. And the difference seems large enough that it would remain true even if we went much faster. I think that's the strongest objection to the current system.
> But I'd like to hear your thoughts on the broader argument of being more aggressive with trials in general. What sticks with me each time this argument comes up, regardless of the particular situation, is this idea that despite some mechanisms for accelerated approvals, we are still far slower than we could be, if we take into account the number of people saved by bringing therapies sooner.
Everything in medicine is trade-off. On the extremes we can practice with no regulation and have immediate access to treatments without evidence accepting that many patients will be harmed as many new treatments are inferior or require phase IIIs on the other end and minimize harms but accept that delayed care will itself cause harm.
Current practice is somewhere in the middle, depending on various factors like efficacy, risks/harms, and alternatives many treatments enter practice after phase I/II or used off-label for close indications.
I like where we're currently at for oncology and don't think we need to change much in the process. The bigger hurdle is funneling those R&D $ into high yield research and perhaps making the cost of trials easier (e.g. research alliances, IT infrastructure to simplify multi-center studies and patient recruitment, ?active government involvement).
There's always fine tuning of that balance that can be done and some cases will prove things wrong on either side of the argument but generally speaking I think we're close to where we need to be. Definitely better than when we didn't have the current approval process.
> It's the counterfactual that makes the argument, the people who do not receive treatment due to delay seems to vastly outnumber the people harmed by experimental treatments.
I don't think this is true and I have not seen evidence to support this claim. There is ample evidence of failed treatment options or treatment causing more harm than good. An example I'm well-versed in is HIPEC for advanced ovarian/peritoneal cancers (we've been doing this for years and it turns out it doesn't do much other than excessive morbidity) or Y-90 for HCC/colorectal metastases to the liver (first trials negative and we recently found out "oops we've been underdosing this and measuring non-target dosing to the lungs incorrectly") both of which are for palliative patients with no good alternatives.
Going back to osimertinib as the example, the main criticism of earlier TKIs (same class of drug, and even osimertinib for that matter) was that the promise of limited data (progression free survival rather than overall) led some patients to get TKI therapy rather than platinum based chemo which was standard of care and has proven OS benefit. Except when the OS data came out it was an "oops, OS didn't pan out like PFS" and people were harmed.
That these happen in the current system strongly suggest patients have access to experimental therapies and that we're not being overly stringent, or this data wouldn't exist.
I would also say that a large proportion of the patients I've interacted with that have disseminated disease are on some trial for experimental therapy with the caveat that I've only worked at tertiary care cancer centers. It's really not that hard to get enrolled if you meet criteria. I believe the stories we read of access challenges are largely a vocal minority with challenging circumstances or a misunderstanding of treatment options.
It's not their risk to take. Getting a drug to market is a complex process that can be derailed by any number of mistakes ranging from the mundane like improper blood draw during clinical trials to the tragic like accidental deaths that puts public pressure on the FDA to shut it down or spook away investors. Any hiccup in this process can kill it and once a patent expires, the chances of someone bringing that drug to market is almost zero, regardless of its efficacy.
The vast majority of drugs and therapies are developed via private investment and many companies go public before they make even a cent of revenue to fund the clinical trials. Public sentiment is the driving force behind their stock prices because they're literally forbidden from making money until the FDA approves their drug. Lots of them go bankrupt every year before finishing clinical trials or releasing a product and rushing the process is quick ticket there.
Patients don't get to put at risk the decades of good a drug can do because they're desperate and afraid of dying.
Michael Jackson, Joan Rivers and Lisa-Marie Presley for example would probably all still be alive if they didn't have the money to simply buy the healthcare they wanted, damn the consequences and cost.
I think this is a sensible take for someone who is not facing their own imminent mortality. But no matter what we do, the game theory of terminal diagnoses means there will always be incentive to go for a Hail Mary in the end.
I don't understand why we can't let people make risk reward judgments. Yes probably more people will die, but they were not forced.
I'm not saying this is the right thing to do. I'm just trying to explain how it happens. People don't make good risk judgements in general, and other people think that it is good to do good by force. This is why seat belts are mandatory, smoking is discouraged, drugs are illegal, public companies traded on exchanges are strongly regulated, and so on and so forth.
> Yes probably more people will die
You really don't understand why we choose the option where less people die? We value life, I guess.
Who does the investing? Not "The Market". The incentive isn't to cure but to treat. The Market wants (repeat) customers.
The government? At least, in the US, we've been dismantling the government's ability to do this since at least Reagan. Even our so-called Liberals aren't pushing hard here. You'd have to look to the "fringe" Progressives within the Democratic Party to even come close.
And why? Because "fuck you, I've got mine" may as well be the national motto of the USA at this point.
People will bristle at this, certainly. Look at Biden: he's done so much!
Biden is no FDR. We need a real social safety net in this country. And, yes, we need a "right to try", even if it means waiving malpractice rights in those cases.
I am fed up with this argument.
Compared to a recurring treatment, a cure will:
- destroy the competing recurring treatment
- sell particularly well initially, when you still have the patent, potentially at a high price
- not stop the influx of repeat customers, since as long as people are alive, they will need medicine, and people who are now healthy because you cured them will be more likely to have a well paying job that will pay for expensive drugs
If that argument was true, no one would do vaccines, especially considering that most vaccines are not particularly expensive.
This example is poorly chosen for a different reason explained in my comment.
Alternatively, we can look at novel curative intent therapies for cancer like focal ablation or stereotactic radiation.
The recurring customer alternative of chemo/immunotherapy or the conventional surgical option are at least an order of magnitude more expensive.
You won’t find much novel systemic therapy that’s curative intent because it’s really hard (?impossible) to do, not because the system wants to make more money slowly killing patients.
Personally/professionally I think this argument comes from non-experts failing to understand the disease process and therapeutic challenges. I’ve seen no evidence or suggestion in my years of clinical practice that this assertion has a shred of truth behind it.
> If that argument was true, no one would do vaccines, especially considering that most vaccines are not particularly expensive.
While I agree with you this statement does not prove your argument. Vaccines aren’t a good example of funding for curative intent treatments.
The economics behind vaccinations are different as you vaccinate orders of magnitude more patients than would ever get the disease so even if the nefarious assumption is valid the economics may still favor this path.
[1] https://www.investors.com/news/technology/can-gilead-withsta...
Additionally, if their drug didn’t work as well they wouldn’t have gotten away with charging 100k for a course and wouldn’t have made 40B+ in revenue.
> Yee, though, says Gilead isn't filling a hole left from its declining HCV unit. It's merely coming down off a "massive bolus of hundreds of thousands of people who came in during the first two years."
> "The drug is still set to do $8 billion in 2017 and is one of the largest drugs in the world. Not exactly a hole," he said.
The Gilead stock is worth 4x today what it was worth in 2012, before they had the cure. It is better than the average "big-pharma" (ex: Pfizer). The stock plateaued because they couldn't follow up, but before you look at the dip, you should look at the massive raise before it.
Funnily, an insurance company would push against that, for a final cure. They would like to avoid to pay for repeat treatments.
But the medical insurance in the US is more of a payment scheme, and apparently is not interested in paying less. I bet there is some regulatory loophole, or a government guarantee, that makes it more profitable.
This is a big point a lot of people ignore. I feel terrible for the author, but if there hasn't been a single drug invented so far that has any real chance of curing him, it's extremely unlikely that this one out of reach drug is going to be the drug that can save his life. I don't really know much about medicine, but I'm pretty sure that progress is usually incremental as well, so you start out with drugs that cure some patients and work from there instead of having some massive breakthrough.
The author is arguing that terminally ill people (with a few months left to live) -- like him -- would be willing participants in trials to help medical research. They already know that mRNA drug or whatever likely won't cure them. It's possible some new scientific knowledge of the drugs' effects can still be gained even when it doesn't cure them.
Given the realistic odds, the primary purpose (from society's perspective) of letting of terminal patients participating in unproven drug trials would be medical research rather than "Hail Mary cures". From the patient's perspective, of course they hope it improves their health.
We already let terminal patients participate in medical research, but only inviting patients at times and meeting criteria that optimizes the research. Also, only where IRBs have found it to be ethical-- this means not replacing a drug with proven benefit with an experimental treatment with unknown benefit recklessly.
But terminally-ill patients push for inclusion beyond this: to be dosed when there is not an active trial, or to be dosed when they are so sick that the outcome would be difficult to interpret or compare, etc. This isn't for medical research, this is for self-preservation.
Your objections are sensible but that's beyond the scope of this author's argument. I'm just taking author's following comment at face value: ">The FDA was loathe to approve initial mRNA human trials, even when those trials would have been full of people like me: those who are facing death sentences anyway."
If it's the drug researchers who don't want the author as a test subject, that's understandable. But he's arguing the _FDA_ shouldn't be the one blocking his participation.
For the situations where there's "no active trial" caused by the FDA not greenlighting the experiments, then of course, the complaint will be that "terminally ill patients want to participate in trials that don't exist". That's sort of a circular argument -- caused by the FDA.
Again, if there's no active trial because the medical researchers themselves are not yet ready, that's understandable. But if the drug scientists are ready but the FDA is not, that's a different issue and it's the focus of the author's essay.
All that said, I don't know how much scientific progress the FDA holds back because of "safety". I'm just trying to explain the author's position.
The FDA doesn’t hold back researchers on inclusion/exclusion criteria.
Inclusion for the Moderna trial he linked to:
> Must have primary refractory or acquired secondary resistance to prior immune checkpoint treatments. Primary refractory is defined as prior exposure to anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) antibody for at least 6 weeks but no more than 6 months with demonstration of progression on 2 separate scans at least 4 weeks apart but no more than 12 weeks apart and progression occurring within 6 months after first dose of anti-PD-1 antibody. Acquired secondary resistance must have confirmed objective response or prolonged stable disease (SD) (>6 months), followed by disease progression in the setting of ongoing treatment and confirmed progression on scans at least 4 weeks apart.
Exclusion criteria:
> Participant has received treatment with prohibited medications (that is, concurrent anticancer therapy including other chemotherapy, radiation [local radiation for palliative care is permitted with approval from the Sponsor]…
From the description of the patient’s treatment course it sounds like he had curative intent radiation (given he subsequently had surgery) and would probably not meet this study’s criteria making the limiting factor Moderna not the FDA.
He also doesn’t mention whether he’s starting immunotherapy/checkpoint inhibitors (or his tumor status) and may be lumping immunotherapy with chemotherapy which is a good new treatment option and would typically be offered if eligible. Definitely better than being enrolled in a dose study and in fact is required by Moderna.
Plenty of mRNA human trials of cancer treatment are in progress. Indeed, as he stated, he wants into two that are underway, but that he is probably too far along for. He wishes that they had been greenlit even earlier and perhaps made their way to be approved drugs that he could just be given by his local doctor.
> For the situations where there's "no active trial" caused by the FDA not greenlighting the experiments,
There's compassionate use exceptions for circumstances like this.
The big thing is, there's two big bars to cross with getting a trial together:
- You probably want to be doing human research in a way that will produce evidence that will convince the FDA to grant you approval. (Hence, drug companies often are nervous that compassionate use will pollute their data).
- The FDA wants to protect human subjects, and if there's a drug that results in 15% survival for a year, vs. 5% for doing nothing and ???% for your new experimental treatment: they want that drug to be tested as part of a protocol that minimizes potential harms, not to randomly replace the 15% survival treatment. Most experimental treatments end up failing.
The author is incorrect on this, he’s not too far along but he does not meet inclusion criteria for either of the studies he cited as both require systemic therapy.
mRNA is not being pitched or tested as a first-line mono therapy by Moderna. I’m not sure why the author is jumping the gun here and ignoring approved systemic treatment options.
My point is that he doesn’t even meet the inclusion criteria for these studies, regardless of aggressiveness. This has nothing to do with the FDA, he can’t join the studies because Moderna doesn’t want to study him at this point and not because he won’t survive long enough to enroll.
Whether or not his prognosis statement is correct.
> Patients generally do not have to pay extra out-of-pocket costs for treatments studied as part of a trial. Every trial is different, but the clinical trial’s sponsor usually pays for all research-related costs and any special testing.
> Typically, the patient or his or her insurance company is asked to pay for any routine tests, treatments, or procedures that would be required as part of standard cancer treatment. Before you join a clinical trial, you will receive an informed consent document that spells out exactly what you’ll have to pay for and what you won’t.
https://www.mskcc.org/cancer-care/clinical-trials/frequently...
> The Copenhagen Interpretation of quantum mechanics says that you can have a particle spinning clockwise and counterclockwise at the same time – until you look at it, at which point it definitely becomes one or the other. The theory claims that observing reality fundamentally changes it.
> The Copenhagen Interpretation of Ethics says that when you observe or interact with a problem in any way, you can be blamed for it. At the very least, you are to blame for not doing more. Even if you don’t make the problem worse, even if you make it slightly better, the ethical burden of the problem falls on you as soon as you observe it. In particular, if you interact with a problem and benefit from it, you are a complete monster. I don’t subscribe to this school of thought, but it seems pretty popular.
The post provides real life examples of government programs, nonprofits, and individuals being criticized for helping in the “wrong” way.
1. https://web.archive.org/web/20210125231725/https://blog.jaib...
https://www.moralmachine.net/
Tl;dr you're arguing the fundamentalist POV that ethics can't exist without a God.
fortunately, Baja California seems to have everything. Or specifically, a different drug approval strategy that is right in the middle of this.
The FDA's main limitation is that it gives a one to one relationship in approvals. A substance is seemingly evaluated for a single narrow ailment. While evaluation process is a threshold of side effects as well as efficacy in treating that single narrow ailment. This process could be expanded to recognize that fulfilling the side effect issue could expand its use in other ways, more easily than whatever semantical distinction of easier the FDA uses now. There could be more possibilities for one to many approvals.
you’re right though, I think this is still limiting as it gets to currently obscure things, liability concerns for the physician if something goes wrong, or what insurance will cover. so its still hit or miss for the patient
If a train is coming with someone pinned to the tracks, and they are begging you to hand them an axe so they can remove their own leg-- knowing they may die from blood loss, do you just do nothing?
It's as if we can't assess tradeoffs anymore.
You see it with the lack of children playing outside - even though random kidnappings are almost a nil risk and that they're more likely to get by a car.
Defective toys. Defective carseats. Millions get recalled for a failed few.
You saw it with masks. You see it with speech, "words are violence".
Everyone wanting the illusion of feeling completely safe.
How would you feel if your child was injured by a car seat that had a defect the manufacturer completely knew about but refused to recall for the sake of saving money?
"Words are violence"? If you were dox'd, would that be violence? Or your life threatened? Or those you love? Or just people who look or love like you? Where is the line? Wherever you personally believe it should be? No.
Experimental treatments often are very expensive, I believe require a lot of study of the patient and so on ...
It's not like a magical pill(s) you take an go home and live or don't and everyone says "well he consented so he took his chances". The entire process of experimental treatments is hugely expensive.
Put simply, If you believe “my body, my choice” then the current regulatory system is pretty messed up.
To be clear, I’m fine with the FDA existing as a labeling body. Sure label something FDA approved. But don’t limit what we can take because it’s not approved.
Otherwise, you end up with cases like this and many others, where an industry can easily be regulatory captured and ensure competitors are slow or unable to enter the market.
The problem is that in the real world, it's extremely rarely the case that you can make an intervention that only has benefits, and doesn't have costs, so honestly applying "do no harm" is paralyzing. The medical ethics field understands this, but often the administrators/regulators are way too conservative.
A better model that generalizes without special-casing is "weigh costs and benefits, and be conservative but bounded about unknown risks before making an intervention". In this case the potential downsides are 1) the patient dies which is irrelevant because they are almost certain to die anyway (and they made the informed decision to take this risk), and 2) some reputational damage to the FDA and medical practice if it's seen to be "preying on patients with no other options".
I think 2) is being weighted way higher than it should.
The problem with this model is it requires an understanding of statistics to determine what is ethical and just, and many doctors don't even know how to properly reason about false positives/negatives, let alone the lay public. Yet members of the public aren't willing to forgo their outrage on a subject that they cannot actually conceptualize.
In some sense we are getting the regulators we deserve, not the ones we need; the FDA is probably rationally and correctly evaluating the political risks, media attention, and public backlash around allowing this sort of case.
It is (a very rational) approach for administrative workers, who get little credit for getting things better, but are at risk when they can be taken accountable for something terrible.
That way, for example, in Germany, there was a halt on the Astra-Zeneca vaccine after a few cases of thrombosis per million. For comparison, it is one in six for COVID. The halt, most likely, caused many deaths. Yet, these deaths "have happened". If there were a death because an administrative organ didn't take action - the organ would be considered responsible.
For the matter, Pontius Pilate was an administrative worker. And his incentives were aligned accordingly.
In the language of the Trolley Problem, it is doing nothing (no matter how many are there on the tracks) or (even better) finding a way to pass the lever to someone else.
My understanding of the current categories of drugs are you have "banned" and "has this specific therapeutic effect that costs billions of dollars to prove".
A category of "this doesn't kill you" in the middle would probably alleviate most of this. Insurance only has to pay for things with proven therapeutic effects, but you can shield people from poison and get a lot more data way cheaper by having his middle category.
Shame. Radical seems to be all the rage these days.
Maybe I can brand it as radically conventional.
Says who? In terminal truly no-option diseases (e.g. glioblastoma multiforme) it’s pretty easy to get access to experimental therapies on compassionate grounds.
The challenge in this particular case brings us to:
> Killing someone in an attempt to help is deeply unethical, while merely letting them die is not your fault.
This is a false dichotomy. What’s unethical is offering experimental therapy with ?? effect when there are evidence based palliative treatments (e.g. conventional chemotherapy) with proven overall survival benefit.
In cases where an experimental therapy has at least some limited evidence (i.e. suggestion it might work) it’s quickly approved and pushed into clinical pipelines, osimertinib/Tagrisso for lung cancer is a recent example of such a treatment.
No one is advocating or suggesting we just let people die.
I think that's the main point of disagreement. There are some encouraging cases where the process works well, and it's fair to point to osimertinib as an example.
But there is a good case to be made (although various blog posts likely state it better than I could in a comment) that the current process introduces enough delay that the opportunity cost is higher than the risk.
Most drugs fail. But getting the drugs that do work to patients even a year earlier may be a much larger benefit than the cost of giving people with serious diseases broader choices, in addition to the current best known standard.
No one is advocating we just let people die, but there's an argument about the cost of delaying therapies and the cost of giving people choices that warrants careful consideration. While proven therapies are good and snake-oil is bad, improving standard of care for everyone historically saves many more lives than sticking with what we know for a longer period of time.
This is contradictory. Most drugs fail, how do we identify the efficacious ones other than through trials?
Depending on the anticipated efficacy from early trials as compared to existing ones it will get fast-tracked before the phase II is completed.
Where is the evidence that we’re delaying efficacious therapies where there is no good alternative?
I sound like a broken record right now but this blog post is suggesting we jump to experimental therapies (which would be off label for the author as he does not meet inclusion criteria) before we even have phase I data let alone efficacy, when good validated treatment options exists.
One idea is to make trials somewhat less costly by relying more on post-approval monitoring, but there are more subtle critiques of the processes that try to address perceived inefficiencies at the organisation/bureaucratic level rather than just adjusting a single big strict/lenient dial.
Some drugs do not make it to trial at all due to the overwhelming cost of the process. We would identify a larger number of efficacious ones if there were less costly, wider trials. A very expensive approval process results in delays for drugs that do make it to trials, but also causes many candidates to never reach trials.
>Depending on the anticipated efficacy from early trials as compared to existing ones it will get fast-tracked before the phase II is completed.
Part of the argument is that this is good, and we should consider going further in that direction
>Where is the evidence that we’re delaying efficacious therapies where there is no good alternative?
Unfortunately, the best I can point to is a series of blog posts and informal discussions, I'm not aware of any formal published evidence. I remember a blog post on ACX post aducanumab (https://astralcodexten.substack.com/p/adumbrations-of-aducan...). The "FDA delenda est" catchprase leads to several more posts.
I'll admit this is not very compelling. I believe it's worth having that argument, and I'd be happy to be wrong on that one, but all of this is hard to quantify.
(I also want to reaffirm that there are good alternatives, it's a question of whether we could be losing less people than we are losing under the current process, not that there are no current alternatives)
>I sound like a broken record right now but this blog post is suggesting we jump to experimental therapies (which would be off label for the author as he does not meet inclusion criteria) before we even have phase I data let alone efficacy, when good validated treatment options exists.
I'm sorry if I'm repeating myself as well or failing to make a good argument. I think your position is very reasonable. It's a complicated topic and I might not be doing it justice.
I'm a radiologist by training with an interventional oncology component in my practice so I can really only speak to acute care emergencies and cancer with any degree of expertise.
Cancer, heart attacks, strokes, aneurysms are different because there's a time crunch. In these situations FDA approval comes quickly for new medical devices and imaging tests. New aneurysms occlusion devices, stent grafts, and thrombectomy devices are all quickly approved with shortened review processes. Sometimes this has been to our detriment (e.g. early abdominal aortic/EVAR grafts which all leaked and caused disasters when the patient needed re-operation).
In these cases we did exactly what you're suggesting with:
> One idea is to make trials somewhat less costly by relying more on post-approval monitoring
How this translates to other diseases like Alzheimer's is not in my wheelhouse. I assume the process is more strictly adhered to in these cases, but it presumably should be because the potential harm of delaying is seemingly less important unless we're discussing disease-modifying treatments that require early initiation.
In your post the author mentions COVID-19 vaccinations, these were made available before full FDA approval. COVID-19 was highly politicized and the entire process did not follow typical medical procedures. Honestly the evidence that has come out for them isn't very compelling (omicron and later) and largely why most places have dropped vaccination requirements. I'm not sure that this is a good example of the "FDA's failure".
Most people (myself included) would not agree to that. Experimental treatment should be made possible - at least if there have been promising results with previous studies (animals, small trials etc.). There must be a safeguard, however, to make it impossible to sell false hope to dying people - because they will pay for everything, even if it does more harm than good.
If you have a system without problems, I’d be more worried.
Edge cases like OP’s can’t be solved by any system. All systems have problems with things falling through the cracks.
That’s why lobbying exists. So people like OP can bring attention to a specific problem and lobby for it.
Taking about changing the system is missing the point.
Are the current regulation regimes perfect? No. Would we be better off without it? I doubt it. Should we try to strike a balance between regulation and innovation? Yes—but doing so is devilishly tricky. No matter what you do, someone somewhere will be unhappy.
https://www.amazon.com/Regulation-Pharmaceutical-Innovation-...
Interesting. Thanks for sharing the "Copenhagen interpretation of Ethics". I've thought many times about this problem, didn't know it had a name.
Comes to mind Dante Alighieri: "The hottest places in Hell are reserved for those who, in a period of moral crisis, maintain their neutrality."
There are companies from which you can order bespoke mRNAs. Lead times vary but are in the weeks. Many are abroad. The other components of mRNA vaccines can be assembled by someone with 2 years of biochemical Ph.D. experience. There are no laws against a person assembling and injecting themselves with anything.
I have extra sympathy for the writer of this article, since mRNA vaccines (even if they were a random sequence) are relatively lower risk than many other sorts cancer interventions which are FDA approved. I happen to be an ex-professor, who is a director at a drug company. I know that if I were the unfortunate author of this article, whose heart is in the right place. I would probably be injecting myself with my own janky version of whatever offered hope.
Whether that would actually change my prognosis? Probably not. I can say though that I _would_ and I believe others are entitled to positive freedoms I'd afford myself.
It actually seems like the kind of problem that could be a good fit for tech: have a registry of clinical trials, make sure it’s widely known and consistently used. I don’t know much about the problem, though, so I don’t know if or whether that’s unrealistic.
Florida would probably outlaw all mRNA technology. Their FDA would refuse to approve any mRNA-based therapies, and so on.
We have seen the disaster that approach can cause in healthcare, insurance, abortion (reproductive health broadly), gay rights, etc. It's insane that we have state by state drivers licensing as an example that is merely highly inconvenient.
It's not a good thing that doctors and nurses are regulated at the state level. It's a horrible thing that contributes to the US healthcare system's vast dysfunction.
Dr's typically practice in ~1 state while drugs are available in all states simultaneously.
Fifty states - of varying ability - trying to independently qualify all available drugs would be a nightmare of redundancy.
The same is true for a lot of cutting edge treatments.
It quite strictly limits where such treatments are likely to be available.
Allowing trials to be bypassed and allowing people to pay for early access to unproven drugs would bring a flood of such be vendors and be bad for society, bad for medicine, and bad for ethics.
The article even cites a case where the bureaucrats are confident in the safety of a trail drug but unable to approve for political reasons.
Not to mention the FDA allows plenty of snake oil supplements, etc. to be sold, so it's not particularly good at the goal you claim it's optimizing for.
I imagine allowing terminal non-trial participants access is more than just regulatory red-tape.
If understood one of the authors points it was that allowing non-candidates access could speed up approval. I think that is true, but that would require the same regimented process for administering the trial to ensure quality of data. The same would hold if there was an adverse event as well—patients need to be monitored closely to capture data to provide valuable to the clinical research results.
> USA refuses to accept rubber stamp European experimental medication. Europe pikachu face
If you think that regulatory bodies make mistakes - then surely you want them checking each other's work?
It's very frustrating to feel you are dying just shy of a breakthrough that can save you. I get that. And the author's contention, that they have a right as a human being to join studies that can potentially save them, is entirely reasonable.
But that's an entire universe apart from rubber stamping medications. We should not give the pharmaceutical industry that much credulity.
If pharmaceuticals have improved the length and quality of our lives, it's because they've been kept on the straight and narrow. This isn't a self regulating industry, they have a desperate base of customers and their "sales people" (doctors) are trusted implicitly - they hold a tremendous amount of power and would abuse it at the drop of a hat.
Thalidomide is what is used to treat erythema nodosum leprosum (ENL) better known as just leprosy.
That they've narrowed it down to some use case is more of a testament to the thoroughness of the investigation, I'm sure there are many chemicals that could treat leprosy this just happens to be the one we understand how to manufacture and when it is safe to use.
I'm sure it's very meaningful for the people who do take it, but that is what I meant by "basically worthless."
https://medlineplus.gov/druginfo/meds/a699032.html
As with any medication there are risks and side effects but that hardly makes it "worthless".
Your comment would be just fine without that first sentence.
Edit: it looks like we've had to warn you about this many times in the past—for example:
https://news.ycombinator.com/item?id=32737135 (Sept 2022)
https://news.ycombinator.com/item?id=30120252 (Jan 2022)
https://news.ycombinator.com/item?id=29598017 (Dec 2021)
https://news.ycombinator.com/item?id=25935223 (Jan 2021)
We end up having to ban accounts that keep doing this and don't listen to warnings. I don't want to ban you, so please fix this!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413435/
Europe approved the use of beta blockers to prevent heart attacks a decade before the US. Although the FDA approved propranolol in the 1960s, and timolol for glaucoma in 1978, they didn’t approve beta blockers for prevention of second heart attacks until the 1980s. This resulted in the deaths of over 80,000 Americans. Amusingly the New York Times article about this approval brags about how many people will be helped by the previously-banned medicine.[1] Nowhere is it pointed out that so many more people could have been saved if the FDA fast-tracked drugs approved in Europe.
1. https://www.nytimes.com/1982/02/02/science/new-class-of-drug...
There are tons of examples of the FDA failing to approve things, resulting in Americans dying unnecessarily. A more recent example was Omegaven, an IV nutritional fluid.[1] The FDA took 14 years to approve it, resulting in hundreds of infant deaths. Before its approval, only a few infants at Boston Children’s Hospital managed to get it. The staff there had to get FDA approval to import the fluid from Europe for every infant they wanted to treat, resulting in a lag time of several days. Even though it was clear that Omegaven was much more effective than previous IV nutrition, the FDA’s bureaucratic hurdles prevented it from being adopted sooner.
1. https://astralcodexten.substack.com/p/adumbrations-of-aducan...
A rubber stamping scheme removes redundancy from the system. Approving drugs faster sounds like a great idea, but there was a reason someone put up that fence you want to tear down, and your arguments haven't addressed it. Furthermore, the fence doesn't need razing to accomplish your goal - I don't see why advocating for the FDA to approve drugs faster should be synonymous with turning them into a rubber stamp.
No one (or at least not me) is contesting the assertion that approving drugs faster may save lives. But I don't want pharmaceutical companies to be able to undermine a single regulatory body and then be able to distribute their drugs everywhere.
If you think the UK, European, and Canadian regulators are competent, then you must believe in the possibility of a competent regulator, right? Let's just have one of those, instead of a differently-incompetant regulator who serves as a rubber stamp.
And if we can't, then I'd rather they were too conservative than that they allowed too many drugs on the market.
It’s as if I were pointing out the uselessness of most TSA screening and someone replied that the solution is to make the TSA more competent.
I’d change my mind if there were more examples of harmful drugs in Europe or Canada that the FDA blocked in the US. The thalidomide scandal was over 60 years ago and caused around 4,000 deaths and 6,000 birth defects. You’d need a dozen thalidomide scandals to equal the FDA’s delays in approving beta blockers.
You've only proposed one fix. I'm only opposed to one idea.
You aren't under any obligation to try and convince me of anything, but surely you don't have to put words into my mouth.
Should doctors be able to prescribe drugs approved elsewhere? When we're talking about lifesaving treatment that isn't available in the US, yeah probably there should be some process to do that. I imagine insurance companies will make this next to impossible, but that's not a reflection on your argument, just a shitty reality.
What would convince me that the FDA should rubber stamp European drug approvals? I don't know, but it would be evidence about the structure of the pharmaceutical market and the incentives in place, not a recitation of misses by the FDA.
Your evidence they aren't approving drugs fast enough is convincing, I absolutely buy that a problem exists. But that evidence doesn't address my separate concerns.
Let's say we do go ahead and rubber stamp everything coming out of Europe. What is going to happen?
There's going to be more pressure on European regulators. How are they going to respond to it?
Possibly by being corrupted and subverted and failing open. That would be bad.
The alternative is that they becoming more careful, more plodding, they start taking into account the views of stakeholders the FDA would otherwise have represented, and the process gets gummed up anyway.
If what you wanted me to agree with is that doctors should be able to get people drugs that there's excellent reason to believe are safe and effective, regardless of whether the FDA has finished approving them, then yeah, I see how that makes sense.
I do buy the author's assertion that people should have right to expose themselves to experimental medicines when it could save their lives though.
But the next day I come to you with an 11th task. I tell you this is the only one that matters. I give you full license to blow through your budget, harass people until they get their paperwork done, whatever it takes - this is the only priority. So you get right to work, and with all the blockers cleared you get it done in 6 months.
"Great," I say, "so you can do all them that fast right? And when I come back in 6 months, all of the original 10 tasks will be done?"
But of course they won't be, because you don't have the resources you had before, the external stakeholders aren't as motivated as they were before, and instead of putting all your effort into 1 task you're going to be spreading it across 10.
Agreed.
I've had this misdiagnosed medical condition for 25 years by multiple doctors. Nothing serious but extremely annoying. There are approved drugs in Europe for decades which are much better than the ones approved in North America. One day the company making the drug that's approved in North America decided to stop making it! You just could not get it. This was the event that finally led to the correct diagnosis for my condition because I was in so much pain I got to see the expert. Turns out my condition has a very simple non-prescription solution and for 25 years I've been taking the wrong meds that happen to alleviate this different condition as well!
So I am good but this condition is not uncommon. What are all the other people that really need this drug in North America doing?
I'm not sure what's the takeaway here. Maybe that efficient/smart organizations generally don't exist. This is just a reflection of human nature.
So if you've been diagnosed with herpes, and anti-virals don't seem to help, maybe you don't have herpes. If you do have herpes of the eye there are good drugs approved in Europe but not in the North America (though there are likely some approved drugs in the US which will still help - it's complicated).
A government issued id, like a driver's license, is often required for various services like opening bank account, a telephone connection, avail some government service etc. Thus a local driver's license can be used for deception by a foreigner who wants to pretend to be a local citizen.
Edit: Also, the federal law applies regardless of location: https://righttotry.org/rtt-faq/
"I do not live in a state with a Right to Try law. Can I still use Right to Try?
"Yes. S.204 makes Right to Try the law of the land. So long as a patient and treatment meet the qualifications of the federal law, Right to Try applies, regardless of whether the patient’s state adopted Right to Try."
Wish there was some country or state where you could try more freely.
This case reminds me a lot of the FAA realizing that safety restrictions for toddlers would increase deaths as more people would drive. (https://www.ntsb.gov/news/events/Documents/child_safety-Clau..., https://www.ucsf.edu/news/2003/10/97119/airline-infant-safet...)
It's a tough line to walk on, still.
It isn't a convincing argument to me, because possible death avoidance is a higher level of morality to me, but harm reduction is extremely prevalent in medicine as a driving factor.
I think we can all see incidents of where some oversight process is loosened because of some legitimate desire to help some, but then you learn that the bad / incompetent / exploitative actors come out of the woodwork to test and take advantage of the changing of rules. Not even saying intentionally, but just by sheer numbers, the change you made allowed things that were being held back by (hopefully proper) regulation to now happen.
Anyway, not saying that the FDA and other bodies couldn't move faster -- that is always the case. And there will always be examples of people/cases stuck in the cracks with legitimately sad situations.
But I would hope that people reading such stories think about why there is a process. It's not like the FDA's purpose in life is to stop people from benefitting from new treatments. It's to prevent the flood of bad effects of companies/individuals from being able to say they offer some drug that doesn't work in the way it says it does.
In general I feel like the sick should not be held responsible for the unintended consequences of things. The principle that it is better for 10 guilty men to go free than 1 innocent man to be punished applies here as well. How many suicides have happened because it took this long for the use of psychedelics and THC for the treatment of depression and PTSD to be approved (partially, in some places). How many people are suffering today, right now in pain or under the care of doctors they would otherwise leave for poor treatment but the "opioid crisis" has limited their access to the treatments they need? I've faced this problem personally more than once, and while I am sympathetic to the law of unintended consequences, I just can't be convinced that it is the duty of myself or my loved ones to suffer because someone else might abuse something. There is a balancing act to be had for sure, but any borderline case should ALWAYS err on the side of reducing the current actual harm in favor of preventing a nebulous potential future harm.
And as bad, sad and frustrating as it sounds to someone in a desperate situation, it is for the greater good of many more human beings, protecting us from snake oil.
*this person takes the drug. Two days later they die of a heart attack. Was it caused by the drug? How many resources should be spent to determine that? Should that death be listed in the potential side effects? What if the news story publishes an article and scares people off from the trial? What if it's later proven that the drug had no effect on the heart attack but the distraction from it delayed 10,000 people's access to the drug?
The world is complicated.
This is untrue, in this case.
Typically, only some phase 2 and phase 3 trials are randomised; the treatments that the author refers to are at an earlier stage of development and so not in either of these phases. All patients will receive the active therapy.
It's also worth noting that for cancer trials, while new treatments in these later phases may be tested against a placebo, it's never just a placebo - that would be unethical. If the new treatment is an add-on to an existing standard-of-care treatment, then they'll receive the standard-of-care treatment in the placebo group. If it's not an add-on, then it will be tested directly against the standard-of-care. If there isn't an established SoC, it can sometimes be approved without a randomised trial, if the results are good enough.
And in this case he would be actively helping humanity as well by being a test case. We would all gain knowledges and information from his treatment, if he could get it.
This policy hurts all of us.
Incentives matter. When you get to make decisions that impact others, but not feel any of the costs associated with that, you do not have the correct incentives. I hope the staff of FDA read this and can’t sleep tonight. We can hope they feel some emotional pain, even if it is only some small subset of the pain they have and continue to cause to others.
FDA delenda est.
Those who establish, support and tolerate that system should be as directly exposed to its consequences as practicable. It is good for them to see these stories and feel the consequences of their decisions.
The consequences to their actions are that millions of people are saved from the consequences of consuming seemingly promising drugs such as Thalidomide: https://en.wikipedia.org/wiki/Thalidomide
I could sleep just fine knowing that some people looking only at a tiny local example while ignoring the big picture considered me the villain
The issue with having a standardized approach to people getting experimental drugs is it opens up its own kind of mini-market unless the implication is they would be required to be free by law. And desperation is not the right mindset to make law or rational decisions.
Not trying to sound heartless, its just not as easy as saying "go faster".
"What's the harm?" you say. The problem is, without any threshold, there are countless Treatment X. Every single snake oil comes out of the woodwork.
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.
Blocking this is effectively murder.
My dad recently died. There are always new treatments being studied and some day one of those treatments might actually be able to cure people with the same disease. That day didn’t come early enough for my dad. That sucks but it doesn’t change the fact that drug policy is made for society as a whole and not only for my dad. This isn’t some conspiracy where a cold bureaucracy is letting people die. Sometimes your luck just runs out.
You appear to think that it is worth letting people die to avoid quack doctors being able to sell them snake oil. I prefer to leave it up to the patient to decide. They are the ones with skin in the game.
It saddens me that you believe such nonsense.
Even if the drug/treatment method were approved, how much would this cost, would the author even be able to pay for / have the insurance company pay for the treatment?
And by the way, what limits are there on the price of a drug that an insurance company or the government will cough up the money to pay, for one person's extension to life for a couple years?
If someone has a very rare or just very advanced cancer, how much should the rest of us (as individuals paying taxes/premiums/etc) be on the hook for paying for last ditch efforts to prolong that person's life?
These are genuine questions I think are legitimate to ask, if not in polite conversation, then at least at the level of policymaking bodies in govt or insurance companies. I'm sure that people in the UK are quite familiar with this concept or debate.
You cannot just say you'll pay whatever it takes to save someone's life no matter what the circumstances.
1. When the FDA has fast-tracked drugs, drug makers have taken advantage of this to hide data, lie, and refuse to comply with timelines for proving those drugs work. https://www.npr.org/sections/health-shots/2022/07/22/1110830...
2. When these accelerated drugs are found to not work or cause harm, the manufacturers continue to push for them and the FDA has tremendous trouble trying to their approval revoked. https://apnews.com/article/science-health-medication-busines...
3. Accelerated drug approval gets mired in advertising. The general public has no idea how to judge if a drug works or not. Plenty of people believe that homeopathy works. The FDA gets massive pushback when trying to take a drug that is worthless away, because people think it works. This hurts us all and creates an incentive for companies to hide data and deceive customers.
4. The FDA is as fast or faster than the Canadian or EU equivalents. The FDA is not specifically slow, bureaucracy everywhere has become much slower because there are no incentives to be fast but countless incentives to be slow.
5. Lawsuits. It's easy to say "I'm hurting, I'll take anything". But, then, there are rights you cannot give away. If a drug harms you, you will sue. If it kills you, your family will sue. The whole system is bogged down by lawsuits with massive disproportionate payouts. The early biotech companies and scientists involved often cannot deal with even a mistaken lawsuit.
We need a much more comprehensive overhaul of the system, starting with open access laws to all data pertaining to any drugs that are on the market (no manufacturer can keep anything secret for a drug that people take), an FDA that has much more authority and much less industry capture, medical tort reform, to create a system where in exchange it actually makes sense to provide fast tracked approval.
But that's not the main problem here. You would expect the FDA to approve everything by that theory.
The media (both traditional ans social) owns a large chunk of the underlying blame, due to their rush to create simplistic narratives in the wake of anything that "goes wrong" without nuance or examination of tradeoffs.
> If anything goes wrong,” he argued, “think how bad it will look that we approved the drug so quickly“
People who take an approved drug are relying on the result and authority of a scientific process — across all drugs. Some scary results and people may start to fear the process, which may end up killing more people.
That said I’m sympathetic to his plight and think that he sounds like a candidate for the compassionate use program. Any result would not help approval as who in such a program would volunteer to be randomized into a placebo arm? They’d just plead in a prior human administration disclosure section of any NDA.
(Also, pragmatically, immunotherapy grate nets are customized and extremely expensive. Who will underwrite it? Not the drug company who would have nothing to gain, not the insurance company, and I doubt the patient could afford it).
It’s a sad story all around.
A common example why government doesn't solve problems well. Because it's an absolute governing law, there's nowhere else to turn to. This creates an industry of snake oil that preys upon people both as regulated medicine and homeopathic remedies. In practice vertical integration is a requirement for economies of scale. This means all medicines must be created by singular centralized corporations. These corps buy out the regulatory and now we have an incredibly inefficient and locked out market that prevents innovation.
All orgs should be sunset after 20 years by law. Repeal the FDA, replace it.
Pair this paradigm with extensive postmarketing surveillance and periodic reviews for efficacy in a patient population. These could be done at two years, five years, and eight years -- and approval automatically rescinded if safety issues arise or efficacy is close to null.
Give people with fatal diseases a "right to try" drugs that haven't passed safety testing -- and use that data.
Ban drug advertising in public-facing media.
Simple as.
agreed on advertising though.
But other than that you can get almost anything even buying it online and get it at home in the next 3 hours.
That's how I buy duloxetine every month.
> it wasn't only because of low-hanging fruit.
Yeah, right. They had such advanced cancer medication back then.
> Give people with fatal diseases a "right to try" drugs that haven't passed safety testing -- and use that data.
That data is practically worthless.
I'm in favor of having people try out medication, but it will need to be heavily regulated. And we know what happens to regulation: a party comes along that doesn't like regulation, or gets bribed, and the regulation goes out the window. It's a good way to start another opium crisis.
This is the reflexive response to every common-sense proposal to roll back the regulatory burden.
I'd raise a couple of points in response:
First, Thalidomide was never approved in the USA -- for safety reasons. The mechanisms that were in place at the time did their job.
Second, the response to Thalidomide was overblown and indeed downright hysterical. "Better to let 100,000 people die of neglect than allow one person to suffer an awful drug reaction" is not rational policy.
> That data is practically worthless.
Enough "practically" worthless data, and you get somewhere. It's a matter of quantity. Obtaining "hiqh quality" data is often unethical in medical practice.
A large data set of highly biased, uncontrolled data is still useless. You can't model yourself out of the factors that have not been recorded. And believe me, the data you'll get on patients that try experimental medication will be very, very incomplete.
It also won't be a large dataset. How many people have squamous cell carcinoma between now and the moment of approval and are willing and wealthy enough to buy this particular medicine? 100 seems too much already.
> The mechanisms that were in place at the time did their job.
Barely, according to wikipedia.
> Second, the response to Thalidomide was overblown and indeed downright hysterical. "Better to let 100,000 people die of neglect than allow one person to suffer an awful drug reaction" is not rational policy.
Thalidomide was never going to save 100,000 people. It did cause 2500 birth defects in West Germany alone, though, plus an unknown number of abortions. Given that it was legal in 46 countries, the number of people with birth defects must be well over 10,000. This drug isn't going to save 100,000 people either, certainly not in the period until admission.
There are many safety issues that placebo-controlled and double-blinded studies didn't catch, but postmarketing surveillance later did. Large data sets are more powerful than you give them credit for --- and, moreover, in the real world drugs are not always used the way they are in clinical trial settings. In the real world, people skip doses, double up on doses, drink grapefruit juice, etc.
If you want a full picture of "factors that have not been recorded," you want as large a dataset as possible, as close to real world conditions as possible. It may not be as clean as you'd like, but it'll give you enough to draw every inference.
> How many people have squamous cell carcinoma between now and the moment of approval and are willing and wealthy enough to buy this particular medicine? 100 seems too much already.
When the alternative is to allow the drug to spend a decade or longer in development hell, I'll take poor data and lives potentially saved over "great data" (not really) and a pile of dead bodies.
Besides, when drugs are potentially curative, and the disease otherwise so invariably fatal, even 50 datapoints should be sufficient. This is trivial to model mathematically.
> Barely, according to wikipedia.
Oh come on. Besides, teratogenicity is now an absolutely basic component of safety tests. You don't need the FDA's failed paradigm of extensive efficacy trials to prevent "Thalidomide part II."
> Thalidomide was never going to save 100,000 people.
The exaggerated response to Thalidomide, exemplified in your first comment, has absolutely condemned more than 100,000 people.
> Say you're a runner. In the beginning of your competitive career, you get the most gains by becoming a better runner. And then at some point, you get more gains by shooting (or bribing) the ref.
For those that don’t know, the 1962 change is the Kefauver–Harris Amendment, which was a response to one of, if not the, largest overall global crisis of conscience in the medical field. From Wikipedia: “When first released, thalidomide was promoted for anxiety, trouble sleeping, "tension", and morning sickness.” After some time it became increasing obvious that while it worked, it caused birth defects in pregnant or soon to be pregnant women, with its manufacturers actively trying to quash the information about such cases; again, from Wikipedia: “Use of thalidomide in pregnancy can cause fetal abnormalities such as phocomelia (malformation of the limbs). In males who are taking the medication, contraception is essential if a partner could become pregnant.”
Thalidomide disfigurements were disturbing. Children born with these disfigurements were not linked to Thalidomide until much later. Thalidomide was in fact not allowed a safety regulation by the FDA initially. It wasn’t until the company producing it, Grünenthal, pressured the FDA. You see, the FDA reviewer for the medication was leery about it after some reports had floated over her desk about a possible remote risk that this could potentially cause birth defects. Grünenthal’s international licensee to the US refused to explain multiple papers that linked Thalidomide usage in pregnant women to birth defects.
As it turns out, not only had Grünenthal known about the issue they had actively worked to silence the information, a ploy that worked until a major change in leadership in Germany.
It was denied usage in East Germany.
For a longer documentary on the subject and how it changed medical safety testing, Plainly Difficult has a very good video on it: https://youtu.be/Vi03zz6eCik
(Note: I am explicitly ignoring the context that the Thalidomide development program was run by an actual Nazi who was responsible for unethical and frankly awful experience on unwilling human subjects in concentration camps. If anything, it only amplifies his concern to hide adverse effects, which he did quite successfully until the company was given what can only be considered “A slap in the face”.)
https://www.fda.gov/patients/learn-about-expanded-access-and...